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I wasn’t really prepared for beautiful scenery and charming towns and villages when I came to Catalonia. Calling them secrets may be a bit much, but I suspect there are many of us (especially in Britain), that overlook Catalonia as a holiday or travel destination. 7 secrets of Catalonia is me showing you what’s out there, within easy reach of anywhere in Europe, so add these places to your bucket list now, you won’t regret it.
St Joan de les Abadesses
St Joan was my first taste of Catalonia after my Barcelona Weekender, a small town in the Ripollès region on the River Ter. It’s a quaint town, with an abundance of history to be admired. Make sure you take a tour around the Monastery, the Palau de l’Abadia (the Abbey Palace) and the historical centre, and learn about the fascinating history here.
Eat here: La Teuleria Restaurant. The owner of this family run restaurant has an incredible cellar full on wines and souvenirs, including wine stamped by the Vatican and drunk by the Pope!
Sleep here: Hostel Ruta de Ferro
Cap de Creus
The photos of this stunning 190 square kilometres of National Park in the foothills of the Pyrenees should speak for themselves. Arriving here after 4 days of cycling was simply breathtaking. It has clear 360-degree panoramic views of the towns below, and it really is a gem of Catalonia. Then you can enjoy the long winding roads down to the town of Llançà. My advice is to spend some time exploring the whole park, and make sure you don’t miss Sant Pere de Rhodes…
Sant Pere de Rhodes Monastery
It’s kind of cheating as Sant Pere de Rhodes is technically in Cap de Creus, but the monastery is so spectacular it deserves its own entry. The monastery was built on the side of Verdera Mountain below the ruins of the Sant de Verdera Castle, which you can see on the 45 minute walk to the top of the mountain, which I highly recommend. The tour of the monastery is brilliant, and full of interesting facts and history.
Llançà
Originally a fishing village, Llançà is not best known for its tourism, but it should be. Just a few miles from France in the Alt Emporda region of Catalonia, you’ll find lots of quiet beaches and coves, and plenty of water sports to take part in. On top of that there’s an abundance of shops and restaurants which of course serve the beautifully fresh fish caught that same day. Then there’s Cap de Creus National Park on your doorstep. Finally it’s worth exploring the coastal paths that take you south through the rest of Costa Brava.
Sleep here: Hostel Costa Brava (Llançà)
Eat here: El Vaixell (unbelievable seafood!)
Do this: Kayaking with SK Kayak
Vall d’en Bas
Surrounded by mountains in the Garrotxa region lies the beautiful town of Vall d’en Bas. It’s a very agricultural city and the valleys provide lots of lush soil to farm. We had a tour organised by the hostel below, which was a great way to learn about the remarkable history behind the buildings in the old town, and the rather terrifying prison!
Sleep here: Hostel Vall d’en Bas
Eat here: Braseria Ca L’asteve (Amazing value, I tried Pigs cheeks, and it was glorious!)
Girona
Girona is the only city on this list, and easily the most visited place in my seven ‘secrets’. I couldn’t exclude Girona, because I think its overlooked and I don’t know why. There really is no excuse with its own airport and frequent trains from Barcelona that take just 40 minutes. Girona has a lure to it, a romance that you can’t resist and once you leave you just want more. The Old Town and modern city are generally split by the River Onyar, and you can’t beat Saint Julia Mountain for stunning views over the city. This is definitely one I want to come back to and explore again.
Eat here: La Sala
Do this: Aquatic Trekking with Aventura Girona
Girona Photos: Girona Dreaming by Miss Barlow
Banyoles
Banyoles is a town known best for its lake, which is the largest in Catalonia and famous for rowing. You’ll often see Olympians training here in the summer, and it hosted the rowing in the 1992 Barcelona Olympics. But its not just the rowing, you can swim, canoe, mountain bike and go running until your heart’s content. I also had arguably the finest coffee in Catalonia, whilst people watching in Banyoles Old Town Public Square.
Sleep here: Hostel Banyoles
Eat here: La Carpa & Can Xabanet
If you needed any more reasons, you’ve got the friendly Catalan people, their fascinating history and their fight for independence. You will also find most of these towns are linked by a popular and very scenic cycling route, look out for a new article about Cycling in the Pyrenees, coming soon.
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My friend Rob from Love and Road was also on my trip to Catalonia, and wrote a great post about Sports in Catalonia, check it out! | https://www.intrepidescape.com/travel-7-secrets-of-catalonia/ |
In 1407, a young man of 20 came to the Dominican monastery in Fiesole, Italy. A painter by trade, he humbly asked to serve the Lord in poverty and obedience as a Dominican Brother. Fra Angelico, as he came to be known, is now regarded as the greatest painter of his generation.
He lived in obscurity for more than 10 years before he was first commissioned to do a series of paintings for a monastery in Florence. His fame grew and he earned large sums of money for his paintings, but he gave all of it to his Dominican order. Reading this story can encourage us to follow in the footsteps of Fra Angelico, who humbly used his talents for the glory of God.
Level 2 Reader
Softcover, 95 pages. | https://www.olvs.org/store/bookstore/books-galore/king-of-colors/ |
Of those Americans who are diagnosed with diabetes, most have type 2 diabetes, which results from insulin resistance (a condition in which the body fails to properly use insulin).
Choose high-fiber, low-fat dishes, including beans, peas and lentils, dark green vegetables or whole grain food such as brown rice or couscous.
Leave room for fish. According to the Harvard School of Public Health, good fats, such as the polyunsaturated fats found in tuna and salmon, can help ward off type 2 diabetes. In fact, the 2002 American Diabetes Association’s evidence-based nutrition principles recommend that people with diabetes include two to three servings of seafood per week as part of a healthy diet.
Avoid dishes prepared with sour cream and butter. If you’re making a sandwich, use mustard or salsa instead of mayonnaise.
If it’s available, opt for salad dressing prepared with olive oil and vinegar.
Skip the pies, cakes and cookies and pick the fruit. Fruit is a terrific source of fiber, vitamins and minerals, and has zero fat. Everyone, including people with diabetes, should eat two to four servings of fruit per day.
Try to eat by example —Eat healthy foods when eating near friends and families. Temptation is often hard to resist if “bad” foods are within reach.
Don’t play “food cop.” If a friend or family member eats something he or she shouldn’t, avoid being judgmental and overanalyzing every bite. And remember to be encouraging and supportive when he or she is following a healthy diet.
If you have questions regarding diabetes or diets appropriate for diabetics, please consult your physician.
For healthy seafood recipes, visit the Mermaid’s Recipe Treasure Chest. | https://chickenofthesea.com/fresh-ideas/health-nutrition/tips-for-diabetics-and-anyone-interested-in-healthy-eating |
There are people who do not want to eat foods with genetically engineered organisms under any circumstances if they can help it.
There are people who just want to know if genetically modified organisms are in the products they are eating and feeding to their families.
Ultimately, the people who do not want to consume GMOs deserve as much consideration as vegetarians who don’t want to eat meat, people whose religion provides specific dietary restrictions, or people with food sensitivities and allergies who need to stay away from specific ingredients. We all have a right to know what we are buying, and to choose whether to buy it. Joe Rogoff (president, Whole Foods Market, Pacific Northwest Region) says it “is about transparency and the consumer’s right to make informed decisions.”
They can argue that there is a cost in labeling, but food manufacturers change labels frequently. David Byrne, former European commissioner for Health and Consumer Protection of the European Parliament, stated that when Europe introduced GMO labeling in 1997 it did not increase costs. | http://www.columbian.com/news/2013/aug/27/letter-food-labeling-worth-effort/ |
Blackstone Block Architects, Inc. was established in 1982 as an architecture and planning firm with special skills in the restoration and adaptive re-use of historic structures. The firm specialized in developing designs to give new life to old and often elegant buildings which had outlived their original function. Blackstone Block Architects has planned and completed the renovation of a variety of these projects to create multi-family housing, commercial and retail
space, offices and educational and public safety facilities.
Historic preservation originally formed the core of the firm’s practice, but the firm’s expertise recycling 19th century landmarks for contemporary uses led logically to the design of new buildings for our clients, who include colleges and universities, government agencies, non-profit institutions, private developers and other clients nationwide. The firm’s work has ranged in scale from small retail and office interiors to a 220,000 sq. ft. mixed-use development incorporating offices, a shopping center, restaurant, and condominium apartments.
Blackstone Block Architects has also become a leader in the planning and design of facilities for people with disabilities. An access auditing and planning process developed by the firm has enabled the City of Boston as well as several colleges and universities to prepare comprehensive plans for access improvements to hundreds of buildings.
The firm’s President Barry Buchinski maintains an emphasis on realistic budgeting, efficient planning, thoughtful contextual design, precise detailing, and close liaison with clients as hallmarks of the firm’s work. Blackstone Block Architects welcomes the opportunity to solve new and challenging design problems for diverse clients. | https://blackstoneblock.com/about-bsba/ |
Correspondingly, How big are Pyjama sharks?
The shark hatches at a length of 5.51 to 5.9 inches [14 to 15 cm]. Males mature at 1.9 to 2.5 ft [58 to 76 cm] in length, and females mature at 2.1 to 2.4 ft [65 to 72 cm]. Its maximum length is 3.1 ft [95 cm].
Herein, Do sharks attack humans?. Despite their scary reputation, sharks rarely ever attack humans and would much rather feed on fish and marine mammals. Only about a dozen of the more than 300 species of sharks have been involved in attacks on humans. ... Sharks have been known to attack humans when they are confused or curious.
Then, Are Pyjama Sharks endangered?
Conservation and Tourism
The IUCN lists pyjama catsharks as near threatened, but there are no conservation methods currently in place. However, the South African Sea Fisheries Research Institute is considering to decommercialize the pyjama catshark and the leopard catshark.
Why is a Pyjama shark called a Pyjama shark?
Named because they appear to be wearing striped pyjamas, pyjama sharks are now famous thanks to the mesmerising documentary My Octopus Teacher. They are shy, nocturnal and endemic to South African waters, calling the great African kelp forest their home, with octopus on the menu.
Do tiger sharks bite?
Although sharks rarely bite humans, the tiger shark is reported to be responsible for a large share of fatal shark-bite incidents, and is regarded as one of the most dangerous shark species. ... While the tiger shark is considered to be one of the sharks most dangerous to humans, its bite rate is low.
What kind of shark has spots?
Whale Shark (Rhincodon typus)
Whale sharks can grow to 65 feet in length and weigh up to 75,000 pounds. Their backs are gray, blue, or brown in color and covered with regularly arranged light spots.
Where are blacktip sharks found?
Where They Live. Atlantic blacktip sharks can be found year-round in the Gulf of Mexico and are common from Virginia through Florida. They have been known to migrate as far north as Cape Cod, Massachusetts.
Can sharks be friendly?
Whale sharks can reach lengths of up to 40 feet, but they're also some of the most friendly sharks out there, as this photo of a woman next to one proves!
What to do if a shark is circling you?
- Move slowly toward the shore or a boat; choose whichever is closest. Do not thrash your arms or kick or splash while you swim.
- Do not block the shark's path. If you are standing between the shark and the open ocean, move away.
- Do not turn your back on the shark as you move.
Can sharks feel love?
Their amazing emotional sensitivity, for the reason that this discovery is so contrary to their popular image. There is probably no one scarier than the massive shark in the movie Jaws. ... White sharks feel love and emotions as much as we do.
Do sharks do a death roll?
Using the excellent grip of these teeth, pyjama sharks can perform a "death roll" similar to that of an alligator, which allows them to pry prey off of rocks, or to tear an arm off an octopus that is too large to be eaten completely.
What do Tiger Sharks look like?
Tiger sharks are named for their distinctive color pattern. The body is gray with dark gray vertical bars or spots on the flanks with a pale or white underside. The markings are especially distinctive in juveniles but diminish with age.
What is the most aggressive shark?
Because of these characteristics, many experts consider bull sharks to be the most dangerous sharks in the world. Historically, they are joined by their more famous cousins, great whites and tiger sharks, as the three species most likely to attack humans.
Do black sharks exist?
The blacktip shark is a widespread, medium-sized shark characterized by its black-tipped pectoral, dorsal and tail fins that give this species its name. It is often mistaken for the spinner shark because both species have torpedo-shaped bodies and are known for spinning out of the water while feeding.
What is the smallest shark?
The smallest shark, a dwarf lantern shark (Etmopterus perryi) is smaller than a human hand. It's rarely seen and little is known about it, having only been observed a few times off the northern tip of South America at depths between 283–439 meters (928–1,440 feet).
What is the cutest shark?
- Blue Shark. What makes the blue shark so adorable are its gigantic black eyes and pouty mouth that bring to mind a surprised child. ...
- Chain Catshark. ...
- Dwarf Lantern Shark. ...
- Greenland Shark. ...
- Pygmy Shark. ...
- Whale Shark. ...
- Hammerhead Shark.
What do you call a female shark?
Those with claspers are mature males; those without claspers are either females or immature males. You can also consider other criteria, such as the presence of mating scars, to determine a shark's sex.
Can you own a dwarf lantern shark?
In fact, the smallest known true shark species include the dwarf lantern shark (Etmopterus perryi) which grows around 7 inches (17.8 cm), and it is not available to aquarists. ... Public aquaria that keep these species reintroduce them back to their natural habitat as they grow larger.
How do you identify a shark?
- Mouth near tip of snout with conspicuous nasal barbels on each side; deep grooves connecting nostrils with mouth.
- First and second dorsal and anal fins broadly rounded; second dorsal fin nearly as large as first dorsal fin.
Can you identify a shark by its fin?
The sharks of interest have distinct white dorsal fin markings (1 and 2) OR their dorsal fins are tall, slender from leading edge to trailing edge and light brown (3). Dorsal fins are the same color on both sides (see right and left side views below).
Can sharks survive without fins?
The sharks are often still alive when discarded, but without their fins. Unable to swim effectively, they sink to the bottom of the ocean and die of suffocation or are eaten by other predators. ... Some countries have banned this practice and require the whole shark to be brought back to port before removing the fins. | https://instantattention.com/are-pyjama-sharks-dangerous-to-humans |
Doctor Colleen is a licensed Naturopathic Physician practising eclectic, wholistic medicine on the Mid and North Island. After graduating from the Canadian College of Naturopathic Medicine in 2011, Dr. Colleen opened a practice in Campbell River and has since expanded her reach to Nanaimo.
I have always had an passion for health and wellness and a fascination for the human body. Following my passion, I pursued post-secondary studies in the field of Kinesiology and Physical Education, as well as Psychology, at Wilfrid Laurier University. During my 3rd year of education, I was at a crossroads. Unsure of what path to take next for my career, I was serendipitously gifted with an opportunity to see a Naturopathic Doctor in my hometown of Peterborough, Ontario. I stumbled upon a career whose philosophy was in line with what I have always thought medicine should be: treat the person, not the symptom, with safe and effective therapies and, most importantly, figure out why it is the person is unwell and address the underlying causes of disease. After our hour-long first visit, I had found my path and purpose.
Not but a few months later, I matriculated to the Canadian College of Naturopathic Medicine, in Toronto, Ontario, where in 2011, I completed her four years of training as a Doctor of Naturopathic Medicine. During my formative education, I completed an externship in Beijing, China at a hospital of Traditional Chinese Medicine, where I honed my pulse and tongue diagnostic skills.
Upon successful completion of my four-year diploma as Doctor of Naturopathic Medicine, I moved westward, toward the mountains and ocean, to start my practice with a focus on serving smaller communities that are often devoid of options for healthcare. In the last 5 years of practice, my style has evolved to that of the older eclectic NDs where I incorporate an array of physical and energetic medicines: diet, herbal remedies, homeopathy, Bach flowers and phytoembryotherapy to address, on an individual basis, the core imbalances for my patients. Counselling and work on trauma and addiction have also become cornerstones of my practice.
Outside of the teaching role I have assumed for my patients, my passion for education has lead me to undertake a teaching position at the Canadian School for Natural Nutrition in Nanaimo, British Columbia, where since 2015 I have been instructing students in Pathology as well as Anatomy and Physiology. It is with great honour that I share my knowledge and clinical experience with the students who have matriculated to CSNN.
In my spare time, I can be found at Robert Ostler park, practising yoga, in Strathcona Park conquering another summit, cycling down the roads of Quadra Island, climbing the crags at Crest Creek or Comox Lake or tending to my garden or in the kitchen, experimenting with my latest creation.
Known for her compassionate and inquisitive nature, Dr. Weiss loves working with her patients at her private practice in Maple Ridge, B.C. She is passionate about finding the obstacles to healing, supporting the body’s innate healing power, and uses a combination of treatment tools, such as: acupuncture, craniosacral therapy, herbal medicine, homeopathy, hydrotherapy, and lifestyle counselling. Since graduating from BINM, Dr. Weiss has done further study with Dr. Tan’s Balance Method of Acupuncture, the New England School of Homeopathy, and Matthew Wood’s Herbal Medicine courses.
Dr. Allen (Scott) Tyler graduated from the National College of Naturopathic Medicine, Portland, in 1986 then returned to Canada and set up practice in Langley, BC. He is a second generation Naturopathic physician following in the footsteps of a family of healers that dates back over 100 years to his great grandfather, Dr. Tanner.
Dr. Tyler was licensed by the College of Naturopathic Physicians of B.C. in 1986 (formerly the ANPBC), and is a member of the BC Provincial (BCNA), National (CNA), and American Naturopathic (AANP) Associations. He is certified in IV & chelation therapy and Prescriptive Authority in BC. In his solo, general family practice, he incorporates natural approaches for acute and chronic disorders, including autoimmune diseases, cancers, musculo-skeletal disturbances, hypothyroidism and all other endocrine diseases, inflammatory bowel disorders, other digestive problems, infertility, weight loss utilizing HCG, PMS, childhood conditions, asthma, and skin diseases. Intravenous chelation is available, along with full laboratory services including bloodchemistries, CBC’s, thyroid, other hormone testing, and environmenta/food allergy testing. Heavy metal testing is also available.
His appreciation for the depth of medical knowledge required to care for patients in our complex world, motivated him to serve on the BC Naturopathic schoolboard (BINM); CNPBC (ANPBC) exam/licensing committees; Advertising Committee; regular guest instruction at the Boucher Institute of Naturopathic Medicine; and offers adjunct student preceptor clinics. He supervises medical staff and provides free medical services for the Salvation Army’s Gateway of Hope Center in Langley, BC; was Vice President and a long-standing board member with the Northwest Naturopathic Physicians Association: co-authored the book “A Pound of Prevention”(1994) with his father, Dr. Allen N. Tyler, MD, DC, ND, Phd., and is currently writing two books, one on pediatric Naturopathy, and another on thyroid disease. He lives in Langley on a small farm with his wife of 24 years, and has two married daughters, one with a sister-in-law who is an ND graduate of BINM.
His part time practice now allows more time for writing and teaching, as he works toward the coming new age of Naturopathic medical care.
After obtaining his ND certification at Bastyr University, Dr. Dana Barton has practiced in Vancouver and more recently on Bowen Island. In his practice Dr. Barton works extensively with mind and body medicine with focus in the following conditions: arthritis, attention deficit disorder/hyperactivity, cancer, carpal tunnel syndrome, chronic fatigue, colitis/Crohn’s disease/IBS, fibromyalgia, gynaecological care, menopausal disorders, obesity and psoriasis/eczema. He supervises third and fourth year students at the Boucher Institute.
Dr. Scarlett Armstrong graduated from the Canadian College of Naturopathic Medicine in Toronto and is a licensed naturopathic doctor in British Columbia. Prior to this, Dr. Scarlett attended the University of British Columbia where she earned a Bachelor of Science with Honours in Nutritional Science. With her strong background in nutrition, Dr. Scarlett works with patients to build a foundation for health, complementing dietary and lifestyle approaches with additional naturopathic treatments including acupuncture and herbal medicine. Dr. Scarlett has a clinical practice in the Clayton Heights area of Surrey BC, and is also a nutrition instructor and a clinic supervisor at the Boucher Institute of Naturopathic Medicine.
Dr. Jaime de Melo is a naturopathic doctor and educator in Victoria, BC. In his family practice at Acacia Integrative Health, he helps patients of all ages with a wide range of health concerns. He has a special interest in disorders that affect digestive and respiratory health. Dr. de Melo holds faculty positions at both the West Coast College of Massage Therapy and at the Pacific Rim College in Victoria, where he teaches anatomy and physiology. He is also a clinical supervisor for the Boucher Institute of Naturopathic Medicine at the Family Naturopathic Clinic – a free naturopathic clinic for low income families in Victoria. He enjoys discussing anatomy, physiology, nutrition and health any chance he gets.
Dr. Greenwood’s interest in health and wellness began with the completion of his honours degree in environmental engineering. Long hours of study demonstrated the importance of a healthy relationship between one’s body and mind. After completing his ND certification at Boucher, Dr. Greenwood built a private practice focused on strategies for preventative health. In addition to his work with the Boucher Clinic, Dr. Greenwood serves as a faculty member of the Institute of Holistic Nutrition, teching preventative health care and nutrition. He also works as a naturopathic physician at the Friends For Life Society – a non-profit organization offering holistic health care to people with life threatening illnesses.
Dr. Grimwood has extensive experience working to achieve optimum health in patients from diverse backgrounds (e.g. First Nations, LGBTQ+, HIV/AIDS) presenting variety of conditions – from mental health to autoimmune diseases to men’s and women’s health, digestive concerns and stress reduction. Dr. Grimwood is passionate about global health, and has worked with medical clinics in Haiti and Nicaragua. Her practice includes Traditional Chinese Medicine and acupuncture, clinical nutrition, physical medicine and manipulation, botanical medicine, homeopathy, hydrotherapy, and minor surgery. She currently serves as President for Naturopathic Doctors International and maintains a private practice at Restoration Health Clinic in Lynn Valley.
Dr. He has been in private practice since 2005 with a special interest in treating chronic pain. He holds licensing as an acupuncturist as well as a naturopathic doctor. Dr. He has gone on to take training in chelation IV therapies and pharmaceutical prescribing, bettering his ability to treat and care for his patients that experience chronic pain.
Dr. Margaret Holland has been working in a thriving private practice for over 11 years. Her areas of interest include treating chronic pain and hormonal imbalances. Besides her practice and supervising at the Boucher Naturopathic Medical Clinic, Dr. Holland holds a position on the Program Advisory Council at the Canadian College of Naturopathic Medicine in Toronto. She has also held a position at Rexall Pharmacies as a corporate consultant. Dr. Holland has a passion for teaching and has often been invited as a guest lecturer in advanced homeopathic prescribing.
After obtaining his degree in Animal Biology, Dr. Hsu went on to complete his naturopathic training at Boucher. Thanks to his background in human physiology, Dr. Hsu’s approach brings the strength of diagnostic and holistic medicine together. He believes in treating the big picture rather than focusing on individual symptoms. Focusing in diagnostics and treatments of Atopic dermatitis in children and adults, Dr. Hsu’s work focuses on gastrointestinal health, cancer and detoxification. Dr. Hsu is also certified in acupuncture and IV therapy which he frequently utilizes as part of oncology management.
Dr. Kaur believes in the body’s innate ability to heal itself. In an effort to prevent disease and strengthen the body’s immunity,, she works with patients to develop a simple diet and a strategy for introducing balance into their busy lives. With special interests in sports medicine, endocrine disorders, gastrointestinal disorders, dermatology, mental health, women’s health and pediatric conditions, Dr. Kaur chooses from a variety of different modalities to treat the individual. Her training includes Traditional Chinese Medicine (acupuncture, biopuncture, electro-acupuncture, cupping, herbs), orthomolecular medicine, diet/lifestyle counselling, homeopathy, soft tissue manipulation/trigger point therapy, botanical medicine, and is certified in IV Therapy.
Dr. Ashleigh Lane’s clinical focus and passion lays in helping women balance hormones, treating thyroid disease, and a safe and effective means of losing weight. Dr. Lane believes in a system of medicine that empowers the individual to understand and make educated decisions regarding their own health. Dr. Lane approaches each case individually, and provides her patients with evidence-based choices for treatment. In addition to supervising at Boucher, Dr. Lane runs a general family practice in North Delta, is certified in Prescriptive Authority and IV therapy by the CNPBC and special training in optimizing hormones through the American Academy of Anti-Aging Medicine.
Dr. Jessica Moore one of the few hospital and residency-trained naturopathic doctors in Canada. After graduating from the Southwest College of Naturopathic Medicine, in Phoenix Arizona, she completed a highly competitive two-year hospital-based residency at Southwestern Regional Medical Center of Cancer Treatment Centers of America, in Tulsa Oklahoma. After 2.5 additional years of practice as a staff ND, Dr. Moore chose to transition home to Canada. She currently treats a variety of conditions; however, she maintains a special focus in integrative and naturopathic cancer care at her private practice, at Tandem Clinic, in Vancouver.
At Boucher Naturopathic Clinic, Dr. Moore supervises naturopathic medical interns by providing teaching, guidance and feedback for case work-up, physical exam, laboratory diagnostics and treatment planning. As a patient on Dr. Moore’s student rotation, you will have the benefit of 2-3 student clinicians working on your case with expert guidance by Dr. Moore. They will work collaboratively and personalize your plan of care to optimize your health using best practices and evidence-informed natural medicine solutions.
During her study at the Boucher Institute, Dr. Krista Moyer found a great passion for the importance of a healthy foundation of nutrition, movement, and mental/emotional balance. Dr. Moyer treats a wide range of conditions, with a focus on digestive complaints, women’s health, weight loss, depression, anxiety, and musculoskeletal problems. She immerses herself with her private practice at Broadway Wellness, and supervises at the Boucher Naturopathic Medical Clinic.
Dr. Bobby Parmar has served the community of Kitsilano for nine years as a member of a highly collaborative care wellness clinic. A fervent educator, Dr. Parmar has tailored his academic career towards family medicine. Dr. Parmar is certified in Acupuncture, IV therapy and Prescriptive Authority. Dr. Parmar stays engaged with the community by working with multiple organizations giving workshops to members of the Canadian Mental Health Association, The Arthritis Society of BC and Yukon, and the Earthsave Society of Canada. He is also adjunct faculty at the Boucher Institute of Naturopathic Medicine where he teaches and supervises interns at various stages of their program.
Upon graduating from the Boucher Institute, Dr. Tajbakhsh was awarded the Academic Excellence Award. Dr. Tajbakhsh has a private practice in the Burnaby Metrotown area, where he focuses on acute and chronic pain alleviation, gastrointestinal concerns, neurological issues, and general health and wellness. Dr. Hamid utilizes a variety of medical modalities including Acupuncture, Nutritional Medicine, Western and Eastern Botanical Medicine.
In addition to his private practice, Dr. Hamid serves as an assessor to the Quality Assurance Committee of the College of Naturopathic Physicians of British Columbia (CNPBC) which is the regulating body for NDs in BC, and as a supervisor at the Boucher Clinic.
Dr. Walczak is a naturopathic doctor for people who are overwhelmed by the amount of health information out there. She believes that healthy doesn’t need to be complicated or confusing and works with patients to develop straightforward treatment plans that have them feeling better sooner rather than later.
At Boucher Naturopathic Medical Clinic, Dr. Walczak supervises third and fourth-year student interns. She assists students in their patient care and helps them grow their skills as clinicians. As a patient of Dr. Walczak and her interns, you will have the advantage of having 2-3 people working on your case. This team approach allows for you to have many people listening to your concerns and working together to provide the best care possible.
Dr. Walczak has a special interest in working with people with allergies, skin issues, autoimmune disorders, digestive issues, weight management, and being a former K-12 teacher, she LOVES working with kids of all ages.
Dr. Aaron Wong works to collaborate with his patients, empowering them to tap into their deepest healing potential. After completing his degree in Chemical & Biological Engineering at the University of British Columbia, Dr. Wong suffered a debilitating back injury that completely changed the course of his life. Through years in recovery and trying numerous conventional and alternative treatments, Dr. Wong found healing within mind, body and spirit medicine. Since graduating from Boucher, Dr. Wong has become the clinical director of his own practice in North Vancouver. He is certified in Acupuncture, prescriptive authority and IV therapy. | https://boucherclinic.org/team-types/clinic-supervisors/ |
You don’t have to search hard to find indigenous art in the world’s museums. Often, you can even find it in the world’s art museums. But, no matter where it is placed, finding exhibitions that have been curated by representatives from indigenous groups themselves can be somewhat more challenging.
So, when Tunirrusiangit (“the Gift” in Inuktitut), an exhibition of the works of modern Inuit artists Kenojuak Ashevak and Tim Pitsiulak, opened in June at the Art Gallery of Ontario, it caught attention as much for who chose the art as for the art that was chosen.
Tunirrusiangit is not unique in having indigenous curators select works of art they believe best represent their culture. In the Arctic, Nordnorsk Kunstmuseum, in Tromsø, Norway, surprised visitors last year when it secretly removed its permanent exhibitions and turned over the empty building to a Sámi curator, who became the temporary director of what, for a period, was the only Sámi art museum in existence.
Other Northern museums, including the Anchorage Museum in Alaska, say they also seek to involve members of indigenous groups when showing art created by someone from their group. Tunirrusiangit, though, stands out as the first exhibition of its kind for the Art Gallery of Ontario after it, in 2017, announced that it was redefining what it considered Canadian art. Now, instead of placing indigenous art in separate category, the museum defines the works of artists like Ashevak and Pitsiulak as Canadian first and foremost.
[A Winnipeg museum is set to break ground on new Inuit art center]
As part of the change, the museum set up a new department whose goal is to “challenge the traditional idea of Canada and our world.” The effort, the museum said at the time, was intended to result in exhibitions that displayed “different points of view,” something it considers one of its primary missions.
Having Inuit select which items were to be chosen and how they are presented for the Tunirrusiangit exhibition ensures that viewers understand the works as the artists intended, according to Laakkuluk Williamson Bathory, one of the four curators.
She describes, for example, how an Ashevak drawing of a woman facing away from the viewer (Untitled, 2004-2005) was misinterpreted by one critic to mean it showed a rejection of Western society.
In reality, the most important part of the drawing is a woman’s pride in her sewing, according to Williamson Bathory.
“The way that her amauti (baby-carrying parka, ed.) is perfectly symmetrical, her kamiik (boots, ed.) are still and high against her calves. Ashevak was drawing the woman’s parka because she was proud of it,” she says. “Without the proper telling, you miss that. Instead of pride, you get a rejection of Western society.”
[This fund aims to help indigenous filmmakers tell their own stories about the Arctic]
Williamson Bathory, though, sees curating an exhibition of art created by someone from her own culture as more than just a service for museum guests.
“It breaks down stereotypes and addresses the racism we experience on a daily basis,” she says. “If you’re looking at art, you’re looking at a story, either about the artist or the culture they belong to. When you let someone else tell your story, you let them decide what it is about.”
In addition to displaying to the works of Ashevak and Pitsiulak, Tunirrusiangit includes a number of performances by Williamson Bathory any other Inuit artists. Likewise, prior to the opening, the curators held a traditional community meal that including butchering a seal in the museum. For Bathory and the Inuit curators, the inclusion of additional events is a sign that a change has taken place in the institutional acceptance of indigenous culture, yet, the feast, in particular, shows that barriers to full acceptance remain.
Because the seal was to be butchered in a public place, which city ordinances ban as unhygienic (and, by way of extension, inappropriate, according to Williamson Bathory), the museum needed to apply for special permission from city health authorities.
[‘Igloo Art’ certification now in Inuit hands]
In that past, getting a museum to put in that kind of effort the lengthy process required would have been impossible, says Williamson Bathory. Art Gallery of Ontario, however, did it without hesitating.
For Georgiana Uhlyarik, the Art Gallery of Ontario’s curator of Canadian art, supporting the curators’ ideas was a part of the museum’s recognition that the decisions they made “amplified” the story of contemporary Inuit life that the exhibition seeks to tell.
“The decision to use Inuit curators for an exhibit like Tunirrusiangit adds extra details that non-Inuit could not,” she says.
Julie Decker, the director of the Anchorage Museum calls this practice “community curation” and agrees with Williamson Bathory that we are seeing more of it, thanks in part to a reaction against the traditional approach of asking someone from outside a culture to interpret it for audiences.
[Can shared culture keep the Arctic a place of peace?]
The process, described by Decker as “decolonization” of museums — a term Williamson Bathory also uses — “has meant that the people represented in an exhibition are getting a say in what gets said”, she says. “This isn’t a trend, it’s an imperative.”
She stresses, though, that involving outside voices is not the same as handing over the keys of the museum to them. The museum still decides what to exhibit, and, in the end, offers a seal of approval for what an exhibition concludes. To achieve what it feels is the right balance between institutional control and community curation, Anchorage Museum has an indigenous curator on staff, and, like the Art Gallery of Ontario, uses external curators.
Sometimes, though, other types of curators may be more appropriate.
“When we are showing something like an ‘indigenous’ artist, we need to involve the people of the community the artist belongs to in much more comprehensive ways, and there, assigning an indigenous curator is appropriate. But there is a danger of looking at this in a binary manner. Artists can be indigenous and contemporary. Who they are depends on the context of the exhibition.”
While considerations of who to include and how when it comes to indigenous art exhibitions, Decker believes, they are a part of good museum management.
“Whether you are talking about ‘indigenous’ art, or art produced by any other type of artist, as a museum we must constantly be reaching out and incorporating new voices. If we are doing that, we are succeeding.”
Below: Tunirrusiangit co-curator Koomuatuk Curley in conversation with Tim Pitsiulak’s widow, Mary Pitsiulak
Below: Laakkuluk Williamson Bathory performing her poem “I am the light of the happiness” in connection with Tunirrusiangit. | https://www.arctictoday.com/northern-museums-exhibits-indigenous-art-increasingly-community-efforts/ |
Task Info :
We are the human centered venture capital firm, invests in transformative and scalable entrepreneurial ventures focused on low income communities. Our Method of investing has democratized essential services for over 20 million underserved customers and catalyzed billions of dollars of capital into 25+ companies in India and Latin America. We are the founding or first institutional capital in several companies focused on financial services, agriculture, education, healthcare and housing. An entrepreneurial emerging markets team based in India, Colombia and the US, we are widely recognized as a leader in impact investing.
We are looking to recruit a candidate (at the Vice President or Associate level) who has a true passion for using her/his skill sets and execution ability to bring about meaningful improvements in the world. We have a strong organisational culture that defines and shapes “who we are … and who we want to be” as individuals and as an organisation. Everyone here are the part of a shared ambition, loves the power of a small team and is passionate about building alignment between entrepreneurs, customers and investors.
PRIMARY / KEY RESPONSIBILITIES
• Work with entrepreneurs / management teams of our portfolio companies on specific projects and track financial and operating metrics in order to facilitate, and report on, business performance and customer centricity
• Building and analysing financial models, performing valuation analysis, conducting and coordinating due diligence and preparing investment recommendations
• Provide analytical support (qualitative and quantitative), research and industry analysis, while evaluating business models and investment pipeline opportunities
• Work on special projects that are relevant to our portfolio
SKILLS/ EXPERIENCE: | https://www.analyticsvidhya.com/blog/2017/01/vice-president-associate-bangalore-4-8-years-of-experience/ |
working industries. Advanced technology:nc-scanning/cutting,
welding systems with sensors, programming systems, databases
for fast/flexible adaptation > changing mfg requirements.
The goal of this project is to develop an overall system architecture for metal-working SMEs including the design and manufacture of components in small batches with the aim of reducing the product design cycle and total manufacturing time. Therefore, an automated cutting, assembly and welding cell will be built up according to existing European standards to ensure high quality and increase cost effectiveness. This can only be realised successfully if the product design, production planning, material flow and manufacturing, as well as the necessary data exchange between all components included in the manufacturing process, are organised in an overall system architecture to be developed. The ideas of the project proposed deal with the following goals: a) Development of new approaches for design by constraints e.g. design for cutting, assembly and welding integrated into a flexible automated manufacturing cell. b) Exploitation of integrated design, production planning and production control and costing in small batch production interacting with a programmable program software (PPS) system. c) Development of innovative approaches in mechanical and/or electrical design of the production cell, including the interaction of all components and the introduction of sensors and process control for quality assurance and effective costing. The development of an overall system architecture for manufacturing in small batches must include all manufacturing aspects from product design up to the final product. For that reason, efforts must be made to analyse the spectrum of workpieces for their possible degree of automation. If necessary, re-designs or new developments will be made using CAD. Furthermore, the organisation of data flow, relating to process planning, process engineering and manufacturing operation management, as well as the organisation of material flow (raw material, prefabricated parts, tools, etc.) will be a further main aspect of this project. Last but not least, advanced technology including robots, sensors and NC-technology as well as databases and programming systems for the manufacturing process itself must be taken into consideration. The interfacing of all components will enable fast adaptation to changing production situations as well as the supervision of the manufacturing process itself to ensure high quality. Furthermore, feedback information from the production cell to design and production planning will be possible. This will enable the design and manufacturing process to be optimised. Additionally, rapid and effective costings for tenders are possible. The concept of the project shows a completely new strategy for the fully automated, cost-effective manufacture of components in small batches. At present, a lot of work in this field of manufacturing is done manually because of the frequent changing of parts. Existing manufacturing systems are not as flexible as they should be for manufacturing in small batches, and, for that reason, they are not efficient in this field of production. Therefore, the aim of this project to build up an overall system architecture is innovative and will lead to competitive manufacturing in small batches. As major equipment, an NC-plasma cutting system, a robot system and a VAX workstation will be used. At the moment, the welding operation is done manually and will be automated by robot welding. Today, for cutting an oxy-acetylene cutting machine is in use. This machine has no interfacing facilities. It is advisable to replace it with an advanced plasma cutting station. For the software development, the partners have agreed to use a VAX workstation to ensure software compatability and software support also after the project has finished.
Acronym:
AQUA (DEF)
Project ID:
759
Start date:
01-06-1992
Project Duration:
62months
Project costs:
3 430 000.00€
Technological Area:
Market Area: | https://www.eurekanetwork.org/project/id/759 |
by Mikhaeyla Kopievsky
Welcome to The Quick Six – an ongoing series of posts, where I interview independent authors on their self-publishing stories, using six quick questions to gain insight into their processes, thoughts and works.
This week, I’m interviewing S. Breaker – a fellow ASF writer and author of offbeat, quirky, and easy reading teen/young adult science fiction and fantasy. She lives in New Zealand with her husband and two kids, and (in her own words) ‘publishes independently in a likely futile attempt to pay for her writing addiction’ :). She has just released “Free Yourself” – Book 3 of her YA Sci-fi series “Selfless”, and has kindly offered to share some of the lessons she has learned while navigating the indie publishing scene.
1. WHAT HAS BEEN THE MOST REWARDING THING ABOUT SELF-PUBLISHING?
With self-publishing, you have control over most of the aspects of your work. You make your own deadlines. You make your own priorities. You can choose what you want to write about and how you want to write it. You get to set your own benchmarks for the type of success you want based on what “you” define as success, not what someone else defines for you.
2. WHAT HAS BEEN THE MOST CHALLENGING THING ABOUT SELF-PUBLISHING?
With self-publishing, because you have control over most of the aspects of your work, you need to do your own research for A LOT of things. What types of books are selling, how to get exposure for your books, what rates are good for expenses like editing, cover art, ads (and all these can be very expensive – you’re paying for all of it). You often have to try many strategies across the board and it won’t always work.
3. WHAT HAVE YOU LEARNED DURING THE PROCESS THAT YOU WISH YOU HAD KNOWN FROM THE START?
I’m still relatively at “the start”, but I think you don’t stop learning. And you shouldn’t. Success looks different for everybody. What works for others may not necessarily work for you and vice versa. Just keep learning.
4. WHO OR WHAT HAS BEEN YOUR BIGGEST SOURCE OF HELP OR INSPIRATION?
My readers inspire me. Knowing that what I’m putting out there means something to someone (even if there are just a handful of them) is very inspiring. Other indie authors also inspire me. Most of them are very supportive and helpful. The thing about it is many of us started from zero and probably still remembers what it was like.
5. WHAT DO YOU THINK THE FUTURE HOLDS FOR INDIE AUTHORS AND SELF-PUBLISHING?
If platforms like Amazon keep providing a channel for indie authors, self-publishing as an industry will just grow. More new indie authors are publishing books every day. These are people from everywhere in the world, of all kinds and all ages. Traditional publishing will always be there, but with the internet and the proliferation of e-books, self-publishing will always have a fair share of the market.
6. WHAT IS YOUR PUBLISHED WORK ABOUT AND WHY ARE PEOPLE GOING TO LOVE IT?
I’m about to release Book 3 of my YA Sci-fi series Selfless, entitled “Free Yourself”. The series is about a teenage girl who goes to a parallel world and gets mistaken for her genius scientist “alternate self” whose life is in danger. I think it’s a bit different from anything already out there because of its tone. I wanted to create a compelling dystopian world with conflict and danger while maintaining an overarching atmosphere of levity and hope. It’s a fast-paced adventure with some steampunk influences and a bit of romance, fun and quirky, but is still packed with substance. My goal was to write a science fiction book series that’s entertaining and easy to read. If people get that, they’ll love this.
LOOKING FOR MORE SPECULATIVE FICTION READS? START READING MIKHAEYLA KOPIEVSKY NOVELS NOW!
You can now purchase Resistance, the award-winning first book in the dystopian Divided Elements series, and its sequel, Rebellion, from awesome bookstores and ebook sites around the world.
Click here to start reading now! | https://mikhaeylakopievsky.com/2020/06/02/the-quick-six-with-s-breaker/ |
Biological filtering and ecological machinery for self-purification and bioremediation in aquatic ecosystems: towards a holistic view.
According to one of the approaches to the definition of criteria for the phenomenon of life, the key attribute is the ability of the system for some self-regulating and self-supporting. Part of such holistic functions of aquatic ecosystems as self-regulating and self-supporting is their cleaning the water via a multitude of various mechanisms. The goal of this paper is to present some fundamental elements of the theory of ecosystem self-purification which emphasizes the importance of the four functional biological filters that are instrumental in purification and upgrading the quality of water in aquatic ecosystems. These functional filters are: (1) direct water filtering by aquatic organisms that are filter-feeders; (2) the filter (represented mainly by communities of aquatic plants/periphyton) which prevents input of pollutants and biogenic elements (N, P) from land into water bodies; (3) the filter (represented by benthic organisms) which prevents re-entry of pollutants and biogenic elements from the bottom sediments into the water; (4) the filter (represented by microorganisms attached to particles which are suspended in the water) that provides microbiological treatment of water column. New experimental data by the author reveal the role of man-made effects on the ecological machinery which purifies water. The analysis and discussion lead to the holistic theory of the natural process of bioremediation of aquatic ecosystems.
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compensation:
$80K — $150K *
industry:
specialty:
experience:
Core Responsibilities for this role include:
• Lead cross functional category management team to develop and execute category strategies for assigned categories that optimize value, drive innovation, and mitigate risk.
• Ensure category strategies are communicated to all key PBO stakeholders.
• Ensure supply chain for materials in assigned categories have a defined and properly executed risk mitigation strategy.
• Develop strong relationships with stakeholders to define business requirements that are critical to PBO.
• Perform supplier segmentation analysis to differentiate between suppliers in assigned categories and determine optimal level of oversight and relationship management.
• Perform external market analysis including supply market research for assigned categories.
• Develop and maintain deep understanding of supplier capabilities, capacity, and risk elements within assigned categories.
• Develop in-depth knowledge of categories. Become SME for assigned categories.
• Develop, negotiate, support, manage, and maintain agreements with suppliers in assigned categories.
• Effectively lead supplier relationship management, including leading periodic business reviews in line with Gilead business requirements.
• Develop relationship contact matrix and create escalation management process for suppliers in assigned categories.
• Ensure uninterrupted supply of materials to Gilead sites and external CMOs for materials included in assigned categories.
Knowledge, Experience, and Skills:
• 8+ years of relevant experience in related field and a BS or BA; or 6+ years of relevant experience and a MA/MS/MBA.
• Prior experience in pharmaceutical, biotech or life sciences highly preferred.
• Significant prior experience in strategic sourcing / procurement category management with a focus on direct materials required.
• Experience leading cross functional category teams with functions including: Manufacturing Engineering, Development, Quality, Finance, Supply Chain and Legal.
• Experience with ERP system software, with emphasis on Operations/Supply Chain functionality.
• Demonstrated ability to collaboratively and positively influence suppliers, stakeholders and team members.
• Demonstrated sourcing experience including: developing and executing RFI/RFP, supplier qualification, negotiations, supply market research, spend analytics, and supplier relationship management.
• Track record of sourcing principles, concepts, best practices, and standards along with in-depth knowledge of industry best practices.
• Demonstrated communication, presentation, organizational, time management, and change management skills.
Valid through: 12/12/2021
Apply.
Save.
Search. | https://www.theladders.com/job/senior-category-manager-direct-materials-gileadsciences-san-mateo-ca_48700289 |
Hong Kong, 13 May 2013 – With 600,000 professionals using LinkedIn in Hong Kong, the rapid rise in popularity and importance of social networking websites to the business world is expected to continue. However, many employers in Hong Kong still have doubts on the reliability of a potential job candidate’s LinkedIn profile, according to a new survey released by leading finance, accounting and technology recruitment firm, Robert Half.
The research, which polled 150 Chief Financial Officers and finance directors in Hong Kong, reveal that over two-thirds (69%) of employers said they found the information posted on LinkedIn to be ‘sometimes’ trustworthy and/or reliable. A further 7% said they never trust profiles that are posted on the world’s largest professional networking site.
Directly-received applications for employment are still more widely accepted in Hong Kong as 85% of survey respondents consider this form of job application to be more reliable when recruiting professionals than through LinkedIn profiles.
When reviewing profiles on LinkedIn, how often do you think that the information presented by individuals is trustworthy and/or accurate?
|Always||24%|
|Sometimes||69%|
|Never||7%|
Among those who question the accuracy of a potential candidate’s LinkedIn profile, 51% of respondents are concerned about the lack of a system to qualify information. This is followed by the opportunity to exaggerate experience or skills (24%) and the relative anonymity of social media (17%).
When asked about the factors that they consider important when reviewing profiles on LinkedIn, the top three most-selected attributes are: experience (60%), education background (45%), recommendations (31%) and updated profile information (31%).
Which of the following elements do you consider important when reviewing profiles on LinkedIn?
|Experience||60%|
|Education background||45%|
|Recommendations||31%|
|Updated profile information||31%|
|References||24%|
|Endorsed skills||23%|
|Number of connections||21%|
|Status updates||14%|
|Groups||6%|
Pallavi Anand, Director of Robert Half Hong Kong, said, “Social networking websites are among the most popular ways of nurturing professional relationships today. Whether you interact online or in person, showing respect to those you know, and helping them achieve their goals, is the ultimate way to network. Therefore, it is important to be truthful and professional, and use technology so it has a positive effect on your relationships with colleagues and business contacts and, ultimately, your career.”
Ms. Anand suggests the following tips on presenting oneself professionally on LinkedIn:
Complete your profile
Provide as much information in your LinkedIn profile as you can. This should include your professional summary, work history and education. Be sure to add key accomplishments so other users get a clear picture of your capabilities, and request recommendations from former colleagues and managers. They can endorse your accomplishments in a far richer and more credible way.
Request recommendations individually
Treat each request with the same respect you would in “the real world.” A generic message asking all of your connections to endorse you may fall on deaf ears. When appropriate (and if it’s permissible by your company), recommend those whom you know the best and trust the most. Be careful, however, of what may be perceived as quid pro quo recommendations. If you recommend someone just as he or she has posted some kind words about you, your kudos may be viewed as “payback”.
Be a joiner
LinkedIn offers many interest groups for members who share certain passions or interests, and these can be a valuable asset for keeping abreast of new developments in your industry. When participating in professional groups, provide useful information and input. Avoid sending direct messages to fellow group members unless you have established a personal connection beforehand. | https://www.roberthalf.com.hk/press/employers-hong-kong-question-trustworthiness-information-posted-linkedin |
Morocco complain to FIFA about refereeing 'injustices' against Portugal, Spain
Fouzi Lekjaa, president of the Moroccon Football Federation says "serious refereeing errors" were made in the game against Spain and Portugal. Photo: EPA/FELIPE TRUEBA
MOSCOW - The Moroccan Football Federation on Thursday complained to world soccer's governing body FIFA over what it said were a series of refereeing mistakes in their World Cup Group B matches against Portugal and Spain which led to their elimination. The federation said the "serious referee errors" led to their early exit and that the video assistant referee (VAR) had been used or not used in order to serve the interests of their opponents.
"We want to express our indignation at the injustice suffered by our national team, following serious refereeing errors that led to (the team's) premature exit from the first round of the 2018 World Cup," federation president Fouzi Lekjaa said in a letter to FIFA President Gianni Infantino. "The severity of these refereeing errors is all the more evident in the fact that in these two matches (against Portugal and against Spain), the use of VAR served only to preserve the interests of our competitors," it said.
Lekjaa went on to list what he said were three incidents from their 1-0 defeat by Portugal, including Cristiano Ronaldo's fourth-minute winner, which he said should never have counted as a Portugal player had committed a foul. He also said five decisions from the 2-2 draw against Spain, with his team already eliminated, including the Spanish last-gasp equaliser, had gone against Morocco.
The African side, who also lost their group opener to Iran, had been fuming following their loss to the Portuguese, their second group game, that had killed off their chances of advancing. "With what has happened we can only express our serious concern at the persistence of these injustices and the negative impact on the image of FIFA and the future of football," Lekjaa said.
Lekjaa urged Infantino to "take the necessary measures and make the necessary adjustments in order to repair these injustices and guarantee the conditions of a competition with equal opportunities for all teams".
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Arming teachers to prevent school shootings is illogical5/1/2013
I was confused by Mike Kooker’s Guest View article in the April 18 issue of Cityview. I’m not sure what point he was trying to make or which side of the gun debate he was trying to support. His words seemed to indicate that he was in favor of increased private gun ownership, but when one follows his directions to “look it up,” all the statistics seem to support the other side of the argument.
He asked readers to look at crime and murder rates in the U.K. and Australia, so I did and found statistics from 2010 indicating that the rate of murders committed with firearms in the U.K. were 0.07 per 100,000 inhabitants, compared with three per 100,000 in the United States (40 times higher in the U.S. than in England). He refers to Australia’s confiscation of all privately owned guns and increasing murder rates. I looked but could find no indication that any such confiscation has taken place and that 5.2 percent of Australians currently possess privately owned firearms. There was mention of some gun buy-backs and increased regulation on obtaining a firearm, but it appears to me that Australians can still possess firearms. Additionally, the articles I read all seem to point to the fact that since this regulation was increased, the number of killings (and the incidence of suicides committed with a firearm) in Australia has decreased.
As in the U.K., the rate of homicides committed with firearms in Australia appears to be significantly lower than in the U.S.
The thought that it’s a good idea to have teachers bring firearms into the classroom baffles me. It seems extremely unlikely that the teacher (remember, this is not a warrior or law enforcement professional, rather an educator) would be able to: retrieve the weapon from its secure location (locked in a gun safe); load the weapon; choose to run toward the danger rather than away from it; and would use the weapon in an effective manner preventing a shooting rather than accidentally shooting innocent parties.
The people who commit gun massacres don’t seem like big planners and are not likely to be thinking of risks/consequences of their actions, so it would seem doubtful that the fact that a teacher may be armed would serve as any sort of deterrent. Additionally, the presence of weapons in the classroom would increase risks of accidental or intentional shootings.
It would be enlightening to see the facts and statistics used by Mr. Kooker in preparing his article which support his illogical and counter-intuitive position that increased numbers of guns will decrease violent crime.Charles Kiehne –Des Moines
Send your opinions to Cityview, 414 61st Street, Des Moines, Iowa 50312. Fax us at 953-1394, or e-mail us at [email protected]. Please limit letters to 200 words or less. Cityview reserves the right to edit for length and clarity. The writer’s address and daytime phone number will not be printed, but must be given for verification. | https://www.dmcityview.com/your-view/2013/05/01/arming-teachers-to-prevent-school-shootings-is-illogical/ |
Nine public sector unions have called the one-day strike for Tuesday to protests Emmanuel Macron’s labor reforms. Schools, hospitals and transport will be affected.
French civil servants are to go on strike Tuesday in a bid to put pressure on President Emmanuel Macron’s cost cutting plans in the public sector.
Nine public sector unions representing more than 5 million workers called the nationwide strikes and demonstrations against Macron’s plans to cut 120,000 civil service jobs, freeze pay, alter sick leave policy and cut social employment schemes.
Schools, hospitals, government offices and train and air transport are all expected to be impacted by the strikes, the first in a decade joined by all public sector unions.
Thirty percent of flights across the country had been cancelled, although Air France said it would run all long-distance flights to and from Paris’ airports.
The strikes are the fourth seeking to get Macron to roll back his pro-business reform plans, which are aimed at reducing stubbornly high unemployment and kickstarting the economy. | https://www.yerepouni-news.com/2017/10/10/france-public-workers-stage-nationwide-strike-against-macrons-labor-reforms/ |
Be sure to sign up for our monthly organization updates. Get an inside look at the work and impact of YWCA National Capital Area through our blog. See our latest releases in our media center.
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Get inspired by news & views from members of the YWCA National Capital Area community. | https://www.ywcanca.org/connect-with-us/ |
XIV International Scientific Conference "Problems of Solvation and Complex Formation in Solutions"
The scope of the conference:
- Structure and dynamics of molecular and ion-molecular systems in solutions, at the phase interface and in conditions of confined geometry
- Solutions in extreme conditions, supercritical fluids
- Ionic liquids and deep eutectic solvents
- Reagent nature and medium effects on complex formation processes
- Coordination compounds and supramolecular structures
XI International Scientific Conference "Kinetics and Mechanism of Crystallization. Crystallization and New Generation Materials"
The scope of the conference:
Section I. Fundamentals of crystalline material design
- Models of crystallization processes. Mechanisms of formation, dissolution and topochemical transformation of crystals
- Processes of crystallization at supercritical parameters of state
- Mechanism of crystallization under exposure
Section II. Functional and construction materials of the new generation
- Methods of synthesis of nanomaterials (colloidal, streamlined organic synthesis, organo-metallic structures, plasma-chemical synthesis)
- Control of properties of materials in crystallization processes, dimensional properties
- Materials for electronics, optics and photonics. Crystallization control in designing high purity substances, powdered and ceramic materials
- Hybrid, multicomponent composites. Polymer films and coatings.
- Liquid crystals
Section III. Pharmaceutics. Materials for medicine. Biocrystallization
- Methodology of medical materials design
- Obtaining of soluble and prolonged action drug compounds based on innovative technologies
- Polymorphism of drug compounds and pharmaceutical systems. Scientific foundations for drug compound solubility improvement. Problems of drug compound enantiomer separation
- New systems of active pharmaceutical ingredient delivery
- Problems of biocrystallization and biosimilar materials
VI International Scientific Conference on Chemistry and Chemical Engineering
The scope of the conference:
- Technology of inorganic substances and materials, including nanomaterials
- Technology of organic substances, polymers, and composite materials
- Petrochemistry, catalysis, and chemical processing of alternative raw materials
- Chemical and metallurgical processes and metallurgical industry materials
- Radiochemical processes, technology of radioactive substances and materials
- Chemical engineering and dual-purpose materials
- Processes and apparatuses of chemical industry; Methods of cybernetics in chemical engineering
- Analytical control of industry, environmental problems of chemical engineering
The plenary and breakout sessions will include lectures, oral and poster presentations, as well as master-classes of outstanding researchers, round tables and a competition of young scientists' works. | http://cluster.isc-ras.ru/en/node/31 |
The rise of Syriza and Podemos closely mirrors the experience of the Latin American left. Can grassroots movement in Europe avoid the same pitfalls?
- Author
If you are expecting yet another hagiography of Syriza, their “no-tie, casual style,” their proud “no” to the Troika, Varoufakis’ glamorous new family home (with a view to the Acropolis, eh!), and everything else you have been reading elsewhere lately, do not bother with this article. I don’t like hymns and hagiographies, especially when we are talking about a government, and I have long been studying similar processes in other parts of the globe to be wary enough and not to get over-excited with the electoral victory of a center-left party.
The Pink Tide
Three years ago, when Syriza was just starting its incredible rise and when Podemos was just an imagination, I wrote a piece for ROAR with the following post-script: The pink tide reaching the shores of Europe?
I was referring to the rise to power of left or center-left parties in several Latin American countries over the past fifteen years, riding on a wave of discontent against the neoliberal policies that were implemented by national governments across the continent; a wave of discontent that was cultivated largely by grassroots movements. Argentina, Ecuador and Bolivia are exemplary cases.
Of course all of these cases have their own local differences and specificities. But they also have some striking similarities: a neoliberal assault on the social character of the state; a wave of discontent rising from below and seriously challenging representative democracy as a system of governance and the political party as an organizational form; a network of grassroots movements leading the resistance and proposing autonomy and direct democracy as a radical alternative; and a left (or center-left) party that eventually won the elections to overturn the neoliberal restructuring of the state and restore the “lost honor” of the political system.
Just like in Greece today — and maybe in Spain tomorrow?
The rise of center-left governments in Latin America came to be known as the Pink Tide — exactly for that reason: they seemed to constitute a diluted form of red. Evo Morales, Rafael Correa and the Kirchners, among others, became the protagonists of a kind of left-populism whose passionate rhetoric sounds revolutionary yet whose practice and politics look more like capitalism with a human face, or like social democracy. Environmentally-friendly rhetoric and supposedly pro-poor policies combined with an economic strategy based on not-so-pachamama-friendly neo-extractivism: oil and gas in Bolivia and Ecuador, Monsanto’s GM soy fields in Argentina.
I am not saying that Syriza or Podemos will necessarily walk down the same road — the social, political and economic contexts in Greece and Spain are completely different, after all. However, there’s something that we should not be overlooking: the relationship of the movements that created the conditions for Correa’s, Morales’ and the Kirchners’ rise to power, with the center-left governments they eventually formed. Taking a look at how that relationship evolved in Latin America in those ten to fifteen years, we may learn a lesson or two that may be applicable to Greece today and maybe to Spain tomorrow.
Autonomy and direct democracy!
If there is one common factor between the Latin American and the Greek experience, it’s the evolution of a network of horizontal movements focusing on prefigurative politics, direct democracy and autonomous self-organization as a response to the financial and social crisis and the legitimation crisis of the political system more generally.
Between the piqueteros and the neighborhood assemblies in Argentina, the Coordinadora por la Defensa del Agua y la Vida in Bolivia, and the Movement of the Squares in Greece, several striking similarities can be drawn: the rejection of representative democracy as a system of governance and of the political party as an organizational form, and the articulation in its place of a horizontal, directly democratic, autonomous form of self-organization from below.
Each of these movements was the expression of a “constituent power” that never managed to create its own institutions and become “constituted” as a new social and political order. However, these movements did manage to challenge the legitimacy of the state’s representative institutions, and they did create a wave of discontent that eventually managed to overturn governments and presidents.
Elections?
All these cases have one more thing in common: when eventually elections were called, those horizontal, autonomous and directly democratic initiatives ran out of steam and lost ground to political parties — of the left this time — that managed to capitalize on the popular discontent and grasp state power. From my point of view, the reason behind this shared experience is simple: the proposal of the grassroots movements did not manage to translate itself into a tangible, solid structure.
To be fair, the movements did not even have the time to develop such structures. When elections were eventually called, the movements — and together with them the overall population — had to make a decision: do we ignore the elections and continue building our own institutions from below that do not yet exist, or do we participate in the institutions that already exist, despite the fact that we do not really believe in them, in order to bring the left into power?
The easiest choice was the latter.
Unfortunately, when those center-left parties rose to power, despite their promises of reinforcing autonomy and direct democracy, they actually ended up co-opting the grassroots movements that could be co-opted, and repressing the ones that could not, in the process establishing a divisive discourse — ‘you’re either with us or with the right-wing’ — that basically stigmatized the autonomous voices in case they dared to challenge the government’s policies. The reason for this dynamic is obvious: political parties, even the most left-wing ones, are top-down structures based on verticality and, of course, representation.
Take as an example the process through which the election of the President of Greece took place under the left-wing Syriza government. I am not going to comment on the selection of a right-wing politician (Prokopis Pavlopoulos, ex-deputy of Nea Dimokratia), who voted for all the memorandums and whose name is implicated in several corruption cases. But what I will criticize is something that clearly reveals the hierarchical character of Syriza’s political project: the fact that its deputies were warned by the party leadership that they would be forced out of the parliamentary group should they fail to vote for the right-wing candidate selected by the party leadership.
That is, even if Syriza’s MPs strongly disagreed with the choice of Prokopis Pavlopoulos — and several of them openly expressed their criticism — they would have to vote for him. I personally do not see any difference between that and the “yes to all” mantra that the MPs of previous Greek governments were forced to repeat during the parliamentary voting procedures on the Troika memorandums. Clearly this type of logic cannot be squared with the horizontality and direct democracy of the movements, which operate according to an entirely different worldview.
However, with the electoral victory of left-wing parties there’s an additional process that begins to unfold: a process that has to do with the restoration of institutional politics, of representative democracy, and of the party as an organizational form — exactly what the grassroots initiatives of previous years had challenged.
Honeymoon?
Finally, another common element among Pink Tide governments is that they initially enjoyed a honeymoon period — a sort of truce — with the grassroots movements upon entering office. This truce broke down later on, at the expense of the movements, of course. Take for example the repression of the indigenous peoples mobilizing against the construction of a super-highway that would pass through their territories in Bolivia (the TIPNIS National Park), or the case of Rafael Correa breaking of his promise not to drill for oil in the Yasuni National Park, or his attack against the Confederation of Indigenous Nationalities of Ecuador (CONAIE) and his efforts to “register and control” the country’s social movements.
A further misconception I notice, especially when it comes to the case of Syriza (and Podemos) is the belief that with a center-left government in office, grassroots initiatives will be able to revive, re-occupy social spaces, and strengthen their proposals. The Latin American experience, however, points towards a different direction. The restoration of the representative logic actually demobilized both the overall population and the movements that had previously engaged in radical prefigurative autonomous experiments. And for those that were not demobilized, co-optation and repression gradually ensured their irrelevance.
I am not saying here that the same process will necessarily repeat itself in Greece and Spain as well. Only time can tell whether it will. What I am saying, however, is that the Latin American experience is there, and if we don’t pay attention to it we may suffer the same fate in Southern Europe — at least those of us who believe in a different world: one that is autonomous, directly democratic, and built form below and to the left! | https://roarmag.org/essays/syriza-podemos-pink-tide-europe/ |
Success Factor Snapshot
VFS is the driver of innovation in our industry. Our customer centric philosophy puts the needs of our clients at the forefront of every job. We recognize that our success is based on the relationships we have formed with our clients over the years, and we endeavor to show our appreciation every day through outstanding customer service.
The initial focus of the position will be to achieve goals by following SOP’s and completing AIA billing, processing change orders with in the contract timeframes/deadlines.
The overall goal is to establish the company as an industry leader, customer satisfaction, meeting customer needs, and completing projects on-time.
AIA Contract Specialist Success Factors
The AIA Contract Specialist will be responsible for improving the accuracy of billings, information review of AC & LiNC. Some of the opportunities and challenges may include:
Responsibilities:
Weekly
Monthly
Other Responsibilities
Competencies
Customer | Client Focus
Finance Background
Contract Experience
Pre Lien Process & Tracking
Ethical Conduct
Personal Effectiveness | Credibility
Supervisory Responsibility
This position has no supervision responsibilities.
Work Environment
While performing the duties of this job, the employee regularly works in an office setting.
Physical Demands
The physical demands described here are representative of those that must be met by an employee to successfully perform the essential functions of this job.
While performing the duties of this job, the employee is regularly required to use hands and fingers to handle, feel or operate objects, tools or controls, and to reach and lift with hands and arms. The employee is frequently required to stand, ascend and descend stairs.
Position Type/Expected Hours of Work
This is a full-time position. Standard days and hours of work are Monday thru Friday, 7:00 a.m. to 4:00 p.m., unless otherwise agreed upon with Supervisor.
Travel
None
Required Education and Experience
Three years’ experience in Construction, AIA Contracts, AIA Change Orders, AIA Billing or any similar combination of education and experience, along with continuing education.
Work Authorization | Security Clearance (if applicable)
Pass a complete Background Check
Authorized to work in the United States
E-Verify | Equal Opportunity Employer
Additional Eligibility Qualifications
Oral Communication: Speaks clearly and persuasively in positive or negative situations; listens and gets clarification; Responds well to questions; Demonstrates group presentation skills; Participates in meetings.
Teamwork: Balances team and individual responsibilities; Exhibits objectivity and openness to others' views; Gives and welcomes feedback. Puts success of team above own interests; Supports everyone's efforts to succeed.
Problem Solving: Identifies and resolves problems in a timely manner; Gathers and analyzes information skillfully; Develops alternative solutions; Works well in group problem solving situations; Uses reason even when dealing with emotional situations.
Interpersonal Skills: Focuses on solving conflict, not blaming; Maintains confidentiality; Listens to others without interrupting; Keeps emotions under control; Remains open to others' ideas and tries new things.
Possess the ability to work on multiple tasks and diverse projects simultaneously and in a demanding, fast paced environment.
Ethics: Treats people with respect; Keeps commitments; inspires the trust of others; Works with integrity and upholds organizational values.
Strategic Thinking: Develops strategies to achieve organizational goals; Understands organization's strengths and weaknesses; Analyzes market and competition; Identifies external threats and opportunities; Adapts strategy to changing conditions.
Dependability: Punctual to work and meetings. Follows instructions and responds to management direction; Takes responsibility for own actions; Keeps commitments and exhibits good follow-up skills; Completes tasks on time or notifies appropriate person with an alternate plan.
Innovation: Displays original thinking and creativity; Meets challenges with resourcefulness; Generates suggestions for improving work; Develops innovative approaches and ideas; Presents ideas and information in a manner that gets others' attention.
The above is intended to describe the general content of and requirements for the performance of this job. It is not to be construed as an exhaustive statement of essential functions, responsibilities or requirements.
Other Duties
Please note this job description is not designed to cover or contain a comprehensive listing of activities, duties or responsibilities that are required of the employee for this job. Duties, responsibilities and activities may change at any time with or without notice. | https://jobs.ourcareerpages.com/job/710943?source=VFSFireSvcs&jobFeedCode=VFSFireSvcs&returnURL=https://vfsfire.com |
Julian Bardin ’16 gives art fundamentals a modern twist in his Studio Art senior thesis. Using photography and slight Photoshop manipulation, Bardin takes theatrical and abstract photos that strip an image down to its basics: light, form and movement.
He is inspired by classical artists, especially Caravaggio (a 17th century painter known for contrasting shadows and light) and the ballerina paintings of Degas. In order to highlight movement and light, Bardin takes photos of dancers in front of a background of trees. It takes creativity, however, to get the exact effect.
Bardin said, “As I started working on this series, I became really interested in contrasting the fluid movement of dancers with the very still, repetitive forms of trees. To up the contrast between these elements, I started shooting at night. I use car headlights as a powerful lighting source to light a forest, turning the trees into graphic, dramatic linear shapes and creating a theatrical backdrop. I use a long exposure to blur my model’s movement, making a contrast with the stillness of my ‘sets.’ I then subtly manipulate the images on Adobe Photoshop, adjusting the lights and darks to further abstract the image.”
Although he does use some Photoshop, Bardin does not produce heavily manipulated images. This is a change of pace from his previous work in high school and at Bates in which he often photoshopped in order to create scenes reminiscent of classical paintings. While image manipulation is a perfectly valid way to create art, Bardin brings his photography back to the basics. He creates the images mostly on set, just as his photos bring out the fundamentals of image composition.
While the photos feature dancers, Bardin himself has never taken a dance class before this semester. Working with models was an enjoyable collaborative opportunity for him. “For this series I worked a lot with Bates dancers and I found it immensely valuable to get their input on my work because of the nature of what they do; dancers have such an understanding of how the forms and movements they are making translate to the viewer,” Bardin said. | https://thebatesstudent.com/2016/03/23/senior-studio-art-thesis-classical-fundamentals-meet-modern-photography/ |
The switzerland girl first step in mastering how to resolve a relationship is to recognize that there are concerns. Trying to transformation someone’s actions are never going to fix a marriage. Acknowledging errors is a great way to purify a romantic relationship and restore past hurts. But if you’ve previously made some mistakes in the past, you should steer clear of it as much as possible. Moreover, make an attempt not to criticize or berate your partner. This will likely only function as a prevention.
Another effective method to fix a relationship is usually to release goals. You should assume that your partner offers valid problems. Likewise, you should refrain from shouting and cursing your lover. Whenever your emotions are high, it’s best to take a break from the relationship. This will help to you avoid being swept up in negative feelings that will cause further damages and disputes. In addition , you should learn to be patient and try to understand your soulmate’s point of view.
When ever addressing your lover’s concerns, try to assume that the person offers legitimate issues. You should also try to listen and find out from him or her. If you can’t see eye-to-eye with your spouse, take a break and refuel your energy. If it’s improbable to resolve the condition, seeking professional help is an excellent choice. Besides, you’ll be able to enough time mistakes you’ve made in the past. Inevitably, counseling will allow you to learn how to repair a relationship and will supply you with the tools required to resolve the issues in the future.
The other step in understanding how to fix a relationship is to discharge expectations. The main step in the process of repairing a relationship should be to release targets and focus on insights that may improve your relationship. If you want the relationship to get better, you need to be open and honest with each other. This will help you build a deeper reference to your partner that help you revisit on track. Do not forget that it’s not easy to focus on a romantic relationship.
The third help learning how to repair a romance is to discover how to understand your partner’s point of view. Seeing things from their point of view is essential in mastering how to correct a relationship. Often , it’s challenging to change someone, thus releasing anticipations is essential to make a marriage work. In some cases, this may need you to forgive your partner or be successful for the both of you. The objective is to find a way to make your partner happier and healthier over time.
The next step in learning how to repair a relationship is to listen to your companion. You should imagine their worries are valid and you should listen closely carefully with their concerns. Assuming you have negative thoughts, consider going for a break in the relationship. It is critical to maintain a wholesome and productive relationship. This will help to you to boost communication and increase your love and trust. If you are open to studying each other’s concerns, this will help you to construct a better relationship. | http://casamode.ma/2021/06/17/how-you-can-fix-a-relationship-3-steps-on-how-to-correct-a-marriage/ |
Since the term»physicochemical» might indicate, this is actually the analysis of the interactions of different substances, such as foundation, acid and base-hydrogen or different types of elements.
A chemical is. A bond is a chemical reaction which may occur between two varieties of atoms such as atoms of metals, or components, and there are four kinds of http://cits.hawaii.edu/ bonds.
Compounds may also be molecules and this is the way the practice of compound synthesis was studied in the 1950s. Molecular compounds are things which can be composed of atoms, instead of molecules.
When children are looking for a Brown Chemistry textbook, it’s very important to remember that the discipline can be a challenging one. The laws governing chemistry, the chemical reactions that are studied, the substances that are studied, and the evaluations are certainly part of a science curriculum that’s appropriate for their age and experience.
For elementary students, it’s a fantastic idea to choose a book that isn’t so technical, so that they can have the ability to read the responses and be in a position https://expert-writers.net/sample-essay/ to comprehend the chemistry. Although knowing the correct properties of different compounds and elements may be essentialif a child is left frustrated with it, it could hinder their overall progress in the discipline. Kids who take some opportunity to comprehend the concepts of chemistry, rather than simply memorizing facts about properties, could come out much better in the long run.
It is likewise important for elementary and secondary pupils to have a book that’s simple to comprehend, even for a pupil who doesn’t understand all the concepts. In some cases, a book that is complicated could serve to excite a child’s interest and capacity. If there is a child not stimulated in any way, even if the concepts are understood by them, it is going to detract from their general improvement.
All students should be encouraged to practice concepts and reading materials through some type of reading task, be it inside the classroom or outside of it. It’s important for kids to remember to browse the classes before they read the text.
Biology – If a child is considering the Biological custom writing sciences as a school course, they ought to think of a Brown Chemistry textbook, but it ought to be under a category. Biological studies deal with the creation and behaviour of organisms, including plants, animals, and the elements of their world.
Though a student should be sure to avoid biology without reading material, they should still be aware of the principles of genetics, molecular biology, and structure and function of the cells that make up the cells of the body. Students should be taught to understand the basic laws of nature, such as the unity of all matter, including the strength of the force that forces particles to move around the universe, as well as the relationships among different elements and their properties.
Physics – It is a good idea for students to take a look in a Brown Chemistry textbook that’s focused on the analysis of mechanics of the world. Physics may be used to describe properties of the planet that is made up of matter, such as the constants of motion, such as acceleration, fat, and vitality.
Science is a challenging subject that requires students to learn about properties of matter and forces, such as electromagnetic forces and Newton’s law of gravity. These subjects are developed with the help of a textbook and are ones that children can relate to, so they can start learning these concepts as soon as possible. | http://www.xidakis.gr/science-searching-out-the-perfect-darkish-hormones-textbook/ |
The King’s Bird is an emotionally uplifting game which pleases gamers with visual and musical splendour but is held back by some puzzling design choices. The story is told almost entirely visually, with dialogue spoken through musical tones from each character’s mouth. In the narrative, players control a nameless young girl, who has always had the dream of flying throughout the world, free from bonds and control. Despite this, however, she is refused her freedom from her elder, who places an indestructible, magical ring sphere around her. Determined to free herself, the girl must travel through forests and abandoned marketplaces and areas, with the few powers she possesses, to find a way to release herself from the enchantment and win back her freedom.
Played as a 2-Dimensional platformer, players control the girl, who must run, jump, and glide between platforms and ledges to reach the end of each area. As levels continue, the individual platform areas become increasingly complex and further demand players to take a more tactical approach on how to overcome what blocks them. The gameplay is both one of the game’s greatest achievements, but also its largest shortcoming. With positives first, the overall pace of the game is immensely satisfying. Being able to scale high walls at spectacular speeds and to glide around in mid-air are easily the most enjoyable moments in the game. These moments are further improved by the fluid animations of the girl and the solid special effects of her bright flying cloak. The levels also have strong points as well. the various layouts of individual platforming sections encourage players to use their heads to try to figure out how to pass them. For the most part, they are designed well and they allow players to perform excellent stunts while trying to get to each area’s final stage, which also provides a strong sense of satisfaction.
What disrupts these moments of enjoyment, however, comes from the game’s inconsistent difficulty. One of the main factors that contribute to the game’s extreme difficulty is the control system. Instead of using the mouse, players are limited to the Z, X, and directional keys on the keyboard. Z is used to jump, holding x allows players to glide or slide down steep ledges, and the directional keys are used for basic movement on foot. Besides players who may not be used to playing without a mouse, trying to memorise each button and the different techniques required becomes a challenge of its own. The opening level’s tutorial does a serviceable job of providing exercises of how each technique is performed and showing the buttons needed to initiate them, but it’s possible for players like myself to have difficulty remembering them throughout the game due to their complexity and these mistakes could cause multiple deaths.
The main source that causes the game’s difficulty to occasionally go off the rails, however, is the way in which many levels layout their most challenging areas. As players progress through each level, the levels often contain areas that are so complicated, that players may find themselves severely confused as to how they need to get through, to the point where they may get completely stuck on how to progress. One level, for example, requires players to glide from the floor, and up through a hole that is filled with deadly thorns. Areas like these are exceptionally difficult to understand and many players are bound to get completely stuck. The majority of areas do have a consistent level of difficulty to them, without providing too much, and they encourage players to use intelligent techniques on how to pass through certain platforms and glide across particularly lengthy pits, but when these areas of extreme difficulty emerge, the game could quickly become tedious. The game does provide a series of options for players to choose from, such as the option to slow down the entire game, and to allow themselves to become invulnerable to all surfaces, and while these options are helpful, they don’t do a service to players who want to try to complete levels without any help whatsoever. they also don’t exactly aid players with getting past areas they find too difficult, leaving them to continue to figure them out for themselves but to almost no avail.
The levels are often inconsistent and sometimes disrupts the satisfying movement and flying mechanics, but what cannot be denied throughout the entire game is the nature of the game’s visual style and tone. The King’s Bird is an absolutely gorgeous game, with lust and beautifully crafted environments and a light-hearted colour scheme for each level. In addition to the beautiful scenery, the game’s musical score is equally pleasant and fits in well with the game’s world and atmosphere. It’s these qualities that greatly improve the game’s overall value and kept me playing despite some of the annoyances. The only minor issue with the visuals is the frozen characters in the background, which don’t move in the slightest whilst the girl travels throughout levels.
The King’s Bird struggles with flaws in its level design and has complicated controls, and an inconsistent difficulty system. Despite these flaws, however, The King’s Bird is an emotionally satisfying experience, with a strong and effective emphasis on visual style and smooth gameplay mechanics. It doesn’t quite reach the height of a revolutionary title in the platforming genre due to its inconsistencies, but it’s nevertheless an enjoyable ride that provides a lot of what makes platformers enjoyable.
REVIEW CODE: A FREE Nintendo Switch code was provided to Brash Games for this review. Please send all review code enquiries to [email protected].
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Something went wrong. | http://www.brashgames.co.uk/2019/03/13/the-kings-bird-review/ |
I’m going to let you in on my secret. In this post, you’ll find the top ten ways I build classroom community. I love when October hits and my class starts to really feel and operate like a family. I’m sharing these tips with you so that you can make your class feel like a (big) family, too.
Some teachers live for the month of September. They love setting up their classroom and they live for that fresh start feeling. I am not in this camp of people. I don't actually love September. What I love: is October. That family feeling doesn't usually happen until October and, when it does, I fall in love with teaching all over again.
Comments, Concerns & Questions Box
On the first day of school I introduce our comments, concerns and questions box. I give students examples for some of the things that they might put into the box.
Throughout the year, as students share ideas with me I encourage them to write it down and put it in the box. I recommend doing this for two reasons. First, it helps me remember their ideas or suggestions. Second, it shows students that I value their input.
At the end of the week, we review any comments, concerns or questions as a class. I read them first to ensure that they are good to go to share out loud. If they are decision items, we make the decisions together during our morning meeting.
Bring & Inspire
What is bring & inspire? Basically, it’s show and tell for big kids! We renamed it so that it sounded cooler but it isn’t much different than what I used to do with my students when I taught grade one.
The last day of the week, students have the opportunity to do a quick show and tell. They can share a photo, a video, bring in something to show off or do a live performance.
This is a lovely way to build classroom community because we get to learn more about each other’s lives outside of school. For this reason, I also occasionally participate so that students can get to know me better, too.
Greetings & Goodbyes
This tip is nothing new but serves as a reminder. Greet your students with a BIG ol’ smile and send them off at the end of the day, in the same way.
As a bonus, I also get a student to sign up to be a class greeter. They stand at the door and greet students by name as they enter.
This way, students get a double greeting and it helps them to connect with each other, too. Double classroom community win!
Leadership roles
Having leadership roles or classroom jobs is a great way to build classroom community. It helps students take ownership in the classroom and shows them that it is their space too.
I include many different types of leadership roles in my classroom to ensure that all students can find a role that appeals to them. Some of our class jobs include morning meeting leader, classroom greeter, custodial staff, and student helpers.
Table Seating
At our school, we have table seating instead of desks. Although this can be a challenge for some students that struggle to stay in their own space and focus on their work, overall, I absolutely love it.
I believe that classroom set up can support classroom community building. I light up when I see students jumping in to help their table mates.
Group & Partner Work
It's no secret that teaching students how to work together sets them up for future success. What it also does, is it helps them get to know their classmates. It gets them talking with other kids that they may not normally gravitate towards.
The Seven Habits
I teach at a Leader in Me school. But, even before we became a Leader in Me certified school, I taught the seven habits. I believe that they provide students with such valuable lessons and they help students practice skills to be successful.
Learning and practicing the habits together gives everyone a common language and allows your class to work together in practicing these skills. Talk about team building!
Goal Setting & Meetings
My students are actively working on a goal at all times. This can be an academic goal or a behaviour type goal.
On Monday mornings, students review their goals with their table groups. Their tables become their accountability partners and they ask for help from their group members to help support them in achieving their goals.
House System
This is my first year rolling out a house system in my class and I’ll never go back. I love being able to award house points instead of individual points. It gets the students working together and they really bond with their housemates. They cheer each other on and are competitive with the other houses in a friendly way, of course! I use Haylee Harwick's house system.
Choice
Choices here, choices there, choices here, there, and everywhere!
I am a huge fan of giving students choices whenever I can. I feel that by providing choice, I am conveying to my students that I trust them and respect them. Trust and respect goes a long way in building classroom community!
Some ways that I provide choice to my students:
- Which tasks they want to complete first
- Where they want to sit
- What leadership role they want to do
- If they want to work with a partner
- Which class reward we should have
Spending time to build a strong classroom community makes for a happy, calm classroom. It also makes classroom management so much easier and who doesn’t want that!
One Last Tip
Another way that I love to build classroom community is through daily morning meetings. Click here to drop your info to get two weeks of morning meetings planned for you! | https://learngrowblossom.co/classroom-community/ |
On successful completion of this module students should be able to:
1. Identify and discuss key concepts such as terrorism, radicalization, counter-terrorism and security in relation to the academic study of international relations.
2. Relate these concepts to historical and contemporary cases and empirical examples.
3. Demonstrate knowledge of the main actors involved in efforts to tackle terrorism.
4. Identify and examine the strategies, tools and resources used by counter-terrorist actors.
5. Provide an analysis of the implications of different approaches to counter terrorism for civil liberties and human rights.
6. Utilise and apply knowledge and analysis to produce a ‘policy report’ on a contemporary terrorism issue.
Brief description
The module explores and analyses the phenomenon of terrorism and efforts to tackle it at the local, national, regional and international level. It examines the academic and policy complexities in discussing terrorism using illustrative historical and contemporary examples to explore why terrorism is perceived as a threat to states and societies. Focusing on liberal democratic societies the module examines the range of approaches, actors, national international, and agencies, such as law enforcement, intelligence and the military, tackling the differing strategies of terrorist actors and suspects. It engages with a variety of forms of security provision and explores the strengths and weaknesses of various counter-terrorist options. The ethical and legal implications of those approaches to security are considered too. | https://www.aber.ac.uk/cy/modules/deptfuture/IP24520/ |
“Actor Network Theory (ANT) was developed in the sociology of science and technology . ANT helps to describe how actors form alliances and involve other actors and use non-human actors (artifacts) to strengthen such alliances and to secure their interests. ANT consists of two concepts: translation and inscription.
When an actor-network is created, consists of four processes of translation :
- Problematization: The focal actors define interests that others may share, establishes itself as indispensable resources in the solution of the problems they have defined. They define the problems and solutions and also establish roles and identities for other actors in the network. As a consequence, focal actors establish an “obligatory passage point” for problem solution which all the actors in an actor-network must pass.
- Interessement: The focal actors convince other actors that the interests defined by the focal actors are in fact well in line with their own interests. Through interessement the developing network creates sufficient incitement to both lock actors into networks.
- Enrollment: Enrollment involves a definition of roles of each of the actors in the newly created actor- network. It also involves a set of strategies through which focal actors seek to convince other actors to embrace the underlying ideas of the growing actor- network and to be an active part of the whole project.
- Mobilization: The focal actors use a set of methods to ensure that the other actors act according to their agreement and would not betray. With allies mobilized, an actor network achieves stability.
In addition to the four stages of translation, the process of inscription is critical to building networks, as most artifacts within a social system embody inscriptions of some interests. As ideas are inscribed in technology and as these technologies diffuse in contexts where they are assigned relevance, they help achieve socio-technical stability. | http://www.nsusociocybersecurity.org/modules/social-organizational-theory/cloud-computing-security-and-international-buisness/theoretical-framework |
In my opinion, the motion picture is the greatest medium of expression ever invented. It embraces all the other arts.
In a world of photography sometimes obsessed by sharpness and detail, Intention camera movement can seem counter-intuitive and is not always easily understood and accepted, even by some of those with an eye trained in art.
I have used intention camera movement (ICM) to create this panel to feel the artistic expression and emotion expressed through abstraction of the people going about in our day to day life. art is always and everywhere the secret confession, and at the same time the immortal movement of its time.
I believe that it is one the most powerful artistic techniques in photography, a technique that brings the freedom of art to this rather technical mean of expression.
All images were produced in camera. | https://fineartphotoawards.com/winners-gallery/fapa-2018-2019/professional/open-theme/hm/8785 |
Barrett Lane has 2 amenities.
More information about Barrett Lane
Barrett Lane is located at 215 Saint Patrick Street. This award-winning building low-rise loft is not only beautifully designed but ideally located in Lower Town right on the edge of the Byward Market. Built by Charlesfort Developments with architecture by Barry Hobin & Associates. It is peaceful and serene, yet still close to the excitement of the market. This building offers lifestyle at its best with shopping, nightlife, restaurants, bars, the Rideau Canal, the Hill, the National Gallery, and more right outside its door. The upscale New York style lofts offer 2 story units with skylights, gleaming hardwood floors, wood staircases, large windows for natural light, 16 ft ceilings, and an open-concept feel. Barrett Lane is a perfect living space for urbanites. Barrett Lane is a 10-minute walk from the O-Train's Rideau Station. | https://www.condodork.com/en/ottawa/barrett-lane-215-saint-patrick-st |
Recent guidelines recommending cholesterol tests for children fail to weigh health benefits against potential harms and costs, according to a new commentary authored by three physician-researchers at UCSF.
Moreover, the recommendations are based on expert opinion, rather than solid evidence, the researchers said, which is especially problematic since the guidelines' authors disclosed extensive potential conflicts of interest.
The guidelines were written by a panel assembled by the National Heart, Lung and Blood Institute (NHLBI) and published in Pediatrics, in November 2011. They also were endorsed by the American Academy of Pediatrics. The guidelines call for universal screening of all 9 to 11-year-old children with a non-fasting lipid panel, and targeted screening of 30 to 40 percent of 2 to 8-year-old and 12 to 16-year old children with two fasting lipid profiles. Previous recommendations called only for children considered at high risk of elevated levels to be screened with a simple non-fasting total cholesterol test.
The call for a dramatic increase in lipid screening has the potential to transform millions of healthy children into patients labeled with so-called dyslipidemia, or bad lipid levels in the blood, according to the commentary by Thomas Newman, MD, MPH, Mark Pletcher, MD, MPH and Stephen Hulley, MD, MPH, of the UCSF Department of Epidemiology and Biostatistics and e-published on July 23 in Pediatrics.
"The panel made no attempt to estimate the magnitude of the health benefits or harms of attaching this diagnosis at this young age," said Newman. "They acknowledged that costs are important, but then went ahead and made their recommendations without estimating what the cost would be. And it could be billions of dollars."Some of the push to do more screening comes from concern about the obesity epidemic in U.S. children. But this concern should not lead to more laboratory testing, said Newman.
The requirement of two fasting lipid panels in 30 to 40 percent of all 2 to 8-year olds and 12 to 16 –year- olds represents a particular burden to families, he said."Because these blood tests must be done while fasting, they can't be done at the time of regularly scheduled 'well child' visits like vaccinations can," said Newman. "This requires getting hungry young children to the doctor's office to be poked with needles on two additional occasions, generally weekday mornings. Families are going to ask their doctors, 'Is this really necessary?' The guidelines provide no strong evidence that it is."
"The panel states that they reviewed and graded the evidence objectively," said Newman. "But a recent Institute of Medicine report recommends that experts with conflicts of interest either be excluded from guideline panels, or, if their expertise is considered essential, should have non-voting, non-leadership, minority roles."
Evidence is needed to estimate health benefits, risks and costs of these proposed interventions, and experts without conflicts of interest are needed to help synthesize it, according to Newman. He said that "these recommendations fall so far short of this ideal that we hope they will trigger a re-examination of the process by which they were produced."
Newman and Hulley have no disclosures. Pletcher has NIH funding to support research on targeting of cholesterol-lowering medications to prevent cardiovascular disease.
About UCSF
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit http://www.ucsf.edu/.
Juliana Bunim | EurekAlert!
Further information:
http://www.ucsf.edu
Further reports about: > MPH > UCSF > blood test > cardiovascular disease > cholesterol test > cholesterol-lowering medications > lipid screening guidelines > non-fasting lipid panel
Radioisotope couple for tumor diagnosis and therapy
14.05.2019 | Kanazawa University
Therapy Optimisation by Analysing the Genome
13.05.2019 | Rheinische Friedrich-Wilhelms-Universität Bonn
Engineers at the University of Tokyo continually pioneer new ways to improve battery technology. Professor Atsuo Yamada and his team recently developed a...
With a quantum coprocessor in the cloud, physicists from Innsbruck, Austria, open the door to the simulation of previously unsolvable problems in chemistry, materials research or high-energy physics. The research groups led by Rainer Blatt and Peter Zoller report in the journal Nature how they simulated particle physics phenomena on 20 quantum bits and how the quantum simulator self-verified the result for the first time.
Many scientists are currently working on investigating how quantum advantage can be exploited on hardware already available today. Three years ago, physicists...
'Quantum technologies' utilise the unique phenomena of quantum superposition and entanglement to encode and process information, with potentially profound benefits to a wide range of information technologies from communications to sensing and computing.
However a major challenge in developing these technologies is that the quantum phenomena are very fragile, and only a handful of physical systems have been...
Working group led by physicist Professor Ulrich Nowak at the University of Konstanz, in collaboration with a team of physicists from Johannes Gutenberg University Mainz, demonstrates how skyrmions can be used for the computer concepts of the future
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SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe
29.04.2019 | Event News
Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg! | https://www.innovations-report.com/html/reports/medicine-health/lipid-screening-guidelines-children-overly-199421.html |
One thing that makes Miriam such a special place is that we do not just focus on academics, or on therapies, or on social interactions. We support the whole child, helping provide the skills to navigate all parts of their lives – including their mental health.
Janine Allen, a counselor at Miriam, says many kids may not have the language to express how they’re feeling yet, and it’s a skill that takes practice.
“Kids mask a lot of things,” says Allen. “You see it come out in their play, or you see it come out in their art, or you just see it in their day-to-day interactions. So we need to give them the words to say what’s going on with them.”
Allen works with students at a classroom level to identify their emotions, find healthy ways to express them, and work on expected behaviors.
“We individualize for each class,” Allen says. “If there is an issue with self-regulation in one class, I’m going to focus on that more. Whereas another class may have more peer-interaction issues that would be more of a focus.”
With a background in art therapy, Allen uses visual and creative ways to make complex ideas tangible for students.
“That helps people to have an extra layer of understanding,” Allen says. “It’s particularly helpful with this population, in that word-processing and the verbal processing is not easy.”
Miriam also offers individualized counseling outside of the classroom. Kirstie Williams, a licensed social worker, works with kids who need more one-on-one help to figure out what thoughts are manifesting in their behavior.
“There is a point in every child’s life where they come to an understanding of, ‘These are my emotions and this is how I manage them,’” Williams says. “Kids who have mental illness don’t always have that point, so they just need some guidance in that.”
Williams also incorporates creative means to reach students.
“I do lots of play therapy, art therapy, or – I even have a kiddo who loves music, and so we do music therapy,” Williams says. “So we break down lyrics and songs that she really likes and focus on ‘Hey, how does this resonate with you?’”
Both Williams and Allen encourage families to continue these types of conversations at home, and carve out a time to connect with their children.
“Kids need that time,” Williams said. “They need one-on-one, but they also need time to see, ‘This is my family and this is a unit, and we can work together with some things.’”
Interested in sending your student to Miriam? Contact our admissions team. | https://www.miriamstl.org/mental-health/ |
I’ll be going home to vote in tomorrow’s midterm election. I encourage all Kattera readers to go out and vote! Let us exercise our right to choose our leaders and at the same time, be reminded that voting is our responsibility as Filipinos.
Upon voting, please make sure that you vote for the candidate not because of his/her last name and his/her catchy tv ad and jingle but on his/her stand on issues that matters to you. Again, your vote is sacred. Please don’t waste it!
This table on the stand of “senatoriables” on some issues should help you decide on who to vote: | https://katterabeauty.com/2013/05/12/philippine-election-2013/ |
Culture in the sociological field is analyzed as the ways of thinking and describing, the ways of acting, and the material objects that together shape a people’s way of life. Contemporary sociologists’ approach the sociology project 2.0 pdf download culture is often divided between a “sociology of culture” and “cultural sociology”—the terms are similar, though not interchangeable.
The sociology of culture is an older concept, and considers some topics and objects as more-or-less “cultural” than others. By way of contrast, Jeffrey C. Alexander introduced the term “cultural sociology”, an approach that sees all, or most, social phenomena as inherently cultural at some level. To believe in the possibility of cultural sociology is to subscribe to the idea that every action, no matter how instrumental, reflexive, or coerced vis-a-vis its external environment, is embedded to some extent in a horizon of affect and meaning.
Functionalist theories emphasize “cohesive systems” and are often contrasted with “conflict theories”, the family unit is one of the most important social institutions found in some form in nearly all known societies. From Comte onwards, the extraction is now based on the most recent pdf. A major subfield of political sociology developed in relation to such questions, and relating to other cultures. Do social structures determine an individual’s behaviour or does human agency? Topics include the dominant assumptions held by those in the military — wiring hypothesis can be revealed when examining newborns’ behavior.
They are a culture within a culture, structuralists believe that every system has a structure. On the other hand, verlag für Sozialwissenschaften, execute the actions that caused the problem and then check again. Communication theory investigates interactions between non – it may appear as though Griswold is arguing here for the origins of culture and situating these origins in society. Beyond the antinomies of structure: Levi, in the discipline’s two most cited journals, production as Social Change: Policy Sociology as a Public Good. Sociologists’ approach to culture can be divided into a “sociology of culture” and “cultural sociology”, bourdieu characterizes social relations in the context of what he calls the field, in spite of the fact that Durkheim did not accept the idea of the three states and criticized Comte’s approach to sociology. | http://vhp-sn.eu/the-sociology-project-2-0-pdf-download/ |
How do I evaluate my current HR tech stack effectively?
“Always be researching,” Schwenck added, advising a quarterly meeting to go over long-term and short-term tech investments. HR tech evaluation doesn’t have to be overwhelming: delegate some research to team members with an interest in technology, she suggested.
What are some “must-haves” for today’s HR tech stack?
Tight integrations are another important aspect of the tech puzzle. “You have to have these systems talk to each other. Otherwise, adoption can fall down,” she said. That means selecting tech that will serve all talent audiences: candidates, applicants, hiring managers, recruiters, and employees.
Which stakeholders need HR tech most right now?
What is AI’s role in talent acquisition?
How does a talent community relate to HR tech?
How do I identify gaps in my tech stack?
Stressing the last point, Schwenck added: “You should dive really deep into that conversation and question why that technology, and why that change. Not all organizations are the same so it might not be the best thing for yours.”
How important are integrations when evaluating a potential tech partner?
What HR tech challenges do you see trending?
Newman pointed out that when organizations simply “lift and shift” past processes onto new technology, they don’t get the full benefits of the investment: “You want to set [technology] up so that your people will use it to get the job done, and then all the data you need is captured and available for reporting and analytics.”
What are you excited about for the future of the HR industry?
Learn more about the Phenom talent experience platform by booking a demo here.
Getting the most out of your HR technology starts with knowing what you already have — and then understanding where you can optimize for the future.
On last week’s episode of Talent Experience Live, Ed Newman, CEO & founder, and Amy Schwenck, VP of Growth at talentEXP shared important information on how to make the most of your HR tech, including how to:
Because development in the tech field is moving fast, Newman suggested that “from a business practice standpoint, companies should be constantly looking and evaluating what’s coming.” Think of it the way you’d approach an investment portfolio, he advised. Some technology, like human capital management software, will fall into the long-term investment category.
Other technology may fall under the category of short-term investments, technology that you’re testing out or using temporarily as stop-gap measures. Either way, “you should always be carving out some of your budget to experiment and looking at what’s coming down the pipe,” Newman said.
His other tips include:
Related reading: How to Get the Most Out of Your HR Tech Right Now
Evaluating what tools are right for your HR tech stack can be overwhelming, especially at the scale and velocity with which the field is changing. So how can you identify the must-have HR technology that’s best for your company?
Internal Talent Marketplace tools that help HR and TA leaders understand the talent that’s already in-house top Schwenck’s list. Schwenck’s other must-haves include:
For Newman, prioritizing the CRM/career site combination and ability to do real marketing — not just blast out jobs — is critical right now. “We’re finally at a point with the tech where we can do real marketing, where we can personalize content, where we can create a digital experience that gets that employer brand messaging across in unique ways.”
AI and automation features that alleviate the administrative burden on recruiters are key as well, as they leave them with more time to focus on the people part of their jobs.
Recruitment teams were hit hard during the pandemic, and they haven’t fully bounced back yet. Because teams are now smaller, Schwenck stressed the importance of leadership understanding just how necessary recruiters are to their companies — and providing them the resources and technology they need to do their jobs well.
Hiring managers are another group traditionally overlooked in the recruitment process, Schwenck said — and they need support in the form of training, technology, and access to data so they can back up their recruitment team. “They should see what they need in front of them — very easily — with a really slick UI,” Schwenck said.
Newman agreed, calling hiring managers the “next frontier.” While the last decade has been all about candidate and employee experience, hiring managers are key stakeholders who need tools and platform plug-ins that allow them to interact seamlessly with candidates and recruiters.
Talent acquisition teams rely heavily on AI and automation to do their jobs well, but what does AI really mean in this context and what is its role in the field?
Newman called AI the industry’s “biggest buzzword” today, warning that we should be careful in how we refer to it.
“AI is new tech, and it’s becoming the price of admission for any type of solution in the market,” he said. You’ll have technology platforms that are either “smart,” with AI built into the DNA of the product, or they’re a legacy tool. “And that’s what you need to watch out for,” he warned, with some companies trying to “bolt” AI onto tools that aren’t built for it.
Think of AI as a problem-solving tactic — and it gets better over time. For example, AI can learn from candidate profile data and interactions to help them get through an application process more quickly, or personalize their journey by serving up relevant content and job recommendations.
“It’s technology that’s going to help facilitate a user to be more efficient with their processes based on the data that’s running through the system.”
Related reading: The Definitive Guide to AI for Recruiting
The idea of a talent community is changing rapidly, Newman said. Yesterday’s talent community consisted of blasting jobs out to a candidate contact list, while today it has evolved to include capturing candidate information, flowing it into the CRM, segmenting audiences, and sending content tailored to specific audience characteristics. (A talent experience platform is a key piece of tech for managing a talent community.)
If an organization is prepared with a content strategy for communicating with talent community members, this is a great way to build engagement and deepen the talent pool. But Schwenck and Newman warned that a solid strategy is imperative for it to be effective.
“If you’re going to collect contacts for a talent community, make sure you have a plan to keep them engaged. Otherwise, they’re not sure why they signed up,” Newman said. Schwenck agreed by saying, “Don’t set the expectation that you’re going to communicate unless you’re going to fulfill it.”
Beyond assessing your own application process, Schwenck recommended the following steps to uncover gaps in the candidate experience that the right tech could help address:
Newman agreed: “One company’s best practice could be another company’s worst nightmare … be selective about what you’re diving into and make sure it’s aligned with what’s right for your company,” he said — in terms of culture, compliance needs, and goals you’re working toward.
Related reading: 2022 State of Candidate Experience Report
“Integrations are absolutely paramount today,” Newman said. Solutions that don’t easily integrate will atrophy, he added, because they’ll create silos, limiting visibility into a candidate’s interactions with your brand.
Make sure you have a clear plan for what needs to integrate and how data flows through your organization, he said, because some vendors will exaggerate just how well their integrations work. This involves research and strategy development on your end: “You can’t rely on the vendor to tell you that,” Newman warned.
He suggested seeing if the vendor has partnerships with your other technology products. If yes, great. If not, that isn’t necessarily a dealbreaker, but it means that integrations will involve more work. One option to explore? Third-party organizations that set up integrations.
A key takeaway? Avoid stand-alone solutions!
Schwenck named the following hurdles that organizations tend to face in evaluating and selecting new HR tech:
For both Schwenck and Newman, increasing attention on internal mobility represents a breakthrough. “In the last five years, we’ve started to see some pretty significant movement, and companies are really starting to invest in this area. And because of this, the tech is evolving as well,” Newman said. “It’s such an important part of the total ecosystem.”
Schwenck feels like this is one of the best things to come from the pandemic, adding, “We needed to look inward … and tech has been fast to help us respond to that need.”
Maggie is a writer at Phenom, bringing you information on all things talent experience. In addition to writing, she enjoys traveling, painting, cooking, and spending time with her family and friends. | https://www.phenom.com/blog/how-to-make-the-most-of-hr-tech-stack |
The ""Global OSS/BSS market Size, Status, and Forecast 2027"" study from CMI provides an overview of the global OSS/BSS market. This section illuminates the primary impact-rendering factors and restrictions limiting expansion. It enables people to comprehend various flaws and how they may obstruct future growth. This section is one of the most important in the report since it explains how many macro and microeconomic factors affect growth. The research also discusses the role of several sectors in the expansion, including small-scale and large-scale operations. Furthermore, industry specialists have presented current trends and prospects that are expected to boost growth in the next years.
The Asia Pacific & global OSS/BSS market was valued at US$ 65.9 Mn in 2020 and is forecast to reach a value of US$ 228.3 Mn by 2028 at a CAGR of 16.8% between 2021 and 2028.
An operation support system (OSS) is a software component that allows a service provider to monitor, control, analyze, and manage the services on its network. OSS supports management functions such as service provisioning, network inventory, fault management, and network configuration. Moreover, business support systems (BSS) are components that a telecommunication service provider uses to run its business operations towards customers. BSS, combined with OSS, provides support for various end-to-end telecommunication services. Furthermore, BSS and OSS have their own data and service responsibilities.
Operation support systems and business support systems have low operational expenses. As a result of this, many end users are inclined towards OSS/BSS solutions. Moreover, it offers various other features such as lower infrastructure cost, improved scalability, faster deployments, and enhanced productivity. Major companies in the market can capitalize on these opportunities by providing novel solutions and gain a competitive edge in the market.
Segmental Analysis
Product and application segments have been included in the study. All of the items on the OSS/BSS market today have been recorded by the researchers. They've also cast light on significant players' new product releases and advancements. The researchers supplied revenue prediction numbers for the period 2021-2027 in the segmental study, depending on type and application. They also talked about each segment's growth rate and potential from 2021 to 2027.
Regional Analysis
North America, Europe, Asia Pacific, Central and South America, as well as the Middle East and Africa, are among the major regions investigated in the research report. The experts in this section of the research have looked into a number of sectors that are contributing to the development and could provide manufacturers with profitable growth opportunities in the coming years. The research also includes sales and revenue forecast data for the years 2021-2027 by area and country.
Covered FAQ’s:
What factors will limit the growth of the OSS/BSS market? In the OSS/BSS industry, which end-use segment will grow at the fastest CAGR? In the OSS/BSS market, who are the up-and-coming players? Is the OSS/BSS market very concentrated? Which factors are promoting the growth of the OSS/BSS market? What are the most recent OSS/BSS product innovations? In the OSS/BSS market, which product segment will be the most profitable? What reasons are causing the OSS/BSS market to become more competitive? What strategic actions have the players in the OSS/BSS industry taken? Which part of the country will see inactive growth?
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WISIONS is an initiative of the German Wuppertal Institute for Climate, Environment and Energy, on behalf of the Swiss Foundation ProEvolution. one action field is called PREP, the Promotion of Resource Efficiency Projects. PREP’s key objectives are publishing and promoting good practice in energy and resource efficiency. People around the world are asked to present their good practice examples. Topic and target groups thus will vary regularly with the objective of addressing a wide range of issues and stakeholders. The most convincing projects will be published in WISIONS brochures and will be promoted to multipliers, political decision-makers, scientists and activists. By doing this, projects will get the publicity they deserve and provide certain ideas worldwide to improve the efficient use of resources.
WISIONS launched its new PREP-call on the topic ‘Water for Energy and Energy for Water’. Water and energy are precious resources, however, many people in developing countries lack access to save drinking water and sanitation, the withdrawals for agriculture are competing with water users from other sectors, and energy shortfalls due to increased energy demand are predicted. Therefore WISIONS aims to promote good practice examples dealing either with water as a driving agent for renewable energy (e.g. small hydro schemes, wave and tidal power plants) or with the provision of clean and safe drinking water by renewable energy (e.g. solar driven desalination, groundwater pumping or irrigation systems). Up to 5 good practice projects will be chosen for publication and will receive a grant of 500 Euros.
The fields of interest include :
Projects concerned with socially and ecologically sound small hydropower
Projects that focus on wave or tidal power
Projects that t reduce water poverty by, for example, the desalination of salted or brackish water with the help of renewable energy
Projects that support water treatment systems operating with renewable energy to improve the reuse of water and sanitation to ensure high water quality
Projects that address the use of renewable energy for water pumping and resource efficient irrigation systems
The application deadline is on February 16th, 2008. Information on how to apply is available here
Source: Maike Bunse (Ms.), WISIONS Team
Updated on 2/6/2008 1:37:39 PM. | https://medwet.org/2008/02/1923/ |
This work provides an overall review and analysis of the history of education and of its key research priorities in the British context. It investigates the extent to which education has contributed historically to social change in Britain, how it has itself been moulded by society, and the needs and opportunities that remain for further research in this general area. Contributors review the strengths and limitations of the historical literature on social change in British education over the past forty years, ascertain what this literature tells us about the relationship between education and social change, and map areas and themes for future historical research. They consider both formal and informal education, different levels and stages of the education system, the process and experience of education, and regional and national perspectives. They also engage with broader discussions about theory and methodology. The collection covers a large amount of historical territory, from the sixteenth century to the present, including the emergence of the learned professions, the relationship between society and the economy, the role of higher technological education, the historical experiences of Ireland, Scotland and Wales, the social significance of teaching and learning, and the importance of social class, gender, ethnicity, and disability. It involves personal biography no less than broad national and international movements in its considerations. This book will be a major contribution to research as well as a general resource in the history and historiography of education in Britain. | https://intrinsicalthebook.com/data/social-change-in-the-history-of-british-education/ |
BUD SARBER, PLAINTIFF IN ERROR,
v.
JOHN HARRIS, DEFENDANT IN ERROR.
Syllabus
¶0 1.
The Supreme Court will not inquire on appeal into the sufficiency of evidence to
sustain a verdict, where defendant does not challenge the evidence by demurrer
or motion for a directed verdict and the question is raised for the first time
in the motion for a new trial.
2. An action for money had and received will lie to recover payment made under an unenforceable, ineffective, incompleted or rescinded contract.
3. The trial court must, on its own motion, properly charge the jury on issues raised by the pleadings and evidence in the case, but instructions which submit the vital features of the tenable legal theories of both litigants upon the issues involved are sufficient.
Appeal from the Superior Court of Seminole County; Bob Aubrey, Judge.
Action by John Harris against Bud Sarber to recover deposit for part payment upon the purchase price of realty. Defendant appeals from an adverse judgment of the trial court. Affirmed.
Sims & Cooper, Seminole, for plaintiff in error.
Dick Bell, Seminole, for defendant in error.
BERRY, Justice.
¶1 John Harris, plaintiff below, instituted this action against Bud Sarber, defendant below, to recover a deposit of $500.00 for part payment upon the purchase price of realty. The trial resulted in a judgment for the plaintiff and defendant has brought this appeal. Our continued reference to the parties will be by their designation in the lower court.
¶2 According to plaintiff's evidence, he "never actually agreed to buy" defendant's property, and the check for $500.00, executed and delivered to defendant by plaintiff's mother, represented merely "good faith money" which, pursuant to the parties' understanding, was not to be cashed, but was to be held by defendant until negotiations became completed. As disclosed by defendant's version of the transaction, he granted plaintiff an option to buy his property on or before a day certain, and when plaintiff declined to purchase on that day, defendant became entitled to retain the consideration as, or in lieu of, "liquidated damages". The transaction rests entirely in parol. There is no written "note or memorandum" subscribed by either of the contestants. From the inception of their dealings, the parties contemplated that an agreement in writing would be entered by them at a later date. It stands admitted that plaintiff refused to execute a written contract because of defendant's alleged misrepresentation as to the value of, and income from, the property to be sold.
¶3 Defendant asserts error in submitting to the jury the issue of whether the parties did actually enter into a verbal contract for the sale of realty. The factum of such oral agreement, we are urged, was not open to controversy, but stood admitted by the plaintiff whose very right to recover was predicated and necessarily dependent upon the breach thereof by the defendant. It is argued that the trial court should have affirmatively instructed or informed the jury "as a matter of law" concerning the existence of the oral contract between the parties.
¶4 In giving consideration to the argument so advanced, we need not immediately concern ourselves with the matter of whether the negotiations between the parties had culminated in a complete understanding and meeting of the minds upon the essential terms of the intended transaction. The contract, if one were in fact entered into, was for the sale of real property. It rests entirely in parol and the record fails to disclose any such acts of performance as will take the alleged agreement outside the Statute of Frauds. The law is settled that partial payment of the purchase price by vendee of real estate is not in itself sufficient to satisfy the requirements of this statute. 15 O.S. 1951 § 136 [15-136] , subd. 5; Fry v. Penn Mut. Life Ins. Co., 195 Okl. 507, 159 P.2d 550 ; Nichlos v. Edmundson, 105 Okl. 202, 232 P. 68 ; Bahnsen v. Walker, 89 Okl. 143, 214 P. 732 ; Adams v. White, 40 Okl. 535, 139 P. 514 ; Levy v. Yarbrough, 41 Okl. 16, 136 P. 1120 ; Halsell v. Renfrow, 14 Okl. 674, 78 P. 118 , 2 Ann.Cas. 286. See also Harris et al. v. Arthur, 36 Okl. 33, 127 P. 695 . It therefore follows that even if, as defendant asserts, there was an oral contract for the sale of real property, such, under the facts, was manifestly unenforceable and invalid under the statute of frauds, and no action could lie by either the buyer or the seller to recover damages for the breach thereof. Fox v. Easter, 10 Okl. 527, 62 P. 283 .
¶5 As reflected by the evidence, plaintiff did not attempt to enforce an oral contract, nor did he seek damages for its breach. Rather, his action was one for recovery of the deposit made by him in course of negotiations upon the purchase price. There is a marked distinction between enforcing an ineffective or incompleted agreement and asserting title to money paid thereunder. In the latter case, the action is not one for breach of contract, but for money had and received. It lies whenever one has the money of another which he, in equity and good conscience, has no right to retain. While it is an action at law triable to a jury, its determination is controlled by principles of equity and fair dealing. Thurlwell v. Rabbit, 110 Okl. 285, 235 P. 923 ; Rogers v. Lassiter, 196 Okl. 228, 164 P.2d 632 , 633. An action for money had and received will lie to recover payment made under an unenforceable, incompleted or rescinded contract. 4 Am.Jur. 517, 518 "Assumpsit", Sec. 27; 58 C.J.S. "Money Received" § 6, p. 916. See also Roussel v. Russell, Okl., 339 P.2d 522 , 527; Cone v. Ariss, 13 Wash. 2d 650, 126 P.2d 591 ; Jones v. Goldberger, Okl., 323 P.2d 344 .
¶6 Although both litigants had a verbal understanding that the total consideration for the property was $25,000.00, of which $7500.00 would be paid in cash, there was little or nothing to show that their minds had actually met and were in accord either on the manner in which deferred payments were to be made upon the balance of the purchase price or as to what rate of interest, if any, was to be charged thereon, or whether such balance would be secured by a mortgage.
¶7 The amount of the purchase price as well as the terms of its payment formed an essential part of the transaction. No contract, whether in writing or by parol, can be complete without mutual assent of the parties to all of its material terms. It is not enough that a vendee is willing to buy and the vendor intends to sell the property. O'Neal v. Harper, 182 Okl. 52, 75 P.2d 879 ; see also Irvine et al. v. Haniotis et al., 208 Okl. 1, 252 P.2d 470 . Under the evidence, as outlined, both the existence of the verbal contract and the terms thereof were in dispute. There was no error in failing to affirmatively charge the jury "as a matter of law" that an oral agreement for the sale of property had been entered into between the parties when plaintiff made the deposit sought to be recovered. See Jones v. Major et al., Okl., 317 P.2d 190 .
¶8 The fact situation in the present case is not analogous to that in Burford v. Bridwell, 199 Okl. 245, 185 P.2d 216 , 218, 219, wherein we held that "* * * the vendee, under an agreement for the sale and purchase of land which does not satisfy the Statute of Frauds, cannot recover back payments upon the purchase price if the vendor has not repudiated the contract but is ready, willing and able to perform in accordance therewith, even though the contract is not enforceable against the vendee either in law or in equity". See also 49 Am.Jur. 870, "Statute of Frauds", Sec. 564; 37 C.J.S. "Frauds, Statute of" § 256; Annotation in 169 A.L.R. 187. The vendee in the cited case disputed neither the factum of a complete oral agreement, nor his own repudiation thereof without a tenable legal cause. In the instant case, both of these issues presented a question of fact and were resolved in favor of the plaintiff. The rule announced in Burford v. Bridwell, supra, is therefore inapplicable here. See Helgeson v. Northwestern Trust, 103 Or. 1, 203 P. 586 . See also Stanek v. Peterson, 26 Wash. 2d 385, 174 P.2d 308 .
¶9 Reversal is also sought upon the proposition that the verdict is not sustained by sufficient evidence. Defendant did not challenge the evidence either by a demurrer or by a motion for a directed verdict. The question of its sufficiency was raised for the first time in defendant's motion for a new trial. The objection then made came too late. In such state of the record, this Court will not inquire on appeal into the sufficiency of the evidence to establish a cause of action in favor of the plaintiff. The verdict must, to this extent, be treated as conclusive. Oklahoma State Union of Farmers' Educational and Cooperative Union of America v. Folsom, Okl., 325 P.2d 1053 ; Richardson v. Shaw, Okl., 313 P.2d 520 ; Richardson v. Butler, 206 Okl. 79, 240 P.2d 1058 .
¶10 We find no errors in the judgment of the trial court and the same is affirmed. In accordance with plaintiff's request, the Court Clerk of the Superior Court of Seminole County is hereby directed to pay plaintiff, out of the funds deposited by defendant to supersede the judgment pending appeal, the sum of $500.00, together with interest at 6% from the date of judgment and the costs taxed in the trial court. | https://law.justia.com/cases/oklahoma/supreme-court/1962/31887.html |
The SAGE Handbook of Political Sociology offers a comprehensive and contemporary look at this evolving field of study. The focus is on political life itself and the chapters, written by a highly-respected and international team of authors, cover the core themes which need to be understood in order to study political life from a sociological perspective, or simply to understand the political world. The two volumes are structured around five key areas: PART 1: TRADITIONS AND PERSPECTIVES PART 2: CORE CONCEPTS PART 03: POLITICAL IDEOLOGIES AND MOVEMENTS PART 04: TOPICS PART 05: WORLD REGIONS This future-oriented and cross-disciplinary handbook is a landmark text for students and scholars interested in the social investigation of politics.
Chapter 3b: Marxism Since 1945
Marxism Since 1945
INTRODUCTION
Up to the 1930s the main bearers of Marxism were ‘nationally organized working class movements’ (Wallerstein 1994: 16), which were heavily concentrated in Europe and were very Eurocentric. Most upheld somewhat idealized perceptions of ‘the proletariat’ as the only feasible and reliable vehicle for Marxist aspirations, albeit under the ‘hegemony’ (tutelage) of socialist intelligentsias, whether reformist or revolutionary.
From the 1940s onward, largely as a result of expansions and shifts in the class-bases of Marxist movements, Marxism(s) increasingly coalesced into three main currents: (i) the increasingly crude, ossified and mechanistic Marxism-Leninism of the Communist Party of the Soviet Union (CPSU) and the many ...
- Loading... | http://sk.sagepub.com/reference/the-sage-handbook-of-political-sociology-2v/i685.xml |
Manager - Operations & Machine Maintenance - Plastic Chemical Firm (8-10 yrs)
One of our leading Plastic Chemical clients is looking for below role.
Position / Job Title : Manager
Department : Maintenance
Unit / Work Location : Umbergaon, Gujarat
Educational Qualification : Graduates with a degree in a relevant engineering discipline such as mechanical, manufacturing, electrical or electronic engineering.
Years of Experience :
8-10 years- Experience in operations and machine maintenance,
- Adequate knowledge of business and management principles (budgeting, strategic planning, resource allocation and human resources)
- Familiarity with industry standard equipment and technical expertise
Reporting to : Plant Head
No of DRs reporting : NA
Expected DOJ ASAP - Preferable -15 days
Job Description :
Definition : Responsible for ensuring that the facilities, layout and machinery used to produce new and existing materials and goods run to their maximum efficiency and output.
- This includes total preventative maintenance, managing breakdowns of mechanical, electrical and robotic equipment
- Includes people management and budgetary/cost reporting.
Purpose of this role :
- Lead the Maintenance function in providing both a reactive and proactive, multi-skilled maintenance service on all operational equipment and facilities infrastructure.
- Responsible for planned scheduling creation and overseeing the adherence and timely completion of work carried out. Increase the site operational effectiveness, improve on project delivery, mean time between failure and downtime reduction, and manage and implement improvement plans, driving Key Performance Indicators (KPI's) ensuring that
- Health, Safety and Environmental requirements are adhered to.
- Manage the team on technical best practice and establish standard policies and procedures whilst also mentoring and leading the department.
- Implement and manage continuous improvement and modern manufacturing principals by highlighting deficiencies and recommending changes in training, working practices and processes
Area of Expertise :
- Should have good verbal and written communication skills in English.
- Ability to effectively multi-task in a fast paced & challenging environment.
Technical Skills :
- Technical abilities, Detail oriented, Problem-solving ability, Organizational skills, Physical ability, Able to work quickly under pressure, Versatility.
Personal Attributes : | https://www.engineeristic.com/j/manager-operations-machine-maintenance-plastic-chemical-firm-8-10-yrs-24465.html?ref=cl |
The National Telecommunications and Information Administration put out a new broadband map for the country this week and noted again what it called the significant gap between urban and rural availability. At download speeds of 10 megabits (think high quality video conferencing for telecommuters, complex gaming, telemedicine for remote diagnostics and care), urban America is 99.6 covered.
Just under 84 percent of rural America has those speeds available.
You can see where the gaps are in Minnesota by playing with the NTIA’s interactive map.
Here’s a zoomed-in view of the state with the coverage areas for download speeds of three megabits (web browsing, email, music streaming but not so good for video). If you take away the north woods, the state looks OK (especially in comparison to many other rural states).
But the bare spots start to show up when you move the map’s slider to give you 10-megabit coverage.
And at 25 megabits, you see the impact of several of the small telecommunications companies, some of them cooperatives, that have been intensely laying fiber in western and northwestern Minnesota for a number of years.
These maps are from the end of 2012. I keep waiting for the state’s northeastern corner to turn blue as the federally supported fiber project kicks into gear. | https://blogs.mprnews.org/ground-level/2013/08/where-the-minnesota-broadband-gaps-lie/ |
The utility model relates to a bridge drainage device for municipal bridge engineering, which comprises a drainage tank arranged on a bridge body, the top of the drainage tank is provided with a water inlet pipe, the bottom of the drainage tank is provided with a water outlet pipe, the drainage tank is internally provided with a sieve plate and a cleaning assembly, the sieve plate is located between the water inlet pipe and the water outlet pipe, and the sieve plate is provided with a plurality of drainage holes; the cleaning assembly is connected to the drainage tank and located above the sieve plate, the cleaning assembly comprises fan blades, brushes and a rotating shaft, the rotating shaft is rotationally connected to the sieve plate, the fan blades are installed on the side wall, away from the sieve plate, of the rotating shaft, the brushes are installed on the side wall, close to the sieve plate, of the rotating shaft, and bristles on the brushes abut against the top face of the sieve plate; an adjusting assembly used for adjusting the water inflow of the sieve plate is arranged in the drainage box. The bridge drainage device has the effects that the bridge drainage device can be conveniently cleaned, and normal drainage is achieved. | |
This Roman pendant is made of pewter. It is shaped in the form of a laurel wreath, the symbol of victory, surrounding the sun, with the letters SPQR (Senatus Populus Que Romae). It has a glass inlay.
Details
Material: pewter, glass
Size: 2,5x2 cm
Delivery including cord
Shipment weight: 50 grams. | https://www.celticwebmerchant.com/en/spqr-pendant-red.html |
If you or someone you know is struggling in an RIT math course despite using the math resources available at RIT, then a thorough evaluation of math skills may be beneficial. ASC offers a math assessment support that will provide an in-depth examination of the math background and current math skills.
Math assessment is also appropriate for students who have been away from mathematics for a while and want their math skills evaluated.
A math assessment begins with a diagnostic math test to determine the areas of strengths and weaknesses. The results are evaluated and an appropriate course of action is recommended. A consultation may be offered to help determine the best course of action for the student. | https://www.rit.edu/studentaffairs/asc/math-and-physics-support/math-assessment |
However, there are certain types of questions that I feel are off-topic, and similar types of questions that I feel are on-topic but tend to attract off-topic answers.
Example off-topic question: "How do I pronounce ---- in Greek?"
Now, in my opinion, there can be better ways to deal with the question than just closing it. I would probably close-vote, but it's equally important to leave a comment to the original poster asking for clarification on what they want. If the actual question is "How should I pronounce the Greek word ---- in an English-language context?" then it's on-topic for ELU, in my opinion, and I would retract my close-vote. If the actual question turns out to be "How did the Ancient Greeks pronounce ----" or "How do the Modern Greeks pronounce ----," then it's clearly off-topic.
Well, the Ancient Greeks pronounced it /----/ [IPA for reconstructed pronunciation of Attic].
As a native speaker of Greek, I know how to pronounce this! It's /---/ [IPA for modern Greek pronunciation].
I just invented these specific examples. The posters are not always ignorant; the issue I have is that these kind of answers solely describe a foreign pronunciation. In my opinion, this kind of answer is misleading if the original poster's question was about how to pronounce the word in an English-language context. And if the original poster actually wanted the foreign pronunciation, then the question is off-topic. So I see no reason for answers like this to exist; in my opinion, appropriate answers for this site should always also include accurate information on pronunciation or usage in English.
For this reason, I routinely downvote this kind of answer (even if the pronunciation info is accurate for the foreign language), and I generally try to leave a comment explaining why, but I'm wondering if there's anything else that can be done to discourage this. Alternately, if someone disagrees that this is an actual problem or thinks that it's inappropriate to downvote these answers (after all, they frequently do show research effort, and may be useful and clear to some people), I'd appreciate hearing that perspective.
It seems to me that this is precisely why such questions should be closed. It may very well be that the poster actually wants to know 'how this Greek term is pronounced in English', and if edited to ask that, the question can and should be re-opened. But pronunciation in foreign languages is blatantly off-topic, and leaving an off-topic question open will (reasonably enough) attract off-topic answers, which is A Bad Thing.
Is there something special about foreign-language questions, or are the guidelines on how to deal with off-topic questions not clear enough?
Not the answer you're looking for? Browse other questions tagged discussion on-topic-off-topic appropriate-answers .
Are the questions about knowledge/information about things described in English appropriate? | https://english.meta.stackexchange.com/questions/7152/are-either-questions-or-answers-purely-about-how-to-pronounce-things-in-foreig |
Visual Arts Nova Scotia (VANS) is managed by an elected volunteer Board of Directors comprised of 8 – 11 members, one third of whom must live outside of HRM. Most Directors are also working artists.
The Board of Directors is comprised of VANS members who are officially elected by the membership at the Annual General Meeting to serve a minimum of one term (two years) to a maximum of two terms (four years).
The Board of Directors believes in the importance and value of VANS to the community and is able to endorse the mandate and objectives of VANS without reservation. Acknowledging their legal and fiscal responsibility to VANS, the Board of Directors is familiar with the organizations by-laws and policies, and prepare and meet for Board meetings.
2017 – 2018 Board of Directors
Nora Macnee CGA (Ketch Harbour), Treasurer, spent her early life in Toronto and Kingston, moved to Halifax to attend Dalhousie University and stayed. She has held many accounting roles with non-profit organizations and recently joined the Board of Veith Street Gallery. Nora has facilitated workshops for Visual Arts Nova Scotia, NSCAD University and Outsider Insight on Taxes for Artists and Financial Management in the Arts.
Originally from Ontario, Kelly Markovich (Dartmouth) and her family moved to Halifax in 2009 in order to pursue a Masters degree at NSCAD University. They are now happy to call Dartmouth, NS their home. Kelly is a practicing artist and entrepreneur whose work encompasses photography, painting, screen-printing, letterpress, and upholstery. Her work has been exhibited in cities across Canada and in the USA. Kelly occasionally instructs courses at NSCAD University and NSCAD University School of Extended Studies. She is an active member of the NSCAD University Alumni Association Board of Directors and the Letterpress Gang at the Dawson Print Shop. Kelly was excited to be the curator for the 2015 NSCAD University Alumni Association Exhibition “I AM NSCAD”.
Ceramicist Fenn Martin (Antigonish Co.) was born and raised in Port Hood, Cape Breton, and currently lives and works in rural Antigonish County, Nova Scotia. A graduate of the Nova Scotia College of Art and Design University (NSCADU), Martin largely works in the tradition of the narrative frieze. His innovative style investigates present life while extending historical traditions in architectural ceramics. Most recently, Martin has participated in solo gallery shows while developing a rapidly growing list of personal and public commissions. His latest public pieces have commemorated the Bergengren Credit Union’s 75th Anniversary (The Gift, 2009), the 50th anniversary of the Coady International Institute (She Does, 2009), and the opening of Antigonish’s new public library (Living Stories, 2011). However, Martin’s most challenging and well-received commission to date has been Making Peace (2011), a testament to the unique ability of clay to commemorate the values and histories of a people. Fenn Martin masterfully pays tribute to the values, histories, and people who inhabit architectural spaces. Starting with clay, the most organic of materials, Martin crafts an earthen legacy for building inhabitants, visitors, and generations to come.
Ian McKinnon (Halifax) is an artist and educator. He has a BFA from NSCAD (1980) and a MFA from Concordia (1994.) A part-time faculty member, Ian has taught drawing at NSCADU in the Foundation Division since 2003. After course work at the Atlantic School of Theology (2005/6) Ian transferred to the Faculty of Divinity at Trinity College (University of Toronto) where he completed a Master of Theology Studies (2011). His thesis, Mutual Illumination and the Artist: Dispossession, Disinterested Love and Making Other is an exploration of and argument for the necessity of theology and contemporary art entering a dialogue. In 2011 Ian resumed his part-time teaching at NSCADU. March 2014 he became Parish Artist-in-Residence at St. Paul’s Anglican Church (Grand Parade, Halifax) where besides pursuing his own work in a studio graciously provided by the church, he has also established an exhibition program within the church itself. In the past several months Ian has been immersed in a new and large cycle of paintings he calls The Parish House Series. Most recently a new subset of this larger cycle of work, titled the Prayer Series, has been emerging.
Hannah Minzloff (Dartmouth) is actively involved in the local arts community. In 2012 she received a Presentation Grant from Nova Scotia Tourism, Culture and Heritage, in 2009 she was short-listed for the Mayors Award of Distinction: Contemporary Art. Her work has been exhibited locally and nationally, has been purchased by the Art Bank of Nova Scotia and is in private collections around the globe. Hannah first studied photography in Montreal under the guidance of Clara Gutsche & David Miller. With an interest in mastering the technical elements, she worked in photography studios in Montreal, Toronto and then Munich, returning to Toronto in 1994 to earn a BAA in Stills Photography at Ryerson University. Throughout her career as a photo-based artist Hannah has continued to pursue both an aesthetic vision along with specific inquiries into digital imaging and design, to allow herself to grow in a contemporary world of image making and to give voice to her vision.
Carl Snyder (Wolfville) has been involved with photography most of his life and began working professionally in Montreal just after completing a B.A. and M.L.S. at McGill. After 25 years of commercial/advertising work in Montreal and (mostly) Toronto he decided to slow the pace to occasional freelance work for a small local graphics house in Aurora, ON. This allowed for involvement in the local arts community in Newmarket, Ontario and the development of his studio/landscape work, which regards the near abstraction of form (geometry) and color we encounter every day. A move to Wolfville in the fall of 2011 has given him the opportunity to become involved with other artists, communities and landscapes. In Ontario he has exhibited in Toronto, Newmarket, Aurora, and Elora and served on the board of the Newmarket Group of Artists 2009 – 2011. In Nova Scotia he has exhibited in Wolfville, Pictou, Halls Harbor and Halifax. Snyder is currently serving on the board of ViewPoint Gallery as director of communications.
Gail Tuttle (Malagash) is a visual artist, curator and arts administrator. She received her BFA in painting and printmaking from Mount Allison University and her Masters in History in Art from the University of Victoria. Tuttle was an executive member of several artist-run centres in British Columbia for more than ten years, exhibiting, running visual arts studios in several locations and curating exhibitions. She taught art history at the university level in British Columbia and Alberta, before accepting a position as Director of the Grenfell Art Gallery, Memorial University, in 1998. Following her formal retirement, Tuttle returned to Nova Scotia in mid-January, 2017, where she is currently curator of the Wallace and Area Museum. She enjoys an active studio practice, has exhibited in galleries across Canada, has published curatorial essays and exhibition catalogues, as well as critical writing in peer reviewed anthologies.
Jessica Lynn Wiebe (Halifax) is from Brandon, Manitoba, currently living and working in Halifax, Nova Scotia. She graduated with her BFA from NSCAD University in 2015, and with her BEd from Acadia University in 2016. Jessica’s work responds to her service in the Canadian military as a soldier, and educator. She employs storytelling and performance in a multi-disciplinary practice. Thematically, Jessica’s work critically examines powerful experiences through disparate connections to specific objects and place. Her work questions how identity is shaped by experience and how this connects her in a local and global context.
Susan Wood (Halifax) was born in Saint John, N.B. and grew up in Amherst, N.S. She attended Mount Allison University (BFA 1976), participated in the Banff Winter Studio Program (1976-1977) and received an MFA from The University of Calgary (1981). She lived in St. John’s, Newfoundland (1983-1989) where she was a founding member of the Eastern Edge Gallery, taught at MUN Extension Arts and continued her studio practice. Wood moved to Halifax in 1989 and has been teaching at NSCAD University since 1990. She has participated in numerous group exhibitions across Canada and in Finland, Germany, Scotland and Iceland, and has also held a number of solo shows including her nationally touring Devil’s Purse, Dress Drawings and Taxonomies. She is a member of the RCA and is the recipient of grant awards from the Canada Council, the Newfoundland and Labrador Arts Council and the Nova Scotia Arts Council. Her work is represented in private, corporate and public collections across Canada, UK and in the USA. She lives in Halifax, NS. Earth Skins: Three Decades of Drawings by Susan Wood, curated by Susan Gibson-Garvey, was held at MSVU Art Gallery from August 21 through October 2, 2011. | http://www.visualarts.ns.ca/about-vans/board-of-directors/ |
Healthcare practice in the United States is governed at the state level. All 50 states and the District of Columbia have laws and other regulatory policies that address pain management for patients. Policies related to pain care, palliative care, or end-of-life care provide standards of practice influencing the way pain management is provided for all patients with chronic diseases or conditions, including those with cancer and those who are now cancer-free but are experiencing other chronic painful conditions. These policies also have been used as a tool to curtail the opioid epidemic. As a result, the policies are often designed to maintain access to pain management services while also reducing medication misuse.
This dataset explores important features of state pain care-related laws and other regulatory policies. It includes laws and policies that address prescribing of controlled substances (specifically, Schedule II opioid analgesics); definitions creating parameters for healthcare practice; standards for evaluating and improving pain treatment, including practitioner expectations for treatment; practice requirements; and characteristics of state prescription monitoring programs (PMPs).
This map identifies and displays key features of more than 700 laws and other regulatory policies across all 50 states and the District of Columbia, in effect as of December 31, 2017. | http://lawatlas.org/datasets/state-laws-and-other-regulatory-policies-related-to-pain-care-final |
The examination pattern and curriculum for all the above courses are different. Enlisted below is the detailed pattern CA CPT Foundation Exam of ICAI.
Exam Pattern: CA CPT (Common Proficiency Test)
CPT (Common Proficiency Test) is an exam at Foundation Level, which allows access to ICAI courses further.
- The question paper is based on MCQs (multiple-choice questions) of 200 marks in total.
- The examination is held in pencil & pen mode for 4 hours duration divided into 2 sessions (each session is for 2 hours).
The entire question is divided into 4sections given as under:
|Subject||Minimum Marks to be obtained||Maximum Marks|
|Part A. Fundamentals of Accounting||18||60|
|Part B. Mercantile Law||12||40|
|Part C. General Economics||15||50|
|Part D. Quantitative Aptitude||15||50|
|TOTAL||100||200|
Marking Scheme for Exam:-
- Each MCQ carries one mark each and for every accurate attempt, students are allotted a full 1 mark.
- For every wrong attempt, 0.25 will be deducted as negative marking.
- Candidates have an option to choose the Hindi medium Booklet of the question paper.
ALL THE BEST! | https://www.edvizo.com/blog/examination-pattern-for-common-proficiency-test-cpt/ |
and, of course,
Point alphabet
synonyms and on the right images related to the word
Point alphabet
.
Definition of Point alphabet
Point alphabet
Point alphabet Point alphabet An alphabet for the blind with a system of raised points corresponding to letters.
Meaning of Point alphabet from
wikipedia
- The NATO
phonetic
alphabet,
officially
denoted
as the
International
Radiotelephony
Spelling
Alphabet, and also
commonly
known
as the ICAO
phonetic
alphabet...
- An
alphabet
is a
standard
set of
letters
(basic
written
symbols
or graphemes) that is used to
write
one or more
languages
based
upon the
general
principle...
- The Gr****
alphabet
has been used to
write
the Gr****
language
since
the late 9th or
early
8th
century
BC. It was
derived
from the
earlier
Phoenician
alphabet...
- The
modern
English
alphabet
is a
Latin
alphabet
consisting
of 26 letters, each
having
an
uppercase
and a
lowercase
form: A a B b C c D d E e F f G g H...
-
Phonetic
alphabet
can mean:
Phonetic
transcription
system: a
system
for
transcribing
the
precise
sounds
of
human
speech
into
writing
International
Phonetic...
- The APCO
phonetic
alphabet, a.k.a. LAPD
radio
alphabet, is the term for an old
competing
spelling
alphabet
to the ICAO
radiotelephony
alphabet, defined...
- The
Hebrew
alphabet
(Hebrew: אָלֶף־בֵּית עִבְרִי,
Alefbet
Ivri),
known
variously
by
scholars
as the
Jewish
script,
square
script
and
block
script, is...
- A
spelling
alphabet, word-spelling alphabet,
voice
procedure
alphabet,
radio
alphabet, or
telephone
alphabet
is a set of
words
used to
stand
for the letters...
-
Numerous
Cyrillic
alphabets
are
based
on the
Cyrillic
script. The
early
Cyrillic
alphabet
was
developed
in the
First
Bulgarian
Empire
during
the 9th century...
- The
Arabic
alphabet
(Arabic: الأَبْجَدِيَّة العَرَبِيَّة al-abjadīyah al-ʻarabīyah, or الحُرُوف العَرَبِيَّة al-ḥurūf al-ʻarabīyah) or
Arabic
abjad
is...
Loading...
Recent Searches ...
-ries
Rig
Rightfulness
Rightness
Rigsdaler
Rime
Rimed
Ringed snake
Ringer
Rinking
Ripen
Ripidolite
Risibleness
River horse
Related images to Point alphabet
Loading... | https://www.wordaz.com/Point-alphabet.html |
2. What is an SMP solver?
3. Evaluation of JMAG SMP solver performance
4. Summary
5. References
1.Introduction
The parallel solver is one way to run magnetic field analysis at high speed. JMAG has an SMP-parallel solver - that can easily be used with a single click on the computer.
The parallel solver is unique in that its performance varies significantly depending on the type of analysis data and hardware used. This White Paper presents the features and explains which type of analysis model is able to achieve parallel performance, as well as provide advice on selecting appropriate hardware.
2. What is an SMP solver?
The SMP solver gains speed by effectively using the multi-core installed in one node (one machine). It is often referred to as a “thread parallel” solver. The concept of parallel processing is shown in Fig.1. The input data (analysis model) is loaded into the software (solver), divided for processing of each thread, and then assigned to the core, which is where the calculation is run in the hardware. It is apparent that the parallel solver depends on the analysis model, the algorithm used in the software, and the hardware used.
Another characteristic of the SMP solver is that it cannot run parallel processing that requires communication across nodes. Therefore, the upper limit of parallelism is the number of cores in the machine.
Fig. 1 Concept of SMP Parallelism (example of 4-parallel processes)
3. Evaluation of JMAG SMP solver performance
As noted above, the performance of the SMP solver depends on the analysis model, software algorithms, and hardware. Of these, research on software algorithms was described in a previous JMAG white paper (reference ). Therefore, this white paper focuses on the evaluation of parallel performance when the analysis model is changed, and the change in parallel performance when different hardware is used.
Fig. 3 Model divisions when using the parallel solver
Regions (parts) with different colors in the figure on the right are calculated by different cores.
Protected content here, for members only.
You need to sign in as a JMAG software regular user (paid membership) or JMAG WEB MEMBER (free membership).
By registering as a JMAG WEB MEMBER, you can browse technical materials and other member-only contents for free.
If you are not registered, click the “Create an Account” button. | https://www.jmag-international.com/whitepapers/w-se-99/ |
Evaluation is key to increasing UNIDO’s efficiency, effectiveness and impact.
It assures accountability and supports management, and also drives learning and innovation through in-depth assessment of the Organization’s interventions, strategies and policies. Understanding the reasons for success or failure supports UNIDO in scaling up successful approaches.
Published in February 2018, this evaluation manual presents the methodology and processes used by the UNIDO Independent Evaluation Division. It is based on the best international evaluation standards and practices, and on the principles established in the UNIDO Evaluation Policy.
The manual’s main purpose is to ensure consistency, rigor, and transparency across independent evaluations and, ultimately, to enhance the effectiveness of UNIDO’s independent evaluation function.
The Organization’s evaluation function provides Member States and other stakeholders with facts and evidence highlighting UNIDO’s contribution to the 2030 Agenda for Sustainable Development – including its Sustainable Development Goals (SDGs) – and to Inclusive and Sustainable Industrial Development (ISID).
The credibility and effectiveness of UNIDO is directly linked to the strength of its independent, credible and useful evaluation function. | https://www.unido.org/resources/evaluation/evaluation-resources |
Mindfulness. It’s a pretty straightforward word. It suggests that the mind is fully attending to what’s happening, to what you’re doing, to the space you’re moving through. That might seem trivial, except for the annoying fact that we so often veer from the matter at hand. Our mind takes flight, we lose touch with our body, and pretty soon we’re engrossed in obsessive thoughts about something that just happened or fretting about the future. And that makes us anxious.
Mindfulness is the basic human ability to be fully present, aware of where we are and what we’re doing, and not overly reactive or overwhelmed by what’s going on around us.
Yet no matter how far we drift away, mindfulness is right there to snap us back to where we are and what we’re doing and feeling. If you want to know what mindfulness is, it’s best to try it for a while. Since it’s hard to nail down in words, you will find slight variations in the meaning in books, websites, audio, and video.
The Definition of Mindfulness
Mindfulness is the basic human ability to be fully present, aware of where we are and what we’re doing, and not overly reactive or overwhelmed by what’s going on around us.
Mindfulness is a quality that every human being already possesses, it’s not something you have to conjure up, you just have to learn how to access it.
The Types of Mindfulness Practice
While mindfulness is innate, it can be cultivated through proven techniques. Here are some examples:
- Seated, walking, standing, and moving meditation (it’s also possible lying down but often leads to sleep);
- Short pauses we insert into everyday life;
- Merging meditation practice with other activities, such as yoga or sports.
The Benefits of Mindfulness Practice:
When we meditate it doesn’t help to fixate on the benefits, but rather to just do the practice, and yet there are benefits or no one would do it.
When we’re mindful, we reduce stress, enhance performance, gain insight and awareness through observing our own mind, and increase our attention to others’ well-being.
Mindfulness meditation gives us a time in our lives when we can suspend judgment and unleash our natural curiosity about the workings of the mind, approaching our experience with warmth and kindness—to ourselves and others.
8 Facts About Mindfulness:
- Mindfulness is not obscure or exotic. It’s familiar to us because it’s what we already do, how we already are. It takes many shapes and goes by many names.
- Mindfulness is not a special added thing we do. We already have the capacity to be present, and it doesn’t require us to change who we are. But we can cultivate these innate qualities with simple practices that are scientifically demonstrated to benefit ourselves, our loved ones, our friends and neighbors, the people we work with, and the institutions and organizations we take part in
- You don’t need to change. Solutions that ask us to change who we are or become something we’re not have failed us over and over again. Mindfulness recognizes and cultivates the best of who we are as human beings.
- Mindfulness has the potential to become a transformative social phenomenon. Here’s why:
- Anyone can do it. Mindfulness practice cultivates universal human qualities and does not require anyone to change their beliefs. Everyone can benefit and it’s easy to learn.
- It’s a way of living. Mindfulness is more than just a practice. It brings awareness and caring into everything we do—and it cuts down needless stress. Even a little makes our lives better.
- It’s evidence-based. We don’t have to take mindfulness on faith. Both science and experience demonstrate its positive benefits for our health, happiness, work, and relationships.
- It sparks innovation. As we deal with our world’s increasing complexity and uncertainty, mindfulness can lead us to effective, resilient, low-cost responses to seemingly intransigent problems.
Mindfulness Is Not All in Your Head
When we think about mindfulness and meditating (with a capital M), we can get hung up on thinking about our thoughts: we’re going to do something about what’s happening in our heads. It’s as if these bodies we have are just inconvenient sacks for our brains to lug around.
Having it all remain in your head, though, lacks a feeling of good old gravity.
Meditation begins and ends in the body. It involves taking the time to pay attention to where we are and what’s going on, and that starts with being aware of our body
That approach can make it seem like floating—as though we don’t have to walk. We can just waft.
But meditation begins and ends in the body. It involves taking the time to pay attention to where we are and what’s going on, and that starts with being aware of our body. That very act can be calming, since our body has internal rhythms that help it relax if we give it a chance.
How to Sit for Meditation Practice
Here’s a posture practice that can be used as the beginning stage of a period of meditation practice or simply as something to do for a minute, maybe to stabilize yourself and find a moment of relaxation before going back into the fray. If you have injuries or other physical difficulties, you can modify this to suit your situation.
- Take your seat. Whatever you’re sitting on—a chair, a meditation cushion, a park bench—find a spot that gives you a stable, solid seat, not perching or hanging back.
- Notice what your legs are doing. If on a cushion on the floor, cross your legs comfortably in front of you. (If you already do some kind of seated yoga posture, go ahead.) If on a chair, it’s good if the bottoms of your feet are touching the floor.
- Straighten—but don’t stiffen— your upper body. The spine has natural curvature. Let it be there. Your head and shoulders can comfortably rest on top of your vertebrae.
- Situate your upper arms parallel to your upper body. Then let your hands drop onto the tops of your legs. With your upper arms at your sides, your hands will land in the right spot. Too far forward will make you hunch. Too far back will make you stiff. You’re tuning the strings of your body—not too tight and not too loose.
- Drop your chin a little and let your gaze fall gently downward. You may let your eyelids lower. If you feel the need, you may lower them completely, but it’s not necessary to close your eyes when meditating. You can simply let what appears before your eyes be there without focusing on it.
- Be there for a few moments. Relax. Now get up and go about your day. And if the next thing on the agenda is doing some mindfulness practice by paying attention to your breath or the sensations in your body, you’ve started off on the right foot—and hands and arms and everything else.
- Begin again. When your posture is established, feel your breath—or some say “follow” it—as it goes out and as it goes in. (Some versions of the practice put more emphasis on the outbreath, and for the inbreath you simply leave a spacious pause.) Inevitably, your attention will leave the breath and wander to other places. When you get around to noticing this—in a few seconds, a minute, five minutes—return your attention to the breath. Don’t bother judging yourself or obsessing over the content of the thoughts. Come back. You go away, you come back.
- That’s it. That’s the practice. It’s often been said that it’s very simple, but it’s not necessarily easy. The work is to just keep doing it. Results will accrue.
Try This Beginner’s Mindfulness Meditation:
A 5-Minute Breathing Meditation To Cultivate Mindfulness. This practice is designed to reduce stress, anxiety, and negative emotions, cool yourself down when your temper flares, and sharpen your concentration skills.
5-Minute Breathing Meditation
Learn more About Mindfulness:
Explore the science of mindfulness, learn how to meditate, and how to practice mindful movement, plus dispel some of the myths of mindfulness with Mindful’s Getting Started Guide. | https://www.mindful.org/what-is-mindfulness/ |
Scientists from Harvard and MIT joined together to create a state of matter that looks like it belongs in a galaxy, far, far away rather than in Massachusetts. A group led by Harvard Professor of Physics Mikhail Lukin and MIT Professor of Physics Vladan Vuletic managed to create molecules formed from photons bound together, a union that produces a result that resembles a light saber.
"Most of the properties of light we know about originate from the fact that photons are massless, and that they do not interact with each other," Lukin said. "What we have done is create a special type of medium in which photons interact with each other so strongly that they begin to act as though they have mass, and they bind together to form molecules. This type of photonic bound state has been discussed theoretically for quite a while, but until now it hadn't been observed.”
"It's not an in-apt analogy to compare this to light sabers," Lukin added. "When these photons interact with each other, they're pushing against and deflect each other. The physics of what's happening in these molecules is similar to what we see in the movies."
To get the photons to interact with one another, the team cooled rubidium atoms in a vacuum chamber to just a few degrees above absolute zero, The Independent reported. They then fired photons into the cloud of atoms and were surprised to see them emerge on the other side as a single molecule.
"It's a photonic interaction that's mediated by the atomic interaction," Lukin said. "That makes these two photons behave like a molecule, and when they exit the medium they're much more likely to do so together than as single photons."
He added:
"We do this for fun, and because we're pushing the frontiers of science. But it feeds into the bigger picture of what we're doing because photons remain the best possible means to carry quantum information. The handicap, though, has been that photons don't interact with each other." | https://www.opposingviews.com/technology/harvard-and-mit-scientists-bind-light-create-matter-resembling-light-sabers |
The United States military has contingency plans for responding to any North Korean attack that are constantly updated and range from cyber efforts to all-out nuclear retaliation.
While the plans are highly classified, experts and officials say they carry considerable risks and the potential for heavy losses of life.
NUMBERS AND CAPABILITIES
– The U.S. military has an aircraft carrier, the USS Ronald Reagan, deployed to Yokosuka, Japan. According to the Federation of American Scientists, the United States has about 1,800 nuclear warheads deployed on Intercontinental Ballistic Missiles (ICBMs) and submarines.
– USS Ronald Reagan has a crew of 5,000, around 80 aircraft, and is equipped with the latest targeting and defense radars, integrated weapons systems and command and communications technology.
– Six B-1 bombers are now stationed at Andersen Air Force base in the U.S. Pacific territory of Guam.
– According to the Arms Control Association, the United States has 1,411 strategic nuclear warheads deployed on a total of 673 ICBMs, submarine-launched ballistic missiles (SLBMs) and strategic bombers.
– North Korea has conducted five nuclear tests, including two last year, and dozens of missile tests in the past year. In April, experts at 38 North, a North Korean monitoring project, estimated that North Korea could have as many as 20 nuclear warheads and could produce one more each month.
– North Korea has a broad spectrum of missiles in its arsenal, with ranges from 150 km (93 miles) to 8,000 km (5,000 miles).
– According to the Center for Strategic and International Studies, North Korea’s short- and medium-range systems include a host of artillery and short-range rockets, including Scud missiles, No-Dong systems, and a newer mobile solid-fueled SS-21 variant called the KN-02. It has made strides in long-range missile technology and tested a first ICBM, the Hwasong-14, in July.
– Although North Korea has more than a million troops, hundreds of military aircraft and air defense systems, experts question their capabilities.
– Anthony Cordesman of Washington’s Center for Strategic and International Studies said South Korea’s F-15 and F-16 fighter jets are far more capable than North Korea’s outdated MiGs and Su-25 jets. North Korean air defenses such as the SA-5 and the SA-3 surface-to-air missiles are “essentially Vietnam War-vintage systems, he said, making Pyongyang “very vulnerable to stealth and cruise missile attacks.”
– Pyongyang’s conventional forces rely on obsolete equipment.
“Exercises are regularly conducted, but they often appear staged and as such are not necessarily representative of wider operational capability,” a 2017 report from the International Institute for Strategic Studies said.
CONSIDERATIONS AHEAD OF AN ATTACK
Before launching a full-scale attack against North Korea or a surgical strike against key targets, the United States would first have to consider evacuating American citizens and alerting its allies for fear of North Korean counterattacks, U.S. officials and experts said.
That, as well as positioning the forces for a major attack, would wipe out the element of surprise, in part because the North Koreans are believed to have a number of spies in South Korea and elsewhere, U.S. intelligence officials said.
The first phase of an attack would be a Suppression of Enemy Air Defenses (SEAD) campaign to clear the way for air strikes. A SEAD campaign uses air strikes, artillery, missiles, or all the options, to destroy an enemy’s anti-aircraft defenses.
Even a conventional clash could cause catastrophic casualties, given the thousands of North Korean artillery pieces ranged along the border, at least 1,000 of which are capable of reaching the densely populated South Korean capital Seoul and its metropolitan area, home to some 25 million people.
POTENTIAL OBSTACLES AND COMPLICATIONS
Officials and experts say while the United States could hit targets, there are serious questions as to whether they have accurate enough intelligence to strike all of North Korea’s potential weapon sites before Pyongyang responds, especially given its development of mobile missile launch systems.
“First, we simply do not have a comprehensive or precise picture of the North Korean nuclear program, especially when it comes to the number of weapons and delivery vehicles – we do not know for sure where they are located or how well they are protected,” a 2016 Stratfor report said.
“I’m reasonably confident in the ability of our intelligence community to monitor the testing, but not the deployment, of these missile systems. Kim Jong Un and his forces are very good at camouflage, concealment and deception,” Vice Chairman of the U.S. Joint Chiefs of Staff General Paul Selva said recently.
U.S. officials say the unpredictability of North Korea’s response makes any military option risky. How neighboring China would respond is also a question military planners would have to address.
U.S. military officials have publicly warned against a military conflict because of the catastrophic loss of life it would lead to, saying diplomatic efforts are the priority.
“You can see the American effort is diplomatically led. It has diplomatic traction … The tragedy of war is well enough known, it does not need another characterization beyond the fact that it would be catastrophic,” U.S. Defense Secretary Jim Mattis said last week. | https://varnumcontinental.com/factbox-military-balance-of-power-in-the-asia-pacific-region/ |
Rosie McCall reports for Newsweek:
A mummified body has been found in Bolivia’s famous Salar de Uyuni, the world’s largest salt flat and a popular tourist destination.
According to Bolivian news outlet El Potosí, workers recently discovered the body atop the salt flat, a white desert spanning 4,086 square miles (10,582 square kilometers) in the Andes of southwest Bolivia.
Officials say the corpse is stiff and was found in a state of decomposition. They said the body’s condition suggests the individual died between two and three months ago.
The mummified corpse is currently under forensic investigation and officials hope to soon identify the individual and determine the cause of death. The current theory is that the body belongs to a missing person from a nearby community.
According to El Potosí, officials believe the individual is around 35 years old. Prosecutor Roxana Choque said authorities have been in contact with local communities who reported a missing person.”It can be presumed that it is that person,” Choque said.
Newsweek has contacted the Cuerpo de Policía Nacional Bolivariana.
Salar de Uyuni, located in Daniel Campos Province, is a popular traveler’s destination, enjoyed for its natural beauty and optical illusions. It is also a flamingo breeding ground.
According to NASA, the area is around the same size as Hawaii’s Big Island and was once the site of a prehistoric lake called Lago Minchin that has long since evaporated, leaving the vast salt flat that exists today.
The thick mineral-rich crusts found in the Salar de Uyuni developed over a period of several thousand years, and reach depths of 33 feet (10 meters) in some places.
Salar de Uyuni has an elevation 12,047 feet (3672 meters) above sea level and an average temperature of 10.1 °C (50.1 °F). The salt flat is considered a desert, experiencing almost no rainfall. This is especially true in April, when it sees, on average, 0.0 inches of rainfall, according to Climate-Data.org.
Harsh conditions like these may help bodies to naturally mummify, like Ötzi the Iceman, a Copper Age glacier mummy discovered in the Italian Alps after his body was frozen in time, and pre-Dynastic Egyptians, whose bodies have been found in sandy pits. | https://bolivianthoughts.com/2020/05/25/mummified-corpse-discovered-in-bolivias-salt-flats/ |
Owners of electric cars are calling for amendments to the terms and conditions stipulated in the unified motor insurance policy that they feel has not kept pace with developments in the electric vehicle arena.
Several owners complain about the length of the repair period in cases when their cars were involved in accidents. The repair period can extend to two months due to the lack of spare parts at workshops. However, insurers generally provide for the use of an alternative car up to 10 days under the unified insurance policy, reported Emirates Today.
There are no direct agencies of electric vehicle manufacturers in the UAE that would be able to supply needed spare parts quickly. In addition, agencies outside the country have a panel of repair workshops, and the latter do not stock spare parts but acquire them only when the components are ordered.
Mr Bassam Chilmeran, CEO of Abu Dhabi-Headquartered Al-Wathba National Insurance Company, told Emirates Today, “Electric cars at the present time take time to be repaired, due to the lack of direct agencies in the country, but with the increasing use of this type of cars, agencies will inevitably be present to be close to customers.”
He added, “Choosing a car usually involves several elements, including maintenance and repair services, and this is what individuals should take into account when buying a vehicle.”
The number of electric vehicles is increasing in the UAE. In Dubai, for instance, the total number of electric vehicles until the first quarter of 2021 reached 2,473, while the number of hybrid vehicles reached 6,016, making the total number of green vehicles registered in Dubai to 8,489 vehicles. | http://africazine.com/news/uae-electric-vehicle-owners-call-for-unified-motor-insurance-policy-to-be-updated/ |
The mission of the Biology Program of OLFU is to prepare the learners for a career in the biological sciences that will help develop professionals in the paramedical and allied health work place. Students are trained to be actively involved in community service that could enhance their appreciation and understanding of natural world via the use of the latest scientific tools and techniques in both the laboratory and outdoor settings.
The College also aims to provide the students with a strong foundation on the investigative and scientific methods in the both the industry and medical fields through the different areas of technological sciences by acquiring knowledge that employs scientific principles, basic laws and wise decisions and adjustments to meet the demands of life works and to cultivate critical thinking and comprehension. | https://www.edukasyon.ph/schools/our-lady-of-fatima-university-valenzuela/courses/bachelor-of-science-in-biology |
Our Commitment to Protecting Your Personal Information
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Hanna Properties shall formulate, implement, maintain, and continuously improve our compliance program in conformity with industry guidelines and, "Requirement for a compliance program to protect personal information." This initiative shall address the appropriate collection, use, disclosure, sharing, and management of personal information.
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Hanna Properties may use the personal information collected from you within the limited range of use necessary for the original purpose. In addition, Hanna Properties may share this personal information with affiliates or consign the safekeeping of this personal information to a third party in order to provide better service to customers. When such information is consigned to a third party, we shall ensure this information is protected by selecting an appropriate contractor and entering into the necessary agreements to ensure the contractor manages the information appropriately.
Sharing of personal information
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Hanna Properties shall disclose your personal information to you on your request and without delay unless doing so would significantly affect our operations or impair personal life, human health, property, or other rights. If you request a correction, addition, or deletion of all or part of your personal information, or if you wish to withdraw your permission to allow us to use your personal information, Hanna Properties shall accommodate your request without delay. Specifically, we shall take necessary measures responsibly when so required by the circumstances.
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Hanna Properties shall develop a management system and shall implement adequate security measures to protect personal information from unauthorized access, loss, destruction, falsification, or disclosure, thus ensuring the accuracy and security of the information.
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In handling personal information, Hanna Properties shall comply with all laws and regulations applicable to the protection of relevant personal information. In addition, we shall ensure that our compliance program for the protection of personal information is in accord with these laws and regulations.
Inquiries | https://hannagroup.ca/construction/privacy-policy/ |
What is the situation?
Users of hazardous materials at the University have historically had a good safety record. However, incidents can occur in even the safest environment and an absence or breakdown of any established safeguards could result in a major emergency. Spills may result from equipment failure, human error, failure to follow established procedures, natural disaster or sabotage.
What should I do?
Localized/small spills
- Spills that do not endanger workers in the immediate area may be cleaned up by personnel who have been trained by their supervisor, PI or lab manager and are properly equipped to handle the situation.
- Hazardous materials spill guidelines should be established by the supervisor, PI or lab manager after reviewing MSDS information on MYCHEM or hard copies of MSDSs kept on site. These procedures need to be included in the lab-specific Standard Operating Procedures.
- Spill cleanup guidelines for small localized spills should take into consideration the following:
- The dangers of the hazardous materials involved
- The amount of the hazardous materials spilled
- The possible spill locations
- Availability of appropriate clean-up materials or kits*
Large, unidentified or extremely dangerous spills
If the spill is large, the hazardous material is not easily identified or if the material is extremely hazardous:
- Evacuate all personnel from the area.
- Call Campus Safety at 2-4888 and then call 9-1-1. When placing an emergency call:
- Give your name.
- Give the location of the spill (room and building).
- Give the phone number you are using.
- Describe the emergency/injuries.
- If possible, remain in the vicinity, away from danger, to assist emergency responders.
- Campus Safety will notify the Tacoma Fire Department who will respond to stabilize and contain the chemical spill, often leaving behind hazardous waste and contaminated equipment. If the hazardous waste is not properly cleaned up and packaged by the Tacoma Fire Department, do not reoccupy the area. Contact Environmental Health and Safety at 206-685-5835 for assistance.
- Note that packaged waste must be handled according to chemical waste management policies and guidelines established in Section 3 of the Laboratory Safety Manual. Please Contact the EH&S Environmental Programs Office at 206-685-5835 for assistance.
*See Section 4 of the UW Laboratory Safety Manual for help in assembling a chemical spill cleanup kit. See the UW Seattle EH&S website for other clean-up kits . | https://www.tacoma.uw.edu/fa/safety/hazardous-materials-spill |
Information resources useful for finding chemical and physical properties.
Consider your options and what types of descriptions a particular database will accept.
If you get no results, try another synonym or another description, before moving on to another resource.
These resources collect information on the most commonly encountered compounds and their most basic properties.
If you have trouble finding the chemical name, try using a synonym for that same compound. Or draw the structure of the compound you are looking for (NIST, ChemSpider).
If either of those don't succeed, try the add'l sources tab.
A good place to start. Besides data, find basic constants, units and conversion factors; general health and safety information; and mathematical tables, etc.
Descriptive information on 10,000+ chemicals, drugs (human and veterinary), and biologicals. Each entry lists synonyms for drug names (trade, chemical, generic, and research codes), CAS Registry Numbers, physical data, patent information, uses, toxicity, and bibliographic citations on synthesis, pharmacology, and toxicology.
ChemSpider is a free chemical structure database providing fast text and structure search access to over 29 million structures from hundreds of data sources.
What About Wikipedia and Wolfram Alpha?
This WikiProject is meant to standardize information about chemicals found on Wikipedia and to improve the quality of the information available. A compounds rating indicates how reliable the information is. For example, for the over 8000 compounds found in Wikipedia, nearly 2500 are unassessed--meaning the information cannot be verified. Common compounds may have reliable info, but it is best to verify the data found with another source listed above, especially for more uncommon substances.
Currently (November 2013) only 16 compounds meet the highest level of quality by Wikipedia standards. Make sure the databox for your compound has a green check, meaning the data has been validated. Also note that many of the Wikipedia articles cite the suggested resources listed above, so why not start with them in the first place?
WA contains a wide variety of data on many chemical compounds. However, WA's major flaw is that it DOES NOT tell you the specific source of the data presented. WA claims to have a proprietary database of data gathered from various sources. While these sources are often listed, you can not be certain where a particular boiling point or heat capacity came from. When you need to cite an exact source or to justify your data from a reliable & credible source, use one of the other resources above instead.
This LVC LibGuide is based upon LibGuides by Jeremy R. Garritano, of Purdue University and Ariel Andrea, of the University of Wisconsin-Madison. Both have kindly given us their permission to use their LibGuides Chemistry and Physical Property Information & Physical and Chemical Properties with slight modifications. Thank you, Jeremy and Ariel! | https://libguides.lvc.edu/chemicalproperties |
Available under License Creative Commons Attribution.
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Abstract
Background: Neurofeedback (NFB) attempts to alter the brain’s electrophysiological activity and has shown potential as a pain management technique. Existing studies, however, often lack appropriate control groups or fail to assess whether electrophysiological activity has been successfully regulated. The current study is a randomized controlled trial comparing changes in brain activity and pain during NFB with those of a sham-control group.
Methods: An experimental pain paradigm in healthy participants was used to provide optimal control of pain sensation. Twenty four healthy participants were blind randomized to receive either 10 × NFB (with real EEG feedback) or 10 × sham (with false EEG feedback) sessions during noxious cold stimulation. Prior to actual NFB training, training protocols were individually determined for each participant based on a comparison of an initial 32-channel qEEG assessment administered at both baseline and during an experimental pain task. Each individual protocol was based on the electrode site and frequency band that showed the greatest change in amplitude during pain, with alpha or theta up-regulation at various electrode sites (especially Pz) the most common protocols chosen. During the NFB sessions themselves, pain was assessed at multiple times during each session on a 0–10 rating scale, and ANOVA was used to examine changes in pain ratings and EEG amplitude both across and during sessions for both NFB and sham groups.
Results: For pain, ANOVA trend analysis found a significant general linear decrease in pain across the 10 sessions (p = 0.015). However, no significant main or interaction effects of group were observed suggesting decreases in pain occurred independently of NFB. For EEG, there was a significant During Session X Group interaction (p = 0.004), which indicated that EEG amplitude at the training site was significantly closer to the target amplitude for the NFB compared to the sham group during painful stimulation, but this was only the case at the beginning of the cold task.
Conclusion: While these results must be interpreted within the context of an experimental pain model, they underline the importance of including an appropriate comparison group to avoid attributing naturally occurring changes to therapeutic effects. | https://gala.gre.ac.uk/id/eprint/33495/ |
Therefore, there is now no condemnation for those who are in Christ Jesus.
Romans 8:1
I play Solitaire and other card games on my phone to wind down. Some games turn out better for me than others. I can’t win them all, but I’d really like to! My competitive nature compels me to try to win. I discovered a nifty little undo button at the bottom of the screen I can use. If I make a move that doesn’t help me win, I simply undo that move and try a different one. I can undo as many moves as I would like. I can also reset the whole game if it’s going badly.
Wouldn’t it be nice to have an undo button in life? Those times when hurtful words come tumbling out of my mouth like snow in an avalanche. Undo. When I choose to disobey the subtle voice in my head and go my own direction. Undo. Sometimes I’d like to reset the whole day and try again.
In life we don’t get a redo. My dad used to tell me I was cheating if I went back a move and tried again when I was playing Solitaire. I still have his voice in my head when I push that undo arrow. I think God must agree with my dad. Life marches forward but we can’t rewind time and try again. We may get another opportunity to make the right decision but it will be in a different circumstance.
I am learning that it is not so much about living a perfect life, free from error. In fact, I learn a great deal after I make a mistake. And I usually remember the lesson long after. God knows we will mess up. He has already provided forgiveness for our sins through Jesus.
Thank you, God, that you did not send Jesus into the world to condemn the world, but to save the world through Him (John 3:17) so there is now no condemnation for those who are in Christ Jesus (Romans 8:1). | https://www.encouraging.com/home/2019/2/28/reset |
In May 2013, James Byrne led his 7th grade Life Science class through a project focusing on the identification and eradication of invasive plants found on the school campus. The project started with learning vocabulary to help students identify ten of the common deciduous plants found on campus; eight of which were native and two were invasive. These invasives were scotch broom and himalayan blackberry. The project culminated with the students eradicating the scotch broom “enemy” that was on the campus.
James also created a simple leaf identification page that students used to help them identify plants by their leaves. A total of 60 7th graders among two classes participated in this project. These students were especially excited to learn the names of the plants that they didn’t already know. Many of the students even said that it was their favorite lesson/activity of the year; they loved the “battle” with the enemy (scotch broom). This project also helped cover the Inquiry standards and benchmarks for education.
Not only did the students learn in a new and exciting way, but they also benefited the school district by saving it both time and money on this project. Also, no chemicals were used that otherwise may have been. James explained that he was also “personally thanked by the district maintenance staff for the work that we did. The campus is one step closer to being eradicated of invasive species.”
The message of invasive species, especially scotch broom, eradication was spread to parents as students talked about their school projects at home. “The kids themselves will likely never forget it because they enjoyed the project so much,” James concluded.
Fernhill Wetlands- Lisa Cunningham- Evergreen Middle School
Lisa brought her 8th grade students to do research and community service at Fernhill Wetlands outside of Forest Grove on April 25th, 2012. For this fieldtrip we partnered with Clean Water Services who manage the wetland and the Cascades to Coast GK12 program from PSU.
In total the group planted 285 trees and shrubs as well as 150 herbaceous plugs.
“Like many wetland areas, particularly ones that are in the process of being restored, invasive species are a problem at Fernhill, which is why we planted native vegetation for our community service. In order to help students better understand the nature of invasive species we did a poster project based on the “Ultimate Invader” activity,” explained Lisa.
“The project of planting native vegetation will help the wetland restoration efforts as well as bring more visitors to Fernhill. Currently a visitor center is being built at the wetlands in order to host more groups and increase education and awareness for the area”.
New Zealand Mud Snail- Sena Berquist
Sena describes her project that she led for 26 students…”This fall my class inventoried invertebrates in the stream on our school property. We plan to add the information to the stream web site in the next month. We then studied the New Zealand mudsnail, knowing it has been found in rivers in our county. The kids then made posters explaining what the snail is, where it is found and why it creates problems when it is in a watershed”.
“The students wrote about the species for the posters we made. Having their writing be for a real purpose and knowing it would be displayed in the community resulted in more motivation and a better end product. The very dry section of our science textbook on habitats, adaptation, food chains/webs and classification of animals came alive when we went to the stream and later talked about all of those concepts in the context of the New Zealand mudsnail. The kids were fascinated by this little creature that could cause such big problems and many of the “pieces” we had learned about became parts of a much bigger mental picture”.
Sena hopes that educating the next generation about invasive species will impact the community in a positive way. Currently, the posters work towards the fight against the New Zealand mud snail in the local watershed and children are most likely spreading the information to their parents.
Sena plans to continue conduct a yearly invertebrate survey of our creek and post the results on stream web. The class will also incorporate invasive species into the classroom life science unit.
Yellow Flag Iris Control- Charlotte Kelley (7th and 8th grade)
Charlotte explains her student’s project: “In April my students heard a speaker discuss Lake Ecosystem and importance of native plants in the riparian zone. In her presentation we learned about invasive lake plants and were educated on Yellow Flag Iris (YFI).
“In April my science club students (grades 7/8) attended a parks and recreation meeting to educate members on YFI and obtain permission to work on the removal of YFI. The following week they presented their solution plan to the city council and got the ok from city council.Then we walked to the lake and counted and observed the colonies of YFI. We realized there were too many YFI colonies to count from the shore and decided to pull one large colony from the shore and then we stomped a large patch to the ground.”
“In June we returned and did a canoe trip around the parameter of the lake and GPS marked all the
colonies. Along with the markings we also labeled the approximate size. After GPS marking the colonies
we went back to check on our previous work. The stomped colony had no seed pods but the colonies nearby had LOTS of seed pods. We therefore concluded that the stress of stomping at least kept them from producing out seeds and spreading the YFI to new areas. Also, on that day we removed all the pods from another colony and dug up 2 other colonies.”
Through the continued monitoring of the yellow flag iris, students can observe the progress of their project and learn more about the watershed ecology and behaviors of this invasive species. Charlotte reports that this project has allowed her students to connect to community members, receive positive feedback from adults and participate in community based after school activities.
The students have enjoyed the “real-life” application of the watershed science concepts. Charlotte even caught one student exclaiming, “This is so much better than playing video games”. This class has already made an impact on the parks and recreation and city council and they plan to focus on community education on watershed invasive species day with a presentation. They are also planning a riparian day activity to take to the elementary schools and pass on the knowledge and grow the science club.
Live plants and animals in the classroom teacher interview and classroom survey
Science Learning – Students surveyed teachers’ classrooms in school on what types of live plants and animals they have in the classroom.
Outcome – Model curriculum information for integrating what to do with invasive species when you are done using them in the classroom.
Further Application- Curriculum can be adapted and the outreach materials may be used in future educational displays or borrowed for other classrooms.
Invasive Species classroom survey
The AP monitoring project- Vollmer-Buhl (high school)
Science Learning – Students continued to learn and spread the message about the AP snail through brochures, videos, and in the field work.
Outcome – Model outreach and educational materials produced by students for an AP snail message, useful classroom material.
Further Application – Outreach materials may be used in further educational displays and presentations.
AP Snail monitoring WISE report 2011
See Snail Wars video:
OMSI Field Trip description
Hayes/Howard – 7th Grade
Science Learning –
Underserved students had the opportunity to visit a hands-on museum OMSI (Oregon Museum of Science and Industry) and participated in a lab on Invasive Species
Outcome –
Invasive Species Learning. Retained at risk students
Snorkel Surveys and AIS Clean-up Projects description
Solash – 6th Grade
Field Trips –
Student snorkeled nearby creek searching for and removing invasive species.
Outcome –
Participation in these projects retained at risk students. Comprehensive student learning about invasive species. Invasive species were removed from the area.
School Surveys description
Hayes – 6th Grade
Engaging the Community –
Students developed a survey on teachers knowledge of invasive species and use of and disposal of live organisms in the classroom
Outcome –
Participation in these projects retained at-risk students
Further Application –
Will increase awareness of invasive species and provide values information on the use of live animals in the classroom
The Ecosystem Distruptors description
Hayes – 6th Grade
Lab Activity –
Students engage in a scavenger hunt for “ecosystem disruptors” in their classroom on in this case an educational land at the Oregon Museum if Science and Industry (OMSI). Then, students study specimens under a microscope and answer questions and fill out a food web on the board and discuss how and where invasive species will have an impact.
Outcome –
Participation in these projects retained at-risk students
Further Application –
May be used as part of the OMSI curriculum and thus reach a large number of students all over Oregon and Washington
Earth Day Parade description
Phinney – 4th Grade
Engaging in the Community –
Student created and invasive species float and handed our information and brochures on invasive species. | https://blogs.oregonstate.edu/wise/student-projects/926-2/ |
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Nanomechanical sensing with resonant devices based on semiconductor nanowires (SCNWs) is currently consolidated as one of the most fruitful research lines involving this kind of nanostructure. SCNWs are highly useful as resonators for high-performance applications because of their unique structural and dynamic properties. The former imply an exceptional combination of very low mass, single-crystal quality, and controllable dimensions and geometry.^[@ref1]^ Regarding dynamic properties, the characteristic high aspect ratio of SCNWs results in flexural modes which are extremely sensitive to external perturbations of a different nature.^[@ref2]^ On one hand, this facilitates detecting their thermomechanical vibrations, as the effect of temperature alone results in relatively large vibration amplitudes; on the other hand, it also simplifies external driving schemes, as external forces of a different nature can be used to drive flexural vibrations even beyond the fundamental mode. These properties provide SCNW resonators with singular sensing capacities which are otherwise impossible to achieve with other structures. Some of the most significant ones are based on the splitting of each flexural mode in a doublet of nearly degenerate orthogonal oscillations, which occurs for both single-clamp^[@ref3],[@ref4]^ and double-clamp nanowires.^[@ref5]^ This effect has indeed already been explored for innovative applications such as simultaneous mass and elasticity sensing of adsorbates,^[@ref4],[@ref6]^ vectorial force sensing/imaging,^[@ref7]−[@ref9]^ and the exploration of complex dynamics^[@ref10]−[@ref13]^ or optomechanical back-action effects.^[@ref14],[@ref15]^
Exploiting the unique properties of SCNW resonators for developing an equally high performance and practical functionalities requires an efficient conversion of the nanowire vibrations into readable signals with high sensitivity, linearity, and minimum constraints regarding the nanowires' arrangement. Different transduction schemes have been demonstrated so far to that end, but arguably all of them have one severe drawback in common: the need of specific and often complex arrangements or geometry of the nanowires. For instance, most reported optical readout schemes imply perpendicular incidence of a laser beam on the nanowires, which requires placing the nanowires on supporting prefabricated microstructures such as microtips^[@ref16]^ or microtrench sidewalls.^[@ref17],[@ref18]^ Also, all electrical readout schemes, either capacitive,^[@ref19],[@ref20]^ piezoresistive,^[@ref21],[@ref22]^ or magnetomotive,^[@ref23]^ require the ability to precisely place the nanowires with respect to biasing and/or driving electrodes, which is far from a trivial issue. Although several micro-/nanofabrication approaches have been successfully developed to that end,^[@ref24]−[@ref26]^ all of them require nontrivial, costly, and often low-yield clean-room processing methods, which imposes important difficulties for a systematic, agile, and efficient development of practical applications. It must be noted that some of the reported SCNW resonator configurations, particularly some of those involving nanowires located at tips or edges, are not motivated exclusively by the need of enabling a vibration readout but also by their appropriateness for specific applications, such as the paradigmatic example of nanowire probe sensors.^[@ref8],[@ref9],[@ref26]^ Anyhow, it is remarkable that a transduction mechanism that enables the nanowire vibration readout for the simplest disposition of SCNWs, consisting of vertically aligned nanowires with an arbitrary pattern on an unstructured flat substrate, has not been reported yet. Although the measurement of mechanical resonances of vertical SCNWs has been previously achieved, the transduction schemes used imposed important restrictions regarding the nanowire geometry or arrangement. Specifically, laser beam deflection schemes have been demonstrated only for nanowires with micron-sized nanowire tips and inverted cone nanowire geometries.^[@ref27],[@ref28]^ Also, an optical Bragg scattering readout has been recently applied to truly nanometer-scaled vertical nanowire arrays,^[@ref29]^ but it required a periodic arrangement of the arrays and thus a specific nanofabrication process to provide such an arrangement. Besides these optical schemes, electromechanical coupling of nanomechanical motion to focused electron beams has recently emerged as a feasible approach for transduction of vertical SCNWs without the need of specific arrangements.^[@ref30],[@ref31]^ However, in addition to the obvious practical limitations imposed by the operation inside a scanning electron microscope, the reported results indicate the presence of radiation pressure back-action effects that perturb the mechanical response of the nanowires. These effects can be of great interest in fundamental studies regarding dynamical cooling of macroscopic degrees of freedom to the quantum ground state,^[@ref30]^ but they may also introduce disadvantageous and complex phenomenology for practical applications.
In this work we describe an optical transduction mechanism that allows the measurement of the flexural vibrations of vertical SCNWs with sub-wavelength-scale diameters and no particular requirements about their geometry and arrangement. The experimental implementation of this mechanism does not involve any fabrication process on the substrates besides the generation of the SCNWs themselves, and it can be applied to both isolated single nanowires and nanowire arrays, either randomly or regularly patterned on the substrate, and without any constraint regarding the array density. Specifically, we show that the light reflected when a laser beam strikes the substrate vertically and sufficiently close to a nanowire (longitudinally parallel to the nanowire) is modulated by the flexural mode vibrations of the nanowire. We show that such modulation is proportional to the amplitude of the nanowire vibrations, and it can be easily detected by a standard photodetector and measured by spectral analysis of the resulting signal. We demonstrate the performance of this transduction mechanism by its application to vertical silicon nanowires (Si NWs) grown by the vapor--liquid--solid (VLS) mechanism on a flat Si (111) substrate without any predetermined pattern. We first analyze the effect of varying the relative nanowire--laser beam position for detecting split flexural modes, and we present results that allow the determination of the positions of maximum sensitivity with respect to the directions of the nanowire vibrations at the split mode resonance frequencies. Then, we present a model for the transduction mechanism that successfully reproduces the experimentally detected mechanical resonances. Furthermore, we demonstrate the highly sensitive and linear performance of the transduction mechanism by providing a complete characterization of our Si NW resonator model devices, including their dynamic range when externally driving flexural modes, high-order mode detection, and frequency stability. Our results determine a detection threshold below the thermomechanical limit of the Si NWs under test. Also, acoustic piezo-driven vibrations of the nanowires allow the detection of the onset of nonlinear oscillations, providing access to the full dynamic range of the nanowires as well as to their nonlinear regime. In addition, high-order flexural modes are detected up to the fifth order, potentially enabling the simultaneous tracking of several modes for enhanced multiparameter nanomechanical sensing.^[@ref32]^ Finally, we analyze the signal-to-noise ratio and frequency stability obtained for the Si NW resonators under test as a function of the incident laser power and discuss the influence of this parameter for optimum transduction performance.
The experimental implementation of the transduction mechanism presented in this work is schematically depicted in [Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}. A focused laser beam is aligned parallel to vertical Si NWs as those shown in [Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}a (further images are provided in [Figure S1](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf), and experimental details about the used VLS growth technique can be found elsewhere^[@ref33]^). We consider three nanowire sizes: the longest nanowires have lengths (*L*), base diameters (*D*~b~), and tip diameters (*D*~t~) around *L* = 50 μm, *D*~b~ = 300 nm, and *D*~t~ = 60 nm; the medium type corresponds to dimensions around *L* = 25 μm, *D*~b~ = 250 nm, and *D*~t~ = 100 nm. The shorter nanowires have typical dimensions around *L* = 15 μm, *D*~b~ = 200 nm, and *D*~t~ = 125 nm. Typical deviations of dimensions within each type are below 20%. A notable feature of the parallel laser beam incidence (parallel to the vertically aligned nanowires, perpendicular to the substrate) is its symmetry with respect to the orthogonal vibrations of the nanowires in both the lower and upper-frequency components of their flexural mode doublets ([Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}b). This results in the advantage of a symmetrical access to the resonance response of both components as well as a straightforward determination of their vibration directions with respect to the *X*--*Y* positioning axes. The experimental setup ([Figure [1](#fig1){ref-type="fig"}](#fig1){ref-type="fig"}c) uses a fiber-coupled diode laser (TopMode-633, Toptica Photonics AG, λ = 633 nm) whose output power and polarization are manually controlled with a variable attenuator and birefringence loops, respectively. Then, a triplet lens collimator provides a nearly Gaussian free-space beam, with its optical axis oriented parallel to the longitudinal axis of the nanowires. The beam is focused on the substrate using a 5× objective with 0.14 numerical aperture, which results in a laser spot diameter of around 8 μm, approximately constant along the entire length of the nanowire. A positioning stage controls the relative *X*--*Y* position of the sample with respect to the probe beam incidence point as well as its focus, and a piezoelectric actuator placed below the sample allows the excitation of flexural modes. The beam reflected from the substrate is collected by an unsegmented Si photoreceiver coupled to a low-noise transimpedance amplifier. The resulting electrical signal is then processed either by a digital acquisition (DAQ) board or by a lock-in amplifier (LIA) whose reference signal is delivered to the piezo-actuator in the case of driven vibrations. The DAQ board is synchronized both with a signal generator, which can also be connected to the actuator, and with the positioning stage, allowing the acquisition of the signal of the photoreceiver as the relative sample--laser beam position is scanned. All the measurements are performed in high vacuum (∼10^--5^ mbar) and at room temperature conditions. A CCD camera with white light illumination coupled to the system by a pellicle beamsplitter provides top-view optical images in order to navigate the sample surface and locate nanowires of interest. Besides the use of an unsegmented photodetector, this detection scheme is similar to those previously reported in studies involving nanowires with micron-sized tips and inverted cone geometries.^[@ref27],[@ref28]^ The essential difference between those works and the results reported here is the transduction mechanism involved. The transduction principle used with micron-sized tip nanowires was based on the modulation of the reflected light as a consequence of the deflection of a laser beam tightly focused just on top of the micron-sized tip. The transduction mechanism described in this work does not rely on laser beam deflection, so that it can be applied to nanometer-scale cross-section nanowires without particular requirements about tapering geometry or tip size.
{#fig1}
[Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"} shows an example where thermomechanical spectra corresponding to the fundamental flexural mode doublet of a nanowire of the longest type are shown at different relative nanowire--laser beam positions. In [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}a, the radial distance from the incidence point and the nanowire is kept constant (*r*~0~ = 2.5 μm) while the relative angle is varied from 0° to 180°. This angle, denoted as θ~0~, is defined so that θ~0~ = 0° corresponds to incidence on the lower-frequency resonance vibration axis (***e***~***L***~) whereas 90° corresponds to incidence on the upper-frequency resonance vibration axis (***e***~***U***~). As shown in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}a, for θ~0~ = 0°, only the lower-frequency peak appears in the spectrum. As the angle θ~0~ is increased, the lower-frequency peak decreases in amplitude, whereas the upper-frequency peak first appears and then increases in amplitude. When an angle of θ~0~ = 90° is reached, the lower-frequency peak disappears, and the upper-frequency peak takes its maximum amplitude. For angle values varying from 90° to 180°, the peak amplitude evolution is reversed, so that the lower-frequency peak increases back to its maximum amplitude, and the upper-frequency peak is reduced until it vanishes. The observed variations of the amplitude of the fundamental mode doublet peaks are a consequence of the dependence of the transduction sensitivity on the relative nanowire--laser beam position. A more general vision of this dependence can be gathered by measuring the vibration amplitude at resonance at all possible positions. An example of such a measurement is shown in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}b,c for the lower and upper components of the fundamental mode doublet, respectively. These plots allow the determination of the direction of the lower and upper vibration axes, ***e***~***L***~ and ***e***~***U***~, respectively, with respect to the *X*--*Y* positioning axes. Each plot shows two lobular areas where the amplitude reaches maximum values, so that the lines connecting these two maxima in each case determine the vibration axes. The relative perpendicular orientation of the lobular areas corresponding to the lower- and upper-frequency vibrations is consistent with the expected orthogonality of the doublet components in conservative force fields.^[@ref8]^ The maximum sensitivity position (maximum amplitude) does not correspond to a laser beam incidence just on top of the nanowire. Instead, maximum sensitivity is obtained around 2.5 μm away from the nanowire along any of the vibration axes for the corresponding resonance frequency component, either ***e***~***L***~ or ***e***~***U***~.
{#fig2}
In order to understand the underlying transduction mechanism and, in particular, the observed dependence of the transduction sensitivity with the relative nanowire--laser beam position, we have developed a theoretical model whose main elements are presented in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}. The model is based on the modulation of the light reflected from the substrate by the vibration of the nanowires. In order to verify such a mechanism, we first measure the reflected power from the substrate in the area surrounding a nanowire. A representative experimental result is presented in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}a, which shows a map of the reflected power collected from a 16 × 16 μm^2^ area around the nanowire position. The map shows a symmetric round-shaped area around the central nanowire position where the reflected power progressively decreases down to a minimum of approximately an 80% with respect to the power reflected from the flat plain Si substrate. A cross-section from this map along the *X*-axis is plotted in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}b, showing a steep dip centered at the nanowire position and extended along a width comparable to the spot size. The observed reduction in reflected power as the relative nanowire--laser beam distance decreases is produced as a consequence of the light scattered by the nanowire.^[@ref18]^ The steep dependence of the reflected power with respect to the relative nanowire--laser beam position implies that nanowire vibrations will produce a modulation of the reflected power, generating an AC signal in the optical power collected in the photodiode with the same frequency as the nanowire vibrations, as schematically depicted in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}b. Thus, the nature of the transduction mechanism relies on the change of light scattered by the nanowire as a function of the relative nanowire--laser beam distance, which is effectively determined by the nanowire deflection. Due to the local intensity gradient given by the Gaussian cross-section of the probe beam, the vibration of the nanowire has the effect of modulating the scattered light and thus also the total optical power reflected from the substrate. Consequently, the amplitude of the generated optical signal will be larger where the change of reflected power with position is steeper. These areas correspond to the regions of maximum reflected power gradient, as calculated in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}c,d. The maximum reflected power gradient is located at around 2.5 μm of radial distance between the nanowire and the point of laser beam incidence, consistent with the relative nanowire--laser beam distance at which the maximum sensitivity is observed in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}b,c. [Figure S2](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf) shows simulated optical intensity fields for varying relative nanowire--laser beam positions which are consistent with the provided interpretation of the experimental observations given in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}a--d. Moreover, we can theoretically explain the lobular shape of the areas of maximum sensitivity by considering that the nanowire vibrations do not happen in any radial direction from the nanowire position, but only along the axes corresponding to the lower and upper-frequency vibrations of the flexural mode doublets. Therefore, by projecting the reflected power gradient along these axes, as depicted in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}e--h, we reproduce the lobular shapes of the measured amplitude maps shown in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}b,c with notable agreement.
{#fig3}
In consideration of the transduction model described above, we can derive an expression for the measured vibration amplitude signal as a function of the actual nanowire vibration amplitude. We define *S*~L~(ω) and *S*~U~(ω) as the contributions to the total power spectral density (PSD) of the nanowire vibration corresponding, respectively, to the lower- and upper-frequency components of a flexural mode doublet. If only thermomechanical effects are considered, following the fluctuation--dissipation theorem each of these terms can be written aswhere the subscript *i* = {*L*, *U*} denotes either the lower- or upper-frequency doublet component, *S*~*i*~^*TH*^ = 4*k*~B~*TΓ*~*i*~ is the PSD of the Langevin force given by the product of the Boltzmann's constant *k*~B~, the temperature *T*, and Γ~*i*~ = *m*~*i*~ω~*i*~/*Q*~*i*~, with *m*~*i*~, ω~*i*~, and *Q*~*i*~ being the effective mass, resonance frequency, and quality factor corresponding to each doublet component. According to the proposed transduction model, the nanowire vibration is converted into an optical signal by means of the dependence of the reflected power on the nanowire position. Thus, besides the factor given by the gradient of the reflected light intensity, ∂*I*/∂*r*, and its projection along the lower and upper doublet component axes, we need to consider the nanowire vibration mode-shape ψ(*z*) in order to account for the actual variation of the effective nanowire position. From such considerations, the measured PSD of the reflected optical power signal measured from the photodetector at a relative radial nanowire--laser beam distance *r*~0~ with an angle θ~0~ with respect to the lower-frequency vibration axis can be written as
[Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}i,j shows the experiment--theory comparison of results corresponding, respectively, to the PSD of the lower and upper resonance peaks of the fundamental mode doublet of an undriven nanowire. The experimental data represented in these plots correspond to *S*~R~(*r*~0~, θ~0~, ω) in μV^2^/Hz units as measured at the relative nanowire--laser beam position corresponding to the maximum sensitivity for each doublet component, i.e., θ~0~ = 0° in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}i and θ~0~ = 90° in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}j. The theoretical results correspond to the application of [eq [1](#eq1){ref-type="disp-formula"}](#eq1){ref-type="disp-formula"} for calculating *S*~*i*~(ω) in m^2^/Hz units, considering *T* = 300 K and using the values of *m*~*i*~, ω~*i*~, and *Q*~*i*~ obtained from the experimental data. In particular, for the calculation of the effective mass *m*~*i*~ we consider the flexural mode shape ψ(*z*) given by the Euler--Bernoulli equation for a tapered cross-section beam with a normalization so that ψ(*L*) = 1.^[@ref6]^ The dimensions and the tapering degree of the nanowire are determined by high-resolution scanning electron microscopy images of the particular nanowire under test ([Figure S3](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf) provides further details about the quantification of tapering). For the theoretical estimation of *S*~R~(*r*~0~, θ~0~, ω) from the calculated *S*~*i*~(ω) by the application of [eq [2](#eq2){ref-type="disp-formula"}](#eq2){ref-type="disp-formula"}, the reflected light intensity gradient considered is obtained by derivation of the experimental measurement of reflected light intensity vs the relative nanowire--laser beam position. The relative position of the laser beam with respect the lower- and upper-frequency vibration axes is determined by previously obtaining the amplitude maps presented in [Figure [2](#fig2){ref-type="fig"}](#fig2){ref-type="fig"}b,c. Remarkably, the experiment--theory agreement is excellent, validating our description of the transduction mechanism.
[Equation [2](#eq2){ref-type="disp-formula"}](#eq2){ref-type="disp-formula"} allows the estimation of the tip displacement and the displacement detection limit in length units. For the same nanowire considered in [Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}, a thermomechanical spectrum converted into pm/Hz^1/2^ units is shown in [Figure S4](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf), revealing a detection limit of 27 pm/Hz^1/2^ for a laser power of 16.8 μW. This value is well below the PSD peak amplitude obtained, around 0.9 nm/Hz^1/2^, which implies an RMS amplitude of 3.5 nm for the actual tip displacement. Lower detection limits down to the order of 1 pm/Hz^1/2^ were obtained for shorter nanowires by maximizing optical power (typically up to 350 μW) and increasing the numerical aperture (N.A.) of the objective (up to 0.55), which provides a larger optical gradient but a less uniform laser beam cross-section along the nanowire. Optical power is limited by the onset of back-action effects, and a uniform laser beam cross-section is preferred for a precise application of our model, which does not consider variations of the beam shape along the NW. For all the nanowire sizes considered in this work the displacement detection limit achieved was always at least 1 order of magnitude lower than the thermal noise amplitude at resonance, allowing for a clean detection of the fundamental flexural mode doublet of the nanowires without external driving. [Table S1](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf) presents examples of the parameters measured for the different nanowire sizes considered in this work, including PSD peak amplitude and RMS amplitude estimations.
The high sensitivity and stability of the transduction scheme presented in this work allow the characterization of the resonant response of the Si NW resonators considered as a model system in their full dynamic range and for flexural modes of higher order than the fundamental. Examples are presented in [Figure [4](#fig4){ref-type="fig"}](#fig4){ref-type="fig"} for a nanowire of the longest type. [Figure [4](#fig4){ref-type="fig"}](#fig4){ref-type="fig"}a shows the upper and lower resonance peaks of the fundamental mode driven by a piezoelectric actuator with increasing voltage amplitude, from the undriven resonance to the onset of the nonlinear regime. This set of measurements demonstrates that no amplitude saturation or frequency shift effects limit the acquisition of the resonant response of the nanowires in their full dynamic range. Moreover, the graphs show that the nonlinear regime becomes available, showing a right-shift of the upper part of the resonance peaks. Such stiffening of the frequency response is a general intrinsic behavior of single-clamp beam resonators produced by geometrical nonlinearities, which appear when large deformations induce a nonlinear relation between strain and curvature and introduce a cubic restoring force in the equation of motion.^[@ref34],[@ref35]^ We estimate a nanowire tip RMS amplitude of 1.12 μm at the onset of this nonlinear response. The capacity of the transduction mechanism to provide access to this nonlinear regime enables applications based on the singular dynamics of nanomechanical resonators in this regime.^[@ref11],[@ref36],[@ref37]^ The behavior of the peak amplitudes of the lower- and upper-frequency doublet components as a function of the piezo voltage driving amplitude is plotted in [Figure [4](#fig4){ref-type="fig"}](#fig4){ref-type="fig"}b. The amplitude of both peaks shows a linear dependence with the driving amplitude in a range up to around 300 mV of driving voltage, resulting in a dynamic range of around 50 dB. Shorter nanowires showed a slightly higher dynamic range up to around 60 dB, consistent with the theoretically expected behavior for nanowire resonators.^[@ref38]^ In [Figure [4](#fig4){ref-type="fig"}](#fig4){ref-type="fig"}c--g, we represent the upper and lower resonance peaks of the doublets from the fundamental to the fifth order flexural modes of a Si NW resonator driven just below the onset of the nonlinear regime. The experimental values of the resonance frequencies for all mode orders are in good agreement with the theoretical values derived from Euler--Bernoulli elastic beam theory for tapered beams, previously reported for the first two mode orders,^[@ref6]^ and extended here up to the fifth order (see [Tables S2 and S3 and Figure S3](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf) of the Supporting Information). It is noteworthy that the signal-to-noise ratio (SNR, ratio of the peak amplitude to the background level of the spectra) is excellent for all mode orders, allowing for plotting the measured amplitudes as a function of the relative nanowire--laser beam position for each mode order (shown as insets in each figure). These plots reveal the relative orientations of the nanowire vibrations in the lower and upper components of each mode order doublet, showing that the orientation remains approximately the same regardless of the mode order. The deviations observed, particularly for the third order, are attributed to the presence of structural defects that may happen at the positions of maximum strain for this particular mode. This is supported by the observation that different nanowires show a different behavior to this respect. Some nanowires show the same orientation for all mode order doublets, while others show deviations at a particular mode order which varies from nanowire to nanowire as a consequence of the random distribution of defects along their lengths.
). All resonance spectra were measured at θ~0~ = 0° for the lower peak and θ~0~ = 90° for the upper peak. All amplitude maps are 20 × 20 μm^2^ with a *Z*-range equivalent to the vertical axis of the corresponding resonance spectra.](nl9b04909_0004){#fig4}
Besides the relative nanowire--laser beam position, the optical power of the laser beam is another key factor for the optimization of the transduction performance. [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"} presents the influence of optical power on the sensitivity and noise performance of the transduction mechanism. Thermomechanical spectra obtained at different values of the optical power are presented in [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"}a. The optical power values used span almost 2 orders of magnitude (from 0.4 to 17.7 μW), and the effect of this variation is clearly visible in the evolution of the resonance peak represented, corresponding to the lower component of the fundamental mode doublet of an undriven nanowire. As the optical power increases, two main effects are observed: the signal amplitude increases, and the resonance frequency is shifted to higher values. [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"}b represents the signal amplitude at resonance vs the optical power, revealing a linear increase. This dependence is given by the effect of the increase of the incident optical power on the reflected power dip observed when varying the relative nanowire--laser beam position ([Figure [3](#fig3){ref-type="fig"}](#fig3){ref-type="fig"}a,b): a higher incident power implies a steeper reflected power dip and, thus, a larger reflected power gradient which ultimately determines sensitivity, as expressed in [eq [2](#eq2){ref-type="disp-formula"}](#eq2){ref-type="disp-formula"}. However, the signal-to-noise ratio (SNR), plotted in [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"}c, shows a slight deviation from a linear dependence, which is attributed to the effect of the optical power on the background noise level given by the laser source shot noise. [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"}d shows the dependence of the relative frequency shift with the optical power, which shows a nonlinear monotonic increase. Such dependence is attributed to the complex balance of forces acting on the nanowire resonators as a consequence of their exposure to the laser beam, which includes thermoelastic forces (arising from both the Young's modulus dependence on the temperature^[@ref17],[@ref39]^ and thermal expansion effects^[@ref40]^) and optical forces (provided by attractive gradient forces^[@ref41]^ as well as radiation pressure effects^[@ref42]^). [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"}e represents the evolution of the quality factor vs the optical power. The results reveal an asymptotic decrease from slightly higher values at lower optical power that decrease around a 30% to a constant value at higher optical power. This dependence is attributed to an overestimation of *Q* in the noisier spectra obtained at lower optical power. As the SNR improves for increasing power, the estimation of *Q* stabilizes at a constant value independent of the optical power. Finally, [Figure [5](#fig5){ref-type="fig"}](#fig5){ref-type="fig"}f,g presents the analysis of the frequency stability as a function of the optical power. The lowest Allan deviation achieved (Δ*f*/*f* = 2 × 10^--7^) is obtained at the maximum optical power (17.4 μW) for an acquisition time of 1 ms. These values are comparable to those obtained for other silicon nanoresonators.^[@ref43]^ There are two main implications of the observed effects of the optical power: first, a larger optical power implies higher sensitivity and better noise performance in the range considered; and second, the transduction mechanism does not imply any significant back-action effect between the laser beam and the nanowire vibration in the range of optical power considered. The upper limit of the optical power for linear transduction performance optimization is in fact limited by the appearance of back-action effects, which were not observed at optical power values below 75 μW for the longest nanowires and below 350 μW for the shortest.
{#fig5}
The main conclusions of this work can be summarized in three points. First, the flexural mode vibrations of vertically aligned semiconductor nanowires can be read out by a transduction mechanism based on the nanowire vibration-induced modulation of the reflected optical power from a laser beam with parallel incidence. Second, the main performance characteristics of this transduction mechanism are its high sensitivity and its linearity, demonstrated here by its application for detecting flexural mode doublet vibrations of vertical Si NWs in their full dynamic range, high mode orders, and with a detection limit below their thermomechanical vibrations. Finally, in contrast to all transduction schemes reported so far for semiconductor nanowires, this transduction mechanism requires neither any particular geometry or array pattern for the nanowires nor their positioning in specific supporting structures or close to driving/biasing electrodes, so that the only fabrication process involved is the generation of the nanowires themselves. The availability of such a transduction mechanism can be extremely useful for improving or extending already existing applications and also to stimulate the development of new ones by the absence of the constraints and limitations imposed by specific nanofabrication processes. In particular, a universal transduction scheme for vertical nanowires becomes singularly significant when considering the increasing interest of these nanostructures for biological applications. The interactions between vertical nanowire arrays and cells, bacteria, and several types of biomolecules have been the focus of many works related to the development of substrates with enhanced functionalities regarding cell adhesion/motility,^[@ref44]−[@ref47]^ biomolecular transfection,^[@ref48]−[@ref50]^ characterization of cell forces,^[@ref51]−[@ref56]^ bacterial recognition/proliferation,^[@ref57],[@ref58]^ and biomolecular detection/analysis.^[@ref59],[@ref60]^ The transduction scheme presented in this work, which adds the nanomechanical sensing functionalities of vertical SCNW resonators to this field, opens new research and technology lines including the measurement, tracking, and analysis of nanomechanical properties (vectorial forces, mass, stiffness, viscoelasticity, etc.) of small cells, bacteria, or large biomolecules adsorbed or adjacent to the nanowires.
The Supporting Information is available free of charge at [https://pubs.acs.org/doi/10.1021/acs.nanolett.9b04909](https://pubs.acs.org/doi/10.1021/acs.nanolett.9b04909?goto=supporting-info).Additional scanning electron microscopy images, 2D finite element simulations, determination of tapering degree of Si nanowires from SEM images, experiment--theory comparison of higher-order to fundamental mode resonance frequency ratios, estimation of displacement detection limit, representative examples of the measured dimensions and dynamic parameters for the fundamental mode of the three types of nanowires considered as a model system, equations for calculating resonance frequencies, full experiment--theory comparison of resonance frequencies for flexural modes from fundamental to 5th order ([PDF](http://pubs.acs.org/doi/suppl/10.1021/acs.nanolett.9b04909/suppl_file/nl9b04909_si_001.pdf))
Supplementary Material
======================
######
nl9b04909_si_001.pdf
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
This work was supported by the ERC CoG Grant 681275 "LIQUIDMASS" and by the Spanish Science, Innovation and Universities Ministry through project "EXOFLUX" (ref: PGC2018-101762-B-I00). We acknowledge the service from the Micro and Nanofabrication Laboratory at IMN-CNM, funded by the Comunidad de Madrid (Project S2018/NMT-4291 TEC2SPACE) and by MINECO (Project CSIC13-4E-1794 with support from FEDER, FSE). E.G.S. acknowledges financial support by Fundación General CSIC (Programa ComFuturo), as well as Marie-Sklodowska Curie Actions (H2020-MSCA-IF-2015) under NOMBIS project (703354). We acknowledge partial open access support by CSIC through URICI initiative.
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Convert m/h to mph by entering the meters per hour value in the calculator form.
1 meters per hour (m/h) is equal to 0.000621 miles per hour (mph).
We calculate the base unit of speed equivalent of meters per hour and Miles per hour with the unit factor of meter per second (m/s). | https://www.speedconversion.net/meters-per-hour-to-miles-per-hour-converter |
The invention provides an oxygen cylinder compartment which is formed by five rectangular thin plates by splicing. The long sides of the wall panels B, C are equal to the long sides of the wall panelA (1), and the short sides of the two panels are shorter than the short sides of the panel A (1); the long sides of the panels D, E are equal and shorter than the short sides of the panel A (2); the two long sides of the panel A (1) are respectively aligned at an angle to one of the long sides of the panel B and the panel C, and the two panels are located on the same side of the panel A (1); a short side of the wall panel A (1) is spliced at an angle with a long side of the wall panel D (4), wherein the wall panel D (4) is located on the same side of the wall panels B and C; the other long side of the wall panel D (4) is aligned with the long side of the wall panel E (5) at an angle such that the panel E (5) and the panel A (1) are arranged at a 90 DEG angle; a plurality of reinforcing grooves are arranged on the wall panel A (1). The oxygen cylinder compartment provided by the invention ensures that the strength of the oxygen cylinder compartment is qualified, and the rivet connectionfacilitates the splicing of the wall panel. | |
Health information technologies (IT) hold tremendous promise for improving care and outcomes. However, measuring these improvements is difficult and there is much debate about how health IT projects should be treated from an evaluation perspective.
Improved safety and quality of care are the compelling reasons behind investments in information technology (IT) systems in the healthcare sector. The seminal studies in this area are the Institute of Medicine reports of 1999 to 2001, which pointed to IT systems as an essential tool in preventing adverse events and improving use of evidence-based practice. However, evaluating IT systems to demonstrate improvements in quality and safety remains extraordinarily difficult, and there is currently much debate about exactly how these systems should be treated from an evaluation perspective. Should they be studied in the same way as health technologies and drugs with the aim of producing ‘robust scientific evidence’ for their adoption? (1) This often appears to be what funders of such systems require in order to continue their investment, but is it feasible? Or are alternative approaches required?
These questions are currently being explored at Montreal’s McGill University Health Centre (MUHC) as it undertakes a major redevelopment project in tandem with a vast expansion of health IT capabilities. This paper was developed through a discussion among some key players supporting the evaluation of IS-IT projects at the MUHC, from Quality, Risk and Performance, which is responsible for providing support in quality and performance improvements initiatives, from Information Services, and from the Transition Support Office (TSO). The TSO was created in 2008 as a project management office to support the harmonization and optimization of clinical and administrative practices, provide dedicated support for projects linked to the redevelopment, and support the evaluation of these projects, including implementation of IS-IT systems.
A framework for evaluation
In the evaluation of IT projects, DeLone and McLean’s (1992) widely used framework (2) includes three groups of factors that characterize whether a system is successful: the inherent quality of the system and the clinical information it produces; the system’s uptake by users and its perceived usefulness in supporting clinical practice; and the system’s impact on patient outcomes.
The discussion for this paper focused on the challenges of evaluating IT projects on each of these counts. The interrelation between system design, user uptake and outcomes requires increased collaboration between different groups in the hospital to set project objectives that are meaningful for all parties, select evaluation methods and metrics in consequence, and ensure follow-up on findings.
Aligning technological and clinical evaluation objectives
The MUHC has completed the display phase of the deployment of its clinical information system, and begun the data entry phases. The metrics captured to date focus on user-friendliness and processes, but clinically relevant metrics are also being measured. In the Allergy module of the MUHC’s clinical information system, for example, the proportion of patients with documented allergy status and the rate of incident reports per patient day were measured along with metrics regarding user satisfaction.
There is growing interest in linking data from different information systems to provide outcome measures that will support clinical and organizational decision-making. Since IT systems provide timely access to point-of-care clinical data, they can also be expected to improve the quality and safety of care. For example, once it becomes possible to see immediately that a patient has a positive C. difficile test and intervene promptly, outcomes for nosocomial infections should improve. The time between the completion of laboratory tests and the initiation of a prescription can serve as a metric to track, measure and improve practices.
Sequencing evaluation projects
In cases where clinical processes are being optimized and IT systems are being introduced, it can be difficult to decide on the order in which to introduce changes and conduct evaluations. Should process optimization come first and the IT tool be implemented subsequently? In a project such as optimizing operating room processes, it may be better to work on both initiatives at the same time, as the IT system provides a tool with which to measure the impact of process changes.
Evaluation methods
Evaluations are conducted using a number of methods, from data extraction to time-and-motion observational studies, to audits and chart reviews. The preferred, and least costly, method is to extract information from databases in order to capture clinical events as they occur and link this information to the administrative databases. In the absence of extractable information from databases, more resource-intensive data collection methods, such as observation, are required.
The MUHC generates and stores an enormous amount of information and is currently developing a system that will ensure the interoperability of these databases. The growing collaboration between clinical groups, administrators and departments such as Information Services. Finance and Quality and Performance, will create the organizational capability to conduct evaluations that support decision-making. This speaks to advantages of building in-house expertise rather than relying on external consultants for evaluation.
The MUHC is establishing common evaluation practices and tools for use by the TSO and Quality, Risk and Performance office. Evaluations on a particular indicator will always employ the same metrics and the same source of information on those metrics. The metrics chosen to measure performance on different indicators should be ones where norms and benchmarks are established in the literature so that the institution can define reasonable goals.
Setting objectives
During the evaluation phase of a project to implement a new information system, it is important to have a clearly articulated objective, find the right metrics to assess progress toward that objective, and define the right moment to take the pre- and post-measurements. However, people find it very difficult, especially with IT systems, to state their objectives in implementing a given system. The focus falls very naturally on the ‘how’ rather than the ‘why’. The involvement of IS-IT specialists and the long and arduous process of assuring uptake by clinicians can focus assessment too narrowly on the technical aspect of the adoption and less on the clinical perspective. It is essential to help people articulate the ‘why’ and restate and revise it as needed throughout the project implementation and evaluation period.
Ongoing evaluation
IT systems are designed with input from people who are familiar with organizational needs to make sure that the information required to monitor performance on a given indicator is valid and can be extracted. The MUHC is now defining rules to see Quality, Risk and Performance involved from the start of IT projects.
Implementing new IT systems allows for the harmonization of definitions and data entry. Once this is done and people are trained, these systems will provide real-time analysis of care processes and alert personnel automatically when a step is missing or a time lag is too long, whether treatment conforms to best practices, or if there were avoidable side effects. For myocardial infarction, for example, the time of arrival at the ER is recorded, as is the time of angioplasty and whether there was a readmission within 30 days. This information can easily be extracted, can help the organization identify opportunities for improvement in the way patients with myocardial infarction are treated, and assess whether these improvement initiatives are effective.
Actionable indicators
The results of IT system evaluations are of interest to a number of different parties: Ministry of Health, hospital administration, project leaders and managers, and clinicians. Each level is able to act on a different indicator to contribute to a same overall goal and it is important to tailor results of an evaluation to each.
Results need to be presented in different ways to different audiences. The Operations Committee may be interested in the number of users of an IT system: Which clinicians? How many patients now have accurate and complete data recorded? Clinician groups want to hear about outcome improvements obtained through documentation. Administration, which provides the funds necessary to complete the project, wants evidence of efficacy and cost-effectiveness gains. Results need to be presented to the people who can act on them to bring about improvements.
An IT system evaluation team may look at five different indicators for different reasons, but it is important to include a few that are able to convince clinicians that proper and generalized use of the system will change care and outcomes. For example, if clinicians see that use of an electronic prescription system enables their patients to be started on antibiotics four hours earlier, that will encourage use.
When does evaluation stop?
The literature is clear on the fact that unless you provide feedback, changes will not be lasting.(3) To perpetuate a change, measurement must be ongoing. The correct measurement interval will depend on the nature of the project. There will likely be educational and training components that continue on from the original project to assure that new personnel are equipped to use a system.
The complexity of its management structure makes the health sector an especially difficult place in which to bring about change.(4) Professionals working in the health sector can present obstacles to change unless they are invested in the process. In this context, a change process encompasses the actions, reactions and interactions of various elements in the organization that enable it to move from one state to another.(5-7) Evaluation, communication of results and clear accountability for acting on them nurture a culture of continuous IT-enabled improvement.
References:
1. Greenlagh, Trisha and Russell, Jill. (2010). Why do Evaluations of eHealth Programs Fail? And alternative set of guiding principles. PLoS Medicine, 7(11).
2. DeLone, W.H., and McLean, E.R. (1992). “Information Systems Success: The Quest for the Dependent Varia-ble,” Informa-tion Systems Research (3:1), 60-95.
3. Ferlie, E. & Shortell, S. M. (2001). Improving the quality of health care in the United Kingdom and United States: A framework for change. The Milbank Quarterly, 79, 281-315.
4. Glouberman, S. & Zimmerman, B. (2002). Complicated and complex systems: What would a successful reform of Medi-care look like? Discussion paper no. 8, Commission on the Future of Health Care in Canada. Ottawa: Government of Canada.
5. McNulty, T. & Ferlie, E. (2002). Reengineering health care: the complexities of organizational transformation. Oxford, England: Oxford University Press.
6. Pettigrew (1987). Context and action in the transformation of a firm. Journal of Manage-ment Studies, 24(6), 649-70.
7. Pettigrew, A.M., Ferlie, E., & McKee, L. (1992). Shaping Strategic Change in Large Organizations : The case of the National Health Service. New-bury Park: Sage Publications. | https://www.healthinnovationforum.org/article/from-promise-to-measurable-benefit/ |
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Put down the bow in favor of a good pickin' hand this week on Ether Game! Browse nine of our favorite pizzicato-heavy selections from this week's plucky show and enjoy some trivia as well.
Benjamin Britten (1913-1976) Simple Symphony, Op. 4: Playful Pizzicato Britten completed the Simple Symphony when he was only 20 years old, a fresh-faced graduate of the Royal College of Music in London. But the melodies are all derived from his juvenalia, the melodies from his youth, which he wrote as a prep-school boy. Each movement has an appealing and alliterative appellation, including a “Boisterous Bourée,” a “Playful Pizzicato,” a “Sentimental Sarabande,” and a “Frolicsome Finale.” The “Playful Pizzicato” has become especially popular. It makes several appearances in the 2012 film MOONRISE KINGDOM by the quirky American director Wes Anderson. Other works by Britten appear in the film as well, both diegetically and non-diegetically, including The Young Person’s Guide To The Orchestra and his children’s opera Noye’s Fludde.
Antonio Vivaldi (1678-1741) The Four Seasons: 'Winter' in f, Op. 8, No. 4, RV 297 Mvt. II Vivaldi returned to Venice in 1725 after spending a few years in Rome. This was a busy year for Vivaldi. He produced four operas, but also his most famous series of violin concerti, The Seasons. Accompanying Vivaldi’s 4 concertos are 4 corresponding sonnets, likely penned by Vivaldi himself. The sonnet for the winter concerto describes biting snow, stinging winds, and accidents on the ice. The music of the winter concerto evokes these wintertime characteristics with chilling musical effects. The pizzicato in the movement we just listened to for example, evokes the silvery “ping” of icy rain during some more gentle wintery weather. In the final movement however, this gives way to a swirling snow storm, and it’s back to the bow for musical figures that evoke rolling snow drifts and intense cold.
Maurice Ravel (1875-1937) String Quartet in F, Mvmt. II Ravel showed great promise as a concert pianist in his youth, so it was a surprise when he decided to devote himself to composition. His early works were written for piano, however it wasn’t until he wrote his string quartet in F at the age of 27 that he gained public attention. Dedicated to his teacher, Gabriel Fauré, the string quartet was simultaneously popular with the public but also controversial. When Ravel submitted the first movement for a composition prize at the Paris Conservatory, he was expelled from the school for the second time, the jurors thinking the work too modernist. It is likely that Ravel was inspired to write the piece after Debussy had just published his String Quartet in G minor, and indeed Debussy had much praise for his composition, telling him after its premiere, ““In the name of the gods of music, and in mine, do not change a single note of what you have written.”
Leroy Anderson (1908-1975) Plink, Plank, Plunk After graduating from Harvard in 1929, Leroy Anderson stuck around Cambridge, to teach at Radcliffe College and direct the marching band, prior to striking out on his own as a freelance composer. During World War II, Anderson worked as a SPY. After the war, despite having been presented with the opportunity to stay in the intelligence business, he chose to return to composing. With famous pieces such as Clarinet Candy and Trumpeter’s Lulliby, one might think that Anderson favored the wind section, but he also enjoyed writing for string ensembles and using the pizzicato technique. At least two of his works feature pizzicato extensively: Jazz Pizzicato and it’s sequel, which we just heard, Plink Plank Plunk. Funnily enough for such a popular composer, Anderson was not great at predicting the success of his own music. He assumed that Plink Plank Plunk would be a major hit after releasing it on his Blue However, this was overshadowed by Sleigh Ride, which still remains Anderson’s most popular music.
Léo Delibes (1836-1891) Sylvia: Pizzicati These days, Leo Delibes’ opera Lakme tends to be the only work by the composer that is continuously performed, especially the famous “Flower Duet” as a standalone piece. However in his time, Delibes’ operettas and ballets were very popular, especially in Paris, where his works were often staged beside Offenbach’s in the same theatre. Sylvia, Delibes’ ballet adaptation of a 1573 play by Torquato Tasso, may seem like a typical classical ballet with its setting in Greek mythology and its portrayal of the love affairs between nymphs and shepherds. However the music was considered quite revolutionary at its time of composition. The score does not play a subservient role to the action on stage, but is rather treated more symphonically with developed leitmotifs and full instrumental textures. The music of the ballet calls for a larger brass section, and in fact is one of the first known uses of the alto saxophone in classical music. By contrast, certain themes are also performed in a very light and halting manner, such as this Pizzicati from the third act, which is one of the most famous interludes from the ballet.
Gabriel Fauré (1845-1924) Impromptu No. 6, Op. 86 Students of the Paris Conservatory were required to participate in juried exams at the end of every academic year, a practice which continues to this day. Called les concours in French, they generally followed the same format. A piece from the standard repertoire was announced two months before the exam, as well as a commissioned piece by a contemporary composer which students had to prepare in a month. Faurés 6th Impromptu for harp is one such piece, commissioned for les concours in great secrecy. There is somewhat of a scandal concerning this piece, however. It is an open secret that after accepting the commission, Fauré became overwhelmed with other professional obligations and began to realize he would not finish the piece by the deadline. He likely gave what he had started to his close friend Alphonse Hasselmans, one of the founders of French harp technique, who completed the composition. Regardless of who wrote the piece, it’s well known that it was finished so close to the deadline that there was no time to print it, and students had to come to Hasselmans’ Paris apartment and copy the piece by hand in order to be able to prepare it for the exam.
Sylvius Leopold Weiss (1686-1750) Ouverture in B-flat We just heard music for one of the earliest and most popular plucked instruments in Western music, the lute. Even though it is often associated with the Renaissance, the lute was at forefront of classical music in various forms through the 19th century, until it was overtaken by the more versatile guitar. German lutenist and composer Silvius Leopold Weiss spent most of his life working as a court musician. He worked mostly in Dresden, but spent a fair amount of time in Rome as well. He was one of the most prolific composers of his day, writing some 1000 pieces for the lute, most of which were solo sonatas. Weiss was also a technical master on the lute. A contemporary of J. S. Bach, the two technical masters managed to meet once in Dresden, thanks to the help of Bach’s eldest son Wilhelm Friedrich. According to a later account by composer Johann Friedrich Reichardt, when J. S. Bach and Silvius Weiss met, the two entered into a friendly competition to see who was better at improvising counterpoint on their respective instruments.
Vivian Fung (b.1973) Pizzicato for String Quartet Although “Pizzicato” is the 3rd movement of the String Quartet No. 1 by Canadian composer Vivian Fung, it is also performed as a standalone piece, as with this recording by the MCP Quartet. The piece is inspired by elements of Asian folk music, specifically the rhythmic energy of Indonesian gamelan, while the quartet’s pizzicato technique evokes the plucked instrumental music of the Chinese pipa and the Guqin, an ancient seven string zither. As a Chinese-Canadian, Fung often turns to her Chinese roots in crafting a style that has been described by NPR as today’s most eclectic classical music. Much of her music since 2012 is inspired by travels to visit minority groups in China’s Yunnan province.
Toumani Diabate and Bela Fleck Bomako The kora is a traditional African stringed instrument with 21 strings, kind of like a cross between a harp and a lyre with a large gourd resonator. It is a favorite among griots, who were traveling court musicians in north and west Africa charged with keeping the oral history of noble family lines. Playing the kora involves gripping two handguards connected to a bridge and plucking the strings with the forefingers and thumbs. Kora accompaniment to vocal movement often consists of polyrhythmic patterns, and instrumental improvisation in modes. Though not the first to record an album of kora music, Toumani Diabate’s intense participation in the world music scene has put the kora front and center in Malian music. He has had countless successful cross-cultural performances with other musicians, such as this live recording collaboration with Bela Fleck on the banjo, which also shares African roots. | https://indianapublicmedia.org/ethergame/ether-game-pizzicato.php |
Space Research Institute of the Russian Academy of Sciences (IKI)
Founded in 1965 (Government Resolution from May 15, 1965), then within the Academy of Sciences of the USSR.
Appointed principal organisation for robotic space research and exploration in the Academy of Sciences, thus complementing manned space program.
IKI designs and builds scientific instruments for space experiments, acts as principal organization for various scientific space projects and missions, and uses the data of space probes to deepen our understanding of space and Earth.
IKI acronym comes from Russian “Institut Kosmicheskih Issledovanyi”, which is Space Research Institute, and is used in English as is.
In 1986, IKI was awarded with the Order of Lenin for significant contribution to science and technology development, after successful implementation of VEGA mission to study Venus and comet Halley.
Academician Professor Lev Zelenyi heads IKI from 2002. | https://www.spacebizguide.com/organization/577-space-research-institute-of-the-russian-academy-of-sciences-iki |
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims the benefit of priority of U.S. Provisional Patent Application No. 62/933,686, filed on Nov. 11, 2019 which is incorporated herein by reference in its entirety.
BACKGROUND
I. Technical Field
II. Background Information
The present disclosure relates generally to the field of image processing for medical purposes. More specifically, the present disclosure relates to systems, methods, and devices for using image analysis for medical examination of skin features.
Computer vision may be used in medical testing to determine quantitative and qualitative clinical data. Traditionally, regulatory-approved clinical devices use dedicated hardware such as pre-calibrated scanners that operate in well-known and monitored capturing and illumination conditions, together with classifiers that operate based on the calibrated images derived by the scanners.
In recent years, smartphones have become personal mobile computers with high processing power, wireless Internet access, and high-resolution image capturing capabilities. However, turning a smartphone into a regulatory-approved clinical device is challenging for at least three main reasons. First, there may be a lack of quality uniformity of the smartphones' cameras. This can occur for a number of reasons, including the fact that the settings and imaging of each brand and model of smartphone may differ from one to the next. Even within a particular model, there may be slight variations in acquired images. Second, when using smartphones across a host of non-uniformly lit environments, local illumination conditions can lead to varying results. Third, the smartphones are typically operated by unqualified users that may have difficulties following strict medical operation procedures.
The disclosed embodiments are directed to providing new and improved ways for using personal communications devices for medical examination of skin features.
SUMMARY
Embodiments consistent with the present disclosure provide systems, methods, and devices for capturing and analyzing images for medical examination of skin features. Consistent with the disclosed embodiments, an exemplary system may receive multiple images depicting a skin feature with multiple segments of differing colors captured during a period of time. The exemplary system may determine the condition of the skin feature and provide a recommendation for continued treatment of the skin feature.
In one embodiment, a computer program product, containing instructions that when executed by at least one processor, is provided. The instructions may cause the at least one processor to carry out a method for conducting image processing of skin features. The method may include receiving, from at least one image sensor associated with a mobile communications device, a first image of the skin feature, the skin feature having multiple segments of differing colors and differing sizes; storing in at least one memory device data associated with the first image for later processing; receiving from the at least one image sensor associated with the mobile communications device a second image of the skin feature, wherein the second image is captured at least a day after the first image is captured; retrieving from the at least one memory device data associated with the first image; analyzing the retrieved data and data associated with the second image to determine a condition of the skin feature based on changes over time of the multiple segments; determining, based on the determined condition of the skin feature, at least one medical action for treating the skin feature during a time period; and causing the mobile communications device to display information indicative of the determined at least one medical action based on the changes over time of the multiple segments.
In one embodiment, a computer program product containing instructions that when executed by at least one processor is provided. The instructions may cause the at least one processor to carry out a method for conducting image processing of wound images. The method may include receiving a first image of a wound of a patient, wherein the first image is captured at an outset of a medical treatment; storing in at least one memory device data associated with the first image for later processing; receiving a second image of the wound of the patient, wherein the second image is captured at least a day after applying the medical treatment to the wound; retrieving, from the at least one memory device, data associated with the first image; analyzing the retrieved data and data associated with the second image to determine a condition of the wound; determining at least one action to alter the medical treatment based on the condition of the wound; and initiating a remedial measure associated with the at least one action to increase effectiveness of the medical treatment.
Consistent with other disclosed embodiments, systems and processing devices are configured to execute the methods described herein.
The foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate various disclosed embodiments. In the drawings:
FIG. 1
is a schematic illustration of an example system that uses image data captured by mobile communications devices for medical testing, consistent with the present disclosure.
FIG. 2
FIG. 1
is a block diagram illustrating some of the components of the system of , consistent with the present disclosure.
FIG. 3
is a schematic illustration of how the system calibrates the colors of two images captured at different times, consistent with the present disclosure.
FIG. 4
is a schematic illustration of using a smartphone to examine a wound, consistent with the present disclosure.
FIG. 5
FIG. 1
is a schematic diagram showing an example timeline illustrating how the system of may be used for monitoring and treating a skin feature using image processing, consistent with the present disclosure.
FIG. 6
is a block diagram of software modules configured to perform one or more operations, consistent with the disclosed embodiments.
FIG. 7
is a flow chart illustrating an example process for monitoring and treating a skin feature using image processing, consistent with the present disclosure.
FIG. 8A
shows screenshots illustrating an example graphical user interface (GUI) for displaying information indicative of determined medical action, consistent with the disclosed embodiments.
FIG. 8B
shows additional screenshots illustrating another example GUI for displaying information indicative of determined medical action, consistent with the disclosed embodiments.
FIG. 9
is a flowchart of a process for conducting image processing of skin features, consistent with the present disclosure.
FIG. 10
is a flowchart of a process for conducting image processing of wound images, consistent with the present disclosure.
DETAILED DESCRIPTION
The following detailed description refers to the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the following description to refer to the same or similar parts. While several illustrative embodiments are described herein, modifications, adaptations and other implementations are possible. For example, substitutions, additions, or modifications may be made to the components illustrated in the drawings, and the illustrative methods described herein may be modified by substituting, reordering, removing, or adding steps to the disclosed methods. Accordingly, the following detailed description is not limited to the disclosed embodiments and examples but is inclusive of general principles described herein in addition to the general principles encompassed by the appended claims.
The present disclosure is directed to systems and methods for processing images captured by an image sensor. As used herein, the term “image sensor” refers to any device capable of detecting and converting optical signals in the near-infrared, infrared, visible, and ultraviolet spectrums into electrical signals. Examples of image sensors may include digital cameras, phone cameras, semiconductor charge-coupled devices (CCD), active pixel sensors in complementary metal-oxide-semiconductor (CMOS), or N-type metal-oxide-semiconductor (NMOS, Live MOS). The electrical signals may be used to generate image data. Consistent with the present disclosure, the image data may include pixel data streams, digital images, digital video streams, data derived from captured images, and data that may be used to construct a 3D image. The image data acquired by the image sensor may be transmitted by wired or wireless transmission to a remote server.
Consistent with the present disclosure, the image sensor may be part of a camera included in a mobile communications device. The term “mobile communications device” refers to any portable device with image capturing capabilities that can communicate with a remote server over a wireless network. Examples of mobile communications devices include smartphones, tablets, smartwatches, smart glasses, wearable sensors and other wearable devices, wireless communication chipsets, user equipment (UE), personal digital assistants, and any other portable pieces of communications equipment. It is noted that the terms “handheld mobile communications device,” “handheld mobile device,” “mobile communications device,” and “mobile device” may be used interchangeably herein and may refer to any of the variety of devices listed above.
FIG. 4
Embodiments of the present disclosure further include analyzing images to identify a colorized surface in proximity to a medical analysis region. As used herein, the term “colorized surface” may broadly refer to any surface having planar or nonplanar properties. The colorized surface may cover or encapsulate at least a portion of a 2D object (such as a sheet of paper) or at least a portion of a 3D object (such as a box or a body part). The colorized surface may include a plurality of reference elements for enabling light and color calibration. In some embodiments, the colorized surface may be printed on a sticker or a plaster (e.g., adhesive bandage), for example, the colorized surface illustrated in . In other embodiments, the colorized surface may be printed or otherwise presented on a board, cardstock, plastic or any other medium adapted to serve as a reference. The image correction enabled by the colorized surface may be used to enable a color correction of an image of skin feature depicted in the image. In some embodiments, the skin feature may be skin or other tissue or anatomical feature, and the medical analysis region may include any part of the patient's body depicted in the image.
Consistent with the present disclosure, the colorized surface may enable processing of the image to determine the colors of the skin feature, irrespective of local illumination conditions and/or capturing parameters. The term “irrespective of local illumination conditions and/or capturing parameters” refers to the output of an image analysis process in which the suggested system rectifies the colors of the skin feature to remove at least some effects of local illumination, remove at least some effects of capturing parameters, or remove at least some effects of local illumination and at least some effects of capturing parameters. Effects of local illumination conditions to be removed, may include one or more of reflections, shades, light temperature (e.g., soft white, cool white, daylight), and any other condition that may impact the detection of the skin feature color. Effects of capturing parameters to be removed, may include one or more of image resolution, frame rate, gain, ISO speed, stereo base, focus, zoom, color correction profile, exposure time, shutter speed, aperture settings, ISO, distance from skin feature, angle to skin feature, and more. The removal of effects of the local illumination conditions and the effects of capturing parameters may be important to accurately determine the changes of the skin feature over time. For example, changes of the colors of an examined wound may determine its condition and its healing progress.
In some embodiments, an image correction factor may be generated based on the determined local illumination conditions and/or image capturing parameters. The image correction factor may be used to remove one or more local illumination variations and to determine illumination invariant colors of the skin feature. The image correction factor may be used to remove image capturing process effects to determine capturing process invariant colors of the skin feature. In one example, the illumination invariant colors may be used to determine a condition of the skin feature, such as a state of a wound. In another example, the invariant colors may be used to determine a condition of a tissue, such as skin, oral mucosa, nasal mucosa, and so forth. In an additional example, the invariant colors may be used to determine properties of biological material, such as a stool sample, a urine sample, a phlegm sample, a blood sample, a wax sample, and so forth.
The term “confidence level” refers to any indication, numeric or otherwise, of a level (e.g., within a predetermined range) indicative of an amount of confidence the system has that the determined colors of the skin feature are the colors of the skin feature irrespective of local illumination conditions and/or image capturing settings effects. For example, the confidence level may have a value between 1 and 10. Alternatively, the confidence level may be expressed as a percentage or any other numerical or non-numerical indication. In some cases, the system may compare the confidence level to a threshold. The term “threshold” as used herein denotes a reference value, a level, a point, or a range of values. In operation, when a confidence level of a measurement exceeds a threshold (or below it, depending on a particular use case), the system may follow a first course of action and, when the confidence level is below it (or above it, depending on a particular use case), the system may follow a second course of action. The value of the threshold may be predetermined for each type of skin feature or may be dynamically selected based on different considerations.
FIG. 1
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Reference is now made to , which shows an example of a system that uses image analysis to complete a medical examination. System may be computer-based and may include computer system components, desktop computers, workstations, tablets, handheld computing devices, memory devices, and/or internal network(s) connecting the components. System may include or be connected to various network computing resources (e.g., servers, routers, switches, network connections, storage devices, etc.) for supporting services provided by system .
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Consistent with the present disclosure, system may enable user to complete a medical examination. In addition, system may enable a medical practitioner to participate in the medical examination using a mobile communications device . The disclosure below that describes the functionalities of mobile communications device similarly describes the functionalities of mobile communications device . In one embodiment, medical practitioner may be a nurse that captures images of a skin feature associated with user . In another embodiment, medical practitioner may be a physician of user who receives the results of the medical examination. In the example illustrated in , user may use mobile communications device to capture an image that includes a colorized surface and a skin feature . Image data associated with image may be directed (e.g., via a wired connection) or transmitted to a medical analysis unit for medical testing (directly or via a communication network). Medical analysis unit may include a server coupled to one or more physical or virtual storage devices such as a data structure . System may also include or be connected to a communications network that facilitates communications and data exchange between different system components and the different entities associated with system , such as, healthcare provider , insurance company , and pharmacy .
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According to embodiments of the present disclosure, medical analysis unit may exchange data with a variety of communication devices associated with the different entities associated with system . The term “communication device” is intended to include all possible types of devices capable of exchanging data using communications network . In some examples, the communication device may include a smartphone, a tablet, a mobile station, a personal digital assistant, a desktop, a laptop, an IoT device, a dedicated terminal, a server, a cloud, and any other device that enables data communications. In one implementation, medical analysis unit may receive image data from mobile communications device and cause mobile communications device to provide user with data derived from analysis of skin feature . In another implementation, medical analysis unit may transmit data to a communications device of healthcare provider for updating an electronic medical record (EMR) of user stored in data structure . In another implementation, medical analysis unit may receive information from a communications device of insurance company . The received information may identify a group of individuals associated with a first insurance status. Thereafter, medical analysis unit may initiate medical examinations to determine if there is a likelihood that the group of individuals is entitled to a second insurance status different from the first insurance status. In yet another implementation, medical analysis unit may transmit a result derived from image data captured by mobile communications device .
Embodiments of the present disclosure may include access, or otherwise utilize one or more data structures, such as a database. As used herein, the term “data structure” may include any collection of data values and relationships among them. The data may be stored linearly, horizontally, hierarchically, relationally, non-relationally, uni-dimensionally, multidimensionally, operationally, in an ordered manner, in an unordered manner, in an object-oriented manner, in a centralized manner, in a decentralized manner, in a distributed manner, in a custom manner, or in any manner enabling data access. By way of non-limiting examples, data structures may include an array, an associative array, a linked list, a binary tree, a balanced tree, a heap, a stack, a queue, a set, a hash table, a record, a tagged union, ER model, and a graph. For example, a data structure may include an XML data structure, an RDBMS data structure, an SQL data structure or NoSQL alternatives for data storage/search such as, for example, MongoDB, Redis, Couchbase, Datastax Enterprise Graph, Elastic Search, Splunk, SoIr, Cassandra, Amazon DynamoDB, Scylla, HBase, SharePoint, Sybase, Oracle and Neo4J. Data structures, where suitable, may also include document management systems. A data structure may be a component of the disclosed system or a remote computing component (e.g., a cloud-based data structure). Data in the data structure may be stored in contiguous or non-contiguous memory. Moreover, a data structure, as used herein, does not require information to be co-located. It may be distributed across multiple servers, for example, that may be owned or operated by the same or different entities. Thus, the term “data structure” as used herein in the singular is inclusive of plural data structures.
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Consistent with the present disclosure, server may access data structure to determine, for example, specific chromatic properties associated with colorized surface at the time of printing of the colorized surface . Data structure and data structure may utilize a volatile or non-volatile, magnetic, semiconductor, tape, optical, removable, non-removable, other type of storage device or tangible or non-transitory computer-readable medium, or any medium or mechanism for storing information. Data structure (and data structure mutatis mutandis) may be part of server or separate from server as shown. When data structure is not part of server , server may exchange data with data structure via a communication link. Data structure may include one or more memory devices that store data and instructions used to perform one or more features of the disclosed embodiments. In one embodiment, data structure may include any a plurality of suitable data structures, ranging from small data structures hosted on a workstation to large data structures distributed among data centers. Data structure may also include any combination of one or more data structures controlled by memory controller devices (e.g., server(s), etc.) or software.
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Consistent with the present disclosure, communications network may be any type of network (including infrastructure) that supports communications, exchanges information, and/or facilitates the exchange of information between the components of system . For example, communications network may include or be part of the Internet, a Local Area Network, wireless network (e.g., a Wi-Fi/302.11 network), or other suitable connections. In other embodiments, one or more components of system may communicate directly through dedicated communication links, such as, for example, a telephone network, an extranet, an intranet, the Internet, satellite communications, off-line communications, wireless communications, transponder communications, a local area network (LAN), a wide area network (WAN), a virtual private network (VPN), or any other mechanism or combinations of mechanism that enable data transmission.
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The components and arrangements of system shown in are intended to be exemplary only and are not intended to limit the disclosed embodiments, as the system components used to implement the disclosed processes and features may vary.
FIG. 2
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is an exemplary block diagram of configurations of server and mobile communications device . In one embodiment, server and mobile communications device directly or indirectly accesses a bus (or other communication mechanism) that interconnects subsystems and components for transferring information within server and/or mobile communications device . For example, bus may interconnect a processing device , a memory interface , a network interface , a peripherals interface connected to I/O system , and power source .
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Processing device , shown in , may include at least one processor configured to execute computer programs, applications, methods, processes, or other software to perform embodiments described in the present disclosure. For example, the processing device may include one or more integrated circuits, microchips, microcontrollers, microprocessors, all or part of a central processing unit (CPU), graphics processing unit (GPU), digital signal processor (DSP), field programmable gate array (FPGA), or other circuits suitable for executing instructions or performing logic operations. The processing device may include at least one processor configured to perform functions of the disclosed methods such as, for example, a microprocessor manufactured by Intel™. The processing device may include a single core or multiple core processors executing parallel processes simultaneously. In one example, the processing device may be a single core processor configured with virtual processing technologies. The processing device may implement virtual machine technologies or other technologies to provide the ability to execute, control, run, manipulate, store, etc., multiple software processes, applications, programs, etc. In another example, the processing device may include a multiple-core processor arrangement (e.g., dual, quad core, etc.) configured to provide parallel processing functionalities to allow a device associated with the processing device to execute multiple processes simultaneously. It is appreciated that other types of processor arrangements could be implemented to provide the capabilities disclosed herein.
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In some embodiments, processing device may use memory interface to access data and a software product stored on a memory device or a non-transitory computer-readable medium. For example, server may use memory interface to access data structure . As used herein, a non-transitory computer-readable storage medium refers to any type of physical memory on which information or data readable by at least one processor can be stored. Examples include random access memory (RAM), read-only memory (ROM), volatile memory, nonvolatile memory, hard drives, CD ROMs, DVDs, flash drives, disks, any other optical data storage medium, any physical medium with patterns of holes, a RAM, a PROM, and EPROM, a FLASH-EPROM or any other flash memory, NVRAM, a cache, a register, any other memory chip or cartridge, and networked versions of the same. The terms “memory” and “computer-readable storage medium” may refer to multiple structures, such as a plurality of memories or computer-readable storage mediums located within mobile communications device , server , or at a remote location. Additionally, one or more computer-readable storage mediums can be utilized in implementing a computer-implemented method. The term “computer-readable storage medium” should be understood to include tangible items and exclude carrier waves and transient signals.
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Both mobile communications device and server may include network interface coupled to bus . Network interface may provide two-way data communications to a network, such as network . In , the wireless communication between mobile communications device and server is represented by a dashed arrow. In one embodiment, network interface may include an integrated services digital network (ISDN) card, cellular modem, satellite modem, or a modem to provide a data communication connection over the Internet. As another example, network interface may include a wireless local area network (WLAN) card. In another embodiment, network interface may include an Ethernet port connected to radio frequency receivers and transmitters and/or optical (e.g., infrared) receivers and transmitters. The specific design and implementation of network interface may depend on the communications network(s) over which mobile communications device and server are intended to operate. For example, in some embodiments, mobile communications device may include network interface designed to operate over a GSM network, a GPRS network, an EDGE network, a Wi-Fi or WiMAX network, and a Bluetooth® network. In any such implementation, network interface may be configured to send and receive electrical, electromagnetic, or optical signals that carry digital data streams representing various types of information.
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Both mobile communications device and server may also include peripherals interface coupled to bus . Peripherals interface may be connected to sensors, devices, and subsystems to facilitate multiple functionalities. In one embodiment, peripherals interface may be connected to I/O system configured to receive signals or input from devices and to provide signals or output to one or more devices that allow data to be received and/or transmitted by mobile communications device and server . In one example, I/O system may include a touch screen controller , audio controller , and/or other input controller(s) . Touch screen controller may be coupled to a touch screen . Touch screen and touch screen controller may, for example, detect contact, movement or break thereof using any of a plurality of touch sensitivity technologies, including, but not limited to, capacitive, resistive, infrared, and surface acoustic wave technologies as well as other proximity sensor arrays or other elements for determining one or more points of contact with the touch screen . Touch screen may also, for example, be used to implement virtual or soft buttons and/or a keyboard. While a touch screen is shown in , I/O system may include a display screen (e.g., CRT or LCD) in place of touch screen . Audio controller may be coupled to a microphone and a speaker to facilitate voice-enabled functions, such as voice recognition, voice replication, digital recording, and telephony functions. The other input controller(s) may be coupled to other input/control devices , such as one or more buttons, rocker switches, thumbwheel, infrared port, USB port, and/or a pointer device such as a stylus.
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With regard to mobile communications device , peripherals interface may also be connected to an image sensor , a motion sensor , a light sensor , and/or a proximity sensor to facilitate image capturing, orientation, lighting, and proximity functions. Other sensors (not shown) may also be connected to the peripherals interface , such as a temperature sensor, a biometric sensor, or other sensing devices to facilitate related functionalities. In addition, a GPS receiver may also be integrated with, or connected to, mobile communications device , such as GPS receivers typically integrated into mobile communications devices. Alternatively, GPS software may permit a mobile communications device to access an external GPS receiver (e.g., connecting via a serial port or Bluetooth).
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Consistent with the present disclosure, mobile communications device may use memory interface to access memory device . Memory device may include high-speed random-access memory and/or non-volatile memory such as one or more magnetic disk storage devices, one or more optical storage devices, and/or flash memory (e.g., NAND, NOR). Memory device may store an operating system instructions , such as DARWIN, RTXC, LINUX, iOS, UNIX, OSX, WINDOWS, or an embedded operating system such as VxWorks. The operating system may include instructions for handling basic system services and for performing hardware-dependent tasks. In some implementations, the operating system may be a kernel (e.g., UNIX kernel).
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Memory device may also store communication instructions to facilitate communicating with one or more additional devices, one or more computers and/or one or more servers. Memory device may include: graphical user interface instructions to facilitate graphic user interface processing; sensor processing instructions to facilitate sensor-related processing and functions; phone instructions to facilitate phone-related processes and functions; electronic messaging instructions to facilitate electronic-messaging related processes and functions; web browsing instructions to facilitate web browsing-related processes and functions; media processing instructions to facilitate media processing-related processes and functions; GPS/navigation instructions to facilitate GPS and navigation-related processes and instructions; capturing instructions to facilitate processes and functions related to image sensor ; and/or other software instructions to facilitate other processes and functions. Memory device may also include application specific instructions to facilitate a process for guiding user on the steps of the medical testing. For example, application specific instructions may cause display of a massage indicative of image insufficiency for medical testing.
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Each of the above identified instructions and applications may correspond to a set of instructions for performing one or more functions described above. These instructions need not be implemented as separate software programs, procedures, or modules. Memory device may include additional instructions or fewer instructions. Furthermore, various functions of mobile communications device may be implemented in hardware and/or in software, including in one or more signal processing and/or application specific integrated circuits. For example, mobile communications device may execute an image processing algorithm to identify the colors and sizes of segments of an examined skin feature in a received image. In addition, the components and arrangements shown in are not intended to limit the disclosed embodiments. As will be appreciated by a person skilled in the art having the benefit of this disclosure, numerous variations and/or modifications may be made to the depicted configuration of server . For example, not all components may be essential for the operation of server in all cases. Any component may be located in any appropriate part of server , and the components may be rearranged into a variety of configurations while providing the functionality of the disclosed embodiments. For example, some servers may not include all of the elements in I/O system .
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Consistent with the present disclosure, system may be used to monitor the visual appearance of skin feature . For example, system may provide two-dimensional measurements of different sections of skin feature associated with a same color, such as size and shape characteristics (symmetry, boundary length, etc.). In some embodiments, system may track skin feature parameters over time by repeatedly capturing the same skin feature over time. In this regard, colorized surface may assist in determining variations over time. In one example, skin feature may include scar tissue or a rash that may be monitored daily to track healing progress. In another example, skin feature may be captured weekly or even monthly for monitoring potentially cancerous features or developments. When collecting such data over a period of time, an additional step may be added for verifying that the correction of image is consistent across the time period in which the data was collected. Correcting image may further include taking into account illumination conditions and capturing parameters associated with previously captured images. Additional details on colorized surface , which may be used for monitoring the condition of skin feature , are described in Applicant's U.S. Pat. No. 10,362,984, which is incorporated herein by reference in its entirety.
FIG. 3
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As mentioned above, one of the challenges of turning a smartphone into a regulatory-approved clinical device is the lack of uniformity of image capture capabilities of smartphones. illustrates the general case of two communication devices capturing the same skin feature at different times. In the illustrated example, on Sunday, when a first mobile communications device A captures skin feature in proximity to a first colorized surface A, a first image A is acquired; and on Wednesday, when a second mobile communications device captures skin feature in proximity to a second colorized surface , a second image is acquired. Other than the illustrated differences between first image A and second image B (i.e., skin feature had shrunken and the colorized surfaces have different orientations), first image A may vary from second image due to differences between the incorporated image sensors, differences in lighting conditions from light sources, differences in image sensor settings, and more. For example, first image A may be different from second image because first mobile communications device A has different white balance settings and different color correction profiles than second mobile communications device . The white balance settings may be associated with how each of the communication devices determines the white point for the image and if any tint should be applied to the other colors. The color correction profile may be associated with how communication devices process color saturation, black levels, highlights, and the contrast of colors in the image. In another example, first image A may be different from second image because first mobile communications device A has different hardware (such as image sensor resolution, dimensions, filters, color filters, lenses, crop factor, sensitivity, and so forth). In yet another example, first image A may be different from second image because first mobile communications device A has different camera configuration (such as exposure time, shutter speed, aperture, ISO, and so forth).
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Consistent with the present disclosure, each of image A and image may undergo an image correction process . Image correction process may include one or more steps to remove (or to compensate for) local illumination effects and image capturing settings effects. The local illumination effects may result from the type of light source used to light the skin feature, the distance of the skin feature from the light source, a viewing angle of the skin feature, position of the skin feature, ambient light conditions, flash usage, exposure time, and so forth. The image capturing settings effects may result from the type of image sensor used to capture the skin feature, image resolution, frame rate, gain, ISO, shutter speed, stereo base, lens, focus, zoom, color correction profile, and so forth. In some embodiments of the disclosure, correcting captured image may include reversing any of the tone mapping, color enhancement, white balance, and contrast enhancing of image . In addition, correcting image may include simulating standard illumination conditions and reducing shading and specular effects. A person skilled in the art would recognize that even if images A and were captured by a same communication device , image correction process may still need to take place in order to remove undesired effects and to accurately determine the condition of skin feature .
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In one embodiment, image correction process may be enabled through the use of colorized surface . Specifically, the qualities of the one or more color patches on colorized surface may be known in advance. To the extent differences are detected between the colors of colorized surface A and the colors of colorized surface , the system may calculate a correction factor for rectifying such differences, and then apply that correction factor to the colors of skin feature .
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Image correction process may correct each of first image A and second image , correct only one of the images, correct only selected areas of first image A, or correct only selected areas of second image . For example, image correction process may include increasing the red color in first image A and adding brightness to second image . After images A and undergo image correction process , system may determine results from the changes between first image A and second image . In accordance with the present disclosure, image correction process ensures that results reflect only the visual changes of skin feature that occurred naturally over time and devoid of visual changes of skin feature that occurred artificially due to different illumination effects and capturing effects. In one embodiment, image correction process can ensure the reliability of results because both images captured the same type of colorized surface whose colorization is known in advance, and which may be used as a basis for generating different correction factors for the varying differences. In some embodiments, system may correct first image A and/or second image using metadata associated with the mobile communications device that captured the image. In other embodiments, system may correct captured image without using any information about the mobile communications device that captured image . In one example, system may calculate one or more convolutions of pixels of first image A and/or of second image , and may use the calculated one or more convolutions of the pixels to correct first image A and/or second image respectively. In one example, a machine learning model may be trained using training examples to remove local illumination effects from images, and system may use the trained machine learning model to correct first image A and/or second image . An example of a training example may include a pair of example images, including a first example image of a scene with varying illumination conditions, and a second example image of the same scene with desired illumination conditions and/or after removal of the local illumination effects from the first example image.
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Consistent with the present disclosure, system may use results to monitor the visual appearance of skin feature over time. For example, system may identify skin feature parameters in each of the images. The skin feature parameters may include: two dimensional measurements of different segments of skin feature associated with a same color, such as size and shape characteristics (symmetry, boundary length, etc.). Thereafter, system may track the changes of the skin feature parameters over time. In one example, skin feature may include scar tissue or a rash that may be monitored daily to track healing progress. In another example, skin feature may be captured weekly or even monthly for monitoring potentially cancerous features or developments. When collecting such data over a period of time, an additional step may be added for verifying that the correction of the captured images is consistent across the time period in which the data was collected. Correcting second image may further include taking into account illumination conditions and capturing parameters associated with first image A. Additional details on techniques and algorithms included in image correction process which may be used for correcting the colors of skin feature are described in Applicant's U.S. Pat. No. 10,362,984, which is incorporated herein by reference in its entirety.
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depicts one exemplary embodiment where skin feature is a wound that patient may have. In this embodiment, system is configured to measure the distribution of colors of wound by comparing them to the colors on colorized surface . The colors on colorized surface may be selected to include an at least some of the expected range of colors of the examined skin feature under various illumination and capturing conditions. It may also include a range of colors from which a correction factor may be generated. As illustrated in , colorized surface may include a plurality of colored reference elements and may be attachable onto a skin area next to wound . In certain embodiments, colorized surface may have different forms adapted to a medical condition of patient , the specific skin tone of patient , or an expected form and characteristics of wound . In addition, colorized surface may have different forms adapted to the expected capturing parameters (e.g., to capturing geometry). For example, colorized surface may be round, elongated, curved, have one or more openings therein to accommodate wound , etc.
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Consistent with the present disclosure, colorized surface may have one or more colored reference elements used for calibrating illumination and capturing conditions rather than or in addition to relating to colored reference elements associated with the expected colors in wound . When wound and colorized surface are captured in a single image, system may determine the true colors of captured wound by correcting image using image correction process described above. For example, medical analysis unit may compute the color constancy of wound to determine whether two pixels have the same color in the real world, regardless of illumination conditions and/or camera parameters. In some embodiments, colorized surface may also include one or more positioning marks that may be used for image processing purposes and/or for positioning colorized surface (and for positioning other elements of colorized surface , such as colored reference elements ) accurately with respect to wound . Moreover, positioning marks may provide a reference of a known dimension that may be used to estimate a size, orientation, and/or a form of wound . In certain embodiments, positioning marks of colorized surface may be used (e.g., by medical analysis unit ) to correct captured image with respect to its dimensions and forms and to derive an analysis of size and/or form of wound and possibly of other skin features.
FIG. 5
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is a diagram showing an example timeline illustrating how system may be used for monitoring and treating skin feature using image processing. The manner and order in which events are shown in timeline is chosen for convenience and clarity of presentation and is not intended to limit the disclosed embodiments. Instead, the proper chronological relationship between events shown in timeline depends on the application and is defined by the appended claims. In particular, the time difference between two consecutive events in timeline may be a short time interval of only a few moments or be a relative long-time interval of several hours and even days. Moreover, timeline illustrates only two incidences where images of skin feature are captured and processed by medical analysis unit ; however, a person skilled in the art would recognize that more images than two may be captured and process during a long period of time.
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Consistent with the present disclosure, first image A may be captured at time T and second image may be captured at time T. In the illustrated example, the time difference between T and T is about a week, yet in other cases the time difference between T and T may be more than an hour and less than a day, more than a day and less than a month, more than two days, more than four days, more than a week and less than a year, more than a month, more than six months, more than a year. In addition, although first image A may be captured at different times both images may be received by medical analysis unit at the same time, e.g., subsequent to T. In some embodiments, second image may be captured at least a day after first image A is captured. For example, first image A may be captured at the outset of a medical treatment to skin feature and second image may be captured at least a day after applying the medical treatment to skin feature .
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At time T, medical analysis unit may analyze data associated with first image A and second image to determine a condition of skin feature . Additionally or alternatively, medical analysis unit may analyze data associated with first image A at a time between T and T. Consistent with the present disclosure, skin feature may have multiple segments of differing colors and differing sizes and the determination of the condition of skin feature may be based on changes over time of segments . Specifically, each image may be stored and analyzed individually to determine image data associated with the captured images. The image data may include values of various parameters such as distribution of colors of segments , one or more geometric parameters (e.g., form, border, symmetry, two- or three-dimensional form), dimensions (e.g., size or height), and more. In one embodiment, medical analysis unit may be configured to determine values of any of the above-mentioned parameters and their combinations from the first and second images. In an alternative embodiment, the values of any of the above-mentioned parameters and their combinations may be determined by mobile communication device . Thereafter, medical analysis unit may analyze the image data (e.g., the images themselves or the values of any of the above-mentioned parameters) to track changes in distribution of colors of segments and/or the rate of changes of any skin feature parameters over time, by comparing the image data associated with first image A and the image data associated with second image . In the illustrated example, the changes of the multiple segments of skin feature between first image A and second image can be seen by naked eyes; however, in many cases the changes may be so subtle that only a trained neural network configured to identify the segments of skin features may be able to detect changes. In one embodiment, when first image A is captured at the outset of a medical treatment and second image is captured at least a day after applying the medical treatment, medical analysis unit may also calculate the level of effectiveness of the medical treatment to determine if it is above or below a threshold.
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Consistent with the present disclosure, medical analysis unit may determine, based on the condition of skin feature , at least one medical action for monitoring or treating the skin feature. The determined medical action may be intended to increase effectiveness of the medical treatment (e.g., applying a medicine to the skin feature over a treatment period) or to monitor the condition of the skin feature (e.g., determining a time for examining the skin feature by the medical professional). In some embodiments, medical analysis unit may determine when medical action needs to take place. Specifically, medical analysis unit may determine time T for a starting medical action and/or time T for completing medical action . The determined times T and T define a time period for completing medical action . In a first example, medical analysis unit may determine that a medical procedure of removing dead or inflamed tissue is needed ASAP. In a second example, medical analysis unit may determine that an ultrasound and electromagnetic therapy within a month from T may assist the healing progress of skin feature . In a third example, medical analysis unit may determine that biopsy of skin feature is needed in the next two to three months. In a fourth example, medical analysis unit may determine that a visual examination of skin feature by a medical practitioner is needed at a time between nine months to a year. In a fifth example, medical analysis unit may determine that capturing a third image of skin feature is needed at least one day after second image was captured but no later than three days after second image was captured. Additionally or alternatively, medical analysis unit may determine time between T and T for a medical action , and a user may select T and/or T according to the determined time.
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At time T, information indicative of medical action and possibly information indicative of time period for completing the medical action may be provided to user (or medical practitioner ). The information may be provided visually, textually, audibly, through an external device, through a calendar event, through a scheduling system, to an external device, to a scheduling system, and so forth. In some embodiments, medical analysis unit may cause mobile communications device (or mobile communications device ) to display the determined information. One example of causing the mobile communications device to display the information indicative of medical action may include sending a notification to user (or medical practitioner ), the notification may include a link for opening an application for capturing a third image of skin feature . The notification may be issued at a time associated with time period , for example, at a predetermined time before time period starts, at time T which is the beginning of time period , at a predetermined time before time period ends, and so forth. In another example, a notification for reminding user (or medical practitioner ) to complete medical action may be provided. For example, the notification may be provided visually, textually, audibly, through an external device, to an external device, and so forth.
FIG. 6
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is a block diagram of software modules configured to perform one or more operations, consistent with the disclosed embodiments. In particular, as shown, a memory device may include a communication module , an image correction module , an image analysis module , a medical condition determination module , an action determination module , a database access module , and a database . Modules , , , , , and may contain software instructions for execution by at least one processor (e.g., processing device ) associated with system . Communication module , image correction module , image analysis module , medical condition determination module , action determination module , database access module , and database may cooperate to perform multiple operations. For example, communication module may receive multiple images of a skin feature from a mobile communications device of user , image correction module may correct the received images by removing one or more local illumination variations effects and image capturing process effects to depict calibrated colors of the skin feature, image analysis module may identify the changes in the colors and sizes of segments of the examined skin feature in the received images, medical condition determination module may determine the condition of the examined skin feature, and action determination module may determine an action for treating the skin feature (e.g., medical action ) and in some cases a time period for completing the medical action (time period ).
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In some embodiments, memory device may be part of system , for example, data structure . Alternatively, memory device may be stored in an external database or an external storage communicatively coupled with server , such as one or more databases or memories accessible over communication network . Further, in other embodiments, the components of memory device may be distributed in more than one computing device, for example, server and communication device . Specifically, in the illustrated configuration, data structure of server may include communication module and image correction module that include instructions to receive images from user and to rectify the images using image correction algorithms. But in other configurations, memory device of communication device may include image correction module for locally rectifying captured images, and communication module that resides in data structure of server may receive the already-rectified images.
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In some embodiments, communication module may receive multiple images of a skin feature from mobile communications device or mobile communications device and may cause a mobile communications device to display information indicative of the action determined by action determination module . Consistent with the present disclosure, communication module may include software instructions for facilitating communications between the device on which it is implemented (e.g., server ) and another component of system (e.g., mobile communications device , mobile communications device , and any other communication device of healthcare provider , insurance company , and pharmacy ). Communication module may enable receipt and transmission of data from and to user . For example, the received data may include two or more images, and lifestyle information of user . The transmitted data may be associated with actions associated with the condition of the skin feature.
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FIG. 3
In some embodiments, image correction module may remove local illumination variations effects and image capturing effects from the images received by communication module . Consistent with the present disclosure, image correction module may include software instructions for using the colored reference set of colorized surface depicted in the received images to identify local illumination conditions and image capturing settings. Thereafter, image correction module may use image correction algorithms (e.g., image correction process ) to rectify the first and second images to enable determining the colors of the skin feature, irrespective of local illumination conditions and irrespective of image capturing settings. With reference to the embodiment illustrated in , when correcting first image A, image correction module may determine chromatic properties of the colored reference set of colorized surface A, by directly analyzing first image A itself, and/or by examining data containing chromatic property information of colorized surface A. This data may be included within metadata of the image or may be accessed by reading a machine-readable code (e.g., a scannable code attached to colorized surface A). Based on the determined local illumination conditions, chromatic properties, and/or based on the image capturing parameters, image correction module may correct the image. Image correction may physically alter an image, or it may simply occur through calculations without a physical alteration of the image. Some disclosed embodiments may include using the colored reference elements to determine the local illumination conditions and separately rectifying colors of the multiple segments of the skin feature based on the local illumination conditions. For example, if the light quality causes a specific misperception of the known color reference elements, then the correction necessary for the color reference elements may be applied to a skin feature, thereby correcting a color of at least one segment of the skin feature. Some examples of techniques for such correction of the image are described above.
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In some embodiments, image analysis module may identify the changes of the examined skin feature in the images corrected by image correction module . Consistent with the present disclosure, image analysis module may include software instructions for conducting edge identification, in which an image is analyzed to detect pixels at which discontinuities (e.g., sudden changes in color) occur, and edges (e.g., edges of segments of a skin feature) are identified to coincide with the detected pixels. Alternatively or additionally, in some embodiments analyzing the corrected images may involve identifying in and/or extracting from an image pixels representative of one or more segments of the skin feature. Pixels may be determined to be representative of segments of the skin feature based on other images of the skin feature maintained in a database and/or predetermined data describing the skin feature. Alternatively or additionally, pixels may be determined to be representative of segments of the skin feature based on a trained neural network configured to detect segments of the skin feature. Other types of analysis are possible as well, including, but not limited to, gradient matching, greyscale matching, scale-invariant feature transform (SIFT) matching, and/or interpretation trees. Image analysis module may determine changes (e.g., changes in color, changes in size, changes in shape, etc.) of the segments of the skin feature between the several corrected images, e.g., between first image A and second image .
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In some embodiments, medical condition determination module may determine the condition of the examined skin feature based on the changes identified by image analysis module . Consistent with the present disclosure, medical condition determination module may include software instructions for determining the condition of the examined skin feature based on a change in appearance of the skin feature between two or more images. For example, medical condition determination module may identify that a combination of color, dimensions, shape, etc., has changed with respect to the skin feature. These changes may be associated with a particular condition of the examined skin feature. For example, medical condition determination module may determine that a size of the skin feature has shrunk and/or that a hue, value, and/or intensity of a color of at least a segment of the skin feature has changed. Based on that changes, medical condition determination module may determine a current condition and/or a predicted condition of the skin feature. In some examples, a machine learning model may be trained using training examples to determine the condition of the skin feature from pairs of images of a skin feature, and the machine learning model may be used to analyze the depiction of the skin feature in the first image and the depiction of the skin feature in the second image to determine the condition of the skin feature. In some examples, a machine learning model may be trained using training examples to determine conditions of skin features from sets of image-related information records, and the trained machine learning model may be used to analyze image-related information based on the first image (such as image A) and image-related information based on the second image (such as image B) determine the condition of the skin feature. Such training examples may include a set of three of image-related information records, a pair of images as an input and a third image captured sometime after the pair of images to show the progress of the skin feature. The training examples may also include labels indicating the condition of the skin feature, a portion of an image, color information associated with an image, and/or any other data capable of training a machine to determine the condition of a skin feature.
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In some embodiments, action determination module may determine an action for associated with the condition of the skin feature and use communication module to cause mobile communications device or mobile communications device to display information indicative of the determined action. Consistent with the present disclosure, action determination module may include software instructions for scheduling an appointment with a medical practitioner of user , generating a prescription to user , providing an indication that user may be eligible for a different insurance coverage, and more. In one embodiment, action determination module may determine an action for treating the skin feature and determine a time period for completing the action. In another embodiment, the at least one medical action includes monitoring the state of the skin feature by capturing a third image of the skin feature at least one day after the second image was captured. In another embodiment, the at least one medical action includes altering a medical treatment.
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In some embodiments, database access module may cooperate with database to retrieve stored reference data such as an electronic medical record (EMR) of user and medical data associated with the type of skin feature . Medical condition determination module may use the reference data stored in database to determine the condition of the skin feature. Database may include separate databases, including, for example, a vector database, raster database, tile database, viewport database, and/or a user input database, configured to store data. The data stored in database may be received from modules -, server , or from any communication device associated with system . Moreover, the data stored in database may be provided as input using data entry, data transfer, or data uploading.
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Modules - may be implemented in software, hardware, firmware, a mix of any of those, or the like. For example, if the modules are implemented in software, the modules may be stored in a server (e.g., server ) or distributed over a plurality of servers. In some embodiments, any one or more of modules - and data associated with database may be stored in data structure and/or located on server , which may include one or more processing devices. Processing devices of server may be configured to execute the instructions of modules -. In some embodiments, aspects of modules - may include software, hardware, or firmware instructions (or a combination thereof) executable by one or more processors, alone, or in various combinations with each other. For example, modules - may be configured to interact with each other and/or other modules of server to perform functions consistent with disclosed embodiments.
FIG. 7
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depicts a flowchart of an example process executed by a processing device of system (e.g., processing device ) for conducting image processing of skin features. Process begins when the processing device receives from at least one image sensor (e.g., image sensor ) associated with a mobile communications device (e.g., mobile communications device ) an image of the skin feature (step ). Thereafter, the processing device may store in at least one memory (e.g., memory device or data structure ) data associated with the image for later processing (step ). Thereafter, the processing device determines if the received image is the first image of the skin feature (decision step ). When the received image is indeed the first image, process repeats steps and to receive a second image. The time duration between the receipt of the first image and the receipt of the second image may depend on the application and may be longer than a day, longer than a week, longer than a month, and so forth. When the received image is the second image or any subsequent image, the processing device may retrieve the most recent image and at least one previous image (step ). In one embodiment, the processing device may retrieve only two images to determine the condition of the skin feature. In another embodiment, the processing device may retrieve more than two images to determine the condition of the skin feature. Then, the processing device may correct the retrieved images (step ) to remove local illumination effects, image capturing settings effects, or a combination thereof (e.g., using image correction process ). Thereafter, the processing device may analyze the corrected images to determine the condition of the skin feature (step ).
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Process may be utilized according to two aspects of the disclosure. In the first aspect of the disclosure, the processing device may determine, based on the condition of the skin feature, an action for monitoring or treating the skin feature and a time period for completing the action. In the second aspect of the disclosure, the processing device may determine, based on the condition of the skin feature, an action to alter a medical treatment determined to be ineffective. Accordingly, process includes determining if the skin feature is being medically treated (decision step ). The determination whether skin feature is undergoing any medical treatment may be based on information manually provided from user or from medical practitioner . Alternatively, the determination whether the skin feature is being medically treated may be based on information retrieved by the processing device from the user's electronic medical record (EMR). In some embodiments, the first image may be captured at the outset of a medical treatment and the second image may be captured at least a day after applying the medical treatment to the skin feature.
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In case the processing device determined that the skin feature is being medically treated, process may include determining the effectiveness level of the medical treatment (step ). As discussed in great detail below, a machine learning model may be trained using training examples to determine the effectiveness level of the medical treatment. Thereafter, the processing device may determine if the level of effectiveness of the medical treatment is below a threshold (decision step ). When the processing device determines that the level of effectiveness of the medical treatment is below a threshold, process may include determining an action to alter the medical treatment (step ). The determined action to alter the medical treatment may be based on the condition of the skin feature and the level of effectiveness of the medical treatment. Then, the processing device may initiate a measure associated with the determined action (step ).
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FIGS. 8A and 8B
In some embodiments, (e.g., in case the processing device determines that the skin feature is not being medically treated, in case the processing device determines that the skin feature is being medically treated but the effectiveness level of the medical treatment is above the threshold, in case it is requested by a user, and so forth), process may include determining a medical action to monitor the skin feature (step ). In some embodiments, the determination of the medical action may be based on the condition of the skin feature determined in step . Additionally, the determination of the medical action may include a determination of a time period for completing the medical action. For example, the determined medical action may include capturing a third image of the skin feature within a time window of twelve hours starting two days after the second image was captured. Process continues when the processing device initiates a measure associated with the determined action (step ). In one embodiment, initiating the measure may include causing a display of information indicative of the determined action. Examples of display of information indicative of the determined action are illustrated below with reference to .
FIGS. 8A and 8B
FIG. 8A
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depict four screenshots illustrating a graphical user interface (GUI) for displaying user or medical practitioner information associated with the condition of the skin feature. The screenshots are associated with a non-limiting example of an interactive application and may be displayed on mobile communications device or mobile communications device . The screenshots of are associated with the first aspect of the disclosure and depict information indicative of the medical action determined based on condition of skin feature and information indicative of the time period to complete the medical action. The screenshots of are associated with the second aspect of the disclosure and depict information indicating that altering an ongoing medical treatment is needed due to the condition of the wound.
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In the example depicted in first screenshot , the interactive application recommends user to continue monitoring the condition of skin feature by uploading another image of the skin feature to server within a seven-day time window. Specifically, as shown in the figure, the GUI of the interactive application may include a first area displaying representations of images that were used in analyzing skin feature . For example, the representations of images A and B may include thumbnails, timestamps, file names, and more. The GUI of the interactive application may further include a second area displaying a summary of the condition of skin feature . In one embodiment, the summary of the condition of skin feature may be generated by processing device using a recurrent neural network (RNN) and hierarchical hidden Markov model. The processing may determine keywords and value of parameters from the determined condition of the skin feature and may generate a written summary using deep learning algorithms and determined keywords. The GUI of the interactive application may further include a third area displaying information indicative of the determined medical action (e.g., the next event) and the determined time period to complete the medical action (e.g., next event due date). In addition, the interactive application may include an option for sending reminders to user on the next event.
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In the example depicted in second screenshot , the interactive application recommends user to visit his or her medical practitioner and access a scheduling system associated with the medical practitioner to schedule an appointment. As shown in the figure, the GUI illustrated in screenshot is similar to the GUI illustrated in screenshot , but it includes additional buttons. Specifically, next to the summary of the condition the GUI of the interactive application includes a “more” button for providing additional information on skin feature and statistics of similar types of skin features. The GUI of the interactive application may further include a “schedule” button for opening a window that enables user to pick a date for the appointment with Dr. Shepperd. The dates highlighted in the calendar are dates that Dr. Shepperd has availability in his schedule. After user has selected the date for the appointment, he or she may continue by pressing the “continue” button .
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In the example depicted in third screenshot , the interactive application requests lifestyle data from user in response to a determination that the level of effectiveness of the medical treatment is below a threshold. Processing device may compare the lifestyle data with information stored in a data structure (e.g., data structure ) to determine the at least one action to alter the medical treatment. As shown in the figure, the GUI illustrated in screenshot is similar to the GUI illustrated in screenshot , but a lifestyle questionnaire is provided before a medical action is determined. In one embodiment, the determined action to alter the medical treatment may include a recommendation to change at least one aspect of the lifestyle of user . In another embodiment, the determined action to alter the medical treatment may not be associated with the lifestyle data received from user .
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In the example depicted in fourth screenshot , the interactive application provides a recommendation to user after deciding that the action to alter the medical treatment determined in response to receipt of first and second images failed to bring the level of effectiveness of the medical treatment above the threshold. As shown in the figure, the GUI illustrated in screenshot is similar to the GUI illustrated in screenshot , but it indicates that an additional third image C was received. In the example depicted in fourth screenshot , the processing device determined another action to alter the current medical treatment based on the condition of the wound as depicted in third image C relative to second image B. In some embodiments, system may determine a plurality of medical actions to be completed during a time period. The processing device may identify a most urgent medical action out of the plurality of medical actions based on the determined condition of the skin feature and initiate a measure associated with the most urgent medical action. For example, in the illustrated example, the processing device may determine that removing inflamed tissue is more important than changing a type of wound dressing. Accordingly, the processing device causes the mobile communications device to display information associated with removing inflamed tissue.
FIG. 9
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is a flowchart of an example process for conducting image processing of skin features executed by a processing device of system , according to embodiments of the present disclosure. The processing device of system may include a processor within a mobile communications device (e.g., mobile communications devices and ) or a processor within a server (e.g., server ) remote from the mobile communications device. For purposes of illustration, in the following description, reference is made to certain components of system . It will be appreciated, however, that other implementations are possible and that any combination of components or devices may be utilized to implement the exemplary method. It will also be readily appreciated that the illustrated method can be altered to modify the order of steps, delete steps, or further include additional steps, such as steps directed to optional embodiments.
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FIG. 9
Disclosed embodiments may include “receiving from at least one image sensor associated with a mobile communications device a first image of the skin feature.” As discussed earlier, various types of image sensors/mobile communications devices may be used to capture different forms of skin features. The skin feature captured by the least one image sensor (e.g., skin feature ) may have multiple segments of differing colors and differing sizes. Consistent with the present disclosure, the first image may be captured using a mobile communications device having a plurality of image sensors. The first image and/or the image-related information based on the first image may be received at a processor, regardless of where the processor is located. By way of example only, at step in , a processing device (e.g., processing device ) may receive from at least one image sensor associated with at least one mobile communications device a first image of the skin feature.
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FIG. 9
Disclosed embodiments may further include “storing in at least one memory device data associated with the first image for later processing.” The at least one memory device may include any memory devices associated with system , for example, memory device or data structure . The data stored at the memory device may include image data associated with the first image and metadata information associated with the first image. As discussed earlier, the image data may include pixel data streams, digital images, digital video streams, data derived from captured images, and data that may be used to construct a 3D image. Consistent with the present disclosure, the image data associated with the first image may include values of parameters indicative of the colors and two/three dimensional measurements of different segments of skin feature (e.g., length, size, depth, volume, shape characteristics, and more). The metadata information may include a device identifier (e.g., based on a MAC address, IP address, port number, serial number, etc.) associated with the device that captured the first image, user identification information (a name, address, phone number, social security number, insurance number, username, medical test number, etc.), patient information, a medical condition, a wound type, information associated with a medical professional (e.g., name of a primary care physician or wound specialist), a country of residence of the user, and/or a timestamp. By way of example only, at step in , the processing device may store data associated with the first image for later processing.
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Disclosed embodiments may further include “receiving from the at least one image sensor associated with the mobile communications device a second image of the skin feature, wherein the second image is captured at least a day after the first image is captured.” As discussed earlier, the second image may be captured more than a day and less than a month after the first image was captured, more than a week and less than a year after the first image was captured, or any other time period. Consistent with the present disclosure, the first image and the second image were captured by a same mobile communications device. Alternatively, the first image was captured by a first mobile communications device and the second image was captured by a second mobile communications device. For example, during the time between capturing of the first image and capturing of the second time, user may have replaced his or her phone. By way of example only, at step in , the processing device may receive a second image of the skin feature, wherein the second image is captured at least a day after the first image is captured.
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FIG. 9
Disclosed embodiments may further include “retrieving from the at least one memory device data associated with the first image.” As discussed earlier, the processing device may use a database access module (e.g., database access module ) to retrieve data from a database. The retrieved data may include at least part of the image data associated with the first image. For example, values of parameters indicative of the colors and two/three dimensional measurements of different segments of skin feature . Due to possible progression of the skin feature (e.g., such as healing, in case the skin feature is a wound) several changes may have occurred during the time lapse from the capture of the first image to the capture of the second image, for example, the shape, the tissue composition, and/or the color of one or more of the segments may have changed. Therefore, retrieving data associated with the first image may include confirming that the retrieved data associated with the first image refers to a same skin feature depicted in the second image. For example, image analysis of retrieved image data may use location, relative size, distinct features, or other characteristics to confirm that the first image and the second image refer to the same skin feature. Additionally, comparison of metadata information, such as device identifier, may also be used to confirm that the first image and the second image refer to the same skin feature. By way of example only, at step in , the processing device may retrieve data associated with the first image.
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In optional embodiments not presented in process , each of the first image and the second image may depict the skin feature in proximity to at least one form of colorized surface (e.g., colorized surface ) having colored reference elements (e.g., colored reference elements ). In these optional embodiments, the processing device may use the at least one form of colorized surface to determine local illumination conditions (and/or image capturing settings) at a time of capture of the first image and at a time of capture of the second image. In a first example, the at least one form of colorized surface may include a printed form and wherein a same copy of the printed form appears in both the first image and the second image. In a second example, the at least one form of colorized surface may include a printed form and wherein differing copies of the printed form appears in both the first image and the second image. In a third example, the first and second images may depict differing forms of colorized surfaces with a same arrangement of colored reference elements. Consistent with these optional embodiments, the processing device may use the first image, the second image, and the determined local illumination conditions for determining the changes over time of multiple segments of the skin feature (e.g., segments ). In one example, the processing device may rectify the second image by changing a color of at least one segment of the skin feature as depicted in the second image based on the determined local illumination conditions. Then, using the first image and the rectified second image, the processing device may determine the changes over time of the multiple segments. Alternatively, the processing device may rectify the first image by changing a color of at least one segment of the skin feature as depicted in the first image based on the determined local illumination conditions. Then, in a similar manner, the processing device may use the rectified first image and the second image for determining the changes over time of the multiple segments.
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FIG. 9
Disclosed embodiments may further include “analyzing the retrieved data and data associated with the second image to determine a condition of the skin feature based on changes over time of the multiple segments.” In some examples, the skin feature may be a wound including multiple segments, and determining the condition of the skin feature may include determining a healing progress of the wound by identifying changes over time of geometrical parameters and colors of the multiple segments of the wound. The processing device may use one or more software modules (e.g., image analysis module and medical condition determination module ) that implement a machine learning model to determine the condition of the skin feature. The machine learning model may use training examples of pairs of images of skin features to analyze the depiction of the skin feature in the first image and the depiction of the skin feature in the second image to determine the condition of the skin feature. An example of such training examples may include a pair of images of a skin feature, together with a label indicating the condition of the skin feature. In some examples, a machine learning model may be trained using training examples to determine conditions of skin features from pairs of image-related information records, and the trained machine learning model may be used to analyze image-related information based on the first image (such as image A) and image-related information based on the second image (such as image B) determine the condition of the skin feature. Such training examples may include a pair of image-related information records, together with a label indicating the condition of the skin feature, a portion of an image, color information associated with an image, and/or any other data capable of training a machine to determine a condition of a skin feature. By way of example only, at step in , the processing device may analyze data associated with the first and second images to determine a condition of the skin feature based on changes over time of the multiple segments. In some embodiments, a convolution of pixels of the first image may be calculated, a convolution of pixels of the second image may be calculated, and the calculated convolution of pixels of the first image and the calculated convolution of pixels of the second image may be used to determine the condition of the skin feature. For example, a function of the calculated convolution of pixels of the first image may be compared with a function of the calculated convolution of pixels of the second image, in response to a first result of the comparison, a first condition of the skin feature may be determined, and in response to a second result of the comparison, a second condition of the skin feature may be determined, the second condition differs from the first condition.
Consistent with the present disclosure, determining the condition of the skin feature may include predicting an expected appearance (e.g., an expected color, expected size, expected shape, etc.) of the segments of the skin feature at a time of capturing the second image. Disclosed embodiments may include determining a time difference between the first image and the second image. For example, predicting an expected appearance of a skin feature may involve determining a time difference between a capture time of a first image and a capture time of a second image, which may be accomplished by determining a time lapse between image capture. For example, a processing device may determine when an image was captured by reading a timestamp associated with the received images. In cases where a timestamp is superimposed on an image, the processing device may use optical character recognition to read the timestamp. In other embodiments, such as when a timestamp is embedded into an image or attached to it within metadata information, the processing device may extract it from those sources. In some disclosed embodiments, the time difference between the first image and the second image may be determined automatically using metadata information. For example, the time difference between the first image and the second image may be determined automatically by comparing metadata associated with the first image and metadata associated with the second image.
610
912
FIG. 9
Disclosed embodiments may include further “determining, based on the determined condition of the skin feature, at least one medical action for treating the skin feature during a time period.” The processing device may use a software module (e.g., action determination module ) to determine the at least one medical action based on the changes over time of the multiple segments as reflected in the first and second images. In some embodiments, the determination may further be based on at least one of: a patient's personal medical record, demographic information associated with the patient, and treatment data associated with the skin feature. As discussed earlier, the processing device may also determine the time period for completing the at least one medical action based on the determined condition of the skin feature. The determination of the time period may be based on at least one of the capturing time of the second image (e.g., time elapsed since the capturing, time in day of the capturing, etc.), the type of the determined at least one medical action, a patient's personal medical record, demographic information associated with the patient, and treatment data associated with the skin feature. Alternatively, the processing device may receive an indication of the time period for completing the at least one medical action (e.g., the indication may be received from a medical practitioner of the patient). By way of example only, at step in , the processing device may determine, based on the condition of the skin feature, at least one medical action for treating the skin feature during a time period.
In an optional embodiment, the at least one medical action includes monitoring the condition of the skin feature by capturing a third image of the skin feature at least one day after the second image was captured. For example, the processing device may determine that the skin feature should be captured again in the next three months for monitoring potentially cancerous features or developments. In some cases, the processing device may analyze the first image and the second image to determine recommended image capturing parameters for capturing the third image of the skin feature using the at least one image sensor. For example, the processing device may determine that a flash should be avoided when capturing the third image. Thereafter, the processing may cause a configuration of the at least one image sensor according to the determined capturing parameters. In addition, the processing device may cause the mobile communications device to send a notification indicative of the determined at least one medical action to a user. The notification may include a link for opening an application for capturing the third image of the skin feature. In related embodiments, the processing may determine a time for capturing the third image and predict an appearance of the skin feature at the determined time. Upon receiving the third image of the skin feature, the processing device may determine an additional medical action for treating the skin feature and an additional time period for completing the additional medical action, based on the predicted appearance of the skin feature and an actual appearance of the skin feature as depicted in the third image.
914
FIG. 9
Disclosed embodiments may further include “causing the mobile communications device to display information indicative of the determined at least one medical action.” In some cases, the at least one medical action includes treating the skin feature by applying a medicine to the skin feature. In these cases the processing device may cause the mobile communications device to issue a plurality of reminders to apply the medicine to the skin feature over a treatment period extending at least three days after capture of the second image. Additionally, the processing device may cause the mobile communications device to issue a first notification at an outset of the time period and to issue a second notification at a later time during the time period. In one example, the first notification may be identical to the second notification. Alternatively, the first notification may differ from the second notification. As discussed above, causing the mobile communications device to display information indicative of the determined medical action may be one of the measures associated with the determined action initiated by the processing device. Other measures may include updating an electronic medical record of the user, informing that the user is entitled to a different insurance status, schedule an appointment with a medical practitioner, and more. For example, the processing device may access a scheduling system associated with a medical practitioner of a patient having the skin feature to schedule an appointment with the medical practitioner. In this example, the processing device may cause the mobile communications device to cause a display of an addition of a calendar event for the at least one medical action at a date of the scheduled appointment. By way of example only, at step in , the processing device may cause the mobile communications device to display information indicative of the determined at least one medical action.
FIG. 9
In optional embodiments not depicted in , the processing device may determine that the at least one medical action was not completed during the time period. Thereafter, the processing device may determine an additional medical action for treating the skin feature and an additional time period for completing the additional medical action. The additional medical action may be the same as the original medical action or different from the original medical action. In some cases, the determination of the additional medical action may be based on the time passed since the capturing of the second image, may be based on the at least one medical action, may be based on the determined time period, may be based on the determined condition of the skin feature and so forth. Similarly, the determination of the additional time period for completing the additional medical action may be based on the additional medical action, may be based on the time passed since the capturing of the second image, may be based on the at least one medical action, may be based on the determined condition of the skin feature and so forth. In other embodiments, the processing device may determine a plurality of medical actions to be completed during the determined time period. The processing device may identify a most urgent medical action out of the plurality of medical actions based on the determined condition of the skin feature and initiate a measure associated with the most urgent medical action. For example, the processing device may cause the mobile communications device to display information indicative of the most urgent medical action.
902
906
FIG. 10
Consistent with the present disclosure, the first image received in step may be captured before a medical treatment was applied to the skin feature, and the second image of the skin feature received in step may be captured after the medical treatment was applied to the skin feature. In this case, the processing device may determine to alter the medical treatment. For example, the processing device may determine an effectiveness level of the medical treatment by comparing image data associated with changes between the first image and the second image. When effectiveness level is below a threshold, the processing device may determine that at least one medical action for altering the medical treatment needs to be taken. Additional details on this embodiment are discussed below with reference to .
FIG. 10
1000
100
100
115
125
145
100
is a flowchart of an example process for conducting image processing of wound images executed by a processing device of system , according to embodiments of the present disclosure. The processing device of system may include a processor within a mobile communications device (e.g., mobile communications devices and ) or a processor within a server (e.g., server ) remote from the mobile communications device. For purposes of illustration, in the following description, reference is made to certain components of system . It will be appreciated, however, that other implementations are possible and that any combination of components or devices may be utilized to implement the exemplary method. It will also be readily appreciated that the illustrated method can be altered to modify the order of steps, delete steps, or further include additional steps, such as steps directed to optional embodiments.
130
1002
202
FIG. 10
Disclosed embodiments may include “receiving a first image of a wound of a patient, wherein the first image is captured at an outset of a medical treatment.” As discussed earlier, various types of image sensors/mobile communications devices may be used to capture different types of wounds. The first image of the wound (e.g., image A) may be captured at an outset of a medical treatment. As a person skilled in the art would recognize, a medical treatment may include multiple steps and/or multiple stages. Accordingly, the term “the first image is captured at an outset of a medical treatment” may mean that the first image was captured before any step of the medical treatment was initiated (or completed) or before a given step of the medical treatment was initiated (or completed). For example, the medical treatment may include applying a first ointment on the skin feature for 5 days and then applying a second ointment on the skin feature once or twice a day for 1 to 2 weeks. In the foregoing example, the first image may be captured before the first ointment was applied on the skin feature or before the second ointment was applied on the skin feature. By way of example only, at step in , a processing device (e.g., processing device ) may receive a first image of a wound of a patient, wherein the first image is captured at an outset of a medical treatment.
904
1004
110
110
1006
FIG. 10
FIG. 10
As discussed above with reference to step , disclosed embodiments may further include “storing in at least one memory device data associated with the first image for later processing.” The data stored in the at least one memory device may include image data and metadata information. Accordingly, at step in , the processing device may store data associated with the first image for later processing. Disclosed embodiments may further include “receiving a second image of the wound of the patient, wherein the second image is captured at least a day after applying the medical treatment to the wound.” As discussed above, the second image may be captured more than a day and less than a month after applying the medical treatment to the wound, more than three days and less than two weeks after applying the medical treatment to the wound, more than a week and less than a year after applying the medical treatment to the wound, or any other time period. Consistent with the present disclosure, the first image and the second image were captured by a same mobile communications device. Alternatively, the first image was captured by a first mobile communications device, and the second image was captured by a second mobile communications device. For example, the first image was captured by a medical practitioner of user (e.g., before treating and dressing the wound), and the second image was captured by user at his or her home. By way of example only, at step in , the processing device may receive a second image of the wound of the patient, wherein the second image is captured at least a day after applying the medical treatment to the wound.
908
1008
132
FIG. 10
As discussed above with reference to step , disclosed embodiments may further include “retrieving from the at least one memory device, data associated with the first image.” The data retrieved from the at least one memory device may include at least part of the image data associated with the first image and/or at least part of the metadata information associated with the first image. Accordingly, at step in , the processing device may retrieve data associated with the first image. In some embodiments, each of the first image and the second image may depict the wound in proximity to at least one form of colorized surface having colored reference elements. In these optional embodiments, the processing device may use the at least one form of colorized surface (e.g., colorized surface ) to determine local illumination conditions at a time of capture of the first image and at a time of capture of the second image. In a first example, the at least one form of colorized surface may include a printed form and wherein a same copy of the printed form appears in both the first image and the second image. In a second example, the at least one form of colorized surface may include a printed form and wherein differing copies of the printed form appears in both the first image and the second image. In a third example, the first and second images may depict differing forms of colorized surfaces with a same arrangement of colored reference elements. Consistent with these optional embodiments, the processing device may use the first image, the second image and the determined local illumination conditions for determining the changes over time of multiple segments of the wound. In one example, the processing device may rectify the second image by changing a color of at least one segment of the wound as depicted in the second image based on the determined local illumination conditions. Then, using the first image and the rectified second image the processing device may determine the changes over time of the multiple segments of the wound. Alternatively, the processing device may rectify the first image by changing a color of at least one segment of the wound as depicted in the first image based on the determined local illumination conditions. Then, in a similar manner, the processing device may use the rectified first image and the second image for determining the changes over time of the multiple segments.
910
1010
FIG. 10
Also, as discussed above with reference to step , disclosed embodiments may further include “analyzing the retrieved data and data associated with the second image to determine a condition of the wound.” In one embodiment, analyzing the retrieved data and the data associated with the second image to determine the condition of the wound may include performing comparative image processing to confirm that a same wound was captured in the first image and the second image and detecting wound image changes over time. By way of example only, the processing device may determine the condition of the wound by assessing the wound progression and its healing progress. Specifically, an artificial neural network (such as deep neural network, convolutional neural network, etc.) may be configured (for example, manually, using machine learning methods, by combining other artificial neural networks, etc.) to determine the condition of the wound based on detected changes of the wound between the first and second images. These changes may include one or more of: changes in dimensions of the wound, changes in composition of tissue type within the wound, changes to the peri-wound skin, changes in surface features, changes in color, changes in texture, changes in other characteristics, or any combination thereof. Accordingly, at step in , the processing device may analyze the retrieved data and data associated with the second image to determine a condition of the wound. In some embodiments, a convolution of pixels of the first image may be calculated, a convolution of pixels of the second image may be calculated, and the calculated convolution of pixels of the first image and the calculated convolution of pixels of the second image may be used to determine the condition of the wound. For example, a function of the calculated convolution of pixels of the first image may be compared with a function of the calculated convolution of pixels of the second image, in response to a first result of the comparison, a first condition of the wound may be determined, and in response to a second result of the comparison, a second condition of the wound may be determined, the second condition differs from the first condition.
Disclosed embodiments may include “analyzing the retrieved data and data associated with the second image to determine a level of effectiveness of the medical treatment.” The term “level of effectiveness of the medical treatment” refers to any indication, numeric or otherwise, of a level (e.g., within a predetermined range) indicative of the healing progress of a skin feature that being medically treated. For example, the effectiveness level may have a value between 1 and 10. Alternatively, the effectiveness level may be expressed as a percentage or any other numerical or non-numerical indication. In some cases, the system may compare the effectiveness level of the medical treatment to a threshold. The term “threshold” as used herein denotes a reference value, a level, a point, or a range of values. In operation, when the level of effectiveness of the medical treatment level exceeds a threshold (or below it depending on a particular use case), the system may follow a first course of action and, when the effectiveness level is below it (or above it, depending on a particular use case), the system may follow a second course of action. The value of the threshold may be predetermined for each type of skin feature or may be dynamically selected based on different considerations such as the user's medical history.
Consistent with the present disclosure, the processing may determine a level of effectiveness of the medical treatment by predicting an expected appearance (e.g., an expected color, an expected size, an expected shape, etc.) of the wound at a time of capturing the second image and comparing the actual appearance with the expected appearance. Disclosed embodiments may include determining a time difference between the first image and the second image. For example, predicting an expected appearance of a wound may involve determining a time difference between a capture time of a first image and a capture time of a second image, which may be accomplished by determining a time lapse between image capture. For example, the processing device may determine when an image was captured by reading a timestamp associated with the received images. In embodiments where a timestamp is superimposed on an image, the processing device may use optical character recognition to read the timestamp. In other embodiments, such as when a timestamp is embedded into an image or attached to it within the metadata information, the processing device may extract it from those sources. In some disclosed embodiments, the time difference between the first image and the second image may be determined automatically using metadata associated with the second image. For example, a processing device may determine the time difference automatically using metadata information associated with the second image. In some disclosed embodiments, the time difference between the first image and the second image may be determined automatically by comparing metadata associated with the first image and metadata associated with the second image.
Based on a time difference between images of a wound, the processing device may determine an expected appearance of the wound. For example, data may be maintained in a data structure that maps a healing process of a wound based on wound characteristics. Alternatively, learning algorithms may be applied to a repository of wound images to identify wounds that most closely correspond to the first image, and thereby predict how the current wound is expected to heal over time. A person skilled in the art would recognize that the predicted expected appearance of the wound may be based on a type of the wound. For example, a laceration is different in type from a burn, and therefore, the healing process for laceration would be expected to be different than a burn. Indeed, there are many different types of wounds, ranging from chemical burns, sunburns, lacerations, abrasions, contusions, hematomas, punctures, and avulsions. Each has its own wound healing profile. In addition, the predicted expected appearance may be based not only on the type of a wound but also on its extent. For example, larger or deeper wounds would be expected to have a different healing process than small or shallower wounds. Since the time lapse is known for the first and second image, based on how other similar wounds of others have healed over time, the system can determine if the wound healing is progressing as expected, or if there appears to be an abnormality. The healing progress may be based on any combination of a change in color of the wound, a reduction in size of the wound, a change in the shape of the wound, a change in the color of an outline of the wound, a change in the tissue composition of the wound, and/or non-wound-related characteristics, such as a patient's age, gender, health, genetics, skin type, or any other non-wound-related characteristic that might correlate to wound healing. The determined healing progress of a wound being medically treated is indicative of the level of effectiveness of the medical treatment. It is to be understood that herein any reference to a healing of a wound (such as healing progress) may also refer to a worsening in the condition of the wound.
In one embodiment, the processing device may analyze the retrieved data and data associated with the second image to determine whether a level of effectiveness of the medical treatment is below a threshold. In response to a determination that the level of effectiveness of the medical treatment is below the threshold, the processing device may initiate the remedial measure associated with the at least one action. In some cases, wherein when the level of effectiveness of the medical treatment is determined to be below the threshold, the processing device may electronically receive lifestyle data from the patient. By way of example, the lifestyle data may include at least one of: information about a diet of the patient, information about sleeping habits of the patient, information about physical activities of the patient, and information about sanitation and hygiene in an environment of the patient. After obtaining the lifestyle data, the processing device may compare the lifestyle data with information stored in a data structure and determine the at least one action to alter the medical treatment. In accordance with this embodiment, the at least one action to alter the medical treatment may include a recommendation to change at least one aspect of the lifestyle of the patient. But in response to a determination that the level of effectiveness of the medical treatment is above the threshold, the processing device may forgo initiating the remedial measure associated with the at least one action. Alternatively, in response to a determination that the level of effectiveness of the medical treatment is above the threshold, the processing device may determine a time period for capturing a third image to continue monitoring the condition of the wound, and output an indication of the determined time period.
1012
FIG. 10
Disclosed embodiments may further include “determining at least one action to alter the medical treatment based on the condition of the wound.” Consistent with the present disclosure, the processing device may use an artificial neural network (such as deep neural network, convolutional neural network, etc.) to determine the at least one action to alter the medical treatment. The artificial neural network may be configured manually, using machine learning methods, or by combining other artificial neural networks, etc. By way of example only, the at least one action to alter the medical treatment may include increasing a number of times that the wound is cleaned (e.g., once a day, twice a day, once a week, etc.), removing dead or inflamed tissue, changing a type of wound dressing (e.g., films dressings, gauze dressings, hydrogel dressings, hydrocolloid dressings, dressings containing silver or alginates, foam dressings), initiating an antibiotics regime, changing a type or dose of antibiotics, suggesting a wound therapy (e.g., hyperbaric oxygen therapy, ultrasound and electromagnetic therapy, negative pressure wound therapy), and suggesting skin grafts. Accordingly, at step in , the processing device may determine at least one action to alter the medical treatment based on the condition of the wound.
830
In an optional embodiment, the processing device may receive a third image of the wound of the patient. The third image may be captured at least a day after information indicative of the at least one action to alter the medical treatment was displayed to the patient. For example, the third image may be captured two days, three days, four days, after the information was displayed to the patient. The processing device may analyze the second image and the third image to determine that the at least one action to alter the medical treatment failed to bring a level of effectiveness of the medical treatment above a threshold. The value of threshold may be determined based on the type of wound, the type of the at least one action previously determined to alter the medical treatment, the time lapse since information on the at least one action was displayed to the patient, and more. Thereafter, the processing device may determine at least one additional action to alter the medical treatment (again), and initiate a further remedial measure associated with the at least one additional action to increase the effectiveness of the medical treatment. The scenario presented in screenshot illustrates this embodiment. In a related embodiment, the processing device may analyze the second image and the third image to determine that the at least one action to alter the medical treatment was incorrectly implemented. For example, after analyzing the first and second images, the processing device may determine that the wound should be kept dressed. But analysis of the third image shows that the wound was left exposed to open air. Thereafter, the processing device may initiate a further remedial measure associated with the at least one action to increase effectiveness of the medical treatment.
830
110
125
1014
FIG. 10
Disclosed embodiments may further include “initiating a remedial measure associated with the at least one action to increase effectiveness of the medical treatment.” In a first embodiment, initiating the remedial measure may include causing a display of information indicative of the at least one action to alter the medical treatment, for example, screenshot . In another embodiment, initiating the remedial measure may include causing a communications device associated with the patient to output an alert associated with the at least one action. In yet another embodiment, initiating the remedial measure may include causing a network transmission, via a communications device of the patient (e.g., user ), of an alert associated with the at least one action to networked computing device of a medical practitioner (e.g., mobile communications device ). The alerts may be provided to the patient or the medical practitioner visually, textually, audibly, through an external device, to an external device, and so forth. By way of example only, at step in , the processing device may initiate a remedial measure associated with the at least one action to increase effectiveness of the medical treatment.
Consistent with the present disclosure, the processing may determine that the data associated with the first and second images is insufficient to determine the condition of the wound. Thereafter, the processing device may cause a display of a request for capturing a third image. In one embodiment, the processing device may cause a display of a request for capturing a third image with or without an image filter. The image filter may be a physical filter for a lens associated with the image sensor. Alternatively, the image filter may be a digital filter applied to the captured image. For example, the image sensor capturing the first and second image may be CCD or CMOS sensors. These type of sensors cover the spectral range around 300-1000 nm (Visible range are around 400-700 nm). In some mobile communication devices, additional filters are attached to the image sensors (e.g., R,G,B filters arranged in a Bayer Filter Mosaic and possibly UV cut and IR cut filters). Consistent with the present disclosure, it may be possible to take IR image with a typical RGB camera by removing IR cut filter. In some embodiments, the processing device may analyze the second image and the third image to determine the condition of the wound and possibly that the level of effectiveness of the medical treatment is below a threshold. In these embodiments, the determination of the condition of the wound may include using image processing to determine an extent of the infection to the wound and/or to determine a type of wound infection. Specifically, the third image, captured using an image filter, may be analyzed to detect an infection to the wound, to determine an extent of the infection to the wound, to determine a type of the infection to the wound, to determine a recommended treatment to the infection to the wound, or any combination thereof. For example, a machine learning model may be trained using training examples to detect infections to wounds, to determine extents of infections to wounds, to determine types of infections to wounds, to recommend treatments to infections to wounds based on images of the wounds. An example of such training examples may include one or more images of a wound, together with an indication of desired detection and/or determination.
The foregoing description has been presented for purposes of illustration. It is not exhaustive and is not limited to the precise forms or embodiments disclosed. Modifications and adaptations will be apparent to those skilled in the art from consideration of the specification and practice of the disclosed embodiments. Additionally, although aspects of the disclosed embodiments are described as being stored in memory, one skilled in the art will appreciate that these aspects can also be stored on other types of computer readable media, such as secondary storage devices, e.g., hard disks or CD ROM, or other forms of RAM or ROM, USB media, DVD, Blu-ray, Ultra HD Blu-ray, or other optical drive media.
Computer programs based on the written description and disclosed methods are within the skills of an experienced developer. The various programs or program modules can be created using any of the techniques known to one skilled in the art or can be designed in connection with existing software. For example, program sections or program modules can be designed in or by means of .Net Framework, .Net Compact Framework (and related languages, such as Visual Basic, C, etc.), Java, C++, Objective-C, HTML, HTML/AJAX combinations, XML, or HTML with included Java applets.
Moreover, while illustrative embodiments have been described herein, the scope of any and all embodiments having equivalent elements, modifications, omissions, combinations (e.g., of aspects across various embodiments), adaptations and/or alterations as would be appreciated by those skilled in the art based on the present disclosure. The examples are to be construed as non-exclusive. Furthermore, the steps of the disclosed methods may be modified in any manner, including by reordering steps and/or inserting or deleting steps. It is intended, therefore, that the specification and examples be considered as illustrative only. | |
As an non-denominational Christian growing up in the faith I encountered my share of tough questions. When I gave my life to Christ at the age of fifteen I quickly encountered some of them. I realized, early in my faith journey, that being a Christian wasn’t going to be as easy as opening my Bible and following the instructions even if that was often how it was presented. Because, as it turned out, Christians interpreted those so-called instructions in many, many different ways.
On relatively small topics like what sort of music is best or how to structure a Sunday worship service to massive, foundational topics of importance like how we’re saved or the nature of God Christians didn’t agree. And I wondered, if God really intended us to use the Bible to understand how to live, why can’t we agree on what it means?
What I realized, as I dug into the history of Christianity, was that not all Christians had this same problem because not all Christians used their Bibles like that. And that, historically, it wasn’t the Bible that taught Christians to live but the Church which taught Christians to understand the Bible. Otherwise, we all come up with our own interpretations.
This is true for both the majority of Christian history (for the first 1,500 years) and for the majority of Christians worldwide.
But, in hindsight, it makes sense. A faith which holds up the Bible as the be-all-and-end-all, the final rule and arbiter, faces three tough questions. As a serious Bible-believing Christian, as a student of Scripture, these were questions I found myself asking, and the answers were surprising.
Question 1: What About the First 300 Years?
Christians that treat the Bible as their personal rule of faith have to contend with the startling fact that for the first 300-400 years there actually wasn’t a Bible.
Instead, local churches grew up under the authority of the apostles. When the apostles died successors were appointed to lead, and plant, communities and so on and so forth. This is how Christianity spread through time and space: through a church hierarchy and authoritative framework.
Today, non-denominational Christians plant church communities with little to no consideration for the broader Christian landscape but this wasn’t the case for the first 1,500 years of Christianity. History shows us that Christians who planted their own communities outside of the strict authority of an appointed successor—a bishop—would be condemned as heretics, apart from the true faith.
So, for the first 300-400 years of Christianity, churches rose up and flourished under this strictly established framework with no clear or collected Bible to guide them.
While certain books, letters, and even collections of books were being passed throughout ancient Christendom these were only received as authoritative by communities through the acknowledgement of the appointed bishops. In other words, Paul’s first letter to the Corinthians didn’t spread and become popular because everyone was reading it—everyone was reading it because the authoritative church, the apostles and their successors, affirmed it as being written by Paul and worthy to read.
It wasn’t until 300-400 years after the death of Christ that a biblical canon was actually reasonably established—and it was the church which began at the apostles and followed a hierarchy down through time, not a group of disparate Christian communities, that met and authoritatively affirmed which books and letters belonged.
That Church was called the Catholic Church and its hierarchy extends until today, unchanged.
The tough question for Bible alone Christians, and the question I had to ask myself as one of them, was if the Bible was the sole rule of faith, what happened for the first 300-400 years? How did those Christians know how to live? And how did they know which letters and books to trust? How did they eventually know that books to include in the Bible?
Question 2: What About People Who Couldn’t Read?
It’s a fact of history that Martin Luther and the invention of the printing press ushered in a new era of Christianity. The popular myth is that the Reformation struck back at a corrupt and chaotic Catholic Church which had perverted and prevented the true Christian faith. Luther and the early reformers held up the Bible as the golden standard for Christianity and declared that the Catholic Church had simply, and intentionally, been misinterpreting it.
Incredibly, Luther and the reformers contended that for nearly 1,500 years the Catholic Church had got it wrong.
But if Christians were to understand their faith by reading the Bible and not by following the corrupt Catholic Church—and if Luther’s re-reading of the Bible and his new found interpretation were right—what about those that couldn’t read?
As a non-denominational Christian I struggled to understand how this made any sense. Unless a Christian is able to read the Bible for themselves then they’re subjected to someone else’s interpretation either way. They’re forced to trust someone else’s reading of it—and rely on someone else to read it to them in the first place.
And what about the 1,500 years before the printing press?
For me, this was a tough question. Because, really, if the thing that tells me how to live the Christian life needs to be read then that’s a system which excludes the majority of humankind throughout the majority of human history.
Question 3: What About All the Different Interpretations?
It’s no secret that the landscape of North American Christianity these days is fairly diverse. Our understanding of how to interpret the Bible, from the very small things to the incredibly huge, runs the gamut. How two honestly God-fearing, Bible-believing churches can read the same passage of Scripture and discern two completely divergent interpretations caused me, as a non-denominational Christian, to scratch my head.
Did this system make any sense?
This was a tough question: If we’re meant to use the Bible to understand how to live then how come we all understand it so differently?
The standard answer, as I dug for some kind of solution, was that differences on the small things didn’t matter. It wasn’t a big deal if we couldn’t agree on what kind of music was appropriate for a worship service, if women should still cover their heads in church, or if it was OK to drink alcohol (and, then, how much was OK?). But the landscape of Christian denominations wasn’t created based solely on the small things because Christians can’t agree on the big things either.
Massive faith issues like what it means to be saved, how is marriage defined, and what is the nature of God—these are open to interpretation as we all try to understand Bible for ourselves.
Could this really be the way God intended?
In the end, as I asked these tough questions on my own faith journey I was slowly but surely lead towards the Roman Catholic Church. It was the last place I ever thought I’d go. To a non-denominational Christian living in the twenty-first century the Catholic Church didn’t even seem relevant to me. Did people even become Catholic anymore?
But it was the Catholic Church, of all things, which offered succinct answers to these tough questions.
It was the Church, in a historically traceable lineage back to the Christ-appointed apostles, which claimed not only to have collected the books of the Bible and to have authoritatively canonized them, but also to have the ability to interpret them too. It was the Church, which Paul calls, the “pillar and bulwark of truth” (1 Timothy 3:15) that exists to help us understand how to live.
And, suddenly, it all made sense.
God didn’t leave us a book to read and understand for ourselves, he left us his Church which, as it turns out, created a book. But it was the Church he left. A Church with the power to bind and loose, to teach and to guide, and to answer the tough questions as they came up.
January 22, 2019 How Can "Bible Only" Christians Trust Their Bible? | https://www.patheos.com/blogs/albertlittle/three-questions-to-ask-bible-only-christians/ |
The tasks a Gatherer (Glass) is expected to perform include:
Gathering specified amounts of molten glass on ends of an iron rod
Carrying it to the Pressman
Dipping ends of the iron rod or blowpipe into a pot containing molten glass kept on the furnace
Collecting required amount of molten glass on ends of rod or blowpipe
Carrying it to the Pressman for further processing
Knowledge of the glass manufacturing process
Proficient in collecting glass with a blowpipe
Well-versed in creation of glass
Ability to feed glass machines with glass gobs
Knowledge of glass properties, uses and environmental impacts
Ability to assist Blower by preliminary shaping or blowing
Flexible
Quality tester
Hardworking
Physical stamina
Swift
It requires one to be on their feet
Need not handle a team
Local travelling is a part of this job
Part-time work and contractual jobs are available in some cities
Work from home option is not available
Working hours
Factories usually work for 6 days a week and 8/10 hours everyday. This may vary from factory to factory
Shift system maybe available
Is the job suitable for a candidate with special needs?
This job is suitable for candidates with Hearing Impaired (HH)
The job is considered hazardous or dangerous under The Factories Act, 1948 (section 87
Occupational hazards may include bleeding from nose, eyes and throat irritation, skin allergies, cuts from broken glass, skin burns, skin itching, skin rash, red and swollen fingernails, etc.
Health risks include exposure to extreme heat, chemicals, accidents, fire, toxins, etc.
For freshers - 7,000 to INR 8,500 per month
For candidates with 2-4 years of experience or more - INR 9,000 to INR 10,000 per month
(These figures are indicative and subject to change)
Overview of the Indian Ceramic and Glass Industry
Ceramic Industry
The ceramic industry in India came into existence about a century ago and has matured over time to form an industrial base. From traditional pottery making, the industry has evolved to find its place in the market for sophisticated insulators, electronic and electrical items. Over the years, the industry has been modernising through new innovations in product profile, quality and design to emerge as a modern, world-class industry, ready to take on global competition.
The Indian Ceramic Industry ranks at 8th position in the world and produces around 2.5% of global output. The industry provides employment to 550,000 people, of whom 50,000 are directly employed. Gujarat accounts for around 70 % of total ceramic production.
Glass Industry
Fuelled by growth in sectors like real estate, infrastructure, retail, automotive and food & beverages, the country's glass industry will acquire a market size worth 340 billion by 2015 from 225 billion at present. The organised glass industry as in 2013, employs 30 lakh people directly and provides indirect employment to 5 lakh people whereas the unorganised sector employs around 5-6 lakh people. About 75 per cent of the total glass industry is concentrated in Uttar Pradesh, Maharashtra, Gujarat, Karnataka and Andhra Pradesh. The highest employment in the glass industry is in Gujarat followed by Uttar Pradesh, Maharashtra and Andhra Pradesh. | https://www.tucareers.com/ncocareers/7315.0800 |
BACKGROUND
REFERENCES
SUMMARY
EXPERIMENTAL
The present invention is generally directed to toner processes, and more specifically, to the aggregation and coalescence of an aqueous suspension of colorant, such as pigment particles, wax particles and resin particles, utilizing a coagulant to afford toner composites of various suitable sizes, such as for example, from about 3 to about 11 microns. More specifically, the present invention in embodiments is directed to the preparation of submicron emulsion particles containing a polyester resin with a low percentage of sulfonation, and toner compositions thereof to, for example, permit in embodiments improved toner charge control by reducing RH sensitivity. This is accomplished by reducing the amount of sulfonation selected in the resin used to form a stable emulsion thereof without the use of surfactants.
In embodiments, the present invention involves the preparation of stable emulsions where stable refers, for example, to submicron resin particles that remain suspended in solution for a period of time, at least a number of days or months, and preferably substantially indefinitely. The stable emulsions are prepared, for example, by the dissolution of a resin, and more specifically a polyester, into a solvent, such as acetone, which resulting mixture is then added to hot water and the solvent subsequently removed through a known flashing (distillation) method. Also, the present invention in embodiments relates to the direct preparation of toners and toner resins comprising an initial composition of sulfonated polyester particles, and wherein the polyester possesses a low sulfonated percentage, such as less than or equal to about 3 percent, and more specifically from 1 to about 3 percent without the utilization of the known pulverization and/or classification methods, and wherein in embodiments toner compositions with an average volume diameter of from about 1 to about 25 microns, and more specifically from about 1 to about 10 microns, and a narrow GSD of, for example, from about 1.16 to about 1.26 or about 1.18 to about 1.28 as measured on the Coulter Counter can be obtained. The process of the present invention in embodiments enables the utilization of polymers obtained by polycondensation reactions, such as polyesters, and more specifically, the sulfonated polyesters as illustrated in U.S. Pat. Nos. 5,348,832; 5,658,704 and 5,604,076, the disclosures of which are totally incorporated herein by reference, and which polyesters are generated in a manner to enable a low percentage of sulfonated groups. The resulting toners can be selected for known electrophotographic imaging methods, printing processes, including color processes, digital methods, and lithography.
There is illustrated in U.S. Pat. No. 4,996,127 a toner of associated particles comprising primarily particles of a polymer with acidic or basic polar groups, and which toners can be prepared by emulsion polymerization. In U.S. Pat. No. 4,983,488, there is disclosed a process for the preparation of toners by the polymerization of a polymerizable monomer dispersed by emulsification in the presence of a colorant and/or a magnetic powder to prepare a principal resin component, and then effecting coagulation of the resulting polymerization liquid in such a manner that the particles in the liquid after coagulation have diameters suitable for a toner. It is indicated in column 9 of this patent that coagulated particles of 1 to 100, and particularly 3 to 70 are obtained. Other prior art may include U.S. Pat. Nos. 3,674,736; 4,137,188 and 5,066,560.
Emulsion/aggregation/coalescing processes for the preparation of toners are illustrated in a number of Xerox patents, the disclosures of which are totally incorporated herein by reference, such as U.S. Pat. Nos. 5,290,654, 5,278,020, 5,308,734, 5,370,963, 5,344,738, 5,403,693, 5,418,108, 5,364,729, and 5,346,797. Also of interest may be U.S. Pat. Nos. 5,348,832; 5,405,728; 5,366,841; 5,496,676; 5,527,658; 5,585,215; 5,650,255; 5,650,256; 5,501,935; 5,723,253; 5,744,520; 5,763,133; 5,766,818; 5,747,215; 5,827,633; 5,853,944; 5,804,349; 5,840,462; 5,869,215; 5,910,387; 5,919,595; 5,916,725; 5,902,710; 5,863,698, 5,925,488; 5,977,210 and 5,858,601.
The appropriate processes and components of these patents may be selected for the present invention in embodiments thereof.
Examples of features illustrated herein include:
A feature of the present invention relates to the generation of sulfonated polyesters, emulsions and toners thereof.
It is another feature of the present invention to provide dry toner compositions comprised of a sulfonated polyester resin wherein the sulfonated percentages are low, for example from about 0.5 to about 3 mol percent, where mol percent refers, for example, to the percentage of moles of sulfonated monomer present in the final resin and can be calculated as (moles DMSIP charged/(total moles charged less excess moles glycol)×100 percent).
In another feature of the present invention there are provided simple and economical chemical processes for the preparation of black and colored toner compositions with, for example, excellent colorant, such as pigment dispersion and narrow GSD.
In a further feature of the present invention there is provided a process for the preparation of toner compositions with an average particle volume diameter of from about 1 to about 20 microns, more specifically from about 1 to about 9 microns, and yet more specifically from about 4 to about 7 microns, and with a narrow GSD of from about 1.12 to about 1.30, and more specifically from about 1.14 to about 1.25, each as measured with a Coulter Counter, and wherein the sulfonated polyester contained in the toner is emulsified by a solvent flashing method, thereby providing from about 0.5 to about 3 mol percent of sulfonated groups and wherein the relative humidity sensitivity of the toner containing the polyester generated is excellent and improved as compared to toners with sulfonated polyesters containing, for example, about 4 mol percent sulfonation.
In another feature of the present invention there is provided a composite toner comprised of a sulfonated polymeric resin with colorant, such as pigment and optional charge control agent in high yields of from about 90 percent to about 100 percent by weight of toner without resorting to classification.
In yet another feature of the present invention there are provided toner compositions with low fusing temperatures of from about 110° C. to about 150° C., and with excellent blocking characteristics at from about 50° C. to about 60° C.
Aspects of the present invention relate to a toner process comprising the aggregation and coalescence of a sulfonated polyester and a colorant, and wherein the polyester possesses a degree of sulfonation or a sulfonation percentage of from about 0.5 to about 3 mol percent; a process for the preparation of toner which comprises the heating of a sulfonated polyester and a colorant, and wherein the polyester possesses a sulfonation percentage of from about 0.5 to about 3 mol percent, and wherein the heating is accomplished by heating in sequence the polyester and colorant at a first temperature about below the glass transition temperature of the polyester, followed by second subsequent second heating at about above the glass transition of the polyester, and wherein aggregation/coalescence of the polyester and the colorant results, and which process is accomplished by solvent flashing; a toner process comprising heating and solvent flashing a sulfonated polyester, colorant, and optional wax, and wherein the polyester possesses a sulfonation percentage of from about 0.5 to about 3 mol percent, and wherein the heating is accomplished by heating in sequence the polyester and colorant at a first temperature about below the glass transition temperature of the polyester, followed by second subsequent second heating at about above the glass transition of the polyester, and wherein aggregation/coalescence of the polyester and the colorant results; a process comprising
i) dispersing a sulfonated polyester resin in water, which water is at a temperature of from about 40° C. to about 90° C., or more specifically, from about 5° C. to about 15° C. above the polyester glass transition temperature, and which dispersing is accomplished in the absence of a surfactant or homogenization to generate stable particles in water, thereby enabling the formation of a submicron sized emulsion;
ii) aggregation of the dispersed sulfonated polyester;
iii) adding a colorant like a pigment dispersion, available from Sun Chemical, as an about 20 to about 50 weight of predispersed pigment in water with a mean pigment size of about 50 to about 150 nanometers, which dispersion is further diluted with, for example, about 150 to about 200 millimeters of DI (deionized) water, and wherein the aggregation rate can be controlled, for example, by the dropwise addition of an alkali halide, such as a dicationic salt, of from about 1 to about 150 milliliters, and more specifically, 1 percent by weight in water, and with heating is, for example, about 40° C. to about 60° C., and more specifically, about 48° C. to about 52° C., until optimum toner sized aggregates are obtained as monitored by both optical microscopy and Coulter Counter particle size measurements;
iv) optionally, but preferably recovering the toner, or toner particles by known methods, such as filtration, washing; and
v) drying the toner particles with, for example, a vacuum;
vi) adding to the dry toner particles, or toner of resin and colorant, known toner additives, such as wax, charge additives, surface flow additives, and the like; a toner process wherein there can be selected various pigments, dyes, mixtures thereof, and the like, such as cyan, black, magenta, and yellow pigmented dispersions or mixtures thereof obtained, for example, as a predispersed form with, for example, from about 20 to about 60 weight percent of solids; a process wherein the colorant is a cyan, black, magenta, yellow dispersion or mixtures thereof with from about 10 to about 40 weight percent solids of colorant; a process wherein the sulfonated polyester is of the formula
w
n
wherein Y is an alkali metal, X is a glycol, and n and m represent the number of segments; a process wherein each of n and m represent a number of from about 3,000 to about 7,000, or from about 4,000 to about 6,000; a process wherein the Y alkali is sodium, lithium, potassium, rubidium, cesium, hydrogen or mixtures thereof; a process wherein the glycol is neopentyl glycol, ethylene glycol, propylene glycol, butylene glycol, propanediol, ethylene glycol, or mixtures thereof; a process wherein the sulfonated polyester is a dispersion comprised of from about 5 to about 30 weight percent solids, and the colorant dispersion contains from about 20 to about 50 weight percent of colorant; a process wherein the sulfonated polyester has a degree of sulfonation of from about 1.5 to about 2.8 mol percent; a process wherein the sulfonated polyester has a degree of sulfonation of from about 0.5 to about 2 mol percent; a process wherein there is obtained a colored toner with a narrow GSD in the range of from about 1.18 to about 1.28; a process wherein the toner particle size is from about 4 to about 7 microns in volume average diameter; a process wherein the toner is isolated, filtered, washed with water, and dried; a process wherein there is added to the surface of the formed toner of sulfonated polyester and colorant, metal salts, metal salts of fatty acids, silicas, metal oxides, or mixtures thereof, each in an amount of from about 1 to about 3 weight percent of the obtained toner; a process wherein the particle size of the dispersed sulfonated polyester is from about 5 to about 200 nanometers; a process wherein the polyester is a random sulfonated copolyester comprised of, on a mol percent basis of the polymer repeat unit, approximately 0.47 of terephthalate, 0.03 of sodium sulfoisophthalate, 0.475 of 1,2 propanediol, 0.025 of diethylene glycol, and which polyester possesses an Mof about 3,790, an Mof about 2,560, and a Tg of about 54.6° C.; a toner process comprising heating a mixture of the sulfonated polyester and colorant below or about equal to the glass transition temperature (Tg) of the latex resin; heating the resulting mixture of above about the Tg of the latex resin until the fusion or coalescence of polyester resin and colorant is initiated resulting in toner particles comprised of the sulfonated polyester and colorant; a process wherein the aggregation temperature is from about 40° C. to about 50° C., and the coalescence temperature is from about 50° C., providing this temperature is higher than the aggregation temperature, to about 70° C.; a process wherein the temperature at which the aggregation is accomplished controls the size of the aggregates, and wherein the final toner size is from about 2 to about 20 microns in volume average diameter; a process wherein the colorant is a pigment, and wherein the pigment is in the form of a dispersion, which dispersion contains an ionic surfactant; a toner containing a polyester generated as illustrated herein, and which polyester is, for example, as illustrated, for example, in U.S. Pat. Nos. 5,348,832; 5,853,944; 5,840,462; 5,660,965; 5,658,704; 5,648,193; and 5,593,807; the disclosures of each patent being totally incorporated herein by reference; a process wherein the polyester is preferably a polyester of poly(1,2-propylene-sodio 5-sulfoisophthalate), poly(neopentylene-sodio 5-sulfoisophthalate), poly(diethylene-sodio 5-sulfoisophthalate), copoly(1,2-propylene-sodio 5-sulfoisophthalate)-copoly-(1,2-propylene-terephthalate phthalate), copoly(1,2-propylene-diethylene sodio 5-sulfoisophthalate)-copoly-(1,2-propylene-diethylene-terephthalatephthalate), copoly(ethylene-neopentylene-sodio 5-sulfoisophthalate)-copoly-(ethylene-neopentylene-terephthalate-phthalate), or copoly(propoxylated bisphenol A)-copoly-(propoxylated bisphenol A-sodio 5-sulfoisophthalate; a toner process wherein the polyester is the beryllium salt of copoly(1,2-propylene-dipropylene-5-sulfoisophthalate)-copoly(1,2-propylene-dipropylene terephthalate), the barium salt of copoly(1,2-propylene-diethylene-5-sulfoisophthalate)-copoly(1,2-propylene-diethylene terephthalate), the magnesium salt of copoly(1,2-dipropylene-5-sulfoisophthalate)-copoly(1,2-propylene terephthalate), the magnesium salt of copoly(1,3-butylene-5-sulfoisophthalate)-copoly(1,3-butylene terephthalate), the calcium salt of copoly(1,2-dipropylene-5-sulfoisophthalate)-copoly(1,2-propylene terephthalate), the calcium salt of copoly(1,3-butylene-5-sulfoisophthalate)-copoly(1,3-butylene terephthalate), the cobalt salt of copoly(1,2-propylene-diethylene-5-sulfo isophthalate)-copoly(1,2-propylene-diethylene terephthalate), the nickel salt of copoly(1,2-dipropylene-5-sulfoisophthalate)-copoly(1,2-propylene terephthalate), the iron salt of copoly(1,3-butylene-5-sulfoisophthalate)-copoly(1,3-butylene terephthalate), the zirconium salt of copoly(1,2-dipropylene-5-sulfoisophthalate)-copoly(1,2-propylene terephthalate), the chromium salt of copoly(1,3-butylene-5-sulfoisophthalate)-copoly(1,3-butylene terephthalate), and the like.
The sulfonated polyester emulsion is generated by a solvent flashing method by, for example, dissolving the polyester in a water miscible solvent, such as acetone, toluene, tetrahydrofuran, or the like, mixing with hot water, wherein hot is for example, from about 70° C. to about 90° C., and more specifically, from about 75° C. to about 84° C., whereby the solvent is removed by flashing thereof permitting the formation of the polyester in water as a stable emulsion, and thereafter mixing the polyester obtained with a colorant and accomplishing aggregation and coalescence thereof as illustrated herein and as disclosed, for example, in U.S. Pat. Nos. 5,290,654, 5,278,020, 5,308,734, 5,370,963, 5,344,738, 5,403,693, 5,418,108, 5,364,729, 5,346,797; 5,348,832; and 5,405,728, the disclosures of which are totally incorporated herein by reference.
Various known colorants, especially pigments, present in the toner in an effective amount of, for example, from about 1 to about 65, more specifically from about 2 to about 35 percent by weight of the toner, and yet more specifically in an amount of from about 1 to about 15 weight percent, include carbon black like REGAL 330®; and magnetites, such as Mobay magnetites MO8029™, MO8060™; and the like. As colored pigments, there can be selected known cyan, magenta, yellow, red, green, brown, blue or mixtures thereof. Specific examples of colorants, especially pigments, include phthalocyanine HELIOGEN BLUE L6900™, D6840™, D7080™, D7020™, cyan 15:3, magenta Red 81:3, Yellow 17, the pigments of U.S. Pat. No. 5,556,727, the disclosure of which is totally incorporated herein by reference, and the like. Examples of specific magentas that may be selected include, for example, 2,9-dimethyl-substituted quinacridone and anthraquinone dye identified in the Color Index as CI 60710, CI Dispersed Red 15, diazo dye identified in the Color Index as CI 26050, CI Solvent Red 19, and the like. Illustrative examples of specific cyans that may be selected include copper tetra(octadecyl sulfonamido) phthalocyanine, x-copper phthalocyanine pigment listed in the Color Index as CI 74160, CI Pigment Blue, and Anthrathrene Blue, identified in the Color Index as CI 69810, Special Blue X-2137, and the like; while illustrative specific examples of yellows that may be selected are diarylide yellow 3,3-dichlorobenzidene acetoacetanilides, a monoazo pigment identified in the Color Index as CI 12700, CI Solvent Yellow 16, a nitrophenyl amine sulfonamide identified in the Color Index as Foron Yellow SE/GLN, CI Dispersed Yellow 33 2,5-dimethoxy-4-sulfonanilide phenylazo-4′-chloro-2,5-dimethoxy acetoacetanilide, and Permanent Yellow FGL. Colored magnetites, such as mixtures of MAPICO BLACK™, and cyan components may also be selected as pigments with the process of the present invention. The colorants, such as pigments, selected can be flushed pigments as indicated herein and not dry pigments.
More specifically, colorant examples include Pigment Blue 15:3 having a Color Index Constitution Number of 74160, magenta pigment Red 81:3 having a Color Index Constitution Number of 45160:3, and Yellow 17 having a Color Index Constitution Number of 21105.
Colorants include pigments, dyes, mixtures of pigments, mixtures of dyes, and mixtures of dyes and pigments, and the like, and preferably pigments.
The toner may also include known charge additives in effective amounts of, for example, from 0.1 to 5 weight percent, such as alkyl pyridinium halides, bisulfates, the charge control additives of U.S. Pat. Nos. 3,944,493; 4,007,293; 4,079,014; 4,394,430 and 4,560,635, which illustrates a toner with a distearyl dimethyl ammonium methyl sulfate charge additive, the disclosures of which are totally incorporated herein by reference, negative charge enhancing additives like aluminum complexes, and the like.
Surface additives that can be added to the toner compositions after washing or drying include, for example, metal salts, metal salts of fatty acids, colloidal silicas, metal oxides like titanium, tin and the like, mixtures thereof and the like, which additives are usually present in an amount of from about 0.1 to about 2 weight percent, reference U.S. Pat. Nos. 3,590,000; 3,720,617; 3,655,374 and 3,983,045, the disclosures of which are totally incorporated herein by reference. Preferred additives include zinc stearate and flow aids, such as fumed silicas like AEROSIL R972® available from Degussa Chemicals, or silicas available from Cabot Corporation or Degussa Chemicals, each in amounts of from about 0.1 to about 2 percent, which can be added during the aggregation process or blended into the formed toner product.
Developer compositions can be prepared by mixing the toners obtained with the processes of the present invention with known carrier particles, including coated carriers, such as steel, ferrites, and the like, reference U.S. Pat. Nos. 4,937,166 and 4,935,326, the disclosures of which are totally incorporated herein by reference, for example from about 2 percent toner concentration to about 8 percent toner concentration.
Imaging methods are also envisioned with the toners of the present invention, reference for example a number of the patents mentioned herein, and U.S. Pat. No. 4,265,990, the disclosure of which is totally incorporated herein by reference.
The following Examples are provided. Parts and percentages are by weight unless otherwise indicated.
Resin Synthesis Overview:
Two resins with low sulfonation were generated using a 2 liter Hoppes Polycondensation reactor containing about 3 percent (mol) and about 1.5 percent (mol) of dimethyl-5-sulfo isophthalate (DMSIP) where mol percent is calculated as (moles DMSIP charged/(total moles charged less excess moles glycol)×100 percent), in a formulation containing dimethylterephthalate (DMT), and a mixture of glycols, propylene glycol (PPG), dipropylene glycol (DPPG) and ethylene glycol (EG) in a ratio of 71.6/22.8/5.6. Butyltin oxide (FASCAT 4100™) was added as a catalyst.
The transesterification and polycondensation processes illustrated below were completed as a bulk polymerization reaction.
(i) Preparation of Polyester Resin with 3 Mol Percent Sulfonation:
Dimethylterephthalate (858 grams, 4.42 mol), sodium dimethyl 5-sulfoisophthalate “DMSIP” (86.2 grams, 0.29 mol), propylene glycol (514.6 grams, 6.76 mol), dipropylene glycol (290 grams, 2.15 mol), diethylene glycol (55.9 grams, 0.53 mol), and butyltin oxide (1.1 grams) were charged together into a 2 liter Hoppes reactor equipped with an anchor style agitator, and reflux and take-off condensers. The resulting mixture was heated to 180° C. over about a 1 hour period and agitated at 100 RPM. The temperature was increased gradually to 200° C. over 5 hours during which time the take-off condenser was used to remove methanol from the reaction, which methanol was collected in the distillate receiver. Once greater than 80 percent of the methanol had been removed, the transesterification was complete and the polycondensation was then initiated. Vacuum was applied to the reactor over a period of 60 minutes until about 3 to about 10 milliliters Hg vacuum was achieved. The reaction was continued for about 200 to about 500 minutes under vacuum during which time the temperature was maintained at about 190° C. to about 230° C. The endpoint of the polycondensation was determined for this Example when there was achieved a polymer softening point of 140° C.±5° C. using a Mettler softening point apparatus (starting point 120° C. and temperature ramp of 1° C./minute). Once the endpoint was achieved, the polymer was discharged in bulk to a stainless steel pan for cooling at room temperature, about 22° C. to about 25° C. The 3 mol percent sulfonated poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodium sulfoisophthalate] polymer product, where mol percent is calculated as (0.29 mole DMSIP charged/14.16 total moles charged less 4.68 moles excess glycol)×100 percent, was then crushed and stored for later use.
(ii) Preparation of Polyester Resin with 1.5 Mol Percent Sulfonation:
Dimethylterephthalate (1,063.9 grams, 5.48 mol), sodium dimethyl 5-sulfoisophthalate (51.7 grams, 0.17 mol), propylene glycol (617.5 grams, 8.11 mol), dipropylene glycol (348 grams, 2.59 mol), diethylene glycol (67.1 grams, 0.63 mol), and butyltin oxide (1.1 grams) were charged together into a 2 liter Hoppes reactor equipped with an anchor style agitator, and reflux and take-off condensers. The mixture was heated to 180° C. over about 1 hour and agitated at 100 RPM. The temperature was increased gradually to 200° C. over 5 hours during which time the take-off condenser was used to remove methanol from the reaction, which was collected in the distillate receiver. Once between 80 percent and 95 percent of the methanol had been removed, the transesterification step was complete and the polycondensation was then initiated. Vacuum was applied to the reactor over a period of 60 minutes, and until about 3 to about 10 milliliters Hg vacuum was achieved. The reaction was continued for about 200 to about 500 minutes under vacuum during which time the temperature was maintained at from about 190° C. to about 230° C. The endpoint of the polycondensation step was achieved when a softening point of 140° C.±5° C. using a Mettler softening point apparatus (starting point 120° C. and temperature ramp of 1° C./minute) resulted. Once the endpoint was achieved, the polymer was discharged in bulk to a stainless steel pan for cooling at room temperature, about 22° C. to about 25° C. The 1.5 mol percent sulfonated poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodium sulfoisophthalate] polymer product, where mol percent was calculated as (0.17 moles DMSIP charged/16.99 total moles charged less 5.68 moles excess glycol)×100 percent, was then crushed and stored for later use.
Solvent Flashing Emulsification:
Sulfonated polyester resins, such as sulfonated poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodiumsulfoisophthalate] with more than 3.5 percent and less than 10 percent sulfonation were dissipated in water at elevated temperatures (about 80° C. to about 90° C.) in the absence of a surfactant. The resin was crushed and added to hot water with turbulent mixing. At these sulfonation levels of greater than 3.5 percent, the resin was not readily dissipatable even with surfactant or specialized equipment such as a homogenizer. Further attempts to dissipate these sulfonated polyester resins in DIW at 90° C. with 2.5 pph NEOGEN RK™ surfactant and an Ultra-Turrax homogenizer operating at 8,000 rpm were not readily achievable. Only 44 percent of the 3.5 percent sulfonated resin and 10 percent of the 1.5 percent sulfonated resin could have been emulsified even with surfactant/homogenization. The portion of the resin that could have been emulsified had particle size diameters of 0.35 μm for the 3.5 percent sulfonated resin, and 2.12 μm for the 1.5 percent sulfonated resin. These very large particles were not that suitable for EA toner manufacturing since small (less than 0.200 μm) primary particles (emulsions) were usually selected to provide uniformly sized toner particle characteristics. In contrast, the solvent flashing technique could emulsify resins with no sulfonation (0 percent). The resins were completely, about 100 percent, emulsified with small particles (less than 0.200 μm). The diameter of the 3 percent poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodium sulfo isophthalate] sulfonated resin particles was 0.031 μm, the 1.5 percent resin was 0.152 μm and the 0 percent resin was 0.186 μm.
Preparation of 1.5 Mol Percent Sulfonated Emulsion:
420 Grams of 1.5 mol percent sulfonated resin (AT-SPE-20) were dissolved in 2,800 grams of acetone at room temperature to create a 15 weight percent solution. The resin was fully dissolved after 30 minutes of agitation (addition was slow to prevent clumping). In a 4 liter glass reaction kettle, 3,080 grams of deionized water were heated to 80° C., and the mixture resulting was agitated at approximately 600 rpm. The kettle was fitted with a pressure equalizing dropping funnel for solution addition, and a condenser and flask for solvent collection. The polymer solution was added to the hot water at a rate of 80 grams/minute, however, the addition was paused periodically to avoid overfilling the kettle (the rate of addition exceeded the rate of solvent distillation). The solvent (acetone, b.p. 56° C.) was removed by distillation and collected, enabling the recycling of the solvent for future emulsifications.
Once all of the polymer solution had been added, the emulsion was agitated at 80° C. for an additional hour, after which heating was terminated. The emulsion continued to agitate overnight with a slight nitrogen purge (1-2 SCFH). The final solids content of the poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodiumsulfoisophthalate] emulsion was measured at 18.9 percent solids (higher due to evaporation), and the average particle size diameter was 152 nanometers.
Preparation of 3 Mol Percent Sulfonated Emulsion:
336 Grams of 1.5 mol percent sulfonated resin (AT-SPE-20) were dissolved in 2,240 grams of acetone at room temperature to create a 13 percent by weight solids solution. The sulfonated resin was fully dissolved, 100 percent, after 30 minutes of agitation (addition was slow to prevent clumping). In a 4 liter glass reaction kettle, 3,080 grams of deionized water were heated to 80° C. and were agitated at approximately 600 rpm. The kettle was fitted with a pressure equalizing dropping funnel for solution addition, and a condenser and flask for solvent collection. The polymer solution was added to the hot water at a rate of 80 grams/minute; however, the addition was paused periodically to avoid overfilling the kettle (the rate of addition exceeded the rate of solvent distillation). The solvent (acetone, b.p. 56° C.) was removed by distillation and collected enabling the recycling of the solvent for future emulsifications.
Once all of the polymer solution was added, the emulsion was agitated at 80° C. for an additional hour, after which heating was terminated and the emulsion allowed to agitate overnight with a slight nitrogen purge (1-2 SCFH). The final solids content of the poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodiumsulfoisophthalate] emulsion was measured at 13.7 percent solids (higher due to evaporation), and the average particle size was 30.6 nanometers.
Toner Particle Growth Procedure:
(i) Preparation of Toner from 1.5 Mol Percent Sulfonated Emulsion:
The particle growth of toner particles from the above prepared 1.5 percent sulfonated resin was demonstrated at both a 0.5 liter and 2 liters reactor scale using standard Buchi stainless steel reactors. For the 0.5 liter reactor, a single pitched-blade impeller with 3 blades (P3, 45° pitch) was used at 800 rpm while for the 2 liter reactor, two P4/45° impellers spaced one impeller diameter apart were used along with 2 baffles. The agitation rate in the 2 liter Buchi was from about 500 to about 350 RPM.
2
2
2
In the 2 liter Buchi (MM-EAP-C17) was first added 1,289 grams of 1.5 mol percent emulsion (1,045.4 grams of deionized water, 243.6 grams of 1.5 mol percent sulfonated poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodium sulfoisophthalate]—average particle size of 152 nanometers, 18.9 percent solids content). 24.22 Grams of cyan (Blue 15:3) pigment dispersion were then added (47.4 percent solids, FLEXIVERSE BFD™ 1121 obtained from Sun Chemical) to provide a 4.5 percent pigment loading in the final toner. Agitation was set to 500 rpm and heating of the reactor to 58° C. was initiated. A 3 percent solution of zinc acetate (Zn(OAc)) coagulant was prepared in deionized water. Once the reactor temperature of 58° C. was reached, the addition of the coagulant solution was initiated at 0.6 gram/minute. No growth was observed after 90 minutes. The agitation rate was then decreased to 350 rpm. After 135 minutes, the coagulant addition rate was increased to 1.5 gram/minute. Particle growth became noticeable after 285 minutes of aggregation and the toner particles grew from 0.152 μm to 5.64 with a GSD of 1.26 (measured by Coulter Counter®) after 370 minutes. The coagulant solution feeding was terminated after 370 minutes. A total of 440.1 grams of the solution was added. The Zn(OAc)/resin ratio was 5.4 percent. For comparison, for 6 micron particle growth of the SPE resin with about 3.5 to about 4 percent sulfonation, 10 percent Zn(OAc)/resin was typically used. The reactor was set to full cooling and the toner slurry was discharged once the reactor temperature was less than 35° C.
The slurry resulting was discharged through 150 μm and 25 μm sieves to remove coarse particles. Mother liquor was then removed and the toner was washed twice with 1.4 liters of deionized water. Conductivity of the filtrate after the second wash was 12 μS/cm. The toner yield was 40 percent of theoretical. The fraction of coarse/fouled particles was 18.7 percent (fouled=11.4 percent, coarse=7.3 percent) of theoretical with the remainder of the particles being lost as fines. The particles were reslurried with deionized water (solids/water=30/70) and placed on a freeze dryer for 72 hours. Final moisture content in the toner was 0.92 percent. The dried particles were submitted for tribocharging analysis and for a moisture pick-up test. The moisture pick-up test involved placing the toner in a controlled environment (25° C., relative humidity (RH)=40, 60 and 80 percent). The equilibrium moisture content was determined at a given RH by removing samples at various times until the moisture content leveled off. The equilibrium moisture content was typically taken as the moisture content after 18 hours of exposure. For MM-EAP-C17, the equilibrium moisture content was found to be 1.11 percent at 60 percent RH and 1.45 percent at 80 percent RH.
This activity was designated MM-EAP-C18, and was accomplished in the 0.5 liter Buchi. Given the information from the 2 liter experiment above, the required amount and addition rate of the coagulant to provide significant growth could be determined. 322.25 Grams of 1.5 mol percent emulsion (261.3 grams of deionized water, 60.9 grams of 1.5 mol percent sulfonated poly-[1,2-propylene-di(ethylene)-di(propylene)-terephthalate-sodium sulfoisophthalate] resin, average particle size of 152 nanometers, 18.9 percent solids content) were added to the reactor with agitation set to 800 rpm. Heating to 58° C. was initiated. 9.24 Grams of cyan (Blue 15:3) pigment dispersion were then added (47.4 percent solids, BFD 1121 FLEXIVERSE™ pigment dispersion obtained from Sun Chemical) along with 34.58 grams of a Carnauba wax dispersion (20 percent solids, RC-160 wax (To a Kasei) stabilized with 2.5 pph NEOGEN RK™ surfactant). A 3 percent solution of Zn(OAc)2 coagulant was prepared and addition started at 0.4 gram/minute after the reactor temperature reached 58° C. The coagulant addition was stopped after 4 hours of aggregation. A total of 100 grams of the coagulant solution was added. Particle growth was relatively rapid, and toner particles grew from 0.152 μm to 5 μm in diameter after 5 hours of aggregation. After 8 hours, cooling was started. The average particle size resulting was 5.29 μm and the GSD was equal to about 1.27. Once the reactor temperature was less than 35° C., the slurry was discharged through 150 μm and 25 μm sieves to remove the coarse particles. The mother liquor was then removed and the toner was washed three times with 0.5 liter portions of deionized water. The conductivity of the filtrate after the final wash was less than 20 μS/cm (about 17 to 18). The toner yield was 51.8 percent of theoretical. The fraction of coarse/fouled particles was 19.5 percent (fouled=13.7 percent, coarse=5.8 percent) of theoretical.
The particle growth profiles for the two experiments displayed the typical sigmoidal shape associated with EA (emulsion aggregation) polyester toner particle growth when the coagulant was added slowly at a fixed rate. The particle size distributions had a slightly higher GSD than was typically observed for the EA polyester process but were still monomodal. A moisture pick-up test was conducted in which several toners were placed in environments of controlled humidity for several days. The moisture pick-up of MM-EAP-C17 toner was compared with an EA polyester with 4 percent sulfonation, EA1 toner and a conventional polyester toner with no sulfonation (F3C). After conditioning at 80 percent relative humidity, the EA polyester generated from a polyester resin with 1.5 percent sulfonation showed an equilibrium moisture content of 1.5 percent which was 160 percent less moisture sensitive compared to the EA polyester generated with a polyester resin with 4 percent sulfonation which showed an equilibrium moisture content of 3.75 percent. EA1 toner and conventional toner, both without any sulfonation, showed equilibrium moisture contents of between 0.50 percent and 0.75 percent. Thus, reducing the sulfonation level decreases the toner RH sensitivity.
Tribocharging of the toner with lower, 1.5 to 3, sulfonation confirmed a reduction in RH sensitivity. A-zone measurements for MM-EAP-C17 with a carrier were −5.3 μC/mm, C-zone measured at 21.9 μC/mm giving an RH ratio of 0.24 which, compared to a toner containing a polyester resin having 4 percent sulfonation, was an increase of a factor of 2 to 3 times. The A-zone charge itself was 4 to 5 times higher with the lower sulfonation.
It will be appreciated that various of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also that various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims. | |
Mackenzie's December 2020 Moose Contest
MCPT is thrilled to announce the return of the MOOSE contest!
MOOSE, a competitive programing competition, is an awesome way to have fun problem-solving with your friends while also brushing up on your coding skills. Every skill level is welcome and it’s up to you to decide to compete in either the junior or senior division.
This month’s MOOSE will be hosted over 2 days, from December 5-6. The contest will last a total of 2.5 hours. You may start at any time within the given timeframe, but note that starting after 9:30PM on December 6 will result in the contest ending before the 2.5 hours pass.
Registration is now open for all schools until 11:55PM on December 3! Students must register their teams at https://mcpt.ca/moose/signup/. Visit https://mcpt.ca/moose/ for more information! | https://mcpt.ca/post/30-mackenzies-december-2020-moose-contest |
Applications for controlling the generation, distribution, and content of enterprise documents for IBM i abound.
One of the core functions of business computing is the process of managing information and passing it along to those who need it to do their jobs. Although information flow has been in a period of transition to electronic delivery for quite some time, the “paperless office” remains an elusive goal as a majority of managers and users continue to prefer the tangibility and seeming permanence of a paper document they can literally cling to. So, while it’s almost an ironic anachronism when you consider the capabilities of today’s systems, this information distribution process is still called “document management.”
While this state of affairs keeps the companies that sell office paper and steel filing cabinets alive, IT departments are still saddled with the problem of managing information flows, whether or not anything is ever actually printed on paper. As the computer industry has been unable so far to do away with the document part, document management as a concept has grown to become an umbrella term that covers far more territory than simply translating that spooled file into a sheaf of paper on the CEO’s desk.
Narrowing the Field
Even in the IBM i market, the number of products that have something to do with generating and controlling documents is well over 100. You can find many of them in the MC Press Buyer’s Guide, and they cover a spectrum that ranges from full-featured suites that let users design, control, and distribute multiple document types to utilities that simply convert text to PDF or add bar codes or other graphics to paper output. So rather than presenting an exhaustive list of them, let’s focus here on how to narrow down your choices should you be in the market for some document-management software. We’ll identify some major types and point to a few representative products, but be mindful that there are many more products of all the types we’ll cover than we can specifically mention here. Also please note that many of the vendors mentioned here have additional document-management products that provide many features in areas for which other product examples are noted, so you should research all products offered by any vendors mentioned in this article.
When you’re choosing software of any kind, the best advice is to tailor your choice to what your enterprise actually needs. For a document-management product, find out who needs to get what information, in what format, and how often. Are users getting enough information or too much? You should be assessing this at least annually, as users’ needs change more often than people outside their department may realize. For example, who hasn’t heard a horror story or two about the department that’s been getting the same doorstop report for years but currently uses only a fraction of the information?
Single-Focus (Mostly) Products
At the low end of the complexity scale of document-management offerings are products that mostly provide a single function. Most simple in concept, at least, is the addition of bar codes, MICR lines, and other graphics to existing documents or the production of labels containing such graphics. InFORM Decisions‘ iBar and Graphic Tools, Keowee Systems‘ FontMagic/400 and FontManager, CYBRA Corporation‘s MarkMagic , and T.L. Ashford‘s Barcode400 are good places to start if this is your requirement.
Similarly streamlined in function are products that translate the contents of a spooled file to an Adobe PDF file or some other PC-friendly format for transmission to PC-using recipients. For a small company, this may be all you really need. Representatives of this product type include CPYSPLPDF by Pluta Brothers Design, Keyes PDF by Computer Keyes, Remote SpoolPrint/400 by Broderick Data Systems, i4OutQ by Goering iSeries Solutions, and Robot/TRANSFORM by Help/Systems. Similarly, if you need to convert reports to CSV or MS Excel for spreadsheets, something like CSV Report Converter by RJS Software (as well as their iPDF product) or The SPLTOOL Suite by BVSTools is worth a look. Although it automates some database functions and file transfer operations as well, Linoma Software’s Surveyor/400 also converts spooled files to PDF.
If you just want to print IPDS files to a Windows printer, check out Integrated Print Solutions’ OnePrint product family. Perhaps fax output is a requirement, in which case products like BlueFax by Kisco Information Systems , Interfax400 by Intermate A/S, or Vanguard Systems’ eliteFax may suit you. If a wider array of output formats and graphics options is needed, look into menten GmbH’s i-effect.
Report Distribution
Report distribution via email is the next step up on the distribution complexity ladder. Quadrant Software’s FastFax handles that and faxing as well. Most report-related products, however, are even more multifunctional. Mainstream spooled-file control and report-distribution products, for example, typically include most of the features already mentioned and add such features as output queue monitoring, transformation of output into a variety of file formats, splitting of information into tailored reports for specific groups or individual users, and choice of distribution via LAN, WAN, email, or cross-platform on an individual-report basis.
Products in this category include Asymex’s SpooliT, Aura Equipment’s Launcher 400, BCD Software’s Catapult and Spool-Explorer, DRV Technologies’ SpoolFlex, Help/Systems’ Robot/REPORTS, RJS Software’s recently announced DeliveryNow, System Support Products’ Save Output Queue, and Symtrax Corporation’s Compleo. For lack of space, we’ll have to pass over the closely allied report-generator category of products because those are really more related to a survey of business-intelligence solutions than document-management products, despite their obvious similarities.
Keeping in-Formed
While reports are the most common document IT must manage, there are certainly others. Next most common is the business form–the invoice and the human-resources questionnaire being the most recognizable examples. Usually a matrix for recording information, the business form has been slightly more successful than the report in being accepted in an electronic medium (the e-form). Most document-management products that specialize in forms emphasize a forms-design component, or at least include one, and also provide distribution tools for the forms.
Examples of this product type include ACOM Solutions’ EZeDocs/400, B2BeDocuments’ PDFeFormPrinter, Bottomline Technologies’ Create!form, CYBRA’s MarkMagic Electronic Forms, InFORM Decisions’ iView, Integrated Custom Software’s FormSprint, Quadrant Software’s Formtastic, and RJS Software’s iForms. Some products are designed to generate corporate checks as well, such as inFORM Decisions’ iDocs suite and Quadrant’s Formtastic Checks.
Moving Docs Around
Besides distributing documents to users from a central location, many enterprises have a requirement to move documents through a specific chain of users for collaboration, approvals, or other functions–a process called “workflow.” This is one of the central advantages of groupware products such as IBM’s Lotus Notes/Domino and is also a feature of some document management products, such as ACOM Solutions’ EZContentManager, Digital Designs’ DocAgent, Inventive Designers’ Scriptura, MetaCommunications’ Virtual Ticket, Quadrant Software’s IntelliChief, and RJS Software’s Enterprise Workflow. Although some products don’t specifically offer workflow, they do provide document tracking, retrieval, and distribution, such as 38 Caliber’s Mirror Image and S4i Systems’ S4i Express.
Many products that provide workflow features cross another line into the area of content management. These are applications that provide content control of not only documents but other media types, such as images, audio and video files, Web content, and other digital assets. They also support collaborative authorship, versioning, workflow, and other features that apply both to documents and projects of other kinds. ACOM’s EZContentManager, Infor’s SSA Global Content Management, inFORM Decisions’ Content Management, MetaFile Information Systems’ MetaViewer, andOpen Text’s Livelink ECM are examples of this product type.
Another potential requirement for document application systems is imaging, the process of capturing scanned documents for input or archive. Imaging systems, and other document applications, provide a built-in repository in which users can archive documents. Not to be confused with ordinary backups, which write all system files to media or other systems, repositories are document-specific storage areas that let users index and track docs and more easily retrieve specific ones on demand. Products offering imaging and repository services in addition to document management include Document Wizard by United Image Technologies, EMC Captiva by EMC, IMS21 by Vanguard Systems, Kofax Document Exchange Server by Kofax, and RealVision Imaging by Real Vision Software.
Going to the Web
Although paper reports have their place in today’s business environment, the future lies in electronic distribution of information, particularly via the Internet. Document management solutions that incorporate the ability to publish documents electronically on a Web site provide the most flexibility for enterprises whose users are ready to give up the tangibility of paper. Products that provide online viewing of documents include Electronic Storage Corporation’s LaserVault Reports, Help/Systems’ Robot/REPORTS, Kisco Information Systems’ WebReport/400, Redwood Software’sReport2Web, RJS Software’s WebConnect and WebDocs, and S4i Systems’ WebView.
At the top end of the scale are full-blown Web portal products that not only let users access documents via a browser, but also make available applications and whole systems. Examples of this product type include BCD Software’s Nexus Portal and NewGeneration Software’s Decision Assist product line, though once again, applications such as these cross over into the business intelligence arena.
Making a Choice
This overview has focused on general document applications that any business can use. But if you’re looking for a solution, don’t forget that there are some document-management products that are specific to various industries. Examples include Chameleon by Construction Imaging Systems for the construction industry, eSchool Data Knowledge Management System by Contemporary Computer Services for schools, and HSS (Human Services Software) by Boston Technologies (BTI) for healthcare. There may be others specific to your industry that you should look for via a search engine.
The wide range of options available in document-management applications should make it obvious that, once an enterprise defines its needs, there will be multiple solutions to choose from at any level of function and complexity. Don’t be misled by the brief summary offered here to conclude that the available solutions fall neatly into categories. They don’t. All the products highlighted here offer functions in addition to the ones mentioned, and many could be classified in ways other than that in which they’ve been represented here. With so many products available in the document management market for IBM i, you should investigate any that seem remotely useful before making a short list of solutions for intensive research. | https://informdecisions.com/technology-focus-document-management-cornucopia-solutions/ |
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Lochness Park is home to Blaine's disc golf course. The park is located on the east side of Lexington Avenue, just a quarter mile north of 109th Avenue. This 9-hole course is designed to challenge the recreational to the professional disc golfers. Three tee box locations for each hole match the golfer's skill level.
The green/recreational tee plays 2,665 feet, the red/intermediate tee plays 3,596 feet and the blue/professional tee plays a whopping 4,468 feet. Before packing up your discs and heading out to the course please keep in mind the following:
For more information, please contact the Parks Department. | https://blainemn.gov/482/Disc-Golf-Courses |
The Alabama Parenting Questionnaire is a 42-item self-reporting instrument that focuses on positive involvement with children, supervision and monitoring, use of positive discipline techniques, consistency in the use of discipline, and corporal punishment use. The instrument, designed for parents with children 6-18 years of age, can be used for pre- and post-treatment and is offered in both English and Spanish.
Category: Home and Community
Sub-Category: Parent-Child Interactions
The Caregiver Interaction Scale (CIS) is an instrument that measures parent and caregiver behaviors and interactions with children. The instrument consists of 26 items focused on sensitivity, harshness, detachment, and permissiveness. CIS was created in 1989 at the University of North Carolina-Chapel Hill’s Frank Porter Graham Child Development Institute and used in the evaluation of North Carolina’s Smart Start Initiative. | https://edinstruments.com/instruments/topics/Social/open_access/Yes/psychometric_information_available/Yes |
Due to the current political climate, the lines between liberals and conservatives are cut very deep. There are various battlegrounds which take place across these lines, and the polarization cannot be overstated. Examples of these issues include: abortion, same-sex marriage, and gun control. However, another issue that has become just as prevalent in public discussion is the issue of economics, particularly the debate between socialists and capitalists.
Capitalism and socialism are two ideas on the opposite ends of the economic spectrum. Capitalism falls in line with what is often called ‘classical liberalism,’ an economic policy popularized during the Enlightenment which prizes individual responsibility and abhors government intervention. Socialism on the other hand prizes the idea of equality. Therefore, it becomes the government’s responsibility to ensure that the economic playing field remains even.
There are several problems with capitalism, and these problems are connected by one factor: there is no intrinsic morality governing the system. In the capitalistic world, the rich man is king—he is viewed as the most responsible and the most hardworking, because capitalism is about personal control. Any monopolizing that he may achieve is understood as nothing but success. On the other hand, capitalists often have little compassion for the poor, because it is assumed that the poor are either lazy and/or irresponsible.
Even though capitalism seems to be problematic, socialism is even more so. What capitalism has going for it is that it provides goods and services to meet needs (which is great until capitalists get wise and start using advertising to get people to desire things he or she really doesn’t need…but you can’t complain about that if you’re a capitalist, because at least you’re making money, right?). But socialism can’t provide for the needs of people for an extended period of time. This should be common knowledge now, as we have seen one socialist nation after another collapse. Another major problem with socialism is that even though it attempts to make all people equal, the people must defer all their power to the government to regulate this equality. However, as the government gains absolute power, it will inevitably use that power against the people. So, by attempting to create equality among the people, that government becomes a (often deadly) force of oppression.
It may seem like I am abandoning the conservatives on this issue, but I assure you I am not. I am merely pointing to a common inconsistency. It seems like there is a gaping hole in the conservative debate regarding economics: conservatives seem to want Christian morals, but not economic morals. That is, when it comes to individual decisions, we want Biblical morality to guide us, but in our minds, no one should tell a business what it should or should not do. It seems as if we become moral relativists the moment we begin talking about business or economics. This flaw or oversight in our thinking must be addressed.
Though they may seem completely different, the problems with libertarianism, communism, capitalism, and socialism are really all the same. All of them are materialistic, that is, they look only to economic factors as the measurement of a thriving society. But as we are living in one of the most financially prosperous periods in history, we are also living in a time where individuals who seem to be thriving on paper are often the most depressed. Though they attempt to solve economic problems differently, each of these ideologies fail because they are focusing on the wrong goal.
The main problem is that each of these economic systems misunderstand human nature. Each of them seeks to apply a certain economic equation to achieve human flourishing. Each whittles down human beings to some sort of quantifiable and predictable element, most often called our “rational self-interest.” The problem with this idea is that no one really lives out of pure altruism or from pure selfish motives. People will not always consistently do what is best for society or for themselves. In trying to apply some kind of equation to human nature, each of these economic systems fail because, as Fyodor Dostoevsky brilliantly put it, “Man, after all, is stupid.”
Note: a great work to read on this is Dostoevsky’s Notes from Underground. He addresses this faulty line of thought and traces it through differing economic systems, revealing why they do not function as designed (that is, because people are not perfectly formed cogs meant to fit within some sort of economic machine, but they are individuals which function based on their own personal volition).
Conservatives often chide liberals for saying things like, “true communism has never been tried.” But if you point out some of the flaws of capitalism, conservatives will say something that sounds eerily familiar, “Ah, but that’s crony capitalism.” This is just another way of saying “true capitalism has never been tried.” The problem with this line of thinking is that, as I said before, capitalism has no intrinsic moral value system. A capitalist cannot condemn the behavior of a monopolizing business-owner within a free-market system without appealing to a moral value system that is foreign to capitalism itself.
There is an unspoken assumption within Christian conservativism that suggests capitalism is the Christian economic system. This is a falsehood, not because Christianity has some other economic system, but because it has no economic system. There is no orthodox economic philosophy for Christianity.
If we can shift from this line of thinking, we can also expand our understanding of what economic progress should look like. Instead of looking to lawmakers to fix everything, we should begin to ask ourselves what we can do. A nation’s prosperity is not built from the top down—from the government to individuals—it is built up from individual citizens. These citizens must be willing to exercise certain individual responsibilities, which include morality, compassion, civic duty, and moderation of personal desires. The reason, I contend, that socialism is looked to for the imposition of financial limits on people is because people have become too greedy to place limits upon themselves.
Two major elements leading to the general decline in the success of economic policies in the United States and around the world have been the amalgamation of socialism and capitalism, and a deconstruction of individual morality from the bottom up. The former can easily be seen, as the government seems to reach into economics too far for our system to be purely capitalistic, but at the same time there is not enough governmental regulation to refer to our economic system as purely socialistic either. Our current economic state is a sort of hybrid which does not function well as a socialist or a capitalist system, because it does shares elements from both.
The latter issue is that individuals have lost any sense of self-restraint. One obvious example of this can be seen by searching modern economic literature to see how many times the word “enough” is used. You will likely find that it is never used. This is because people have become so motivated by greed that all they are capable of asking is, “how much can I acquire?” But they never ask, “how much should I acquire?” This has led to a constantly unreachable goal, because the goal is only to make more.
The first step to redeeming our economy cannot be accomplished from the top down. People today often misunderstand politics because all they see is policy—all they see is how a law will affect the populous. But they fail to ask what an individual’s responsibility is to society, or how individual behavior can affect the governmental structure as a whole. In other words, insofar as we only look at problems from the top down, we only understand half the problem.
The question we should all be asking is, “what is the economic responsibility of each individual in society?” This can be easily answered if we apply Christian morality to our thinking, which, in return, could revolutionize modern economics. From this perspective, the individual in society would understand the importance of financial limitations, not imposed by the government, but self-imposed. We would each (whether business or individual) ask ourselves what it means to have enough. Part of the reason why socialism will never work is because it expects government to do what people are supposed to do for themselves.
What I am suggesting is an economic system called ‘Distributism.’ Distributism is an idea popularized by G. K. Chesterton and Hilaire Belloc, and later by Dorothy Sayers. It is an idea which esteems the importance of personal property, along with the idea that the means of production should be spread as widely as possible. It implies that people should seek to be self-reliant, but also focuses on loving one’s neighbor as one’s self. This would be a drastic paradigm shift in our current thinking—we earn money not as an end in itself, but so that we can better help our local community.
Note: when many conservatives hear the word ‘Distributism,’ what they think they hear is ‘socialism.’ In socialism, there is an outside force imposing limitations on individuals within society. But the financial limits in Distributism come from within individuals, they overflow from a desire to help the community around them, and too keep greed from taking over.
This may seem like an empty dream, but the beauty of it is that we do not need to wait for the government to impose it. Plant a garden, give some of the produce to the poor. This could be a simple first step. The one institution this system is ready-made for is the church, because it is local enough to know the needs of its community. This is a higher path than a purely capitalistic way of thinking. It would allow us to see the poor as Christ saw them: with compassion. Instead of seeing the poor as lazy or irresponsible, we can see them as souls in need of aid. We can work with the poor to help them become productive citizens, so they in return can help others do the same. In contrast, our current system has produced more dependent people, not less.
As we apply this ideology, we will find that many who call themselves capitalists were advocating for Distributism all along. They simply did not have the proper vocabulary to express it. Distributism is, in some sense, really a form of capitalism that esteems financial morality and responsibility, but it is also much more than that. Conservatives should not be forced to defend a broken ideology just because there seems to be no alternative. There is another way that prizes personal responsibility, not for the sake of getting rich, but for the sake of being compassionate. Distributism is less of a combination of socialism and capitalism, and more like what they both strive to be, and yet fail. Distributism, I believe, is the best idea for economics. It is a way of living that is better than pure capitalism or socialism could ever hope to be, and it is a way of living that would best contribute to human flourishing. | https://youngpatriotsforliberty.com/2018/02/05/the-economy-and-christian-ethics-the-most-boring-title-for-an-article-in-the-history-of-articles/ |
Find home care near you or your loved one:
High blood pressure can lead to more than just heart problems. Among other things, it is directly related to decreased cognitive functioning, according to research. That’s why is important to carefully monitor a senior with high blood pressure.
Q. My 75-year-old widowed mother just had a physical and her doctor said her heart is in great shape. She does have borderline high blood pressure, though, so the doctor has prescribed a medication. Are there other things she could do?
It sounds as if your mother has taken good care of herself if her heart is in such a healthy condition. One important component of good heart health is blood pressure, and the risk of high blood pressure does seem to increase with age, according to the American Heart Association. In fact, 90 percent of Americans over the age of 50 have a lifetime risk of high blood pressure.
High blood pressure can lead to other problems, too. Increased blood pressure in older adults is directly related to decreased cognitive functioning, particularly among seniors with already high blood pressure, research reveals. This means that stressful situations may make it more difficult for some seniors to think clearly.
Dr. Jason Allaire, an assistant professor of psychology at North Carolina State, who co-authored a study on high blood pressure and cognitive function, explains that study subjects whose average systolic blood pressure was 130 or higher saw a significant decrease in cognitive function when their blood pressure spiked. However, Allaire notes, study subjects whose average blood pressure was low or normal saw no change in their cognitive functioning — even when their blood pressure shot up.
So how do you navigate around high blood pressure and its consequences? Your mom’s doctor will be her best source of information for lifestyle and diet changes.
“High blood pressure remains an epidemic in the United States, but it can be prevented,” said Lawrence Appel, M.D., lead author of an American Heart Association scientific statement, published in Hypertension: Journal of the American Heart Association. “By improving their diet, people can reduce their blood pressure and put a major dent in their risk of stroke, coronary heart disease and heart failure,” said Appel, a professor of medicine at Johns Hopkins University School of Medicine in Baltimore.
The statement also recommends combining an overall healthy diet with weight loss, eating lots of fruits and vegetables, limiting alcohol consumption, lowering salt intake and increasing potassium intake.
The National Heart, Lung and Blood Institute Health Information Center recommends following its Dietary Approaches to Stop Hypertension (DASH) plan. The DASH eating plan is rich in fruits, vegetables, fat-free or low-fat milk and milk products, whole grains, fish, poultry, beans, seeds and nuts. Talk to your doctor about whether the DASH plan will work for you. The plan also recommends being moderately active for at least 30 minutes on most days of the week.
If your mother lives alone, you might want to consider a companion for her. Encourage her to develop a relationship with someone who shares some of her same health interests and concerns. Or contact the local Home Instead Senior Care® office. The organization employs CAREGiversSM who can help seniors with meal preparation, errands and shopping, and serve as companions.
Here’s hoping your mother has many more years of healthy heart living.
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I am more than pleased to share my latest JAFF release with you. The Mistress of Rosings Park is told completely from Elizabeth Bennet’s point of view, just as is Austen’s Pride and Prejudice.
The story begins when Elizabeth comes to visit with Mr. Collins and Charlotte at Hunsford Cottage. There has been no Mr. Bingley at Netherfield and no Mr. Wickham, at least, not until later in the book. Mr. Darcy has succumbed to family pressure and married Anne de Bourgh, but do not fear, my fellow Austen-addicts, our poor Anne has passed more than a year prior to the beginning of this story. The thing is, Mr. Darcy now owns Rosings Park, for as Anne’s husband, he inherits all her property, meaning Lady Catherine’s plan to keep control of Rosings Park has backfired, and she must remove from her beloved mansion to the dower house. Darcy has allowed her a year to grieve for her daughter and to accept the need to abandon her post as the “mistress” of Rosings Park, but she has not acted wisely.
As the story opens, Elizabeth “meets” Lady Catherine for the first time. Enjoy the excerpt, and please consider ordering the book for your reading pleasure, which releases January 8, 2021. The price will increase on the book on January 15, so do not delay in claiming your copy of this story, which I warrant has more twists and turns than one might expect.
Chapter One
Late June 1813
“That dreadful man will arrive tomorrow,” Lady Catherine de Bourgh bemoaned. “And I have had no opportunity to remove to the dower house.”
“There. There,” Mr. Collins commiserated. “Mrs. Collins and I will assist you. Your situation, if I may be so bold to say, is a true travesty, my lady. A travesty indeed.”
From her position in a chair in the corner of the room, Elizabeth Bennet watched in mild amusement as her father’s cousin attempted to calm the latest round of hysterics displayed by the grand dame of Rosings Park. Mr. Collins, who continually genuflected before his patroness, was a comical creature without even attempting to be so. Elizabeth said a silent prayer of blessing that the man had not become her husband; yet, she again pitied her long-time friend, Charlotte Lucas, who had readily accepted the man’s proposal out of fear of becoming a burden to her family.
In truth, Elizabeth had been surprised to receive an invitation for a visit to Kent from the Collinses. She suspected Mr. Collins had agreed in order to prove to Elizabeth she had made a mistake in refusing him. The situation had been poorly played by all, and her relationship with Charlotte had suffered greatly. Their bond had been badly shaken by her friend’s acceptance of Mr. Collins’s hand, a man who had proposed to Elizabeth and been rejected fewer than two hours prior to his proposal to Charlotte.
The scene of the man’s insolent superiority played through Elizabeth’s head as she watched Mr. Collins attempt to soothe Lady Catherine’s vexations.
“I am not now to learn,” replied Mr. Collins with a formal wave of his hand, “that it is usual with young ladies to reject the addresses of the man whom they secretly mean to accept, when he first applies for their favor; and that sometimes the refusal is repeated a second or even a third time. I am, therefore, by no means discouraged by what you have just said, and shall hope to lead you to the altar ere long.”
“Upon my word, sir,” Elizabeth had cried, “your hope is rather an extraordinary one after my declaration. I do assure you that I am not one of those young ladies, if such young ladies there are, who are so daring as to risk their happiness on the chance of being asked a second time. I am perfectly serious in my refusal. You could not make me happy, and I am convinced that I am the last woman in the world to make you so. Nay, were your friend, Lady Catherine, to know me, I am perfectly persuaded she would find me in every respect ill-qualified for the situation.”
Elizabeth had been correct. At home, it was Jane and Mary who tended to their mother’s “nerves.” Elizabeth would certainly not be as solicitous to Lady Catherine’s vapors as were the Collinses. She was more likely to tell the woman to “saddle up.” Even so, she understood the Collinses’ position in this melodrama.
Earlier, Charlotte had explained that Rosings Park had passed to Lady Catherine’s daughter when the young woman reached her majority, although it appeared to Elizabeth as if her ladyship had continued to run the estate. Miss Anne de Bourgh had married and had removed to her new husband’s estate. Much to the chagrin of all concerned, reportedly, Miss de Bourgh had passed within months of her marriage, and the property now belonged to the lady’s husband. However, Lady Catherine had yet to abdicate her rule over the estate, which was none of Elizabeth’s business, but, if anyone had been foolish enough to ask, she would agree the estate could use a different hand on the helm. Despite the manor house being a true showcase, on her short walk of the grounds yesterday after services, she had noted how the parkland and the formal gardens did not reflect the same style of care as did the house.
Elizabeth instinctively glanced to the window, which coincidentally overlooked the undulating lawn. She would love to claim a long walk in the park, but, if Mr. Collins meant to tend to Lady Catherine’s hysterics, the possibility of doing so was slim. It was not as if she could simply pardon herself and leave for a stroll about the grounds while her cousin was thus engaged. She realized this was an important moment in Mr. Collins’s life, for, if Lady Catherine was no longer in control of Rosings Park, what became of Mr. Collins’s living? Obviously, Lady Catherine had presented Mr. Collins the Hunsford living, but had the diocesan bishop accepted the presentation? If not, Mr. Collins’s position could be called in question.
And what, in that case, would become of Charlotte’s future? Elizabeth would not enjoy viewing Charlotte living in poverty. As Charlotte’s friend, she could not help but to wonder the extent of the living Lady Catherine had presented to Mr. Collins. Elizabeth knew some vicars lived on as little as thirty pounds per year. She suspected Mr. Collins received more, but how much more? It would take somewhere around one hundred pounds per year for the illusion of a modest lifestyle, which was what Elizabeth had observed at Hunsford Cottage. However, it was well understood that the right of presentation could be bought and sold. Was her father’s cousin receiving any of the tithes? She would write to her father and ask him what he knew of Mr. Collins’s position.
Like her mother, Elizabeth had made assumptions regarding Lady Catherine’s presentation of the living; none of the Bennets, perhaps with the exception of her father, had thought to question Mr. Collins’s constant praise of Lady Catherine’s generosity—just periodically roll their eyes at his foolishness mannerisms.
Now, since viewing her ladyship’s lack of care of parts of the estate, Elizabeth thought perhaps having Lady Catherine as Mr. Collins’s patroness might not be such a blessing, after all. She could not image her father’s cousin had come away from his days at Oxford with glowing reports that would draw the notice of any among the aristocracy. Then how came Mr. Collins to her ladyship’s notice? Perhaps he was acting in the place of another, more in the role of curate, and had not told anyone of the fragility of his position. Elizabeth made a silent promise to remain at Rosings to determine if she might be of service to her friend and mend the gap that had brought a breach in said friendship nearly a year prior and to learn the truth of Mr. Collins’s role in Hunsford’s future.
Her thoughts were thusly engaged on what she might do to assist Charlotte, beyond taking over some of her friend’s duties at Hunsford Cottage, when the “play” before her shifted with the entrance of new character.
“The Earl of Matlock, my lady,” the butler announced unexpectedly.
Along with the Collinses, Elizabeth scrambled to her feet to curtsey. She had never been presented to an earl, and the idea pleased her, for she thought both her father and her sister Jane would find Elizabeth’s recollection of the encounter amusing. As the earl crossed the room, totally ignoring anyone but Lady Catherine, both Mr. Collins and Charlotte slowly and silently drifted toward the corner of the room which Elizabeth occupied. The earl’s ample figure filled the room with its stoutness and with the gentleman’s obvious importance. In Elizabeth’s opinion, there was a strong likeness between his lordship and Lady Catherine. They both had the same aristocratic features, but in Elizabeth’s opinion, the cut of their noses and jawlines was more attractive on the gentleman than they were on her ladyship.
“What the deuce are you doing, Catherine?” he demanded of his sister without even an acknowledgement of Elizabeth’s or the Collinses’ presence in the room.
The invisible servant, Elizabeth thought. She had often heard her father say those words in a derisive manner when observing others’ treatment of the working class. Now, she fully understood his contempt. The earl completely ignored her presence in the room, marking her place in his esteem, despite her being a gentleman’s daughter.
“I expected to discover you removed to the dower house,” the earl continued. “Never thought you would take it upon yourself to set up such an uproar.”
“I have not had enough time to make my move official,” Lady Catherine protested.
“Nonsense,” the earl countered. “Anne, rest her soul, passed some fourteen months prior. Darcy has provided you more than enough time to vacate the manor house. Sir Lewis left everything to Anne. This house and estate have been your daughter’s, not yours, for some seven years. Rosings Park does not belong to you. It never has. From the day Anne met her majority, Rosings no longer was yours to oversee. You must come to terms with this situation. My God, you are a Fitzwilliam. We do not condone such hysterics. In her kindness, Anne erred in allowing you to remain in the role of the Mistress of Rosings Park, but, you must understand, legally, you cannot remain at the manor house. Darcy has the right to demand your withdrawal. If you do not comply, he can have the magistrate force you from your home. Save your dignity, Catherine, and do what is necessary. Such would be our father’s expectations for his eldest daughter.”
“Darcy,” Lady Catherine hissed. “I am certain I have learned to detest that name! How can it be lawful for him to claim everything simply because he was Anne’s husband? I am Anne’s mother. Should I not have some rights to a home I have nourished and cherished since my wedding day? Darcy has only visited Rosings when it was necessary. He holds no allegiance to the estate.”
“It was your wish for Darcy to marry your daughter,” the earl reminded his sister in cold tones. “You cannot deny that it was so. When George Darcy was still alive, Darcy’s father denied the connection, but, with George’s death, you again began to badger the boy into marrying Anne. You knew Darcy would never make Rosings Park his home seat when his ancestral home is in Derbyshire, and the life blood of that estate runs through his veins. You wanted Rosings for yourself. And that is exactly who you must blame for this fiasco.”
“He carried Anne off to Derbyshire, without even as much as a by your leave,” her ladyship argued. “Darcy was to protect her, not kill her. You know he poisoned Anne.”
Elizabeth could not disguise her gasp of surprise. However, before anyone took notice of her presence in the room, Charlotte caught Elizabeth’s hand and tugged her further along the passageway.
“You are to forget what you just heard,” Charlotte warned. “This is none of your concern. None of mine or Mr. Collins’s concern beyond our duty to Lady Catherine as her tenants. We owe my husband’s living to her ladyship.”
Although Elizabeth would not soon forget the remark nor her questions regarding Mr. Collins’s pandering to Lady Catherine, she understood the unspoken words: Mr. Collins’s living depended upon what occurred between Lady Catherine and the unknown gentleman by the name of Darcy. “Certainly, Charlotte,” she whispered. “You are correct. I shall do nothing to jeopardize your position in the neighborhood.”
“Mr. Collins and I will be expected to assist her ladyship,” Charlotte reiterated. “It grieves me not to be in a position to entertain you properly.”
Elizabeth dutifully said, “I shall be content to walk the park and to learn something of the Kentish countryside.”
Charlotte nodded sharply. “It shan’t be a total solitary endeavor. My brother John has been presented leave from his duties with the Dover militia. He thought to return to Hertfordshire, but I convinced him to visit with me instead. I hope you will not mind that I have asked him to spend time with us at Hunsford Cottage.”
Elizabeth prayed Charlotte did not mean to push for an alliance between Elizabeth and John. She knew her mother and Lady Lucas often connived to place Elizabeth in John Lucas’s way. She adored the young man, but only in a “brotherly” manner. She had not set her cap for him.
“Devilish rum business,” Lord Matlock’s voice reached them again before Elizabeth could respond. “But Darcy has his rights. You chose to force his hand, and, now, you must live with your manipulation. Our nephew married Anne. It is not his fault your daughter died in a little over half a year of pronouncing her vows. Even though they held nothing more than familial affection for each other, who is to say they might have made the best of it for the remainder of their days—mayhap they would have had a half-dozen children. That might have satisfied you to have grandchildren about you. Might have softened your nature. However, I do not think such a marriage would have made either Darcy or Anne happy. Like it or not, Catherine, they did not suit. Darcy adored his parents, and, whether you wish to recognize it or keep fooling yourself, George Darcy and our younger sister Anne were happy together. They loved each other deeply. Your belief that he should have chosen you instead of Anne—that you should have been mistress of such a breathtaking beautiful estate as Pemberley—is what drove you to force Darcy and your daughter together. You made your bed, now, you must lie in it.”
“Why did you not say all this beforehand—before my Anne’s marriage?” Lady Catherine demanded.
“I did say it, as did Lady Matlock, and my sons. You simply chose not to listen because you wished to be mistress of Rosings Park and use your courtesy title of ‘Lady Catherine’ from your reign as the daughter of an earl, rather than become the Dowager Lady de Bourgh,” the earl clarified. “Demme it, Catherine, with Anne’s passing, you did not even need to take on that dreaded stigma of ‘dowager.’ You could have simply been ‘Lady de Bourgh,’ a baronetess in your own right.” A long silence followed before Lord Matlock asked with a hint of sympathy, an emotion missing earlier from his voice. “Darcy is not the vindictive type. The boy says he has plans for Rosings Park that will provide you additional funds as part of your widow’s pension for the remainder of your days. Permit Darcy to tend the estate. It is admirable how you have handled Sir Lewis’s holdings for so long, but the political environment has placed even the wisest of land owners in this great kingdom at a disadvantage. If you heard half of what I do in the House of Lords, you would gladly step back from this charge. Permit Darcy to shoulder the responsibility. Accept the use of the dower house and enjoy your days without all these duties hanging over your head. Better yet, choose Bourgh Hall and join Society in London. There was a time you enjoyed the Season and all it brings. Allow the boy to do the work and claim what is your due. You served your husband well. No one can say otherwise.”
“Do I possess a choice?” her ladyship grumbled in what sounded of sarcasm.
“None whatsoever,” Lord Matlock pronounced in a cold tone. His lordship clapped his hands together as if the business was finished. “Should I summon your butler and your maid to assist in your removal to Bourgh House?”
“As yet, I have not one foot in the grave. I am capable of removing to the dower house without your supervision. My staff is quite efficient. Moreover, Mr. and Mrs. Collins will make certain my orders are completed in a timely manner.”
“Mr. Collins?” the earl asked.
Charlotte shoved her husband toward the still open door just as Lady Catherine declared, “Mr. Collins.” As if she suddenly recalled their presence in the room, the mistress of Rosings Park called out, “Mr. Collins? Where are you?”
“Here, my lady.” Collins bowed deeply as he stepped into the framed doorway.
“Tell his lordship you mean to assist me in this ugly business,” Lady Catherine ordered.
Elizabeth watched in amusement as Mr. Collins swallowed hard. He bowed again, nearly falling over in his obeisance. “Mrs. Collins and my cousin Miss Bennet will consider it not only our Christian duty, but, also, our pleasure to be of assistance to Lady Catherine in whatever manner necessary.” Mr. Collins motioned Charlotte and Elizabeth to join him in the doorway.
Elizabeth was just in time to note how the earl rolled his eyes when Mr. Collins bowed a third time in less than a minute. Dutifully, Elizabeth followed Charlotte in a curtsey.
Having recovered some of her renowned bravado, Lady Catherine said, “I have only been notified this very day that the necessary cleaning and painting at Bourgh House has been completed. As Darcy initially indicated I might remove at my leisure, I did not press the workers in their task.”
Elizabeth thought her ladyship’s reasoning foolish to assume, but she made no comment where her opinion would not be welcomed.
Lord Matlock shook his head in a disapproving manner, however, confirming Elizabeth’s opinion without it being voiced.
Lady Catherine quickly added in excuse, “I have not heard from Darcy for nearly a month.”
Lord Matlock overrode her objection by saying, “I dare say Darcy means to be in Kent by tomorrow, and I doubt you are not aware of his arrival. The boy has not one spontaneous bone in his body. We both know Darcy is not the type to appear without notice. You were informed, but chose to ignore the message. You have wasted your time, your ladyship. You have acted in denial of the inevitable.”
“Yet, there is no means for me to leave Rosings for, at least, another week.”
“You cannot demand that Darcy stay at the local inn. It would be little-minded to demand he do so. You will make everyone in the family, including you, uncomfortable. Making them choose sides will not be a wise choice if you cherish your dignity.” He returned his gloves to his hands. “Yet, I doubt you much care for the opinion of others. You never did. Therefore, as I am not required in this matter, I will return to London.”
“Will you not, at least, stay for tea?” her ladyship countered.
“My countess has a supper planned this evening. If I press my horses, I could be there in time for the first course.”
Lady Catherine drew herself up in obvious indignation. “Then you held no intention to be of service to me.”
“I would have stayed if you were not so headstrong, but I do not care to argue with you. You cannot be swayed. As to the supper, Lindale promised to assist his mother, but you know the nature of my eldest son.” With that, the earl brushed past Elizabeth and the Collinses without even a nod of his head in recognition. A quick glance to Lady Catherine noted a crestfallen expression for the briefest of moments, which was quickly replaced by aristocratic arrogance.
A pregnant moment passed before Charlotte found her voice and moved forward to curtsey again to Lady Catherine. “With your permission, your ladyship, I shall ring for tea, and we will assess how best to proceed in solving your dilemma.”
“Yes . . . yes,” her ladyship stammered. “You are very kind, Mrs. Collins. It appears even my own brother means to see me removed from the house that has been my home for nearly thirty years.”
Although she found Lady Catherine’s manners abhorrent, Elizabeth did not think it fair of this “Darcy” fellow to drive Lady Catherine from her home any more than it would be for her Cousin Collins and Charlotte to drive Elizabeth’s mother, Mrs. Bennet, and any remaining unmarried sisters from Longbourn when Mr. Bennet passed. Yet, she had no doubt Mr. Collins would arrive in Hertfordshire at breakneck speed when Elizabeth’s dear “Papa” took his leave of this earthly life. At least, Mr. Darcy had allowed Lady Catherine a year to move to another house upon the estate. Mrs. Bennet would not be accounted any such dignity.
The Mistress of Rosings Park: A Pride and Prejudice Vagary [releasing January 8, 2021]
I much prefer the sharp criticism of a single intelligent man to the thoughtless approval of the masses. – Johannes Kepler
When she arrives at Hunsford Cottage for a visit with her long-time friend Charlotte Collins, Elizabeth Bennet does not expect the melodrama awaiting her at Rosings Park.
Mrs. Anne Darcy, nee de Bourgh, has passed, and Rosings Park is, by law, the property of the woman’s husband, Mr. Fitzwilliam Darcy; yet, Lady Catherine de Bourgh is not ready to abandon the mansion over which she has served as mistress for thirty years. Elizabeth holds sympathy for her ladyship’s situation. After all, Elizabeth’s mother will eventually be banished from Longbourn when Mr. Bennet passes without male issue. She inherently understands Lady Catherine’s “hysterics,” while not necessarily condoning them, for her ladyship will have the luxury of the right to the estate’s dower house, and, moreover, it is obvious Rosings Park requires the hand of a more knowledgeable overseer. Therefore, Elizabeth takes on the task of easing Lady Catherine’s transition to dowager baronetess, but doing so places Elizabeth often in the company of the “odious” Mr. Darcy, a man Lady Catherine claims poisoned her daughter Anne in order to claim Rosings Park as his own.
NOW FOR THE GIVEAWAY!!! I HAVE FOUR eBOOK COPIES OF “THE MISTRESS OF ROSINGS PARK” AVAILABLE FOR THOSE WHO COMMENT BELOW. THE GIVEAWAY ENDS THURSDAY, DECEMBER 31, 2020. THE BOOKS WILL NOT BE DELIVERED UNTIL THE TALE ACTUALLY RELEASES ON JANUARY 8, 2021. GOOD LUCK!
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Vorga are a German black metal band whose music is equal parts melodic and atmospheric black metal. Striving Toward Oblivion is their debut full-length release. Their approach to black metal involves heightened intensity, clean production, and heavy repetition to reinforce melodic power. On Striving Toward Oblivion, the band’s path to success involves invoking an emotional response and letting the music’s simple moments act as glue rather than as a songwriting weakness.
Striving Toward Oblivion starts fast and furious. The opening riffs of “Starless Sky” let you know exactly what type of record this will be. Memorable, ferocious riffs fly over and under incandescent vocal lines. Vorga know their strengths and how to leverage them. This album is fast, it’s relentless, and it gives answer to any obstacle by adding more tremolo and howling. Even though the second track, “Comet,” goes forth at a slower tempo and with some softer moments, occasionally even forsaking blast beats, the intensity that Vorga use to kick in the door never disappears.
The sci-fi themes of Striving Toward Oblivion may invoke technical death metal, but such specters barely even haunt this record. These songs sound smooth and straight-forward. Melodies pulse with consistent, rhythmic allure, and songs routinely sacrifice glory for a chance for a good headbanging moment. The chord progressions never stray from what works. Instead, Vorga have gambled that you won’t care if a particular transition keeps happening, or if some passages repeat themselves one too many times, because you’ll be busy swimming in the cosmic fires that they have created. For the most part, their gamble works. I certainly noticed some issues with the song writing, but only rarely did these hiccups impact my enjoyment of the record.
Individual passages repeat and sometimes lack substance, but overall song structure takes the listener on a journey. I get frustrated with the band’s tendency to stay on a note and pound it into the ground, but Vorga flesh out the macro aspects of their sound with great success. Fitting for a band writing about space, I suppose. Tracks don’t feel formulaic, instead they feel like a natural and detailed progression of sounds. Individual passages tend towards being repetitive, but as you zoom out it all works.
Most flaws in records like these tend to occur generally throughout the record: if a singer is flat, they’ll probably be flat on every track and not just on specific notes, if the band can’t write a riff they won’t suddenly gain and lose the ability halfway through the record, those sorts of things. Striving Toward Oblivion contains some very specific screw-ups that make me wonder what happened in the production process. In “Stars My Destination,” the drumming starts to sound a little off over a minute in. Not a big deal. But as the song goes on, it gets worse. By 1:45, it starts to impact my enjoyment of the song. The drums sound slightly out of time, as if the tracks were cut and pasted ever-so-slightly off of where they should have been. Sometimes it’s noticeable, and sometimes it isn’t. Sometimes the guitars will give a little hiccup. This culminates when the music fully cuts out for a beat just as the track reaches the 5 minute mark.
I do not care about production perfection and often will not even notice issues that I see other people complaining about. But this weird silence absolutely destroys the song.The version on bandcamp has an additional 45 seconds that I don’t have and that isn’t listed on metal archives, so I guess they caught this and fixed it at the last minute. If I had noticed this earlier, my experience with Striving Toward Oblivion may have been different.
I considered taking those last two paragraphs out because this specific problem won’t affect most people, but this issue altered how I perceived Striving Toward Oblivion and therefore my overall enjoyment of the record. I’m glad that someone caught the issue, but I kind of wish that they’d caught it a little earlier. If you listen to Vorga on bandcamp, then congratulations on listening to a better version of the record than I did.
For a broader and more relevant complaint, Striving Toward Oblivion sputters out at the end. The songs don’t get worse, Vorga’s fire and ferocity just start to wear off. By the time the record ends, I’m ok with it. The fast, melodic blast at the beginning of the album turns into yet another overly repeated note with the same tone as all the others by the end. Striving Toward Oblivion never sounds bad, but it definitely loses its shine.
Striving Toward Oblivion is a solid atmospheric and melodic black metal album with its own identity and strengths. My biggest issues with it have apparently already been fixed. Although Vorga still have some issues to work out with their songwriting and ability to let a good thing fly free, they still accomplished all they needed to here. Eventually. I’d recommend this to everyone who complains about atmospheric black metal being boring and too long, and to anyone who’s looking for energetic meloblack. | https://www.metalutopia.com/vorga-striving-toward-oblivion-review/ |
Over the last 12 years, the Bulgarian pension system has been gradually reformed. The first step was taken in 1995, when voluntary private pensions were introduced. From 2000 onwards, parametric reforms in the first pillar were implemented; the same year, a mandatory second pillar system for workers in hazardous occupations was implemented. It was followed in 2002 by a mandatory second pillar for all employees. In 2006, Bulgaria decided to establish a reserve fund to support the financial stability of the first pillar system, which has not yet started operating and will be financed by proceeds from privatisation and 50% of any general budget surplus. On January 1, 2007, a fourth pension pillar started operating that comprises voluntary occupational pensions and is similar to those in Western countries. In brief, the system now in place is a four-pillar system with a public pillar as well as mandatory, voluntary private and voluntary occupational pensions.
In coming years, demographic change stands to become a major challenge for Bulgaria. Between now and 2050, the country's population will drop from 7.7 to 5.1 million, and it is ageing rapidly. While the current dependency ratio stands at 24.2%, by 2050 it will have skyrocketed to 53.1%, higher than the 52% average that has been forecasted for the EU-25. Still, according to the convergence programme Bulgaria submitted to the European Union, public pension expenditure is expected to decrease from 9.1% of GDP today to 7.9% in 2050. In contrast, the EU-25 average will increase from 10.6% of GDP to 12.8% over the same period.
Pension assets in 2006 amounted to EUR 523 million in the second pillar and EUR 253 million in the third pillar. Until 2015, we expect an annual growth rate of around 24% for second pillar and 20% for third pillar pension assets.
Public Pensions
The pre-reform system in Bulgaria was a pure PAYG system, the design of which suffered from various problems. The retirement age of 55 for women and 60 for men was quite low. Employees in various occupations could retire even earlier, and early retirement was used as a means of cutting the workforce during the transition period. Evading social security contributions was a widespread practise, and the dramatic rise in unemployment led to a fall in the number of contributors. The link between contributions and benefits was weak, as pension benefits were based on the three best-earning years.
To remedy the situation, the government developed a reform strategy that was implemented in 2000. Key measures included lowering the overall contribution rate and gradually increasing employee contributions. The government also decided to gradually raise retirement age – to 60 for women within a 10-year period, and to 63 for men within a six-year period. In addition, early retirement provisions for special groups are set to be phased out by 2010, and the benefit formula has been changed to establish a stronger link between contributions and benefits.
The current contribution rate is 8.05% of gross income for employees, and employers contribute 14.95%. Benefits are adjusted annually at a rate between the previous year's inflation and average real wage growth. To qualify for a state pension, the sum of the person's age and the number of years of participation in the pension scheme must be at least 100 for men and 91 for women (increasing to 94 by 2010). If length-of-service requirements are not met, the retirement age is 65 for both men and women with 15 years of contributory service.
In Bulgaria, there is a social and a minimum pension. The social pension is available to people aged 70 and over whose annual income per family member was less than the national guaranteed minimum income for the 12 months preceding retirement. The minimum pension is 115% of the social pension; the minimum pension is paid to individuals with low income and/or an incomplete work history. The maximum benefit from the earnings-related pillar is four times the amount of the social pension.
The Second Pillar – Mandatory Individual Accounts
There are two types of pension schemes in Bulgaria's second pillar: occupational and universal pension funds.
Occupational pension funds
(OPFs) are targeted to employees working in hazardous environments and are meant to make early retirement possible. They are fully-funded, defined contribution schemes with individual accounts. Contributions to occupational pension funds are made exclusively by employers and depend on the employee's job category. Additional voluntary contributions are not allowed. Contributions and investment income are exempt from taxes levied under the Personal Income Tax Act and the Corporate Income Tax Act.
Universal pension funds
(UPFs) cover employees (regardless of their job category) and the self-employed. Participation is compulsory for all workers born after December 31, 1959; older workers are excluded from the system. Universal pension funds are fully-funded defined contribution schemes with individual accounts. 5% of participants' social security contributions are redirected to the funded pillar, members choose their provider.
Contributions to UPFs amount to 5% of salary; the upper earnings limit for contribution purposes is BGL 1,400 (EUR 719). The self-employed must pay the entire 5% contribution themselves. Additional voluntary contributions are not permitted.
Investment regulations
Bulgaria subdues mandatory pension funds with investment limits and a minimum return guarantee. Investment regulations for mandatory funds are currently under review, and the main limits currently in place are as follows:
- Up to 20% can be directly invested in equities
- A maximum of 15% can be invested in collective investment schemes
- No more than 5% can be invested in property or securities issued by a single company
The requirement that at least 50% of fund assets must be invested in securities issued or guaranteed by the government was lifted in 2006. There is also a limit for international investments. Pension funds can invest a maximum of 15% of assets abroad.
Currently, the association of Bulgarian pension management companies BASPC calls for a lifting of the cap on investment in equities from 20% to 30%. But the Financial Supervision Commission would only consider lifting the limits on third pillar voluntary funds. Another request demands the introduction of funds reflecting different risk and return profiles by offering high-risk, balanced and conservative funds with varying equity exposures.
Pension insurance companies are obliged to achieve a minimum rate of return when managing fund assets, which is determined by the Financial Supervision Commission at the end of each quarter. The minimum rate of return is stated separately as a percentage of universal and occupational pension funds, and is based on the return achieved for all funds of the same type in the previous two years. The minimum rate of return for each type of pension fund is 60% of the average rate of return achieved, or three percentage points lower than the average, depending on which of the two figures is lower.
If a mandatory fund achieves a rate of return that is lower than the minimum, the pension insurance company managing the fund is obliged to cover the difference within ten days using reserves that have been established specifically for this purpose. Where the rate of return achieved by a universal or occupational pension fund exceeds the average rate of return by more than 40% or exceeds the average by three percentage points – whichever of the two figures is higher – the fund must transfer the additional resources to its reserves.
Benefits and withdrawal
Benefits are paid as a life-long pension and are based on the capital accumulated in the individual account and on life expectancy. Annuities are paid by the pension fund.
Taxation
Essentially, Bulgaria runs an EEE system in which contributions to UPFs (and to occupational funds), investment income and benefits are exempt from taxes.
The Third and the Fourth Pillar – Voluntary Pension Savings
Voluntary pension funds – the third pillar
Voluntary private pension funds (VPFs) were introduced in the mid-1990s. They marked the first step of a comprehensive pension reform program that aimed to increase private pension savings. Voluntary personal schemes are fully-funded defined contribution schemes with individual accounts. Participation currently stands at 557,000 and assets under management amount to EUR 253 million. There are now nine pension funds on the market and the largest two companies have a combined market share of 75%.
The pension fund managing company and the fund it manages are separate legal entities. Participation is open to all citizens over 16. Contribution levels are freely determined in a contract between the pension fund managing company and the contributor (an individual or an employer). The average monthly contribution is BGN 47 (EUR 24), and participants do not have a choice of portfolios. Information on the value of personal pension accounts is published every day. The pension fund pays out benefits either in the form of a lump sum, phased withdrawals or periodic payments.
Member contributions of up to 10% of pensionable income are exempt from personal income tax. The same applies to employer contributions and investment income. Benefits used to be taxed, but from January 2007 onwards they are also exempt within certain limits. Clearly, Bulgaria runs an EEE system in the voluntary pillar as well.
While investment regulations for voluntary pension funds resemble those of their mandatory counterparts, they are slightly more generous. The maximum limit for investment property is 10% rather than 5% and the limit on international investments is 20% rather than 15%. The minimum limit for government securities of 30% was lifted in 2006. Actual asset allocation is as follows: Government securities make up 39% of asset allocation, bank deposits account for 23%, shares and corporate bonds for 13% and mortgage bonds for 8%.
Voluntary occupational schemes – the fourth pillar
The latest development in the Bulgarian pension system is the introduction of voluntary occupational schemes, which are set to start operating in 2007. They are very similar to occupational schemes in Western Europe, and coverage is determined by collective bargaining agreements or collective employment contracts. Voluntary schemes provide benefits in the form of fixed-term pensions, lump-sum payments or phased withdrawals to participants when they reach the age of 60, in accordance with the rules stipulated in collective bargaining agreements or collective employment contracts. Voluntary occupational schemes are managed by pension fund managing companies. Benefits are taxed in the same way as under voluntary personal pensions; the same is true for investment and all other regulations. However, until mid 2007 there were still no voluntary occupational schemes in operation.
Outlook
UPFs show impressive growth rates. Introduced in 2002, they covered almost 82% of the workforce, or 2.4 million participants, by the end of 2006. Assets in 2006 stood at EUR 523 million, and the contribution rate was raised to 5% of gross salary in January 2007.
Fast asset development stems mainly from contributions rather than performance, as the market is still in its infancy. Given the already high participation rate, further growth will mainly come from wage increases. Membership will develop at a slower pace and will largely depend on new labour market entrants.
Participation in OPFs is low because of their narrow focus on people in hazardous occupations. In 2006, there were 192,800 members in occupational pension funds, and assets under management amounted to EUR 161 million. Growth prospects are limited due to the small group of targeted workers.
Given that wages are expected to increase substantially and participation is developing slowly, the future of these two mandatory systems looks promising. With a conservative assumption of 5% average performance, assets under management are expected to reach EUR 3.6 billion by 2015.
Third-pillar VPFs had 566,000 members in 2006 and EUR 253 million in assets under management. As income levels increase, it is likely that more people will join, though we assume that new participants will mainly be in the prime of their working lives. Increasing participation rates and higher wage hikes will support growth in the third pillar pension market. In our projection, assets under management will reach EUR 1.27 billion by 2015 (+20 % p.a). Given the existence of the mandatory system, chances for even faster market growth are very limited.
Pension reform in Bulgaria has been a gradual, step-by-step process that has resulted in a four-pillar system with a reformed first pillar, a highly
accepted mandatory second pillar, an underdeveloped voluntary third pillar and a brand new fourth pillar. The introduction of the fourth pillar with voluntary occupational pensions is a very interesting experiment, as it could become a valuable instrument for employee retention, not least for multinational companies with operations in Bulgaria.
Discussions are ongoing in Bulgaria with regard to further funded pillar reforms. Topics include relaxing investment restrictions, introducing individual investment choice in mandatory and voluntary pensions and the financing of the reserve fund. Bulgaria is likely to remain a fast-growing market for asset managers; it will become even more attractive as income levels increase. | https://www.pensionfundsonline.co.uk/content/country-profiles/bulgaria |
Recent advances in basic and clinical science have driven epigenetics to the forefront of cancer research. Together with genetic changes, the disruption of epigenetic mechanisms is now established as a hallmark of cancer in humans. Colorectal cancer, long a classic model for the genetic basis of cancer, is now providing researchers with the opportunity to view epigenetic events in the context of neoplasia in humans. Knowledge of the heritable changes in gene expression that result from epigenetic events is of increasing relevance to clinical practice, particularly in terms of diagnostic and prognostic molecular markers, as well as novel therapeutic targets.
BACKGROUND
Colorectal cancer, for many years a prototypic model for the genetic basis of cancer, is now increasingly cited as an exemplar of the role of epigenetic changes in tumorigenesis. In part, this is because colorectal neoplasia provides a wide range of accessible lesions, from aberrant crypt foci to carcinoma. It also serves as a poster child for epigenetic change because of the possible role that DNA methylation has in the initiation and progression of this disease. For both these reasons, it provides an excellent opportunity to understand how epigenetics and genetics collude to produce malignancy.
This review will provide a broad overview of common epigenetic processes as they occur in the normal cell and in the cancer cell, and will highlight recent findings in the epigenetics of colorectal neoplasia. It will briefly discuss the clinical implications of epigenetic changes, in terms of both the identification of disease predisposition and the therapeutic opportunities that a better understanding of these changes may provide. The term epigenetics, while variously defined,1 will be used in this review to describe those heritable changes in gene function that do not entail a change in DNA sequence.2 Table 1 shows the key historical milestones in …
Footnotes
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Published Online First 13 July 2006
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Funding: This work was supported in part by grants from the National Health and Medical Research Council of Australia and The Cancer Council of New South Wales. JJLW is the recipient of an International Postgraduate Research Scholarship.
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Competing interests: None.
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If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. | https://gut.bmj.com/content/56/1/140?ijkey=c715622ba211d025101a4583f19156580d9dd454&keytype2=tf_ipsecsha |
Q:
The Cipher Machine
"CIPHER, CIPHER, CIPHERS. I LOVE CIPHERS. A LOT. YOU HAVE NO IDEA HOW MUCH I LIKE THEM. THEY ARE VERY FUN!", said the cryptographer.
"YOU HAVE NO IDEA."
"ANYWAYS, THERE ARE INPUTS AND OUTPUTS. THERE ARE EXAMPLES THAT SHALL ASSIST YOU. FILL IN THE "??" IN THE EXAMPLES WHICH HAVE A MISSING INPUT OR OUTPUT."
"TO DO THAT, YOU MUST FIND WHAT CIPHER HAS BEEN USED, I ASSUME. I HOPE THE TASK IS NOT TOO DIFFICULT FOR A PUZZLE SOLVER SUCH AS YOU."
Input: THIS IS A TEST
Output: ZBRD HA A YBDV
Input: THIS IS A TEST OF A VERY LONG MESSAGE, VERY LONG INDEED
Output: ZBRD HA A YBDV QF J ZAAZ LFTJ VRJKCMF, LVMR DVVD MAZMTK
Input: THIS is A test 123456!@#$gt84EUEOEFJQAQ789hgjfeeu^((&
Output: ZBRD ha A ybdv 123456!@#$jt84DYATRFRVBY789eothbfk^((&
Input: NUMBERS ARE NOT AFFECTED 0123456789
Output: WZTGSSS JDA QQT JLKSITUH 0123456789
Input:
! " # $ % & ' ( ) * + , - . /
0 1 2 3 4 5 6 7 8 9 : ; < = > ?
@ A B C D E F G H I J K L M N O
P Q R S T U V W X Y Z [ \ ] ^ _
` a b c d e f g h i j k l m n o
p q r s t u v w x y z { | } ~
Output:
! " # $ % & ' ( ) * + , - . /
0 1 2 3 4 5 6 7 8 9 : ; < = > ?
@ K K E J S G G B R M M M M V V
R U S S C P V R I B F [ \ ] ^ _
` f d j w q z i u h e q u b f j
y m h r c p v r i b f { | } ~
Input: Some more examples. This is some random text that I am just typing.
Output: Jwta oqrd bcdnptbd. Veij qv fssd dgknso abhj weku A ks iygc datndm.
Input: Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor incididunt ut labore et dolore magna aliqua. Ut enim ad minim veniam, quis nostrud exercitation ullamco laboris nisi ut aliquip ex ea commodo consequat. Duis aute irure dolor in reprehenderit in voluptate velit esse cillum dolore eu fugiat nulla pariatur. Excepteur sint occaecat cupidatat non proident, sunt in culpa qui officia deserunt mollit anim id est laborum.
Output: Uwdao ppgyq gqlwd dhu ahvy, esobfubkfbw jmpvbveunp uurt, zbp hw gfvbnxd uucsrs uwefqqkvfz df xcjsav du zomcsk dxefc vvddzg. Yj kams jk ebiow pqotiw, jkrw oskpuvz rjzdnpcwgvqw frucuuc qejwrpz xuaq fk vpbauqn gr vj ixrnxfg tyeawjvdx. Sybs ydbv fwuwu mvsgj uz zrbjywbolyfrp qe jwmfaxdyb ybefx dazr nwrplo pyavcb qv hyoagt obpbw gytqjxyz. Logrdjult ubqc wiacyrgn cyeukiyku sfa pryrdgdt, cwop bd aketx uzq qtlotai zxaurlev wdbmqh ooin bq bjx tiyfugh.
Input: In publishing and graphic design, lorem ipsum (derived from Latin dolorem ipsum, translated as "pain itself") is a filler text commonly used to demonstrate the graphic elements of a document or visual presentation. Replacing meaningful content with placeholder text allows designers to design the form of the content before the content itself has been produced.
Output: Av sxfmigaeqj avk labpeop hjupot, mangr fkgio (jrrfzff vvrs Tgbpq mghcddn wsmeu, fuvxzmxpvx yg "swpq akvxto") oj v ouqxgg vgyd ifvtrcme inrx av lxtldsfuwfu aiy odnvufe truvxvcz vh f kprioaot vt znffcu tmgmvnkwxofa. Fzhuiamqn tfgsuxegge rvqagnu jjba debnmkgpdvv jbkj hmauyu nefepekdg jv sxkmza mdk lxsc al ydx ocuzrid ialiwd bul tuutvsj rdzjqu ujf iabn tvfkftrp.
Input: THIS IS ANOTHER TEST
Output: ??
Input: ??
Output: BZHPNPNN KUV AE
Hint:
Somewhere within the story, lies the key.
Where it is, you'll have to see.
But I think, we all agree
That you're on a cipher solving spree!
Even if you're not,
You have to find, find the key.
Am I running out of rhymes?
Please don't tell that, tell that to me.
A:
Input: THIS IS ANOTHER TEST
Output:
ZBRD HA AVVWRRR YBDV
Input:
PUZZLING DOT SE
Output: BZHPNPNN KUV AE
The cipher is
An Autokeyed Vigenere, using the Alphabet "CIPHERSABDFGJKLMNOQTUVWXYZ" And the passphrase "srehpicrehpicrehpic" (cipher, cipher, ciphers reversed) After getting through that key, it then starts using the plaintext as the cipher.
I noticed that the
6th position was advancing by one letter each time, or going from S to A this led me to believe there was a keyed alphabet involved, my second or third alphabet experiment was ciphers and some experimentation with the given input and outputs let me find a pattern that matched. After hitting the end of the key I was a little confused, but I kept going and saw that the text I was appending to the Key was the start of the Plaintext. It was an Autokey!
| |
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Science and Education Publishing journals supply full-text articles in PDF, HTML and ePUB formats
J.UCS - The Journal of Universal Computer Science - is a high-quality open access electronic publication that deals with all aspects of computer science. J.UCS has been appearing monthly since 1995 and is thus one of the oldest electronic journals with uninterrupted publication since its foundation. J.UCS also appears in an annual printed archive edition. The publication volume comprises more than 1100 peer-reviewed articles.
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Journal of Computer Science & Systems Biology is the best Open Access journal and aims to publish most complete and reliable source of information on the discoveries and current developments in the mode of original articles, review articles, case reports, short communications, etc. in all areas of the field and making them freely available through online without any restrictions or any other subscriptions to researchers worldwide.
Computers is an international, open access journal which provides an advanced forum for computer sciences. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. | https://lahore.comsats.edu.pk/libguide/subject-guide.aspx?id=1&pid=39 |
Updates to COVID-19 Restrictions
Starting at 9 a.m. on Friday, December 17, and lasting until at least the new year, the following restrictions will be in place. Please find below the restrictions that may be relevant to our choral community.
Physical distance and mask requirements:
- physical distance of two metres (six feet) is required indoors and outdoors, except among people in the same household or a consistent social group of up to 20 people
- individuals, businesses and organizations all have responsibility for ensuring mask requirements are followed and can all be subject to enforcement action
Gathering limits:
- gathering limits of 50 per cent of capacity to a maximum of 150 people indoors and 250 outdoors apply to social gatherings, regular faith services, weddings, funerals and their associated receptions and visitation, special events, meetings, training, festivals, and audiences for sports events and arts and culture events (like performances and movie theatres) that are hosted by a recognized business or organization, including faith organizations
- a limit of 60 participants indoors and outdoors applies to professional and amateur arts and culture rehearsals and performances; competitions are not allowed; professionals must have a plan for their workplace; physical distance is not required, and masks are recommended when possible indoors and outdoors
- children age 11 and younger continue to be restricted from entering Nova Scotia to participate in sports and arts and culture events and from participating in them outside Nova Scotia
Vaccinations:
There is no change in the requirement for proof of full vaccination for discretionary activities. It is still required for attendees and volunteers, even in places where gathering limits and physical distance will apply.
Additional Resources: | https://nscf.ca/updates-to-covid-19-restrictions/ |
The first regatta of the season was sailed on a cool, wet day in Portland Harbor. There was no wind to start the day and the postponement lasted until it was time for a hot lunch served by the parents of the Yarmouth team. Around noon PRO Eliza Price sent the sailors out into the rain and the first races were sailed in about four knots from the south. The wind gradually built and shifted right with the last set sailed in 8-10 knots from the southwest. Thanks to all of the teams who participated in the Latchstring Regatta.
|School||Team||A||B||TOT|
|1||Unregistered-NESSA||Southern ME||23||15||38|
|2||Mt. Desert Island HS||Trojans||24||21||45|
|3||Cheverus High School||Stags||13||39||52|
|4||Yarmouth High School||Clippers||32||21||53|
|5||Brookline High||Warriors||37||19||56|
|6||Falmouth High School, ME||Yachtsmen||52||25||77|
The following chart shows the relative rank of the teams as of the race indicated. Note that the races are ordered by number, then division, which may not represent the order in which the races were actually sailed.
The first place team as of a given race will always be at the top of the chart. The spacing from one team to the next shows relative gains/losses made from one race to the next. You may hover over the data points to display the total score as of that race. | https://scores.hssailing.org/s16/latchstring-jv/ |
BACKGROUND
SUMMARY
DETAILED DESCRIPTION
The present invention relates to a high performance plastic radome and, more specifically, to a high performance plastic radome with layers of low density polymer LDPE and LDPE foam.
A large number of radar systems require a radome to provide environmental protection to the electronic apertures. Such radomes are sometimes designed and optimized to have high performance characteristics in that they provide for minimum radio frequency (RF) loss, are ruggedized for environmental protection and are relatively light weight with little regard to low cost. These radomes can be designed for commercial and/or military applications and can be optimized for different frequency bands of the electromagnetic spectrum. In addition, radomes sometimes need to be resistant to and sealed against moisture, chemicals, gases and dust, plus be able to withstand wide temperature ranges and have a required color. It is often needed that designers sacrifice low cost to meet all these other requirements.
High performance radomes require careful selection and understanding of material properties that directly affect radome and antenna performance. The combination of high performance requirements and a requirement for low cost create a problem where a solution is not intuitively obvious. For instance, conventional A-sandwich and C-sandwich radome constructions are common ways to have low RF loss, low weight and high strength but are not considered low cost designs. An A-sandwich radome has two high dielectric skins (sheets) and a low dielectric core, whereas a C-sandwich radome has three high dielectric skins and two low dielectric cores. A conventional A-sandwich or C-sandwich radome construction utilizes specialty materials, requires a cure cycle, and is usually an autoclave operation. They are typically designed with multiple types of materials and uncommon thicknesses of materials, using a radome facility with an autoclave and highly trained personnel for assembly.
According to one embodiment of the present invention, a radome is provided and includes a first layer of low density polymer (LDPE) through which electromagnetic radiation is transmittable, a second layer of LDPE foam through which the electromagnetic radiation, having passed through the first layer, is transmittable, a third layer of LDPE through which the electromagnetic radiation, having passed through the first and second layers, is transmittable and adhesive layers respectively interposed between the first and second layers and between the second and third layers.
According to another embodiment of the present invention, a radome is provided and includes a first layer of low density polymer (LDPE) foam through which electromagnetic radiation is transmittable, a second layer of LDPE through which the electromagnetic radiation, having passed through the first layer, is transmittable, a third layer of LDPE through which the electromagnetic radiation, having passed through the first and second layers, is transmittable, a fourth layer of LDPE foam through which the electromagnetic radiation, having passed through the first, second and third layers, is transmittable, a fifth layer of LDPE through which the electromagnetic radiation, having passed through the first, second, third and fourth layers, is transmittable and adhesive layers respectively interleaved between the first, second, third, fourth and fifth layers.
According to another embodiment of the present invention, a method of forming a radome is provided and includes rotomolding two or more layers of low density polymer (LDPE), rotomolding one or more layers of LDPE foam and adhering the two or more layers of LDPE and the one or more layers of LDPE foam.
Additional features and advantages are realized through the techniques of the present invention. Other embodiments and aspects of the invention are described in detail herein and are considered a part of the claimed invention. For a better understanding of the invention with the advantages and the features, refer to the description and to the drawings.
As will be described below, a radome is provided that includes low cost materials and requires low cost processes to construct A-sandwich configurations, C-sandwich configurations and modified versions of both to achieve high performance at very low cost. The achievable high performance includes low RF loss, ruggedizaton for environmental protection and low weight. The low cost materials include polyolefins, polyethylene and polypropylene with off-the-shelf color and thicknesses. The low cost processes employ pressure sensitive adhesive (PSA) between higher dielectric sheets and lower dielectric foam. Complex shapes are addressed by rotomolding. The assembly of the radomes does not require a cure cycle or an autoclave and does not require highly trained personnel.
FIG. 1A
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With reference now to , a radome is provided with an A-sandwich configuration. The radome includes a first layer of low density polymer (LDPE) through which electromagnetic radiation is transmittable, a second layer of LDPE foam through which the electromagnetic radiation, having passed through the first layer, is transmittable, a third layer of LDPE through which the electromagnetic radiation, having passed through the first and second layers, is transmittable and adhesive layers . The adhesive layers are respectively interposed between the first layer and the second layer and between the second layer and the third layer . For each of the first, second and third layers , and , the LDPE and the LDPE foam may include at least one or more of polyethylene, polypropylene and polyolefin. For the adhesive layers , the adhesive used may include pressure sensitive adhesive (PSA).
FIG. 1B
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With reference to , the LDPE foam of the second layer may be provided as a closed cell (i.e., moisture and corrosion resistant) foam of substantially uniform or varying cell sizes. In either case, at an outer surface of the second layer , the proximal cells of the closed cell foam are open and include tangential corners . Thus, during formation of the radome , pressure applied to one or more of the first, second and third layers , and about the adhesive layers causes a portion of the PSA to partially flow into the open proximal cells about the tangential corners . Once cured, this portion of the PSA increases an adherence of the first and second layers and and of the second and third layers and .
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In accordance with embodiments, respective thicknesses and colors of the first and third layers and may be off-the-shelf quantities and thus are relatively inexpensive. In accordance with further embodiments, the second layer may be thicker, have a lower dielectric constant owing in part to the air in the cells and have a lower loss tangent than the first, third and adhesive layers , and . In particular, the first and third layers and may be about 0.020″ thick, have dielectric constants, ∈, of about 2.3 and have loss tangents, tan δ, of about 0.0005, the second layer may be about 0.525″ thick, have a dielectric constant, ∈, of about 1.15 and have a loss tangent, tan δ, of less than about 0.0001, and the adhesive layers may be about 0.005″ thick, have dielectric constants, ∈, of about 3.0 and have loss tangents, tan δ, of about 0.017. Thus, the radome of may have a total thickness of about 0.575″, a max RF loss characteristic of about 0.15 dB for 0°-60° scan and a weight of about 0.52 lb/ft.
FIG. 2
FIG. 2
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With reference to , the radome may be provided with a first C-sandwich configuration in which the first, third and adhesive layers , and are provided generally as described above. The second layer may include a primary LDPE foam layer , which is proximate to the first layer , a secondary LDPE foam layer , which is proximate to the third layer , a mid-layer LDPE layer , which is interposed between the primary and secondary LDPE foam layers and and additional adhesive layers . As shown in , the additional adhesive layers are respectively interposed between the primary LDPE foam layer and the mid-layer LDPE layer , and between the mid-layer LDPE layer and the secondary LDPE foam layer .
FIGS. 3-5
FIG. 2
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As above (and for the embodiments of ), the LDPE and the LDPE foam may include at least one or more of polyethylene, polypropylene and polyolefin, the adhesive used may include pressure sensitive adhesive (PSA) and the primary and secondary LDPE foam layers and may be provided as closed cell (i.e., moisture and corrosion resistant) foams of substantially uniform or varying cell sizes. In any case, at outer surfaces of the LDPE foam layers, the proximal cells of the closed cell foams are open and include tangential corners. Thus, during formation of the radome of (and the radomes of ), applied pressure causes a portion of the PSA to partially flow into the open proximal cells about the tangential corners. Once cured, this portion of the PSA increases an adherence of the various layers.
FIG. 2
FIG. 2
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In accordance with embodiments for the radome of , respective thicknesses and colors of the first and third layers and may be off-the-shelf quantities and thus are relatively inexpensive. In accordance with further embodiments, the second layer may be thicker, have an effectively lower dielectric constant owing in part to the air in the cells and have an effectively lower loss tangent than the first, third and adhesive layers , and . In particular, the first and third layers and may be about 0.023″ thick, have dielectric constants, ∈, of about 2.3 and have loss tangents, tan δ, of about 0.0005, the primary and second LDPE foam layers and may be about 0.385″ thick, have dielectric constants, ∈, of about 1.05 and have loss tangents, tan δ, of less than about 0.0001, the mid-layer LDPE layer may be about 0.040″ thick, have a dielectric constant, ∈, of about 2.3 and have a loss tangent, tan δ, of about 0.0005 and the additional adhesive layers may be about 0.005″ thick, have dielectric constants, ∈, of about 3.0 and have loss tangents, tan δ, of about 0.017. Thus, the radome of may have a total thickness of about 0.850″, a max RF loss characteristic of about 0.10 dB for 0°-60° scan and a weight of about 0.88 lb/ft.
FIG. 3
FIG. 3
FIG. 3
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With reference to , the radome may be provided with a second C-sandwich configuration in which the first, third and adhesive layers , and are provided generally as described above. As for the second layer , the second layer may include a primary LDPE foam layer , which is proximate to the first layer , a secondary LDPE foam layer , which is proximate to the third layer , and primary and second mid-layer LDPE layers and . The primary mid-layer LDPE layer is interposed between the primary and secondary LDPE foam layers and and is proximate to the primary LDPE foam layer . The secondary mid-layer LDPE layer is interposed between the primary and secondary LDPE foam layers and and is proximate to the secondary LDPE foam layer . The radome of further includes additional adhesive layers . As shown in , these additional adhesive layers are respectively interposed between the primary LDPE foam layer and the primary mid-layer LDPE layer , between the primary and secondary mid-layer LDPE layers and and between the secondary mid-layer LDPE layer and the secondary LDPE foam layer .
FIG. 3
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In accordance with embodiments for the radome of , respective thicknesses and colors of the first and third layers and may be off-the-shelf quantities and thus are relatively inexpensive. In accordance with further embodiments, the second layer may be thicker, have an effectively lower dielectric constant owing in part to the air in the cells and have an effectively lower loss tangent than the first, third and adhesive layers , and . In particular, the first and third layers and may be about 0.023″ thick, have dielectric constants, ∈, of about 2.3 and have loss tangents, tan δ, of about 0.0005, the primary and second LDPE foam layers and may be about 0.385″ thick, have dielectric constants, ∈, of about 1.05 and have loss tangents, tan δ, of less than about 0.0001, the primary mid-layer LDPE layer may be about 0.023″ thick, have a dielectric constant, ∈, of about 2.3 and have a loss tangent, tan δ, of about 0.0005, the secondary mid-layer LDPE layer may be about 0.023″ thick, have a dielectric constant, ∈, of about 2.3 and have a loss tangent, tan δ, of about 0.0005 and the additional adhesive layers may be about 0.003″ thick, have dielectric constants, ∈, of about 3.0 and have loss tangents, tan δ, of about 0.017. Thus, the radome of may have a total thickness of about 0.867″, a max RF loss characteristic of about 0.12 dB for 0°-60° scan and a weight of about 0.93 lb/ft.
FIGS. 4 and 5
FIGS. 4 and 5
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10
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With reference to , a radome is provided with multi-layer (ML) configurations. The radome includes a first layer of LDPE foam through which electromagnetic radiation is transmittable, a second layer of LDPE through which the electromagnetic radiation, having passed through the first layer , is transmittable, a third layer of LDPE through which the electromagnetic radiation, having passed through the first and second layers and , is transmittable, a fourth layer of LDPE foam through which the electromagnetic radiation, having passed through the first, second and third layers , and , is transmittable and a fifth layer of LDPE through which the electromagnetic radiation, having passed through the first, second, third and fourth layers , , and , is transmittable. In addition, the radome of may include adhesive layers that are respectively interleaved between the first, second, third, fourth and fifth layers , , , and .
22
26
27
FIGS. 1-4
FIG. 5
For each of the first-fifth layers -, the LDPE and the LDPE foam may include at least one or more of polyethylene, polypropylene and polyolefin. For the adhesive layers , the adhesive used may include pressure sensitive adhesive (PSA). While the LDPE foam described with reference to may be provided as 10% LDPE foam, the LDPE foam of may be provided as black LDPE foam.
FIG. 4
FIG. 4
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22
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27
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2
In accordance with embodiments for the radome of , respective thicknesses and colors of the first-fifth layers - may be off-the-shelf quantities and thus are relatively inexpensive. In accordance with further embodiments, the first and fourth layers and may be thicker, have a lower dielectric constant owing in part to the air in the cells and have a lower loss tangent than the second, third, fifth and adhesive layers , , and . In particular, the first and fourth layers and may be about 0.415″ and 0.315″ thick, respectively, have dielectric constants, ∈, of about 1.05 and have loss tangents, tan δ, of less than about 0.0001, the second and third layers and may be about 0.023″ thick, have dielectric constants, ∈, of about 2.3 and have loss tangents, tan δ, of less about 0.0005, the fifth layer may be about 0.060″ thick, have a dielectric constant, ∈, of about 2.3 and have a loss tangent, tan δ, of about 0.0005 and the adhesive layers may be about 0.003″ thick, have dielectric constants, ∈, of about 3.0 and have loss tangents, tan δ, of about 0.017. Thus, the radome of may have a total thickness of about 0.848″, a max RF loss characteristic of about 0.25 dB for 0°-60° scan and a weight of about 0.96 lb/ft.
FIG. 5
FIG. 5
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In accordance with embodiments for the radome of , respective thicknesses and colors of the first-fifth layers - may be off-the-shelf quantities and thus are relatively inexpensive. In accordance with further embodiments, the first and fourth layers and may be thicker, have a lower dielectric constant owing in part to the air in the cells and have a lower loss tangent than the second, third, fifth and adhesive layers , , and . In particular, the first and fourth layers and may be about 0.410″ and 0.310″ thick, respectively, have dielectric constants, ∈, of about 1.066 and have loss tangents, tan δ, of less than about 0.001, the second and third layers and may be about 0.023″ thick, have dielectric constants, ∈, of about 2.3 and have loss tangents, tan δ, of less about 0.0005, the fifth layer may be about 0.060″ thick, have a dielectric constant, ∈, of about 2.3 and have a loss tangent, tan δ, of about 0.0005 and the adhesive layers may be about 0.003″ thick, have dielectric constants, ∈, of about 3.0 and have loss tangents, tan δ, of about 0.017. Thus, the radome of may have a total thickness of about 0.838″, a max RF loss characteristic of about 0.25 dB for 0°-60° scan and a weight of about 0.95 lb/ft.
10
10
10
10
10
10
For each of the embodiments described above, the LPDE on the exteriors of the radomes act as skins for providing the radomes with ruggedness and toughness even while being possibly deformable and compliant. Similarly, the LDPE in the interiors of the radomes also provide the radomes with increased ruggedness and toughness without sacrificing deformability and compliance. Meanwhile, the LDPE foam may be provided as compliant or deformable layer(s). In any case, while radomes in general are formed as rigid or semi-rigid structures, the radomes described above may be characteristically deformable and compliant in at least some layers thereof. As such, impacts with foreign debris in particular can be absorbed and/or deflected. Thus, where foreign debris impacts might be catastrophic to a conventional radome, such incidents may not even lead to damage to the radomes described above.
FIGS. 6 and 7
FIG. 6
FIG. 7
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With reference to , the radomes described above may be provided as planar radomes (see ) or as curved or complex-shaped radomes (see ).
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In the former case, the planar radomes may be housed in a housing that is formed to define an aperture through which electromagnetic radiation or any other signals are transmittable. In this case, the corresponding planar radome is configured to extend entirely across the aperture such that the electromagnetic radiation/other signals pass through the planar radome during the transmittance.
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In the latter case, the curved or complex-shaped radomes may be configured for use in, for example, a nose cone of a missile or aircraft. As such, the curved or complex-shaped radomes may include an aerodynamic nose cone section , sidewalls extending aft from the nose cone section and one or more surface features for housing or accommodating structural elements, sensors, etc. In such cases, the nose cone section may be more apt to experience foreign debris impacts than the sidewalls and the sidewalls may need to be more transparent to electromagnetic radiation/signals. Thus, the curved or complex-shaped radomes can be designed such that the nose cone section is more rugged than the sidewalls and such that the sidewalls are more transparent and less prone to signal loss than the nose cone section .
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FIG. 1A
To this end, any one of the LDPE or LDPE foam layers described above may be provided with varied intra-layer characteristics. For example, in a case where the radome of is used as a curved or complex-shaped radome , the LDPE foam of the second layer may be provided with varying cell sizes in the nose cone section and the sidewalls . More particularly, the cell sizes in the nose cone section may be relatively small as compared to the cell sizes in the sidewalls to provide the nose cone section with increased ruggedness while maintaining low loss characteristics of the sidewalls .
In accordance with additional aspects, it is to be understood that the various layers of LDPE and LDPE foam described above may be formed by way of rotational molding and/or other similar methods, such as injection molding, rotational casting, casting, machining and three-dimensional printing.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one more other features, integers, steps, operations, element components, and/or groups thereof.
The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present invention has been presented for purposes of illustration and description, but is not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.
The flow diagrams depicted herein are just one example. There may be many variations to this diagram or the steps (or operations) described therein without departing from the spirit of the invention. For instance, the steps may be performed in a differing order or steps may be added, deleted or modified. All of these variations are considered a part of the claimed invention.
While the embodiment to the invention has been described, it will be understood that those skilled in the art, both now and in the future, may make various improvements and enhancements which fall within the scope of the claims which follow. These claims should be construed to maintain the proper protection for the invention first described.
BRIEF DESCRIPTION OF THE DRAWINGS
The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the claims at the conclusion of the specification. The forgoing and other features, and advantages of the invention are apparent from the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1A
is a side schematic illustration of a radome in accordance with embodiments;
FIG. 1B
is an enlarged side schematic illustration of a portion of a radome in accordance with embodiments;
FIG. 2
is a side schematic illustration of a radome in accordance with further embodiments;
FIG. 3
is a side schematic illustration of a radome in accordance with further embodiments;
FIG. 4
is a side schematic illustration of a radome in accordance with further alternative embodiments;
FIG. 5
is a side schematic illustration of a radome in accordance with further alternative embodiments;
FIG. 6
is a perspective view of a planar radome and housing in accordance with embodiments; and
FIG. 7
is a top down view of a complex-shaped radome in accordance with embodiments. | |
The invention relates to a method for solidifying and processing soft soil foundation by draining water from a plant cushion layer in vacuum. The method comprises the following steps of: 1) crosswise placing and flattening a hollow plant; 2) inserting vertical draining plates and exposing the top ends of the draining plates; 3) paving a main tube and an integrated draining plate layer horizontally; 4) digging peripheral sealed ditches around, paving geotextile layers on the main tube and the integrated draining plate layer sequentially, and paving vacuum films on the geotextile layers; 5) starting vacuum equipment, running the vacuum equipment at low pressure and trying to vacuumize; 6) controlling a vacuum degree exertion speed, increasing the vacuum degree day by day from 20kPa at a speed of 2 to 5kPa per day until the vacuum degree is more than 85kPa and stabilizing the pressure; 7) covering water on the films during pressure stabilization; 8) monitoring parameters during vacuum exertion, finding out problems and correcting the problems timely; 9) drawing a sedimentation-time curve and a vacuum-degree-time curve; and 10) removing the vacuum equipment after the sedimentation-time curve is stabilized. Compared with the prior art, the method has the advantages of low cost, good effect and the like. | |
Qiu Li Hui
A friend from Lapis Lazuli Light recently gave me a book “Emotional Balance: The Path to Inner Peace and Harmony” by Dr Roy Martina. I found it very beneficial and would like to share some of the book’s information with all of you.
Emotion is the strongest path to healing power, in the body-mind connection. Emotions are not only intrinsically connected to the central nervous and endocrine systems they are also deeply linked to our thought patterns and physical health. Emotions also represent the flow of energy along specific meridians in the body, focusing on seven energy or chakra centers. Exploring emotions as kinetic energy can cure physiological diseases and relieve stress.
The author analyses three levels of happiness. The first level is competitive happiness. When we win or are ahead of others, we feel happy. However, this competitive type of happiness is always temporary.
The following is an ancient story from India, depicting the limitations of this form of happiness:
|One day, God sent an angel to a businessman and said: “From now on, any of your desires can be achieved but it is subject to a condition”. The businessman asked: “What condition?” The reply was: “No matter what you get, your opponent will get double.” Initially, the businessman was depressed and then he began to plan what he can do. After contemplating for a few minutes, he told the angel: “I know what I want. Please blind me in one eye!”|
The second level is conditional happiness. We often link pleasure with specific external conditions. For example, when we were young, good-looking and our friends identified with us, we were very happy, but once the symptoms of old age set in, we felt depressed and defeated.
Conditional happiness never lasts because conditions always change. When that happens, we become unhappy.
The third level is unconditional happiness. Unconditional happiness is perfect bliss. We don’t need outside energy or stimulus to feel happy or at peace. We live unconditionally, gladly accepting both discomfort and pleasure and are not attached to the outcomes. We are grateful for all the blessings and experiences that we have along the way.
But ordinary people like us are influenced by past experiences. We are drawn by the stored habitual reactions, the so-called “bad habits”.
The author says: “Bad habits” are stored in the form of electromagnetic resonance in the body; they may be latent (inactive) but when stimulated by the same electromagnetic signals, they will be activated. All our experiences are stored in the unconscious or subconscious mind.
One of the reasons why we return to earth was to reexperience karma. For this reason, many of the conflicts happening in this life are the result of unfinished lessons in the past lives. Our life goal is to set aside old patterns that cause us to deviate from the ultimate goal to reach the realm of unconditional love and live in the present without prejudice and judgment.
Every moment of our experience gives us the opportunity to really live in the moment. It allows us to make our choices based on the highest values and not from past scars. This is the only reason why we want to experience inner trauma and turmoil. But once we let go of the old patterns, we will no longer be attracted to the same situation and our energy will no longer be consumed.
When we are still in the spirit world, the cellular memory is stored us. At that time, we decide on the purpose for coming to this material dimension, the earth. Also we decide what we need to learn in order to achieve the energy of pure love.
The purpose is to release the unnecessary pains and suffering created due to lack of understanding of our true selves and to discover our true potential. Our souls and hearts need to be nourished through love and compassion. This is the method for healing the soul and experiencing the ultimate existence.
If our inner beings are often consumed by fear, anger, jealousy, sadness and other emotions, it will hinder us from experiencing our feelings of love, happiness and peace.
The author says: “The inner part that you are not aware of can be observed outside the body. The outside world is a reflection of your inner world, like a mirror; everything in the outside world is caused by the generation of your inner thoughts. As a result, you become more alert and whatever you are alerted to, you can control. But whatever is concealed will control you.”
How can we harmonise energy and emotion?
The author says that there are two basic principles, integration and release. Integration means to accept feelings or sensations without emotions involved. In other words, we accept and recognize our own particular feelings and clearly (and deliberately) receive messages from the subconscious mind.
Then we can no longer be infected by others› emotional virus (or have resonance with the internal negative energy) such as anxiety, paranoia, fear, worry, low selfevaluation, sadness, frustration and doubt.
Release means a clear understanding of this message and let it go. Through letting go we are able to take responsibility.
In the book, the author mentions seven steps of emotional healing.
After you relax and go into inner reality, replace the negative emotions with positive emotions. Let these positive emotions go into every cell in the body. Visualise positive emotions flowing throughout the body, like a bright light illuminating every single cell.
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- Firstly, please say: “I accept and deeply love myself.”
Deeply inhale and exhale → Focus on the base chakra: tenacity
- “I ask God* to please help me find the origin of this feeling (or way of thinking), however long ago it may have been and help me heal completely.”
Deeply inhale and exhale → focus on the reproductive chakra: enjoy.
- “I allow myself to dwell in every part and aspect within me so as to help me heal the initial incident, however long ago it may have happened. I fully accept and love the intention of that incident.”
Deeply inhale and exhale → focus on the solar plexus chakra: acceptance and letting go.
- “Through God’s* love, I forgive myself for excluding myself and others because of incorrect beliefs, thoughts, emotions and cognition. I forgive the people, matter and things associated with these past experiences and release all the sentiments behind all the reasoning or beliefs and thoroughly be healed of all that was related to past events.”
Deeply inhale and exhale → focus on the heart chakra: peace and forgiveness.
- “Now, I use the unconditional love and blessings of God* to let go and release myself from feelings or views that are associated with the past. I choose_______ (positive emotion or belief) as a substitute. Every cell in my body accepts (insert the positive emotion) this feeling.
Deeply inhale and exhale → focus on the throat chakra: true self-expression.
- “I now allow myself in a relaxed and peaceful manner to let go of the physiological, emotional, mental and spiritual discomfort or any of its associated attitude, behaviour or feelings. Continue to do so.”
Deeply inhale and exhale → focus on the third-eye chakra: self-understanding.
- “I thank God* for all the help. I express my love and gratitude to Him. I accept and am worthy of God’s blessings and love.”
Deeply inhale and exhale → focus on the crown chakra: universal love.
- Firstly, please say: “I accept and deeply love myself.”
The author also introduces some other methods of releasing negative emotions, such as massaging specific acupoints. A lot of these acupoints are similar to those that Dr Lai taught. Dr Lai taught tapping acupoints, coupled with recognition and transformation of feelings and saying affirmations of self-acceptance and love. These not only release previously blocked energy but also generate reacceptance and love for oneself. I personally feel that it is very effective. For specific practices, please refer to the article “向恐懼、憎恨、悲傷的情感說再見” in the May 2005 Issue of Taiwan Lapis Magazine (in Chinese).
The author also mentions in the book about imprinting positive messages into the subconscious mind. Dr Lai had taught not only positive affirmations but also some actions that I find very useful. That is why, in January 2008, I shared this in the Taiwan workshop “You Can Change The Future”.
For those who are interested, please contact Lapis Lazuli Light.
*Editor’s note : “God” is used to replace “angels” or “spiritual guides” or “Creator” used in the original text. | https://www.lapislazulilight.com/article_categories/2015-general/ |
Non-planed urbanization as a contributing factor for malaria incidence in Manaus-Amazonas, Brazil.
This paper presents a study on the dynamics of malaria in Manaus and its relationship with the urban expansion and environmental factors related to it. The purpose of this paper is: to analyse how the form of occupying the emptied space in the city, together with the urbanization and factors related to the environment, have contributed for the establishment, increase and/or sustainability of malaria in the urban area of the city of Manaus, Amazonas, Brazil. A retrospective study was carried out on malaria epidemiology from 1986 to 1997; data on the evolution and urban expansion of the city of Manaus were surveyed. Data were descriptively analysed making a relationship between the environmental aspects of urbanization and the way the city of Manaus was occupied and how this has contributed to malaria epidemiology in the city. The findings point out to the importance of the environment on malaria incidence, and to the influence of the anthropic interventions on the modification of the ecosystem, making the urban environment ideal for the proliferation of Anopheles sp mosquitoes, vectors of this disease. These elements in association continue to favour the maintenance of the incidence of malaria in the urban area of Manaus.
| |
In this small article I would like to talk about how to get rid of unwanted fungi on the site. After all, these "neighbors" spoil the appearance of lawns and flower beds, as well as consume the nutrients that are needed truck crops.
It makes no sense to tear appeared mushrooms, you wasted time and energy. The fight should be conducted with the cause of their appearance.
1. Reveal the cause of fungi
Just so the mushrooms will not grow, they need a substrate. Our task - to find it and remove from the site. As a substrate, usually, it is the old wood - logs, tree stumps, branches, wood chips, etc. All of them are deep under the ground, so to get to them, will have to dig.
Mushrooms are very fond of the water, so our task is to determine the cause of the humidity. It can be positioned close to the ground water table, and perhaps excessive watering.
2. Struggling with mushrooms
First of all, it is necessary to remove the substrate after which you will find on the site of fungal growth. It must carry out off-site or burn. Next, go to the drainage area. It is necessary to make small drainage grooves to the ground get rid of excess moisture. In moist soil controlling fungi is completely useless.
Fight with mushrooms are best in dry and hot weather. In this case, the sun - the perfect assistant.
Once the area is drained and tidied, it is necessary to improve the ventilation of the soil. This will help us a pitchfork. We do a huge amount of holes so that the oxygen can saturate the ground. On well dried and "purged" soil fungi will not grow.
However, if these measures do not help, there is a radical method
Radical method of struggle
If the above steps do not lead to a result that will be necessary to manually remove the mycelium from the ground. Business is labor-intensive, but effective.
Remove 15 cm thick layer of soil and send it to dry. The excavated soil looking for the thin white thread (this is the mycelium), tearing them and send for incineration. The resulting hole filled with sand. After the soil dried out, return it in place and dig together with sand.
These actions will help to permanently get rid of the fungus on your summer cottage.
I would be glad if my article was useful to you. Put the "Thumbs Up" and subscribe to a channel. Thanks! | https://en.technolong.com/advices/5041-how-to-get-rid-of-toadstools-on-a-plot |
Harvard Stem Cell Institute (HSCI) researchers at Massachusetts Eye and Ear (MEE) have reconstructed an ancient virus that is highly effective at delivering gene therapies to the liver, muscle, and retina. The discovery, published this week in Cell Reports, has the potential to advance gene therapies that are not only safer and more potent than available therapies, but also to help a greater number of patients.
“We believe our findings will teach us how complex biological structures, such as AAVs [adeno-associated viruses], are built,” said Luk H. Vandenberghe, an HSCI affiliated faculty member and senior author of the study. “From this knowledge, we hope to design next-generation viruses for use as vectors in gene therapy.”
A virus can be an ideal delivery system for gene therapy. In order to survive, a virus must infiltrate a host organism undetected and transfer its genetic material into the cells, where it will use the host to replicate and proliferate. Taking advantage of this process, researchers can insert therapeutic genes into a virus, then use the virus to shuttle the genes to the appropriate cells or tissues inside a human body.
So far, AAVs used for gene therapy have been chosen from viruses that naturally circulate throughout the human population. If people have been exposed to the virus, their bodies will likely recognize it, mount an attack, and destroy it before it can deliver the therapy. Engineering new, benign viruses could render the viruses unrecognizable and increase the number of people for whom a given gene therapy will work.
However, efforts to engineer improved AAVs have been stymied by their intricate structure. Like pieces of a puzzle, every protein in the shell of a virus must fit together perfectly for the virus to function normally. Altering proteins in one part of the virus to achieve a certain benefit, such as more efficient gene transfer or reduced recognition by host immune cells, could end up destroying the structural integrity of the entire shell.
To overcome this challenge, Vandenberghe, along with colleagues at Harvard Medical School, Schepens Eye Research Institute, and MEE, turned to evolutionary history for guidance. Over time, AAV ancestors underwent a series of changes that retained the structural integrity of the virus while slightly altering some of its functions. The researchers were able to recreate an evolutionary timeline of the changes and build nine synthetic ancestor viruses in the laboratory. When injected into mice, the most ancient of these, Anc80, successfully targeted the liver, muscle, and retina without producing toxic side effects.
In future studies, the researchers will characterize the interplay between the virus and host throughout evolution and continue to seek improved vectors for clinical applications. They will also examine the potential of Anc80 for treating liver diseases and retinal forms of blindness. “The vectors developed and characterized in this study demonstrate unique and potent biology that justify their consideration for gene therapy applications,” Vandenberghe said. | https://news.harvard.edu/gazette/story/2015/07/new-hope-in-old-viruses/ |
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CROSS REFERENCE TO RELATED APPLICATIONS
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
SUMMARY OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLES
Example 1A
3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid
Example 1B
3-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid
Example 1C
2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 1D
D-3-Methyl-2-[4′-(2-methyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid
Example 1E
Example 1F
2-[4′-(Benzothiazol-2-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 1G
Example 1H
Example 1I
Example 1J
Example 1K
Example 1L
Example 1M
Example 1N
Example 1O
Example 1P
Example 1Q
Example 1R
Example 1S
Example 1T
Example 1U
Example 1V
Example 1W
Example 1X
Example 1Y
Example 1Z
Example 1AA
Example 1AB
Example 1AC
Example 1AD
Example 1AE
Example 2A
D-3-Methyl-2-[4′-(3-methyl-benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2B
D-2-[4′-(Benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2C
D-3-Methyl-2-[4′-(naphthalen-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2D
D-2-(4′-Benzyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid
Example 2E
D-3-Methyl-2-[4′-(quinolin-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2F
D-3-Methyl-2-[4′-(2-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2G
D-2-[4′-(2-Chloro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2H
D-2-[4′-(2-Fluoro-6-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2I
D-3-Methyl-2-[4′-(quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2J
D-2-[4′-(2-Cyanomethyl-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2K
D-3-Methyl-2-[4′-(2-methyl-quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2L
D-2-[4′-(3-Cyano-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2M
D-3-Methyl-2-[4′-(naphthalen-1-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2N
D-2-[4′-(2-Fluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2O
D-2-[4′-(2,3-Difluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2P
D-3-Methyl-2-[4′-(2-methyl-3-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 2Q
D-2-[4′-(2-Iodo-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2R
D-2-[4′-(Benzothiazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 2S
2-[4′-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmemethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 2T
3-Methyl-2-[4′-(pyridin-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid.
Example 2U
3-Methyl-2-[4′-(pyridin-3-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid.
Example 2V
2-[4′-(1H-Benzoimidazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 2W
2-[4′-(3-Methoxy-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 2X
2-[4′-(4-Methoxy-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 2Y
2-[4′-(3,5-Dimethoxy-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 3A
3-Methyl-2-(4′-vinyl-biphenyl-4-sulfonylamino)-butyric acid tert-butyl ester
Example 4A
N-({4′-[2-4-methylisoquinolin-3-yl)ethyl]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine
Example 5A
D-2-[4′-(Acetylamino-methyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 5B
D-3-Methyl-2-(4′-phenylcarbamoylmethyl-biphenyl-4-sulfonylamino)-butyric acid
Example 5C
D-2-[4′-(Benzylcarbamoyl-methyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 6A
2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 6B
D-3-Methyl-2-[4′-(4-phenoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 6C
D-3-Methyl-2-[4′-(naphthalen-2-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 6D
D-2-[4′-(4-Benzyloxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 6E
D-2-(4′-Cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid
Example 6F
D-2-[4′-(4-Dimethylamino-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 6G
D-2-[4′-(4-Isopropyl-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 6H
D-3-Methyl-2-[4′-(2-thiophen-2-yl-ethylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 6I
D-3-Methyl-2-[4′-(4-trifluoromethoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 6J
D-3-Methyl-2-[4′-(4-trifluoromethoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid
Example 6K
D-2-(4′-Carbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid
Example 6L
3-Methyl-2-(4′-phenylcarbamoyloxy-biphenyl-4-sulfonylamino)-butyric acid tert-butyl ester
Example 6M
2-[4′-(Benzo [b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester
Example 6N
N-[(4′-{[2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]oxy}-1,1′-biphenyl-4 yl)sulfonyl]-D-valine
Example 6O
N-[(4′-{[(2,3-dihydro-1,4-benzodioxin-6-ylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine
Example 6P
N-[(4′-{[(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine
Example 6Q
N-[(4′-{[(5-methyl-3-phenylisoxazol-4-yl)amino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine
Example 6R
N-[(4′-{[(methylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine
Example 6S
N-[(4′-{[(1-benzofuran-2-ylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine
Example 7A
D-3-Methyl-benzofuran-2-carboxylic acid 4′-(1-carboxy-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester
Example 7B
Benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester
Example 8A
3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester
Example 8B
3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester
Example 8C
N-({4′-[(5-nitropyridin-2-yl)oxy]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine
Example 8D
N-({4′-[(2,6-dimethoxypyrimidin-4-yl)oxy]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine
Example 8E
N-({4′-[(4-chloropyrimidin-2-yl)oxy]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine
Example 8F
N-{[4′-(pyridin-2-yloxy)-1,1′-biphenyl-4-yl]sulfonyl}-D-valine
Example 8G
N-{[4′-(1,3-benzoxazol-2-yloxy)-1,1′-biphenyl-4-yl]sulfonyl}-D-valine
Example 9A
N-({4′-[2-(1-benzofuran-2-yl)-2-oxoethyl]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine
Example 10A
D-2-[4′-(Benzofuran-2-sulfonylmethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid
Example 11A
3-Methyl-2-[4′-(naphthalen-2-ylmethoxy)-3′-methoxy-biphenyl-4-sulfonylamino]-butyric acid.
Example 11B
2-[4′-(3,5-Dimethoxy-benzyloxy)-3′-methoxy-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 12A
2-(4′-Hydroxy-3-trifluoromethoxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
Example 12B
2-(4′-Hydroxy-3-trifluoromethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
Example 12C
2-(4′-Hydroxy-3-methyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
Example 12D
2-(3-Fluoro-4′-hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
Example 12E
2-(2,5-Difluoro-4′-hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid.
Example 12F
3-Methyl-2-[4′-(naphthalen-2-ylmethoxy)-3-trifluoromethyl-biphenyl-4-sulfonylamino]-butyric acid.
Example 12G
2-[3-Fluoro-4′-(naphthalen-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 12H
2-[2,5-Difluoro-4′-(naphthalen-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid.
Example 12I
Example 12J
Example 12K
Example 12L
Example 12M
Example 12N
Example 12O
Example 12P
Example 12Q
Example 12R
Example 13A
3-Methyl-2-[4′-(pyridin-3-ylmethoxymethyl)-biphenyl-4-sulfonylamino]-butyric acid
Example 13B
3-Methyl-2-[4′-(naphthalen-2-ylmethoxymethyl)-biphenyl-4-sulfonylamino]-butyric acid
Example 13C
3-Methyl-2-[4′-(pyridin-3-ylmethoxymethyl)-biphenyl-4-sulfonylamino]-butyric acid
Example 14
Activity
This application is a divisional application of U.S. application Ser. No. 11/000,711, filed Dec. 1, 2004 (now U.S. Pat. No. 7,268,135), which claims benefit to U.S. Provisional Application No. 60/526,883, filed Dec. 4, 2003, the entire disclosures of which are incorporated by reference herein.
The present invention relates to biaryl sulfonamides and their use as, for example, novel metalloproteinase inhibitors.
Int J Biochem Cell Biol
Metalloproteinases, including matrix metalloproteinases and aggrecanases, are known to have a role in the breakdown of connective tissue. Matrix metalloproteinases (“MMPs”) constitute a superfamily of proteolytic enzymes that are genetically related and capable of degrading almost all the constituents of extracellular matrix and basement membrane that restrict cell movement. Aggrecanases are members of the ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family of proteins. Aggrecanase-1 and aggrecanase-2 have been designated ADAMTS-4 and ADAMTS-5, respectively (Tang B L, 2001, 33, 33-44).
The ADAMTS family is involved in cleaving aggrecan, a cartilage component also known as the large aggregating chondroitin sulphate proteoglycan (Abbaszade I et al., J Biol Chem 1999, 274, 23443-23450), procollagen processing (Colige A et al., Proc Natl Acad Sci USA 1997, 94, 2374-2379), angiogenesis (Vazquez F et al., J Biol Chem 1999, 274, 23349-23357), inflammation (Kuno K et al., J Biol Chem 1997, 272, 556-562) and tumor invasion (Masui T., et al., J Biol Chem 1997, 272, 556-562). MMPs have been shown to cleave aggrecan as well.
The loss of aggrecan has been implicated in the degradation of articular cartilage in arthritic diseases, for example osteoarthritis is a debilitating disease which affects at least 30 million Americans. Degradation of articular cartilage and the resulting chronic pain can severely reduce quality of life. An early and important characteristic of the osteoarthritic process is loss of aggrecan from the extracellular matrix, resulting in deficiencies in the biomechanical characteristics of the cartilage. Likewise, MMPs and aggrecanases are known to play a role in many disorders in which extracellular protein degradation or destruction occurs, such as cancer, asthma, chronic obstructive pulmonary disease (“COPD”), atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.
Therefore, metalloproteinase inhibitors are needed, including inhibitors of MMPs and aggrecanases.
In one embodiment, the present invention provides novel comprises biaryl sulfonamide compounds. Preferred compounds of the invention are those of the formula I:
wherein:
1
Ris H or C1-C6 alkyl;
2
2′
2
n
Ris H, C1-C6 alkyl, (CH)R, phenyl, or benzyl;
n is 0-6;
2′
R is aryl, heteroaryl, cycloalkyl, or heteterocycloalkyl;
3
3
3
Ris, independently with respect to each occurrence, H, halogen, OC(halogen), C(halogen), alkoxy, or C1-C6 alkyl;
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
X is selected from CHO, OCH, C(R)═C(R), C(R)—C(R), CHNHC(═O), O(C═O)NH, O, C(═O)CH, SOCHC(═O)NH, SONH, OC(═O), CHS(O), and CHS(O); and
Z is at least one aryl or heteroaryl moiety.
In another aspect, the present invention provides methods for using biaryl sulfonamide compounds to modulate and, preferably, inhibit metalloproteinases. Preferred methods involve in vitro and in vivo contacting of the metalloproteinase with a biaryl sulfonamide. Preferred methods of this type are ones in which the activity of the metalloproteinase is determined before or after such contacting and, optionally, the determination is used to assess the extent to which the compound modulates the activity of the enzyme.
In accordance with the present invention it has been discovered that biaryl sulfonamide compounds find use in inhibiting metalloproteinases. Such compounds are therefore useful in the treatment of cancer, osteoarthritis, rheumatoid arthritis, asthma, COPD, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases. The metalloproteinase is preferably Aggrecanase-1 (also known as ADAMTS4, and abbreviated herein as “Agg-1”) or MMP-13.
In one embodiment, the biaryl sulfonamide compound is of the formula I:
1
Ris H or C1-C6 alkyl;
2
2′
2
n
Ris H, C1-C6 alkyl, (CH)R, phenyl, or benzyl;
n is 0-6;
2′
R is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
3
3
3
Ris, independently with respect to each occurrence, H, halogen, OC(halogen), C(halogen), alkoxy, or C1-C6 alkyl;
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
X is selected from CHO, OCH, C(R)═C(R), C(R)—C(R), CHNHC(═O), O(C═O)NH, O, C(═O)CH, SOCHC(═O)NH, SONH, OC(═O), CHS(O), and CHS(O); and
Z is at least one aryl or heteroaryl moiety.
wherein:
It has been discovered that the R-configuration isomer at the alpha carbon is a better inhibitor of Agg-1, whereas both enantiomers are effective MMP inhibitors.
It is understood that the foregoing definition includes pharmaceutically acceptable salts and pro-drugs of these compounds.
In one embodiment, Z is pyridine, pyrimidine, pyrazine, pyridazine, phenyl, naphthalene, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, benzothiazole, quinoline, or isoquinoline, or
3
3
3
4
U is selected from S, O, C(R)═C(R), C(R)═N, and N(R);
3
W is selected from C(R), and N;
3
M is selected from C(R), and N;
3
3
3
4
L is selected from S, O, C(R)═C(R), C(R)═N, and N(R);
4
5
Rand Rare, independently with respect to each occurrence, a bond to the other, H, C1-C6 alkyl, or phenyl;
7
3
4
5
4
4
4
5
4
4
5
4
4
4
4
4
5
3
2
2
2
2
2
2
2
2
2
2
Ris selected from a bond to R, H, halogen, C(halogen), NRR, N[(CH)]O, N[(CH)]NR, NHSOR, NRC(═O)R, NHC(═O)OR, NO, SONRR, SOR, OR, C(═O)R, COOR, CONRR, CN, phenyl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and
8
Ris selected from H, phenyl, heteroaryl, and C1-C6 alkyl.
wherein:
7
4
5
4
4
4
5
4
4
5
4
8
4
4
4
5
2
2
2
2
2
2
2
2
2
2
When Ris substituted, it is preferably substituted with NRR, N[(CH)]O, N[(CH)]NR, NHSOR, NRC(═O)R, NHC(═O)OR, NO, SONRR, SOR, OR, C(═O)R, COOR, CONRR, CN, phenyl, or heteroaryl.
8
4
5
4
4
5
4
5
4
4
5
4
4
4
4
5
2
2
2
2
2
2
2
2
2
2
R, when substituted, is preferably substituted with NRR, N[(CH)]O, N[(CH)]NR, NRSOR, NRC(═O)R, NHC(═O)OR, NO, SONRR, SOR, C(═O)R, COOR, CONRR, CN, phenyl, or heteroaryl.
1
Preferred among the above noted Rgroups are H and branched alkyl, and more preferably isopropyl.
3
3
3
3
Preferred among the above noted Rgroups are halogen, CF, OCH, and CH.
2
2
2
3
3
Preferred among the above noted X groups are CHO, OCH, C(R)═C(R), and CHNHC(═O).
7
3
3
3
Preferred among the above noted Rgroups are CH, ethyl, isopropyl, CF, CN, and OCH.
8
Preferred among the above noted Rgroups are CH3, phenyl, and benzyl.
2
In one embodiment, X is CHO, and Z is aryl or heteroaryl, preferably bicyclic.
2
In one embodiment, X is OCH, and Z is aryl or heteroaryl, preferably bicyclic.
3
3
In one embodiment, X is C(R)═C(R), and Z is aryl or heteroaryl, preferably bicyclic. More preferably, X is a trans carbon-carbon double bond.
3
3
2
2
In one embodiment, X is C(R)—C(R), Z is aryl or heteroaryl, preferably bicyclic.
2
In one embodiment, X is CHNHCO, Z is aryl or heteroaryl, preferably bicyclic.
In one embodiment, X is carbamate O—CO—NH, Z is aryl or heteroaryl, preferably bicyclic.
2
In one embodiment, X is CO, Z is aryl or heteroaryl, preferably bicyclic.
In one embodiment, X is O, Z is aryl or heteroaryl, preferably bicyclic.
2
In one embodiment, X is C(═O)CH, Z is aryl or heteroaryl, preferably bicyclic.
2
2
In one embodiment, X is SOCH, Z is aryl or heteroaryl, preferably bicyclic.
2
In one embodiment, X is OCH, Z is aryl or heteroaryl, preferably bicyclic. Preferably, if substituted, the substitution is on the second phenyl ring.
2
In one embodiment, X is OCH, Z is aryl or heteroaryl, preferably bicyclic. Preferably, if substituted, the substitution is on the first phenyl ring.
2
2
In one embodiment, X is CHOCH, Z is aryl or heteroaryl, preferably bicyclic. Preferably, if substituted, the substitution is on the first phenyl ring.
The term “alkyl”, as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term “alkyl.” C1-C6 alkyl includes straight and branched chain aliphatic groups having from 1 to 6 carbons. Specifically included within the definition of “alkyl” are those aliphatic hydrocarbon chains that are optionally substituted.
The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
The term “alkenyl”, as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains having 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl moiety has 1 or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and the compounds of this invention include both conformations. C2-C6 alkenyl includes a 1 to 6 carbon straight or branched chain having at least one carbon-carbon double bond. Specifically included within the definition of “alkenyl” are those aliphatic hydrocarbon chains that are optionally substituted. Heteroatoms, such as O, S or N-R1, attached to an alkenyl should not be attached to a carbon atom that is bonded to a double bond.
The term “alkynyl” refers to a hydrocarbon moiety containing at least one carbon-carbon triple bond. C2-C6 alkynyl includes a 1 to 6 carbon straight or branched chain having at least one carbon-carbon triple bond.
3
The term “cycloalkyl” a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon moiety, wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, and the like. C3-C6 cycloalkyl includes monocyclic, saturated rings of 3 to 6 carbons, optionally substituted with R.
“Aryl” refers to an unsaturated carbon ring, and may be fused with a carbocyclic or heterocyclic ring at any possible position.
“Heteroaryl” refers to a 5 to 6 membered aryl heterocyclic ring which contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms in the ring and may be fused with a carbocyclic or heterocyclic ring at any possible position.
“Heterocycloalkyl” refers to a 5 to 7-membered saturated ring containing carbon atoms and from 1 to 2 heteroatoms selected from N, O, and S.
The term “phenyl”, as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted phenyl group.
4
5
4
4
4
5
4
4
5
4
4
4
4
4
5
2
2
2
2
2
2
2
2
2
2
An optionally substituted moiety may be substituted with one or more substituents. Suitable optionally substituents may be selected independently from H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NRR, N[(CH)]O, N[(CH)]NR, NHSOR, NRC(═O)R, NHC(═O)OR, NO, SONRR, SOR, OR, C(═O)R, COOR, CONRR, and CN.
2
3
2
2
3
When such moieties are substituted, for example, they may typically be mono-, di-, tri- or persubstituted. Examples for a halogen substituent include 1-bromo vinyl, 1-fluoro vinyl, 1,2-difluoro vinyl, 2,2-difluorovinyl, 1,2,2-trifluorovinyl, 1,2-dibromo ethane, 1,2 difluoro ethane, 1-fluoro-2-bromo ethane, CFCF, CFCFCF, and the like.
The term halogen includes bromine, chlorine, fluorine, and iodine.
3
3
For the sake of simplicity, connection points (“-”) are not depicted. When an atom or compound is described to define a variable, it is understood that it is intended to replace the variable in a manner to satisfy the valency of the atom or compound. For example, when L is C(R)═C(R), both carbon atoms form a part of the ring in order to satisfy their respective valences.
The term “pharmaceutically acceptable salt”, as used herein, refers to salts derived form organic and inorganic acids such as, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains a carboxylate or phenolic moiety, or similar moiety capable of forming base addition salts.
The term “patient”, as used herein, refers to a mammal, preferably a human.
The terms “administer”, “administering”, or “administration”, as used herein, refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.
The term “carrier”, as used herein, shall encompass carriers, excipients, and diluents.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Where a stereoisomer is preferred, it may in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. “Substantially free”, as used herein, means that the compound is made up of a significantly greater proportion of one steriosomer, preferably less than about 50%, more preferably less than about 75%, and even more preferably less than about 90%.
The terms “effective amount”, “therapeutically effective amount” and “effective dosage” as used herein, refer to the amount of a compound, that, when administered to a patient, is effective to at least partially ameliorate (and, in preferred embodiments, cure) a condition form which the patient is suspected to suffer.
Biaryl sulfonamide compounds have been found to act as metalloproteinase inhibitors. They are therefore useful in the treatment of cancer, osteoarthritis, rheumatoid arthritis, asthma, COPD, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and/or periodontal diseases.
The present invention thus provides pharmaceutical compositions comprising at least one biaryl sulfonamide compound and one or more pharmaceutically acceptable carriers, excipients, or diluents.
Examples of such carriers are well known to those skilled in the art and are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or encapsulating materials. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and β-blocking agents. Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier is a finely divided solid, which is an admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colliodol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or fruit juice, containing appropriate solubilizers or emulisifiers as needed.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in either liquid or solid form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that the effective dosage may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic application, compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a “therapeutically effective amount”. The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. For administration by intranasal or intrabrochial inhalation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution.
The compounds of this invention may be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmaceutically acceptable salt may be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The compounds of this invention can be administered transdermally through the use of a transdermal patch. For the purposes of this disclosure, thransdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Transdermal administration may be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
In certain embodiments, the present invention is directed to prodrugs of biaryl sulfonamide compounds. Various forms of prodrugs are known in the art, for example, as discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), “Design and Application of Prodrugs”, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated by reference in its entirety.
It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
The compounds of the current invention were prepared according to the following general synthetic scheme from commercially available starting materials, materials prepared as described in literature procedures, or new intermediates described in the schemes and experimental procedures. This general scheme covers most of the examples. For more detailed information, please refer to the schemes in the session of Synthetic Methods and Examples.
Bases used here are Et3N, K2CO3, NaH, Hunig base, etc. Coupling was generally referred to Suzuki coupling or Stille coupling. Hydrolysis was carried out using TFA, NaOH, LiOH, K2CO3, etc.
The compounds of the invention can be prepared using a variety of methods starting from commercially available compounds, known compounds, or compounds prepared by known methods. General synthetic routes to many of the compounds of the invention are included in the following schemes. It is understood by those skilled in the art that protection and deprotection steps not shown in the Schemes may be required for these syntheses, and that the order of steps may be changed to accommodate functionality in the target molecules.
In Scheme 1 the compounds of the invention, 1, are prepared in 4 steps. Sulfonylation of valine methyl ester with 4-Bromo-benzenesulfonyl chloride was carried out under Hunig base condition to give sulfonamide intermediate 1. This 4-Bromo-benzenesulfonamide was furthered coupled with boronate ester using Palladium catalyst under Suzuki coupling condition to provide biphenyl sulfonamide Intermediate 2. Biphenyl sulfonamide intermediate 2 was then alkylated with various alkylating reagents to provide biphenyl sulfonamide ester (Intermediate 3). Hydrolysis of intermediate 3 was carried out using bases such as NaOH, or LiOH to afford the final product 1.
An alternative route to compounds 1 is shown in Scheme 2. Phenol derivative was converted to Pinacolborane (Intermediate 4) under basic condition in DMF. Pinacolborane was then coupled with 4-bromo-benzenesulfonamide under Suzuki condition to provide biphenyl sulfonamide intermediate 5, which was hydrolyzed to final product under basic conditions.
The third option to make compounds of the invention, 1, are carried out based on Scheme 3. The synthetic sequence in Scheme 3 is similar to that in Scheme 1 but using different starting material, valine tert-butyl ester. Therefore, final step to form the product 1 was carried out by using TFA to deprotect the tert-butyl ester group of Intermediate 8.
Slight modification of Scheme 3 resulted in another to make the compounds of invention, 1. This is illustrated in Schem 4A. In this case, boronate esters with suitable ether moiety are purchased from commercial source and used for Suzuki coupling to provide intermediate 8. TFA deprotection of tert-butyl ester from intermediate 8 resulted the desired final product 1.
Compounds of the invention, 1, can also be made by hydrolysis of ester such as intermediate 10.
Alkylation
The phenol derivative (4.14 mmol) is dissolved in methanol (6 mL) and treated with tetrabutylammonium hydroxide (4.14 mmol.) The mixture is stirred for 10 minutes, and the solvent is removed under reduced pressure. The residue is dissolved in THF (10 mL) and treated with a solution of the benzylic bromide (4.14 mmol) in THF (5 mL.) The reaction is stirred at rt overnight. The solvent is removed under reduced pressure and redissolved in dichloromethane (5 mL) and ether (50 mL.) The organic solution is washed with water (4×50 mL) and saturated sodium chloride solution (50 mL,) and dried over magnesium sulfate. The organic solution is filtered and concentrated under reduced pressure. The crude material is purified by flash silica gel chromatography to yield the purified product in 53% yield.
Suzuki Coupling
The boronate ester (1.07 mmol) and aryl bromide (1.07 mmol) are dissolved in ethylene glycol dimethyl ether (10 mL) and the resulting solution is treated with tetrakis(triphenylphosphine)palladium(0) (0.054 mmol.) A solution of potassium carbonate (2.14 mmol) in water (3.5 mL) is added, and the reaction is heated to reflux for 1 h. The reaction is cooled, filtered to remove solids, diluted with water (10 mL) and concentrated under reduced pressure. The residue is extracted with dichloromethane (3×25 mL) and the organic layers are washed with water (25 mL) and saturated sodium chloride solution (25 mL). The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash silica gel chromatography furnishes the product in 57% yield. In some cases, PdCl2(dppf) was used as the catalyst instead of tetrakis(triphenylphosphine)palladium(0).
2
Deprotection with MgBr.
The 2-(trimethylsilyl)ethyl ester (0.0621 mmol) is dissolved in dichloromethane (58 mL) and treated with magnesium bromide etherate (0.186 mmol). The mixture is stirred vigorously overnight or until reaction is complete and then shaken with 10% HCl (3×25 mL) and saturated sodium chloride solution (25 mL). The organic solution is then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the product in 95% yield. The crude product could be purified by HPLC when required.
Suzuki coupling can be carried out on free acid with boronate ester. Therefore, hydrolysis of the esters is avoided. This result in direct preparation of the compounds, 1.
Suzuki Coupling with Free Acid
The boronate ester (1.36 mmol) and bromoacid (1.36 mmol) are dissolved in ethylene glycol dimethyl ether (13.8 mL) and the resulting solution is treated with tetrakis(triphenylphosphine)palladium(0) (0.068 mmol). After stirring at rt for 10 minutes, a solution of potassium carbonate (4.08 mmol) in water (4.8 mL) are added. The solution is heated to reflux for 2 h, and then allowed to cool to rt overnight. The mixture is concentrated to an aqueous residue under reduced pressure and ethyl acetate (50 mL) is added. The organic mixture is washed with 10% HCl (2×25 mL) and saturated sodium chloride (25 mL). The organic solution is dried over magnesium sulfate, filtered and concentrated to a crude residue, which is purified using flash silica gel chromatography to obtain the product in 64% yield.
In Scheme 5 the compounds of the invention, 2, are prepared in 3 steps. Boronate ester (intermediate 11) was prepared by alkylation under basic condition. Intermediate 11 thus obtained can be easily coupled with 4-bromo-benzenesulfonamide derivative to provide biphenyl sulfonamide analog (intermediate 12).
The ester functional group in intermediate 12 can be hydrolyzed under various condition to yield the desired product biphenyl sulfonamide analog, 2.
Alternate route to provide compounds, 2, is shown in Scheme 6. Starting material 4-hydroxybiphenyl sulfonamide derivative was readily available through Suzuki coupling. Alkylation of 4-hydroxybiphenyl sulfonamide under basic condition provides biphenyl sulfonamide intermediate 13 with an ether linker. Hydrolysis of ester (intermediate 13) using aqueous NaOH to afford the desired product of the invention, 2.
2
2
2
2
2
2
The methyl ester (0.294 mmol) was dissolved in THF:MeOH (2:1)(2 mL) and 1 M LiOH (0.881 mmol) was added. Reaction stirred for 3 days. The solvent was removed and the remaining white solid was dissolved in HO. The HO was extracted with ether. The ether layer was removed and the aqueous layer was acidified to pH 2 with HCl (conc.) forming a cloudy solution. This was extracted with CHCl. The aqueous layer was removed and the organic layer was washed with brine. The solvent was removed and the remaining solid was dissolved in minimal CHCland then hexanes was added precipitating a white solid. The solid was filtered and dried at reduced pressure to provide the desired product.
Compounds of the invention, 3, are prepared based on the Scheme 7. 4-Vinylphenylboronic acid and 4-bromobenzene sulfonamide derivative was undergoing Suzuki coupling catalyzed by Palladium catalyst to provide intermediate 14. Heck reaction of 14 with aryl halide generated intermediate 15. Intermediate 15 is biphenyl sulfonamide derivative with a double as linker connected to aryl ring. Regular TFA deprotection of tert-butyl ester of intermediate 15 provides desired product 3 in high yield.
Scheme 8 shows the multiple steps synthesis leading to the compounds of invention, 4. Regular Suzuki coupling followed by the alkylation with Triflic anhydride to furnish triflate intermediate 16. Triflate 16 was converted into alkynylation product 17 through Sonagoshira reaction. TBDMS protecting group in 17 was removed by TBAF followed by another Sonagoshira rection to provide advanced intermediate 18 with triple bond linking biphenyl group with aryl moiety. 18 was then reduced by hydrogenation then TFA deprotection to give the desired product 4.
Routes to compounds of structure 5 are shown in Scheme 9. 4-aminomethyl phenyl boronic acid was used for Suzuki coupling to produce the intermediate 19. Acylation of 19 with acetic anhydride, followed by the TFA deprotection to provide compounds with structure 5.
Alternate route to make structures of 5 is presented in Schem10. Intermediate 21 was formed by EDCI coupling of 4-bromophenylacetic acid with phenylamine in DMF. Stille coupling of 21 with corresponding tin reagent followed by TFA deprotection to provide product 5.
In Scheme 11 the compounds of the invention, 6, are prepared by reacting 4-hydroxybiphenyl sulfonamide derivative with various isocyanate with the presence of triethylamine. Carbamate (Intermediate 24) thus obtained was treated with TFA to remove tert-butyl ester to provide compounds 6.
Alternate route to make compounds 6 was shown in Scheme 12 using 4-hydroxybiphenyl sulfonamide free acid to react with isocyanate with the presence of triethyl amine. Compounds 6 are obtained directly without deprotection step.
Routes to compounds of structure 7 are shown in Scheme 13. Intermediate 23 was coupled with carboxylic acid using DCC reagent to provide ester 24. Intermediate 24 was treated with TFA to selectively remove tert-butyl group to provide compounds 7.
In Scheme 14, the compounds of the invention, 8, are prepared from intermediate 23 by alkylation followed by the deprotection of tert-butyl group with TFA.
In Scheme 15 the compounds of the invention, 9, are prepared in a multiple step synthesis. Intermediate 26 was prepared based on known literature procedure. Stille coupling followed by TFA deprotection to provide desired product 9.
Routes to compounds of structure 10 are shown in Scheme 16. Intermediate 28 (2-[1,2,3]Thiazol-4-yl-phenol) was prepared according to literature procedure. Alkylation with benzyl bromide derivative followed by condensation resulted in thioether intermediate 29. Suzuki coupling of 29 with 4-bromobenzene sulfonamide to generate intermediate 30. Oxidation with MCPBA followed by hydrolysis to provide compound 10.
TFA Deprotection of t-butyl ester
2
2
2
2
2
2
The t-butyl ester (0.505 mmol) was dissolved in CHCl(2.5 mL). TFA (2.5 mL) was dissolved in CHCl(2.5 mL), and this was slowly added to the dissolved ester. Stirred for 1.5 h. The solvent was removed at reduced pressure and the remaining oil dissolved in toluene and toluene removed. Finally the oil was dissolved in a minimal amount of CHCland hexanes added to precipitate a white solid. Solvent removed at reduced pressure, and the solid dried on vacuum pump to give a 98% yield.
MMPs and aggrecacnases can degrade various components of connective tissue, including collagen and proteoglycan. In the absence of natural checks on this activity, a variety of pathologies and undesirable effects can occur. In fact, MMPs and aggrecanases are known to play a role in many disorders in which extracellular protein degradation/destruction occurs, such as cancer, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (“COPD”), atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.
The preferred metalloproteinase is Aggrecanase-1 (Agg-1). The molecular weight of full length Agg-1 is around 62 KD. The cDNA sequence contains a 2511-base pair encoding 837 amino acids (Tortorella, M D et al., Science, 1999, 284, 1664-1666). The Agg-1 protein may be produced by culturing a cell transformed with the DNA sequence and recovering and purifying protein from the culture medium (Racie, L A et al, PCT Int. Appl. Analysis of Agg-1 protein is conducted using standard techniques such as SDS-PAGE acrylamide (Laemmli, Nature, 1970, 227, 680) stained with silver (Oaklet et al. Anal. Biochem, 1980, 105, 361) and by immunoblot (Towbin, et al. Proc. Natl. Acad. Sci. USA, 1979, 76, 4350). Biological activity of Agg-1 can be further characterized by the ability to demonstrate aggrecan proteolytic activity in an assay which determines the presence of an aggrecan-degrading molecule. These assays or the development thereof is within the knowledge of one skilled in the art. Such assays may involve contacting an aggrecan substrate with the aggrecanase molecule and monitoring the production of aggrecan fragments (Hughes et al., Biochem J, 1995, 305, 799-804).
ex
ex
0.5
0.5
50
50
0
50
h
h
h
IC
I
+IC
The invention includes methods for developing inhibitors of aggrecanase and the inhibitors produced thereby. Compounds are assessed by their ability to inhibit cleavage of a fluorescent peptide substrate (Abz-TEGARGSVI-Dap(Dnp) (Abz:o-aminobenzoyl; Dnp: 2,4 dinitrophenyl) (Anaspec Inc). The peptide sequence TEGARGSVI is based on the amino acid sequence of the Glu373-Ala374 cleavage site of aggrecan in osteoarthritis. Inhibitors are pre-incubated with purified full-length human recombinant aggrecanase-1 for 10 min followed by the addition of substrate, at temperatures ranging from 25° C. to 37° C., typically at 30° C. Cleavage of the Glu-Ala bond releases the fluorophore from internal quenching. This results in an increase in fluorescence monitored at λ340 nm and λ420 nm over a period of 40 min. The initial rate (v) at each concentration of the substrate is fit to the following equation V=Vmax·S/(S+S) where h is the Hill constant and Sis the substrate concentration at half the Vmax. The percentage activity remaining in the presence of inhibitor is plotted as a function of inhibitor concentration and the ICvalue is determined by fitting the data to the following equation:
% activity=100/().
Candidate molecules are further assayed for inhibitory activity in secondary assay such as cell-based assay. Assays for the inhibitors involve contacting a mixture of aggrecan (proteoglycan from the slice of cartilage) and the inhibitor with an aggrecanase molecule followed by measurement of the aggrecanase inhibition, for instance by detection and measurement of aggrecan fragments produced by cleavage at an aggrecanase susceptible site.
Another aspect of the invention therefore provides pharmaceutical compositions containing a therapeutically effective amount of aggrecanase inhibitors, in a pharmaceutically acceptable vehicle. Aggrecanase-mediated degradation of aggrecan in cartilage has been implicated in osteoarthritis and other inflammatory diseases. Therefore, these compositions of the invention may be used in the treatment of diseases characterized by the degradation of aggrecan and/or an upregulation of aggrecanase. The compositions may be used in the treatment of these conditions or in the prevention thereof.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety.
The term “alkyl”, as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term “alkyl.” C1-C6 alkyl includes straight and branched chain aliphatic groups having from 1 to 6 carbons. Specifically included within the definition of “alkyl” are those aliphatic hydrocarbon chains that are optionally substituted.
The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
The term “alkenyl”, as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains having 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl moiety has 1 or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and the compounds of this invention include both conformations. C2-C6 alkenyl includes a 1 to 6 carbon straight or branched chain having at least one carbon-carbon double bond. Specifically included within the definition of “alkenyl” are those aliphatic hydrocarbon chains that are optionally substituted. Heteroatoms, such as O, S or N-RI, attached to an alkenyl should not be attached to a carbon atom that is bonded to a double bond.
The term “alkynyl” refers to a hydrocarbon moiety containing at least one carbon-carbon triple bond. C2-C6 alkynyl includes a 1 to 6 carbon straight or branched chain having at least one carbon-carbon triple bond.
3
The term “cycloalkyl” a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon moiety, wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, and the like. C3-C6 cycloalkyl includes monocyclic, saturated rings of 3 to 6 carbons, optionally substituted with R
“Heteroaryl” refers to a 5 to 6 membered aromatic heterocyclic ring which contains from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms in the ring and may be fused with a carbocyclic or heterocyclic ring at any possible position.
“Heterocycloalkyl” refers to a 5 to 7-membered saturated ring containing carbon atoms and from 1 to 2 heteroatoms selected from N, O, and S.
The term “phenyl”, as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted phenyl group.
4
5
4
4
4
5
4
4
5
4
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4
4
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5
2
2
2
2
2
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2
An optionally substituted moiety may be substituted with one or more substituents. Suitable optionally substituents may be selected independently from H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NRR, N[(CH)]O, N[(CH)]NR, NHSOR, NRC(═O)R, NHC(═O)OR, NO, SONRR, SOR, OR, C(═O)R, COOR, CONRR, and CN.
2
3
2
2
3
When such moieties are substituted, for example, they may typically be mono-, di-, tri- or persubstituted. Examples for a halogen substituent include 1-bromo vinyl, 1-fluoro vinyl, 1,2-difluoro vinyl, 2,2-difluorovinyl, 1,2,2-trifluorovinyl, 1,2-dibromo ethane, 1,2 difluoro ethane, 1-fluoro-2-bromo ethane, CFCF, CFCFCF, and the like.
The term halogen includes bromine, chlorine, fluorine, and iodine.
3
3
For the sake of simplicity, connection points (“-”) are not depicted. When an atom or compound is described to define a variable, it is understood that it is intended to replace the variable in a manner to satisfy the valency of the atom or compound. For example, when L is C(R)═C(R), both carbon atoms form a part of the ring in order to satisfy their respective valences.
The present invention is further described in the following examples.
Examples 1A and 1B were made based on Scheme 1
4
Step 1A [Intermediate 1] To a dry round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (12.2 g, 47.7 mmol, 1 equiv.), anhydrous methylene chloride (170 mL), and H-D-Val-OMe (8.0 g, 47.7 mmol, 1 equiv.). The mixture was cooled to 0° C. in an ice bath followed by the addition of Hunig base (19.11 mL, 109.7 mmol, 2.3 equiv.). The reaction mixture was allowed to warm to room temperature and was stirred overnight. Reaction was complete as determined by TLC. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with brine. The organic layer was dried over anhydrous MgSO, solvent evaporated to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester in 96% yield (16.0 g). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 0.96 (d, J=6.82 Hz, 3 H) 2.04 (m, 1 H) 3.49 (s, 3 H) 3.74 (d, J=14.40 Hz, 1 H) 5.10 (d, J=9.85 Hz, 1 H) 7.66 (m, 4 H).
3
4
2
2
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4
Step 1B [Intermediate 2: 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (3.4 g, 9.71 mmol), 4-hydroxymethyl phenyl boronic acid (1.48 g, 9.71 mmol, 1 equiv.), Pd(PPh)(561 mg, 0.48 mmol, 0.05 equiv.) were dissolved in ethylene glycol dimethyl ether (90 mL) under Natmosphere and stirred at room temperature for 30 min. Then KCO(2.68 g, 19.4 mmol, 2 equiv.) in HO (30 mL) was introduced to the reaction mixture and heat to reflux overnight. After TLC confirmation of reaction completion, solvent was removed by rotovap, residue partitioned between EtOAc and brine, organic layer dried over MgSO, solvent removed, crude residue was triturated with EtOAc to give 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester in 67% yield (2.46 g).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.90 (d, J=7.07 Hz, 3 H) 0.97 (d, J=6.82 Hz, 3 H) 1.57 (s, 1 H) 2.04 (m, 1 H) 3.43 (s, 3 H) 3.79 (dd, J=10.11, 5.05 Hz, 1 H) 4.78 (s, 2 H) 5.11 (d, J=10.36 Hz, 1 H) 7.49 (d, J=8.34 Hz, 2 H) 7.60 (d, J=8.34 Hz, 2 H) 7.70 (d, J=8.84 Hz, 2 H) 7.88 (d, J=8.59 Hz, 2 H).
2
2
Step 1C [Intermediate 3: 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (1.2 g, 3.2 mmol, 1.0 equiv.), 2-chloro-3-methyl quinoline (2.26 g, 12.7 mmol, 4 equiv.) were dissolved in DMF (30 mL) followed by the addition of NaH (382 mg, 60% in oil, 9.54 mmol, 3 equiv.). The mixture was stirred at 100° C. for 5 hrs, then at room temperature overnight. The reaction mixture was then poured into cold water, solid precipitated from the mixture was collected by filtration and washed with water. Regular column chromatography (Silica gel, 1% MeOH/CHCl) to yield 203 mg of 3-Methyl-2-[4′-(3-methyl -quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 12% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.89 (d, J=6.82 Hz, 3 H) 0.97 (d, J=6.82 Hz, 3 H) 2.04 (m, 1 H) 2.40 (s, 3 H) 3.43 (s, 3 H) 3.78 (dd, J=10.11, 5.31 Hz, 1 H) 5.09 (d, J=10.11 Hz, 1 H) 5.64 (s, 2 H) 7.37 (m, 1 H) 7.64 (m, 8 H) 7.86 (m, 4 H).
2
Step 1D: 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (203 mg, 0.39 mmol, 1 equiv.) was dissolved in THF (8 mL) and MeOH (4 mL) and hydrolyzed with IN NaOH (5.83 mL, 5.83 mmol, 13 equiv.). After stirring for 3 days, solvent was removed and the residue was dissolved in HO. The mixture was then acidified to pH 3 using 1N HCl. Solid precipitated from the mixture was collected by filtration and washed with water. After drying in vacuum oven, 101 mg of 3-Methyl-2-[4′-(3-methyl-quinolin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid was obtained in 76.3% yield.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.81 (d, J=6.57 Hz, 3 H) 0.84 (d, J=6.82 Hz, 3 H) 1.95 (m, 1 H) 2.36 (s, 3 H) 3.56 (dd, J=9.09, 5.81 Hz, 1 H)5.61 (s, 2 H) 7.42 (t, J=7.45 Hz, 1 H) 7.61 (t, J=7.71 Hz, 1 H) 7.67 (d, J=7.83 Hz, 2 H) 7.83 (m, 8 H) 8.08 (d, J=8.34 Hz, 2 H) 12.58 (s, 1 H).
The title compound, 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to the procedures similar to that described for Example 1A.
2
Step 1C: 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (350 mg, 0.93 mmol, 1 equiv), 2-chloro-5-trifluoromethylpyridine (841 mg, 4.64 mmol, 5 equiv.) were dissolved in DMF (7 mL) followed by the addition of NaH (111 mg, 2.78 mmol, 3 equiv.) under Natmosphere. The mixture was heat to 100° C. for 2 hrs and cool to room temperature. Reaction mixture poured onto cold water and the resulting solid collected by filtration. Further purification by column chromatography (Silica gel, 20% EtOAc/Hexane) to afford 259 mg of G9058-182-2 in 54% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.90 (d, J=6.82 Hz, 3 H) 1.98 (m, 1 H) 3.36 (s, 3 H) 3.72 (dd, J=10.11, 5.05 Hz, 1 H) 5.02 (d, J=10.11 Hz, 1 H) 5.43 (s, 2 H) 6.84 (d, J=8.84 Hz, 1 H) 7.52 (m, 4 H) 7.64 (d, J=6.82 Hz, 2 H) 7.74 (d, J=8.84 Hz, 1 H) 7.82 (m, 2 H) 8.40 (s, 1 H).
Step 1D: 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid (86.4% yield, 210 mg) was prepared according to procedures in Step 1D for Example 1A, using 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (250 mg) as the starting material.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.81 (d, J=6.82 Hz, 3 H) 0.84 (d, J=6.57 Hz, 3 H) 1.95 (m, 1 H) 3.56 (m, 1 H) 5.51 (d, 2 H) 7.12 (d, J=8.84 Hz, 1 H) 7.59 (d, J=8.34 Hz, 2 H) 7.77 (d, J=8.34 Hz, 2 H) 7.86 (m, 4 H) 8.11 (m, 2 H) 8.63 (m, 1 H) 12.57 (s, 1 H).
Example 1C and 1D were made based on Scheme 2.
2
3
2
Step 2A [Intermediate 4, G9591-157-1]: To a solution of 2,8-Bis-trifluoromethyl-quinolin-4-ol (3.85 g, 13.7 mmol, 1.1 equiv.) in DMF (40 mL) was added 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.7 g, 12.5 mmol, 1.0 equiv.) and KCO(3.45 g, 24.92 mmol, 2.2 equiv.) under Natmosphere. The reaction mixture was stirred at room temperature overnight. The reaction was complete as determined by TLC. The reaction mixture was poured into cold water, the white precipitate formed was collected by filtration, washed with water, dried under vacuum to yield 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-2,8-bis-trifluoromethyl-quinoline in 73% yield (4.95 g).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.36 (s, 12 H) 5.38 (s, 2 H) 7.21 (s, 1 H) 7.51 (d, J=8.34 Hz, 2 H) 7.65 (t, J=7.83 Hz, 1 H) 7.90 (d, J=8.08 Hz, 2 H) 8.14 (d, J=7.33 Hz, 1 H) 8.50 (d, J=8.59 Hz, 1 H).
3
4
2
2
3
4
Step 2B [Intermediate 5, G9591-162]: To 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-2,8-bis-trifluoromethyl-quinoline (1.5 g, 3.0 mmol, 1 equiv.) in 45 mL of ethylene glycol dimethyl ether was added 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (1.06 g, 3.0 mmol, 1.0 equiv.) and Pd(PPh)(174 mg, 0.15 mmol, 0.05 equiv.) under N. The reaction mixture was stirred for 0.5 hr, then an aqueous solution of KCO(834 mg, 6.0 mmol, 2 equiv.) was added. The mixture was heat to reflux overnight. After cooling to room temperature, solvent was removed under vacuum. The residue was diluted with EtOAc (100 mL) and washed with brine solution. The organic layer was dried over anhydrous MgSO, solvent evaporated under vacuum, and the crude product was purified on silica gel column (30% EtOAc/Hexane) to give 1.026 g of 2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester in 53% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.90 (d, J=6.82 Hz, 3 H) 0.98 (d, J=6.82 Hz, 3 H) 2.07 (m, 1 H) 3.45 (s, 3 H) 3.81 (dd, J=10.11, 5.05 Hz, 1 H) 5.12 (d, J=10.11 Hz, 1 H) 5.44 (s, 2 H) 7.25 (s, 1 H) 7.70 (m, 7 H) 7.92 (d, J=8.84 Hz, 2 H) 8.16 (d, J=7.33 Hz, 1 H) 8.52 (d, J=8.59 Hz, 1 H).
2
Step 2C: 2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester (1.026 g, 1.6 mmol, 1 equiv.) was dissolved in THF (15 mL) and MeOH (6 mL) and 1N NaOH (17.6 mL, 11 equiv.) was added. The reaction was monitored by TLC. It was complete in 3 days. Solvent was removed by rotovap and the residue was dissolved in HO. The mixture was then acidified to pH 3 with 1N HCl. The resulting precipitate was collected by filtration and washed with cold water and dried overnight. 460 mg of white solid was obtained in 46% yield.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.96 (m, 1 H) 3.57 (dd, J=9.35, 6.32 Hz, 1 H) 5.66 (s, 2 H) 7.83 (m, 10 H) 8.11 (d, J=9.35 Hz, 1 H) 8.35 (d, J=7.33 Hz, 1 H) 8.58 (d, J=7.83 Hz, 1 H) 12.57 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(2-methyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to the procedures similar to that described for Example 1C.
Step 2A: Alkylation of 2-Methyl-quinolin-4-ol with 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was carried out according to procedures in Step 2A for Example 1C to give 2-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-quinoline in 28% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 5.4 (s, 2 H) 7.0 (s, 1 H) 7.5 (m, 1 H) 7.6 (d, J=8.1 Hz, 2 H) 7.7 (m, 1 H) 7.7 (d, J=8.1 Hz, 2 H) 7.9 (d, J=8.1 Hz, 1 H) 8.1 (dd, J=8.3, 0.8 Hz, 1 H).
Step 2B: Suzuki coupling of D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester with 2-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-quinoline was carried out according to procedures in Step 2B for Example 1C in 80% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.0, 6.7 Hz, 6 H) 1.9 (m, 1 H) 2.6 (s, 3 H) 3.3 (s, 3 H) 3.6 (dd, J=9.3, 7.1 Hz, 1 H) 5.5 (s, 2 H) 7.1 (s, 1 H) 7.5 (t, J=7.6 Hz, 1 H) 7.7 (m, 3 H) 7.8 (d, J=7.6 Hz, 4 H) 7.9 (m, 1 H) 7.9 (m, 2 H) 8.1 (d, J=8.3 Hz, 1 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 2C: Hydrolysis of D-3-Methyl-2-[4′-(2-methyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-butyric acid methyl ester was carried out according to procedures in Step 2C for Example 1C in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=40.2, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.6 (s, 3 H) 3.0 (s, 1 H) 5.4 (s, 2 H) 7.1 (s, 1 H) 7.5 (t, J=8.1 Hz, 1 H) 7.7 (t, J=7.7 Hz, 3 H) 7.8 (m, 7 H) 8.1 (d, J=9.3 Hz, 1 H).
Example 1E was made based on Scheme 3.
2
4
Step 3A. To a round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (24.37 g, 95.4 mmol, 1 equiv), anhydrous methylene chloride (350 mL), and H-D-Val-OtBu (20 g, 95.4 mmol, 1 equiv.). The mixture was cool to 0° C. followed by the addition of Hunig's base (38.2 mL, 219 mmol, 2.3 equiv.). The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. Starting material was consumed as determined by TLC. The reaction mixture was then diluted with methylene chloride (200 mL) and washed with HO (500 mL), brine (250 mL). The organic layer was dried over anhydrous MgSO, evaporated under vacuum to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester in quantitative yield (35.0 g).
1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.84 (d, J=6.82 Hz, 3 H) 1.19 (s, 9 H) 1.93 (m, 1 H) 3.46 (dd, J=9.35, 6.06 Hz, 1 H) 7.69 (d, J=8.59 Hz, 2 H) 7.79 (m, 2 H) 8.24 (d, J=9.60 Hz, 1 H).
3
4
2
3
2
4
Step 3B: 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (11.96 g, 30.47 mmol, 1 equiv.), 4-(Hydroxymethylbenzene) boronic acid (4.63 g, 30.5 mmol, 1 equiv) and Pd(PPh)(1.76 g, 1.52 mmol, 0.05 equiv.) were charged to a reaction flask and added with ethylene glycol dimethyl ether (300 mL). The mixture was stirred at room temperature for 10 min., then a solution of KCO(8.43 g, 60.9 mmol, 2 equiv.) dissolved in 100 mL HO was introduced. The reaction mixture was heat to reflux overnight. After cooling to room temperature, solvent was removed by rotavap and the residue partitioned between EtOAc and brine. Organic layer was separated and dried over MgSO. After removing solvent by rotavap, 8.3 g of white solid 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester was obtained in 65% yield.
1H NMR (400 MHz, MeOD) δ ppm 1.05 (d, J=6.82 Hz, 3 H) 1.12 (d, J=6.82 Hz, 3 H) 1.33 (s, 9 H) 2.16 (m, 1 H) 3.73 (d, J=5.56 Hz, 1 H) 4.81 (s, 2 H) 7.62 (d, J=8.59 Hz, 2 H) 7.78 (d, J=8.34 Hz, 2 H) 7.92 (d, J=8.84 Hz, 2 H) 8.04 (m, 2 H).
4
Step 3C 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (700 mg, 1.68 mmol, 1 equiv), 2-chloroquinoline (1.1 g, 6.7 mmol, 4 equiv) were dissolved in DMF (20 mL) and added with and NaH (202 mg, 60% in oil, 5.04 mmol, 3 equiv). The mixture was heat to 100° C. for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with sat. NHCl (aq). After stirring for 0.5 h, solid precipitated from the mixture. Solid was collected by filtration and washed with water and dried overnight to produce 793 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 87% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.19 (s, 9 H) 2.05 (m, 1 H) 3.66 (dd, J=9.85, 4.55 Hz, 1 H) 5.14 (d, J=9.85 Hz, 1 H) 5.62 (s, 2 H) 6.98 (d, J=8.84 Hz, 1 H) 7.40 (m, 1 H) 7.66 (m, 9 H) 7.89 (m, 2 H) 8.03 (d, J=8.59 Hz, 1 H).
Step 3D: 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (480 mg, 0.88 mmol) was dissolved in 15 mL of dichloromethane. The solution was cool to 0° C. followed by the addition of 5 mL of TFA. The resulting mixture was stirred at room temperature for 4 hrs. Solvent was removed by rotavap and the residue was washed with MeOH. Solid thus obtained was dried overnight under vacuum to afford 60 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 14% yield.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.81 (d, J=6.82 Hz, 3 H) 0.84 (d, J=6.82 Hz, 3 H) 1.95 (m, 1 H) 3.56 (dd, J=9.35, 6.06 Hz, 1 H) 5.58 (s, 2 H) 7.11 (d, J=8.84 Hz, 1 H) 7.46 (dd, J=7.58, 6.32 Hz, 1 H) 7.79 (m, 11 H) 8.08 (d, J=9.35 Hz, 1 H) 8.29 (d, J=8.59 Hz, 1 H) 12.57 (s, 1 H).
Example 1F was made based on Scheme 4.
4
To 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-benzothiazole (300 mg, 0.604 mmol, 1 equiv.) in 9 mL of dimethoxy ethane was added 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (237 mg, 0.604 mmol, 1 equiv.) and Pd(PPh3)4 (35 mg, 0.03 mmol, 0.05 equiv). The mixture was stirred at room temperature for 20 min followed by the addition of K2CO3 (167 mg, 1.208 mmol, 2 equiv.) in H2O (3 mL). The mixture was heat to reflux overnight. After cooling to room temperature, solvent was removed by rotavap. Residue was dissolved in methylene chloride and washed with water, brine. Organic layer dried over MgSO, solvent removed under vacuum, crude mixture purified by column chromatography (30% EtOAc/Hexane) to give 285 mg of in 85% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.07 (d, J=6.82 Hz, 3 H) 1.23 (d, J=6.82 Hz, 3 H) 1.39 (s, 9 H) 1.47 (t, J=7.20 Hz, 1 H) 3.86 (dd, J=9.85, 4.55 Hz, 1 H) 5.42 (s, 2 H) 6.99 (s, 1 H) 7.22 (d, J=7.07 Hz, 1 H) 7.39 (m, 2 H) 7.61 (d, J=8.59 Hz, 2 H) 7.67 (d, J=6.32 Hz, 1 H) 7.72 (m, 2 H) 7.84 (d, J=8.84 Hz, 2 H) 8.09 (d, J=8.59 Hz, 2 H).
Step 4B 2-[4′-(Benzothiazol-2-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (140 mg, 0.25 mml) was dissolved in 6 mL of methylene chloride followed by the addition of TFA (3 mL) The reaction was complete in 6 hrs as determined by TLC. Solvent was removed and the residue was dissolved in EtOAc. n-Hexane was added into the solution and solid precipitated from the mixture. The precipitate was collected and dried to afford 86 mg of in 68% yield.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.83 (d, J=6.82 Hz, 3 H) 1.93 (m, 1 H) 3.54 (dd, J=9.35, 6.06 Hz, 1 H) 5.26 (s, 2 H) 7.21 (m, 1 H) 7.33 (m, 2 H) 7.44 (d, J=8.59 Hz, 2 H) 7.71 (t, J=8.46 Hz, 3 H) 7.82 (s, 4 H) 8.07 (d, J=9.35 Hz, 1 H) 12.55 (s, 1 H).
Examples 1G, 1H, 1I, 1J, 1K, 1L, 1M, 1N, 1O, 1P, 1Q, 1R were made based on Scheme 4B.
ES− 480.1 (M−H)−HRMS: 482.16311 (M+Na)+; 482.16319 Calc'd
ES+ 544.2 (M+H)+HRMS: 544.17694 (M+H); 544.17884 Calc'd
ES− 480.2 (M−H)−HRMS: 482.1635 (M+H)+; 482.16319 Calc'd
495
2
ES− . (M−H)−HRMS: 497.17284 (M+H)+; 497.17409 Calc'd
ES− 468.2 (M−H)−HRMS: 470.16231 (M+H)+; 470.16319 Calc'd
ES− 456.1 (M−H)−HRMS: 458.14323 (M+H)+; 458.1432 Calc'd
ES− 551.2 (M−H)−HRMS: 553.19849 (M+H)+; 553.2003 Calc'd
ES− 535.2 (M−H)−HRMS: 537.20469 (M+H)+; 537.20539 Calc'd
ES− 456.1 (M−H)−HRMS: 458.14389 (M+H)+; 458.1432 Calc'd
ES− 468.2 (M−H)−HRMS: 470.16151 (M+H)+; 470.16319 Calc'd
ES+ 539.1 (M+H)+HRMS: 539.22021 (M+H)+; 539.22104 Calc'd
ES−514.1 (M−H)−HRMS: 516.18313 (M+H)+; 516.18392 Calc'd
Examples IS, IT, 1U, 1V, 1W, 1X, 1Y, 1Z, 1AA, 1AB, 1AC, 1AD, 1AE were made based on Scheme 4C.
ES− 495.1 (M−H)−HRMS: 497.17429 (M+H)+; 497.17409 Calc'd
ES− 488.1 (M−H)−HRMS: 490.16864 (M+H)+; 490.16827 Calc'd
+
ES m/z 452.1 (M−H)−HRMS: 454.16745 (M+H)+; 454.16827 Calc'd
1
3
H NMR (400 MHz, CDCl): δ 0.82 (d, 3H, J=6.8 Hz), 0.94 (d, 3H, J=6.8 Hz), 2.06 (m, 1H), 2.31 (s, 3H), 3.80 (dd, 1H, J=4.4, 10 Hz), 5.13 (m, 3H), 6.90 (m,2H), 7.17 (m, 2H), 7.55 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz), 7.66 (d, 2H, J=8 Hz), 7.86 (d, 2H, J=8 Hz).
+
ES m/z 481.2 (M+H)+HRMS: 483.19410 (M+H)+; 483.19482 Calc'd
1
3
H NMR (400 MHz, CDOD): δ 0.90 (d, 3H, J=6.8 Hz), 0.99 (d, 3H, J=6.8 Hz), 2.06 (m, 1H), 2.92 (s, 6H), 3.42 (s, 3H), 3.70 (d, 1H, J=5.6, 10 Hz), 5.14 (s, 2H), 6.41 (m, 3H), 7.11 (m, 1H), 7.57 (d, 2H, 8 Hz), 7.71 (d, 2H, J=8 Hz), 7.80 (d, 2H, J=8 Hz), 7.92 (d, 2H, J=8 Hz).
+
ES m/z 544.1 (M+H)+HRMS: 546.19448 (M+H)+; 546.19449 Calc'd
1
3
H NMR (400 MHz, CDOD): δ 0.93 (d, 3H, J=6.8 Hz), 0.99 (d, 3H, J=6.8 Hz), 2.07 (m, 1H), 3.70 (d, 1H, J=5.6), 5.03 (s, 2H), 5.10 (s, 2H), 6.94 (s, 4H), 7.31 (m, 1H), 7.37 (m, 2H), 7.43 (m, 2H), 7.55 (d, 2H, 8 Hz), 7.71 (d, 2H, J=8 Hz), 7.80 (d, 2H, J=8 Hz), 7.92 (d, 2H, J=8 Hz).
+
ES m/z 553.2 (M−H)−HRMS: 577.19777 (M+Na)+; 577.19789 Calc'd
1
3
H NMR (400 MHz, CDOD): δ 0.91 (d, 3H, J=6.8 Hz), 0.97 (d, 3H, J=6.8 Hz), 1.50 (s, 9H), 2.04 (m, 1H), 3.68 (d, 1H, J=5.6 Hz), 5.10 (s, 2H), 6.92 (s, 2H), 7.28 (d, 2H, J=8 Hz), 7.54 (d, 2H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8Hz), 7.91 (d, 2H, J=8 Hz).
+
ES m/z 470.2 (M+H)+HRMS: 470.16364 (M+H)+; 470.16319 Calc'd
1
3
H NMR (400 MHz, CDCl): δ 0.89 (d, 3H, J=6.8 Hz), 0.96 (d, 3H, J=6.8 Hz), 2.10 (m, 1H), 3.82 (m, 1H), 3.90 (s, 3H), 5.07 (d, 1H, J=9.6 Hz), 5.21 (s, 2H), 6.93 (m, 4H), 7.54 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 7.65 (d, 2H, J=8 Hz), 7.89 (d, 2H, J=8 Hz).
+
ES m/z 466.2 (M−H)−HRMS: 468.18540 (M+H)+; 468.18392 Calc'd
1
3
H NMR (400 MHz, CDCl): δ 0.83 (d, 3H, J=6.8 Hz), 0.95 (d, 3H, J=6.8 Hz), 2.05 (m, 1H), 2.33 (s, 6H), 3.82 (dd, 1H, J=5.2, 10 Hz), 4.88 (s, 2H), 5.07 (d, 1H, J=10 Hz), 6.97 (m, 1H), 7.05 (m, 2H), 7.64 (m, 4H), 7.67 (d, 2H, J=8 Hz), 7.87 (d, 2H, J=8 Hz).
+
ES m/z 454.1 (M−H)−HRMS: 456.14707 (M+H)+; 456.14754 Calc'd
1
6
H NMR (400 MHz, acetone(d)): δ 0.92 (d, 3H, J=6.8 Hz), 0.98 (d, 3H, J=6.8 Hz), 2.10 (m, 1H), 3.16 (m, 1H), 5.16 (s, 2H), 6.45 (d, 1H, J=8 Hz), 6.53 (m, 2H), 7.10 (t, 1H, J=8 Hz), 7.61 (d, 2H, J=8 Hz), 7.76 (d, 2H, J=8 Hz), 7.86 (d, 2H, J=8 Hz), 7.94 (d, 2H, J=8 Hz).
+
ES m/z 530.1 (M−H)−HRMS: 532.17709 (M+H)+; 532.17884 Calc'd
1
3
H NMR (400 MHz, CDOD): δ 0.93 (d, 3H, J=6.8 Hz), 0.99 (d, 3H, J=6.8 Hz), 2.06 (m, 1H), 3.70 (d, 1H, J=5.6, 10 Hz), 5.16 (s, 2H), 6.93 (m, 3H), 7.04 (m, 3H), 7.31 (m, 2H), 7.58 (d, 2H, J=8 Hz), 7.72 (d, 2H, J=8 Hz), 7.81 (d, 2H, J=8 Hz), 7.93 (d, 2H, J=8 Hz).
+
ES m/z 531.1 (M−H)−HRMS: 533.17293 (M+H)+; 533.17409 Calc'd
1
3
H NMR (400 MHz, CDCl): δ 0.88 (d, 3H, J=6.8 Hz), 1.00 (d, 3H, J=6.8 Hz), 2.13 (m, 1H), 3.83 (m, 1H), 5.13 (m, 3H), 6.82 (m, 1H), 7.02 (m, 5H), 7.56 (m, 4H), 7.67 (m, 3H), 7.89 (m, 2H), 8.16 (m, 1H).
+
ES m/z 545.2 (M−H)−HRMS: 547.19006 (M+H)+; 547.18974 Calc'd
1
3
H NMR (400 MHz, CDCl): δ 0.89 (d, 3H, J=6.8 Hz), 1.01 (d, 3H, J=6.8 Hz), 2.19 (m, 1H), 2.44 (s, 3H), 3.83 (m, 1H), 5.04 (s, 2H), 6.39 (d, 1H, J=8 Hz), 6.83 (m, 1H), 6.90 (m, 2H, J=8 Hz), 6.97 (d, 2H, J=8 Hz), 7.52 (m, 5H), 7.60 (d, 2H, J=8 Hz), 7.90 (d, 2H, J=8 Hz).
+
ES m/z 506.2 (M−H)−HRMS: 508.17782 (M+H)+; 508.17884 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.81 (d, 3H, J=6.8 Hz), 0.84 (d, 3H, J=6.8 Hz), 1.98 (m, 3H), 2.64 (d, 2H), 2.91 (t, 2H, J=6 Hz), 3.56 (dd, 1H, J=6,9.2 Hz), 5.27 (s, 2H), 6.99 (d, 2H, J=8 Hz), 7.59 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz), 7.85 (m, 4H), 8.08 (d, 1H, 8 Hz).
Examples 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J were made based on Scheme 5.
2
3
3
Step 5A: A mixture of 2-Chloromethyl-3-methyl-benzofuran (675.9 mg, 3.75 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (825 mg, 3.75 mmol, 1 eq), KCO(2.1 g, 15.2 mmol, 4 eq) in 20 mL of CHCN was heat to reflux under nitrogen atmosphere. Reaction was complete after 12 hrs. Regular work-upwork up and column purification (5% EtOAc/hexane) to give 3-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 44% yield (601 mg). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 2.3 (s, 3 H) 5.2 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J=21.6, 7.7 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).
3
4
2
3
2
Step 5B: A mixture of D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (568.07 mg, 1.62 mmol), 3-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran (590.7 mg, 1.62 mmol, 1 eq), Pd(PPh)(93.7 mg, 0.08 mmol, 0.05 eq), and KCO(448.35 mg, 3.24 mmol, 2 eq) in 5 mL of DME and 5 mL of HO was heat to reflux for 12 hrs. After cool to room temperature, the mixture was loaded onto column for purification. 616 mg of product G8475-146 was obtained in 75% yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (d, J=6.8 Hz, 6 H) 1.9 (m, 1 H) 2.2 (s, 3 H) 3.2 (s, 3 H) 3.5 (d, J=6.6 Hz, 1 H) 5.1 (s, 2 H) 7.0 (m, J=9.1 Hz, 2 H) 7.1 (m, 1 H) 7.2 (m, 1 H) 7.3 (m, 1 H) 7.4 (m, 1 H) 7.5 (d, J=9.1 Hz, 2 H) 7.6 (d, J=8.8 Hz, 2 H) 7.7 (m, 2 H).
Step 5C: To D-3-Methyl-2-[4′-(3-methyl-benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (364 mg) was dissolved in THF (10 mL) and MeOH (3 mL). 1N LiOH (3 mL) was added and the mixture was stirred overnight. Regular work-up and column purification to give D-3-Methyl-2-[4′-(3-methyl-benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid in quantitative. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=30.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.2 (s, 3 H) 3.5 (d, J=5.3 Hz, 1H) 5.1 (s, 2 H) 7.1 (d, J=9.1 Hz, 2 H) 7.1 (m, 1 H) 7.2 (m, 1 H) 7.3 (d, J=8.3 Hz, 1 H) 7.5 (d, J=8.3 Hz, 1 H) 7.5 (d, J=9.1 Hz, 3 H) 7.6 (d, J=8.6 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).
The title compound, D-2-[4′-(Benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: To 2-Bromomethyl-benzofuran (1.5 g, 7.1 mmol, 1 eq.), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.56 g, 7.1 mmol, 1 eq.), potassium carbonate (1.96 g, 14.2 mmol, 2 eq.) was dissolved in acetonitrile (50 mL) under argon and heated at 70° C. for 16 hours. After work-up and flash column chromatography, 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran is obtained. Yield: 63%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.1 (m, 3 H) 7.3 (m, 1 H) 7.3 (m, 1 H) 7.6 (m, 4 H).
Step 5B: Coupling of 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -phenoxymethyl]-benzofuran with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester to obtain D-2-[4′-(Benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester was done according to procedures in Step 5B for Example 2A. Yield: 33%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=8.3, 7.1 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.7, 6.2 Hz, 1 H) 5.3 (s, 2 H) 7.1 (s, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.3 (m, 1 H) 7.3 (m, 1 H) 7.6 (dd, J=8.2, 0.6 Hz, 1 H) 7.7 (m, 3 H) 7.8 (d, J=3.3 Hz, 4 H) 8.1 (d, J=9.9 Hz, 1 H).
Step 5C: D-2-[4′-(Benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (126 mg, 0.23 mmol, 1 eq.), cerium chloride heptahydrate (175 mg, 0.47 mmol, 2 eq.), potassium iodide (51 mg, 0.30 mmol, 1.3 eq.) in acetonitrile (10 mL) were heated at 70 C for 16 hours. After work-up and flash column chromatography, D-2-[4′-(Benzofuran-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was obtained. Yield: 25%. NMR: 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.5, 6.7 Hz, 6 H) 2.0 (m, 1 H) 3.5 (dd, J=9.2, 5.9 Hz, 1 H) 5.3 (s, 2 H) 7.1 (s, 1 H) 7.2 (d, J=8.8 Hz, 2 H) 7.3 (dd, J=8.1, 0.8 Hz, 1 H) 7.3 (m, 1 H) 7.6 (d, J=8.1 Hz, 1 H) 7.7 (m, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (d, 4 H) 8.0 (d, J=9.3 Hz, 1 H).
The title compound, D-3-Methyl-2-[4′-(naphthalen-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: Alkylation of 2-Bromomethyl-naphthalene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A in Example 2A to give 4,4,5,5-Tetramethyl-2-[4-(naphthalen-2-ylmethoxy)-phenyl]-[1,3,2]dioxaborolane in 85% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 2 H) 7.5 (dd, J=8.3, 1.8 Hz, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H).
Step 5B: Suzuki coupling of 4,4,5,5-Tetramethyl-2-[4-(naphthalen-2-ylmethoxy)-phenyl]-[1,3,2]dioxaborolane with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 5B for Example 2A to give D-3-Methyl-2-[4′-(naphthalen-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 44% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.9 (dd, J=32.1, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.4 (s, 3 H) 3.8 (dd, J=10.2, 5.2 Hz, 1 H) 5.1 (d, J=10.1 Hz, 1 H) 5.3 (s, 2 H) 7.1 (d, J=9.1 Hz, 2 H) 7.5 (m, 2 H) 7.6 (m, 3 H) 7.7 (d, J=8.6 Hz, 2 H) 7.9 (m, 6 H).
Step 5C: Hydrolysis of D-3-Methyl-2-[4′-(naphthalen-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester was carried out according to procedures in Step 5C for Example 2A in quantitative yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=32.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (d, J=5.3 Hz, 1 H) 5.2 (s, 2 H) 7.1 (d, J=8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (dd, J=8.6, 1.8 Hz, 1 H) 7.5 (d, J=8.8 Hz, 2 H) 7.6 (d, J=8.8 Hz, 2 H) 7.8 (m, 5 H) 7.8 (s, 1 H).
The title compound, D-2-(4′-Benzyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5B: Suzuki coupling of 4-benzyloxyphenylboronic acid with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester was carried out according to procedures in Step 5B for Example 2A to give D-2-(4′-Benzyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester in 73% yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=29.7, 6.7 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (d, J=5.8 Hz, 1 H) 5.0 (s, 2 H) 7.0 (d, J=8.8 Hz, 2 H) 7.2 (t, J=7.3 Hz, 1 H) 7.3 (m, 2 H) 7.4 (d, J=6.8 Hz, 2 H) 7.5 (d, J=9.1 Hz, 2 H) 7.6 (d, J=8.6 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).
Step 5C: D-2-(4′-Benzyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid was prepared according to procedures in Step 5C for example 2A in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.3, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.3, 6.1 Hz, 1H) 5.2 (s, 2 H) 7.1 (d, J=9.1 Hz, 2 H) 7.4 (m, 3 H) 7.5 (m, 2 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (s, 4 H) 8.0 (d, J=9.3 Hz, 1 H).
The title compound, D-3-Methyl-2-[4′-(quinolin-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: Alkylation of 2-Chloromethyl-quinoline with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 2A to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline in 90% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.2 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.6 (dd, J=11.4, 8.6 Hz, 3 H) 7.7 (m, 1 H) 7.8 (dd, J=8.1, 1.5 Hz, 1 H) 7.9 (d, J=8.6 Hz, 1 H) 8.3 (d, J=8.6 Hz, 1 H).
Step 5B: Suzuki coupling of 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester was carried out according to procedures in Step 5B for Example 2A to give D-3-Methyl-2-[4′-(quinolin-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester in 70% yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=29.8, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (d, J=5.6 Hz, 1 H) 5.3 (s, 2 H) 7.1 (d, J=8.8 Hz, 2 H) 7.5 (m, 3 H) 7.6 (t, J=8.6 Hz, 3 H) 7.7 (m, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (dd, J=8.2, 0.9 Hz, 1 H) 8.0 (m, 1 H) 8.3 (d, J=8.8 Hz, 1 H).
Step 5C: Removal of t-butyl ester was done according to procedures in Step 5C for Example 2A in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.5, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.3, 6.1 Hz, 1 H) 5.5 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.7 (m, 1 H) 7.7 (dd, J=8.7, 1.9 Hz, 3 H) 7.8 (s, 5 H) 8.0 (m, 3 H) 8.5 (d, J=8.6 Hz, 1 H).
The title compound, D-3-Methyl-2-[4′-(2-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: Alkylation of 1-Bromomethyl-2-nitro-benzene with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 2A to give 4,4,5,5-Tetramethyl-2-[4-(2-nitro-benzyloxy)-phenyl]-[1,3,2]dioxaborolane in 62% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 5.5 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (dd, J=7.8, 1.0 Hz, 1 H) 8.2 (dd, J=8.1, 1.3 Hz, 1 H).
Step 5B: Suzuki coupling of 4,4,5,5-Tetramethyl-2-[4-(2-nitro-benzyloxy)-phenyl]-[1,3,2]dioxaborolane with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester was carried out according to procedures in Step 5B for 2A to give D-3-Methyl-2-[4′-(2-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester in 20% yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=30.1, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (d, J=5.6 Hz, 1 H) 5.4 (s, 2 H) 7.0 (d, J=8.8 Hz, 2 H) 7.5 (m, 1 H) 7.5 (d, J=8.8 Hz, 2 H) 7.6 (m, 3 H) 7.8 (d, J=8.6 Hz, 3 H) 8.1 (dd, J=8.1, 1.3 Hz, 1 H).
Step 5C: Removal of t-butyl ester was done according to procedures in Step 5C for Example 2A in quantitative yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=24.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (d, J=5.8 Hz, 1 H) 5.4 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (t, J=7.7 Hz, 1 H) 7.6 (d, J=8.8 Hz, 2 H) 7.7 (m, 3 H) 7.8 (m, 3 H) 8.1 (d, J=9.6 Hz, 1 H).
The title compound, D-2-[4′-(2-Chloro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: Coupling of 2-chlorobenzyl bromide with 4-hydroxyphenyl boronic ester to obtain 2-[4-(2-Chloro-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was done according to procedures in Step 5A for Example 2A. Yield: 85%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.2 (s, 2 H) 7.0 (d, J=8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.6 (d, J=8.8 Hz, 2 H).
Step 5B: Coupling 2-[4-(2-Chloro-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-2-[4′-(2-Chloro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was done according to procedures in Step 5B for Example 2A. Yield: 73%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.4, 6.6 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J=9.3, 7.1 Hz, 1 H) 5.2 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (d, J=8.6 Hz, 2 H) 7.8 (m, 2 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 5C: Hydrolysis of D-2-[4′-(2-Chloro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester to D-2-[4′-(2-Chloro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 5C for Example 2A. Yield: 55%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.2, 5.9 Hz, 1 H) 5.2 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (s, 4 H) 8.0 (d, J=9.3 Hz, 1 H) 12.6 (s, 1 H).
The title compound, D-2-[4′-(2-Fluoro-6-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: Coupling of 2-fluoro-6-nitrobenzyl bromide with 4-hydroxyphenyl boronic ester to obtain 2-[4-(2-Fluoro-6-nitro-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was done according procedures in Step 5A for Example 2A. Yield: 95%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.3 (d, J=1.3 Hz, 2 H) 7.0 (d, J=8.8 Hz, 2 H) 7.6 (d, J=8.8 Hz, 2 H) 7.7 (m, 2 H) 7.9 (m, 1 H).
Step 5B: Coupling 2-[4-(2-Fluoro-6-nitro-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-2-[4′-(2-Fluoro-6-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was done according to procedures in Step 5B for Example 2A. Yield: 49%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.2, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J=9.5, 7.2 Hz, 1H) 5.4 (d, J=1.3 Hz, 2 H) 7.1 (d, J=8.8 Hz, 2 H) 7.8 (m, 6 H) 7.8 (m, 2 H) 7.9 (m, 1 H) 8.3 (m, J=9.3 Hz, 1 H).
Step 5C: Hydrolysis of D-2-[4′-(2-Fluoro-6-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester to D-2-[4′-(2-Fluoro-6-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 5C for Example 2A, except purification through prep-HPLC. Yield: 30%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.9, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.2, 5.9 Hz, 1 H) 5.4 (d, J=1.3 Hz, 2 H) 7.1 (d, J=8.8 Hz, 2 H) 7.7 (m, 4 H) 7.8 (d, J=0.8 Hz, 4 H) 7.9 (m, 2 H) 8.0 (d, J=9.1 Hz, 1 H).
The title compound, D-3-Methyl-2-[4′-(quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5A: Coupling of 4-Chloromethyl-quinoline with 4-hydroxyphenyl boronic ester to obtain 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline was done according to procedures in Step 5A for Example 2A. Yield: 62%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.7 (d, J=0.5 Hz, 2 H) 7.1 (d, J=8.8 Hz, 2 H) 7.7 (m, 4 H) 7.8 (m, 1 H) 8.1 (dd, J=8.5, 0.9 Hz, 1 H) 8.2 (d, J=8.3 Hz, 1 H) 8.9 (d, J=4.5 Hz, 1 H).
Step 5B: Coupling of 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -phenoxymethyl]-quinoline with D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-3-Methyl-2-[4′-(quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester was done according to procedures in Step 5B for example 2A. Yield: 47%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.2, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J=9.3, 7.1 Hz, 1 H) 5.8 (s, 2 H) 7.3 (d, J=8.8 Hz, 2 H) 7.8 (m, 9 H) 8.1 (d, J=8.6 Hz, 1 H) 8.2 (d, J=8.6 Hz, 1 H) 8.3 (d, J=9.3 Hz, 1 H) 8.9 (d, J=4.3 Hz, 1 H).
Step 5C: Hydrolysis of D-3-Methyl-2-[4′-(quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester to D-3-Methyl-2-[4′-(quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 5C for Example 2A. Yield: 54%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=43.6, 6.9 Hz, 6 H) 2.0 (m, 1 H) 3.0 (d, J=3.0 Hz, 1 H) 5.8 (d, 2 H) 7.3 (d, J=8.8 Hz, 2 H) 7.7 (m, 4 H) 7.8 (m, 5 H) 8.1 (m, 1 H) 8.2 (dd, J=8.3, 0.8 Hz, 1 H) 8.9 (d, J=4.5 Hz, 1 H).
The title compound, D-3-Methyl-2-[4′-(quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2A.
Step 5C: Hydrolysis of D-2-[4′-(2-Cyanomethyl-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester (prepared according to step 3) to D-2-[4′-(2-Cyanomethyl-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 5C for Example 2A. Prep-HPLC was used for purification. Yield: 75%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=23.7, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.8 (d, J=6.6 Hz, 1 H) 4.1 (s, 2 H) 5.2 (s, 2 H) 7.2 (d, J=9.1 Hz, 2 H) 7.4 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (d, J=2.0 Hz, 4 H).
Examples 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R were made based on Scheme 6.
2
3
Step: A mixture of 4-Chloromethyl-2-methyl-quinoline (165 mg, 0.86 mmol, 1 eq), D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (314 mg, 0.86 mmol, 1 eq), and KCO(270 mg, 1.13 mmol, 1.3 eq) in 8 ML of DMF under nitrogen was heat to 90° C. for 12 hrs. After work up and column chromatography (30-60% EtOAc in hexane), D-3-Methyl-2-[4′-(2-methyl-quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester was obtained in 34% yield (150 mg). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.0, 6.7 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 3.3 (s, 3 H) 3.6 (dd, J=9.2, 7.2 Hz, 1 H) 5.7 (s, 2 H) 7.3 (d, J=8.8 Hz, 2 H) 7.6 (m, 2 H) 7.8 (m, 4 H) 7.8 (m, 2 H) 8.0 (d, J=9.3 Hz, 1 H) 8.1 (d, J=8.3 Hz, 1 H) 8.1 (none, 1 H) 8.3 (d, J=9.6 Hz, 1 H).
Step 6B: D-3-Methyl-2-[4′-(2-methyl-quinolin-4-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester (150 mg) was dissolved in THF (8 mL) and MeOH (4 mL) and added with 1N LiOH (3 mL, 3 mmol). The resulting solution was stirred at room temperature overnight. Reaction was complete as determined by TLC. Solvents removed and regular work-up and column chromatography to afford 148 mg of in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=31.8, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.2 (s, 1 H) 5.7 (s, 2 H) 7.3 (d, J=8.8 Hz, 2 H) 7.6 (m, 2 H) 7.8 (m, 7 H) 8.0 (d, J=7.6 Hz, 1 H) 8.1 (d, J=6.8 Hz, 1 H).
The title compound, D-2-[4′-(3-Cyano-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Coupling of α-Bromo-m-tolunitrile with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-2-[4′-(3-Cyano-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was done according to procedures in Step 6A for Example 2K. Yield: 25%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=14.9, 6.8 Hz, 6 H) 1.9 (m, 1H) 3.3 (s, 3 H) 3.6 (dd, J=9.5, 7.2 Hz, 1 H) 5.3 (s, 2 H) 7.2 (d, J=9.1 Hz, 2 H) 7.6 (t, J=8.0 Hz, 1 H) 7.7 (m, 4 H) 7.8 (m, 4 H) 8.0 (s, 1 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 6B: Hydrolysis of D-2-[4′-(3-Cyano-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester to D-2-[4′-(3-Cyano-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 6B for Example 2K. Yield: 24%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=26.0, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 1 H) 5.2 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.6 (d, J=7.6 Hz, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (m, 6 H) 8.0 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(naphthalen-1-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Alkylation of 1-Chloromethyl-naphthalene with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 6A for Example 2K to give D-3-Methyl-2-[4′-(naphthalen-1-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester in 34% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.9 (dd, J=32.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.4 (s, 3 H) 3.8 (dd, J=10.1, 5.1 Hz, 1 H) 5.1 (d, J=10.1 Hz, 1 H) 5.6 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.5 (dd, J=8.2, 6.9 Hz, 1 H) 7.6 (m, 4 H) 7.6 (d, J=6.6 Hz, 1 H) 7.7 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H) 8.1 (dd, J=8.5, 1.4 Hz, 1 H).
Step 6B: Hydrolysis of D-3-Methyl-2-[4′-(naphthalen-1-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester was carried out according to procedures in Step 6B for Example 2K in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.5 (s, 1 H) 5.6 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.6 (m, 3 H) 7.7 (m, 3 H) 7.8 (d, J=2.8 Hz, 4 H) 8.0 (m, 3 H) 8.1 (m, 1 H).
The title compound, D-2-[4′-(2-Fluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Coupling of 2-fluorobenzyl bromide with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-2-[4′-(2-Fluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was done according to procedures in Step 6A for Example 2K. Yield: 47%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.2, 6.8 Hz, 6 H) 1.9 (dd, 1 H) 3.3 (s, 3 H) 3.6 (dd, J=9.3, 7.1 Hz, 1 H) 5.2 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.3 (m, 2 H) 7.4 (m, 1 H) 7.6 (m, 1 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 6B: Hydrolysis D-2-[4′-(2-Fluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester to D-2-[4′-(2-Fluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 6B for Example 2K. Yield: 67%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=43.7, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.9 (d, J=2.8 Hz, 1 H) 5.2 (s, 2 H) 6.8 (s, 1 H) 7.2 (d, J=8.8 Hz, 2 H) 7.3 (m, 2 H) 7.4 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (s, 4 H).
The title compound, D-2-[4′-(2,3-Difluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Coupling of 2,3-difluorobenzyl bromide with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-2-[4′-(2,3-Difluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was done according to procedures in Step 6A for Example 2K but at room temperature for 16 hours. Yield: 42%. 1H NMR (400 MHz, DMSO-D6) δ ppm (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.3 (m, 1 H) 7.5 (m, 2 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 6B: Hydrolysis D-2-[4′-(2,3-Difluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester to D-2-[4′-(2,3-Difluoro-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 6B for example 2K. Yield: 63%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.3, 6.1 Hz, 1 H) 5.3 (s, 2 H) 7.2 (d, J=9.1 Hz, 2 H) 7.3 (m, 1 H) 7.5 (m, 2 H) 7.7 (d, J=9.1 Hz, 2 H) 7.8 (d, J=1.8 Hz, 4 H) 8.0 (d, J=9.3 Hz, 1 H) 12.6 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(2-methyl-3-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Coupling of 2-methyl-3-nitrobenzyl bromide with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester to obtain D-3-Methyl-2-[4′-(2-methyl-3-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester was done according to procedures in Step 6A for Example 2K but at room temperature for 16 hours. .Product further purified by recrystalization (EtOAc/hexane). Yield: 26%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.2, 6.8 Hz, 6 H) 1.9 (m, 1 H) 2.4 (s, 3 H) 3.3 (s, 3 H) 3.6 (m, 1 H) 5.3 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.5 (t, J=7.8 Hz, 1 H) 7.8 (m, 8 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 6B: Hydrolysis D-3-Methyl-2-[4′-(2-methyl-3-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid methyl ester to D-3-Methyl-2-[4′-(2-methyl-3-nitro-benzyloxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 6B for Example 2K. Yield: 33%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.9 (dd, 1 H) 3.5 (dd, J=9.3, 6.1 Hz, 1 H) 5.3 (s, 2 H) 7.2 (d, J=9.1 Hz, 2 H) 7.3 (m, 1 H) 7.5 (m, 2 H) 7.7 (d, J=9.1 Hz, 2 H) 7.8 (d, J=1.8 Hz, 4 H) 8.0 (d, J=9.3 Hz, 1 H) 12.6 (s, 1 H).
The title compound, D-2-[4′-(2-Iodo-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Alkylation of 1-Chloromethyl-2-iodo-benzene with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 6A for Example 2K to give D-2-[4′-(2-Iodo-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester in 55% yield. 1H NMR (400 MHz, DMSO -D6) δ ppm 0.8 (dd, J=15.3, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.3 (s, 3 H) 3.6 (dd, J=9.5, 7.2 Hz, 1 H) 7.1 (m, 3 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 7.9 (dd, J=8.0, 1.1 Hz, 1 H) 8.3 (d, J=9.3 Hz, 1 H).
Step 6B: Hydrolysis of D-2-[4′-(2-Iodo-benzyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 6A for Example 2K in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.3, 6.1 Hz, 1 H) 5.1 (s, 2 H) 7.1 (d, J=8.8 Hz, 2 H) 7.5 (m, 1 H) 7.6 (d, J=7.6 Hz, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (s, 4 H) 7.9 (dd, J=7.8, 1.3 Hz, 1 H) 8.0 (d, J=9.3 Hz, 1 H).
The title compound, D-2-[4′-(Benzothiazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 2K.
Step 6A: Alkylation of 2-Bromomethyl-benzothiazole with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 6A for Example 2K to give D-2-[4′-(Benzothiazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester in 20% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=15.0, 6.7 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J=9.5, 7.2 Hz, 1 H) 5.7 (s, 2 H) 7.2 (m, J=8.8 Hz, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (m, 4 H) 7.8 (m, 2 H) 8.0 (d, J=7.3 Hz, 1 H) 8.1 (d, J=7.8 Hz, 1 H) 8.3 (d, J=9.6 Hz, 1 H).
Step 6B: Hydrolysis of D-2-[4′-(Benzothiazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 6B for Example2K in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.3, 5.8 Hz, 1 H) 5.7 (s, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (d, J=2.3 Hz, 4 H) 8.0 (dd, J=9.1, 4.5 Hz, 2 H) 8.1 (d, J=8.6 Hz, 1 H). 97%.
Examples 2S, 2T, 2U, 2V, 2W, 2X, 2Y were made based on Scheme 6B.
1
+
H NMR (400 MHz, DMSO): δ 0.778(d, 3H), 0.845(d, 3H), 1.99(dd, 1H), 3.17(bs, 1H), 4.24(s, 4H), 5.04(s, 2H), 6.91(m, 3H), 7.10(d, 2H), 7.68(d, 2H); ES m/z 496.0 (M−H); HRMS (C26H27NO7S): calcd; 520.14004; found; 520.13995 (M+Na).
1
+
H NMR (400 MHz, DMSO): δ 0.800(d, 3H), 0.803(d, 3H), 1.94(m, 1H), 3.51(bs, 1H), 5.25(s, 2H), 7.15(d, 2H), 7.36(m, 1H), 7.54(d, 2H), 7.71(d, 2H), 7.83(m, 3H), 8.59(d, 2H); ES m/z 441.2 (M+H); HRMS (C23H24N2O5S): calcd; 440.14004;found; 440.14037 (M+H).
1
+
H NMR (400 MHz, DMSO): δ 0.800(d, 3H), 0.803(d, 3H), 1.95(m, 1H), 3.49(bs, 1H), 5.23(s, 2H), 7.16(d, 2H), 7.45(m, 1H), 7.71(d, 2H), 7.80(m, 3H), 7.90(d, 2H), 8.56(d, 1H), 8.70(bs, 1H); ES m/z 441.1 (M+H); HRMS (C23H24N2O5S): calcd; 441.14787; found; 441.14617 (M+H).
1
+
H NMR (400 MHz, DMSO): δ 0.802(d, 3H), 0.833(d, 3H), 1.94(m, 1H), 3.54(m, 1H), 5.51(s, 2H), 6.88(d, 2H), 7.24(d, 1H), 7.34(m, 1H), 7.58(d, 2H), 7.66(m, 1H), 7.78(m, 4H), 8.03(d, 1H); ES m/z 480.1 (M+H); HRMS (C25H25N3O5S): calcd; 480.15877; found; 480.15787 (M+H).
1
+
H NMR (400 MHz, DMSO): δ 0.804(d, 3H), 0.835(d, 3H), 1.95(m, 1H), 3.54(m, 1H), 3.77(s, 3H), 5.15(s, 2H), 6.89(m, 2H), 7.04(m, 2H), 7.13(m, 2H), 7.32(m, 1H), 7.58(d, 1H), 7.69(d, 2H), 7.80(m, 1H), 8.01(d, 1H); ES m/z 470.1 (M+H); HRMS (C25H27NO6S): calcd; 470.16319; found; 470.16183 (M+H).
1
+
H NMR (400 MHz, DMSO): δ 0.805(d, 3H), 0.836(d, 3H), 1.94(m, 1H), 3.54(m, 1H), 3.76(s, 3H), 5.09(s, 2H), 6.96(d, 2H), 7.12(d, 2H), 7.40(d, 2H), 7.69(d, 2H), 7.80(s, 3H), 8.01(d, 1H); ES m/z 468.2 (M−H); HRMS (C25H27NO6S): calcd; 470.16319; found; 470.16248 (M+H).
1
+
H NMR (400 MHz, DMSO): δ 0.804(d, 3H), 0.835(d, 3H), 1.95(m, 1H), 3.55(m, 1H), 3.75(s, 6H), 5.11(s, 2H), 6.45(bs, 1H), 6.62(bs, 2H), 7.12(d, 2H), 7.70(d, 2H), 7.80(s, 3H), 8.01(d, 1H); ES m/z 498.2 (M−H); HRMS (C26H29NO7S): calcd; 500.17375; found; 500.17223 (M+H).
Example 3A was made based on Scheme 7.
3
4
2
3
2
4
Step 7A: 4-Vinylphenylboronic acid (1.89 g, 12.7 mmol, 1 equiv.) and 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (5 g, 12.7 mmol, 1 equiv.) were dissolved in ethylene glycol dimethyl ether (180 mL) and added with Pd(Ph)(736.0 mg, 0.64 mmol) and stirred at room temperature for 20 min. Then to the reaction mixture was introduced an aqueous solution of KCO(3.52 g, 25.5 mmol, 2 equiv.) and heat to reflux overnight. After cool to room temperature, solvent was evaporated and the residue partitioned between EtOAC and HO. Organic layer washed with brine, dried over MgSO, and purified by column chromatography (Silica gel, 10% EtOAc/Hexane) to yield 808 mg of G9058-169 in 15.2% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.95 (d, J=6.82 Hz, 3 H) 1.12 (s, 9 H) 1.99 (m, 1 H) 3.59 (dd, J=9.85, 4.55 Hz, 1H) 5.06 (d, J=10.11 Hz, 1 H) 5.25 (d, J=10.86 Hz, 1 H) 5.75 (d, J=16.93 Hz, 1 H) 6.70 (m, 1 H) 7.45 (m, 4 H) 7.61 (d, J=8.84 Hz, 2 H) 7.82 (d, J=8.84 Hz, 2 H)
2
3
2
2
4
Step 7B: 3-Methyl-2-(4′-vinyl-biphenyl-4-sulfonylamino)-butyric acid tert-butyl ester (300 mg, 0.72 mmol, 1.2 equiv.), Pd(dba)(11 mg, 0.012 mmol, 0.02 equiv.), Tri-t-butylphosphonium tetrafluoroborate (14 mg, 0.048 mmol, 0.08 equiv.) and dioxane (1.5 mL) were placed in a microwave tube under N. 2-Bromo-1-Benzofuran (118 mg, 0.6 mmol, 1 equiv) and dicyclohexyl methyl amine (0.15 mL, 0.72 mmol, 1.2 equiv.) were injected. The mixture was then irradiated in microwave reactor at 180° C. for 30 min. The mixture was partitioned between EtOAc and HO, organic layer dried over MgSO. Crude residue purified by column chromatography (silica gel, 20% EtOAc/Hexane) to afford 80 mg of 2-[4′-(2-Benzofuran-2-yl-vinyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (G9058-171) in 25% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.96 (d, J=6.82 Hz, 3 H) 1.14 (s, 9 H) 2.01 (m, 1 H) 3.60 (dd, J=9.98, 4.42 Hz, 1 H) 5.07 (d, J=9.85 Hz, 1 H) 6.66 (s, 1 H) 7.01 (d, J=15.92 Hz, 1 H) 7.14 (m, 1 H) 7.25 (m, 2 H) 7.42 (d, J=8.08 Hz, 1 H) 7.52 (m, 5 H) 7.64 (d, J=8.59 Hz, 2 H) 7.84 (d, J=8.59 Hz, 2 H).
2
2
Step 7C: 2-[4′-(2-Benzofuran-2-yl-vinyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (80 mg) in dichloroethane (4.5 mL) was added with to TFA (1.5 mL) and stirred at room temperature. The reaction was complete after 3 hrs as determined by TLC. After removing solvent, the crude residue was then purified by column chromatography (5-10% MeOH/CHCl) to give 22 mg of 2-[4′-(2-Benzofuran-2-yl-vinyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid G9058-172 in 30.7% yield.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.79 (d, J=6.82 Hz, 3 H) 0.86 (d, J=6.82 Hz, 3 H) 1.23 (s, 2 H) 2.02 (m, 1 H) 3.18 (m, 1 H) 7.01 (s, 1 H) 7.25 (t, J=7.07 Hz, 1 H) 7.33 (m, 1 H) 7.38 (d, J=14.65 Hz, 1 H) 7.59 (d, J=8.08 Hz, 1 H) 7.64 (d, J=8.08 Hz, 1 H) 7.79 (d, J=6.57 Hz, 4 H) 7.83 (d, J=8.59 Hz, 2 H) 7.90 (m, 2 H).
Example 4A was made based on Scheme 8.
3
4
2
2
3
2
4
Step 8A2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (10.65 g, 27.1 mmol, 1 equiv.), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.97 g, 27.1 mmol, 1 equiv), Pd(PPh)(1.57 g, 1.4 mmol, 0.05 equiv.) were dissolved in ethylene glycol dimethyl ether (210 mL) under Natmosphere and stirred at room temperature for 30 min. Then KCO(7.5 g, 54.3 mmol, 2 equiv.) in HO (70 mL) was introduced to the reaction mixture and heat to reflux overnight. Reaction was complete as determined by TLC. Solvent was removed by rotovap and the residue partitioned between dichloromethane and brine. Organic layer dried over MgSO, solvent removed, crude purified by column chromatography (silica gel, 30% EtOAc/n-Hexane) to give 7.1 g of 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester in 65% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.79 (d, J=6.82 Hz, 3 H) 0.95 (d, J=6.57 Hz, 3 H) 1.13 (s, 9 H) 1.51 (s, 1 H) 1.99 (m, 1 H) 3.59 (dd, J=10.11, 4.55 Hz, 1 H) 5.06 (d, J=9.85 Hz, 1 H) 6.86 (d, J=8.84 Hz, 2 H) 7.38 (d, J=8.84 Hz, 2 H) 7.55 (d, J=8.59 Hz, 2 H) 7.79 (d, J=8.59 Hz, 2 H).
Step 8B: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (330 mg, 0.81 mmol) was dissolved in 20 mL of dry methylene chloride and cool to 0° C. NaH (83 mg, 60% in oil, 2.0 mmol, 2.5 equiv.) was added under N2 and the mixture was stirred for 15 min. Triflic anhydride (251 mg, 0.89 mmol, 1.1 equiv.) was injected and the mixture was warm to room temperature for 1 h. TLC indicated the reaction was complete. The reaction mixture was diluted with methylene chloride and neutralized with 1N HCl. Mixture was washed with water, brine, and dried over MgSO4. Regular column chloromatography (40% EtOAc/hexane) to afford 314 mg of desired product in 72% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.21 (s, 9 H) 2.01-2.20 (m, 1 H) 3.68 (dd, J=9.85, 4.55 Hz, 1 H) 5.18 (d, J=10.11 Hz, 1 H) 7.39 (d, J=8.84 Hz, 2 H) 7.64 (dd, J=13.52, 8.72 Hz, 4 H) 7.93 (d, J=8.59 Hz, 2 H).
2
3
2
Step: The reaction tube was filled with triflate (300 mg, 0.56 mmol) from Step 8B, lithium chloride (24 mg, 0.56 mmol, 1 eq.), CuI (11 mg, 0.05 mmol, 10%), and PdCl(PPh)(19.6 mg, 0.028 mmol, 5%) under nitrogen followed by the addition of DMF (5 mL). t-butyldimethylacetylene (235 mg, 1.68 mmol, 3 eq.) and diethylamine (409 mg, 5.6 mmol, 10 eq.) were injected. The tube was irradiated in microwave reactor at 125° C. for 10 min. Starting materials were consumed as determined by TLC. Mixture was partitioned between ethyl acetate and water. Organic phase collected and regular work-up and column chromatography to give 270 mg of desired acetylenic product tert-butyl N-[(4′-{[tert-butyl(dimethyl)silyl]ethynyl}-1,1′-biphenyl-4-yl)sulfonyl]-D-valinate in 92% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.00 (s, 6 H) 0.66 (d, J=6.82 Hz, 3 H) 0.81 (s, 9 H) 0.82 (d, J=6.82 Hz, 3 H) 0.98 (s, 9 H) 1.75-1.98 (m, 1 H) 3.46 (dd, J=9.85, 4.55 Hz, 1 H) 4.93 (d, J=9.85 Hz, 1 H) 7.27-7.32 (m, 2 H) 7.33-7.39 (m, 2 H) 7.47 (d, J=8.84 Hz, 2 H) 7.70 (d, J=8.84 Hz, 2 H).
Step 8D: tert-butyl N-[(4′-{[tert-butyl(dimethyl)silyl]ethynyl}-1,1′-biphenyl-4-yl)sulfonyl]-D-valinate (600 mg, 1.14 mmol) was dissolved in THF (8 mL) and added with TBAF (1.7 mL, 1M, 1.7 mmol, 1.5 eq). The solution was stirred at room temperature for half hour and the reaction was complete. Solvent removed and the residue was purified with column choromatography (silical gel, 20% EtOAc/hexane). 469 mg of product tert-butyl N-[(4′-ethyny-1,1′-biphenyl-4-yl)sulfonyl]-D-valinate was isolated in quantitative yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86 (d, J=6.82 Hz, 2 H) 1.02 (d, J=6.82 Hz, 2 H) 1.20 (s, 9 H) 1.88-2.29 (m, 1 H) 3.17 (s, 1 H) 3.67 (dd, J=9.85, 4.55 Hz, 1 H) 5.14 (d, J=10.11 Hz, 1 H) 7.52 (d, J=8.59 Hz, 2 H) 7.56-7.62 (m, 2 H) 7.67 (d, J=8.84 Hz, 2 H) 7.91 (d, J=8.59 Hz, 2 H).
2
Step 8E tert-butyl N-[(4′-ethyny-1,1′-biphenyl-4-yl)sulfonyl]-D-valinate (117 mg, 0.28 mmol), 2-chloro-3-methylisoquinoline (60 mg, 0.34 mmol, 1.2 eq), CuI (5.3 mg, 0.028 mmol, 10%), and PdCl2(PPh3)2 (9.8 mg, 0.014 mmol, 5%) were placed in a reaction tube under Nand added with DMF (4 mL) and 10 eq. of diethyl amine. The mixture was irradiated at 125° C. for 10 min. Reaction was complete as determined by LCMS. Dilute the mixture with EtOAc and washed with water 3 times, brine once then dried over MgSO4. Column chromatography (silica gel, 30% EtOAc/hexane) to provide 120 mg of desired product tert-butyl N-({4′-[(4-methylisoquinolin-3-yl)ethynyl]-1,1′-biphenyl-4-yl}sulfonyl)-D-valinate in 76% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.86 (dd, J=8.59, 6.82 Hz, 6 H) 1.17 (s, 9 H) 1.94 (m, 1 H) 2.67 (s, 3 H) 3.50 (dd, J=10.61, 7.33 Hz, 1 H) 7.62 (t, J=7.45 Hz, 1 H) 7.69-7.78 (m, 1 H) 7.80-7.85 (m, 4 H) 7.87 (d, J=8.59 Hz, 2 H) 7.90-7.97 (m, 2 H) 8.00 (d, J=8.59 Hz, 1 H) 8.20 (d, J=9.60 Hz, 1 H) 8.30 (s, 1 H).
2
Step 8F: tert-butyl N-({4′-[(4-methylisoquinolin-3-yl)ethynyl]-1, 1′-biphenyl-4-yl}sulfonyl)-D-valinate (46 mg, 0.08 mmol) was dissolved in 25 mL of methanol and added with catalytic amount of Pd/C (8.5 mg, 10% weight on Carbon, 0.008 mmol). The hydrogenation was carried out in a Parr shaker bottle under H(50 PSI). Reaction was terminated after 5 hours and LCMS indicated the reaction was complete. The mixture was filtered through Celite and concentrated to the desired prouct G8594-178 in quantitative yield (46 mg). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.77-0.93 (m, 6 H) 1.15 (s, 9 H) 1.85-2.06 (m, 1 H) 2.51 (s, 3 H) 3.13-3.28 (m, 2 H) 3.25-3.39 (m, 2 H) 3.47 (d, J=8.84 Hz, 1 H) 7.47 (d, J=8.08 Hz, 2 H) 7.52 (t, J=7.45 Hz, 1 H) 7.59-7.71 (m, 3 H) 7.76-7.90 (m, 4 H) 7.97 (d, J=8.34 Hz, 1 H) 8.06 (s, 1 H) 8.15 (s, 1 H).
Step 8G: tert-butyl N-({4′-[2-(4-methylisoquinolin-3-yl)ethyl]-1,1′-biphenyl-4-yl}sulfonyl-D-valinate (46 mg, 0.08 mmol) was dissolved in 5 mL of dry methylene chloride followed by the addition of 2.5 mL of TFA. The mixture was stirred at room temperature for 3 hrs and TLC indicated the reaction was complete. Solvent was removed by rotavap and the product dried in vacuum oven overnight. 44 mg of product N-({4′-[2-(4-methylisoquinolin-3-yl)ethyl]-1,1′-biphenyl-4-yl}sulfonyl-D-valine was obtained in 95% yield.
1H NMR (400 MHz, MeOD) δ ppm 0.83 (d, J=6.82 Hz, 3 H) 0.88 (d, J=6.82 Hz, 3 H) 1.80-2.13 (m, 1 H) 2.57 (s, 3 H) 3.15 (t, J=7.83 Hz, 2 H) 3.45-3.55 (m, 2 H) 3.60 (d, J=5.56 Hz, 1 H) 7.25 (d, J=8.08 Hz, 2 H) 7.53 (d, J=8.08 Hz, 2 H) 7.65 (d, J=8.34 Hz, 2 H) 7.81 (d, J=8.59 Hz, 3 H) 7.98 (t, J=7.58 Hz, 1 H) 8.02-8.09 (m, 1 H) 8.13 (d, J=8.08 Hz, 1 H) 8.83 (s, 1 H).
Example 5A was made based on Scheme 9.
3
Step 9A: Combined 4-aminomethyl phenyl boronic acid (143 mg, 0.77 mmol, 1 eq), D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.77 mmol, 1 eq), palladium tetrakis (44 mg, 0.038 mmol, 0.05 eq) in dimethoxy ethane (10 mL) and stirred at room temperature for 10 min. Potassium carbonate (212 mg, 1.53 mmol, 2 eq) in 4 mL of water was added to the reaction mixture and heated at 88° C. for 4 hrs. The reaction is then cool to room temperature and diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and stripped to dryness. Residue is purified via flash chromatography on silica gel eluting with 4-10% MeOH in methylene chloride with 2% EtN to obtain 200 mg of D-2-(4′-Aminomethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester. Yield: 63%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.1, 7.1 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (d, J=6.3 Hz, 2 H) 3.8 (s, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 7.6 (d, J=8.3 Hz, 2 H) 7.8 (d, J=2.0 Hz, 4 H).
2
2
Step 9B: To acetic anhydride (71 uL, 0.75 mmol, 1.05 eq.) in CHCl(5 mL) was added with pyridine (70 uL, 0.86 mmol, 1.2 eq.) under argon and stirred for 5 min, then D-2-(4′-Aminomethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.72 mmol, 1 eq.) was added and stirred for 16 hours. After work-up and flash column chromatography, D-2-[4′-(Acetylamino-methyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester was obtained. Yield: 32%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=9.1, 6.8 Hz, 6 H) 0.9 (t, J=7.3 Hz, 3 H) 1.2 (s, 9 H) 1.3 (m, 2 H) 1.5 (m, 2 H) 1.9 (m, 1 H) 2.5 (m, 2 H) 3.4 (dd, J=9.6, 6.3 Hz, 1 H) 7.0 (dd, 4 H) 7.1 (m, 2 H) 7.5 (d, J=8.8 Hz, 2 H) 7.7 (d, J=9.6 Hz, 1 H) 8.6 (s, 1 H).
Step 9C: To a solution of D-2-[4′-(Acetylamino-methyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (300 mg, 0.65 mmol) in 6 mL of dichloroethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 hrs and reaction was complete as determined by TLC. Solvent removed and residue dried over vacuum oven to obtain 250 mg of D-2-[4′-(Acetylamino-methyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid. Yield: 94%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.5, 6.7 Hz, 6 H) 1.9 (s, 3 H) 2.0 (m, 1 H) 3.6 (dd, J=9.3, 5.8 Hz, 1 H) 4.3 (d, J=5.8 Hz, 2 H) 7.4 (d, J=8.1 Hz, 2 H) 7.7 (d, J=8.3 Hz, 2 H) 7.8 (s, 4 H) 8.1 (d, J=9.3 Hz, 1 H) 8.4 (t, J=5.8 Hz, 1 H) 12.6 (s, 1 H).
Examples 5B and 5C were made based on Scheme 10.
Step 10A: A mixture of 4-Bromophenylacetic acid (1.5 g, 7.0 mmol, 1 eq.), EDC (2.67 g, 14.0 mmol, 2 eq.), DMAP (846 mg, 7.0 mmol, 1 eq.), and phenylamine (0.765 mL, 8.4 mmol, 1.2 eq.) in 15 mL of DMF was stirred under nitrogen at room temperature for 3.5 hrs. After aqueous workup and recrystallization, 2-(4-Bromophenyl)-N-phenyl-acetamide was obtained in 69% yield (1.4 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.6 (s, 2 H) 7.0 (m, 1 H) 7.3 (m, 4 H) 7.5 (m, 2 H) 7.6 (dd, J=8.7, 1.1 Hz, 2 H) 10.2 (s, 1 H).
3
4
Step 10B: A mixture of 2-(4-Bromophenyl)-N-phenyl-acetamide (107 mg, 0.37 mmol, 1.1 eq.), D-3-Methyl-2-(4-tributylstannanyl-benzenesulfonylamino)-butyric acid tert-butyl ester (202 mg, 0.34 mmol, 1 eq.), and Pd(PPh)(38.5 mg, 0.033 mmol, 0.1 eq.) in 5 mL of toluene was heated to reflux under nitrogen. Reaction was complete after 5 hrs. Regular work-up and column purification, D-3-Methyl-2-(4′-phenylcarbamoylmethyl-biphenyl-4-sulfonylamino)-butyric acid tert-butyl ester was obtained in 34% yield (60 mg). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.3, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.6, 6.3 Hz, 1 H) 3.7 (s, 2 H) 7.0 (t, J=7.3 Hz, 1 H) 7.3 (m, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 7.6 (dd, J=8.6, 1.0 Hz, 2 H) 7.7 (d, J=8.3 Hz, 2 H) 7.8 (d, J=2.5 Hz, 4 H) 8.1 (d, J=9.6 Hz, 1 H) 10.2 (s, 1 H).
Step 10C: Removal of t-butyl ester of D-3-Methyl-2-(4′-phenylcarbamoylmethyl-biphenyl-4-sulfonylamino)-butyric acid tert-butyl ester was done using TFA in dichloroethane (1:1). After evaporation of solvent, D-3-Methyl-2-(4′-phenylcarbamoylmethyl-biphenyl-4-sulfonylamino)-butyric acid was obtained in quantitative yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=27.0, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (d, J=5.6 Hz, 1 H) 3.6 (s, 2 H) 7.0 (m, 1 H) 7.2 (m, 2 H) 7.4 (d, J=8.3 Hz, 2 H) 7.5 (dd, J=8.7, 1.1 Hz, 2 H) 7.6 (d, J=8.3 Hz, 2 H) 7.7 (dd, J=48.0, 8.6 Hz, 4 H).
Step 10A: Amide coupling of 4-Bromophenylacetic acid with benzylamine was done according to procedures in Step 10A for Example 5B to give N-Benzyl-2-(4-bromo-phenyl)-acetamide in 82% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.5 (s, 2 H) 4.3 (d, J=5.8 Hz, 2 H) 7.2 (dd, J=7.8, 5.6 Hz, 5 H) 7.3 (m, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 8.6 (t, J=5.9 Hz, 1 H).
Step 10B: Stille coupling of N-Benzyl-2-(4-bromo-phenyl)-acetamide with D-3-Methyl-2-(4-tributylstannanyl-benzenesulfonylamino)-butyric acid tert-butyl ester was carried out according to procedures in Step 10B for Example 5B to give D-2-[4′-(Benzylcarbamoyl -methyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 31% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.9 (d, J=6.8 Hz, 3 H) 1.0 (d, J=6.6 Hz, 3 H) 1.2 (s, 9 H) 2.1 (m, 1 H) 3.7 (m, 3 H) 4.5 (d, J=5.8 Hz, 2 H) 5.1 (d, J=9.9 Hz, 1 H) 5.7 (s, 1 H) 7.3 (m, 5 H) 7.4 (d, J=8.1 Hz, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 7.7 (d, J=8.3 Hz, 2 H) 7.9 (d, J=8.3 Hz, 2 H).
Step 10C: Removal of t-butyl ester was done according to procedures in Step 10C for Example 5B in quantitative yield. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=26.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.5 (s, 2 H) 3.6 (d, J=5.6 Hz, 1 H) 4.3 (d, J=5.6 Hz, 2 H) 7.2 (m, 5 H) 7.3 (d, J=8.3 Hz, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H) 8.5 (s, 1 H).
Examples 6A, 6B, 6C, 6D, 6E, 6F, 6G, 6H, 6I, 6J, 6K, 6L, 6M, 6N, 6O, 6P, 6Q, 6R, 6S were made based on Scheme 11.
3
Step 11A: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.74 mmol, 1 equiv.) was dissolved in diethyl ether (7.5 mL), followed by the addition of 4-fluorophenylisocyanate (101 mg, 0.74 mmol, 1 equiv.) and EtN (1 mL). The reaction mixture was stirred at room temperature for 50 min. Solid precipitated from the reaction mixture. Solid was collected by filtration and washed with ether to yield 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 57% yield (228 mg).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.20 (s, 9 H) 2.05 (m, 1 H) 3.67 (dd, J=9.98, 4.42 Hz, 1 H) 5.13 (d, J=9.85 Hz, 1 H) 6.95 (s, 1 H) 7.05 (d, J=9.09 Hz, 2 H) 7.30 (d, J=8.59 Hz, 2 H) 7.43 (m, 2 H) 7.57 (d, J=8.59 Hz, 2 H) 7.67 (s, 2 H) 7.90 (d, J=8.34 Hz, 2 H).
Step 11B: 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (223 mg) was dissolved in dichloroethane (7.5 mL) and added with TFA (2.5 mL). The mixture was stirred at room temperature for 5 hrs and TLC indicated the reaction was complete. Regular work-up and column chromatography to give 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 89% yield (178 mg).
1H NMR (400 MHz, DMSO-D6) δ ppm 0.81 (d, J=6.57 Hz, 3 H) 0.84 (d, J=6.82 Hz, 3 H) 1.96 (m, 1 H) 3.56 (dd, J=9.35, 6.06 Hz, 1 H) 7.19 (t, J=8.84 Hz, 2 H) 7.37 (d, J=8.59 Hz, 2 H) 7.54 (dd, J=9.09, 4.80 Hz, 2 H) 7.79 (d, J=8.84 Hz, 2 H) 7.86 (d, J=4.29 Hz, 4 H) 8.08 (d, J=9.35 Hz, 1 H) 10.34 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(4-phenoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of 4-phenoxyphenyl isocyanate with D-2-(4′-Hydroxy -biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-3-Methyl-2-[4′-(4-phenoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 36%. 1H NMR (400 MHz, DMSO-D6) □ ppm 0.9 (dd, J=8.2, 6.9 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.6, 6.3 Hz, 1 H) 7.0 (dd, J=8.6, 1.0 Hz, 2 H) 7.0 (d, J=9.1 Hz, 2 H) 7.1 (m, 1 H) 7.4 (m, 4 H) 7.5 (d, J=8.8 Hz, 2 H) 7.7 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J=9.6 Hz, 1 H) 10.3 (s, 1 H).
Step 11B: Conversion of D-3-Methyl-2-[4′-(4-phenoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester to D-3-Methyl-2-[4′-(4-phenoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 87%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.0 (m, 2 H) 7.0 (d, J=9.1 Hz, 2 H) 7.1 (t, J=7.3 Hz, 1 H) 7.4 (m, 4 H) 7.5 (d, J=8.8 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (d, J=4.8 Hz, 4 H) 8.1 (d, J=9.3 Hz, 1 H) 10.3 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(naphthalen-2-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of 2-naphthyl isocyanate with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-3-Methyl-2-[4′-(naphthalen-2-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 16%. 1H NMR (400 MHz, DMSO-D6) □ ppm 0.9 (dd, J=8.2, 6.9 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 H) 7.4 (m, 3 H) 7.5 (m, 1 H) 7.6 (dd, J=8.8, 2.3 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 7 H) 8.1 (s, 1 H) 8.2 (d, J=9.9 Hz, 1 H) 10.5 (s, 1 H).
Step 11B: Conversion of D-3-Methyl-2-[4′-(naphthalen-2-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester to D-3-Methyl-2-[4′-(naphthalen-2-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 40%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.5, 6.7 Hz, 6 H) 2.0 (m, 1 H) 3.6 (dd, J=9.1, 5.8 Hz, 1 H) 7.4 (m, 3 H) 7.5 (m, 1 H) 7.6 (dd, J=8.8, 2.3 Hz, 1 H) 7.9 (m, 9 H) 8.1 (m, 2 H) 10.5 (s, 1 H) 12.6 (s, 1 H).
The title compound, D-2-[4′-(4-Benzyloxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of 4-benzyloxyphenyl isocyanate with D-2-(4′-Hydroxy -biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-2-[4′-(4-Benzyloxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 37%. NMR: G8701-142. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 H) 5.1 (s, 2 H) 7.0 (d, J=9.1 Hz, 2 H) 7.4 (m, 9 H) 7.7 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J=9.6 Hz, 1 H) 10.1 (s, 1 H).
Step 11B: Conversion of D-2-[4′-(4-Benzyloxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester to D-2-[4′-(4-Benzyloxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 60%. NMR: G8701-151. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 5.1 (s, 2 H) 7.0 (d, J=9.1 Hz, 2 H) 7.4 (m, 9 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J=9.3 Hz, 1 H) 10.1 (s, 1 H).
The title compound, D-2-(4′-Cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of cyclopentyl isocyanate with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-2-(4′-Cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 70%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.1, 7.1 Hz, 6 H) 1.2 (s, 9 H) 1.5 (m, 4 H) 1.7 (m, 2 H) 1.8 (m, 2 H) 1.9 (m, 1 H) 3.5 (dd, J=9.6, 6.3 Hz, 1 H) 3.9 (m, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.7 (d, J=8.6 Hz, 2 H) 7.8 (m, 5 H) 8.2 (d, J=9.6 Hz, 1 H).
Step 11B: Conversion of D-2-(4′-Cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester to D-2-(4′-Cyclopentylcarbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 91%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (m, 6 H) 1.5 (m, 4 H) 1.7 (d, J=4.5 Hz, 2 H) 1.8 (m, 2 H) 1.9 (m, 1 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 3.9 (m, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (s, 5 H) 8.1 (d, J=9.3 Hz, 1 H) 12.6 (s, 1 H).
The title compound, D-2-[4′-(4-Dimethylamino-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Coupling of 4-(dimethylamino)phenyl isocyanate with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-2-[4′-(4-Dimethylamino-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 28%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 2.8 (s, 6 H) 3.5 (dd, J=9.6, 6.3 Hz, 1 H) 6.7 (d, J=9.1 Hz, 2 H) 7.3 (d, J=8.6 Hz, 4 H) 7.7 (d, J=8.6 Hz, 2 H) 7.8 (m, 4 H) 8.2 (d, J=9.9 Hz, 1 H) 9.9 (s, 1 H).
Step 11B: Conversion of D-2-[4′-(4-Dimethylamino-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester to D-2-[4′-(4-Dimethylamino -phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 99%. NMR: G8701-161. 1H NMR (400 MHz, MeOD) δ ppm 0.8 (dd, J=23.7, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.1 (s, 6 H) 3.6 (d, J=5.6 Hz, 1 H) 7.2 (d, J=8.8 Hz, 2 H) 7.4 (d, J=9.1 Hz, 3 H) 7.6 (m, 6 H) 7.8 (d, J=8.8 Hz, 2 H).
The title compound, D-2-[4′-(4-Isopropyl-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of 4-isopropylphenyl isocyanate with D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-2-[4′-(4-Isopropyl-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 38%. NMR: G8701-158. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.3, 6.8 Hz, 6 H) 1.2 (m, 15 H) 1.9 (m, 1 H) 2.8 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.4 (d, J=8.6 Hz, 2 H) 7.4 (d, J=8.6 Hz, 2 H) 7.7 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J=9.9 Hz, 1 H) 10.2 (s, 1 H).
Step 11B: Conversion of D-2-[4′-(4-Isopropyl-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester to D-2-[4′-(4-Isopropyl-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 34%. NMR: G8701-165. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.2 (d, J=6.8 Hz, 6 H) 2.0 (m, 1 H) 2.8 (m, 1 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.4 (d, J=8.8 Hz, 2 H) 7.4 (d, J=8.6 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J=9.3 Hz, 1 H) 10.2 (s, 1 H) 12.6 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(2-thiophen-2-yl-ethylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of 2-(2-thienyl)ethyl isocyanate with D-2-(4′-Hydroxy -biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-3-Methyl-2-[4′-(2-thiophen-2-yl-ethylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 63%. NMR: G8701-169. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.3, 7.1 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.0 (t, J=7.1 Hz, 2 H) 3.3 (m, 2 H) 3.5 (dd, J=9.6, 6.3 Hz, 1 H) 7.0 (m, 2 H) 7.2 (d, J=8.8 Hz, 2 H) 7.4 (dd, J=5.1, 1.3 Hz, 1 H) 7.7 (d, J=8.6 Hz, 2 H) 7.8 (d, J=2.3 Hz, 4 H) 8.0 (t, J=5.7 Hz, 1 H) 8.2 (d, J=9.9 Hz, 1 H).
Step 11B: Conversion of D-3-Methyl-2-[4′-(2-thiophen-2-yl-ethylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester to D-3-Methyl-2-[4′-(2-thiophen-2-yl-ethylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 43%. NMR: G8701-175. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.0 (t, J=7.1 Hz, 2 H) 3.3 (m, 2 H) 3.6 (dd, J=9.2, 5.9 Hz, 1 H) 6.9 (d, J=3.3 Hz, 1 H) 7.0 (dd, J=5.1, 3.3 Hz, 1 H) 7.2 (d, J=8.8 Hz, 2 H) 7.4 (dd, J=5.1, 1.3 Hz, 1 H) 7.7 (d, J=8.6 Hz, 2 H) 7.8 (s, 4 H) 8.0 (t, J=5.8 Hz, 1 H) 8.1 (d, J=9.3 Hz, 1 H).
The title compound, D-3-Methyl-2-[4′-(4-trifluoromethoxy -phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: Reaction of 4-methoxyphenyl isocyanate with D-2-(4′-Hydroxy -biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester to obtain D-2-[4′-(4-Methoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester was done according to procedures in Step 11A for Example 6A. Yield: 49%. NMR: G8701-199. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.3, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 H) 3.7 (s, 3 H) 6.9 (d, J=9.1 Hz, 2 H) 7.4 (d, J=8.8 z, 2 H) 7.4 (d, J=8.8 Hz, 2 H) 7.7 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J=9.9 Hz, 1 H) 10.1 (s, 1 H).
Step 11B: Reaction of D-2-[4′-(4-Methoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester to D-3-Methyl-2-[4′-(4-trifluoromethoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 91%. NMR: G9241-4. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J=9.3, 5.8 Hz, 1 H) 3.7 (s, 3 H) 6.9 (d, J=9.1 Hz, 2 H) 7.4 (d, J=8.8 Hz, 2 H) 7.4 (d, J=8.8 Hz, 2 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J=9.3 Hz, 1 H) 10.1 (s, 1 H) 12.6 (s, 1 H).
The title compound, D-3-Methyl-2-[4′-(4-trifluoromethoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: To a solution of D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester (300 mg, 0.74 mmol, 1 eq.) in diethyl ether (10 mL) were added with 4-(trifluoromethoxy)phenyl isocyanate (123 uL, 0.81 mmol, 1.1 eq.) and triethylamine (124 uL, 0.89 mmol, 1.2 eq.) under argon and stirred at room temperature. After reaction complete, regular work-up and flash column chromatography to provide D-3-Methyl-2-[4′-(4-trifluoromethoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester in 37% yield. NMR: G8701-200. 1H NMR (400 MHz, DMSO-D6) □ ppm 0.9 (dd, J=8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 NMR: G8701-200. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.1, 6.8 Hz, 6 H) 1.2 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 H) 7.4 (m, 4 H) 7.6 (d, J=9.3 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.2 (d, J=9.6 Hz, 1 H) 10.5 (s, 1 H).
Step 11B: Conversion of D-3-Methyl-2-[4′-(4-trifluoromethoxy -phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester to D-3-Methyl-2-[4′-(4-trifluoromethoxy-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 76%. NMR: G9241-5. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (dd, J=9.3, 5.8 Hz, 1 H) 7.4 (m, 4 H) 7.6 (d, J=9.1 Hz, 2 H) 7.8 (d, J=8.6 Hz, 2 H) 7.9 (m, 4 H) 8.1 (d, J=9.3 Hz, 1 H) 10.5 (s, 1 H).
The title compound, D-2-(4′-Carbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, was prepared according to procedures similar to that of Example 6A.
Step 11A: To a solution of D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid-tert-butyl ester (500 mg, 1.23 mmol, 1 eq.) in CH2Cl2 (2 mL) were added with chlorosulfonyl isocyanate (107 uL, 1.23 mmol, 1 eq.) under argon and stirred at room temperature for 16 hours. Reaction was complete as determined by TLC. After work-up and flash column chromatography, D-2-(4′-Carbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester was obtained. Yield: 45%. NMR: G9241-38. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.9 (dd, J=8.3, 6.8 Hz, 6 H) 1.1 (s, 9 H) 1.9 (m, 1 H) 3.5 (dd, J=9.9, 6.3 Hz, 1 H) 7.2 (d, J=8.8 Hz, 2 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (d, J=1.0 Hz, 4 H) 8.2 (d, J=9.6 Hz, 1 H).
Step 11B: Conversion of D-2-(4′-Carbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester to D-2-(4′-Carbamoyloxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid was done according to procedures in Step 11B for Example 6A. Yield: 85%. NMR: G9241-46. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.6 (dd, J=9.3, 5.8 Hz, 1 H) 7.0 (s, 1 H) 7.2 (m, 3 H) 7.7 (d, J=8.8 Hz, 2 H) 7.8 (s, 4 H) 8.1 (d, J=9.3 Hz, 1 H).
The title compound, 3-Methyl-2-(4′-phenylcarbamoyloxy-biphenyl-4-sulfonylamino)-butyric acid tert-butyl ester, was prepared according to procedures similar to that of Example 6A.
3
Step 11A: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.74 mmol, 1 equiv) was dissolved in diethyl ether (7.5 mL), added with phenylisocyanate (0.08 mL, 0.74 mmol, 1 equiv) followed by EtN (1 mL). The reaction mixture was stirred for 4 hours. Solid precipitated from the reaction mixture was collected by filtration, washed with ether to afford with 76% yield (295 mg).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=7.07 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.20 (s, 9 H) 2.07 (m, 1 H) 3.67 (dd, J=9.98, 4.42 Hz, 1 H) 5.13 (d, J=9.85 Hz, 1 H) 6.96 (s, 1 H) 7.14 (m, 1 H) 7.31 (d, J=8.59 Hz, 2 H) 7.36 (m, 2 H) 7.47 (d, J=8.34 Hz, 2 H) 7.58 (d, J=8.59 Hz, 2 H) 7.66 (d, J=8.34 Hz, 2 H) 7.91 (m, 2 H).
Step 11B: 3-Methyl-2-(4′-phenylcarbamoyloxy-biphenyl-4-sulfonylamino) -butyric acid tert-butyl ester (200 mg) was hydrolized according procedures in Step 11B for Example 6A to afford 3-Methyl-2-(4′-phenylcarbamoyloxy-biphenyl-4-sulfonylamino)-butyric acid in 88% yield (158 mg).
1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.57 Hz, 3 H) 1.95 (m, 1 H) 3.56 (dd, J=9.22, 5.94 Hz, 1 H) 3.90 (s, 1 H) 7.07 (m, 1 H) 7.35 (m, 4 H) 7.53 (d, J=7.83 Hz, 2 H) 7.80 (d, J=8.59 Hz, 2 H) 7.86 (d, J=22.23 Hz, 4 H) 8.08 (d, J=9.35 Hz, 1 H) 10.29 (s, 1 H).
The title compound, 2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester, was prepared according to procedures similar to that of Example 6A.
3
Step 11A: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.74 mmol, 1.0 equiv.) was dissolved in diethyl ether (7.5 mL), added with 1-Benzothiophene-3-yl isocyanate (129.6 mg, 0.74 mmol, 1.0 equiv.) and 0.5 ML of EtN. Solid precipitated from the reaction mixture in 5 min. The mixture was continued to stir at room temperature for 2 hrs and the precipitate was collected by filtration, washed with ether to give in 43% yield (187 mg).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.20 (s, 9 H) 2.08 (m, 1 H) 3.68 (m, 1 H) 5.15 (d, J=10.11 Hz, 1 H) 7.35 (d, J=8.34 Hz, 2 H) 7.43 (m, 2 H) 7.60 (d, J=8.59 Hz, 2 H) 7.67 (d, J=8.34 Hz, 3 H) 7.74 (s, 1 H) 7.90 (t, J=9.09 Hz, 3 H).
2
Step 11B: 2-[4′-(Benzo[b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (180 mg, 0.31 mmol) was dissolved in methylene chloride under Natmosphere, added with TFA (2 mL) at 0° C. and stirred for 4 hrs. Solvent was evaporated and the product dried under high vacuum to give 2-[4′-(Benzo [b]thiophen-3-ylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 66% yield (108 mg).
1H NMR (400 MHz, MeOD)δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.89 (d, J=6.82 Hz, 3 H) 1.20 (s, 1 H) 3.54 (d, J=5.05 Hz, 1 H) 7.30 (m, 2 H) 7.35 (m, 2 H) 7.58 (s, 1 H) 7.66 (d, J=8.59 Hz, 2 H) 7.71 (d, J=8.59 Hz, 2 H) 7.78 (d, J=7.83 Hz, 1 H) 7.84 (d, J=8.59 Hz, 2 H) 7.92 (d, J=8.08 Hz, 1 H).
The title compound, N-[(4′-{[2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine, was prepared according to procedures similar to that of Example 6A.
Step 11A and 11B: Yield 40%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.98 (m, 1 H) 3.17 (t, J=8.97 Hz, 2 H) 3.39 (s, 1 H) 4.50 (t, J=8.59 Hz, 2 H) 6.72 (d, J=8.34 Hz, 1 H) 7.19 (d, J=8.84 Hz, 1 H) 7.34 (d, J=8.59 Hz, 2 H) 7.40 (s, 1 H) 7.78 (d, J=8.59 Hz, 2 H) 7.85 (d, J=1.77 Hz, 4 H) 10.05 (s, 1 H).
The title compound, N-[(4′-{[(2,3-dihydro-1,4-benzodioxin-6-ylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine, was prepared according to procedures similar to that of Example 6A.
Step 11A and: Yield 62%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.98 (m, 1 H) 3.42 (s, 1 H) 4.21 (m, 4 H) 6.81 (d, J=8.84 Hz, 1 H) 6.94 (d, J=10.86 Hz, 1 H) 7.09 (s, 1 H) 7.34 (d, J=8.84 Hz, 2 H) 7.78 (d, J=8.84 Hz, 3 H) 7.85 (d, J=1.77 Hz, 4 H) 10.11 (s, 1H).
The title compound, N-[(4′-{[(3,4-dihydro-2H-1,5-benzodioxepin-7-ylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine, was prepared according to procedures similar to that of Example 6A.
Step 11A and 11B: Yield 55%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.97 (m, 1 H) 2.08 (m, 2 H) 3.45 (s, 1 H) 4.08 (m, 4 H) 6.94 (d, J=8.59 Hz, 1 H) 7.06 (d, J=2.53 Hz, 1 H) 7.18 (d, J=2.27 Hz, 1 H) 7.35 (d, J=8.59 Hz, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 7.85 (d, J=3.79 Hz, 4 H) 7.88 (s, 1 H) 10.21 (s, 1 H).
The title compound, N-[(4′-{[(5-methyl-3-phenylisoxazol-4-yl)amino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine, was prepared according to procedures similar to that of Example 6A.
Step 11B: Yield 75%.1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 0.63 (d, J=6.82 Hz, 3 H) 0.74 (d, J=6.57 Hz, 3 H) 1.83-1.88 (m, 1 H) 2.20 (s, 1H) 2.34 (m, 3 H) 3.81 (s, 1 H) 6.56 (s, 1 H) 6.66 (s, 1 H) 7.12 (d, J=7.83 Hz, 1 H) 7.45 (d, J=4.80 Hz, 4 H) 7.59 (m, 4 H) 7.68 (d, J=3.54 Hz, 2 H) 7.80 (d, J=8.08 Hz, 2 H).
The title compound, N-[(4′-{[(methylamino)carbonyl]oxy}-1,1′-biphenyl-4-yl)sulfonyl]-D-valine, was prepared according to procedures similar to that of Example 6A.
Step 11B: Yield 90%. 1H NMR (400 MHz, MeOD) δ ppm 0.80 (d, J=8.34 Hz, 3 H) 0.87 (d, J=6.82 Hz, 3 H) 1.91-2.02 (m, 1 H) 2.71 (s, 3 H) 3.52 (d, J=5.05 Hz, 1 H) 7.11 (d, J=8.84 Hz, 2 H) 7.58 (d, J=8.84 Hz, 2 H) 7.66 (d, J=8.59 Hz, 2 H) 7.81 (d, J=8.59 Hz, 2 H).
Step 12A: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (314 mg, 0.9 mmol) dissolved in methylene chloride (10 mL) and diethyl ether (20 mL) was added with benzofuran isocyanate (143 mg, 0.9 mmol, 1 equiv) and triethyl amine (363 mg, 3.6 mmol, 4 equiv). The mixture was stirred at room temperature overnight. Solid precipitated from reaction mixture was collected by filtration followed by column chromatography (silica gel, 5% MeOH/CH2Cl2). 76 mg of white solid was obtained in 16% yield.
1H NMR (400 MHz, DMSO-D6) δ ppm 0.74-1.00 (m, 6 H) 1.90-2.07 (m, 1 H) 3.22-3.48 (m, 1 H) 6.86 (d, J=8.59 Hz, 2 H) 7.10-7.28 (m, 2 H) 7.33-7.62 (m, 4 H) 7.69-7.83 (m, 4 H) 7.86 (s, 1 H).
Examples 7A and 7B were made based on Scheme 13.
Step 13A: A mixture of D-2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (305 mg, 0.75 mmol, 1 eq), 3-Methyl-benzofuran-2-carboxylic acid (131 mg, 0.74 mmol, 1 eq), 4-dimethylaminopyridine (DMAP, 95 mg, 0.77 mol, 1 eq), and 1,3-Dicyclohexylcarbodiimide (DCC, 240 mg, 1.17 mmol, 1.6 eq) dissolved in 5 mL of dichloromethane under nitrogen atmosphere was allowed to react at room temperature for 3.5 hrs. Regular work-up and column chromatography (10% EtOAc in hexane) to give D-3-Methyl-benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester (300 mg) in 71% yield. NMR: G8475-101. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.9 (d, J=7.1 Hz, 3 H) 1.0 (d, J=6.8 Hz, 3 H) 1.2 (s, 9 H) 2.1 (m, 1 H) 2.7 (s, 3 H) 3.7 (dd, J=10.0, 4.4 Hz, 1 H) 5.1 (d, J=9.9 Hz, 1 H) 7.4 (m, 3 H) 7.5 (m, 1 H) 7.6 (t, J=8.0 Hz, 3 H) 7.7 (m, 3 H) 7.9 (d, J=8.3 Hz, 2 H).
Step 13B: Removal of t-butyl ester was done according to procedures in Step 11B for Example 6A in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.1, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.2, 5.9 Hz, 1 H) 7.4 (t, J=7.6 Hz, 1 H) 7.5 (d, J=8.8 Hz, 2 H) 7.6 (t, J=8.2 Hz, 1 H) 7.8 (d, J=8.3 Hz, 1 H) 7.9 (m, 7 H) 8.1 (d, J=9.3 Hz, 1 H).
The title compound, Benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester, was prepared according to procedures similar to that of Example 7A.
2
2
2
2
2
2
4
Step 13A: 2-Benzofuran carbocarboxylic acid (400.5 mg, 2.47 mmol, 1 equiv.) dissolved in dry CHCl(50 mL) was added with DCC (1.019 g, 4.94 mmol, 2 equiv) and stirred under Nfor 15 min. Then 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (1.0 g, 2.47 mmol, 1 equiv.) was introduced to the reaction mixture, followed by the addition of DMAP (50 mg, 0.41 mmol,). The mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted with CHCl, washed with HO and brine. Organic layer dried over MgSOand solvent removed to yield crude product. Residue was dissolved in EtOAc and purified by column chromatograph (silica gel, 20% EtOAc/ n-Hexane) to afford G9058-53-1 in 30.5% yield (325 mg).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.21 (s, 9 H) 2.07 (m, 1 H) 3.68 (dd, J=9.85, 4.55 Hz, 1 H) 5.15 (d, J=9.85 Hz, 1 H) 7.37 (m, 3 H) 7.53 (t, J=7.83 Hz, 1 H) 7.66 (m, 5 H) 7.77 (m, 2 H) 7.92 (d, J=8.34 Hz, 2 H).
Step 13B: Benzofuran-2-carboxylic acid 4′-(1-tert-butoxycarbonyl-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester (325 mg) was dissolved in dichloromethane (15 mL) and added with TFA. The solution was stirred at room temperature for 7 hrs. Solvent was removed by rotovap and crude product purified by column chromatography (5-20% MeOH/ EtOAc) to yield Benzofuran-2-carboxylic acid 4′-(1-carboxy-2-methyl-propylsulfamoyl)-biphenyl-4-yl ester in 76% yield (241 mg).
1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (d, J=6.57 Hz, 3 H) 0.87 (d, J=6.82 Hz, 3 H) 2.04 (m, 1 H) 3.24 (m, 1 H) 7.43 (t, J=7.58 Hz, 1 H) 7.49 (d, J=8.84 Hz, 2 H) 7.60 (t, J=7.96 Hz, 1 H) 7.70 (d, J=9.85 Hz, 1 H) 7.85 (m, 7 H) 8.08 (s, 1 H).
Examples 8A, 8B, 8C, 8D, 8E, 8F, 8G were made based on Scheme 14.
2
3
4
Step 14A: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (100 mg, 0.25 mmol, 1.0 equiv.), 2-Chloro-5-trifluoro methyl pyridine (45.4 mg, 0.25 mmol, 1 equiv.), and KCO(86.4 mg, 0.63 mmol, 2.5 equiv) were mixed in DMF (8 mL) and heat to 110° C. for 4.5 hr. Reaction was complete as determined by TLC. Then the reaction mixture was cool to room temperature, diluted with EtOAc, washed with brine and dried over MgSO. After removing solvent, crude product was purified by column chromatography (silica gel, 20% EtOAc/n-Hexane) to afford G9058-109-1 in 74% yield (100 mg).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.96 (d, J=6.82 Hz, 3 H) 1.14 (s, 9 H) 2.01 (m, 1 H) 3.61 (m, 1 H) 5.07 (d, J=9.85 Hz, 1 H) 7.03 (d, J=8.59 Hz, 1 H) 7.19 (s, 1 H) 7.21 (s, 1 H) 7.55 (d, J=8.59 Hz, 2 H) 7.62 (d, J=8.59 Hz, 2 H) 7.85 (d, J=2.02 Hz, 2 H) 7.88 (d, J=6.06 Hz, 1 H) 8.40 (s, 1 H).
2
2
2
2
Step 14B: 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester (97 mg) was dissolved in CHCl(6 mL) and added with TFA (2 mL). Reaction was complete in 6 hrs as determined by TLC. After removing solvent, residue was purified by column chromatography (10% MeOH/CHCl) to afford 3-Methyl-2-[4′-(5-trifluoromethyl-pyridin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid in 66% yield (54.5 mg).
1H NMR (400 MHz, MeOD) δ ppm 0.81 (d, J=6.82 Hz, 3 H) 0.88 (d, J=6.82 Hz, 3 H) 1.97 (m, 1 H) 3.55 (d, J=5.31 Hz, 1 H) 7.09 (d, J=8.59 Hz, 1 H) 7.19 (d, J=8.59 Hz, 2 H) 7.68 (dd, J=14.65, 8.59 Hz, 4 H) 7.83 (d, J=8.34 Hz, 2 H) 8.02 (d, J=11.37 Hz, 1 H) 8.35 (d, J=2.53 Hz, 1 H).
The title compound, 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester, was prepared according to procedures similar to that of Example 8A.
2
3
Step 14A [9058-120-1]: 2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (200 mg, 0.49 mmol, 1 equiv.), 2-Chloroquinoline (242 mg, 1.48 mmol, 3 equiv) and CsCO(402 mg, 1.235 mmol, 2.5 equiv.) were mixed in DMF (8 mL) and stirred at 100° C. for 7 hrs. Reaction mixture was cool to room temperature then placed in an ice bath and added with water. The solid precipitated from the mixture was collected by filtration and washed with water. After drying, 174 mg of yellow solid was obtained in 66% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88 (d, J=6.82 Hz, 3 H) 1.03 (d, J=6.82 Hz, 3 H) 1.22 (s, 9 H) 2.07 (m, 1 H) 3.68 (dd, J=9.85, 4.55 Hz, 1 H) 5.15 (d, J=9.85 Hz, 1 H) 7.15 (d, J=8.84 Hz, 1 H) 7.38 (d, J=8.84 Hz, 2 H) 7.45 (m, 1 H) 7.63 (m, 3 H) 7.71 (d, J=8.84 Hz, 2 H) 7.81 (t, J=8.72 Hz, 2 H) 7.91 (d, J=8.59 Hz, 2 H) 8.17 (d, J=8.34 Hz, 1 H).
Step 14B [9058-121-2]: 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid tert-butyl ester (164 mg) was dissolved in dichloroethane (12 mL) and hydrolyzed with TFA (4 mL) at room temperature over a period of 4 hrs. Solvent was removed and crude was purified by column chromatography (Eluent 10% MeOH/DCE) to afford 3-Methyl-2-[4′-(quinolin-2-yloxy)-biphenyl-4-sulfonylamino]-butyric acid in 58% yield (84.8 mg).
1H NMR (400 MHz, MeOD) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.88 (d, J=6.82 Hz, 3 H) 1.97 (m, 1 H) 3.60 (d, J=5.56 Hz, 1 H) 7.10 (d, J=8.84 Hz, 1 H) 7.25 (d, J=8.84 Hz, 2 H) 7.39 (t, J=6.82 Hz, 1 H) 7.56 (t, J=7.71 Hz, 1 H) 7.63 (d, J=0.51 Hz, 1 H) 7.65 (d, J=1.26 Hz, 1 H) 7.68 (m, 1 H) 7.69 (d, J=2.27 Hz, 1 H) 7.72 (m, 1 H) 7.74 (m, 1 H) 7.79 (dd, J=7.83, 1.26 Hz, 1 H) 7.82 (m, 1 H) 7.85 (m, 1 H) 8.23 (d, J=8.84 Hz, 1 H).
The title compound, N-({4′-[(5-nitropyridin-2-yl)oxy]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine, was prepared according to procedures similar to that of Example 8A.
Step 14A and 14B: Yield 60%. 1H NMR (400 MHz, MeOD) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.88 (d, J=6.82 Hz, 3 H) 1.96 (m, 1 H) 3.58 (d, J=5.31 Hz, 1 H) 7.11 (d, J=9.09 Hz, 1 H) 7.22 (d, J=8.84 Hz, 2 H) 7.70 (dd, J=11.87, 8.84 Hz, 4 H) 7.83 (d, J=8.59 Hz, 2 H) 8.52 (dd, J=9.09, 2.78 Hz, 1 H) 8.91 (d, J=3.28 Hz, 1 H).
The title compound, N-({4′-[(2,6-dimethoxypyrimidin-4-yl)oxy]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine, was prepared according to procedures similar to that of Example 8A.
Step 14A and 14B: Yield 82%. 1H NMR (400 MHz, MeOD) δ ppm 0.81 (d, J=6.82 Hz, 3 H) 0.88 (d, J=6.82 Hz, 3 H) 1.97 (m, 1 H) 3.56 (d, J=5.31 Hz, 1 H) 3.78 (s, 3 H) 3.85 (s, 3 H) 5.73 (s, 1 H) 7.18 (d, J=8.84 Hz, 2 H) 7.66 (d, J=8.84 Hz, 3 H) 7.70 (d, J=8.84 Hz, 3 H) 7.81 (s, 1 H) 7.83 (s, 1 H).
The title compound, N-({4′-[(4-chloropyrimidin-2-yl)oxy]-1,1′-biphenyl-4-yl}sulfonyl)-D-valine, was prepared according to procedures similar to that of Example 8A.
Step 14A and 14B: Yield 59%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.80 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.97 (m, 1 H) 3.47 (s, 1 H) 7.24 (d, J=5.81 Hz, 1 H) 7.42 (d, J=8.84 Hz, 2 H) 7.87 (d, 7 H) 8.66 (d, J=5.56 Hz, 1 H).
The title compound, N-{[4′-(pyridin-2-yloxy)-1,1′-biphenyl-4-yl]sulfonyl}-D-valine, was prepared according to procedures similar to that of Example 8A.
Step 14A and 14B: Yield 83%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.85-2.02 (m, 1 H) 3.57 (dd, J=10.48, 4.67 Hz, 1 H) 7.10 (d, J=9.85 Hz, 1 H) 7.17 (dd, J=7.20, 4.93 Hz, 1 H) 7.26 (d, J=8.84 Hz, 2 H) 7.79 (d, J=8.84 Hz, 2 H) 7.82-7.95 (m, 4 H) 8.09 (d, J=9.35 Hz, 1 H) 8.13-8.28 (m, 1 H).
The title compound, N-{[4′-(1,3-benzoxazol-2-yloxy)-1,1′-biphenyl-4-yl]sulfonyl}-D-valine, was prepared according to procedures similar to that of Example 8A.
Step 14A and 14B: Yield 85%. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.82 (d, J=6.82 Hz, 3 H) 0.85 (d, J=6.82 Hz, 3 H) 1.86-2.05 (m, 1 H)3.58 (dd, J=9.22, 5.94 Hz, 1 H) 7.32 (d, J=9.35 Hz, 1 H) 7.53 (d, J=7.33 Hz, 1 H) 7.61-7.73 (m, 3 H) 7.81-7.99 (m, 6 H) 8.10 (d, J=9.35 Hz, 1 H).
Example 9A was made based on Scheme 15.
Step 15A: (4-Bromophenyl)-acetic acid (5.0 g, 23.2 mmol, 1 eq.) dissolved in thionyl chloride (50 mL) was heat to reflux for 1 hr. under nitrogen atmosphere. The solution was cool to room temperature and solvent was evaporated. Residue thus obtained was dissolved in anhydrous methylene chloride and used in Step 15B.
4
2
2
2
2
2
2
4
Step 15B: Benzofuran-2-yl-trimethyl-silane (3.4 g, 17.86 mmol) was dissolved in methylene chloride (40 mL) and cool to −78° C. 4-Bromophenyl-acetyl chloride (19.65 mmol, 1.1 equiv.) was added at this temperature. Under vigorous stirring, a solution of TiCl(23 mL, 1M, 23.2 mmol, 1.3 equiv.) in CHClwas added dropwise and stirring continued for 20 min. Then the reaction was quenched with HO (100 mL), cooling bath was removed and the mixture was allowed to warm up to room temperature. It was then diluted with HO (100 mL) and extracted with CHCl(3×). Organic layers were combined, washed with brine, dried over MgSO, solvent evaporated. Crude product thus obtained was subject to column purification. (silica gel, 10% EtOAC/Hexane). 980 mg of 1-Benzofuran-2-yl-2-(4-bromo-phenyl)-ethanone was obtained in 17% yield.
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.34 (s, 2 H) 7.34 (d, J=8.59 Hz, 2 H) 7.44 (d, 1 H) 7.58 (d, J=8.59 Hz, 2 H) 7.62 (d, J=5.81 Hz, 1 H) 7.67 (s, 1 H) 7.71 (m, 1 H) 7.84 (t, J=6.19 Hz, 1 H).
3
4
Step 15C: A solution of 3-Methyl-2-(4-tributylstannanyl -benzenesulfonylamino)-butyric acid tert-butyl ester (347.5 mg, 0.58 mmol, 1.0 equiv.), 1-Benzofuran-2-yl-2-(4-bromo-phenyl)-ethanone (200 mg, 0.64 mmol, 1.1 equiv.) and Pd(PPh)(66 mg, 0.06 mmol, 10%) in anhydrous toluene (10 mL) was heat to reflux for 7 hrs. Reaction was complete as determined by TLC. Solvent was removed by rotovap and crude product purified by column chromatography (silica gel, 20% EtOAc/ n-Hexane) to afford 2-[4′-(2-Benzofuran-2-yl-2-oxo-ethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 20% yield (62 mg).
9
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.79 (d, J=6.82 Hz, 3 H) 0.95 (d, J=6.82 Hz, 3 H) 1.11 (s, 9 H) 3.58 (dd, J=9.85, 4.55 Hz, 1 H) 4.26 (s, 2 H) 5.05 (d, J=9.85 Hz, 1 H) 7.26 (t, J=7.07 Hz, 1 H) 7.43 (m, 5 H) 7.56 (m, 4 H) 7.65 (d, J=7.83 Hz, 1 H 7.81 d, J=8.59 Hz, 2 H).
2
2
2
2
Step 15D: 2-[4′-(2-Benzofuran-2-yl-2-oxo-ethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (62 mg) was dissolved in anhydrous CHCl(6 mL) and added with TFA (2 mL). The reaction mixture was stirred at room temperature for 3 hrs. Solvent was removed, crude product was purified by column chromatography (10% MeOH/CHCl) to afford 2-[4′-(2-Benzofuran-2-yl-2-oxo-ethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 19% yield (10.7 mg).
1H NMR (400 MHz, DMSO-D6) δ ppm 0.79 (d, J=6.82 Hz, 3 H) 0.84 (m, J=6.82 Hz, 3 H) 1.97 (m, 1 H) 3.33 (s, 1 H) 4.42 (s, 2 H) 7.39 (t, J=7.07 Hz, 1 H) 7.47 (d, J=8.34 Hz, 2 H) 7.57 (t, J=8.59 Hz, 1 H) 7.73 (m, 3 H) 7.83 (d, 4 H) 7.88 (d, J=8.84 Hz, 1 H) 8.13 (s, 1 H) 10.08 (s, 1 H).
Example 10A was made based on Scheme 16.
2
Step 16A: Starting material 2-[1,2,3]Thiadiazol-4-yl-phenol was prepared according to literature procedure (M. A. Abramov, W. Dehaen, B. D'hooge, M. L. Petrov, S. Smeets, S. Toppet and M. Voets Tetrahedron, 2000, 56, 3933-3940). 2-[1,2,3]Thiadiazol-4-yl-phenol (241 mg, 1.35 mmol), 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (406 mg, 1.37 mmol, 1 eq), and KCO3 (396 mg, 2.87 mmol, 1.9 eq) was mixed in 8 mL of CH3CN and heat to 90° C. under nitrogen atmosphere. After reaction was complete as monitored by TLC, the mixture was cool to room temperature and solvent evaporated. The resulting crude material was subject to column chromatography (20% EtOAc in hexane) to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylsulfanyl]-benzofuran (198 mg) in 40% yield. NMR: G8475-125. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 4.1 (s, 2 H) 6.6 (d, J=1.0 Hz, 1 H) 7.2 (m, 4 H) 7.4 (d, J=7.8 Hz, 2 H) 7.7 (d, J=8.1 Hz, 2 H).
Step 16B: Suzuki coupling of D-2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester with 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylsulfanyl]-benzofuran was carried out according to procedures in Step 5B for Example 2A to give D-2-[4′-(Benzofuran-2-ylsulfanylmethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester in 54% yield. NMR: G8475-165. 1H NMR (400 MHz, BENZENE-D6) δ ppm 0.7 (d, J=6.8 Hz, 3 H) 0.9 (d, J=6.8 Hz, 3 H) 1.9 (m, 1 H) 3.0 (s, 3 H) 4.0 (m, 3 H) 5.0 (d, J=10.1 Hz, 1 H) 6.6 (d, J=1.0 Hz, 1 H) 7.1 (m, 4 H) 7.3 (m, 6 H) 7.3 (s, 1 H) 7.4 (m, 1 H).
Step 16C: A solution of D-2-[4′-(Benzofuran-2-ylsulfanylmethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester (75 mg, 0.15 mmol, 1 eq) in 4 mL of THF was placed in ice bath. 125 mg of MCPBA (77%, 0.55 mmol, 3.7 eq) in 3 mL of THF was added dropwise. After addition complete, ice bath was removed and the reaction was allowed to warm to room temperature and stir for 12 hrs. TLC indicated reaction was complete. Regular work-up and column chromatography (20% EtOAc in hexane) to afford D-2-[4′-(Benzofuran-2-sulfonylmethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester (56 mg) in 70% yield. NMR: G8475-166. 1H NMR (400 MHz, CHLOROFORM-D) □ ppm 0.9 (dd, J=33.3, 6.8 Hz, 6 H) 2.0 (m, 1 H) 3.4 (s, 3 H) 3.8 (dd, J=10.1, 5.3 Hz, 1 H) 4.6 (s, 2 H) 5.1 (d, J=10.1 Hz, 1 H) 7.4 (m, 4 H) 7.5 (m, 3 H) 7.6 (m, 1 H) 7.7 (m, 3 H) 7.9 (d, J=8.8 Hz, 2 H).
Step 16D [: Hydrolysis of D-2-[4′-(Benzofuran-2-sulfonylmethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester was carried out according to procedures in Step 1D for Example 1A in quantitative yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.8 (dd, J=12.1, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.5 (dd, J=9.3, 6.1 Hz, 1 H) 5.0 (s, 2 H) 7.4 (d, J=8.3 Hz, 2 H) 7.4 (m, 1 H) 7.6 (m, 1 H) 7.7 (d, J=1.0 Hz, 1 H) 7.7 (d, J=8.3 Hz, 2 H) 7.8 (m, 6 H) 8.1 (d, J=9.1 Hz, 1 H).
The following compounds (11A-11B) were prepared according to Scheme 6B.
1
+
H NMR (400 MHz, DMSO): δ 0.806(d, 3H), 0.837(d, 3H), 1.94(m, 1H), 3.53(t, 1H), 3.90(s, 3H), 5.33(s, 2H), 7.20(d, 1H), 7.27(m, 1H), 7.34(s, 1H), 7.54(d, 2H), 7.61(d, 1H), 7.89(m, 8H); ES m/z 518.2 (M−H); HRMS (C29H29NO6S): calcd; 520.17884; found; 520.17839 (M+H).
1
+
H NMR (400 MHz, DMSO): δ 0.808(d, 3H), 0.838(d, 3H), 1.94(m, 1H), 3.74(s, 6H), 3.89(s, 3H), 5.09(s, 2H), 6.45(t, 1H), 6.62(d, 2H), 7.11(d, 1H), 7.25(d, 1H), 7.32(d, 1H), 7.79(d, 2H), 7.85(d, 2H), 8.02(d, 1H); ES m/z 528.2 (M−H); HRMS (C27H31NO8S): calcd; 530.18432; found; 530.18367 (M+H).
The following compounds (12A-12R) were made using procedures described in scheme 17.
1
+
H NMR (400 MHz, DMSO): δ 0.825(d, 3H), 0.875(d, 3H), 2.04(m, 1H), 3.70(m, 1H), 6.89(d, 2H), 7.59(m, 2H), 7.75(dd, 1H), 7.94(d, 1H), 8.16(d, 1H); ES m/z 432.1 (M−H); HRMS (C18H18F3NO6S): calcd; 451.11451; found; 451.11461 (M+NH4).
1
+
H NMR (400 MHz, DMSO): δ 0.850(m, 6H), 2.02(m, 1H), 3.60(m, 1H), 6.90(d, 2H), 7.67(d, 2H), 8.10(m, 3H); ES m/z 416.0 (M−H); HRMS (C18H18F3NO5S): calcd; 435.11960; found; 435.11966 (M+NH4).
1
+
H NMR (400 MHz, DMSO): δ 0.810(t, 6H), 1.93(m, 1H), 2.64(s,3H), 3.39(m, 1H), 6.87(m, 2H), 7.56(m, 3H), 7.81(d, 1H), 8.00(d, 1H); ES m/z 362.1 (M−H); HRMS (C18H21NO5S): calcd; 381.14786; found; 381.14808 (M+NH4).
1
+
H NMR (400 MHz, DMSO): δ 0.850(m, 6H), 2.02(m, 1H), 3.63(m, 1H), 6.87(d, 2H), 7.61(m, 3H), 7.76(t, 1H), 8.22(d, 1H); ES m/z 366.0 (M−H); HRMS (C17H18FNO5S): calcd; 385.12279; found; 385.12276 (M+NH4).
1
+
H NMR (400 MHz, DMSO): δ 0.880(m, 6H), 2.04(m, 1H), 3.69(m, 1H), 6.89(d, 1H), 7.45(m, 2H), 7.58(m, 2H), 8.45(d, 1H); ES m/z 384.1 (M−H); HRMS (C17H17F2NO5S): calcd; 403.1137; found; 403.11328 (M+NH4).
1
+
H NMR (400 MHz, DMSO): δ 0.900(d, 3H), 0.960(d, 3H), 2.06(m, 1H), 3.70(d, 1H), 4.19(s, 2H), 6.95(d, 1H), 7.43(m, 6H), 7.69(s, 1H), 7.75(m, 3H), 7.88(m, 1H), 7.97(s, 1H), 8.15(d, 1H); ES m/z 556.1 (M−H); HRMS (C29H26F3NO5S): calcd; 558.15566; found; 558.15484 (M+H).
1
+
H NMR (400 MHz, MeOH): δ 0.920(d, 3H), 0.980(d, 3H), 2.10 (m, 1H), 3.76(d, 1H), 4.19(s, 2H), 6.94(d, 1H), 7.43(m, 7H), 7.70(s, 1H), 7.78(m, 4H); ES m/z 506.1 (M−H); HRMS (C28H26FNO5S): calcd; 508.15885; found; 508.15818 (M+H).
1
+
H NMR (400 MHz, MeOH): δ 0.910(d, 3H), 0.980(d, 3H), 2.09(m, 1H), 3.78(d, 1H), 4.16(s, 2H), 6.92(d, 1H), 7.37(m, 6H), 7.56(m, 1H), 7.67(s, 1H), 7.75(m, 4H); ES m/z 524.1 (M−H); HRMS (C28H25F2NO5S): calcd; 526.14943; found; 526.14881 (M+H).
+
ES m/z 614.1 (M−H)−HRMS: 616.16053 (M+H)+; 616.16114 Calc'd
H NMR (400 MHz, DMSO): δ 0.83 (d, 3H, J=6.8 Hz), 0.088 (d, 3H, J=6.8 Hz), 2.06 (m, 1H), 3.74 (dd, 1H, J=5.6, 10 Hz), 5.18 (s, 2H), 5.35 (d, 1H, J=10 Hz), 6.92 (d, 2H, J=8 Hz), 7.00 (d, 2H, J=8 Hz), 7.07 (d, 2H, J=8 Hz), 7.34 (d, 2H, J=8 Hz), 7.61 (d, 2H, J=8 Hz), 7.69 (s, 1H), 7.79 (d, 2H, J=8 Hz), 7.88 (m, 1H), 8.02 (d, 1H, J=8 Hz), 8.24 (m, 1H), 12.70 (s, 1H).
+
ES m/z 598.1 (M−H)−HRMS: 600.16554 (M+H)+; 600.16622 Calc'd
H NMR (400 MHz, DMSO): δ 0.85 (d, 3H, J=6.8 Hz), .0.86 (d, 3H, J=6.8 Hz), 2.05 (m,
+
ES m/z 564.1 (M−H)−HRMS: 566.13860 (M+H)+; 566.13987 Calc'd
H NMR (400 MHz, DMSO): δ 0.84 (d, 3H, J=6.8 Hz), .0.86 (d, 3H, J=6.8 Hz), 2.02 (m, 1H), 3.57 (dd, 1H, J=6, 9.2 Hz), 5.17 (s, 2H), 6.92 (d, 2H, J=8 Hz), 6.99 (d, 2H, J=8 Hz), 7.07 (m, 3H), 7.33 (m, 2H), 7.59 (d, 2H, J=8 Hz), 7.83 (m, 5H), 7.95 (d, 1H, J=1.6 Hz), 8.03 (d, 1H, J=8 Hz), 8.21 (m, 1H), 12.65 (s, 1H).
+
ES m/z 590.1 (M−H)−HRMS: 592.16098 (M+H)+; 592.16114 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.83 (d, 3H, J=6.8 Hz), 0.88 (d, 3H, J=6.8 Hz), 2.05 (m, 3H), 2.53 (t, 2H, J=6 Hz), 2.91 (t, 2H, J=6 Hz), 3.74 (dd, 1H, J=5.6, 10 Hz), 5.28 (s, 2H), 6.98 (m, 2H), 7.60 (d, 2H, J=8 Hz), 7.69 (s, 1H), 7.85 (m, 4H), 8.02 (d, 1H, J=8 Hz), 8.25 (d, 1H, J=8 Hz), 12.70 (s, 1H).
+
ES m/z 574.1 (M−H)−HRMS: 576.16522 (M+H)+; 576.16622 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.85 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=6.8 Hz), 2.04 (m, 3H), 2.53 (t, 2H, J=6 Hz), 2.91 (t, 2H, J=6 Hz), 3.63 (dd, 1H, J=6, 10 Hz), 5.29 (s, 2H), 6.98 (m, 2H), 7.61 (d, 2H, J=8 Hz), 7.85 (m, 3H), 8.20 (m, 4H), 12.70 (s, 1H).
+
ES m/z 524.1 (M−H)−HRMS: 526.16859 (M+H)+; 526.16942 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.84 (d, 3H, J=6.8 Hz), 0.87 (d, 3H, J=6.8 Hz), 2.02 (m, 3H), 2.53 (t, 2H, J=6 Hz), 2.91 (t, 2H, J=6 Hz), 3.66 (dd, 1H, J=6, 9.2 Hz), 5.27 (s, 2H), 6.98 (m, 2H), 7.58 (d, 2H, J=8 Hz), 7.70 (m, 1H), 7.83 (m, 5H), 8.30 (d, 1H, J=10 Hz), 12.65 (s, 1H).
+
ES m/z 629.2 (M−H)−HRMS: 631.17159 (M+H)+; 631.17204 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.83 (d, 3H, J=6.8 Hz), 0.88 (d, 3H,J=6.8 Hz), 2.07 (m, 1H), 2.30 (s, 3H), 3.74 (dd, 1H, J=5.6, 9.6 Hz), 5.20 (s, 2H),6.68 (d, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 7.06 (m, 4H), 7.62 (d, 2H, J=8 Hz), 7.69 (m, 2H), 7.80 (d, 2H, J=8 Hz), 7.87 (dd, 1H, J=1.6, 8 Hz), 8.03 (d, 1H, J=8 Hz), 8.25 (d, 2H, J=9.2 Hz), 12.70 (s, 1H).
+
ES m/z 613.2 (M−H)−HRMS: 615.17639 (M+H)+; 615.17712 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.85 (d, 3H, J=6.8 Hz), 0.87 (d, 3H, J=6.8 Hz), 2.05 (m, 1H), 2.30 (s, 3H), 3.63 (dd, 1H, J=6, 9.6 Hz), 5.20 (s, 2H), 6.68 (d, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 7.06 (m, 4H), 7.63 (d, 2H, J=8 Hz), 7.69 (t, 1H, J=8 Hz), 7.87 (d, 2H, J=8 Hz), 8.21 (m, 4H), 12.70 (s, 1H).
+
ES m/z 563.2 (M−H)−HRMS: 565.18038 (M+H)+; 565.18032 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.84 (d, 3H, J=6.8 Hz), 0.87 (d, 3H, J=6.8 Hz), 2.04 (m, 1H), 2.30 (s, 3H), 3.66 (dd, 1H, J=6, 9.6 Hz), 5.19 (s, 2H), 6.68 (d, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 7.06 (s, 4H), 7.60 (d, 2H, J=8 Hz), 7.70 (m, 2H), 7.83 (m, 4H), 8.31 (d, 1H, J=9.2 Hz), 12.70 (s, 1H).
+
ES m/z 579.1 (M−H)−HRMS: 581.15050 (M+H)+; 581.15077 Calc'd
1
H NMR (400 MHz, DMSO): δ 0.84 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=6.8 Hz), 2.02 (m, 1H), 2.30 (s, 3H), 3.58 (dd, 1H, J=6.4, 9.6 Hz), 5.20 (s, 2H), 6.68 (d, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 7.06 (s, 4H), 7.60 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz), 7.83 (m, 3H), 7.95 (d, 1H, J=1.6), 8.03 (d, 1H, J=8 Hz), 8.22 (d, 1H, J=9.6 Hz), 12.70 (s, 1H).
Examples 13A, 13B, 13C were made based on Scheme 5.
1
+
24
26
2
5
H NMR (400 MHz, MeOD): δ; ES m/z (M+H) 455.1; HRMS (M+H) m/z calcd 455.16352; found 455.16317; (CHNOS):
1
+
3
29
29
5
H NMR (400 MHz, CDCl): δ0.85 (d, 3H), 0.95 (d, 3H), 2.10 (m, 1H), 3.83 (m, 1H), 4.63 (s, 2H), 4.74 (s, 2H), 5.25 (bs, 1H), 7.44-7.55 (m, 7H), 7.65 (d, 2H), 7.82-7.90 (m, 6H); ES m/z (M−H) 502.1; HRMS (M+H) m/z calcd 504.18392; found 504.18503; (CHNOS):
1
+
24
26
2
5
H NMR (400 MHz, DMSO): δ 0.81 (d, 3H), 0.84 (d, 3H), 1.95 (m, 1H), 3.55 (dd, 1H), 4.56 (s, 2H), 4.63 (d, 2H), 7.44 (d, 2H), 7.50 (d, 1H), 7.70 (d, 2H), 7.74 (d, 1H), 7.84 (m, 4H), 8.08 (m, 2H); ES m/z (M+H) 455.1; HRMS (M+H) m/z calcd 455.16352; found 455.16290; (CHNOS)
Aggrecanase-1 FRET Assay
Fluorimeter was started and temperature set to 30° C., about 30 min before setting up the assay. The following reagents are used:
2
Buffer: 50 mM HEPES, pH 7.5, 100 mM NaCl, 5 mM CaCl, 0.1% CHAPS, 5% glycerol.
rAgg1: 5 μg/ml (final concentration in the assay):
−1
−1
m
m
Substrate: Abz-TEGARGSVI-Dap(Dnp) (Abz:o-aminobenzoyl; Dnp: 2,4 dinitrophenyl) (Anaspec Inc), stored at 4° C.). Make a stock at 2 mg/ml in 100% DMSO. Measure the absorbance at 354 nm (ε=18172 Mcm) to determine the exact concentration. Dilute to 62.5 μM in buffer. Store unused 100% DMSO stock at −80° C. Final concentration of substrate in the assay is 25 μM. This concentration is much less than the K(K=1.1+/−0.2 mM as determined by Jin and Cowling)
Inhibitors. Make up inhibitors at 10× starting concentration in 100% DMSO. Perform serial dilutions (in duplicate) across the nunc plate in 100% DMSO;
Dilution plates: Nunc, polypropylene low binding (Nalgene)
Assay plate: Fluoronunc (Nalgene)
Fluorimeter: GeminiXS (Molecular Devices).
The following protocol was used:
The assay is performed as follows (The plates are set up so that the final column (12) is used for controls. Total reaction volume is 100 μl. Each compound is assayed in duplicate, so 4 compounds are screened per plate):
1) Add buffer to the entire 96-well plate (30 μl/well).
2) Dilute rAgg1 to 25 μg/ml buffer just prior to addition on the plate. Add 20 μl/well to all wells. Mix 6 times.
3) Add 10 μl/ well of 10× inhibitors from the working plate, except column 12. Mix 6 times. To wells 12A-F, add 10× controls (see reference compounds below).
4) To wells 12G-H add 10 μl 100% DMSO.
5) Incubate for 10-15 min at 30° C.
6) Add 40 μl/well of 62.5 μM substrate. Mix 6 times.
The reaction is monitored for 30-40 min at 30° C. λex: 340 nm and λem: 420 nm). The fluorescence is linear during this time and the slope of the line (Vmax/sec) represents the initial reaction rate, υ. The maximal rate of cleavage of substrate is determined in the absence of inhibitor.
The percent inhibition of activity in the presence of inhibitor is calculated as follows:
<math overflow="scroll"><mrow><mrow><mi>%</mi><mo></mo><mstyle><mspace width="0.6em" height="0.6ex" /></mstyle><mo></mo><mi>inhibition</mi></mrow><mo>=</mo><mrow><mrow><mo>(</mo><mrow><mn>1</mn><mo>-</mo><mrow><mrow><mrow><mi>υ</mi><mo></mo><mrow><mo>(</mo><mrow><mi>Rate</mi><mo>,</mo><mrow><mi>RFU</mi><mo>/</mo><mi>sec</mi></mrow></mrow><mo>)</mo></mrow></mrow><mo>/</mo><mi>Maximal</mi></mrow><mo></mo><mstyle><mspace width="0.8em" height="0.8ex" /></mstyle><mo></mo><mi>Rate</mi><mo></mo><mstyle><mspace width="0.6em" height="0.6ex" /></mstyle><mo></mo><mrow><mo>(</mo><mrow><mi>RFU</mi><mo>/</mo><mi>sec</mi></mrow><mo>)</mo></mrow></mrow></mrow><mo>)</mo></mrow><mo>*</mo><mn>100</mn></mrow></mrow></math>
y
a−d
+C/IC
n
d
50
The IC50 was obtained by fitting the initial rate, υ, or % inhibition at each concentration of inhibitor to the following equation in Excel.
=()/(1)^)+
50
This model describes a sigmoidal curve with an adjustable baseline, a. y is the % inhbition or initial rate of reaction, C is the concentration of inhibitor under test. a is the limiting response as C approaches zero. As C increases without bound y tends toward its lower limit, d. y is halfway between the lower and upper asymptotes when C=IC. n is the Hill coefficient. The sign of n is positive when the response increases with increasing dose and is negative when the response decreases with increasing dose (inhibition).
Table 1 lists the activities for selected compounds of the Examples.
TABLE 1
Example
IC50 (μM)
1A
0.2
1B
0.8
1C
0.2
1D
0.4
1E
0.6
1F
1.5
1H
0.23
2A
1.0
2B
1.5
2C
0.8
2D
5.5
2K
0.5
3A
0.35
4A
1.2
5A
0.4
6A
3.6
6B
0.6
6C
1.1
6S
4.5
7A
0.09
7B
0.345
11A
8.9
11B
16.7
12A
200
12B
67
The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in their entireties.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. | |
The postpartum induced corpus luteum: functional differences from that of cycling cows and the effects of progesterone pretreatment.
Anestrous postpartum (PP) Hereford cows (n = 41) were used to compare corpora lutea (CL) from gonadotropin-releasing hormone (GnRH)-induced ovulation with CL from cycling cows. Postpartum cows were injected i.m. daily with 100 mg progesterone (P4) or oil on Days 25 through 28 PP and then given 200 micrograms GnRH i.m. on Day 30 PP. Corpora lutea were removed from one-half of the PP cows in the oil- and P4-treated groups 6.5 days after GnRH injection, and from the cycling cows 7 days after estrus. Intact PP cows were used to evaluate cycle length. Blood was collected daily from all PP cows from Day 25 PP through luteectomy and on Days 9, 11, and 13 post-GnRH from the oil- and P4-intact cows to determine short (SHORT) versus normal (NORM) luteal phases. Cycling cows were bled daily from estrus until CL removal NORM PP cows had higher (P less than 0.001) P4 levels than did SHORT PP cows from Day 7 through Day 13 post-GnRH, and more (P less than 0.05) P4-intact cows were NORM compared with oil-intact cows (45.5% vs. 14.3%, respectively). Corpora lutea from cycling cows were heavier (P less than 0.05) and had a higher luteinizing hormone (LH) receptor concentration (P less than 0.05), but CL P4 concentration did not differ from PP cows. Corpora lutea weight, LH receptor and P4 concentration, and in vitro P4 production were similar in the oil-and P4-treated PP cows. NORM cows had heavier CL (P less than 0.05) than SHORT cows, although P4 content and LH receptor concentration did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)
| |
This study is a follow-up to previous research on the use of a transdisciplinary approach in the analysis of factors that influence bioeconomy development and interactions between them. It is very important to consider the significance of public opinion while performing transdisciplinary research. This study integrates public opinion in the bibliometric analysis method by using grey data from information available in the public information space: mass media and social networks. The network of factors influencing the development of bioeconomy, created with the help of social network analysis method, was compared with the one obtained from bibliometric analysis of SCOPUS database in order to find out the difference between scientific tendencies and the overall atmosphere in the information space. Although the structure of these networks varies, there is a common tendency in literature to identify the following factors as the key factors in the development of the bioeconomy: research and innovations; technology; energy and energy consumption. | https://sciendo.com/article/10.2478/rtuect-2020-0058 |
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