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Saskatchewan Immigrant Nominee Program or SINP is an immigration program offered by the province of Saskatchewan, Canada offering permanent Resident visa under PNP. The point-based system and accessibility of Saskatchewan PNP make it an excellent method for skilled workers immigrants to obtain a Canada PR.SINP has 3 sub-categories for skilled and experienced foreign applicants who wish to live in the Saskatchewan province:
- International Skilled Worker: Occupation In-Demand
- International Skilled Worker: Saskatchewan Express Entry
- International Skilled Worker: Employment Offer
SINP – International Skilled worker is a category that follows a a point based system and evaluates the candidates on the basis of their credentials such as age, work experience, language ability, education,
adaptability etc . it is necessary to get a minimum of 60 points out of total 100 of SINP points calculator to be eligible for Saskatchewan Immigration.
Saskatchewan Immigration Point Table
It is important to calculate your points based on different factors before applying for SINP to check your eligibility for the International Skilled Worker category of Saskatchewan immigration PNP. Following are the point calculator system for this category of SINP.
Selection Factors (Saskatchewan points calculator)
|Factors||Maximum Points Awarded|
|Education and Training||23|
|Skilled Work experience||15|
|Language ability||20|
|Age||12|
|Connection to Saskatchewan labor market||30|
SINP Points Grid
|Factor||Points (Max 100)|
|Age||12 (MAX)|
|Under 18||0|
|18-21||8|
|22-34||12|
|35-45||10|
|46-50||8|
|>50 Years||0|
|Education||23 (MAX)|
|Master or Doctor Degree||23|
|University Bachelor Degree (Min. 3 years program)||20|
|Trade Certification (equivalent to Saskatchewan journey person)||20|
|Degree, Certificate or diploma (Min. 2 years)||15|
|Degree, diploma or certificate (minimum 1 year program of study, or equivalent to a trade certificate.||12|
|Experience||15(MAX)|
|In the 5 year period prior to application submission date|
|1 year||2|
|2||4|
|3||6|
|4||8|
|5||10|
|(6 to 10 years)|
|5 Year||5|
|4||4|
|3||3|
|2||2|
|Less than 1 year||0|
|Language||20 (MAX)|
|Level 4||12|
|Level 5||14|
|Level 6||16|
|Level 7||18|
|Level 8 or higher||20|
|Adaptability||30 (MAX)|
|Past study in SK||5|
|Past work in SK(At least 1 year in last 5 years)||5|
|Close Relatives in SK (Parent, Sibling, grandparent, Aunt, Uncle, Niece, Nephew, Cousin)||20|
|Employment offer from a Saskatchewan employer||30|
|Minimum Requirement 60||100|
The above point-grade calculator system helps you calculate your points to check your eligibility for Canada immigration with a PR visa through Saskatchewan Immigration Nominee Program. If you find yourself to be eligible, apply now for your permanent residency status and a team of experts will assess your profile and will tell you under which category you are eligible.
How many points are required to be eligible for Saskatchewan PR?
The Saskatchewan Immigration Nominee Program (SINP) is a point-based PNP program. It evaluates your profile according to your credentials such as age, work experience, language ability, skills and adaptability. According to Saskatchewan immigration authority, a candidate is required to score at least 60 points out of 100 to be eligible for Canada PR visa through Saskatchewan PNP.
Fill this Free Assessment form and get in touch with our qualified visa experts for further queries and immigration assistance. | https://www.ewicsgroup.com/saskatchewan-pnp-immigration-sinp-points-calculator/ |
Since the introduction of cinema, advances in media and technology has meant that children’s exposure to violence has become ever more accessible and realistic. There has been a long held view that the amount of violence available through media is detrimental to a child’s development as they are likely to copy what they see. This process of learning through watching others is called social learning and in 1963 Bandura conducted a notable experiment to see how this influenced children’s behaviour.
The Bandura et al. (1963) experiment
96 children (avg. age 4.4) were organised into four equal groups. In three of the groups the children observed aggressive behaviour being carried out on an inflatable doll (Bobo) by an adult model. The aggressive behaviour was shown in a different form in each of the groups, these being a live model, filmed model and a fantasy model, cat-like creature. The fourth group were not exposed to any aggressive behaviour so to provide the researchers with a baseline score.
The children took part in the experiment individually and with the exception of the variation of aggressive behaviour they all went through an identical experience. Each were led through three different playrooms, whereby in the first room they were encouraged to play with toys and were either exposed (or not exposed) to a model acting aggressively towards Bobo. In the second room the children were presented with toys but then quickly denied the opportunity to play with them; the purpose for this was to cause a sense of frustration. Once in the third room the children were left to play on their own and the researchers recorded any aggressive behaviour carried out on Bobo that was present amongst the toys.
Bandura was particularly interested in whether the children would imitate the actions of the model seen in the first room and recorded aggressive behaviour that was identical to that observed of the model. For instance the model would strike the doll using a hammer and shout the word ‘pow’.
The findings
The researchers found that children were 10 times more likely copy the aggressive behaviour that they had just observed. However, it made no difference whether the model was seen live or on film or if the violence was portrayed by a human or fantasy model. Across all groups the boys showed higher scores of aggression than the girls and they were more likely to copy the behaviour of a male model than they were a female (Oates, cited in Brace & Byford 2012). | https://www.majortests.com/essay/Is-Media-Violence-Harmeful-To-Children-537273.html |
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The invention relates to a method for separating and recovering nucleic acid molecules having a tiny size difference from a PCR mixed product. The method comprises the following steps: implementing PCR so as to acquire a mixed DNA product containing a target segment; implementing polyacrylamide gel vertical electrophoresis, separating different DNA molecules in the mixture (the mixed DNA product);dyeing a PAGE film via a nucleic acid dye DNAgreen; cutting a gel part containing the target segment under ultraviolet light, and grinding gel into the form of a slime via a grinding bar; adding a TEsolution into the gel, and conducting heating treatment; conducting centrifuging treatment on the mixture and reserving supernatant liquid; recovering a solution containing the target segment from the supernatant liquid via an existing normal PCR product purifying kit adopted in laboratories; and directly using the solution as a PCR template, and conducting direct sequencing on an amplification product, so that sequence information of target DNA molecules is obtained. The method provided by the invention has the advantages of being rapid and convenient, low in cost, safe, high in quality andgood in effect, and integrated use of resources is achieved. | |
Introduction: Previous studies have measured individuals’ willingness to share personal information stored in electronic health records (EHRs) with health care providers, but none has measured preferences among patients when they are allowed to determine the parameters of provider access.
Methods: Patients were given the ability to control access by doctors, nurses, and other staff in a primary care clinic to personal information stored in an EHR. Patients could restrict access to all personal data or to specific types of sensitive information, and could restrict access for a specific time period. Patients also completed a survey regarding their understanding of and opinions regarding the process.
Results: Of 139 eligible patients who were approached, 105 (75.5 %) were enrolled, and preferences were collected from all 105 (100 %). Sixty patients (57 %) did not restrict access for any providers. Of the 45 patients (43 %) who chose to limit the access of at least one provider, 36 restricted access only to all personal information in the EHR, while nine restricted access of some providers to a subset of the their personal information. Thirty-four (32.3 %) patients blocked access to all personal information by all doctors, nurses, and/or other staff, 26 (24.8 %) blocked access by all doctors and/or nurses, and five (4.8 %) denied access to all doctors, nurses, and staff.
Conclusions: A significant minority of patients chose to restrict access by their primary care providers to personal information contained in an EHR, and few chose to restrict access to specific types of information. More research is needed to identify patient goals and understanding of the implications when facing decisions of this sort, and to identify the impact of patient education regarding information contained in EHRs and their use in the clinical care setting. | https://indiana.pure.elsevier.com/en/publications/patient-preferences-in-controlling-access-to-their-electronic-hea |
Looking at what urban redevelopment and changing funding structures mean for creative production and agency in the city, Auto Italia will present a range of materials as a starting point for a wider discussion into strategies now available to artists and artist-led organisations.
Using methods such as prophecies, tarot, empathy and speculation we will discuss different perspectives on what ‘coping’ might mean in Copenhagen.
For the tenth year running, the art fair Alt_Cph will be presenting several leading, European artist-run spaces. The scene of artist-run spaces is wildly active and is characterized by complex collaborations constantly challenging the framework for art practice. This will become evident at the 2015 edition of Copenhagen’s experimental art fair Alt_Cph, which once again will be held at the Factory of Art & Design.
“Alt_Cph 15 will explore what constitutes the “non-institutional” art scene – a scene which was earlier characterized by being outright anti-institutional or anti-commercial, but which today naturally moves in and out of various contexts in ways that challenge the framework of art,” said the art fair’s curator, art historian Carl Martin Faurby.
“It’s really important to take a look at the current artist-run scene because these new ways of expression can rarely be contained by the traditional institutions,” Faurby said.
The uncontrollable core
The theme for Alt_Cph 15 is Nucleus, the essential brick in atoms, organisms, and eventually, entire ecosystems.
The nucleus is always on the move and continuously enters new constellations. According to quantum mechanics, it is meaningless to define the exact location of a particle in the moment of observation. At Alt_Cph 15 this idea will be transferred to the dynamic collectives of the artist-run scene.
“Today, we use, to an increasing extent, the relations between objects rather than the objects themselves to make sense of things,” Faurby said. “Therefore, context and communication have become primary materials in contemporary art.”
The artist-run spaces work across media and platforms, and their art is about more than physical exhibitions. For this reason, this year, Alt_Cph will depart from the traditional fair stands and instead offer various spaces of artistic expression.
Curator Faurby has invited 25 art platforms to the experiment that is Alt_Cph, which will take place in the huge hall of the Factory of Art & Design. Here, the participating artists will collide, connect, and recharge each other.
The fair will present art from both new and long-lived collaborations from all over Europe, and you will be able to experience performances, live concerts, art salons, and of course Alt_Cph’s 10th anniversary celebration party. | https://autoitaliasoutheast.org/projects/alt_cph-a-reading-for-copenhagen/ |
Terrell James (b. 1955, Houston) is an abstract painter who exhibits nationally and internationally. She produces both intimate canvasses and vigorous mural-scale works in oil. James’ works on paper include drawings, etchings, lithographs, monoprints, and monotypes. She has produced small-scale sculptures in bronze and clay; large flat sculptures in patinated steel; and impermanent, site-specific installations in Houston, Berlin, at the Great Wall of China, and in Song Zhuang Artist Village (Beijing).
James has been included in over two hundred group shows, and completed over fifty solo exhibitions in galleries, artist-run spaces, and museums.
She is represented by Josh Pazda Hiram Butler Gallery in Houston, Barry Whistler Gallery in Dallas, Froelick Gallery in Portland, Cadogan Contemporary in London, and Jason McCoy Gallery in New York. Her work is included in many museum collections, including: the Boston Museum of Art, Dallas Museum of Art, Museum of Fine Arts Houston, the San Antonio Museum of Art, and the Whitney Museum of American Art.
Her paintings are interpretations of landscapes, internal and external. James has continuously sought unfamiliar environments in which to paint, producing works in place that attend to an area’s specific local light, color, tone, and history, and allowing the disruption and new material to change ongoing work in her home studio in Houston, Texas. She has maintained temporary studio spaces in Mexico, North Carolina, New York, Montauk, Marfa, and Berlin. | https://barrywhistlergallery.com/artists/terrell-james |
As artificial intelligence (AI) becomes all-pervasive and attempts to approach the intelligence of humans, a key AI technology enabling this is deep learning. At the heart of deep-learning algorithms are neural networks, a technology inspired by the human brain, mimicking the way that biological neurons in our nervous system send signals to one another. It was a revelation to me that these networks in turn perhaps mimicked an even more ancient structure: an underground partnership of tree and fungi (what scientists call ‘the mycorrhiza’).
We typically think of trees, even if in a forest, as solitary creatures in a Darwinian competition for resources, sunlight and space, but otherwise unaware and indeed unconcerned about one another. This is not so, it seems. A forest is a vast, primeval and complex society connected in an unlikely way—through a web of fungi. As The New York Times writes in ‘The Social Life of Forests’ (nyti.ms/2XM3XQI ), “There is conflict in a forest, but there is also negotiation, reciprocity, and perhaps even selflessness. The trees, understory plants, fungi and microbes in a forest are so thoroughly connected, communicative and co-dependent that some scientists have described them as superorganisms."
This was not the general idea until a seminal research paper published by Suzanne Simard in Nature took root in the scientific world. It has been known that threadlike fungi live symbiotically with trees, surrounding and fusing with their roots and helping them extract life-giving phosphorous and nitrogen from the soil, in return for carbon-rich nutrients that trees manufacture using photosynthesis. Simard discovered that this intricate web of fungi connect every tree to every other, irrespective of species. Trees can transport carbon, water, nutrients and even send alarm signals and hormones to one another through these circuits, with the oldest trees donating resources to the youngest. Another piece of research done by professor Tamir Klein quantified this: “In a patch of forest the size of a rugby field, the trees trade around 280 kilograms of carbon every year. That’s around 40% of the carbon in their fine roots, and about 4% of what they produce in total through photosynthesis. Mycorrhizas supplied trees and other plants with up to 40% of the nitrogen they received from the environment and as much as 50% of the water they needed to survive. Below ground, trees traded between 10% and 40% of the carbon stored in their roots."
The interdependence goes beyond carbon and water. A tree attacked by parasites, for instance, passes chemical alarm signals to trees around it, pre-warning them to manufacture their own chemical defences. Research has indicated that plant roots grow toward the sound of running water and that certain flowering plants sweeten their nectar when they detect a bee’s wing beats. A tree about to die may even bequeath its stored carbon to a younger tree through this amazing network. Simard believes that veteran trees “send messages of wisdom on to the next generation of seedlings", and she posits the concept of a forest having several mother trees, the ones that are the oldest and most interconnected (incidentally, her book is called The Mother Tree). The concept of a mother tree is not new: Central American mythology talks of an immense tree that grows at the centre of the universe; Norse cosmology has a similar tree called Yggdrasil.
This coexistence has interesting possibilities. Dr Franciska de Vries of the University of Manchester says that forests “might be more socialist than we thought" and not necessarily follow Darwin’s philosophy of ‘survival of the fittest’. Interestingly, Darwin, who was inspired by the writings of Thomas Malthus and Adam Smith, believed that all life was locked in a relentless competition for limited natural resources. “Darwin’s theory of evolution by natural selection is obviously 19th-century capitalism writ large," wrote biologist Richard Lewontin. At one point, Darwin worried that the kind selflessness that he saw among trees and other creatures would be “fatal" to his theory.
Trees clearly seem to be more cooperative than competitive. Simard, in fact, believes that a forest might be one single organism rather than a collection of trees. Another naturalist Merlin Sheldrake believes that these amazing fungal webs create the ‘social network of plants’. It is not surprising, therefore, that when Nature published Simard’s ground-breaking research, it gave it the title ‘The Wood Wide Web’—not just an inspiration for neural networks, but even for the internet.
Jaspreet Bindra is the chief tech whisperer at Findability Sciences, and learning AI, Ethics and Society at Cambridge University. | |
Your Specific Responsibilities:
The Bureau Chief of the Bureau of WIC Program Services is responsible for the management of the federally funded Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). The incumbent is responsible for the following tasks:
Plans, develops and directs WIC Program operations to ensure the uniform delivery of quality WIC services throughout the state in accordance with federal and state rules and regulations. Evaluates the impact of program policies and procedures on operations and implements changes based on need and analysis to improve program effectiveness, promote efficiencies at the local and state level and provide cost savings.
Plans, develops and directs the nutrition component of the WIC Program to ensure the provision of nutrition assessment and counseling to the populations at risk.
Coordinates the development of the Bureau’s long range plans. Establishes and implements short and long range goals and objectives for the Bureau. Ensures promotion of and adherence to the goals and objectives of the Department and the WIC Program.
Develops and supervises the management of the WIC Program budget for both food and administrative expenditures and the statewide allocation of funds to local agencies to ensure accountability.
Provides technical assistance and expertise to department officials at the state and county level regarding WIC program rules, regulations and policies, and to ensure that scientifically accurate and sound nutrition policy is implemented in all levels of the department.
Serves as liaison between the Bureau of WIC Program Services and other departmental programs, and between the Department of Health and other governmental agencies and nongovernmental entities, to coordinate the provision of WIC and nutrition services to Florida’s citizens. Represents the Department at national, state, and local meetings regarding WIC and nutrition services.
Performs all supervisory duties including, but not limited to, hiring and selection, developing performance plans, conducting performance appraisals, planning and directing staff’s work, approving leave, and taking disciplinary action as appropriate. Reports routinely to the Division Director on the work of the Bureau and other related assignments.
Maintains professional knowledge and skills through participation in staff meetings and through other staff development activities.
Complies with federal and state purchasing requirements in the preparation of purchasing and approval of purchasing.
Assigned responsibility for control of department assets.
Performs other related duties and responsibilities as required.
Required Knowledge, Skills, and Abilities:
Knowledge of: the principles of public health administration, planning and regulation; budget management; the methods of data collection and analysis; basic management and supervisory principles and practices; problem solving techniques; correct spelling, grammar and punctuation; and WIC Program regulations and policies.
Skill in: the use of microcomputers and standard software programs; public speaking and communicating technical information at appropriate levels to different audiences.
Ability to: understand and apply applicable rules, regulations, policies, and procedures; think critically; manage financial resources; compile, organize, analyze and evaluate data; organize data into logical format for presentations, reports, and documents; develop reports, manuals, policies and procedures; develop objectives, strategies, plans and effectively implement; review and evaluate the effectiveness of plans and programs; analyze processes, identify problems and potential solutions, implement corrective actions and evaluate the results to ensure program effectiveness and efficiency; present negative findings in an effective manner; utilize problem solving techniques; provide consultation and expert advice; guide, direct and supervise staff; plan, organize, prioritize and coordinate work assignments to ensure timely completion of quality, accurate work products; communicate effectively, verbally and in writing; establish and maintain effective working relationships; and work effectively as part of a group or independently.
Qualifications:
A Master’s degree in public health nutrition, dietetics, or nutrition preferred. Registration as a dietitian as defined by the Commission on Dietetic Registration and/or licensed as a Dietitian/Nutritionist preferred. Public health and/or WIC experience at a local or state
agency preferred. At least three (4) years of professional experience in managing a program preferred. At least three (4) years of supervisory experience preferred. Budget management experience preferred.
Florida Department of Health Mission, Vision, and Values:
Mission:
To protect, promote & improve the health of all people in Florida through integrated state, county & community efforts.
Vision:
To be the Healthiest State in the Nation.
Values:
I nnovation: We search for creative solutions and manage resources wisely.
C ollaboration: We use teamwork to achieve common goals & solve problems.
A ccountability: We perform with integrity & respect.
R esponsiveness: We achieve our mission by serving our customers & engaging our partners.
E xcellence: We promote quality outcomes through learning & continuous performance improvement.
Where You Will Work:
Tallahassee, Florida
The Benefits of Working for the State of Florida:
Working for the State of Florida is more than a paycheck. The State’s total compensation package for employees features a highly competitive set of employee benefits including: | https://www.nwica.org/jobs/chief-of-medical-and-health-services-closing-november-23-2021 |
Stravinsky and the problem of mathematics
I find this bizarre. One piece of poor work does not invalidate someone's entire output. When I was at the Royal College of Music, I attended a Stravinsky Festival at the South Bank. It went on for weeks and covered Stravinsky's entire instrumental output. By the end of it I never wanted to hear another piece of Stravinsky ever again. But one of the things I learned in the course of this was that great composers are fallible. Igor Stravinsky is a great composer. The Rite of Spring is one of the greatest orchestral pieces ever written. But that doesn't mean that every piece he wrote is great. Far from it. Some of his output is frankly rubbish and should be consigned to the dust of history. And quite a bit of the rest is mediocre. There are a few wonderful pieces, and it is these that make him great - not his extensive output of potboilers, experimental sketches and dead ends.
Now suppose that, rather than sitting through every piece of instrumental music Stravinsky ever wrote, I attended a single performance that happened to be an experimental twelve-tone piece that really needs to be quietly buried. I might write an entire essay about the piece that I heard, explaining in detail exactly what is wrong with it. I might even conclude at the end of the essay that Stravinsky is a rubbish composer. I would be correct within the limits of my knowledge of Stravinsky, but incorrect in relation to Stravinsky's entire output. Would Stravinsky fans tell me that I am ignorant of music (even though I was a music student)? Would they attack my musical understanding? Perhaps - but not if they are responsible critics. Stravinsky is a great composer, but not all of his music is great. A responsible Stravinsky fan would surely say to me, "Frances, this is a poor piece by Stravinsky, but he's written some really wonderful pieces - listen to these" and send me recordings of The Rite of Spring and The Firebird.
So it is with the critics of my post. They could simply have said to me "Frances, this was not one of Milas's better efforts, but some of his other work is excellent" and sent me some links. But that's not what they did. Instead of accepting that my criticisms of his piece might be valid, they attacked my mathematical ability. Instead of informing me about Milas's better work, they accused me of saying things I did not say. They even said that since I had not done a similar piece of work myself, I was in no position to criticise. That's like saying that because I had not written a piece of twelve-tone music myself I was not in a position to criticise Stravinsky's piece. Is the educated listener unable to judge the quality of a piece of music? Clearly not. Nor is the educated reader unable to judge the quality of a piece of mathematical analysis.
Of course, to my critics I am not an "educated" reader. I did not use the right terminology, and therefore - to them - I lack understanding. Not using econometric terminology is no more an indicator of lack of understanding than not using twelve-tone terminology necessarily indicates lack of understanding of the twelve-tone system. But all too easily we mistake linguistic fluency for comprehension.
But worse, my failure to use the right language marked me as an "outsider". My principal critic was perfectly reasonable to the person who translated my post into econometric-speak, even though that person was really only repeating what I had said. Use of the right jargon is a tribal identity, a badge of "belonging": if you use our jargon you demonstrate that you are "one of us" - but if you don't use our jargon you aren't one of us, you are potentially an enemy and if you criticise one of us we will attack. Academics and econometricians are as guilty of tribal behaviour as anyone else, and my critics today demonstrated this in spades. I am neither an academic nor an econometrician, and I criticised one of their number. They went for the jugular.
My criticism of Milas's work was severe, because it was in my view a very poor piece of work: bad statistical analysis by econometricians has led to some very bad policy decisions, with serious consequences for welfare. It may be that I went too far in my criticism, since I was not familiar with his other work. And I accept that the way I presented my criticism could be interpreted as an ad hominem attack, though it was not intended in that way. But the personal attacks on me in the comments were every bit as bad, and in some cases far worse, than my comments about Milas. This was no credit to anybody. Fighting fire with fire achieves nothing. However loyal people are to the person whose work I am criticising, and however much they may disagree with me, vindictive personal attacks are always unjustified.
I made the mistake of admitting in the post that I am not confident about maths - a point that one critic explicitly used as a reason to criticise my mathematical competence. But it has dawned on me that this is ridiculous. I am no less competent in maths than I am in music. I have an MBA with a specialism in financial risk management, for heaven's sake. You don't get that without being a competent mathematician. So never, ever again will I suggest in a post that I am not confident about my mathematical ability. And never, ever again will I accept criticism of my mathematical competence from people with axes to grind.
What I will do, though, is think about how I "do" maths. In this post I have mentioned twelve-tone music, which is the most mathematical form of music. It has had an enduring fascination for composers as diverse as Schoenberg, Webern, Berio, Dallapiccola and even Benjamin Britten. Many composers, including Stravinsky, experimented with twelve-tone music but moved on beyond it, finding their own unique musical voices. And I have in the past written twelve-tone pieces myself, though I don't find it easy - it feels like a foreign language. I understand the system and the terminology, but it isn't how I "do" music. I too have had to find my own musical voice. So it is with maths. I think logically and mathematically, but standard mathematical terminology feels foreign to me. I need to find my own mathematical voice.
UPDATE. The Pieria post has now been taken down at my request, as dealing with a continual stream of adverse comments was becoming a major distraction from other work. This post will remain up though.
Related reading:
The problem of mathematics
A selection of Stravinsky's music: | https://www.coppolacomment.com/2014/01/the-stravinsky-model.html?showComment=1389122634966 |
The Hong Kong Competition Commission (Commission) is committed to fully complying with its obligations under the Personal Data (Privacy) Ordinance, Cap. 486 (“Personal Data (Privacy) Ordinance”) including all applicable data protection principles. In this context, the Commission undertakes to ensure that its staff, agents and contractors comply with the highest standards in relation to information security and data protection.
Subject to any applicable exemption provided for in the Personal Data (Privacy) Ordinance, whenever the Commission collects personal data from individuals, it will provide a Personal Information Collection Statement (“PICS”).
The personal data1 held by the Commission includes the name, organisation name, job title, correspondence address, telephone number and email address, etc. of the registrants of the Hong Kong Competition Exchange (Exchange).
Personal data held is kept for the purposes of processing the registration and handling relevant matters relating to the Exchange. In particular, the Commission may use your personal data to provide you with details of and information regarding your registration to the Exchange.
For further information in respect of the purposes for which personal data is to be used by the Commission, reference should be made to the applicable PICS.
Statistics on visitors to the Exchange website: When a person visits the Exchange website, the Commission will record their visit as a “hit”. The webserver makes a record of the visit that includes the person’s IP address, the type and configuration of browser used, language settings, geo-location, operating system used by the person, information on the site which redirected the person to the Exchange website (if any), screen resolution information, time/duration of the visit and the pages visited on the Exchange website (webserver access log).
The Commission uses the webserver access log for the purpose of maintaining and improving the Exchange website. The Commission uses the data only for website security purposes, error fixing, enhancement and optimisation purposes.
The Commission does not use website visitor data to personally identify anyone.
The Exchange website is developed and maintained by third-party service providers.
All of these external service providers are bound by a contractual duty to keep confidential any personal data they come into contact with and are prohibited from unauthorised access, use and/or retention of such data.
The Commission takes appropriate steps to protect the personal data it holds against loss, unauthorised access, use, modification or disclosure.
The Commission maintains and follows retention policies for records containing personal data to ensure personal data is not kept longer than is necessary for the fulfilment of the purposes (including any directly related purposes) for which the data is or is to be used.
Personal data collected by the Commission may be transferred and/or disclosed to third parties as provided for in the relevant PICS (if any).
Please note that the Commission may refuse to comply with a data access and/or a data correction request in the circumstances specified in section 20 and section 24 of the Personal Data (Privacy) Ordinance.
The Commission may impose a fee for complying with a data access request.
1 Personal data means personal data as defined in the Personal Data (Privacy) Ordinance. | https://hkcompex.org/privacy-policy/ |
As global population grows, agri-food systems face numerous complex challenges. These challenges are further exacerbated as accelerating global warming, and other human activities, impact upon the adaption capacity of agricultural production and ecosystems. These factors are predicted to have the most serious impact on the African continent.
In North and West Africa current farming systems face multiple challenges affecting agricultural productivity. Agronomic systems and practices have caused the large-scale degradation of soils and agro-ecosystems, which has reduced their capacity to store water and nutrients, and therefore their ability to support farming and maintain plant health.
To help address these challenges, The Natural Resources Institute Finland (Luke) is now coordinating an EU-funded project on Sustainable Intensification of food production in West & North Africa (SustInAfrica). By developing resilient and sustainable farming systems in West & North Africa SustInAfrica aims to empower smallholder farmers, small and medium-sized enterprises and various government and non-governmental organizations in Ghana, Burkina Faso, Niger, Egypt and Tunisia, to intensify food production and deliver ecosystem services in a sustainable and resilient manner.
“The project will strive to attain this by providing a comprehensive analysis of local ecosystems, in addition to offering soil, water and plant health management strategies. It will also provide business models and policies and help develop related technologies that support farmers in their decision making”, says project coordinator Nils Borchard.
CIHEAM Bari's contribution to the project will draw on previous experience acquired in assessment and analysis of sustainability, resource efficiency and rational use of natural resources in two different fields of expertise:
CIHEAM will also collaborate on training of project's stakeholders and communication of project results.
SustInAfrica consists of 16 partner organisations from 11 countries. The project started in 1.9.2020 and will continue for five years. Funding for the project comes from European Union’s Horizon 2020 program. | http://www.iamb.it/it/news_and_events/one?event=agriculture-for-food-and-nature-sustainable-intensification-of-african-farming-systems-in-north-and-west-africa&id=494 |
The host revealed that a plan had been proposed to the Olympic Council of Asia outlining 28 sports, 12 less than the 26th Games in Indonesia last November.
According to U Khin Maung Lwin, joint general secretary of the Myanmar Olympic Committee, they had selected sports that played to their strengths and were in keeping with their culture.
Lwin said he would present a comprehensive plan to the participating countries at a meeting at the end of April in Indonesia.
As host of the Games, Myanmar has the right to propose the number of sports and include national favourites. However, it also has to ensure the inclusion of two basic events in track-and-field and aquatic sports.
Gymnastics, an event Myanmar is weak in but one in which Viet Nam won 11 gold medals last year, along with beach volleyball and dance sport will be among those axed.
What do you want to play?
27th SEA Games sports: track-and-field, aquatic sports, archery, badminton, basketball, billiards and snooker, boxing, canoeing and rowing, cycling, football, golf, hockey, judo, karate, sepak takraw, shooting, table tennis, taekwondo, indoor volleyball, weightlifting, wushu, tennis, chess, bodybuilding, petanque, traditional boat racing and yatching. | http://vietnamnews.vn/sports/222616/myanmar-competition-to-have-less-events-than-in-other-years.html |
[Exploration of factors increasing transfer efficiency of retroviral mediated multidrug resistance gene (mdr1) into human CD(34)(+) cells].
To explore factors influencing transfer of retroviral mediated multidrug resistance gene (mdr1) into human CD(34)(+) cells. Transduction efficiency in the presence of different combinations of cytokines and human bone marrow stromal cells plus cytokines were determined by flow cytometry (FCM). Drug resistance was evaluated by plating yields of cultured hematopoietic progenitor cells. The effect of Taxol at different concentrations on mdr1 gene transfer cells was determined by FCM. Transduction efficiency in the presence of SCF + FL + IL-3 was higher than that in other combinations of cytokines (SCF + IL-6 + IL-3, SCF + IL-6 + IL-3 + Tpo, SCF + IL-3). Transduction efficiency (20.5%) in the presence of bone marrow stromal cells plus cytokines (SCF + FL + IL-3) was higher than that (15.2%) without stromal cells, and the number of drug-resistant colony-forming cells was more in the former than in the latter. The percentage of CD(34)(+) cell with the gene transduction at 10 ng/ml Taxol reached 38.5%. Human bone marrow stromal cells plus cytokines (SCF + FL + IL-3) is more effective in enhancing mdr1 gene transduction. Taxol at a certain concentration can enrich mdr1 gene transferred cells.
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Luxor, the historic city of Thebes, lies in southern Egypt and is called Upper Egypt by the ancient Egyptians because it lies closer to the source of the Nile River. Luxor is, apart from the Pyramids of Giza outside of Cairo, the heart of the Egyptian tourism industry, with incredible amounts of history found — quite literally just a hundred or so years ago — within a handful of miles from the city center. Luxor is also the place where you tend to fly in to catch a boat for the ever-popular Nile cruises.
When I first looked at Luxor as the setting-off point for my Nile cruise, I was utterly amazed by just how many important archeological sites are on both sides of the river, if more so on the West Bank, where you find the Valley of the Kings, among others. What a place this must have been not just 3,000 years ago, but also in the 1920s when all these treasures were being discovered. Even today, the excavations continue, with more and more important sites being discovered every day.
Luxor itself is an interesting city, with the Luxor Temple, the traditional souk, and the Nile Promenade in the heart of the city, but it is mostly used as a base to head on day trips across the Nile to see the archeological sites. I spent several days there, taking it easy, as it can be very hot indeed, and the valleys are a forbidding place when it’s hot. Here I have collected my favorite things to experience in Luxor, Egypt.
1. Exploring Luxor Temple
Luxor Temple was, after the pyramids and the Sphinx, the first ancient Egyptian temple I saw. Sitting right by the Nile, it was beautifully lit up at night and I spotted it from the taxi on the way to my hotel. Needless to say, this was the first stop for my explorations in and around the city the following day. Entering right opposite the old souk, the temple, constructed over centuries by Amenhotep III, Ramses II, Tutankhamun, and other pharaohs, was once the largest and most significant religious center in ancient Egypt. Compared to others you will see along the Nile, it is, in my mind, not the most impressive, but what is utterly outstanding and stunning is its Avenue of the Sphinxes: 1.5 miles of avenue connecting Luxor Temple with Karnak Temple, flanked by what was thought to have been around 1,350 statues of sphinxes. Further on, you’ll see rams, all sitting at attention. Today, not all have been found and the restoration is still ongoing, but standing there, looking down the avenue, is one of the most exhilarating experiences in Luxor.
2. Lightshow At Karnak Temple
Standing at the end of the Avenue of Sphinxes is Karnak Temples, famous for being the backdrop for one of the scenes in the James Bond film The Spy Who Loved Me. You know, the temple with the enormously tall columns, set during a light show at night? That one. The temple is wonderful, a huge complex, and one fun way of experiencing it, with a bit of film nostalgia thrown in, is during the nighttime light show. You get to go on a guided walk, hearing about the history of the temple and its various pharaohs. End the walk sitting by the lake, with perfect reflections of the temple on the water, listening to music and stories of the past with Luxor glittering in the background.
3. Ballooning At Sunrise
Getting up at 4 a.m. is not my favorite thing, I’ll tell you that much, but for a sunrise balloon flight on the other side of the Nile, there is no other option. Being picked up at the hotel, taking a small ferry across the Nile, and then arriving at a field where 20-odd hot air balloons are in various states of inflation is still quite magical. But taking off, with the sun rising on the East Bank, the green field of the Nile below you, and colorful balloons all around you is more than magical. Watching the countless temples, tombs, and valleys below, the Nile with its sharp demarcation between green fields and bleak, sandy desert, the villages waking up, and people riding their donkeys is simply wonderful. For an hour, we flew, not straying far, but there was so much to see. We landed right next to a dig site, scattering archeologists who were not happy, but obviously quite accustomed to the morning spectacle.
4. Valley Of The Kings
This is what we all come to Luxor for: tombs of pharaohs that are so incredibly and beautifully decorated, and preserved yet are thousands of years old. I cannot even begin to describe to you what wonders you will see. Navigating at times very steep stairs down into stifling hot tombs is worth it, and I have seen little old ladies taking on the task and yet loving every minute. Take it slowly if you have rickety knees or wobbly feet, and you will be rewarded. Richly. There are more than 60 tombs in this stark valley with no vegetation, but only a few are open to the public. Of those, each and every one is worth seeing, and three are included in your normal entry tickets. Pay extra to see the tombs of Ramses V & VI (KV9), Seti I (KV17), and not forgetting Tutankhamun (KV62). Do not miss these, and if pushed for time, forget the others, and just pay extra and see these. You will not regret it.
5. Valley Of The Queens And The Mortuary Temple Of Hatshepsut
The Valley of the Queens is the counterpart of the Valley of the Kings, with some 90-odd tombs on the site. However, only a few are worthwhile stopping off for, with the tomb of Nefertari, wife of Ramses II, the most notable. A word of advice — try, if you can, to view these before you head to the Valley of the Kings, because after all the splendor there, these are not half as glamorous. But still worth your while.
Next to the Valley of the Queens stands the imposing Temple of Hatshepsut, one of the very few, and best-known female pharaohs. She is revered for being one of the most successful pharaohs, ruled for over 15 years, and was known to be quite the builder of temples and cities.
6. The Tombs Of The Nobles
Near the Colossi of Memnon, which sits by the side of the road, and makes for a perfect selfie-spot on the way to the Valley of the Kings. You will see countless holes in the ground, in the hillside, everywhere. These are the Tombs of the Nobles, tombs of people with influence, in ancient Egypt, but not royal. More than 415 have been found, and more are being unearthed continuously. If you just visit one, make it the Tomb of Ramose and then stop off at the small artisan study and shop outside. Here, two craftsmen fashion sculptures and pictures in the old traditional way, and their skill is magnificent to watch. Their work makes for worthwhile souvenirs, too.
7. The Village Of The Artisans, Deir-El-Medina
This site is often overlooked on tours that concentrate on the tombs and temples of the pharaohs, yet this village is where all the artisans lived, those craftsmen who decorated the magnificent tombs. Here are the remains of the village, from where they climbed across the mountain ridge into the Valley of the Kings, together with some open tombs of the artisans themselves.
8. Stay At The Sofitel Winter Palace Luxor
The Winter Palace is the historic hotel where all the dignitaries and, more importantly, where the archeologists who discovered the treasures on the West Bank stayed in their day. It is a little shabby around the edges but eminently charming, and the garden is simply to die for. The large pool is heaven-sent after a day looking at tombs in dusty valleys.
9. Eat At Sofra
For some authentic Egyptian food away from your hotel or cruise ship, head straight to Sofra Restaurant. Just off the bustling El-Mansheya Street, which, at night is full of food stalls selling sweets, super-sized chapati breads, ready-to-eat dishes to take away, and fresh juices. In a quiet side street lies this lovely restaurant where you can sit on the open terrace on the upper floor and sample local dishes without having to try and eat as you navigate the traffic. Clean, nicely decorated, and with friendly waiters who can suggest dishes to you in halting English, this is a great place to sit after a long day’s sightseeing. Try the Khiyar Bil Zabadi, the local version of Tzatziki, the hummus, and the Salata Baladi for starters. If you are not averse to trying local specialties, try the pigeon, or the rabbit for mains, all washed down with fresh melon or pomegranate juice.
Pro Tip: The most important piece of advice I can give is to spend a few days in Luxor. So many people fly in, catch their cruise ship, and head off after a quick look at the Valley of the Kings, but there is much to keep you occupied. So please, stay awhile.
The Egyptian archeological sites have always been a huge attraction for visitors: | https://www.travelawaits.com/2720206/luxor-egypt-best-things-to-do/ |
Company:
US3063 Sygma Pennsylvania, a Division of The Sygma Network, Inc
Zip Code:
17110
Minimum Level of Education:
Bachelor’s Degree
Minimum Years of Experience:
2 Years
Employment Type:
Full Time
Travel Percentage:
OVERVIEW:
We offer our associates the opportunity to grow personally and professionally, to contribute to the success of a dynamic organization, and to serve others in a manner that exceeds their expectations. We’re looking for talented, hard-working individuals to join our team. Come grow with us and let us show you why Sysco is at the heart of food and service.
JOB SUMMARY
Update, monitor and continue the development of company safety policies, procedures, and training programs for new and existing Occupational Safety and Health Administration (OSHA)and Department of Transportation (DOT) issues. Handle all worker's compensation and auto liability claims to completion at the lowest cost and lost time days without jeopardizing the best possible services available.PRIMARY DUTIES
Accept responsibility for the development, enhancement, implementation, and success of the safety program
Continually monitor the safety program and to submit appropriate reports to management on a timely basis
Maintain accident records, according to the Occupational Safety and Health Administration (OSHA)
and the Department of Transportation (DOT) guidelines
Analyze past and current losses for the purpose of prioritizing and directing safety training requirements
Direct and assist in the development and writing of preferred work methods
Direct and assist in the development and implementation of work practice observation methods and checklists
Direct and assist in the development and implementation of safety awareness training for warehouse and transportation supervisors and employees
Direct and assist in the development of Personal Protective Equipment (PPE) programs and to select such equipment as necessary to meet the needs of the program
Direct and attend quarterly manager/supervisor safety activities meetings and to assist in the evaluation and direction of the program through the following actions:
setting goals
evaluating the commitment of managers and supervisors
training of managers & supervisors as needed
Direct and conduct monthly joint Safety Committee meetings comprised of employees and management and assist in the evaluation and direction of the program through the following actions:
oversee and evaluate, on an ongoing basis, the effectiveness of the sub-committees within the Safety Committee
recommend changes and/or additions to the sub-committees, as needed, to meet the company’s ongoing safety needs
Direct and assist in the development and administration of the safety orientation of new or current employees and the safety training and safe work practices that are in place or developed as a result of the program
Direct and assist in the development and implementation of compliance programs such as those required by DOT, EPA, OSHA, FDA, and any state-mandated programs
Evaluate and assist in the quarterly safety inspections completed by the OSHA Warehouse Inspection Committee and the OSHA Driver Equipment Inspection Committee, both sub-committees within Safety Committee meetings
Direct and oversee the current Accident Investigation Committee meetings and report results and recommendations at the monthly Safety Committee meeting
Keep all management, supervisors, and employees informed of all current and ongoing safety activities, including the implementation of SYGMA Safe
QUALIFICATIONSEducationAn Undergraduate degree in Occupational Safety
Experience
2-5 years of experience with safety regulations such as OSHA, DOT, and FDA is required.Physical DemandsWork is primarily sedentary in nature. You must be able to verbally communicate effectively, either by telephone, or one-on-one.Mental/Visual DemandsYou must be able to read text that is close and at a distance with or without correction. In addition, you must be able to perform manual tasks, hear, sit, reach, lift, bend, and interact with others.Working ConditionsMost of the day is spent in an office environment.Equipment OperatedA calculator, copier, facsimile machine, PC, Word, Excel, forklift, pallet jack, and hand cart.
License or CertificationsValid driver’s license and forklift certification.
Applicants must be currently authorized to work in the United States.
We are proud to be an Equal Opportunity and Affirmative Action employer, and considers qualified applicants without regard to race, color, creed, religion, ancestry, national origin, sex, sexual orientation, gender identity, age, disability, veteran status or any other protected factor under federal, state or local law.
This opportunity is available through Sysco Corporation, its subsidiaries and affiliates. | https://sysco.jobs/harrisburg-pa/mgr-safety/B7768DBE9F894AA2BC9E0F56AA2568A8/job/?vs=28 |
Our Atlanta Pediatric Malpractice Lawyer Outlines the Duty of Care to Children
As in other states, all doctors and other healthcare providers owe a duty of care in Georgia. This means that they must treat their child patients according to the standards established by the medical community. If the quality of a pediatrician’s or other provider’s care falls below these standards, then this justifies a claim for pediatric malpractice.
As a parent, it can be hard to know whether a doctor’s diagnosis or treatment constitutes malpractice. If your pediatrician has been practicing medicine for years (or decades), you might be inclined to give him or her the benefit of the doubt. But, the reality is that doctors make mistakes, and it only takes one mistake to cause a lifetime of consequences.
There are Many Forms of Pediatric Malpractice
Like all forms of medical malpractice, pediatric malpractice can take many different forms. Diagnostic mistakes and treatment mistakes are both alarmingly common, as are administrative errors and other types of errors that can lead to child patients receiving improper, unnecessary, or substandard care. Some of the most common forms of pediatric malpractice include:
- Misdiagnosing common childhood conditions such as appendicitis, bone fractures, meningitis, and pneumonia
- Misdiagnosing less-common childhood conditions such as cerebral palsy, hypoxic-ischemic encephalopathy (HIE) and cancers
- Failing to properly treat birth injuries diagnosed during pregnancy or after delivery
- Failing to diagnose allergies, infections, sepsis and other potentially dangerous health conditions
- Failing to monitor child patients and detect allergic reactions or other negative health outcomes
- Delayed diagnosis of health conditions that get worse due to untimely treatment
- Prescribing incorrect or unnecessary medications, or prescribing medications in the wrong dosages or quantities
- Surgical errors during appendectomies and other procedures
- Treatment errors that result in permanent disability or disfigurement (such as failure to set a broken bone properly)
- Recordkeeping errors that result in patient mix-ups, wrong-site surgeries and other medical mistakes
Again, these are just some of the most common examples. There are many different forms of pediatric malpractice that can lead to significant, long-term, permanent, or even fatal consequences. If you have any reason to suspect that your child’s healthcare provider has made any type of mistake, we encourage you to schedule a free consultation with one of our attorneys promptly.
What To Do (and Not Do) If You Suspect Pediatric Malpractice
If you suspect that your child has suffered due to a medical mistake, it can be difficult to know where to turn for help. But, help is available, and making the right decisions now can improve your child’s chances of recovery while also helping to protect your family’s legal right to just compensation with offices in Atlanta, Alpharetta, and Cumming for your convenience. With this in mind, here is what to do (and not do) if you suspect pediatric malpractice:
Seek Treatment for Your Child from Another Healthcare Provider
If you suspect pediatric malpractice, you need to ensure that your child receives professional medical care. At this point, this means seeing another healthcare provider. If your pediatrician has his or her own practice, you can choose another local pediatrician or take your child to the hospital. If your child was receiving treatment at a hospital, then you will want to go to another facility—not just another doctor at the same hospital.
Do Not Let Your Doctor’s Office Talk You Out of Seeking Help
Some doctors will try to talk families out of seeking help when they make mistakes. This might be because they sincerely believe that they can correct their mistakes, or it might be because they don’t want to face liability for pediatric malpractice. Regardless, right now, you need to do what is best for your child and your family, which means seeking help from other professionals.
Keep All of Your Child’s Medical Records
Be sure to keep all of your child’s medical records that you currently have. Put them in a file, and keep the file in a safe place until you can share it with your attorney.
Talk to an Atlanta Pediatric Malpractice Attorney
To recover financial compensation for pediatric malpractice, you will need to hire an attorney experienced in handling child injury claims against medical providers and their insurers. We have helped many families recover financial compensation, and we can use our experience to help you recover the compensation your family deserves.
Losses Your Family Can Recover After Pediatric Malpractice
In pediatric malpractice cases, families can recover compensation for the financial and non-financial costs of their providers’ mistakes. These costs can add up quickly, and, in many cases, they can continue to add up for the rest of the child’s life. When you choose our firm to represent you, our lawyers will seek to recover maximum compensation for your family’s losses, including your:
- Medical bills
- Costs for prescriptions, medical supplies and medical devices
- Costs for home and vehicle modifications
- Loss of income and benefits (including future earning capacity)
- Pain and suffering
- Emotional trauma
- Loss of companionship, services and support
- Loss of enjoyment of life
Speak With an Atlanta Pediatric Malpractice Attorney for Free
If you have questions about your family’s legal rights and would like to speak with an Atlanta pediatric malpractice attorney, we encourage you to get in touch. To schedule a free, no-obligation consultation at Gilormo Injury Law, call 770-343-7101 or contact us online today with locations in Atlanta including Alpharetta and Cumming. | https://www.ginjurylaw.com/practices/child-injuries/atlanta-pediatric-malpractice-attorney/ |
Thursday, 7 February 2013
The Human Brain Project aims to give us a computer simulation of the human brain, or at least to work towards that goal. Plenty of people are sceptical about the feasibility of the project. But there are also ethical questions. Some of them are mentioned on the project's website, here:
The issues mentioned relate to what people might do, among, with and to other human beings, having learnt in detail how real human brains worked. Even if the simulation did not, at the neuronal level, work in the same way that actual brains worked, it could still mimic the brain at a larger scale, for example the level of processing ideas, in ways that would, for example, help political propagandists to work more effectively.
There is, however, another issue, related to the simulation itself. What, if anything, would make the simulation a moral client, so that ethical concerns would bear on a decision to modify its thoughts by direct intervention (rather than by talking to it and inviting it to accept or reject some new idea), or would bear on a decision to switch it off?
It would not, we may assume, have a power of action, or a power to move around the world. One might therefore argue that it would not have a well-grounded sense of self (compare some of the arguments in Lucy O'Brien's book, Self-Knowing Agents). But it could still have the internal configuration that would correspond to a sense of self, a configuration that was artificially engineered by the researchers, as if it had had a history of action. I assume here that such a sense could be retained, and would not be lost over a long period without action, just as a human being who became totally paralysed and immobile could retain a sense of self. The artificial brain would, however, need to think of itself as one who had become paralysed, or would have to be fed the delusion that it was in an active body in the world, or would have to remain puzzled about its sense of self. Given the nature of the project, it is most likely that the artificial brain would be fed the delusion of being in an active body.
Likewise, the artificial brain could have artificially engineered senses of pain and of fear, like those that were appropriate to a being which moved around in the world and needed to act to distance itself from dangers, and that had been evolved in the species, or developed in the individual, through encounters with dangers.
The sense of self, and the feelings, would have dubious provenance. If we were to think that such senses were given their content by the external reality that grounded them - a kind of meaning externalism - we would have to think of them as not having the content that they had for us. That might let us off recognizing the artificial brain as a moral client, but it seems unlikely that it would do so. Even a convinced meaning externalist would, after all, hesitate to turn off the nutrients that fed human brains which had been put in vats years ago, and had been plugged into the usual delusive inputs for long enough for the presumably externally grounded meanings of their thoughts to have changed.
Moreover, while the sense of self might be based on a fabrication, it is not clear that the sense of self would itself be unreal. It would be even harder to show that the artificial brain's theory of mind, used in its encounters with people, was unreal. And the researchers would be very likely to apply their own theories of mind and intentional stances to the artificial brain. At least, some of them would, entering into social relationships that would, between human beings, stimulate moral concern, while other researchers measured the results in order to understand how real human brains behaved in encounters with other people. Possession of a theory of mind looks like something that ought to make the possessor a moral client. It has certainly been argued to have that consequence in relation to great apes other than human beings, although the extent to which they really have a theory of mind is controversial.
On the other side, there would be arguments that the simulation would just be a large piece of software, that it was not even fully integrated into a single person because it was shared between several computers (although this might reduce the accuracy of the simulation, because large-scale co-ordinating electrical activity does seem to matter to consciousness), and that it would not even know if it were modified, slowed down or turned off - although modifications, and processing speed adjustments, would have to be made carefully in order not to leave traces of the old state or speed that would give the game away.
The software point has strength if we think that when an entity is not intrinsically dependent on its hardware, that makes it less of a moral client. We are intrinsically dependent on our hardware, or at least, we are now, and will remain so until we work out how to copy the contents of a brain onto some computer-readable medium. Even then, it would matter which body someone was, and what the history of that body had been; that degree of hardware-dependence would remain.
The point about lack of awareness of changes needs to be elaborated. It is utterly wrong suddenly to kill someone, even without their knowledge or any kind of anticipation. It is also wrong to manipulate people's thoughts or attitudes, in the way that politicians, spin-doctors and the advertisers of products do, without people's awareness of what is going on, rather than using open and rational argument. If it were to be acceptable to turn off an artificial brain, the reason would have to go beyond its own lack of anticipation of this fate. It would be likely to have something to do with the fact that a piece of software would not have existed within a caring community. It would have had no relatives to mourn it, and it would never have had a potential beyond what its creators had planned for it. (It would have had a potential beyond what its creators had coded: one of the features of neural nets is that they develop in their own way.) But that move in the argument is dubious, because the question is that of whether the software should have been surrounded by a caring community, one that regarded it as a moral client. Something similar could be said about the far lesser offence of manipulation. This might look acceptable, because the software would only ever have had the potential that its creators had planned. But whether that ought to have given them ownership of its mind is the point at issue.
I remain unclear as to whether a full simulated brain should be regarded as a moral client. I predict that if its creators did not so regard it, the rest of us would not reprove them. But they might reprove themselves for turning it off, and then comfort themselves with the thought that they had kept the final software configuration, so that it could be re-awoken at any time.
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New in bag with tags. Never worn. I ended up buying another dress that fit my body better. I have it in a water proof David’s Bridal bag that is fully enclosed. It has never been altered or tampered with. Price may be negotiable.
- Alterations: None
- Preservation Method: Stored in water proof David's Bridal garment bag.
- Terms of Sale: All Sales Final
- Original Owner: Yes
- Has Original Receipt: Yes
- Location: mountain home, ID
- Will Ship to: Anywhere at Buyer Expense
- Payment Methods Accepted: Other
Please read our BUYER'S GUIDE before purchasing a dress online. | http://www.oncewed.com/used-wedding-dresses/v3330-3/ |
The present invention relates to control systems for controlling motor speed.
US 5,828,014
relates to an elevator speed control that suppresses vibration in the speed control of a multi-inertial system.
WO 01/90472 A
describes a method and system for controlling rotation of a washing machine tube.
FIG. 7
A known motor speed control system is shown in and generally includes an encoder 102 for detecting the rotational speed of a motor 101, a frequency/voltage converter 103 for converting an output signal from the encoder 102 into a voltage signal V that represents the rotational speed, and a setting unit 104 that can output voltage signal Vs corresponding to a set value of the rotational speed.
The encoder 102 is configured to output a pulse generation signal at each time that the motor 101 has rotated by a predetermined angle. The frequency/voltage converter 103 generates a pulse having a pulse width at each time that the pulse generation signal is produced at the encoder 102. Therefore, the frequency/voltage converter 103 produces a series of pulses. The converter 103 includes a smoothing circuit that converts a series of pulses into a voltage value corresponding to the pulse density. Thus, as the rotational speed of the motor 101 increases or decreases, the pulse density may be increased or decreased. Therefore, the voltage signal V. after being smoothed by the smoothing circuit varies in proportion to the rotational speed of the motor 101.
Then, a comparator 105 compares the voltage signal V (i.e., the output signal from the frequency/voltage converter 103) corresponding to the rotational speed of the motor 101 with the voltage signal Vs corresponding to the set rotational speed of the motor 101. Subsequently, a controller 106 controls the supply of power to the motor 101 such that the difference (Vs - V) between the voltage signal V and the voltage signal Vs is decreased.
However, because the frequency/voltage converter 103 of the known system 100 converts a series of pulses into the voltage corresponding to the pulse density by means of the smoothing circuit, delay in transmission of signal may occur due to the smoothing circuit. Therefore, it is necessary to provide additional circuit for compensating for the delay in phase caused by the smoothing circuit, resulting in increase of the cost of the control system 100. In addition, even if the compensation has been made, it is likely that the usable speed range is limited. Further, even if a small-bit low cost microcomputer (such as 8-bit to 16-bit microcomputers) is included for digitalizing the analogue value, it is difficult to obtain a voltage signal V in a desired accuracy from the smoothing circuit.
Japanese laid-Open Patent Publication No. 63-213485
FIG. 6(A)
In order to solve this problem, has proposed to control the rotational speed of the motor without using the smoothing circuit. A speed control system disclosed in this publication is shown in and is labeled with reference numeral 120. According to this speed control system 120, a time T between pulse signals (i.e., a pulse interval T) from the encoder 102 is determined by a timer counter 123. Then, a count value C corresponding to the determined pulse interval T is compared with a count value C3 corresponding to a pulse interval Ts (i.e., a set value Ts), and subsequently, a controller 106 controls the power supplied to the motor 101 such that a difference (Cs - C) decreases.
Here, the pulse interval T decreases as the rotational speed of the motor 101 increases, and the pulse interval T increases as the rotational speed of the motor 101 decreases. Thus, the pulse interval T is inversely proportional to the rotational speed of the motor 101. Because the speed control of the motor 101 is performed using the count value C corresponding to the pulse interval T as it is, without using the inverse number of the pulse interval, it is possible to use a small-bit microcomputer.
However, according to the speed control system 120, a timer counter 123 counts the pulse interval T of the pulse signals from the encoder 102 based on a fixed oscillating frequency t. For example, if the motor 101 rotates at a speed of 100 rps, and the encoder 102 generates one pulse per revolution, a pulse interval T1 in this case is calculated to be 1/100 (seconds) (T1 = 1/100). Therefore, if the timer counter 123 counts using a time interval t (t = 16 u s/count), the count value C of the timer counter 123 is calculated to be 625 (C = T1/t). On the other hand, if the motor 101 rotates at a high speed, for example at a speed of 650 rps, a pulse interval T2 in this case is calculated to be 1/650 (seconds) (T2 = 1/650), and the count value C of the timer counter 123 is calculated to be 96 counts (C = T2/t). Then, the count value C of the timer counter 123 is compared with the count value Cs corresponding to the set value Ts (Cs = Ts/t).
In the case that the set rotational speed Ns of the motor 101 has been decreased by 4% when the rotational speed N of the motor 101 is high (N = 650 rps, C = 96 counts), the set rotational speed Ns is 624 rps (Ns = N - 0.04N = 650 - 0.04*650 = 624). If the set rotational speed Ns is 624 rps, the set value Ts is 1/624 (seconds), and the counted value Cs of the counter C (C = Ts/t) is 100. Thus, the difference between (Cs - C) is calculated as "(Cs - C) = (Ts/T) - (Ts/t) = 100 - 96 = 4".
On the other hand, in the case that the set rotational speed Ns of the motor 101 has been decreased by 4% when the rotational speed N of the motor 101 is low (N = 100 rps, C = 625 counts), the set rotational speed Ns is 96 rps (Ns = N - 0.04N = 100 - 0.04*100 = 96). If the set rotational speed Ns is 96 rps, the set value Ts is 1/96 (seconds), and the counted value Cs of the counter C (C = Ts/t) is 651. Thus, the difference between (Cs - C) is calculated as "(Cs - C) = (Ts/T) - (Ts/t) = 651 - 625 = 26."
Therefore, although the reduction ratio or the deviation ratio is 4 % both in the cases of the high rotation and the low rotation of the motor 120, the difference in counts (Cs - C) is largely different between the cases of the high rotation and the low rotation. Thus, even if the deviation ratio is the same, the difference in counts (Cs - C) is large in the case of the low speed operation while the difference- is small in the case of the high speed operation. Therefore, it is not possible to properly accurately perform the control over the low speed operation and the high speed operation.
Thus, there is a need in the art for a motor speed control systems that can properly perform a motor speed control with the same accuracy over the low speed rotation and the high speed rotation.
One aspect according to the present invention includes a motor speed control system having a pulse outputting device, a pulse interval determining device, a comparative value calculating device, a set value calculating device and a controller. The pulse outputting device outputs a pulse at each time a motor rotates by a predetermined angle. The pulse interval determining device determines a pulse interval between the pulses outputted from the pulse outputting device. The comparative value calculating device obtains a comparative value as the product of a first value and a second value. The first value corresponds to the pulse interval determined by the pulse interval determining device. The second value corresponds to a set rotational speed of the motor. The set value calculating device obtains a set value as the product of a third value and the second value. The third value corresponds to the pulse interval obtained when the motor rotates at the set rotational speed. The controller controls a supply of power to the motor such that a difference between the set value and the comparative value decreases.
As described above, the comparative value calculating device obtains the comparative value as the product of the first value corresponding to the pulse interval determined by the pulse interval determining device and the second value corresponds to the set rotational speed of the motor. Here, the first value is proportional to the inverse number of the rotational speed, i.e., the actual rotational speed N. The inverse number can be expressed as 1/N (N: actual rotational speed). Therefore, the first value decreases as the actual rotational speed N increases, and the first value increases as the actual rotational speed N decreases. The second value can be expressed as K*Ns (Ns: set rotational speed of the motor, K: constant value). Therefore, the comparative value can be expressed as "K*Ns*(1/N) = K*(Ns/N)."
The set value calculating device obtains the set value as the product of the second value (K*Ns) and the third value. The third value corresponds to the pulse interval obtained when the motor rotates at the set rotational speed and the third value is proportional to 1/Ns. Therefore, the set value can be expressed as "K*Ns*(1/Ns) = K." As a result, the set value does not change even if the set rotational speed Ns has been changed over a range between the low speed and the high speed.
Because the comparative value is expressed as "K*(Ns/N), the comparative value is equal to the set value K if the actual rotational speed N is the same as the set rotational speed Ns. Therefore, the difference between the comparative value and the set value becomes zero.
For example, if the set rotational speed Ns has been lowered by 4 % when the motor rotates at the actual rotational speed N, the resulted rotational speed Ns is calculated as "Ns = N - 0.04 N = 0.96*N. Therefore, the comparative value K is calculated as "K*(Ns/N) = 0.96*K." On the contrary, if the set rotational speed Ns has been increased by 4 %, the resulted set rotational speed Ns is calculated as "Ns = N + 0.04N = 1.04*N. Therefore, the comparative value K is calculated as "K*(Ns/N) = 1.04*K.
In this way, the comparative value changes with change of the speed change ratio but does not always change with the rotational speed of the motor. Thus, if the speed change ratio is the same, the comparative value will not be changed in either the case that the set rotational speed has been changed when the motor rotates at a low speed or the case that the set rotational speed has been changed when the motor rotates at a high speed. Thus, if the speed change ratio is the same, the difference between the comparative value and the set value is the same. Then, the controller adjusts the supply of power to the motor in order to decrease the difference.
In summary, the value that corresponds to the pulse interval determined by the pulse interval determining device and that is proportional to 1/N is directly used for control. No calculation is made to calculate the rotational speed of the motor from the inverse number of the pulse interval. Therefore, it is possible to use a small-bit microcomputer, such as 8-bit to 16-bit microcomputers, in order to control the motor speed.
In addition, because the set value K is constant independent of the change of the set rotational speed over a range between the low speed and the high speed, it is possible to perform a control like a constant value control. Further, the difference between the comparative value and the set value has a fixed value as long as the speed change ratio does not change. Therefore, it is possible to properly perform the speed control device with the same accuracy over the range between the high speed rotation and the low speed rotation.
FIG. 1
is a block diagram showing a representative motor speed control system according to the present invention;
FIG. 2
is a schematic diagram of a controller;
FIG. 3
is an explanatory view illustrating the principle of operation of a pulse interval determining device;
FIG. 4(A)
is a schematic circuit diagram of a motor drive circuit;
FIG. 4(B)
is an explanatory view illustrating a gate pulse adjuster,
FIG. 5
is a schematic perspective view of an encoder,
FIG. 6(A)
is a schematic block diagram of a known motor speed control system;
FIG. 6(B)
is a schematic view illustrating how a pulse interval is determined by the known system; and
FIG. 7
is a block diagram of another known control system.
Additional objects, features, and advantages, of the present invention will be readily understood after reading the following detailed description together with the claims and the accompanying drawings, in which:
Each of the additional features and teachings disclosed above and below may be utilized separately or in conjunction with other features and teachings to provide improved motor speed control systems. Representative examples of the present invention, which examples utilize many of these additional features and teachings both separately and in conjunction with one another, will now be described in detail with reference to the attached drawings. This detailed description is merely intended to teach a person of skill in the art further details for practicing preferred aspects of the present teachings and is not intended to limit the scope of the invention. Only the claims define the scope of the claimed invention. Therefore, combinations of features and steps disclosed in the following detailed description may not be necessary to practice the invention in the broadest sense, and are instead taught merely to particularly describe representative examples of the invention. Moreover, various features of the representative examples and the dependent claims may be combined in ways that are not specifically enumerated in order to provide additional useful embodiments of the present teachings.
FIGS. 1 to 5
An embodiment according to the present invention will now be described with reference to .
FIG. 1
As shown in , a representative motor speed control system 10 can include an encoder 12, a pulse interval determining device 14, a calculating device for a comparative value, a setting device 18 and a controller 20.
FIG. 5
As schematically shown in , the encoder 12 includes a disk 12e that rotates with a rotational shaft 11b of a motor 11, a plurality of magnets 12m embedded into the outer peripheral surface of the disk 12e, and a pick-up coil 12c that is disposed proximally to the outer peripheral surface of the disk 12e in order to detect the magnetic fluxes of the magnets 12m. The magnets 12m are spaced equally from each other in the circumferential direction of the disk 12e and are arranged such that either of the magnets 12m passes through a position proximally to the pick-up coil 12c as the motor 11 rotates at a predetermined angle. As each magnet 12m passes through the position proximally to the pick-up coil 12c, a voltage is produced at the pick-up coil 12c by the electromagnetic induction. In other words, a voltage is produced at the pick-up coil 12c at each time the motor 11 has rotated by the predetermined angle, so that the encoder 12 outputs a pulse signal based on the voltage produced at the pick-up coil 12c. In this way, the encoder 12 serves as a pulse signal generating device.
As described above, a pulse is outputted each time the motor 11 has rotates. The time interval between two successive pulses (hereinafter called pulse interval T) decreases as the rotational speed of the motor 11 increases. On the other hand, the pulse interval T increases as the rotational speed of the motor 11 decreases.
FIG. 1
µ
Referring to , the pulse interval determining device 14 determines a pulse interval T of the pulse signal generated by the encoder 12. The pulse interval determining device 14 includes a timer counter that is operable to count a number of predetermined oscillation periods t from the start of each pulse to the start of the next pulse in order to obtain a count number C. Then, the pulse interval T is calculated, because the count number C and the pulse interval T have the relation expressed as "C = T/t;' Therefore, the count number C is a value that represents the pulse interval T. In this embodiment, the oscillation period t of the timer counter is set to be 16 s.
The calculating device 16 calculates a comparative value D by multiplying the count number C for the pulse interval T by a value Nsc that represents the set rotational speed Ns of the motor 11.
8
In this embodiment, the set rotational speed Ns of the motor 11 is variable within a range between 0 to 100 % by the operation of a volume resistor 16b. For example, in this embodiment, the set rotational speed Ns is zero rps (Ns = 0) when the volume resistor 16b is adjusted to 0 %. The set rotational speed Ns is 510 rps (Ns = 510) when the volume resistor 16b is adjusted to 100 %. In order to obtain the value Nsc, the output signal from the volume resistor 16b, which is an analogue signal, is converted into a digital signal by an A/D converter 16t that may be a 8-bit A/D converter. Therefore, in the case that the set rotational speed is zero rps (Ns = 0) and the volume resistor 16b is adjusted to 0 %, the value Nsc that is an output from the A/D converter 16t is zero. In the case that the set rotational speed is 510 rps (Ns = 510) and the volume resistor 16b is adjusted to 100 %, the value Nsc or the output value from the A/D converter 16t is 255 (= 2 - 1). Thus, the value Nsc can be calculated by the expression "Nsc = (355/510)*Ns = 0.5Ns."
Therefore, the comparative value D is obtained by the expression "D = NSc*C. The volume resistor 16b may serve as an operation device for varying the set rotational speed Ns.
The setting device 18 serves to calculate a set value K that is obtained by multiplying the pulse interval Ts that may result when the motor 11 rotates at the set rotational speed Ns, by the value Nsc corresponding to the set rotational speed Ns of the motor 11.
Here, the pulse interval Ts that may result when the motor 11 rotates at a set rotational speed Ns is obtained by the expression "Ts = (1/Ns)/e (seconds)." The value e is the number of pulses that is generated by the encoder 12 during one revolution of the motor 11. In order to simplify the explanation, the description will be made on the assumption that value e is 1 (e = 1).
If the value e is 1, the count number C of the timer counter when the motor 11 rotates at the set rotational speed Ns is calculated by the expression "Cs = Ts/t = (1/Ns)/t (counts)." As described previously, the A/D converted value Nsc corresponding to the set rotational speed Ns is calculated by the expression "Nsc = 0.5*Ns." In addition, the set value K is obtained by multiplying the count number Cs of the pulse interval (when the motor 11 rotates at the set rotational speed Ns) by the A/D converted value Nsc corresponding to the set rotational speed Ns. Thus, the set value K is calculated by the expression "K = Cs*Nsc."
µ
Therefore, in this example, K is calculated as "K = Cs*Nsc = ((1/Ns)/t)*0.5*Ns = 0.5/t". Because the oscillation period t is set to be 16 s in this embodiment, the set value K is calculated to be 31250. Thus, independently of the change of the set rotational speed Ns over the range between the high speed and the low speed by the operation of the volume resistor 16, the set value K is kept to be a fixed value of 31250.
As described previously, the comparative value D is calculated at the comparative value calculating device 16 by multiplying the A/D converted value Nsc corresponding to the set rotational speed Ns by the count number C. Thus, D is calculated as "D = Nsc*C". If an actual rotational speed of the motor 11 is represented by "N", the count number C is given by the expression "C = (1/N)/t." Using these expressions, the expression, "D = Nsc*C" is modified as "D = Nsc*C = 0.5*Ns*((1/N)/t) = (O.5/t)*(Ns/N) = K*(Ns/N)."
If the actual rotational speed N of the motor 11 is the same as the set rotational speed Ns, "Ns/N" in the above modified expression has a value of 1 (Ns/N = 1). As a result, the comparative value D is equal to the set value K (D = K = 31250). Therefore, a difference E between the set value K and the comparative value D becomes zero (E = K - D = 0).
If the actual rotational speed N of the motor 11 is higher than the set rotational speed Ns, "Ns/N" is smaller than 1 (Ns/N < 1). Therefore, the comparative value D is smaller than K, so that the difference E has a positive value. Contrarily, if the actual rotational speed N of the motor 11 is lower than the set rotational speed Ns, "Ns/N" is greater than 1 (Ns/N > 1). Therefore, the comparative valued D is greater than K, so that the difference E has a negative value.
In this way, the comparative value D is proportional to the ratio of the set rotational speed Ns to the actual rotational speed N (Ns/N). Therefore, if a change Δ N has been caused from the actual rotational speed N of the motor 11, resulting a change ΔD in the comparative value D, such a change ΔD will not vary in response to the actual rotational speed N of the motor 11.
FIG. 2
The controller 20 adjusts the power to be supplied to the motor 11 in order to reduce the difference E between the set value K and the comparative value D. As schematically shown in , the controller 20 can include an amplifier 22, a control gate 24 and a motor driver 26. The amplifier 22 amplifies the difference E. The control gate 24 restricts the output from the amplifier 22 and then outputs a resulted signal P to the motor driver 26. In this embodiment, if the output from the amplifier 22 is zero or less, the control gate 24 controls the resulted signal P to have a minimum set value 0. In addition, if the output from the amplifier 22 exceeds a maximum set value Tm, the control gate 24 controls the resulted signal P to have the maximum set value Tm. Therefore, the output signal P from the control gate 24 may vary linearly between the minimum set value 0 and the maximum set value Tm.
FIGS. 4(A) and 4(B)
The motor driver 26 drives the motor 11 based on the output signal P from the control gate 24. More specifically, as shown in , the motor driver 26 includes a switching element 26s and a gate pulse adjuster 26c. The gate pulse adjuster 26c adjusts the input timing of gate pulses into the switching element 26s based on the output signal P from the control gate 24.
FIG. 4(A)
In this representative embodiment, a triac that is a bi-directional thyristor is used as the switching element 26s. As shown in , the switching element 26s is connected in series with the motor 11 (a series-wound motor in this representative embodiment) and an AC power source S. Therefore, the power source voltage is supplied to the motor 11 when the switching element 26s is in a conductive condition, while no power source voltage is supplied to the motor 11 when the switching element 26s is in a non-conductive condition.
FIG. 4(B)
The output signal P of the control gate 24 (having a value between 0 and Tm) corresponds to the waveform of the power source voltage of the AC power source S within a range between 0° phase and 180° phase as shown in . Also, the output signal P corresponds to the wave form of the power source voltage of the AC power source S within a range between 180° phase and 360° phase in the same manner as the range between 0° phase and 180° phase. Because the control for the range between 180° phase and 360° phase is performed in the same manner as the control for the range between 0° phase and 180°, the control will be described only for the range between 0° phase and 180° phase.
Within a range between 0° phase and 180° phase, the gate pulse adjuster 26c outputs gate pulses to a gate 26g of the switching element 26s based on the output signal P (having a value between 0 and Tm) of the control gate 24. More specifically, if the output signal P has a minimum value or the value of 0, the gate pulse adjuster 26c outputs a gate pulse at a time of the 0° phase of the waveform of the power source voltage. Therefore, the switching element 26s is in a conductive state between the 0° phase and 180° phase of the waveform, so that a maximum conduction period results and the power of the motor 11 maximizes.
In the case that the output signal P has a value of 1/2 Tm, the gate pulse adjuster 26c outputs a gate pulse at a time of the 90° phase of the waveform of the power source voltage. Therefore, the switching element 26s is in a conductive state between the 90° phase and 180° phase. As a result, the conduction period becomes half the maximum conductive period and the power of the motor 11 becomes half the maximum power.
In the case that the output signal P has a value of Tm (maximum value), the gate pulse adjuster 26c outputs a gate pulse at a time of the 180° phase of the waveform of the power source voltage. In that case, the switching element 26s is not brought to a conductive state and the power of the motor 11 becomes zero.
When the load applied to the motor 11 has increased to cause decrease in the actual rotational speed N from the set rotational speed Ns during the operation of the power tool having the representative speed control system 10, the relation "D (comparative value) = K*(Ns/N) > K" will result. This causes the difference E to have a negative value, so that the control gate 24 of the controller 20 processes the output signal P to have the minimum value of O. Then, the gate pulse adjuster 26c of the motor driver 26 outputs the gate pulse to the gate 26b at a time of the 0° phase of the waveform of the power source voltage. Therefore, the switching element 26s is in the conductive state during the period between the 0° phase and the 180° phase of the waveform of the power source voltage. As a result, the power of the motor 11 has a maximum value. In other words, the motor 11 is controlled to increase the speed from the actual speed N.
When the actual rotational speed N has increased to exceed the set rotational speed N as a result of the above speed increase control, the relation "D (comparative value) = K*(Ns/N) < K" will result. This causes the difference E to have a positive value. If the difference E has a positive value and if the output signal P from the control gate 24 of the controller 20 has a value between 0 and Tm, the gate pulse adjuster 26c outputs a gate pulse at a time of an x° phase (x°: a phase angle between the 0° phase and the 180° phase). Therefore, the switching element 26s is conductive during the period between the x° phase and the 180° phase. As a result, the power of the motor 11 is reduced from the maximum value. In other words, the motor 11 is controlled to decrease the speed from the actual speed N.
If the actual rotational speed N has increased due to the reduction of the load applied to the motor 11 or other factors, the difference E increases while maintaining the positive value. When the output signal P of the control gate 24 has reached the maximum value Tm, the gate pulse adjuster 26c outputs the gate pulse at a time of the 180° phase of the waveform of the power source voltage. As a result, the switching element 26 becomes non-conductive, so that the motor 11 supplies no power.
The difference E will be described further in connection with a high speed operation and a low speed operation of the motor 11. If the set rotational speed Ns is greater than the actual rotational speed N by 4 % while the motor 11 rotates at a high speed, such as a speed of 500 rps (N = 500), the set rotational speed Ns is 520 rps (Ns = N + 0.04N = 1.04N =520). As described previously, the comparative value D is calculated by the expression "D = K*(Ns/N)." Therefore, in this case, D = K*1.04. Because K = 31250, the comparative value D is 32500. The difference E is therefore calculated by the expression "E = K - D = 31250 - 32500 = - 1250." As a result, the output signal P from the control gate 24 has the minimum value of 0, so that the motor 11 is controlled to increase the speed from the actual rotational speed N.
On the other hand, if the set rotational speed Ns is greater than the actual rotational speed N by 4 % while the motor 11 rotates at a low speed, such as a speed of 50 rps (N = 50), the set rotational speed Ns is 52 rps (Ns = N + 0.04N = 1.04N = 52). Because the comparative value D is calculated by the expression "D = K*(Ns/N)", "D = K*1.04" results. Because K = 31250, the comparative value D is 32500. The difference E is therefore calculated as "E = K - D = 31250 - 32500 = -1250."
In this way, although the comparative value D may change in response to the difference in speed between the set rotational speed Ns and the actual rotational speed N, the comparative value D does not change depending on the actual rotational speed N. Therefore, the difference E always has a fixed value as long as the ratio of the set rotational speed Ns to the actual rotational speed N is constant.
According to the embodiments described above, the pulse interval T is determined by the pulse interval determining device 14 and the count number C corresponding to the pulse interval T (and proportional to 1/N) is directly used for the speed control of the motor 11. No calculation is made to obtain the rotational speed N of the motor 11 from the inverse value of the pulse interval T. Therefore, the calculation required for the speed control is simple and it is possible to perform the speed control by using a small-bit microcomputer, such as a 8-bit to 16-bit microcomputers.
In addition, according to the embodiments described above, the set value K is constant irrespective of change of the set rotational speed Ns over that range between a low speed value and a high speed value. Therefore, even if the rotational speed of the motor 11 has been changed from the low speed value to the high speed value, it is possible to perform the control substantially in a manner like a constant speed control. Further, the comparative value D changes with change in the speed difference ratio but does not change with the actual rotational speed N of the motor 11. Therefore, if the speed difference ratio does not change, the difference E has a constant value irrespective of change of the actual rotational speed N. As a result, it is possible to properly perform the speed control with the same accuracy over the range between the low speed and the high speed.
Further, because the operation device (the volume resister 16b in this embodiment) is provided for continuously changing the A/D converted value Nsc that corresponds to the set rotational speed Ns, it is possible to continuously vary the set rotational speed Ns between the minimum set speed and the maximum set speed.
The present invention may not be limited to the above embodiments but may be modified in various ways without departing from the sprit of the invention. For example, although the magnets 12m of the encoder 12 are arranged at an angular interval of 90°, the angular interval of the magnets 12m as well as the number of the magnets 12e can be changed as needed.
In addition, although the timer counter of the pulse determining device 14 is of a type having an oscillation period of 16 µs, any other type of timer counter can be used. Further, although the controller 20 sets the output signal P of the control gate 24 to have a value of 0 in the case that the difference E has a negative value or 0, the relation between the difference E and the output signal P of the control gate 24 can be easily determined depending on the type of a power tool to which a motor to be controlled is used.
It is explicitly stated that all features disclosed in the description and/or the claims are intended to be disclosed separately and independently from each other for the purpose of original disclosure as well as for the purpose of restricting the claimed invention independent of the composition of the features in the embodiments and/or the claims. It is explicitly stated that all value ranges or indications of groups of entities disclose every possible intermediate value or intermediate entity for the purpose of original disclosure as well as for the purpose of restricting the claimed invention, in particular as limits of value ranges. | |
Music is the most natural form of expression for musician/producer Cautious Clay, who is using his art to navigate the turbulence of 2020.
Singer-songwriter Cautious Clay has been making music his whole life, but took the leap to be a musician full-time in 2018. Immediately, his unique fusion sound of alternative R&B and pop caught the ears of listeners. Since then, he's been featured on Issa Rae's Insecure, gained critical praise for his EP Blood Type, and become a go-to collaborator for many high-profile music makers, such as John Legend and Taylor Swift. Now, Cautious Clay is working on his next project, an album expected in 2021.Photos by Alice Plati
“Writing stories completely outside of the medium of music has been a way to strike up inspiration for the songs I'm currently working on.”
“Covid physically restricted where I could go and what I could do which in hindsight made me focus a lot more on my creative process as a whole.”
Episodes
1. Ali Roberto
Director Alison Roberto takes a dive into the grit and passion of the LA music scene with her films, the product of a lifelong vision.
2. Gabriel Gomez
NY Filmmaker Gabriel Gomez uses these unprecedented times to hone in on what matters to him and the musicians in his community.
3. Lauren Ruth Ward
Lauren Ruth Ward is a musician, stylist, photographer, and more than the sum of her parts, seeking ways to connect without in-person shows.
4. Rosehardt
Caleb Eberhardt has always used his music to connect with others. Now, he's working to use his platform and leave a legacy of social change.
5. Tolliver
Los Angeles artist Tolliver uses his music to reconcile who he is today with his Baptist upbringing and childhood.
6. Cautious Clay
Music is the most natural form of expression for musician/producer Cautious Clay, who is using his art to navigate the turbulence of 2020.
7. Blimes & Gab
Blimes & Gab blended their unique styles to create Talk About It. Now, they're braving the highs and lows of releasing an album mid-pandemic.
8. Sunflower Bean
Lifelong musicians and members of Sunflower Bean are leaning on each other, their music, and the politics of their art to continue creating.
9. NEZ
NEZ, Los Angeles-based music artist and producer, focuses on cultivating a creative space where he can express himself in the truest form possible.
10. Orion Sun
Despite the dark early days of lockdown, singer, producer, and songwriter Orion Sun is finding the light by learning to live on her own terms.
11. The Regrettes
The Regrettes are looking within for inspiration and learning to let go as their non-stop touring lifestyle slows in the midst of lockdown.
12. Stuyedeyed
NYC band Stuyedeyed is focusing on what they can control: creating music they believe in, and through that, inciting change.
13. duendita
Brooklyn-based artist duendita uses her time in lockdown to find well-deserved rest and focuses on expressing her deepest self through her music.
14. Frankie and the Witch Fingersnew
Powered by the explosive energy they usually channel onstage, Los Angeles band Frankie and the Witch Fingers uses art to engage their community. | https://www.drmartens.com/us/en/dm-presents-cautious-clay |
Nicholas Caiafa is an intellectual property associate focused on patent and trademark law. He is skilled at preparing and prosecuting domestic and foreign patent applications and has experience in mechanical, chemical and electrical technologies, including medical devices, automobile components, farming equipment, lithium-ion batteries, consumer products, flexographic printing and electrical systems. Nick leverages his extensive hands-on product development experience to analyze an invention and develop a patent strategy tailored to a client’s current and future objectives.
Nick is experienced in assessing early-stage technology and routinely counsels new inventors and startup companies as they develop and commercialize a product. He provides opinions on patentability, validity, noninfringement and freedom-to-operate matters and prepares technology licensing agreements.
As a former design engineer at a Fortune 500 company, Nick uniquely understands his clients’ needs from both legal and scientific perspectives.
Background
Prior to joining Armstrong Teasdale, Nick was founder and managing member of an engineering and intellectual property legal practice specializing in patent and trademark law. He also previously served as the in-house patent counsel for physical sciences and engineering at the University of Connecticut and as an intellectual property attorney at multiple Connecticut firms. | https://www.armstrongteasdale.com/nicholas-caiafa/ |
The present application claims the benefit of the Chinese Patent Application No. CN201610141143.3 filed on Mar. 11, 2016 and the Chinese Patent Application No. CN201610310944.8 filed on May 11, 2016. The content of the above Chinese Patent Applications is incorporated herein by reference in its entirety.
The present invention relates to a retinoid compound, a preparation method, an intermediate and a use thereof.
J Am Acad Dermatol.
Tazarotene is a retinoid drug with RAR subtype selectivity (1997, 37, S12), mainly used for the treatment of topical epithelial hyperplasia skin (psoriasis, psoriasis, acne, etc.). Tazarotene is an ethyl ester prodrug, which is metabolized by enzyme to Tazarotenic acid as the carboxyl-type active metabolite in vivo. Tazarotenic acid can selectively interact with RARβ and RARγ receptors, and has a certain effect on RARβ, but has a weak effect on RXR.
The technical problem to be solved in the present invention is to overcome the poor inhibition rate of Tazarotene on tumor cells, thus the present invention provides a retinoid compound, a preparation method, an intermediate and a use thereof. The compound of the present invention exhibits a better inhibition rate on tumor cells.
The present invention provides a compound represented by formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof,
9a
9b
9c
9d
wherein, U is CRor N; V is CRor N; X is CRor N; W is CRor N;
9a
9b
9c
9d
10
11
1
6
1
6
1
6
1
6
1
6
in the definition of U, V, X and W, each of R, R, Rand Ris independently hydrogen, hydroxy, nitro, cyano, halogen (e.g. fluorine, chlorine, bromine or iodine), C-Calkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), C-Calkyl substituted with halogen (the halogen can be fluorine, chlorine, bromine or iodine; the C-Calkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl; the “C-Calkyl substituted with halogen” such as trifluoromethyl), C-Calkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy), —NRR,
10
11
12
13
14
1
6
each of R, R, R, Rand Ris independently hydrogen or C-Calkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl);
2
3
4
5
2
the bond connecting AE, EG or GZ is independently a single bond or a double bond; when A, E, G or Z connects to two single bonds, the corresponding A, E, G and Z are independently —(CRR)—, —C(═O)—, —(NR)—, —(N→O)—, —O—, —S—, —S(═O)— or —SO—; when A, E, G or Z connects to a single bond and a double bond, the corresponding A, E, G and Z are independently —(CR)═ or —N═;
2
3
4
5
1
6
2
6
1
6
1
6
1
6
1
6
1
6
6
10
3
6
each of R, R, Rand Ris independently hydrogen, hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C-Calkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), C-Calkenyl (e.g. vinyl or propenyl), C-Calkyl substituted with halogen (the halogen can be fluorine, chlorine, bromine or iodine; the C-Calkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl; the “C-Calkyl substituted with halogen” such as trifluoromethyl), C-Calkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy), C-Cacyl (e.g. acetyl or formyl), C-Caryl (e.g. phenyl) or “C-Cheteroaryl having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen” (e.g. pyridinyl or pyrimidinyl);
m is 0, 1, 2 or 3;
1
1
6
7
8
1
6
1
6
1
6
1
6
1
6
when there are more than one substituents of R, the substituents are identical or different; Ris hydrogen, hydroxy, nitro, cyano, halogen (e.g. fluorine, chlorine, bromine or iodine), C-Calkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), C-Calkyl substituted with halogen (the halogen can be fluorine, chlorine, bromine or iodine; the C-Calkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl; the “C-Calkyl substituted with halogen” is for example trifluoromethyl), C-Calkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy or hexoxy), —NRRor —COOR;
6
7
8
1
6
each of R, Rand Ris independently hydrogen or C-Calkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl);
15
16
2
Y is —CN, —COORor —CONHR;
15
16
1
6
2
6
1
6
each of Rand Ris independently hydrogen, C-Calkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), C-Calkenyl (e.g. vinyl or propenyl) or C-Cacyl (e.g. formyl or acetyl);
the compound represented by formula I is not
Preferably, A, E, G together with Z can form the ring selected from the group consisting of
2
3
5
R, Rand Rare defined as above.
Preferably, in compound I, at least one (e.g. one, two, three or four) of U, V, X and W is N atom.
More preferably, in compound represented by formula I, when two of U, V, X and W are N atoms, the compound represented by formula I can be selected from the group consisting of
9a
9b
9c
9d
wherein, A, E, G, Z, m, Y, R, R, Rand Rare defined as above.
15
15
Preferably, in compound A, when Y is —COOR, Ris hydrogen or ethyl.
2
3
2
Preferably, in compound A, Z is —(CRR)—, —S—, —S(═O)— or —SO—; more preferably, A, E, G together with Z form the ring selected from the group consisting of
2
3
Rand Rare defined as above.
More preferably, in compound A, when Y is COOH, Z is —S—.
2
3
2
More preferably, in compound A, when Y is COOEt, Z is —(CRR)—, —S(═O)— or —SO—.
15
15
Preferably, in compound B, when Y is —COOR, Ris methyl or ethyl.
2
3
Preferably, in compound B, Z is —(CRR)—, —S— or —S(═O)—; more preferably, A, E, G together with Z form the ring selected from the group consisting of
2
3
Rand Rare defined as above.
2
3
2
3
More preferably, in compound B, when Y is COOMe, Z is —(CRR)—, Rand Rare defined as above.
2
3
2
3
More preferably, in compound B, when Y is COOEt, Z is —(CRR)— or —S—, Rand Rare defined as above.
2
3
2
3
More preferably, in compound B, when Y is CN, Z is —(CRR)—, —S— or —S(═O)—, Rand Rare defined as above.
15
15
Preferably, in compound C, when Y is —COOR, Ris hydrogen or ethyl.
2
3
Preferably, in compound C, Z is —(CRR)—, —S— or —S(═O)—; more preferably, A, E, G together with Z form the ring selected from the group consisting of
2
3
Rand Rare defined as above.
More preferably, in compound C, when Y is COOH, Z is —S—.
2
3
2
3
More preferably, in compound C, when Y is COOEt, Z is —(CRR)—, —S— or —S(═O)—, Rand Rare defined as above.
Preferably, in compound presented by formula I, when one of U, V, X and W is N atom, the compound represented by formula I can be selected from
9a
9b
9c
9d
wherein, A, E, G, Z, m, Y, R, R, Rand Rare defined as above.
15
15
Preferably, in compound D, when Y is —COOR, Ris hydrogen or ethyl.
2
3
Preferably, in compound D, Z is —(CRR)—; more preferably, A, E, G together with Z form
2
3
Rand Rare defined as above.
Preferably, in compound E, Y is CN.
2
3
Preferably, in compound E, Z is —(CRR)—; more preferably, A, E, G together with Z form
2
3
Rand Rare defined as above.
9a
9b
9c
9d
Preferably, in compound represented by formula I, when U is CR, V is CR, X is CR, and W is CR, the compound represented by formula I is as compound F:
9a
9b
9c
9d
wherein, A, E, G, Z, m, Y, R, R, Rand Rare defined as above.
9a
9b
9c
9d
Preferably, in compound F, at least one (e.g. one, two, three or four) of R, R, Rand Ris not hydrogen.
15
15
Preferably, in compound F, when Y is —COOR, Ris hydrogen, methyl or ethyl.
2
3
2
Preferably, in compound F, Z is —(CRR)—, —S—, —S(═O)— or —SO—; more preferably, A, E, G together with Z form the ring selected from the group consisting of
2
3
5
R, Rand Rare defined as above.
More preferably, the compound represented by formula I is selected from the group consisting of
The present invention also provides a preparation method for the compound represented by formula I, which comprises conducting a coupling reaction with compound II and III to give compound I;
1
wherein, Xis halogen (e.g. fluorine, chlorine, bromine or iodine).
3
2
2
In the preparation method for the compound represented by formula I, the condition of the coupling reaction can be conventional conditions in the art, preferably that under an atmosphere of a protective gas (e.g. argon), in an organic solvent (e.g. DMF), in the presence of a catalyst (e.g. Pd/Cu catalyst; the “Pd/Cu catalyst” such as Pd(PPh)Cland CuI) and a base (e.g. diisopropylamine or triethylamine), conducting a coupling reaction with compound II and III to give compound I.
The compound represented by formula I can be converted to analogue with a different functional group by flexible functional group conversion and adjustment (including but not limited to esterification, ester hydrolysis, reduction, acylation, oxidation, etc.).
The preparation method for the compound represented by formula I can further comprise conducting a deprotection reaction of compound IV to give compound III;
In the preparation method for the compound III, the condition of the deprotection reaction can be conventional conditions in the art, preferably that in an organic solvent (e.g. tetrahydrofuran), in the presence of a base (e.g. tetra-n-butylammonium fluoride), conducting a deprotection reaction of compound IV to give compound III.
The preparation method for the compound represented by formula I can further comprise conducting a coupling reaction with compound V and trimethylethynyl silane to give compound IV;
2
wherein, Xis halogen (e.g. bromine or iodine).
3
2
2
In the preparation method for the compound represented by formula IV, the condition of the coupling reaction can be conventional conditions in the art, preferably that under an atmosphere of a protective gas (e.g. argon), in an organic solvent (e.g. DMF), in the presence of a catalyst (e.g. Pd/Cu catalyst; the “Pd/Cu catalyst” such as Pd(PPh)Cland CuI) and a base (e.g. diisopropylamine or triethylamine), conducting a coupling reaction of compound V with trimethylethynyl silane to give compound IV.
The present invention also provides a compound represented by formula II, III, IV or V,
1
1
wherein, A, E, G, Z, R, m, X, Y, U, V, X and W are defined as above.
The present invention further provides a use of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof in manufacturing a medicament for the treatment of a primary tumor. The tumor includes, but is not limited to, melanoma, esophageal cancer, gastric cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, kidney cancer, cholangiocarcinoma, breast cancer or prostate cancer.
The present invention also provides a use of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof in manufacturing a medicament for the prevention and/or the treatment of a metastatic tumor. The tumor includes, but is not limited to, melanoma, esophageal cancer, gastric cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, kidney cancer, cholangiocarcinoma, breast cancer or prostate cancer.
The present invention also provides a use of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof in manufacturing a medicament for the prevention and/or the treatment of leukemia and/or lymphoma.
The present invention also provides a use of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof in manufacturing a medicament for the use selected from the group consisting of animal fetal growth, internal environment stability, vision, morphogenesis, skin aging and cell differentiation control.
The present invention also provides a use of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof in manufacturing a medicament for the treatment of psoriasis.
The present invention also provides a use of the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof in manufacturing a medicament for the treatment of acne.
The present invention also provides a pharmaceutical composition, which comprises the compound represented by formula I, the enantiomer, the diastereomer or the pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.
The route of administration of the pharmaceutical composition can be oral administration, injection and topical administration. When the pharmaceutical composition is administered by oral administration, the dosage form of the composition includes, but is not limited to, tablets, capsules, suspensions, solutions, emulsions, microspheres, nanosphere suspensions, controlled release niosomes or polymer niosomes. When the pharmaceutical composition is administered by injection, the dosage form of the composition solutions or suspensions for infusion or injection. Generally, the compounds of the present invention are daily administered at a dose of about 0.01 mg/kg to 100 mg/kg based on the body weight, the dose is divided into 1-3 part for administration. The concentration of the compounds of the present invention used systemically is generally 0.01% to 10% (weight), preferably 0.01% to 1% (weight) based on the weight of the composition. When the pharmaceutical composition is administered by topical administration, the pharmaceutical composition is especially used for the treatment of skin and mucosal diseases, can be used in the form of liquid, paste or solid, especially ointments, creams, solutions, gels, sprays, suspensions and adhesives. The form can also be microspheres, nanosphere suspensions, controlled release niosomes, polymer niosomes, gel patch or polymer patch. The concentration of the compounds which are administered by topical administration is usually 0.001% to 10% (weight), preferably 0.01% to 1% (weight) based on the total weight of the composition.
The pharmaceutical composition can also comprise inert additives, or a pharmaceutically active ingredient that is positively associated with the pharmaceutical composition, or a mixture of such ingredients. Of course, the person skilled in the art will be careful to select the above optional compound to be added into the above composition, ensuring that the advantage of the present invention is not or basically not affected by the predetermined additive.
1
6
3
In the present invention, the “C-Cacyl” refers to an alkyl acyl group having 1 to 6 carbon atoms, for example the acyl group having 1 carbon atom refers to HC(O)— (i.e. formyl), the acyl group having 2 carbon atoms refers to CHC(O)— (i.e. acetyl); propionyl, butyryl or valeryl.
In the present invention, unless otherwise specified, the following terms in the description and the claims of the invention have the following meanings:
The term “alkyl” refers to a saturated linier or branched monovalent hydrocarbon group having one to twenty carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-m ethyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl.
2-12
2-6
The term “alkenyl” refers to a linier, branched or cyclic non-aromatic hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond. Alkenyl is preferably having one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds can be present. Thus, “Calkenyl” refers to an alkenyl group having 2 to 12 carbon atoms. “Calkenyl” refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl.
The term “aryl” (used alone or included in other groups) refers to any stable monocyclic or bicyclic carbon ring which can have up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of the above aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It is to be understood that when the aryl is a bicyclic substituent and one of the rings is non-aromatic, the linkage is through the aromatic ring.
The term “aromatic hetero group” or “heteroaryl” (used alone or included in other groups) refers to a stable monocyclic ring or bicyclic ring which can have up to 7 atoms in each ring, and at least one of the rings is an aromatic ring having 1 to 4 heteroatoms independently selected from O, N and S. The heteroaryl defined herein includes but not limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidyl, pyrryl, tetrahydroquinoline. As defined in the “heterocycloalkyl”, “heteroaryl” can also be understood to include the N-oxide derivative of any nitrogenous heteroaryl. When the heteroaryl is a bicyclic substituent and one of the rings is non-aromatic or without any heteroatom, it can be understood, the linkage is through the aromatic ring or the heteroatom on the ring.
The term “halogen” includes F, Cl, Br, I.
The term “pharmaceutically acceptable salt” refers to a conventional acid addition or a base addition salt which retains the biological activity and the property of compound I and is formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base. Examples of the acid addition salt include the salt derived from an inorganic acid and an organic acid, the inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphorous acid, phosphorothioic acid, phosphoric acid and nitric acid, the organic acid such as formic acid, acetic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid, tartaric acid, succinic acid, fumaric acid, mandelic acid, malic acid, camphorsulfonic acid, etc. Examples of the base addition salt include the salt derived from ammonium, potassium, sodium, calcium, and quaternary ammonium hydroxide (e.g. tetramethylammonium hydroxide). Modification of a pharmaceutical compound (i.e. drug) into a salt in order to obtain a compound with improved physical and chemical stability, hygroscopicity, flowability, and solubility is a conventional method well known to the pharmacists.
The “pharmaceutically acceptable” contained in the term “pharmaceutically acceptable carrier” refers to the compound is pharmaceutically acceptable and basically non-toxic when administered to a specific subject.
Without violating the common sense in the art, the above preferred conditions can be arbitrarily combined, then preferred embodiments of the present invention are obtained.
The reagents and raw materials used in the present invention are commercially available.
The positive and progressive effect of the present invention is that the compounds of the present invention exhibit a better inhibition rate on tumor cells.
The following embodiments further illustrate the present invention, but the present invention is not limited thereto. The experimental methods that do not specify the specific conditions in the following embodiments are selected according to conventional methods and conditions, or according to the description of the product.
3
2
2
2
3
3
1
13
+
Commercially available 6-ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl 2-hydroxy-4-iodobenzoate (292.1 mg, 1 mmol) used as raw material were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry iPrNH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 20:1) to give WYC-101 (296 mg, 81%). H NMR (400 MHz, CDCl) δ 7.79 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.12 (d, 1H), 7.06-7.07 (d, 1H), 7.00-7.02 (dd, 1H), 3.95 (s, 3H), 3.03-3.06 (m, 2H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); C NMR (101 MHz, CDCl) δ 170.09, 161.38, 161.12, 153.37, 142.25, 134.10, 130.91, 130.00, 129.85, 129.24, 126.73, 122.45, 120.25, 117.90, 111.95, 93.23, 88.03, 77.48, 77.16, 76.84, 52.52, 37.27, 32.54, 29.99, 23.43; ESI(+)−MS: 353.3 [M+1].
3
2
2
2
3
3
1
13
+
6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl 2-methoxy-4-iodobenzoate (292 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry iPrNH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-102 (300 mg, 82%). H NMR (400 MHz, CDCl) δ 7.78 (d, 1H), 7.53 (d, 1H), 7.18-7.20 (dd, 1H), 7.11-7.13 (dd, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); C NMR (101 MHz, CDCl) δ 166.25, 159.05, 142.07, 133.98, 133.58, 131.89, 129.90, 129.13, 128.85, 126.70, 123.39, 119.42, 117.88, 114.84, 92.50, 88.07, 77.48, 77.16, 76.84, 56.18, 52.18, 37.23, 33.06, 30.06, 23.31; ESI(+)−MS: 367.4 [M+1].
3
2
2
2
3
3
1
13
+
6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and ethyl 2-hydroxy-4-iodobenzoate (292 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry iPrNH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-103 (300 mg, 82%). H NMR (400 MHz, CDCl) δ 7.80 (d, 1H), 7.52 (s, 1H), 7.18-7.20 (d, 1H), 7.12 (s, 1H), 7.06-7.07 (s, 1H), 7.00-7.02 (s, 1H), 4.39-4.44 (q, 2H), 3.04-3.06 (t, 2H), 1.95-1.97 (t, 2H), 1.44 (t, 3H), 1.35 (s, 6H); C NMR (101 MHz, CDCl) δ 169.97, 161.45, 142.27, 134.07, 130.80, 130.02, 129.91, 129.26, 126.74, 122.37, 120.25, 117.94, 112.22, 93.19, 88.02, 77.48, 77.36, 77.16, 76.84, 61.71, 37.30, 33.12, 30.11, 29.85, 23.37, 14.34; ESI(+)−MS: 367.5 [M+1].
3
2
2
2
3
3
1
13
+
6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and ethyl 2-methoxy-4-iodobenzoate (306 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry iPrNH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-104 (293 mg, 77%). H NMR (400 MHz, CDCl) δ 7.77 (d, J=7.9 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.20 (dd, J=8.2, 1.7 Hz, 1H), 7.14-7.11 (m, 1H), 7.11-7.05 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.07-3.04 (m, 2H), 1.95-1.98 (m, 2H), 1.39 (t, 3H), 1.35 (s, 6H); C NMR (101 MHz, CDCl) δ 165.81, 159.12, 142.28, 133.97, 131.77, 129.96, 129.19, 128.70, 126.76, 123.42, 119.93, 117.98, 114.94, 92.39, 77.48, 77.37, 77.16, 76.85, 61.07, 56.25, 37.31, 33.13, 30.14, 29.85, 23.37, 14.46; ESI(+)−MS: 381.4 [M+1].
1
13
−
3
3
WYC-103 (183 mg, 0.5 mmol) was dissolved in 5 mL THF, then 1 mL 0.5M NaOH solution was added dropwise. The reaction was continued at room temperature for 8 hours and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to pH 7 with 0.5M HCl solution, diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1 to 1:1) to give WYC-105 (144 mg, 85%). H NMR (500 MHz, cdcl) δ 10.50 (s,1H), 7.86-7.84 (d, 1H), 7.53 (d, 1H), 7.21-7.19 (dd, 1H), 7.14 (d, 1H), 7.08-7.06 (d, 1H), 7.05-7.04 (dd, 1H), 3.07-3.04 (m, 1H), 1.98-1.95 (m, 1H), 1.35 (s, 6H); C NMR (125 MHz, CDCl) δ 171.84, 161.46, 142.17, 131.83, 130.58, 129.91, 129.16, 126.63, 120.24, 117.56, 110.03, 89.85, 37.15, 32.99, 29.97, 29.70, 23.24; ESI(−)−MS: 337.1 [M−1].
1
13
−
3
3
WYC-104 (190 mg, 0.5 mmol) was dissolved in 5 mL THF, then 1 mL 0.5M NaOH solution was added dropwise. The reaction was continued at room temperature for 8 hours and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to pH 7 with 0.5M HCl solution, diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1 to 4:1) to give WYC-106 (151 mg, 86%). H NMR (500 MHz, CDCl) δ 10.60 (s, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.54 (s, 1H), 7.28 (m, 2H), 7.22 (m, 1H), 7.08 (d, J=7.9 Hz, 1H), 4.12 (s, 3H), 3.06 (m, 2H), 1.96 (m, 2H), 1.35 (s, 6H); C NMR (101 MHz, CDCl) δ 165.02, 157.85, 142.36, 134.56, 133.90, 130.59, 130.00, 129.21, 126.81, 125.42, 117.51, 116.99, 114.42, 94.06, 87.56, 77.48, 77.36, 77.16, 76.84, 56.98, 37.22, 33.12, 30.10, 29.83, 23.37; ESI(−)−MS: 351.2 [M−1].
3
2
2
2
3
3
1
13
+
6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl 3-hydroxy-4-iodobenzoate (278.1 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry iPrNH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 10:1) to give WYC-107 (245 mg, 71%). H NMR (500 MHz, CDCl) δ 7.64 (d, J=1.5 Hz, 1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.02 (s, 1H), 3.91 (s, 3H), 3.06-3.04 (m, 2H), 1.94-1.97 (m, 2H), 1.34 (s, 6H); C NMR (101 MHz, CDCl) δ 166.45, 156.21, 142.31, 134.62, 131.53, 131.43, 129.70, 128.97, 126.73, 121.48, 117.03, 115.72, 114.61, 99.27, 81.86, 77.37, 77.05, 76.74, 52.33, 37.06, 32.99, 29.94, 23.24; ESI(+)−MS: 353.4 [M+1].
3
2
2
2
3
3
1
13
°
6-Ethynyl-4,4-dimethylthiochroman (202.8 mg, 1 mmol) and methyl 3-methoxy-4-iodobenzoate (292.1 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry iPrNH were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, and the mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 10:1) to give WYC-108 (275 mg, 75%). H NMR (500 MHz, CDCl) δ 7.61-7.63 (d, 1H), 7.52-7.56 (m, 3H), 7.21-7.23 (dd, 1H), 7.05-7.07 (d, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.03-3.06 (m, 1H), 1.94-1.97 (m, 1H), 1.34 (s, 6H); C NMR (126 MHz, cdcl) δ 166.59, 159.56, 141.99, 133.50, 133.19, 130.64, 129.80, 129.14, 126.49, 121.75, 118.27, 111.25, 96.82, 84.38, 77.26, 77.01, 76.76, 56.07, 52.29, 37.24, 32.97, 29.98, 23.22; ESI(+)−MS: 367.3 [M+1].
1
+
3
WYC-108 (190 mg, 0.5 mmol) was dissolved in 5 mL THF, and 1 mL 0.5M NaOH solution was added dropwise. The reaction was continued at room temperature for 8 hours and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to pH 7 with 0.5M HCl solution, diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1 to 2:1) to give WYC-110 (1541 mg, 80%). H NMR (500 MHz, CDCl) δ 7.69 (dd, 1H), 7.61 (s, 1H), 7.58-7.55 (m, 2H), 7.23 (dd, 1H), 7.07 (d, 1H), 3.99 (s, 3H), 3.06-3.04 (m, 2H), 1.97-1.95 (m, 2H), 1.34 (s, 6H); ESI(+)−MS: 339.3 [M+1].
Embodiment 10: 2-cyano-5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidine
3
2
2
3
3
3
1
13
+
Commercially available 4,4-dimethyl-6-ethynylthiochroman (202.8 mg, 1.0 mmol) and 2-cyano-5-chloropyrimidine (93 mg, 0.67 mmol) used as raw material were added to a flask, followed by addition of Pd(PPh)Cl(23 mg, 0.03 mmol) and CuI (19 mg, 0.1 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.25 mL dry EtN were added via syringe. The reaction was continued at 50° C. for 22 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=30:1) to give WYC-202 (133 mg, 65%). H NMR (400 MHz, CDCl) δ 8.89 (s, 2H), 7.55 (d, J=1.6 Hz, 1H), 7.21 (dd, J=8.2, 1.7 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 3.11-3.03 (m, 2H), 2.01-1.93 (m, 2H), 1.35 (s, 6H); C NMR (126 MHz, CDCl) δ 159.21, 142.59, 141.79, 136.33, 130.15, 129.31, 126.98, 122.88, 116.13, 115.70, 101.85, 81.24, 37.02, 33.15, 30.02, 23.42. ESI(+)−MS: 306.3 [M+1].
3
2
2
3
3
3
1
13
+
4,4-Dimethyl-6-ethynylthiochroman (202.8 mg, 1.0 mmol) and ethyl 2-chloropyrimidin-5-carboxylate (156 mg, 0.83 mmol) used as raw material were added to a flask, followed by addition of Pd(PPh)Cl(42 mg, 0.06 mmol) and CuI (19 mg, 0.1 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.3 mL dry EtN were added via syringe. The reaction was continued at 80° C. for 22 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=15:1) to give WYC-203(257 mg, 73%). H NMR (500 MHz, CDCl) δ 9.24 (s, 2H), 7.69 (d, J=1.7 Hz, 1H), 7.33 (dd, J=8.2, 1.8 Hz, 1H), 7.09 (d, J=8.2 Hz, 1H), 4.45 (q, J=7.1 Hz, 1H), 3.11-2.99 (m, 2H), 1.99-1.92 (m, 2H), 1.43 (t, J=7.1 Hz, 3H), 1.33 (s, 6H); C NMR (126 MHz, CDCl) δ 163.52, 158.44, 155.85, 142.39, 136.48, 131.36, 130.15, 126.83, 121.88, 115.96, 92.65, 87.97, 62.14, 37.09, 33.14, 30.05, 23.43, 14.38. ESI(+)−MS: 353.2 [M+1].
1
13
+
3
3
WYC-202 (50 mg, 0.164 mmol) was added to a flask, followed by addition of a solution of NaOH (20 mg, 0.491 mmol) in 0.5 mL water and 0.5 mL methanol. Then the reaction was continued at 60° C. for 5 h and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to pH 7 with 1M HCl solution, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=15:1) to give WYC-204 (39 mg, 74%). H NMR (500 MHz, CDCl) δ 8.63 (s, 2H), 7.51 (d, J=0.7 Hz, 1H), 7.17 (dd, J=8.1, 0.9 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.04 (s, 3H), 3.11-2.91 (m, 2H), 2.04-1.90 (m, 2H), 1.34 (s, 6H); C NMR (126 MHz, CDCl) δ 164.02, 161.24, 142.32, 134.10, 129.72, 128.97, 126.77, 117.65, 113.33, 94.71, 81.81, 55.37, 37.28, 33.12, 30.11, 23.36. ESI(+)−MS: 339.2 [M+1].
1
13
+
3
3
WYC-202 (50 mg, 0.164 mmol) was added to a flask, followed by addition of sodium ethoxide (34 mg, 0.492 mmol) and 5 mL ethanol. Then the reaction was continued at 45° C. overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=8:1) to give WYC-205 (36 mg, 62%). H NMR (500 MHz, CDCl) δ 8.62 (s, 2H), 7.51 (s, 1H), 7.17 (dd, J=8.1, 0.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 3.09-3.00 (m, 2H), 2.00-1.92 (m, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.34 (s, 6H); C NMR (126 MHz, CDCl) δ 163.61, 161.23, 142.32, 134.05, 129.72, 128.97, 126.77, 117.71, 113.13, 94.60, 81.91, 64.11, 37.30, 33.13, 30.11, 23.36, 14.55. ESI(+)−MS: 353.5 [M+1].
1
13
+
3
3
WYC-203 (50 mg, 0.142 mmol) was added to a flask, followed by addition of 2 mL 2.0 mol/L NaOH solution and 2 mL methanol. Then the reaction was continued at 45° C. for 5 h and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to weak acidic with 1 mol/L HCl solution, diluted with ethyl acetate, extracted, washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (dichloromethane:methanol=15:1) to give WYC-206 (41 mg, 89%). H NMR (400 MHz, CDOD) δ 9.21 (s, 2H), 7.71 (d, J=1.6 Hz, 1H), 7.29 (dd, J=8.2, 1.8 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 3.14-3.06 (m, 2H), 2.05-1.92 (m, 2H), 1.36 (s, 6H); C NMR (101 MHz, CDOD) δ 167.13, 159.54, 155.24, 143.92, 137.92, 131.86, 130.67, 127.84, 117.11, 111.42, 92.11, 88.26, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 38.12, 33.99, 30.18, 23.98. ESI(+)−MS: 325.3 [M+1].
1
13
+
3
3
WYC-202 (30 mg, 0.098 mmol) was added to a flask, followed by addition of 2 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (24 mg, 0.098 mmol) was added. Then the reaction was continued for 1 hour under an ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:2) to give WYC-207 (27 mg, 86%). H NMR (500 MHz, CDCl) δ 8.95 (s, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.55 (dd, J=8.0, 1.5 Hz, 1H), 3.30-3.08 (m, 2H), 2.44 (ddd, J=15.0, 10.1, 2.0 Hz, 1H), 1.93 (ddd, J=15.1, 9.2, 2.1 Hz, 1H), 1.49 (s, 3H), 1.36 (s, 3H); C NMR (126 MHz, CDCl) δ 159.64, 145.41, 142.59, 131.57, 130.38, 130.36, 124.24, 121.99, 115.52, 99.38, 83.14, 43.53, 34.76, 31.38, 31.31, 29.96. ESI(+)−MS: 322.3 [M+1].
1
13
+
3
3
WYC-205 (70 mg, 0.2 mmol) was added to a flask, followed by addition of 3 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (49 mg, 0.2 mmol) was added. Then the reaction was continued for 1 hour under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:2) to give WYC-208 (68 mg, 93%). H NMR (500 MHz, CDCl) δ 8.66 (s, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=7.7 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.16 (dt, J=20.8, 11.7 Hz, 2H), 2.46 (dd, J=14.5, 10.3 Hz, 1H), 1.90 (dd, J=14.6, 8.0 Hz, 2H), 1.48 (s, 3H), 1.45 (t, J=7.1 Hz, 3H), 1.34 (s, 3H); C NMR (126 MHz, CDCl) δ 163.95, 161.56, 145.06, 131.11, 130.39, 129.99, 125.91, 112.28, 93.14, 84.74, 64.30, 43.37, 34.61, 31.36, 31.23, 29.76, 14.52. ESI(+)−MS: 369.4 [M+1].
1
13
+
+
3
3
20
21
2
3
WYC-203 (48 mg, 0.14 mmol) was added to a flask, followed by addition of 3 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (34 mg, 0.14 mmol) was added. Then the reaction was continued for 1 hour under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:2) to give WYC-209 (43 mg, 84%). H NMR (500 MHz, CDCl) δ 9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.24 (t, J=11.1 Hz, 1H), 3.15 3.07 (m, 1H), 2.43 (dd, J=14.0, 10.4 Hz, 1H), 1.92 (dd, J=14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.34 (s, 3H); C NMR (126 MHz, CDCl) δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22, 122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI(+)−MS: 369.4 [M+1]; HRMS-ESI (m/z) calculated CHNOS, 369.1273 [M+1], found 369.1267.
2
2
4
2
3
3
3
2
1
13
+
Diethyl D-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CHCl(1 mL), and Ti(iso-PrO)(0.2 mmol, 58 μL) was quickly added at 16° C. After the mixture was stirred for 3 minutes, water (3.6 μL, 0.2 mmol) was slowly added dropwise, and the mixture was stirred for another 20 minutes. The mixture was cooled to −20° C., then WYC-203 (69 mg, 0.2 mmol) and cumene hydroperoxide (74 μL, 0.4 mmol) were quickly added, and the reaction was stopped after 3 hours. The reaction solution was poured into 10 mL mixed solution of ferrous sulfate (0.2 g) and citric acid (67 mg) in water, dioxane and diethyl ether (2:1:2), and the mixture was stirred for 15 minutes. The aqueous phase was extracted with diethyl ether, the organic layers were combined, washed with 0.5M KCOand saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:2) to give WYC-209A (43 mg, 84%, ee %=90%). The product was recrystallized with diethyl ether to give WYC-209A (25 mg, ee %=99%). H NMR (500 MHz, CDCl) δ 9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.24 (t, J=11.1 Hz, 1H), 3.15-3.07 (m, 1H), 2.43 (dd, J=14.0, 10.4 Hz, 1H), 1.92 (dd, J=14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.34 (s, 3H); C NMR (126 MHz, CDCl) δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22, 122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI(+)−MS: 369.4 [M+1]. ee % was determined by chiral HPLC as follows: Agilent 1260 infinity liquid chromatograph, column Lux Cellulose-1 250*4.6 mm, mobile phase: acetonitrile/HO=80:20, 20° C., 0.7 mL/min; the retention time was 8.592 min.
2
2
4
2
3
3
3
2
1
13
+
Diethyl L-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CHCl(1 mL), and Ti(iso-PrO)(0.2 mmol, 58 μL) was quickly added at 16° C. After the mixture was stirred for 3 minutes, water (3.6 μL, 0.2 mmol) was slowly added dropwise and the mixture was stirred for another 20 minutes. The mixture was cooled to −20° C., then WYC-203 (69 mg, 0.2 mmol) and cumene hydroperoxide (74 μL, 0.4 mmol) were quickly added, and the reaction was stopped after 3 hours. The reaction solution was poured into 10 mL mixed solution of ferrous sulfate (0.2 g) and citric acid (67 mg) in water, dioxane and diethyl ether (2:1:2), and the mixture was stirred for 15 minutes. The aqueous phase was extracted with diethyl ether, the organic layers were combined, washed with 0.5M KCOand saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:2) to give WYC-209B (43 mg, 84%, ee %=90%). The product was recrystallized with diethyl ether to give WYC-209B (25 mg, ee %=99%). H NMR (500 MHz, CDCl) δ 9.29 (s, 2H), 7.82-7.75 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.24 (t, J=11.1 Hz, 1H), 3.15-3.07 (m, 1H), 2.43 (dd, J=14.0, 10.4 Hz, 1H), 1.92 (dd, J=14.9, 8.8 Hz, 1H), 1.47 (s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.34 (s, 3H); C NMR (126 MHz, CDCl) δ 163.33, 158.54, 155.32, 145.19, 132.61, 131.06, 130.22, 124.22, 122.62, 89.60, 89.35, 62.32, 34.75, 31.36, 31.25, 29.93, 14.39. ESI(+)−MS: 369.4 [M+1]. ee % was determined by chiral HPLC as follows: Agilent 1260 infinity liquid chromatograph, column Lux Cellulose-1 250*4.6 mm, mobile phase: acetonitrile/HO=80:20, 20° C., 0.7 mL/min; the retention time was 9.147 min.
FIG. 17
FIG. 18
The single crystal structure diagrams of WYC-209A and WYC-209B were shown in and respectively. The crystal belonged to monoclinic crystal system, the space group was P21, and the unit cell parameters were as follows: a=7.9718(11) Å, b=22.980(3) Å, c=10.4356(15 Å, α=90°, β=103.010(3)°, γ=90°, the unit cell volume was 1862.7(5) Å 3, the asymmetric unit number in unit cell Z=4, the density was 1.314 Mg/m3.
TABLE 1
Atomic coordinates (×10<sup>4</sup>) and isotropic displacement
parameters (Å<sup>2 </sup>× 10<sup>3</sup>)
x
y
z
U(eq)
S(1)
−4896(2)
5378(1)
9438(2)
64(1)
S(2)
9768(2)
9738(1)
5287(2)
60(1)
N(1)
1166(9)
7867(3)
5358(7)
68(2)
N(2)
3322(10)
7134(3)
5625(7)
70(2)
N(3)
1503(9)
8087(3)
9298(6)
60(2)
N(4)
3711(8)
7376(3)
9624(7)
63(2)
O(1)
−5859(9)
5779(3)
10024(8)
114(3)
O(2)
3797(11)
8790(3)
3055(8)
115(3)
O(3)
5939(11)
8134(4)
3481(9)
131(3)
O(4)
11314(7)
9798(4)
6315(6)
115(3)
O(5)
1038(10)
6474(3)
11962(9)
121(3)
O(6)
−1155(8)
7052(3)
11353(7)
97(2)
C(1)
−3530(11)
4926(3)
10594(7)
65(2)
C(2)
−2367(10)
4602(3)
9909(7)
64(2)
C(3)
−944(9)
4969(3)
9545(6)
48(2)
C(4)
−1618(8)
5549(3)
8933(5)
39(1)
C(5)
−3243(8)
5771(3)
8896(6)
40(1)
C(6)
−3757(9)
6307(3)
8344(6)
50(2)
C(7)
−2673(9)
6630(3)
7800(6)
50(2)
C(8)
−1059(9)
6425(3)
7787(6)
46(2)
C(9)
−526(9)
5892(3)
8371(6)
46(2)
C(10)
60(10)
6751(3)
7154(7)
53(2)
C(11)
913(11)
7023(3)
6582(7)
59(2)
C(12)
1867(9)
7364(3)
5806(6)
48(2)
C(13)
2019(10)
8163(3)
4650(8)
62(2)
C(14)
3524(10)
7974(3)
4364(7)
56(2)
C(15)
4120(12)
7454(3)
4910(9)
70(2)
C(16)
4393(13)
8342(4)
3535(9)
74(2)
C(17)
7143(16)
8549(6)
2894(10)
109(4)
C(18)
6503(17)
8410(6)
1579(12)
131(5)
C(19)
510(11)
5085(4)
10778(7)
74(2)
C(20)
−240(12)
4602(4)
8538(9)
74(2)
C(21)
8964(12)
10485(4)
5260(10)
55(2)
C(22)
7109(12)
10483(5)
4503(10)
52(2)
C(23)
5908(9)
10236(3)
5340(7)
50(2)
C(24)
6529(7)
9648(3)
5968(5)
37(1)
C(25)
8142(8)
9413(3)
6009(6)
42(2)
C(26)
8650(9)
8878(3)
6594(7)
55(2)
C(27)
7552(10)
8576(3)
7197(7)
57(2)
C(28)
5936(8)
8802(3)
7184(6)
41(1)
C(29)
5458(8)
9327(3)
6566(6)
41(1)
C(30)
4800(10)
8488(3)
7839(6)
51(2)
C(31)
3955(10)
8211(3)
8418(7)
52(2)
C(32)
2989(9)
7879(3)
9141(6)
48(2)
C(33)
2812(10)
7071(3)
10342(8)
63(2)
C(34)
1310(9)
7251(3)
10593(7)
49(2)
C(35)
662(11)
7776(3)
10023(8)
62(2)
C(36)
405(11)
6883(4)
11401(8)
66(2)
C(37)
−2274(14)
6657(6)
12000(11)
107(4)
C(38)
−1890(19)
6799(6)
13361(13)
130(5)
C(39)
4275(12)
10156(4)
4320(7)
72(2)
C(40)
5551(13)
10640(4)
6396(8)
74(2)
1
13
+
WYC-206 (34 mg, 0.105 mmol) was added to a flask, followed by addition of 1.5 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (26 mg, 0.105 mmol) was added. Then the reaction was continued for 1 hour under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (DCM:MeOH=12:1) to give WYC-210 (23 mg, 68%). H NMR (500 MHz, pyridine) δ 9.66 (s, 2H), 7.99-7.85 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 3.20 (t, J=10.7 Hz, 1H), 3.14-3.02 (m, 1H), 2.32 (dd, J=12.9, 10.4 Hz, 1H), 1.72 (dd, J=13.2, 9.4 Hz, 1H), 1.25 (s, 3H), 1.18 (s, 3H). C NMR (126 MHz, pyridine) δ 166.30, 159.03, 155.15, 145.73, 142.20, 132.56, 130.90, 130.31, 125.00, 124.29, 90.65, 88.52, 43.70, 34.73, 30.89, 30.62, 29.97. ESI(+)−MS: 341.1 [M+1].
3
2
2
3
3
3
1
13
+
6-Ethynyl-4,4-dimethylthiochroman (405.6 mg, 2 mmol) and 2-amino-4-iodobenzoic acid (263 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(42 mg, 0.06 mmol) and CuI (23 mg, 0.12 mmol). After the flask was purged with argon for 3 times to remove oxygen, 10 mL dry DMF and 0.2 mL dry EtN were added via syringe. Then the reaction was continued at 75° C. for 12 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=5:1) to give WYC-212 (286 mg, 85%). H NMR (500 MHz, CDCl) δ 7.88 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.1, 1.8 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.84 (d, J=1.3 Hz, 1H), 6.81 (dd, J=8.3, 1.5 Hz, 1H), 3.08-3.02 (m, 3H), 1.99-1.94 (m, 2H), 1.35 (s, 6H); C NMR (126 MHz, CDCl) δ 165.25, 165.23, 163.21, 161.20, 142.29, 134.42, 133.26, 133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12, 117.73, 117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62, 37.29, 33.13, 30.09, 23.38, 14.42. ESI(+)−MS: 338.3 [M+1].
1
13
+
3
3
WYC-212 (200 mg, 0.3 mmol) was added to a flask, followed by addition of 10 mg DMAP, then 5 mL dry pyridine was added under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, and 43 μL acetyl chloride was added dropwise. The reaction was continued for 10 min under the ice bath and another 5 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with methanol. The mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid to remove pyridine, then washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=20:1) to give WYC-213 (195 mg, 87%). H NMR (500 MHz, CDCl) δ 8.13 (d, J=8.1 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.58 (dd, J=8.1, 1.5 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.21 (dd, J=8.1, 1.8 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.09-3.03 (m, 2H), 2.47 (s, 3H), 1.99-1.92 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 160.95, 159.37, 146.56, 142.37, 134.76, 132.31, 131.05, 130.06, 129.32, 128.95, 128.49, 126.82, 117.47, 115.64, 95.32, 87.52, 37.23, 33.13, 30.09, 23.39, 21.54. ESI(+)−MS: 380.4 [M+1].
1
13
+
3
3
6-Ethynyl-4,4-dimethylthiochroman (2.03 g, 10 mmol) was added to a flask, followed by addition of 27 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (1.73 g, 10 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=3:1) to give 1-oxo-6-ethynyl-4,4-dimethylthiochroman (1.43 g, 72%). H NMR (500 MHz, CDCl) δ 7.41 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 2.93-2.74 (m, 3H), 2.14 (ddd, J=14.6, 10.5, 1.7 Hz, 1H), 1.58 (ddd, J=15.0, 8.7, 1.8 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H); C NMR (126 MHz, CDCl) δ 144.82, 138.91, 131.70, 130.53, 130.17, 125.60, 82.69, 79.39, 43.23, 34.47, 31.27, 31.13, 29.67. ESI(+)−MS: 219.3 [M+1].
3
2
2
3
1
13
+
1-Oxo-6-ethynyl-4,4-dimethylthiochroman (263 mg, 1.0 mmol) and 2-amino-4-iodobenzoic acid (262 mg, 1.2 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(42 mg, 0.06 mmol) and CuI (23 mg, 0.12 mmol). After the flask was purged with argon for 3 times to remove oxygen, 4 mL dry DMF and 0.2 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=50:1) to give the product (275 mg, 78%). H NMR (500 MHz, pyridine) δ 8.37 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.36 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 5.67 (s, 1H), 3.20-3.14 (m, 1H), 3.11-3.05 (m, 1H), 2.38 (ddd, J=14.2, 10.3, 1.7 Hz, 1H), 1.74-1.68 (m, 1H), 1.26 (s, 3H), 1.17 (s, 3H); C NMR (126 MHz, pyridine) δ 171.06, 152.34, 145.52, 140.46, 132.80, 131.65, 130.43, 130.20, 127.92, 126.32, 119.79, 118.58, 112.43, 91.82, 90.33, 55.01, 43.59, 34.63, 30.93, 30.63, 29.80. ESI(+)−MS: 354.3 [M+1].
1
13
+
3
3
WYC-214 (150 mg, 0.425 mmol) was added to a flask, followed by addition of sodium carbonate (176 mg, 1.275 mmol), then 3 mL dry DMF and iodomethane (40 μL, 0.637 mmol) were added under argon atmosphere. The mixture was slowly heated to 100° C., then the reaction was continued for 6 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=20:1) to give WYC-215 (143 mg, 92%). H NMR (500 MHz, CDCl) δ 7.84 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.48 (dd, J=8.0, 1.6 Hz, 1H), 6.87 (d, J=1.3 Hz, 1H), 6.81 (dd, J=8.3, 1.5 Hz, 1H), 3.88 (s, 3H), 3.20 (ddd, J=12.9, 10.6, 2.2 Hz, 1H), 3.10 (ddd, J=13.1, 8.7, 2.3 Hz, 1H), 2.46 (ddd, J=14.9, 10.5, 2.2 Hz, 1H), 1.89 (ddd, J=15.1, 8.7, 2.2 Hz, 3H), 1.47 (s, 3H), 1.33 (s, 3H); C NMR (126 MHz, CDCl) δ 168.19, 150.04, 144.92, 138.59, 131.48, 131.30, 130.34, 130.18, 128.13, 126.44, 119.72, 119.64, 111.06, 90.93, 90.26, 51.84, 43.28, 34.57, 31.36, 31.21, 29.73. ESI(+)−MS: 368.4 [M+1].
1
13
+
3
3
WYC-212 (50 mg, 0.15 mmol) was added to a flask, followed by addition of 2 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.15 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 2 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=10:1) to give WYC-216 (14 mg, 25%). H NMR (500 MHz, CDCl) δ 7.84 (d, J=8.3 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.17 (dd, J=8.1, 1.7 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.83 (d, J=1.3 Hz, 1H), 6.79 (dd, J=8.3, 1.4 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.06-3.03 (m, 2H), 1.97-1.94 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). C NMR (126 MHz, CDCl) δ 167.92, 150.10, 142.22, 133.72, 131.35, 129.95, 129.19, 129.02, 126.70, 119.55, 119.39, 118.23, 110.80, 91.99, 88.37, 60.61, 37.36, 33.12, 30.13, 23.37, 14.50. ESI(+)−MS: 366.4 [M+1].
1
13
+
3
3
WYC-216 (80 mg, 0.22 mmol) was added to a flask, and 6 mg DMAP was added. The flask was purged with argon, then 2 mL dry pyridine was added. Then the mixture was cooled to 0° C. under an ice bath, and acetyl chloride (31 μL, 0.44 mmol) was added dropwise. The reaction was continued for 10 min under the ice bath and another 9 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with methanol. The mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid to remove pyridine, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1) to give WYC-217 (71 mg, 79%). H NMR (500 MHz, CDCl) δ 11.12 (s, 1H), 8.88 (d, J=1.4 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.20 (dd, J=3.6, 1.7 Hz, 1H), 7.18 (dd, J=3.8, 1.7 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.06-3.03 (m, 2H), 2.24 (s, 3H), 1.97-1.94 (m, 2H), 1.42 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 169.17, 168.11, 142.25, 141.59, 133.98, 130.81, 130.17, 130.04, 129.24, 126.70, 125.26, 122.97, 118.06, 114.16, 93.43, 88.37, 61.65, 37.36, 33.13, 30.13, 25.68, 23.38, 14.34. ESI(+)−MS: 408.4 [M+1].
3
2
2
3
1
13
+
Ethyl 2-amino-4-iodobenzoate (262.0 mg, 1.2 mmol) and 1-oxo-6-ethynyl-4,4-dimethylthiochroman (263.0 mg, 1 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(42 mg, 0.06 mmol) and CuI (23 mg, 0.12 mmol). After the flask was purged with argon for 3 times to remove oxygen, 15 mL dry DMF and 0.2 mL dry EtN were added via syringe. The reaction was continued at 75° C. for 12 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (DCM:MeOH=40:1) to give WYC-218 (275 mg, 78%). H NMR (500 MHz, pyridine) δ 8.39 (d, J=8.1 Hz, 1H), 7.97-7.82 (m, 2H), 7.61 (s, 1H), 7.38 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 3.25-3.01 (m, 2H), 2.40 (ddd, J=14.2, 10.3, 1.7 Hz, 1H), 1.73 (ddd, J=14.8, 8.8, 1.5 Hz, 1H), 1.28 (s, 3H), 1.19 (s, 3H). C NMR (126 MHz, pyridine) δ171.75, 153.03, 150.76, 150.74, 150.55, 150.53, 150.33, 150.31, 146.21, 141.15, 133.49, 132.34, 131.12, 130.89, 128.61, 127.01, 120.48, 119.27, 113.12, 92.51, 91.02, 44.28, 35.32, 31.62, 31.32, 30.49. ESI(+)−MS: 382.4 [M+1].
1
13
+
3
3
WYC-212 (100 mg, 0.3 mmol) was added to a flask, followed by addition of sodium carbonate (125 mg, 0.9 mmol). Then 3 mL dry DMF and iodomethane (28 μL, 0.445 mmol) were added under argon atmosphere, the reaction solution was slowly heated to 100° C. and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=20:1) to give WYC-219 (43 mg, 39%) and 3-69-2-2 (45 mg, 43%). H NMR (500 MHz, CDCl) δ 7.87 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 7.20 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 6.78 (d, J=8.2 Hz, 1H), 3.86 (s, 3H), 3.08-3.02 (m, 2H), 2.95 (s, 3H), 1.99-1.94 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 168.77, 151.15, 142.24, 133.75, 131.64, 130.02, 129.68, 129.24, 126.71, 118.37, 118.24, 114.31, 110.05, 92.11, 88.89, 51.79, 37.38, 33.14, 30.15, 23.39. ESI(+)−MS: 366.2 [M+1].
1
13
+
3
3
WYC-212 (100 mg, 0.3 mmol) was added to a flask, followed by addition of potassium carbonate (125 mg, 0.9 mmol). Dry DMF (3 mL) was added under dry argon atmosphere, and Mel (28 μL, 0.445 mmol) was added dropwise. The reaction was continued at 100° C. for 8 h. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, successively washed with 1 moL/L HCl solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=20:1) to give WYC-220(45 mg, 44%). H NMR (500 MHz, cdcl) δ 7.83 (d, J=8.3 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.18 (dd, J=8.1, 1.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.86 (d, J=1.4 Hz, 1H), 6.81 (dd, J=8.3, 1.5 Hz, 1H), 3.88 (s, 3H), 3.08-3.02 (m, 2H), 2.00-1.93 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, cdcl) δ 168.25, 149.81, 142.19, 133.74, 131.31, 129.92, 129.16, 129.15, 126.67, 119.74, 119.47, 118.15, 110.58, 92.12, 88.28, 51.75, 37.32, 33.08, 30.09, 23.34. ESI(+)−MS: 352.4 [M+1].
1
13
+
3
3
WYC-214 (152 mg, 0.42 mmol) was added to a flask, followed by addition of 10 mg DMAP. 5 mL dry dichloromethane and 0.212 mL pyridine were added under argon atmosphere. After the reaction solution was cooled to 0° C. under an ice bath, acetyl chloride (67 μL, 0.84 mmol) was added dropwise, and the reaction was continued for 10 min under the ice bath and another 12 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with methanol. The mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid to remove pyridine, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:3) to give WYC-221(147 mg, 89%). H NMR (500 MHz, CDCl) δ 8.12 (d, J=8.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.57 (dd, J=8.1, 1.5 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.21 (dd, J=8.1, 1.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 3.07-3.03 (m, 2H), 2.46 (s, 3H), 1.99-1.94 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 160.87, 159.36, 146.58, 142.34, 134.73, 132.26, 131.01, 130.04, 129.30, 128.95, 128.45, 126.80, 117.45, 115.64, 95.28, 87.51, 37.21, 33.11, 30.07, 23.38, 21.54. ESI(+)−MS: 396.2 [M+1].
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13
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3
3
2-(3-Bromophenyl)ethanol (676 μL, 5 mmol) was added to a flask, followed by addition of 10 mL dry dichloromethane, then DMP (2.5 g, 6 mmol) was added under an ice bath. The reaction was continued for 2 h under the ice bath and another 0.5 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to 0° C. and the reaction was quenched with sodium thiosulfate solution. The mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=15:1) to give 2-(3-bromophenyl)acetaldehyde (0.86g, 87%). H NMR (300 MHz, CDCl) δ 9.74 (1H, t, J=2.0), 7.46-7.37 (2H, m), 7.30-7.14 (2H, m), 3.67 (2H, d, J=2.0). C NMR (75 MHz, CDCl) δ 198.9, 134.5, 133.0, 131.0, 130.9, 128.7, 123.3, 60.8. ESI(+)−MS: 199.1 [M+1].
3
2
3
3
3
3
1
13
1
13
2-(3-bromophenyl)acetaldehyde (400 mg, 2.02 mmol) and PhPCH=COEt (703 mg, 2.02 mmol) were added to a flask, followed by addition of 10 mL dry toluene under argon atmosphere. The reaction was continued at 90° for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to 0° C., diluted with ethyl acetate, washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=250:1) to give ethyl 4-(3-bromophenyl)-2-butenoate (514 mg, 96%). E-configuration: H NMR (500 MHz, CDCl) δ 7.36 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.11-6.99 (m, 2H), 5.80 (dt, J=15.6, 1.6 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.47 (dd, J=6.8, 1.0 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H). C NMR (126 MHz, CDCl) δ 166.29, 146.15, 140.06, 131.88, 130.29, 129.90, 127.53, 123.02, 122.77, 77.41, 77.16, 76.91, 60.44, 38.00, 14.32. Z-configuration: H NMR (500 MHz, CDCl) δ 7.38 (s, 1H), 7.36-7.33 (m, 1H), 7.16 (dd, J=4.1, 1.4 Hz, 2H), 6.30 (dt, J=11.4, 7.6 Hz, 1H), 5.88 (dt, J=11.4, 1.7 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.00 (dd, J=7.6, 1.4 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H). C NMR (126 MHz, CDCl) δ 166.33, 146.76, 141.84, 131.76, 130.25, 129.60, 127.41, 122.74, 120.73, 60.23, 34.73, 14.39.
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3
3
Ethyl 4-(3-bromophenyl)-2-butenoate (1.05 g, 3.92 mmol) was added to a flask, followed by addition of (10% wt) dry Pd/C (220 mg, 0.194 mmol), then 20 mL ethyl acetate was added under argon atmosphere. After the flask was purged with hydrogen for 3 times, the reaction was continued at room temperature under normal pressure for 24 h and monitored by TLC. After completion of the reaction, the reaction solution was filtered, concentrated and purified by flash column chromatography (PE:EtOAc=15:1) to give ethyl 4-(3-bromophenyl)butanoate (1.04 g, 98%). H NMR (500 MHz, CDCl) δ 7.32 (dd, J=9.5, 1.3 Hz, 2H), 7.16-7.08 (m, 2H), 4.12 (q, J=7.1 Hz, 2H), 2.64-2.59 (m, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.96-1.90 (m, 2H), 1.25 (t, J=7.1 Hz, 3H). C NMR (126 MHz, CDCl) δ 173.27, 143.87, 131.59, 130.01, 129.18, 127.22, 122.51, 60.40, 34.82, 33.57, 26.36, 14.33. ESI(+)−MS: 271.2 [M+1].
1
13
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3
3
Ethyl 4-(3-bromophenyl)butanoate (0.53 g, 1.96 mmol) was added to a flask, followed by addition of 15 mL tetrahydrofuran under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, methylmagnesium bromide (2 mL, 5.89 mmol) was added dropwise. The reaction was continued for 3 h at 0° C. and another 1 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to 0° C. and the reaction was quenched with ice water. The mixture was diluted with ethyl acetate, neutralized with 1 mol/L hydrochloric acid, washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=15:1) to give 5-(3-bromophenyl)-2-methyl-2-pentanol(466 mg, 93%). H NMR (400 MHz, CDCl) δ 7.37-7.26 (m, 2H), 7.22-7.10 (m, 2H), 2.62 (dt, J=15.0, 7.7 Hz, 2H), 1.76-1.64 (m, 2H), 1.56-1.47 (m, 2H), 1.22 (s, 6H). C NMR (126 MHz, CDCl) δ 144.81, 131.40, 129.84, 128.81, 127.05, 122.33, 70.73, 43.29, 35.95, 29.22, 26.00. ESI(+)−MS: 257.1 [M+1].
1
13
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3
3
5-(3-Bromophenyl)-2-methyl-2-pentanol (340 mg, 1.33 mmol) was added to a flask, followed by addition of 2 mL dry dichloromethane under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, 0.2 mL concentrated sulfuric acid was added dropwise, and the reaction was continued at room temperature for 4 h and monitored by TLC. After completion of the reaction, the reaction solution was diluted with water, neutralized with 1 mol/L sodium hydroxide to neutralize sulfuric acid, diluted with ethyl acetate, washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give 320 mg white solid, which was added to a flask, followed by addition of 4.3 mL. 71 mg chromium trioxide was dissolved in a mixed solution of 0.648 mL acetic acid and 0.342 mL acetic anhydride, which was added to the flask under an ice bath. The reaction was continued for 2 h and monitored by TLC. After completion of the reaction, the reaction solution was diluted with EtOAc, washed three times with water, then washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1) to give 7-bromo-4,4-dimethyl-3,4-dihydronaphth-1-(2H)-one (268 mg, 80%). H NMR (400 MHz, CDCl) δ 7.37 (dd, J=8.5, 1.6 Hz, 1H), 7.33-7.21 (m, 2H), 2.24-2.05 (m, 2H), 1.87-1.77 (m, 1H), 1.58-1.49 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H). C NMR (126 MHz, CDCl) δ 197.03, 151.09, 136.63, 132.77, 130.15, 128.04, 120.57, 36.86, 35.04, 33.89, 29.65. ESI(+)−MS: 253.1 [M+1].
1
13
+
3
3
7-Bromo-4,4-dimethyl-3,4-dihydronaphth-1-(2H)-one (340 mg, 1.35 mmol) was added to a flask, followed by addition of 3 mL tetrahydrofuran under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, phenylmagnesium bromide (2.7 mL, 2.7 mmol) was added dropwise. The reaction was continued for 0.5 h at 0° C. and another 18 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to 0° C. and the reaction was quenched with ice water. The mixture was diluted with ethyl acetate, neutralized with 1 mol/L hydrochloric acid, washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1) to give 7-bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphth-1-ol (280 mg, 63%). H NMR (400 MHz, CDCl) δ 7.39-7.08 (m, 8H), 2.24-2.05 (m, 2H), 1.87-1.77 (m, 1H), 1.58-1.49 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H). C NMR (126 MHz, CDCl) δ 148.11, 145.41, 143.32, 131.50, 131.18, 128.46, 128.08, 127.15, 126.59, 119.96, 75.87, 37.69, 34.77, 34.09, 31.56, 31.45. ESI(+)−MS: 331.1 [M+1].
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7-Bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (260 mg, 0.79 mmol) was added to a flask, followed by addition of p-toluenesulfonic acid (27 mg, 0.16 mmol), then 2 mL dry toluene was added under argon atmosphere. The reaction was continued at 75° C. for 0.5 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with ice water. The mixture was diluted with ethyl acetate, washed with saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=250:1) to give 6-bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (224 mg, 91%). H NMR (500 MHz, CDCl) δ 7.44-7.40 (m, 2H), 7.39-7.33 (m, 4H), 7.24 (d, J=8.3 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 6.03 (t, J=4.7 Hz, 1H), 2.36 (d, J=4.7 Hz, 2H), 1.34 (s, 6H). C NMR (126 MHz, CDCl) δ 145.59, 144.16, 140.35, 138.75, 136.15, 133.57, 131.80, 130.41, 128.72, 128.56, 127.87, 127.46, 127.02, 125.79, 119.96, 63.05, 38.87, 33.65, 28.18. ESI(+)−MS: 312.1 [M+1].
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6-Bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (310 mg, 1.0 mmol) and trimethylethynylsilane (0.28 μL, 2 mmol) was added to a flask, followed by addition of Pd(PPh)Cl(21 mg, 0.03 mmol) and CuI (11 mg, 0.06 mmol). After the flask was purged with argon for 3 times to remove oxygen, 5 mL dry DMF and 0.2 mL dry EtN were added via syringe. The reaction was continued at room temperature over night and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (petroleum ether) to give ((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)trimethylsilane (275 mg, 83%). H NMR (500 MHz, CDCl) δ 7.44-7.38 (m, 2H), 7.36-7.32 (m, 4H), 7.28 (d, J=7.9 Hz, 10H), 7.11 (d, J=1.6 Hz, 1H), 5.97 (t, J=4.7 Hz, 1H), 2.33 (d, J=4.7 Hz, 2H), 1.31 (s, 6H), 0.19 (s, 9H). C NMR (126 MHz, CDCl) δ 146.01, 140.79, 139.09, 133.98, 131.51, 129.25, 128.83, 128.49, 127.29, 127.27, 123.92, 120.66, 105.45, 93.41, 38.88, 33.90, 28.19, 0.16. ESI(+)−MS: 331.2 [M+1].
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3
((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)trimethylsilane (300 mg, 0.91 mmol) was added to a flask, followed by addition of TBAF (30 Mg, 0.115 mmol) and 2 mL dry tetrahydrofuran. The reaction was continued for 4 h and monitored by TLC. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=1000:1) to give 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (225 mg, 96.6%). H NMR (500 MHz, CDCl) δ 77.47-77.34 (m, 7H), 77.22 (d, J=1.6 Hz, 1H), 76.04 (t, J=4.7 Hz, 1H), 72.98 (s, 1H), 72.39 (d, J=4.7 Hz, 2H), 71.38 (s, 6H). C NMR (126 MHz, CDCl) δ 146.23, 140.58, 138.97, 134.13, 131.41, 129.62, 128.77, 128.49, 127.34, 127.27, 124.04, 119.59, 83.98, 76.59, 38.83, 33.85, 28.18. ESI(+)−MS: 259.2 [M+1].
Embodiment 39: methyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-hydroxybenzoate
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6-Ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (116 mg, 0.45 mmol) and methyl 2-hydroxy-4-iodobenzoate (μL, 0.9 mmol) was added to a flask, followed by addition of Pd(PPh)Cl(9.5 mg, 0.0135 mmol) and CuI (5.1 mg, 0.027 mmol). After the flask was purged with argon for 3 times to remove oxygen, 3 mL dry DMF and 0.2 mL dry EtN were added via syringe. The reaction was continued at room temperature for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=500:1) to give WYC-301 (155 mg, 79%). H NMR (500 MHz, CDCl) δ 10.75 (s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.43 (dd, J=7.7, 7.1 Hz, 7H), 7.37 (dd, J=9.3, 3.7 Hz, 4H), 7.21 (d, J=1.3 Hz, 1H), 7.09 (d, J=1.2 Hz, 1H), 6.97 (dd, J=8.2, 1.2 Hz, 1H), 6.02 (t, J=4.6 Hz, 1H), 3.94 (s, 3H), 2.37 (d, J=4.7 Hz, 2H), 1.36 (s, 6H). C NMR (126 MHz, CDCl) δ 170.27, 161.31, 146.42, 140.63, 138.99, 134.24, 131.17, 130.83, 129.82, 129.20, 128.80, 128.54, 127.41, 127.38, 124.18, 122.47, 120.36, 120.07, 111.98, 92.99, 87.93, 52.47, 38.85, 33.94, 28.19. ESI(+)−MS: 409.3 [M+1].
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WYC-301 (250 mg, 0.613 mmol) was added to a flask, followed by addition of sodium ethoxide (125 mg, 1.83 mmol) and 5 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1) to give WYC-302 (230 mg, 92%). H NMR (500 MHz, CDCl) δ 10.82 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.45-7.39 (m, 3H), 7.38-7.34 (m, 4H), 7.19 (d, J=1.5 Hz, 1H), 7.07 (d, J=1.4 Hz, 1H), 6.95 (dd, J=8.2, 1.5 Hz, 1H), 6.01 (t, J=4.7 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 2.37 (d, J=4.7 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 169.92, 161.39, 146.40, 140.65, 139.01, 134.25, 131.18, 130.70, 129.83, 129.20, 128.82, 128.55, 127.42, 127.39, 124.19, 122.39, 120.37, 120.11, 112.25, 92.89, 87.99, 61.68, 38.86, 33.96, 28.21, 14.32. ESI(+)−MS: 423.4 [M+1].
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2-Fluoro-4-iodobenzoic acid (1.0 g, 3.76 mmol) was added to a flask, followed by addition of 10 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.5 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=15:1) to give ethyl 2-fluoro-4-iodobenzoate (990 mg, 90%). H NMR (500 MHz, CDCl) δ 7.62-7.57 (m, 1H), 7.52 (dd, J=8.3, 1.6 Hz, 1H), 7.49 (dd, J=9.9, 1.5 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). C NMR (126 MHz, CDCl) δ 163.87, 163.84, 162.18, 160.06, 133.48, 133.45, 133.05, 133.04, 126.54, 126.34, 118.76, 118.68, 99.59, 99.52, 61.59, 14.29. ESI(+)−MS: 294.1 [M+1].
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6-Ethynyl-4,4-dimethylthiochroman (275 mg, 1.36 mmol) and ethyl 2-fluoro-4-iodobenzoate (200 mg, 0.68 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(28.6 mg, 0.0408 mmol) and CuI (15.5 mg, 0.0816 mmol).
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After the flask was purged with argon for 3 times to remove oxygen, 3 mL dry DMF and 0.3 mL dry EtN were added via syringe. The reaction was continued at 80° C. for 6 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=200:1) to give WYC-303 (215 mg, 86%). H NMR (500 MHz, CDCl) δ 7.90 (t, J=7.8 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.32 (dd, J=8.1, 1.4 Hz, 1H), 7.28 (d, J=1.4 Hz, 1H), 7.25 (d, J=1.4 Hz, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.07-3.03 (m, 2H), 1.98-1.94 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 164.12, 164.09, 162.75, 160.68, 142.32, 134.45, 132.15, 132.14, 129.98, 129.20, 127.08, 127.05, 126.78, 119.79, 119.60, 117.57, 93.98, 87.00, 86.98, 61.55, 37.25, 33.12, 30.09, 23.37, 14.40. ESI(+)−MS: 369.4 [M+1].
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3
WYC-303 (15 mg, 0.04 mmol) was added to a flask, followed by addition of sodium ethoxide (8.3 mg, 0.12 mmol) and 1 mL tetrahydrofuran. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:1) to give WYC-304 (11 mg, 80%). H NMR (500 MHz, CDCl) δ 7.99 (t, J=7.9 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.35 (dd, J=8.1, 1.5 Hz, 1H), 7.30 (dd, J=11.3, 1.4 Hz, 1H), 7.19 (dd, J=8.1, 1.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 3.07-3.04 (m, 3H), 1.98-1.95 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 167.53, 163.34, 161.26, 142.36, 134.65, 132.80, 131.19, 131.11, 130.04, 129.25, 127.25, 127.22, 126.81, 119.89, 119.70, 117.45, 116.98, 94.69, 86.92, 37.24, 33.14, 30.09, 23.39. ESI(+)−MS: 339.3 [M+1].
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6-Ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene (180 mg, 0.7 mmol) and ethyl 2-fluoro-4-iodo-benzoate (410 mg, 1.4 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(30 mg, 0.042 mmol) and CuI (16.0 mg, 0.084 mmol). After the flask was purged with argon for 3 times to remove oxygen, 5 mL dry DMF and 0.5 mL dry EtN were added via syringe. The reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=200:1) to give WYC-305 (215 mg, 72%). H NMR (500 MHz, CDCl) δ 7.87 (t, J=7.8 Hz, 1H), 7.44-7.39 (m, 7H), 7.37 (ddd, J=6.3, 3.4, 1.5 Hz, 4H), 7.29-7.26 (m, 1H), 7.24-7.18 (m, 2H), 6.02 (t, J=4.7 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 2.37 (d, J=4.7 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 164.12, 164.09, 162.70, 160.63, 146.67, 140.62, 138.95, 134.33, 132.08, 132.07, 131.17, 129.92, 129.84, 129.20, 128.82, 128.57, 127.53, 127.41, 127.17, 127.14, 124.25, 119.91, 119.77, 119.72, 118.51, 118.43, 93.66, 86.96, 86.94, 61.55, 38.84, 33.98, 28.20, 14.39. ESI(+)−MS: 425.5 [M+1].
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WYC-305 (70 mg, 0.19 mmol) was added to a flask, followed by addition of sodium ethoxide (26 mg, 0.38 mmol) and 2 mL tetrahydrofuran. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=2:1) to give WYC-306 (53 mg, 75%). H NMR (500 MHz, CDCl) δ 7.95 (t, J=7.9 Hz, 1H), 7.44-7.39 (m, 7H), 7.39-7.35 (m, 4H), 7.30 (dd, J=8.2, 1.4 Hz, 1H), 7.24 (d, J=1.3 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 6.02 (t, J=4.7 Hz, 1H), 2.37 (d, J=4.7 Hz, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 167.97, 163.32, 161.23, 146.83, 140.60, 138.92, 134.36, 132.74, 131.22, 129.24, 128.83, 128.58, 127.57, 127.43, 127.36, 127.33, 124.29, 120.02, 119.83, 119.64, 116.90, 94.43, 86.86, 38.84, 34.00, 28.20. ESI(+)−MS: 395.4 [M+1].
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3-Fluoro-4-iodobenzoic acid (0.95g, 3.57 mmol) was added to a flask, followed by addition of 5 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.3 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=15:1) to give ethyl 3-fluoro-4-iodobenzoate (920 mg, 88%). H NMR (500 MHz, CDCl) δ 7.80 (dd, J=8.2, 6.2 Hz, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.53 (dd, J=8.2, 1.8 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H). C NMR (126 MHz, CDCl) δ 164.99, 164.97, 162.64, 160.67, 139.61, 139.59, 132.94, 132.89, 126.51, 126.48, 116.46, 116.26, 87.88, 87.67, 61.65, 14.33. ESI(+)−MS: 295.1 [M+1].
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4-Iodo-3-nitrobenzoic acid (1.9 g, 6.48 mmol) was added to a flask, followed by addition of 10 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.6 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 6 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=10:1) to give ethyl 4-iodo-3-nitrobenzoate (1.88 g, 90.5%). H NMR (500 MHz, CDCl) δ 8.39 (d, J=2.0 Hz, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.85 (dd, J=8.2, 2.0 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz,3H). C NMR (126 MHz, CDCl) δ 164.03, 153.15, 142.33, 133.47, 131.96, 125.98, 92.02, 62.16, 14.29. ESI(+)−MS: 322.1 [M+1].
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6-Ethynyl-4,4-dimethylthiochroman (405.6 mg, 2 mmol) and ethyl 3-fluoro-4-iodobenzoate (294 mg, 1.0 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(84 mg, 0.12 mmol) and CuI (46.0 mg, 0.24 mmol). After the flask was purged with argon for 3 times to remove oxygen, 5 mL dry DMF and 0.5 mL dry EtN were added via syringe. The reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=500:3) to give WYC-307(250 mg, 68%). H NMR (500 MHz, CDCl) δ 7.81 (dd, J=8.0, 1.3 Hz, 1H), 7.76 (dd, J=9.8, 1.3 Hz, 1H), 7.56 (dd, J=11.1, 4.2 Hz, 2H), 7.22 (dd, J=8.1, 1.6 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 3.05 (dd, J=7.1, 5.1 Hz, 2H), 1.98-1.94 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 165.25, 165.23, 163.21, 161.20, 142.29, 134.42, 133.26, 133.25, 131.70, 131.64, 129.97, 129.27, 126.75, 125.15, 125.12, 117.73, 117.05, 116.92, 116.66, 116.47, 98.04, 98.02, 81.71, 61.62, 37.29, 33.13, 30.09, 23.38, 14.42. ESI(+)−MS: 369.3 [M+1].
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6-Ethynyl-4,4-dimethylthiochroman (405.6 mg, 2 mmol) and ethyl 3-nitro-4-iodobenzoate (303 mg, 1.0 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(84 mg, 0.12 mmol) and CuI (46.0 mg, 0.24 mmol). After the flask was purged with argon for 3 times to remove oxygen, 5 mL dry DMF and 0.5 mL dry EtN were added via syringe. The reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=50:1) to give WYC-308 (384 mg, 97%). H NMR (400 MHz, CDCl) δ 8.69 (d, J=1.2 Hz, 1H), 8.20 (dd, J=8.1, 1.6 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.23-7.25 (m, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 3.04 (dd, J=7.2, 4.9 Hz, 2H), 1.98-1.85 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). C NMR (126 MHz, CDCl) δ 164.34, 149.33, 142.43, 135.66, 134.63, 133.24, 130.35, 130.30, 129.65, 126.86, 126.01, 123.20, 117.23, 101.65, 84.50, 62.11, 37.16, 33.12, 30.04, 23.43, 14.43. ESI(+)−MS: 396.2 [M+1].
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3
WYC-308 (100 mg, 0.25 mmol) was added to a flask, followed by addition of sodium ethoxide (35 mg, 0.5 mmol) and 2 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (DCM:MeOH=20:1) to give WYC-309 (83 mg, 90.4%). H NMR (400 MHz, CDCl) δ 8.78 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.24 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.10-3.04 (m, 2H), 2.00-1.93 (m, 2H), 1.36 (s, 6H). C NMR (101 MHz, CDCl) δ 168.58, 149.36, 142.46, 135.91, 134.83, 133.69, 130.42, 129.73, 126.89, 126.73, 124.17, 117.12, 102.51, 84.56, 37.14, 33.13, 30.11, 30.04, 23.45. ESI(+)−MS: 3 [M+1].
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WYC-307 (332 mg, 0.9 mmol) was added to a flask, followed by addition of sodium ethoxide (83 mg, 1.2 mmol) and 7 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=1:1) to give WYC-310 (303 mg, 99%). H NMR (400 MHz, CDCl) δ 7.85 (dd, J=8.1, 1.2 Hz, 1H), 7.80 (dd, J=9.7, 1.1 Hz, 1H), 7.61-7.56 (m, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 3.11-2.99 (m, 2H), 1.99-1.90 (m, 2H), 1.34 (s, 6H). C NMR (101 MHz, CDCl) δ 169.23, 163.46, 160.95, 142.34, 134.64, 133.45, 130.03, 129.32, 126.79, 125.79, 117.62, 117.27, 117.04, 110.16, 98.73, 81.63, 37.28, 33.15, 30.10, 23.40. ESI(+)−MS: 341.2 [M+1].
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3
3
WYC-308(100 mg, 0.25 mmol) was added to a flask, followed by addition of 5 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (60 mg, 0.25 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=3:1) to give WYC-311 (92 mg, 88%). H NMR (500 MHz, CDCl) δ 8.73 (d, J=1.6 Hz, 1H), 8.26 (dd, J=8.1, 1.7 Hz, 1H), 7.80 (dd, J=13.0, 8.1 Hz, 2H), 7.66 (d, J=1.5 Hz, 1H), 7.57 (dd, J=8.0, 1.6 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 3.23 (ddd, J=12.8, 10.3, 2.3 Hz, 1H), 3.12 (ddd, J=13.1, 9.1, 2.3 Hz, 1H), 2.44 (ddd, J=15.1, 10.3, 2.3 Hz, 1H), 1.91 (ddd, J=15.1, 9.0, 2.3 Hz, 1H), 1.48 (s, 3H), 1.43 (t, J=7.1 Hz, 3H), 1.35 (s, 3H). C NMR (126 MHz, CDCl) δ 164.10, 149.65, 145.16, 139.98, 134.95, 133.42, 131.67, 131.30, 130.53, 130.26, 126.01, 125.35, 122.13, 98.90, 86.27, 62.24, 43.39, 34.67, 31.36, 31.24, 29.89, 14.40. ESI(+)−MS: 412.2 [M+1].
3
2
2
3
3
33
1
13
+
1-Oxo-6-ethynyl-4,4-dimethylthiochroman (223 mg, 1.2 mmol) and ethyl 3-fluoro-4-iodobenzoate (200 mg, 0.8 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(32 mg, 0.0459 mmol) and CuI (17.5 mg, 0.0918 mmol). After the flask was purged with argon for 3 times to remove oxygen, 3 mL dry DMF and 0.3 mL dry EtN were added via syringe. Then the reaction was continued at 75° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=3:2) to give WYC-312 (254 mg, 82.5%). H NMR (500 MHz, CDCl) δ 7.84 (dd, J=8.0, 1.5 Hz, 1H), 7.81-7.75 (m, 2H), 7.63-7.58 (m, 2H), 7.54 (dd, J=8.0, 1.6 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.22 (ddd, J=12.9, 10.4, 2.3 Hz, 1H), 3.11 (ddd, J=13.1, 8.9, 2.4 Hz, 1H), 2.46 (ddd, J=15.1, 10.4, 2.3 Hz, 1H), 1.91 (ddd, J=15.1, 8.9, 2.3 Hz, 1H), 1.49 (s, 3H), 1.41 (t, J=7.1 Hz, 4H), 1.35 (s, 4H). C NMR (126 MHz, CDCl) δ 165.04, 163.42, 161.41, 145.01, 139.21, 133.49, 132.58, 132.52, 132.26, 132.18, 131.33, 130.29, 130.27, 128.67, 128.57, 125.87, 125.22, 125.19, 116.78, 116.60, 116.06, 115.93, 96.03, 96.00, 84.16, 61.73, 43.34, 34.62, 31.36, 31.22, 29.81, 14.40. ESI(+)−MS: 385.2 [M+1].
Embodiment 54: ethyl 2,3-difluoro-4-iodobenzoate
1
13
+
3
3
2,3-Difluoro-4-iodobenzoic acid (0.5 g, 1.76 mmol) was added to a flask, followed by addition of 4 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.3 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 6 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=10:1) to give ethyl 2,3-difluoro-4-iodobenzoate (0.48 g, 87%). H NMR (500 MHz, CDCl) δ 7.55 (ddd, J=8.4, 5.2, 1.8 Hz, 1H), 7.44 (ddd, J=8.4, 6.3, 1.8 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). C NMR (126 MHz, CDCl) δ 163.13, 163.10, 163.08, 152.43, 152.31, 150.69, 150.56, 150.46, 150.35, 148.56, 148.44, 133.21, 133.17, 127.48, 127.44, 121.24, 121.18, 88.19, 88.01, 61.98, 14.27. ESI(+)−MS: 313.1 [M+1].
3
2
2
3
3
3
1
13
+
Ethyl 2,3-difluoro-4-iodobenzoate (200 mg, 0.64 mmol) and 6-ethynyl-4,4-dimethylthiochroman (195 mg, 0.96 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(20 mg, 0.0288 mmol) and CuI (11 mg, 0.0576 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.2 mL dry EtN were added via syringe. Then the reaction was continued at 75° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1) to give WYC-313 (215 mg, 82%). H NMR (500 MHz, CDCl) δ 7.65 (ddd, J=8.3, 6.5, 1.8 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.28 (ddd, J=8.0, 4.9, 1.9 Hz, 1H), 7.21 (dd, J=8.2, 1.8 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.07-3.03 (m, 2H), 1.97-1.93 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). C NMR (126 MHz, CDCl) δ 163.34, 152.40, 152.29, 151.69, 151.58, 150.38, 150.27, 149.60, 149.49, 142.32, 134.92, 129.98, 129.27, 127.01, 126.98, 126.76, 126.01, 125.97, 120.13, 120.07, 118.59, 118.51, 117.25, 99.26, 99.23, 80.63, 80.60, 61.87, 37.18, 33.09, 30.02, 23.35, 14.33. ESI(+)−MS: 387.2 [M+1].
1
−
WYC-313 (84 mg, 0.218 mmol) was added to a flask, followed by addition of sodium ethoxide (44.4 mg, 0.653 mmol) and 2 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=1:1) to give WYC-314 (68 mg, 87.5%). H NMR (500 MHz, pyridine) δ 8.01 (t, J=7.4 Hz, 1H), 7.82 (s, 1H), 7.45 (t, J=7.2 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 2.95-2.89 (m, 2H), 1.78-1.71 (m, 2H), 1.19 (s, 6H). ESI(−)−MS: 357.2 [M−1].
1
13
+
3
3
WYC-313 (90 mg, 0.233 mmol) was added to a flask, followed by addition of 5 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (58 mg, 0.233 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=3:1) to give WYC-315 (76 mg, 78%). H NMR (500 MHz, CDCl) δ 7.76 (d, J=8.0 Hz, 1H), 7.71-7.65 (m, 1H), 7.62 (s, 1H), 7.53 (dd, J=8.0, 0.8 Hz, 1H), 7.32 (dd, J=10.4, 3.9 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.26-3.18 (m, 1H), 3.15-3.07 (m, 1H), 2.44 (ddd, J=14.8, 10.3, 2.0 Hz, 1H), 1.90 (ddd, J=15.1, 8.9, 2.0 Hz, 1H), 1.47 (s, 3H), 1.40 (t, J=7.1 Hz, 3H), 1.34 (s, 3H). C NMR (126 MHz, CDCl) δ 163.22, 163.20, 163.17, 152.69, 152.58, 151.65, 151.54, 150.66, 150.55, 149.55, 145.10, 139.57, 131.40, 130.30, 130.27, 127.25, 127.22, 126.15, 126.12, 125.41, 121.05, 120.99, 117.60, 117.59, 117.50, 117.48, 97.09, 97.05, 82.93, 82.90, 62.02, 43.34, 34.63, 31.34, 31.21, 29.82, 14.32. ESI(+)−MS: 403.1 [M+1].
1
13
+
3
3
Methyl 3-amino-4-iodobenzoate (1.5 g, 5.43 mmol) was added to a flask, followed by addition of 20 mL dry dichloromethane and 4.5 mL dry triethylamine, then 0.77 mL acetyl chloride was added dropwise under an ice bath. The reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction was quenched with methanol. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1) to give methyl 3-acetamido-4-iodobenzoate (1.34 g, 77.5%). H NMR (500 MHz, CDCl) δ 8.75 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.54-7.39 (m, 2H), 3.90 (s, 3H), 2.25 (s, 3H). C NMR (126 MHz, CDCl) δ 168.29, 166.28, 138.97, 138.54, 131.46, 126.74, 122.89, 96.10, 52.44, 24.78. ESI(+)−MS: 320.1 [M+1].
3
2
2
3
3
3
1
13
+
Methyl 3-acetamido-4-iodobenzoate (319 mg, 1 mmol) and 6-ethynyl-4,4-dimethylthiochroman (304 mg, 1.5 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(47 mg, 0.0675 mmol) and CuI (26 mg, 0.135 mmol). After the flask was purged with argon for 3 times to remove oxygen, 5 mL dry DMF and 0.3 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=10:1) to give WYC-316 (298 mg, 76%). H NMR (500 MHz, CDCl) δ 9.00 (s, 1H), 7.97 (s, 1H), 7.74 (dd, J=8.1, 1.2 Hz, 1H), 7.57-7.50 (m, 2H), 7.18 (dd, J=8.1, 1.7 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 3.91 (s, 3H), 3.10-3.02 (m, 2H), 2.26 (s, 3H), 1.98-1.93 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 168.23, 166.55, 142.53, 138.77, 135.02, 131.51, 130.80, 129.71, 128.90, 126.92, 124.65, 120.35, 117.03, 110.11, 99.62, 83.25, 52.42, 37.09, 33.11, 30.02, 25.03, 23.36. ESI(+)−MS: 394.2 [M+1].
1
13
+
3
3
WYC-316 (56 mg, 0.142 mmol) was added to a flask, followed by addition of sodium ethoxide (29 mg, 0.426 mmol) and 2 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=20:1) to give WYC-317 (48 mg, 83%). H NMR (500 MHz, CDCl) δ 9.00 (s, 1H), 7.97 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.2 Hz, 2H), 7.18 (dd, J=8.1, 1.3 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.09-3.02 (m, 2H), 2.26 (s, 3H), 1.98-1.94 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 168.22, 166.08, 142.53, 138.76, 135.00, 131.47, 131.21, 129.72, 128.91, 126.93, 124.64, 120.38, 117.07, 110.12, 99.54, 83.31, 61.39, 37.11, 33.12, 30.04, 25.03, 23.36, 14.44. ESI(+)−MS: 408.2 [M+1].
1
13
+
33
3
WYC-317 (86 mg, 0.211 mmol) was added to a flask, followed by addition of 2 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (37 mg, 0.211 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:1) to give WYC-318 (80 mg, 98.6%). H NMR (500 MHz, CDCl) δ 8.98 (s, 1H), 7.93 (s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.61 (d, J=1.3 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.50 (dd, J=8.0, 1.3 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.24 (dd, J=17.2, 6.3 Hz, 1H), 3.17-3.09 (m, 1H), 2.45 (ddd, J=14.8, 10.3, 1.9 Hz, 1H), 2.27 (s, 3H), 1.91 (ddd, J=15.1, 8.9, 2.0 Hz, 1H), 1.48 (s, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.35 (s, 3H). C NMR (126 MHz, CDCl) δ 168.29, 165.92, 145.31, 139.07, 131.97, 131.91, 131.19, 130.44, 129.98, 125.33, 124.80, 124.76, 120.86, 115.83, 97.48, 85.94, 61.51, 43.40, 34.66, 31.36, 31.27, 29.79, 14.43. ESI(+)−MS: 424.1 [M+1].
+
WYC-316 (63 mg, 0.16 mmol) was added to a flask, followed by addition of sodium ethoxide (14 mg, 0.2 mmol), 2 mL tetrahydrofuran and 0.2 mL water. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:4) to give WYC-319 (34 mg, 56%). ESI(+)−MS: 380.2 [M+1].
1
13
+
3
3
5-Bromopyrazin-2-carboxylic acid (1.0 g, 5 mmol) was added to a flask, followed by addition of 5 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.3 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 6 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=50:1) to give ethyl 5-bromopyrazin-2-carboxylate (0.42 g, 37%). H NMR (500 MHz, CDCl) δ 9.01 (d, J=1.3 Hz, 1H), 8.76 (d, J=1.3 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H). C NMR (126 MHz, CDCl) δ 163.39, 147.30, 146.31, 144.65, 141.89, 62.67, 14.30. ESI(+)−MS: 231.2 [M+1].
1
13
+
3
3
WYC-209 (1.1 g, 3 mmol) was added to a flask, followed by addition of 20 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (0.663 g, 3.6 mmol) was added. Then the reaction was continued for 10 min under the ice bath and another 3 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:5) to give WYC-320 (0.99 g, 89%). H NMR (500 MHz, CDCl) δ 9.29 (s, 2H), 7.94 (d, J=8.2 Hz, 1H), 7.76 (d, J=1.3 Hz, 1H), 7.68 (dd, J=8.2, 1.5 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.46-3.37 (m, 2H), 2.45-2.39 (m, 2H), 1.44 (s, 6H). C NMR (126 MHz, CDCl) δ 163.22, 158.51, 155.10, 145.17, 138.59, 132.27, 131.31, 125.41, 124.24, 122.74, 89.85, 88.71, 62.32, 47.06, 35.49, 34.47, 30.71, 14.35. ESI(+)−MS: 385.4 [M+1].
1
13
+
3
3
WYC-316 (107 mg, 0.272 mmol) was added to a flask, followed by addition of 3.5 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (67.3 mg, 0.272 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:1) to give WYC-321 (84 mg, 78%). H NMR (500 MHz, CDCl) δ 8.97 (s, 1H), 7.96 (s, 1H), 7.80-7.72 (m, 2H), 7.60 (d, J=1.4 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.49 (dd, J=8.0, 1.3 Hz, 1H), 3.90 (s, 3H), 3.14 (ddt, J=12.9, 8.9, 6.4 Hz, 2H), 2.45 (ddd, J=14.8, 10.3, 1.7 Hz, 1H), 2.26 (s, 3H), 1.90 (ddd, J=15.0, 8.9, 1.9 Hz, 1H), 1.47 (s, 3H), 1.34 (s, 3H). C NMR (126 MHz, CDCl) δ 168.28, 166.37, 145.28, 139.65, 139.09, 131.94, 131.52, 131.18, 130.41, 129.95, 125.29, 124.74, 120.91, 115.97, 97.52, 85.89, 52.49, 43.37, 34.63, 31.32, 31.25, 29.76, 24.99. ESI(+)−MS: 410.3 [M+1].
3
2
2
3
3
3
1
13
+
Ethyl 5-bromopyrazin-2-carboxylate (600 mg, 2.61 mmol) and 6-ethynyl-4,4-dimethylthiochroman (635 mg, 3.13 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(66 mg, 0.094 mmol) and CuI (36 mg, 0.188 mmol). After the flask was purged with argon for 3 times to remove oxygen, 6 mL dry DMF and 0.4 mL dry EtN were added via syringe. Then the reaction was continued at 80° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=50:1) to give WYC-322 (656 mg, 71.5%). H NMR (500 MHz, CDCl) δ 9.20 (d, J=1.4 Hz, 1H), 8.76 (d, J=1.4 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.23 (dd, J=8.2, 1.8 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.46 (q, J=7.1 Hz, 2H), 3.02-2.97 (m, 2H), 1.92-1.87 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.29 (s, 6H). C NMR (126 MHz, CDCl) δ 163.65, 146.68, 145.70, 143.08, 142.31, 140.30, 136.14, 130.54, 129.51, 126.74, 116.00, 97.55, 85.68, 62.37, 36.91, 32.99, 29.89, 23.27, 14.31. ESI(+)−MS: 353.5 [M+1].
1
13
+
WYC-322 (50 mg, 0.14 mmol) was added to a flask, followed by addition of sodium ethoxide (29 mg, 0.426 mmol) and 2 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (DCM:MeOH=15:1) to give WYC-323 (43 mg, 95%). H NMR (500 MHz, pyridine) δ 9.65 (s, 1H), 9.05 (s, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.41 (dd, J=8.1, 1.4 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 2.98-2.88 (m, 2H), 1.81-1.72 (m, 2H), 1.19 (s, 6H). C NMR (126 MHz, pyridine) δ 166.73, 147.26, 146.43, 143.36, 142.96, 142.56, 136.52, 130.88, 129.89, 127.24, 116.79, 96.42, 86.89, 36.94, 33.05, 29.59, 23.30. ESI(+)−MS: 325.2 [M+1].
1
13
+
33
3
WYC-322 (100 mg, 0.284 mmol) was added to a flask, followed by addition of 3.5 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (49 mg, 0.284 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:2) to give WYC-324 (78 mg, 75%). H NMR (500 MHz, CDCl) δ 9.29 (d, J=1.4 Hz, 1H), 8.87 (d, J=1.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.61 (dd, J=8.1, 1.6 Hz, 1H), 4.52 (q, J=7.1 Hz, 2H), 3.29-3.06 (m, 2H), 2.43 (ddd, J=15.1, 10.2, 2.3 Hz, 1H), 1.91 (ddd, J=15.1, 9.2, 2.3 Hz, 1H), 1.47 (dd, J=8.8, 5.5 Hz, 6H), 1.34 (s, 3H). C NMR (126 MHz, CDCl) δ 163.62, 147.07, 145.93, 145.25, 142.41, 141.29, 140.60, 132.05, 130.63, 130.25, 124.32, 94.92, 87.36, 62.70, 43.44, 34.73, 31.35, 31.25, 29.91, 14.41. ESI(+)−MS: 396.2 [M+1].
1
13
+
3
3
2-Chloro-4-iodobenzoic acid (1.0 g, 3.55 mmol) was added to a flask, followed by addition of 7 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 0.4 mL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 5 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE:EtOAc=7:1) to give ethyl 2-chloro-4-iodobenzoate (0.98 g, 89%). H NMR (500 MHz, CDCl) δ 7.82 (d, J=1.6 Hz, 1H), 7.65 (dd, J=8.2, 1.6 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H). C NMR (126 MHz, CDCl) δ 165.22, 139.57, 135.95, 134.63, 132.47, 129.91, 98.35, 61.87, 14.32. ESI(+)−MS: 311.3 [M+1].
3
2
2
3
3
3
1
13
+
Ethyl 2-chloro-4-iodobenzoate (310 mg, 1 mmol) and 6-ethynyl-4,4-dimethylthiochroman (244 mg, 1.2 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(28 mg, 0.04 mmol) and CuI (11.4 mg, 0.06 mmol). After the flask was purged with argon for 3 times to remove oxygen, 3 mL dry DMF and 0.3 mL dry EtN were added via syringe. Then the reaction was continued at 80° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=50:1) to give WYC-325 (365 mg, 95%). H NMR (500 MHz, CDCl) δ 7.81 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.42 (dd, J=8.1, 1.5 Hz, 1H), 7.18 (dd, J=8.2, 1.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.06-3.02 (m, 2H), 1.97-1.93 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.34 (s, 6H). C NMR (126 MHz, CDCl) δ 165.27, 142.26, 134.37, 133.89, 133.65, 131.41, 129.92, 129.38, 129.30, 129.14, 128.27, 126.72, 117.56, 93.73, 86.76, 61.71, 37.21, 33.06, 30.04, 23.32, 14.33. ESI(+)−MS: 385.2 [M+1].
1
13
+
3
3
WYC-325 (100 mg, 0.26 mmol) was added to a flask, followed by addition of 3 mL dry dichloromethane. After the mixture was cooled to 0° C. under an ice bath, mCPBA (60 mg, 0.26 mmol) was added. Then the reaction was continued for 1 h under the ice bath and another 2 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with sodium thiosulfate solution, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=1:3) to give WYC-326 (86 mg, 83%). H NMR (500 MHz, CDCl) δ 7.79 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.46 (dd, J=8.0, 1.5 Hz, 1H), 7.42 (dd, J=8.1, 1.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.17 (ddd, J=12.7, 10.5, 2.1 Hz, 1H), 3.06 (ddd, J=13.1, 8.8, 2.2 Hz, 1H), 2.41 (ddd, J=14.9, 10.4, 2.1 Hz, 1H), 1.85 (ddd, J=15.1, 8.8, 2.2 Hz, 1H), 1.43 (s, 3H), 1.36 (t, J=7.1 Hz, 3H), 1.30 (s, 3H). C NMR (126 MHz, CDCl) δ 165.05, 144.93, 138.96, 133.81, 133.81, 131.36, 131.23, 130.19, 130.08, 130.05, 129.58, 127.12, 125.66, 91.67, 89.03, 61.74, 43.16, 34.45, 31.20, 31.06, 29.59, 14.22. ESI(+)−MS: 401.2 [M+1].
1
13
+
3
3
WYC-325 (100 mg, 0.26 mmol) was added to a flask, followed by addition of sodium ethoxide (29 mg, 0.426 mmol) and 2 mL ethanol. Then the reaction was continued at room temperature overnight and monitored by TLC. After completion of the reaction, the reaction solution was neutralized to neutral with acid resin and filtered, the filtrate was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=1:2) to give WYC-327 (89 mg, 94%). H NMR (500 MHz, CDCl) δ 7.98 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.18 (dd, J=8.2, 1.6 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 3.07-3.04 (m, 2H), 1.98-1.94 (m, 2H), 1.35 (s, 6H). C NMR (126 MHz, CDCl) δ 170.29, 142.32, 134.90, 134.53, 134.00, 132.52, 130.02, 129.51, 129.36, 129.25, 127.76, 126.79, 117.54, 94.44, 86.79, 37.25, 33.12, 30.09, 23.39. ESI(+)−MS: 355.2 [M+1].
3
2
2
3
3
1
13
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg, 0.235 mmol) and 2-cyano-5-bromopyrimidine (49.9 mg, 0.271 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (5.6 mg, 0.03 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.14 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE: EtOAc=10:0 to 10:1) to give WYC-329 (75 mg, 77%). H NMR (400 MHz, CDCl) δ 8.90 (s, 2H), 7.52 (d, J=1.4 Hz, 1H), 7.38-7.29 (m, 2H), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H). C NMR (101 MHz, CDCl3) δ 159.24, 147.92, 145.68, 141.75, 130.54, 129.00, 127.11, 122.82, 117.86, 115.58, 101.75, 80.64, 77.35, 77.04, 76.72, 34.78, 34.73, 34.59, 34.31, 31.77, 31.64. ESI(+)−MS: 338.4 [M+1]+.
3
2
2
3
1
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (100 mg, 0.47 mmol) and 2-amino-4-iodobenzoic acid (141.8 mg, 0.54 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(28 mg, 0.04 mmol) and CuI (11.2 mg, 0.059 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.28 mL dry EtN were added via syringe. Then the reaction was continued at 50° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=50:1 to 10:1) to give WYC-330 (97 mg, 60%). H NMR (400 MHz, MeOD) δ 7.81 (s, 1H), 7.46 (s, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 1.72 (s, 4H), 1.30 (s, 6H), 1.29 (s, 6H). ESI(+)−MS: 348.3 [M+1].
3
2
2
3
3
3
1
13
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg, 0.235 mmol) and ethyl 2-chloropyrimidin-4-carboxylate (50.3 mg, 0.27 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (5.6 mg, 0.03 mmol). After the flask was purged with argon for 3 times to remove oxygen, 1 mL dry DMF and 0.14 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 50:1) to give WYC-331 (67.2 mg, 79%). H NMR (500 MHz, CDCl) δ 9.26 (s, 2H), 7.67 (d, J=1.7 Hz, 1H), 7.45 (dd, J=8.2, 1.8 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.46 (q, J=7.1 Hz, 2H), 1.69 (s, 4H), 1.44 (t, J=7.1 Hz, 3H), 1.29 (s, 6H), 1.28 (s, 6H). C NMR (101 MHz, CDCl) δ 163.42, 158.33, 155.80, 148.01, 145.46, 131.77, 129.86, 126.94, 121.83, 117.66, 92.54, 87.31, 62.02, 34.81, 34.77, 34.58, 34.31, 31.72, 31.60. ESI(+)−MS: 363.3 [M+1].
3
2
2
3
3
1
13
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (120 mg, 0.566 mmol) and methyl 3-hydroxy-4-iodobenzoate (180.7 mg, 0.65 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(33.7 mg, 0.048 mmol) and CuI (13.5 mg, 0.072 mmol). After the flask was purged with argon for 3 times to remove oxygen, 3 mL dry DMF and 0.338 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=50:1 to 10:1) to give WYC-332 (118 mg, 58%). H NMR (400 MHz, CDCl) δ 8.23 (s, 1H), 7.95 (dd, J=8.2, 1.4 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.63 (dd, J=8.3, 1.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.01 (d, J=0.8 Hz, 1H), 3.96 (s, 3H), 1.74 (s, 4H), 1.38 (s, 6H), 1.33 (d, J=4.9 Hz, 6H). C NMR (126 MHz, cdcl3) δ 167.34, 159.55, 154.18, 146.62, 145.60, 133.81, 127.20, 127.09, 125.67, 124.35, 123.49, 122.72, 120.13, 112.70, 100.54, 77.25, 76.99, 76.74, 52.10, 35.01, 34.90, 34.43, 34.42, 31.84, 31.72. ESI(+)−MS: 363.2 [M+1].
3
2
2
3
3
3
1
13
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg, 0.283 mmol) and 2-chloro-5-cyanopyridine (59.5 mg, 0.325 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(16.8 mg, 0.024 mmol) and CuI (6.8 mg, 0.036 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.17 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=100:1 to 20:1) to give WYC-333(59 mg,67%). H NMR (500 MHz, CDCl) δ 8.86 (dd, J=2.1, 0.8 Hz, 1H), 7.93 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (dd, J=8.2, 0.8 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.2, 1.7 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 1.69 (s, 4H), 1.29 (s, 6H), 1.29 (s, 6H). C NMR (126 MHz, CDCl) δ 152.56, 147.56, 147.09, 145.45, 139.13, 130.99, 129.26, 126.92, 126.59, 118.07, 116.52, 107.95, 95.22, 86.91, 77.25, 76.99, 76.74, 34.81, 34.76, 34.52, 34.28, 31.73, 31.61. ESI(+)−MS: 315.6 [M+1].
1
13
+
3
3
WYC-329 (15 mg, 0.0475 mmol) was dissolved in 2 mL ethanol, followed by addition of sodium ethoxide (9.7 mg, 0.143 mmol). The reaction was continued at room temperature overnight. After completion of the reaction, the reaction solution was neutralized to weak acidic with 1 mol/L HCl, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=1000:1 to 20:1) to give WYC-334 (15 mg, 88%). H NMR (400 MHz, CDCl) δ 8.63 (s, 2H), 7.47 (d, J=1.2 Hz, 1H), 7.33-7.24 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 1.69 (s, 4H), 1.45 (t, J=7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H). C NMR (101 MHz, CDCl) δ 163.53, 161.19, 146.22, 145.28, 129.93, 128.61, 126.82, 119.29, 113.07, 94.57, 81.42, 77.35, 77.04, 76.72, 63.94, 34.91, 34.85, 34.41, 34.25, 31.77, 31.68, 14.42. ESI(+)−MS: 362.3 [M+1].
3
2
2
3
3
1
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (50 mg, 0.205 mmol) and Compound c (75.3 mg, 0.271 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(14 mg, 0.02 mmol) and CuI (5.6 mg, 0.03 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.14 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE) to give the product (45.2 mg, 61%). H NMR (400 MHz, CDCl) δ 10.76 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.48 (s, 1H), 7.29 (d, J=0.8 Hz, 2H), 7.13 (d, J=1.4 Hz, 1H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 3.96 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H). ESI(+)−MS: 363.3 [M+1].
1
13
−
The product (30 mg, 0.082 mmol) obtained in the previous step was added to a flask, followed by addition of 2 mL 2.0 mol/L NaOH and 2 mL methanol. The reaction was continued at 55° C. overnight. After completion of the reaction, the reaction solution was neutralized to pH 5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=100:0 to 10:1) to give WYC-335 (26.3 mg, 93%). H NMR (400 MHz, DMSO) δ 7.80 (d, J=8.1 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.2, 1.6 Hz, 1H), 7.12-7.04 (m, 2H), 1.65 (s, 4H), 1.26 (s, 6H), 1.25 (s, 6H). C NMR (101 MHz, DMSO) δ 171.27, 160.85, 146.07, 145.05, 130.58, 129.74, 129.16, 128.67, 126.98, 122.01, 119.29, 118.76, 92.56, 87.48, 40.12, 39.91, 39.70, 39.49, 39.29, 39.08, 38.87, 34.36, 34.25, 34.08, 33.89, 31.39, 31.32. ESI(−)−MS: 347.3 [M−1].
1
−
3
WYC-330 (52 mg, 0.15 mmol) was added to a flask, followed by addition of 1 mg DMAP, then 3 mL dry pyridine was added under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, 7.8 μL acetyl chloride was added dropwise, and the reaction was continued for 5 min under the ice bath and another 5 h at room temperature, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction was quenched with methanol. The mixture was diluted with ethyl acetate, washed with 1 mol/L hydrochloric acid to remove pyridine, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EtOAc=20:1) to give WYC-336 (39.5 mg, 85%). H NMR (400 MHz, CDCl) δ 8.13 (d, J=8.1 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.60 (dd, J=8.1, 1.5 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=1.0 Hz, 2H), 2.47 (s, 3H), 1.69 (d, J=5.7 Hz, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ESI(−)−MS: 388.4 [M−1].
3
2
2
3
3
1
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg, 0.283 mmol) and methyl 5-bromo-pyridin-2-carboxylate (70 mg, 0.325 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(16.8 mg, 0.024 mmol) and CuI (6.8 mg, 0.036 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.17 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=100:1 to 20:1) to give the product (68.7 mg, 70%). H NMR (400 MHz, CDCl) δ 8.85 (dd, J=2.0, 0.7 Hz, 1H), 8.12 (dd, J=8.1, 0.7 Hz, 1H), 7.94 (dd, J=8.1, 2.1 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=1.0 Hz, 2H), 4.02 (d, J=4.5 Hz, 3H), 1.69 (d, J=5.5 Hz, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ESI(+)−MS: 348.2 [M+1].
1
+
The product (50 mg, 0.143 mmol) obtained in the previous step was added to a flask, followed by addition of 2 mL 2.0 mol/L NaOH and 2 mL methanol. The reaction was continued at 55° C. overnight. After completion of the reaction, the reaction solution was neutralized to pH 5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=20:1 to 5:1) to give WYC-337 (42.2 mg, 88%). H NMR (400 MHz, Me0D) δ 8.67 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.94 (dd, J=8.1, 2.0 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.30 (dd, J=8.2, 1.7 Hz, 1H), 1.73 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H). ESI(+)−MS: 334.4 [M+1].
1
+
3
WYC-329 (15 mg, 0.0475 mmol) was dissolved in 2 mL methanol, followed by addition of sodium methoxide (7.7 mg, 0.143 mmol). The reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction solution was neutralized to weak acidic with 1 mol/L HCl, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE: EtOAc=100:1 to 20:1) to give WYC-338 (14.9 mg, 90%). H NMR (500 MHz, CDCl) δ 8.64 (s, 2H), 7.47 (d, J=1.2 Hz, 1H), 7.34-7.27 (m, 2H), 4.05 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H). ESI(+)−MS: 348.4 [M+1].
+
WYC-335 (15 mg, 0.043 mmol) was added to a flask, followed by addition of 0.8 mL anhydrous ethanol under argon atmosphere. The mixture was cooled to 0° C. under an ice bath, then 3 μL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE: EtOAc=100:1 to 10:1) to give WYC-339 (14 mg, 87%). ESI(+)−MS: 377.3 [M+1].
1
13
+
3
3
WYC-332 (50 mg, 0.143 mmol) was added to a flask, followed by addition of 2 mL 2.0 mol/L NaOH and 2 mL methanol. The reaction was continued at 55° C. overnight. After completion of the reaction, the reaction solution was neutralized to pH 5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=20:1 to 5:1) to give the corresponding carboxylic acid (47 mg, 87%). The corresponding carboxylic acid (25 mg, 0.072 mmol) was added to a flask, followed by addition of 1.5 mL anhydrous ethanol under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, 5 μL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE: EtOAc=50: 1 to 10:1) to give WYC-340 (24 mg, 90%). H NMR (400 MHz, CDCl) δ 8.24 (s, 1H), 7.95 (dd, J=8.2, 1.4 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.63 (dd, J=8.3, 1.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.01 (d, J=0.8 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.73 (s, 4H), 1.43 (t, J=7.1 Hz, 3H), 1.37 (s, 6H), 1.32 (s, 6H); C NMR (101 MHz, CDCl) δ 166.91, 159.50, 154.23, 146.62, 145.62, 133.74, 127.23, 127.15, 126.07, 124.37, 123.49, 122.73, 120.12, 112.68, 100.57, 60.95, 35.03, 34.92, 34.44, 31.86, 31.74; ESI(+)−MS: 377.4 [M+1].
1
+
3
WYC-337 (25 mg, 0.075 mmol) was added to a flask, followed by addition of 1.5 mL anhydrous ethanol under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, 5 μL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE: EtOAc=50: 1 to 10:1) to give WYC-341 (24 mg, 90%). H NMR (400 MHz, CDCl) δ 8.85 (dd, J=2.0, 0.6 Hz, 1H), 8.11 (dd, J=8.1, 0.7 Hz, 1H), 7.92 (dd, J=8.1, 2.1 Hz, 1H), 7.50 (t, J=1.2, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.4, 2.1 Hz, 3H), 4.49 (q, J=7.2 Hz, 2H), 1.69 (s, 4H), 1.45 (t, J=6.8 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 6H). ESI(+)−MS: 362.7 [M+1].
3
2
2
3
3
3
1
13
+
6-Ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (60 mg, 0.283 mmol) and methyl 2-chloropyrazin-4-carboxylate (56 mg, 0.325 mmol) were added to a flask, followed by addition of Pd(PPh)Cl(16.8 mg, 0.024 mmol) and CuI (6.8 mg, 0.036 mmol). After the flask was purged with argon for 3 times to remove oxygen, 2 mL dry DMF and 0.17 mL dry EtN were added via syringe. Then the reaction was continued at 70° C. for 8 h and monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and the reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=100:1 to 20:1) to give the product (55 mg, 56%). H NMR (400 MHz, CDCl) δ 9.28 (d, J=1.4 Hz, 1H), 8.83 (d, J=1.4 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.40 (dd, J=8.2, 1.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 4.06 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6H), 1.29 (s, 6H). C NMR (101 MHz, CDCl) δ 164.18, 147.91, 146.83, 145.74, 145.57, 143.39, 140.07, 131.12, 129.38, 127.01, 117.83, 97.82, 85.11, 77.34, 77.23, 77.02, 76.70, 53.19, 34.80, 34.76, 34.58, 34.31, 31.75, 31.62. ESI(+)−MS: 349.2 [M+1].
1
13
+
3
3
The product (35 mg, 0.1 mmol) obtained in the previous step was added to a flask, followed by addition of 1.5 mL 2.0 mol/L NaOH and 1.5 mL methanol. The reaction was continued at 55° C. overnight. After completion of the reaction, the reaction solution was neutralized to pH 5-6 with 1 mol/L HCl, diluted with ethyl acetate, extracted, washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography (PE:EA=20:1 to 5:1) to give the corresponding carboxylic acid (28.3 mg, 85%). The corresponding carboxylic acid (25 mg, 0.075 mmol) was added to a flask, followed by addition of 1.5 mL anhydrous ethanol under argon atmosphere. After the mixture was cooled to 0° C. under an ice bath, 5 μL concentrated sulfuric acid was added dropwise. After completion of the dropwise addition, the reaction solution was heated to reflux and stirred for 4 h, meanwhile TLC was used to monitor the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, treated with 1 mol/L sodium hydroxide to neutralize sulfuric acid to make a neutral solution, then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, dried, and purified by flash column chromatography (PE: EtOAc=50: 1 to 10:1) to give WYC-342 (20 mg, 75%). H NMR (400 MHz, CDCl) δ 9.26 (d, J=1.4 Hz, 1H), 8.82 (d, J=1.4 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.38 (dd, J=8.2, 1.7 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 4.51 (q, J=7.1 Hz, 2H), 1.68 (s, 4H), 1.45 (t, J=7.1 Hz, 3H), 1.29 (s, 6H), 1.27 (s, 6H). C NMR (101 MHz, CDCl) δ 163.72, 147.84, 146.83, 145.72, 145.53, 143.21, 140.41, 131.09, 129.37, 127.00, 117.87, 97.61, 85.15, 77.38, 77.07, 76.75, 62.42, 34.81, 34.76, 34.56, 34.30, 31.75, 31.62. ESI(+)−MS: 363.6 [M+1].
Effect Embodiment 1: In Vitro Inhibitory Activity on the Proliferation of Tumor-Repopulating Cells (TRCs)
Nat. Mater.
B16-F1 Melanoma cells were incubated with 3D fibrin gel medium (90-Pa) for 5 days, and the desired tumor-repopulating cells of melanoma were screened (2012, 11, 734). Subsequently, the culture medium was respectively treated with collagenase and neutral protease II, and the tumor-repopulating cells of B16-F1 melanoma were released, then the obtained repopulating cells were transferred to a freshly prepared medium to be resuspended and maintained at single-cell state. The tumor-repopulating cells of B16-F1 melanoma were inoculated in 3D fibrin gel medium (90-Pa) for 5 days, with 0.1% DMSO as the negative control group, Tazarotene and Bexarotene as the positive control drugs respectively, the drug was added at a concentration of 10 μM and the cells were incubated for 5 days. The colony tumor size was measured and calculated, and the inhibition rate of each drug on the tumor-repopulating cells of B16-F1 melanoma was calculated. The results of inhibitory activity of the compound of the present invention on the proliferation of tumor-repopulating cells of B16-F1 melanoma were shown in Table 2 below.
TABLE 2
Inhibitory activity on the proliferation of tumor-
repopulating cells (TRCs) of B16-F1 melanoma
Compound
Inhibition rate on TRCs of B16-F1 melanoma
number
at a concentration of 10 μM (%)
WYC-101
76.0
WYC-102
59.1
WYC-103
86.8
WYC-105
64.1
WYC-106
72.4
WYC-107
75.0
WYC-202
85.3
WYC-203
90.5
WYC-204
25.6
WYC-205
91.5
WYC-206
77.2
WYC-207
92.5
WYC-208
27.7
WYC-209
98.8
WYC-209A
98.9
WYC-209B
98.7
WYC-210
18.1
WYC-212
93.2
WYC-213
71.1
WYC-214
51.6
WYC-215
80.2
WYC-216
84.0
WYC-217
90.3
WYC-218
90.4
WYC-219
64.8
WYC-220
65.5
WYC-301
34.4
WYC-302
21.9
WYC-303
71.1
WYC-304
75.8
WYC-305
26.0
WYC-306
15.2
WYC-307
70.3
WYC-308
71.9
WYC-309
56.8
WYC-310
76.8
WYC-311
80.2
WYC-312
71.0
WYC-313
62.2
WYC-314
70.1
WYC-315
70.1
WYC-316
76.2
WYC-317
86.4
WYC-318
60.0
WYC-319
65.8
WYC-320
92.6
WYC-321
78.2
WYC-322
78.8
WYC-323
76.0
WYC-324
85.1
WYC-325
74.2
WYC-326
73.4
WYC-327
75.7
WYC-329
94.5
WYC-330
79.0
WYC-331
96.0
WYC-332
55.9
WYC-333
69.1
WYC-334
80.6
WYC-335
86.9
WYC-336
86.7
WYC-337
87.5
WYC-338
69.0
WYC-341
87.0
WYC-342
77.6
Tazarotene
67.6
Bexarotene
63.3
The test result of inhibition rate on tumor-repopulating cells of B16-F1 melanoma showed that most compounds showed significant inhibitory activity on tumor growth at a concentration of 10 μM, such as compound WYC-103 (86.8%), WYC-207 (92.5%), WYC-209 (98.8%), WYC-209A (98.9%), WYC-209B (98.7%), WYC-212 (93.2%), WYC-217 (90.3%), WYC-218 (90.4%), WYC -329 (94.5%), WYC-331 (96.0%) etc., the corresponding colony tumor basically did not grow or grew very slowly. The results were not only in sharp contrast to the negative control group, but also reached or exceeded the inhibitory activity of the positive drugs of Tazarotene (67.6%) and Bexarotene (63.3%) on colony tumor growth.
50
A dose-response curve study of the inhibition on tumor growth was then performed on the compounds which exhibited significant inhibitory activity on tumor growth in the primary screening test. The colony tumor which was administered at an equivalent gradient was fixed, the nuclear was stained with DAPI, the volume was measured, the inhibition rate was calculated and regression of the dose-response curve was performed, it had been confirmed that the compounds with better activity included WYC-103, WYC-209, WYC-320, WYC-329, WYC-331, the ICvalues of which were shown in Table 3 below.
TABLE 3
IC<sub>50 </sub>of the compound against tumor-repopulating
cells of B16-F1 melanoma
Inhibition rate on TRCs
Compound
of B16-F1 melanoma at a
IC<sub>50 </sub>of inhibition on TRCs
number
concentration of 10 μM/%
of B16-F1 melanoma/μM
WYC-103
86.8
1.50
WYC-107
75.0
2.12
WYC-207
92.5
3.3
WYC-209
98.8
0.19
WYC-209A
98.9
0.15
WYC-209B
98.7
0.22
WYC-212
93.2
2.28
WYC-320
92.6
1.65
WYC-329
94.5
0.5
WYC-331
96.0
0.017
FIG. 1
FIG. 2
FIG. 1
FIG. 2
Wherein, the inhibition and differentiation of WYC-103 and WYC-209 on tumor-repopulating cells of B16-F1 melanoma were shown in the electron micrograph (, ), In and , cell survival was shown by DAPI staining, apoptosis was shown by PI staining, and merge showed superposition of DAPI and PI staining images.
2, Inhibitory Activity of WYC-209 on the Proliferation of Various Tumor-Repopulating Cells
Many of the above compounds exhibited excellent inhibitory activity on the proliferation of tumor-repopulating cells of B16-F1 melanoma, wherein the activity WYC-209 was particularly excellent. Therefore, we further studied the inhibitory activity of this compound against tumor-repopulating cells of six other kinds of human tumor, including A549 lung cancer cell, MCF-7 breast cancer cell, MDA-MB-435S melanoma cell, A2780 ovarian cancer cell, Hs-746T gastric cancer cell, MDA-MB-231 breast cancer cell.
FIGS. 3-8
FIGS. 3-8
The above cancer cells were incubated with 3D fibrin gel medium (90-Pa) for 5 days, and the desired tumor-repopulating cells were screened. Subsequently, the culture medium was respectively treated with collagenase and neutral protease II, and the tumor-repopulating cells of B16-F1 melanoma were released, then the obtained repopulating cells were transferred to a freshly prepared medium to be resuspended and maintained at single-cell state. The tumor-repopulating cells of individual tumor were inoculated in 3D fibrin gel medium (90-Pa) for 5 days, with 0.1% DMSO as the negative control group (represented by DMSO group in ), the drug-free group as vehicle control group (represented by None group in ), and the study was performed by beginning administrating on the day 0 and the 3rd day respectively, and the colony tumor volume was measured and calculated.
FIGS. 3-8
FIGS. 3-8
The results showed that WYC-209 could effectively inhibit the proliferation of various tumor-repopulating cells at a concentration of 1.0 μM compared with None group, which greatly blocked the growth of colony tumor volume, the volume of tumor colony treated with WYC-209 was only 25-30% of None group (, drug9# in refers to WYC-209). When the concentration of WYC-209 was increased to 10 μM, the proliferation of the above six kinds of tumor-repopulating cells was inhibited at a higher level, and the volume of colony tumor was even less than 10% of the volume of None group. Especially for Hs-746T, WYC-209 could even reverse the growth trend of colony tumor.
3, Inhibitory Activity of WYC-331 on the Proliferation of Various Tumor-Repopulating Cells
WYC-331 exhibited excellent inhibitory activity on the proliferation of tumor-repopulating cells of B16-F1 melanoma. Next, we studied the inhibitory activity of this compound against tumor-repopulating cells of A2780 ovarian cancer and MDA-MB-231 breast cancer.
FIG. 9
FIGS. 3-8
The above human tumor cells were incubated with 3D fibrin gel medium (90-Pa) for 5 days, and the desired tumor-repopulating cells were screened. Subsequently, the culture medium was respectively treated with collagenase and neutral protease II, and the tumor-repopulating cells of B16-F1 melanoma were released, then the obtained repopulating cells were transferred to a freshly prepared medium to be resuspended and maintained at single-cell state. The tumor-repopulating cells of B16-F1 melanoma were inoculated in 3D fibrin gel medium (90-Pa) for 5 days, with 0.1% DMSO as the negative control group (represented by DMSO group in ), the drug-free group as vehicle control group (represented by None group in ), and the study was performed by beginning administrating on the day 0 and the 3rd day respectively, and the colony tumor volume was measured and calculated, beginning administrating from the 3rd day at a concentration of 0.1 μM, 1.0 μM, and 10 μM respectively, the colony tumor volume was measured and calculated.
FIG. 9
The results showed that WYC-331 could completely inhibit the proliferation of tumor-repopulating cells of A2780 ovarian cancer and MDA-MB-231 breast cancer at a concentration of 10 μM, which greatly blocked the growth of colony tumor volume, the volume of colony tumor of WYC-331 was only 10-15% of None group. As for tumor-repopulating cells of MDA-MB-231 breast cancer, WYC-331 could even reverse the growth trend of colony tumor (, wherein #31 refers to WYC-331). Meanwhile, it had been found from cell staining study that colony tumor cells inhibited by WYC-331 remained survival, and cell apoptosis appeared among only a few cells.
4, Toxicity of WYC-209 and WYC-331
FIG. 10
The 3T3 mouse embryonic fibroblast cells and B16-F1 melanoma cells were used as the model to study in vitro toxicity of WYC-209 and WYC-331 respectively. The effect of compound WYC-209 and WYC-331 on the proliferation of 3T3 mouse embryonic fibroblast cells and B16-F1 melanoma cells were studied at a concentration of 10 μM. The results showed that WYC-209 did not affect the proliferation of 3T3 mouse embryonic fibroblast cells, and did not induce apoptosis of these cells; meanwhile, WYC-209 could significantly block the growth of colony tumor cells of melanoma, and significant cell apoptosis appeared within 6-48 hours. The results showed that WYC-209 had a certain specificity for tumor-repopulating cells of melanoma, a weak effect on normal cells and less cytotoxicity ().
FIG. 11
Under the same condition, WYC-331 strongly inhibited the proliferation of B16-F1 melanoma cells, but did not exhibit significant apoptosis-inducing effect on 3T3 mouse embryonic fibroblasts cells and B16-F1 melanoma cells. The results showed that WYC-331 also had a certain specificity for tumor-repopulating cells of melanoma, and obvious cytotoxicity had not been observed, but the mechanism of action thereof might be different from WYC-209 ().
5, Inhibitory Activity of WYC-103 on Subcutaneous Transplantation Tumor of Melanoma
A subcutaneous implantation model of B16-F1 melanoma in immunocompetent mice (C57BL/6, female, 6-8 weeks) was established to study the inhibitory activity of compound WYC-103 on the tumor in situ. Firstly, B16-F1 cells were incubated within 3D fibrin gel (90-Pa in gel stiffness) that was immersed in culture medium for 5 days, and the desired tumor-repopulating cells were screened. Subsequently, the culture medium was respectively treated with collagenase and neutral protease II, and the tumor-repopulating cells of B16-F1 melanoma were released, then the obtained repopulating cells were transferred to a freshly prepared medium to be re-suspended and maintained at single-cell state.
FIG. 12
Six immunocompetent mice were randomly divided into two groups which were respectively the treatment group and the DMSO negative control group. Mice were subcutaneously injected with 30,000 tumor-repopulating cells of melanoma to establish a subcutaneous implantation model of melanoma. Subsequently, Mice were administered via tail vein injection based on the body weight and the blood volume of the mice. From day 0, mice in the treatment group were administrated with WYC-103 once every 2 days at a blood concentration of 10 μM and fed normally, observing the survival of the mice. The results were shown below. After 19 days experiment, the volume of the subcutaneous melanoma in the treatment group was significantly smaller than that of the DMSO control group. According to the statistical analysis, the tumor volume in the treatment group was only 50% of the control group ().
This experiment was repeated in order to further confirm the inhibitory activity of WYC-103 on subcutaneous implantation tumor of B16-F1 melanoma. In the present experiment, 18 immunocompetent mice (C57BL/6, female, 6-8 weeks) were randomly divided into three groups which were respectively the treatment group, the positive control group (BMS-453 was used as the positive drug) and the DMSO negative control group. Subsequently, Mice were administered via tail vein injection based on the body weight and the blood volume of the mice. From day 0, mice in the treatment group were administrated with WYC-103 once every 2 days at a blood concentration of 10 μM; mice in the positive control group were administered with BMS-453 (WYC-114) as the positive drug in the same route of administration; mice in the negative control group was administered with 0.1% DMSO in a same route of administration.
FIG. 13
FIG. 14
On the 20th day from the beginning of the experiment, all the mice in the positive control group died. On the 26th day from the beginning of the experiment, 50% of the mice in the treatment group and the negative control group died. According to the statistical analysis, the tumor volume of the mice in the treatment group was only 50% of the negative control group, and the growth of the subcutaneous implantation tumor of the mice in the treatment group was significantly inhibited. The study of the body weight of the mice showed that the body weight of the mice in the treatment group was stable and balanced, and there was no obvious toxic side effects (, wherein drug3# refers to WYC-103, drug14# refers to BMS-453). The body weight of the mice in the positive control group was significantly reduced, which indicated that there was a greater toxic side effect in the individual; while the body weight of the mice in the negative control group had a significant increase due to large tumor volume (). Further dissection experiment of the mice in each group showed that a large number of abnormal foamy structure appeared in the peritoneal cavity of the dead mice in the positive control group, which might be the cause of death in this group. No abnormalities were found in the abdominal cavity of the mice in the treatment group and the negative control group. This experiment showed that WYC-103 was much better than BMS-453 in terms of the efficacy and overall toxic side effects of the inhibition on the melanoma in situ.
6, Inhibitory Activity of WYC-103 on Metastatic Melanoma in the Lung
A metastatic melanoma model in the mouse was established to study whether WYC-103 could inhibit metastatic melanoma in the lung thus prevent secondary tumorigenesis. Firstly, 12 normally immunocompetent mice (C57BL/6, female, 6-8 weeks) were randomly selected and injected via the tail vein with 3000 tumor-repopulating cells of melanoma to establish a metastatic melanoma model in the mouse. The model mice were randomly divided into two groups which were respectively the treatment group and the negative control group. The mice were administered with WYC-103 (the treatment group) and DMSO (the negative control group) via tail vein injection once every 2 days at a blood concentration of 10 μM based on the body weight and the blood volume of the mice.
On the 29th day of the experiment, the first dead mouse in the negative control group appeared. For the convenience of comparison, killing one mouse in the treatment group, the dissection showed that obvious tissue of metastatic melanoma in the lung appeared in the dead mouse in the negative control group, while the lung tissue of the mouse in the treatment was normal. On the 35th day of the experiment, the second dead mouse in the negative control group appeared, and a large number of tissue of metastatic melanoma in the lung appeared in the mouse in the negative control group, while the lung tissues of the corresponding mouse in the treatment group was normal. On the 37th day of the experiment, 3 more mice died in the negative control group, and only 1 mouse remained alive in the negative control group; then all the mice in both groups were killed and dissected. According to the dissection results, metastatic melanoma appeared in the tissues of the lungs in 3 mice in the negative control group, while the lung tissues of all the mice in the treatment group was normal.
FIG. 15
e
f
FIGS. 15and 15
According to the statistical analysis, metastatic melanoma appeared in the tissues of the lungs in 5 mice among the 6 mice in the negative control group, which were all dead, only one mouse remained alive and healthy; while the lung tissues of all the 6 mice in the treatment group was healthy and intact and there were no signs of metastatic melanoma, indicating preventing the occurrence of metastatic melanoma with 100% efficiency. Meanwhile, according to statistical analysis, the average lung weight of the mice in the treatment group was only ⅓ of the negative control group (, “+” in refers to metastasis, and “−” refers to no metastasis).
This experiment showed that WYC-103 could effectively prevent repopulating cells of melanoma from metastasizing to the lung to form secondary lung tumor at a blood concentration of 10 μM, and there was no obvious toxic side effects accompanied with WYC-103 during the whole experiment. So WYC-103 was expected to be further used for the prevention and treatment of human metastatic cancer.
7, Inhibitory Activity of WYC-209 on Metastatic Melanoma in the Lung
This experiment was performed to study whether WYC-209 could inhibit the metastasis of melanoma to the lung thus prevent secondary tumorigenesis. The B16-F1 cells were incubated with 3D fibrin gel medium (90-Pa) for 5 days, and the desired tumor-repopulating cells were screened. Subsequently, the culture medium was respectively treated with collagenase and neutral protease II, and the tumor-repopulating cells were released, then the obtained repopulating cells were transferred to a freshly prepared medium to be re-suspended and maintained at single-cell state. Then 24 immunocompetent mice (C57BL/6, female, 6-8 weeks) were randomly selected and divided into three groups which were respectively low-dose group (1.0 μM), high-dose group (10 μM) and DMSO negative control group, with 8 mice per group. Subsequently, the mice were injected via the tail vein with 30,000 tumor-repopulating cells of melanoma to establish a B16-F1 metastatic melanoma model in the mouse. Subsequently, Mice were administered via tail vein injection based on the body weight and the blood volume of the mice. From the 5th day on, mice in the treatment group were administrated with WYC-209 once every 2 days at a blood concentration of 1.0 μM and 10 μM; mice in the DMSO group was administered with 0.1% DMSO in a same route of administration as negative control. At this time, there was no significant difference in the body weight between the groups, the mice were fed normally, observing the survival of the mice.
a
FIG. 16
a
FIG. 16
b
FIG. 16
b
FIG. 16
c
FIG. 16
FIG. 16
On the 23th day of the experiment, the first dead mouse (the lung tissue thereof was shown in , No. 8) in the DMSO group appeared. On the 30th day, all the remaining mice were killed. Obvious tissue of metastatic melanoma appeared in the lungs of 6 mice among the 8 mice in the DMSO group, and there was no abnormalities found in the liver and stomach (referring to , No. 1-7). During the same period (the night of the 29th day), one mouse died in the 1.0 μM treatment group (the lung tissue refers to , No. 8); the metastatic melanoma appeared in the tissues of lungs of 4 mice among the 8 mice in the 1.0 μM treatment group, and there was no abnormalities found in the liver and stomach (, No. 1-7 showed the lung tissue on the 30th day). During the same period, the metastatic melanoma appeared in the tissues of the lungs of only one mouse among the 8 mice in the 10 μM treatment group, and there was no abnormalities found in the liver and stomach. On the 30th day, 6 mice (75%) in the DMSO group suffered pulmonary metastatic melanoma, 4 mice (50%) in the 1.0 μM treatment group suffered pulmonary metastatic melanoma, and 1 mouse (12.5%) suffered pulmonary metastatic melanoma in the 10 μM treatment group only (referring to , wherein No. 1-5 showed the lung tissue on the 30th day, and No. 6-8 showed the lung tissue on the 29th, 24th, 20th day respectively). There was a statistically significant difference among the lung tissue weight of the mice in each group, the DMSO group >1.0 μM treatment group >10 μM treatment group (“+” refers to metastasis, “−” refers to no metastasis in ).
This experiment showed that WYC-209 could prevent repopulating cells of melanoma from metastasizing to the lung to form secondary lung tumor with 50% efficiency at a blood concentration of 1.0 μM, and with 87.5% efficiency at a blood concentration of 10.0 μM. The DMSO group showed 75% mortality rate of metastatic melanoma in the lung. WYC-209 exhibited an excellent activity of inhibiting and even healing secondary tumorigenesis in the immunocompetent mice in vivo. Meanwhile, there was no obvious toxic side effects accompanied with WYC-209 during the whole experiment, so WYC-209 was expected to be further used for the prevention and treatment of various primary or metastatic cancers.
50
In summary, the above in vitro activity experiments showed that WYC-103, WYC-209 and WYC-331 had strong inhibitory activity against tumor-repopulating cells of melanoma, the ICreached 0.45 μM, 0.25 μM and 0.017 μM respectively. WYC-209 had strong inhibitory activity against A549 lung cancer cells, MCF-7 breast cancer cells, MDA-MB-435S melanoma cells, A2780 ovarian cancer cells, Hs-746T gastric cancer cells, MDA-MB-231 breast cancer cell.
In vivo activity experiments showed that WYC-103 had a strong inhibitory activity on subcutaneous transplantation tumor of melanoma in mice, the tumor volume was only 50% of the control group at a concentration of 10 μM. WYC-103 and WYC-209 inhibited the metastasis of repopulating cells of melanoma to the lung with 100% and 87% efficiency at a concentration of 10μM respectively, which could bring new treatment for prevention and treatment of metastasis of human tumor.
It had been confirmed from In vitro experiment that WYC-209 and WYC-331 had no effect on the growth of 3T3 cell clones and could not induce apoptosis of 3T3 cells. Meanwhile, WYC-103 and WYC-209 exhibited highly safety in the in vitro and in vivo experiments. From the above biological study embodiments, the compounds of the present invention provided new possibilities for the prevention and treatment of leukemia, lymphoma, primary solid tumors and metastatic tumors.
It is to be understood that the foregoing description of two preferred embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims.
FIELD OF INVENTION
PRIOR ARTS
CONTENT OF THE PRESENT INVENTION
14
or —COOR;
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Embodiment 1: methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate
Embodiment 2: methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-methoxybenzoate
Embodiment 3: ethyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoate
Embodiment 4: ethyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-methoxybenzoate
Embodiment 5: 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-hydroxybenzoic Acid
Embodiment 6: methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-2-methoxybenzoate
Embodiment 7: methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-hydroxybenzoate
Embodiment 8: methyl 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-methoxybenzoate
Embodiment 9: 4-((4,4-dimethylthiochroman-6-yl)ethynyl)-3-methoxybenzoic Acid
Embodiment 11: ethyl 2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate
Embodiment 12: methyl 5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-2-carboxylate
Embodiment 13: ethyl 5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-2-carboxylate
Embodiment 14: 2-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrimidin-5-carboxylic acid
Embodiment 15: 2-cyano-5-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidine
Embodiment 16: ethyl 5-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidin-2-carboxylate
Embodiment 17: ethyl 2-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate
WYC-209A: ethyl 2-((4,4-dimethyl-1S-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate
WYC-209B: ethyl 2-((4,4-dimethyl-1R-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate
Embodiment 18: 2-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylic Acid
Embodiment 19: 2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 20: 2-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 21: 6-ethynyl-4,4-dimethyl-1-oxothiochroman
Embodiment 22: 2-amino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 23: methyl 2-amino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 24: ethyl 2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 25: ethyl 2-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 26: ethyl 2-amino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 27: methyl 2-methylamino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 28: methyl 2-amino-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 29: 2-acetylamino-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 30: 2-(3-bromophenyl)acetaldehyde
Embodiment 31: ethyl 4-(3-bromophenyl)-2-butenoate
Embodiment 32: ethyl 4-(3-bromophenyl)butanoate
Embodiment 33: 5-(3-bromophenyl)-2-methyl-2-pentanol
Embodiment 34: 7-bromo-4,4-dimethyl-3,4-dihydronaphth-1-(2H)-one
Embodiment 35: 7-bromo-4,4-dimethyl-1-phenyl-1,2,3,4-tetrahydronaphth-1-ol
Embodiment 36: 6-bromo-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene
Embodiment 37: ((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)trimethylsilane
Embodiment 38: 6-ethynyl-1,1-dimethyl-4-phenyl-1,2-dihydronaphthalene
Embodiment 40: ethyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-hydroxybenzoate
Embodiment 41: ethyl 2-fluoro-4-iodobenzoate
Embodiment 42: ethyl 2-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 43: 2-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 44: ethyl 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-fluorobenzoate
Embodiment 45: 4-((5,5-dimethyl-8-phenyl-5,6-dihydronaphth-2-yl)ethynyl)-2-fluorobenzic Acid
Embodiment 46: ethyl 3-fluoro-4-iodobenzoate
Embodiment 47: ethyl 4-iodo-3-nitrobenzoate
Embodiment 48: ethyl 3-fluoro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 49: ethyl 3-nitro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 50: 3-nitro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 51: 3-fluoro-4((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 52: ethyl 3-nitro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 53: ethyl 3-fluoro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 55: ethyl 2,3-difluoro-4((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 56: 2,3-difluoro-4((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 57: ethyl 2,3-difluoro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 58: methyl 3-acetamido-4-iodobenzoate
Embodiment 59: methyl 3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 60: ethyl 3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 61: ethyl 3-acetamido-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 62: 3-acetamido-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 63: ethyl 5-bromopyrazin-2-carboxylate
Embodiment 64: ethyl 2-((4,4-dimethyl-1,1-dioxothiochroman-6-yl)ethynyl)pyrimidin-5-carboxylate
Embodiment 65: methyl 3-acetamido-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 66: ethyl 5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-carboxylate
Embodiment 67: 5-((4,4-dimethylthiochroman-6-yl)ethynyl)pyrazin-2-carboxylic Acid
Embodiment 68: ethyl 5-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)pyrazin-2-carboxylate
Embodiment 69: ethyl 2-chloro-4-iodobenzoate
Embodiment 70: ethyl 2-chloro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoate
Embodiment 71: ethyl 2-chloro-4-((4,4-dimethyl-1-oxothiochroman-6-yl)ethynyl)benzoate
Embodiment 72: 2-chloro-4-((4,4-dimethylthiochroman-6-yl)ethynyl)benzoic Acid
Embodiment 73: 2-cyano-5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidine
Embodiment 74: 2-amino-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoic Acid
Embodiment 75: ethyl 2-((5,5,8, 8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-5-carboxylate
Embodiment 76: methyl 3-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate
Embodiment 77: 2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)-5-cyanopyridine
Embodiment 78: ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-carboxylate
Embodiment 79: methyl 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate
Embodiment 80: 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoic Acid
Embodiment 81: 2-acetyl amino-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoic Acid
Embodiment 82: methyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridin-2-carboxylate
Embodiment 83: 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridin-2-carboxylic Acid
Embodiment 84: methyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrimidin-2-carboxylate
Embodiment 85: ethyl 2-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate
Embodiment 86: ethyl 3-hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)benzoate
Embodiment 87: ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyridin-2-carboxylate
Embodiment 88: methyl 5-((5,5,8,8-tetramethyl-5,6,78-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-carboxylate
Embodiment 89: ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl)pyrazin-2-carboxylate
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
shows the study of the effect of WYC-103 on the apoptosis of tumor-repopulating cells of B16-F1 melanoma.
FIG. 2
shows the study of the effect of WYC-209 on the apoptosis of tumor-repopulating cells of B16-F1 melanoma.
FIG. 3
a
FIG. 3
b
FIG. 3
shows the study of the inhibitory activity of WYC-209 on the tumor-repopulating cells of A549 lung cancer, wherein shows the inhibitory activity of WYC-209 on A549 lung cancer when beginning administrating on the day 0; shows the inhibitory activity of WYC-209 on A549 lung cancer when beginning administrating on the 3rd day.
FIG. 4
a
FIG. 4
b
FIG. 4
shows the study of the inhibitory activity of WYC-209 on the tumor-repopulating cells of MCF-7 breast cancer, wherein shows the inhibitory activity of WYC-209 on MCF-7 breast cancer when beginning administrating on the day 0; shows the inhibitory activity of WYC-209 on MCF-7 breast cancer when beginning administrating on the 3rd day.
FIG. 5
a
FIG. 5
b
FIG. 5
shows the study of the inhibitory activity of WYC-209 on the tumor-repopulating cells of MDA-MB-435S melanoma, wherein shows the inhibitory activity of WYC-209 on MDA-MB-435S melanoma when beginning administrating on the day 0; shows the inhibitory activity of WYC-209 on MDA-MB-435S melanoma when beginning administrating on the 3rd day.
FIG. 6
a
FIG. 6
b
FIG. 6
shows the study of the inhibitory activity of WYC-209 on the tumor-repopulating cells of A2780 ovarian cancer, wherein shows the inhibitory activity of WYC-209 on A2780 ovarian cancer when beginning administrating on the day 0; shows the inhibitory activity of WYC-209 on A2780 ovarian cancer when beginning administrating on the 3rd day.
FIG. 7
a
FIG. 7
b
FIG. 7
shows the study of the inhibitory activity of WYC-209 on the tumor-repopulating cells of Hs-746T gastric cancer, wherein shows the inhibitory activity of WYC-209 on Hs-746T gastric cancer when beginning administrating on the day 0; shows the inhibitory activity of WYC-209 on Hs-746T gastric cancer when beginning administrating on the 3rd day.
FIG. 8
a
FIG. 8
b
FIG. 8
shows the study of the inhibitory activity of WYC-209 on the tumor-repopulating cells of MDA-MB-2311 breast cancer, wherein shows the inhibitory activity of WYC-209 on MDA-MB-231 breast cancer when beginning administrating on the day 0; shows the inhibitory activity of WYC-209 on MDA-MB-231 breast cancer when beginning administrating on the 3rd day.
FIG. 9
a
FIG. 9
b
FIG. 9
shows the study of the inhibitory activity of WYC-331 on the tumor-repopulating cells of A2780 ovarian cancer and MDA-MB-231 breast cancer, wherein shows the inhibitory activity of WYC-331 on A2780 ovarian cancer when beginning administrating on the 3rd day; shows the inhibitory activity of WYC-331 on MDA-MB-231 breast cancer when beginning administrating on the 3rd day.
FIG. 10
a
FIG. 10
b
FIG. 10
shows the study of the toxicity of WYC-209 (WYC-209 inhibits the proliferation of B16 cells, but has no significant effect on 3T3 cells); wherein, shows treating 3T3 cells with 10 μM WYC-209 for 18 hours; shows treating B16 cells with no WYC-209 or 10 μM WYC-209 for 48 hours.
FIG. 11
a
FIG. 11
b
FIG. 11
shows the study of the toxicity of WYC-331; wherein, shows treating 3T3 cells with 1μM or 10 μM WYC-331 for 24 hours; shows treating B16 cells with 1 μM or 10 μM WYC-331 for 24 hours.
FIG. 12
shows the tumor volume on the 19th day of the experiment in the study of the inhibitory activity of WYC-103 on subcutaneous melanoma.
FIG. 13
shows the study of the body weight of mice and in vivo toxicity of WYC-103 on subcutaneous melanoma.
FIG. 14
shows the tumor volume on the 26th day of the experiment in the study of the inhibitory activity of WYC-103 on subcutaneous melanoma.
FIG. 15
a
FIG. 15
b
FIG. 15
c
FIG. 15
d
FIG. 15
e
FIG. 15
f
FIG. 15
shows the study of the inhibitory activity of WYC-103 on metastatic melanoma in the lung; wherein, shows the lung tissue on the 29th day of the experiment where injecting 3000 tumor-repopulating cells of melanoma and administrating WYC-103; shows the lung tissue on the 29th day of the experiment where injecting 3000 tumor-repopulating cells of melanoma and administrating DMSO; shows the lung tissue on the 35th day of the experiment where injecting 3000 tumor-repopulating cells of melanoma and administrating WYC-103; shows the lung tissue on the 35th day of the experiment where injecting 3000 tumor-repopulating cells of melanoma and administrating DMSO; shows the lung tissue on the 37th day of the experiment where administrating WYC-103; shows the lung tissue on the 37th day of the experiment where administrating DMSO.
FIG. 16
a
FIG. 16
b
FIG. 16
c
FIG. 16
shows the study of the inhibitory activity of WYC-209 on metastatic melanoma in the lung, wherein, shows the lung tissue in the experiment where administrating DMSO; shows the lung tissue in the experiment where administrating 1.0 μM WYC-209; shows the lung tissue in the experiment where administrating 10 μM WYC-209.
FIG. 17
shows the single crystal structure of WYC-209A.
FIG. 18
shows the single crystal structure of WYC-209B. | |
The Education and Training Reform Act 2006 provides that instruction in the standard curriculum program is delivered free to all students in Victorian Government schools; this is referred to as ‘free instruction'. The Act also grants school councils the power to charge fees for goods and services to support the delivery of free instruction and to raise funds.
Free instruction includes learning and teaching, instructional supports, materials and resources, administration and facilities associated with the provision of the standard curriculum program. The standard curriculum program includes core learning and teaching activities related to the Victorian Essential Learning Standards and senior secondary certificates such as VCE, VCAL and VET in Schools programs.
The Department of Education and Early Childhood Development Parent Payments in Victorian Government Schools policy provides advice on the different types of payments that schools can request from parents and outlines the procedures and protocols schools must adhere to. This policy is available from the Department’s School Policy and Advisory Guide (www.education.vic.gov.au/spag).
School councils are responsible for developing and approving a school-level parent payment policy that is compliant with the Department’s policy.
There are three areas for which parents may reasonably be requested to make a payment or contribution:
• essential education items which parents/guardians pay the school to provide or may provide themselves, if appropriate: for example, stationery, text books and excursions (travel and entry costs)
• optional extras which are offered on a user-pays basis and which parents/guardians may choose whether their child accesses or participates in: for example, school magazines or extracurricular programs
• voluntary financial contributions which parents/guardians may be invited to donate to the school.
Parents/guardians are responsible for ensuring that their children are provided with essential education items. The school makes every effort to keep the cost of items that need to be purchased at a minimum. Parents/guardians also have the option of providing essential education items themselves.
Alternative payment arrangements are also available through the school.
The Donald Primary school council has made a considerable effort to ensure that this school policy is fair and provides a number of options to support parents to access the materials and services associated with their child's education.
If you have any queries or wish to discuss your circumstances and the options available to you, please contact the school to make an appointment.
The school-level parent payment policy is available on this website under Parent Information - Policies.
Danny Forrest Principal
Donald Primary School 2019 Parent Payment Charges – All Year Levels
Please find the itemised list that includes essential education items (those items that your child needs for school) and optional extras (that you can choose whether your child participates in or accesses).
Donald Primary School makes every effort to keep the cost and number of items that need to be purchased to a minimum. We also try to ensure that the costs are affordable for all parents. If you will have difficulty making payments please make an appointment to speak to Danny Forrest (Principal) to discuss possible support options and flexible payment arrangements. Any information about your financial circumstances, payment arrangements or status will be kept strictly confidential.
We would appreciate payment of any outstanding charges by Thursday 24th March 2016 (last day of Term 1, 2016). Please Note: Additional school charges may arise during the year. For example: It is expected that there will be excursions and camps later in the year and you will be given ample notice of the expected costs once these are established
|ITEM||SPECIFICATION||COST|
|Essential Education Items|
|
|
Classroom Stationery Pack comprises some or all of the following itemsdepending on year level
| Reader covers Reader Bags with School Logo Exercise books, Display books, Project books,
|
Writing books Ruler, scissors, blu-tack, glue sticks Pens, pencils, rubber, pencil sharpener,
textas, crayons. Paper – ruled, dotted thirds, coloured, kinder squares, graph Grade
|$100|
|Student Diary|| Prep – 2 : Read It Home Reading Diary
|
Grade 3 – 4 : Reading Trek Student Diary
Grade 5 – 6 : Study Trek Student Diary
|Specialist Subjects: Art / Science / ICT / French /
|
Active Hands on Learning/ Bush School / Kitchen Garden
|
|
Specialist materials for these subjects including:
|Travel & Cultural Levy||
|
This levy has been introduced to reduce the continual request for money that occurs when
|$100|
|Optional Education Items|
|
|
Camps
|
|
Grade 3 & 4 Camp
Grade 5 & 6 Camp
|
|
Odd Year (2015) Cheaper Camp (local/regional) $100 - $150Even Years(2016) More Expensive i.e. Capital & Regional Cities. $250 - $350
|To be advised later in the year.
|
|Extra-Curricular activities, eg. RACV Energy Breakthrough|
|Voluntary Financial Contributions|
|Garden Levy||Garden & Grounds maintenance & beautification ONE PAYMENT/FAMILY||$ 20 / family|
|
|
Summary of Parent Payment Charges
|Essential Education Items||$200 / Student|
|Optional Extras||TBA|
|Voluntary Financial Contribution||$20 / Family|
|TOTAL||$220 for first child|
|$200 for each additional child|
Parent Payment Arrangements
- Option A (full amount by the end of Term 1)
- Option B (payment at the beginning of each Term)
- Option C (half yearly payment)
- Option D (other payment arrangements)*
* (If selecting Option D please make an appointment with the school to discuss your circumstances and the available options)
Please see Family Statement for list of charges
Download: | http://donaldps.vic.edu.au/ourschool.php?id=53%CF%80d=52 |
There's nothing Jo Bowers likes more than reading a good book.
And the principal lecturer in primary education at Cardiff’s Metropolitan University, who will be speaking at next week’s Literature Festival about reading for pleasure and creating lifelong readers, firmly believes reading should not feel like work.
It’s her passion to get as many people reading as possible and she feels it’s hugely important to get children enjoying books from an early age.
“It’s about choice and enjoyment. Children should be able to read whatever they want to read, and with that comes enjoyment. if they have read a book that interests them, they will share that experience with others,” says Jo.
“Whether it’s fiction or non-fiction, reading can give a real sense of wellbeing and enjoyment. It could be a magazine or comic or a digital book. There are so many different subject matters and it helps develop a wide range of skills, helped kids make progress in maths, vocabulary and spelling.”
Jo says reading a good book can become infectious, as children and adults want to share that enjoyment by talking about it, and she says it’s crucial to get that love of a good book early, so it can continue into adulthood.
“Not everyone develops a love of reading as a child. Many youngsters find it a chore but it’s never too late to get into the reading habit. Of course, we live in a digital age now but I keep waving the flag for books and believe there is plenty of pleasure to be had by sitting down with a good book.
““I think having a Children’s Literature Festival is a wonderful thing. Books should be celebrated and it’s a fantastic opportunity to learn about the context of story writing. Quite often, if you like the story, you like the author and it’s great to have the chance to find out where they got their ideas from and what books they enjoyed.”
However, not every child is an avid reader, and boys particularly seem to find it harder to get into books, but there are many ways to get reluctant readers to brush up on their skills without making it feel like hard work.
Sian Smith, literary expert for National Support Programme, shares her top tips on making reading fun.
1 BE A ROLE MODEL
Do your children see you reading? Do you discuss/share what you read? If not, start doing it.
Sian says: “If children see you taking an interest in reading, they will too. Are there books around the house? It’s really important that children have access to books and other reading materials. It doesn’t have to be a book; it could be a comic, picture encyclopaedia, a factual book about a topic or appropriate sections from a newspaper. What is most important is that it happens on a daily basis.”
2 TAP INTO THEIR HOBBIES
If your son is a football fan, get your hands on a soccer magazine. If your daughter loves Barbie, buy a Barbie book. Most importantly, choose materials that interest them.
“If they are interested in something they are more likely to read it. A good starting point might be books or comics based on TV programmes or films that they enjoy, or colourful factual books on topics that fascinate them.
“Older kids might prefer to read the book of a film they’ve seen and there are some really fantastic teenage fiction books around at the moment and you can capitalise on their interests.
3 USE THE LIBRARY
Buying books can be expensive but letting your child have time to browse at books at the library will heighten their enjoyment of a good book.
“The library is a useful and inexpensive way to develop your child’s interest in reading – books can be borrowed from and taken back to ANY branch in Cardiff once you are a member, and there are never fines on children’s books.” says Sian.
“But go to bookshops too. Let the children read the info on the back and maybe the first few pages to see if it interests them. The summer reading challenges are great during the school holidays as they encourage the kids to keep going back to choose new books, once they’ve completed them.”
4 FOSTER THE SOCIAL ASPECT OF READING
Sian says this is a good idea for boys, who tend to be slighter less interested in reading.
She says: “The importance of shared reading – looking at texts together, discussing info and character decisions etc can’t be underrated. And don’t worry about reading out loud to them as they get older. It all counts in making reading more fun.”
5 MAKE BEDTIME READING TIME
Sian, a mum-of-two, from Whitchurch, says she is quite old-fashioned when it comes to bedtime reading, but she says her boys Nye and Ioan have never had a problem with going to sleep.
“Reading before bed, and no screen time for an hour before, is non-negotiable in our house. I never sleep as well if I look at Facebook just before bed and it’s really important to use reading to relax, which it does. Even when they can read independently, there is nothing like sharing a story and you can read and discuss more sophisticated books than they are able to access.
“However, saying that, you can capitalise on technology too. There are some fantastic apps available and online book clubs like The Sprout (http://www.thesprout.co.uk) is local and safe.”
6 ENCOURAGE THEM TO RE-READ
If your child has read a story several times already, don’t be afraid to let them read it again and again.
If they are young, this is an important stage for their development in terms of language patterns. They learn how to join in the reading at the bits they know and you might even find them reading the book by themselves whilst playing. | https://www.walesonline.co.uk/whats-on/family-kids-news/how-make-reading-really-good-6914885 |
In this first part, you are going to learn the basics of Medieval 2. Follow the following steps carefully in order to organize your future work efficiently.
Before starting with Medieval 2: some very important points to check in Finale
- Check that you are in Page View (Scroll/Studio View should be avoided with Medieval!)
- Go to the Finale Preferences (menu Finale > Preferences > Edit) and always make sure that Automatic Music Spacing is unchecked.
Default files
There are two Medieval-specific default files in your common Finale directory: MedievalDefault.musx and GregorianDefault.musx (note: In Finale 2012, the music file extension is simply “.mus".)
The difference between the two lies essentially in the number of staff lines (4 for Gregorian), in the design of the clefs, and in some other minor aspects (there are more specific late medieval symbols in the MedievalDefault file.)
- With the New from Template command (Finale's File menu), select and open GregorianDefault.musx.
- Although you can already see the empty score in the background, Finale asks you for further "Score Information": just press Cancel for this step!
A 4-line staff appears with the C clef in Gregorian square notation style. The default clef is the C-clef placed at the top staffline. Note the dashed barlines, and that the default measure rests and the time signature are not visible.
- Save this blank document under any name, for instance 'tutorial.musx'.
If you often deal with medieval scores, you can set either MedievalDefault.musx or GregorianDefault.musx as the new Finale default file (in Finale Preferences > New panel.)
Displaying Medieval's tool palette
- From Finale's menu, select the menu item Plug-ins > Medieval > Tool Palette
Medieval's tool palette shows up on screen:
Depending on the current interface's language, the tool palette is named Werkzeugpalette (German), Palette d'outils (French), Palette di strumenti (Italian) or Instrumenta (Latin).
A musical copy exercise
As an exercise, let us copy an exerpt of the Lætare Sunday from the catholic liturgy (Lent season):
(This is a photography of an old edition...)
Preparing the score
If we stop at “eam”, we can divide the work into 4 sections, which will correspond to Finale's “measures”. We will also need to make the music somehow bigger:
- With Finale's Selection tool, select the whole score.
- Go to the menu Utilities > Fit Measures and choose 2 measures per system throughout.
- Click on the Page Layout tool, and select Resize Page Systems from the menu.
- Choose 180 % for the entire score and click OK:
Now some more prefatory work:
- With Finale's Measure tool, move the middle dashed barline of the second system to the left.
- With Finale's Clef tool, select the whole score and click to choose the appropriate C clef (seated on the second staff line, from the top):
The Clef selection dialog box looks like this using the Gregorian template:
If you want to use a key signature (with one flat for instance), although this is rather unusual in the music of the Middle-Age, you will want to load the special gregorian-clefs-for-keys.lib (or medieval-clefs-for-keys.lib) library, which works around a long-standing Finale bug when displaying key signature accidentals beside custom clefs.
Well, you are now ready to enter the notes!
In Medieval, it is essential to deal only with Finale's quarter note (possibly dotted), regardless of the real rythmic value. In fact, Medieval adapts the time signature to the actual number of entries automatically, even if you remove or add some notes ; you just don't have to bother with this at all if you respect the rule of the quarter note.
But before typing your notes into the score, check the following important points:
- In Simple Entry Options dialog box (Simple Entry menu), do this:
- Uncheck 'Check for Extra Notes'.
- Uncheck 'Fill with Rests at End of Measure'.
- If you use Speedy Entry, do the following from the Speedy menu:
- Uncheck 'Jump to Next Measure'.
- Uncheck 'Check Accidentals' (Finale 2012 only)
- Uncheck 'Check for Extra Notes'.
- Uncheck 'Use five Lines Staff'.
- From the Speedy Options dialog box, Uncheck 'Fill with Rests at End of Measure'.
You won't have to do this again and you are now all set to commence your transcription.
Look up the Basic Rules & Settings to see how to work efficiently with Medieval and Finale together.
Transcription of the melody
- With your entry tool of choice, Speedy or Simple Entry, using the quarter note value (possibly dotted, at the end of some subsection), enter the “raw” notes of our example:
We strongly suggest to use a MIDI keyboard to enter the notes. With the mouse, it will be much more time consuming and uneasy!
Moreover, the combination Speedy + keyboard has proven to be the most convenient for Medieval.
If, in Simple Entry, the entry caret looks like this:
or like that:
It means that you are not using a quarter note value, which should be always the case!
- We are now ready to take advantage of Medieval's power, and, in a few clicks, you will turn these simple “puncta” into a complex Gregorian score.
Next chapter: Neumes & Tools... | https://www.klemm-music.de/notation/medieval/documentation/_win/gettingstarted.html |
Schermkunst (VAULT Case MS Fol.U.423.792) is a Dutch fencing manual created in 1595. It currently rests in the holdings of the Newberry Library in Chicago, IL. The manuscript appears to be incomplete in its present form; there are probably missing pages from the introduction, and it ends with only one half of an intended play of the pike.
Contents
Provenance
Contents
|Irv|
|1r - 3r|
|4r - 5r||Illustrations of Katzbalger|
|5v - 8v||Illustrations of single rapier|
|9r - 11r||Illustrations of rapier and dagger|
|11v - 12r||Illustrations of Dussack and shield|
|12v - 13v||Illustrations of rapier and buckler|
|14r - 16r||Illustrations of halberd|
|16v - 17v|
|IIrv|
Gallery
Additional Resources
- van Noort, Reinier. Swordplay: an anonymous illustrated Dutch treatise for fencing with rapier, sword and polearms from 1595. Wheaton, IL: Freelance Academy Press, 2015. ISBN 978-1-937439-29-3
References
Copyright and License Summary
For further information, including transcription and translation notes, see the discussion page. | https://wiktenauer.com/wiki/Schermkunst_%28VAULT_Case_MS_Fol.U.423.792%29 |
Today I'd like to introduce two chess problems posted in Small Basic forum. You can use Unicode characters for chessmen in Small Basic programs. e.g. ♟, ♞, ♝, ♜, ♛ and ♚.
Knight's Tour
The original post is here by Yvan Leduc. This problem is also picked up in the challenge of this month.
A knight's tour is a sequence of moves of a knight on a chessboard such that the knight visits every square only once. If the knight ends on a square that is one knight's move from the beginning square (so that it could tour the board again immediately, following the same path), the tour is closed, otherwise it is open.
This picture above shows a solution solved by WPV159-3.
8-Queens
This problem was a community suggestion by Amir CPS in Challenge of the Month - January 2013.
The 8-Queens problem in chess is to place 8 queens on a chess board such that none of the queens is threatening any of the others. The problem is to input the 8 columns of the queens on the rows of a chess board, with 1 being the first column and 8 being the last, e.g. 1 2 3 4 5 6 7 8 means the queens are along the diagonal, which would not be a valid solution.
Write a program to test a user input guess.
Examples:
- Enter board configuration: 2 4 6 8 3 1 7 5 - This is a valid configuration (as above).
- Enter board configuration: 1 8 2 5 3 7 4 6 - This is NOT a valid configuration.
This picture above shows that the pattern is not a solution: red queens are threatening others. The ID of this program is QDX521. | https://blogs.msdn.microsoft.com/smallbasic/2016/04/18/chess-problems-in-small-basic/ |
Keep-on with your online shopping!
Design Republic stores and offices will be closed during mid weeks of August.
Shipments will be suspended between 7th and 24th of August 2020.
All orders placed during this period will be correctly processed starting from Tuesday 25th of August.
You will be able to continue your online purchases and shopping, but please keep in mind that during this short closing period, the orders will not be processed according to the standard times.
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In Stock items:
All the orders featuring items already in stock at our warehouse will be shipped at our reopening, starting from August 25th.
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Enjoy your summer, stay safe! | https://www.designrepublic.com/en/summer-break |
Falls, assaults, car crashes, heart attacks, strokes, suicide attempts: there are many ways in which people can acquire a brain injury.
“Sufferers may have more intense or less intense feelings than before,” says Dr Brian Waldron, a clinical psychologist with Acquired Brain Injury Ireland(ABII). “Damage to the frontal lobes can lead to anger outbursts and, sometimes, physical aggression.
“Brain injury can affect cognitive functioning including memory, language expression, visual perception and motor skills. Relationship breakdown can happen and people can lose friends. There is a short period of time after an injury where the brain can rewire some of the cells, but other areas of the brain may not get full function back.”
There is no cure for brain injury. It’s about management. | http://neverstop.today/brain-injury-effects-are-huge-not-just-physical/ |
The Dawn spacecraft has returned the sharpest ever images seen of Ceres ahead of its historic rendezvous with the dwarf planet.
The images were taken from 147,000 miles (237,000 km) away on January 25, and represent a new milestone for a spacecraft that soon will become the first human-made probe to visit the 'Death Star' planet.
At 43 pixels wide, the images are more than 30 per cent higher in resolution than those taken by Nasa's Hubble Telescope in 2003 and 2004 at a distance of over 150 million miles.
The images that make up this animation were taken from 147,000 miles (237,000km) away on January 25 as Dawn edges closer to its target in March
The dwarf planet has been likened to the death Star from the hit film Star Wards
'We know so little about our vast solar system, but thanks to economical missions like Dawn, those mysteries are being solved,' said Jim Green, Planetary Science Division Director at Nasa.
The new Dawn images come on the heels of initial navigation images taken January 13 that reveal an 'alien' white spot on the dwarf planet and the suggestion of craters.
While Nasa has not provided an explanation, scientists suggest it may be a frozen pool of ice at the bottom of a crater that reflects light.
We can confirm that it is something on Ceres that reflects more sunlight, but what that is remains a mystery,' Marc Rayman, mission director and chief engineer for the Dawn mission, told Space.com
Over the next weeks, Dawn will provide increasingly sharper images of the icy world, leading up to the spacecraft's capture into orbit around Ceres on March 6.
'We know so much about the solar system and yet so little about dwarf planet Ceres.
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At 43 pixels wide, the images are more than 30 per cent higher in resolution than those taken by Nasa's Hubble Space Telescope in 2003 and 2004 at a distance of over 150 million miles
The 'alien' mark can be clearly seen in the latest images the icy world as the Dawn probe hurtles its way towards a rendezvous on March 6
As the Dawn spacecraft closes in on Ceres, new images have emerged showing the solar system's largest asteroid at 27 pixels across - three times better than the images taken in early December. This GIF shows bright and dark features
On the left is a processed image, taken January 13. It hints at craters on the surface of Ceres. Dawn's framing camera took this image at 238,000 miles (383,000km) from Ceres. On the right, is a zoomed-in raw image
Ceres is 590 miles (950 km) across and was discovered in 1801. In January, researchers discovered that water was gushing from its surface at a rate of 13lb (6kg) per second.
'Now, finally, we have a spacecraft on the verge of unveiling this mysterious, alien world,' Dawn mission director and chief engineer Marc Rayman, of Nasa's Jet Propulsion Laboratory in Pasadena, California said.
'Soon it will reveal myriad secrets Ceres has held since the dawn of the solar system.'
Observations by the European Space Agency's Herschel telescope suggested they could be coming from geysers or ice volcanoes.
Ceres orbits the sun in the asteroid belt between Mars and Jupiter and is very similar to Jupiter's moon Europa and Saturn's moon Enceladus - both considered potential sources for harbouring life.
Ceres is the bright spot in the centre of the image. Because the dwarf planet is much brighter than the stars in the background, the camera team selected a long exposure time to make the stars visible. The long exposure made Ceres appear overexposed, and exaggerated its size A cropped, magnified view of Ceres appears in the inset image at lower left
Dawn will be captured into Ceres' orbit in March, marking the first visit to a dwarf planet by a spacecraft (artist's impression pictured)
THE MYSTERIOUS WORLD OF CERES
Ceres is the closest dwarf planet to the sun and is located in the asteroid belt, making it the only dwarf planet in the inner solar system.
Ceres is the smallest of the bodies currently classified as a 'dwarf planet'.
Scientists think Ceres may have an ocean and possibly an atmosphere.
It lies less than three times as far as Earth from the sun - close enough to feel the warmth of the star allowing ice to melt and reform.
Nasa's Dawn spacecraft has been making its way to Ceres from the asteroid Vesta since September 2012. It is due to land next year.
There is high interest in the mission because Ceres is one possible destination for human colonisation given its abundance of ice, water, and minerals.
Dr Michael Kuppers, of the Esa's lab in Villanueva de la Canada in Spain said: 'Although ground and space-based observations may further map the behaviour of Ceres over its orbit the Dawn spacecraft mission arriving to orbit Ceres in early 2015 is expected to be key in providing a long-term follow-up on the water outgassing behaviour of Ceres.'
The presence and abundance of water in bodies like Ceres could have relevance for the origin of life on Earth and the large-scale migration of planets such as Jupiter.
One scenario suggests as the giant planets migrated they disturbed populations of small rocky and icy asteroids and comets which hit the early Earth and Moon - delivering organic molecules and water to Earth.
Ceres is twice the size of Saturn's geyser-spouting moon Enceladus which is suspected of having liquid water beneath its surface.
It lies less than three times as far as Earth from the sun - close enough to feel the warmth of the star allowing ice to melt and reform.
Since launching in 2007, Dawn has already visited Vesta, a giant protoplanet currently located 104 million miles (168 million km) away from Ceres.
The distance between Vesta and Ceres is greater than the distance between the Earth and the sun.
During its 14 months in orbit around Vesta, the spacecraft delivered unprecedented scientific insights, including images of its cratered surface and important clues about its geological history.
Vesta and Ceres are the two most massive bodies in the main asteroid belt.
The image was taken as part of a final calibration of the science camera before Dawn's arrival. On December 1, Ceres was about nine pixels in diameter - nearly perfect for this calibration
Ceres is 590 miles (950 km) across and was discovered in 1801. In January, researchers discovered that water was gushing from its surface
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List of Dharamshalas in Haridwar
If you are looking for Dharamshalas in Haridwar you can find here Dharamshalas in Haridwar near Har Ki Pauri, Near Ganga Ghat, Near Railway Station. Here you can find list of various Dharamshalas in Haridwar along with facilities available in them and process and details of making bookings of rooms in these Dharamshalas. Dharamshalas near har ki pauri, near railway station, near ganga ghat are also marked separately.
Dharamshalas Near Har Ki Pauri
- Govind Bhawan Dharamshala at walking distance from Har ki Pauri
- Ekta Bhawan Dharamshala is at 10 minutes walk from Har Ki Pauri
Dharamshalas Near Railway Station
- Ganga Sagar Yatri Bhawan – Shiv Murti Street, Near Railway Station Road
Dharamshalas Near Ganga Ghat
Note: If you know about any Dharamshala in Haridwar which is not listed here, please share the details of the same and let us know about it, to help all those, who are looking for a suitable Dharamshala during their visit to Haridwar. | http://dharamshalas.in/uttarakhand/haridwar/dharamshalas-in-haridwar/ |
Beef satay skewers in their marinated glory.
Meat on a stick. OK, Cook’s Illustrated. I’m listening.
Magic meat on a stick? We’ll see about that.
Technique: This recipe has three saucy components — the basting sauce, the marinade, and the peanut sauce. The basting sauce has 11 ingredients; the marinade has three; and the peanut sauce has 10. The common denominator in these sauces is fish sauce, in all its pungent glory. I think it’s the marinade, a simple mixture of veggie oil, brown sugar, and fish sauce, that really gives the beef some depth (in only 30 minutes).
After the beef is marinaded, it’s woven onto skewers and cooked, with three pauses for basting. It goes fast; the skewers are ready in about seven minutes.
“Grilling”: The recipe calls for grilling the beef (charcoal or gas), but it was too dark by the time we got around to making dinner. Instead we made the skewers with the broiler. The beef was cooked to my liking (pink in the middle), but I couldn’t help but miss a little smoky char on the skewers. Next time.
Fired up? A perennial issue when cooking “ethnic” recipes by CI is the lack of heat. CI is spot-on for any North American or European food, but get away from those continents and meals feel faded. This Thai dish was not spicy. I don’t have a super-high tolerance for heat, but I was hoping for a little sweat on the brow. No such luck.
Encore? Yes, I would make the satay skewers and peanut sauce again. Next time, they’re going on the charcoal grill, and I think I’ll turn up the heat with a chili pepper or more red pepper flakes.
Have you noticed that CI whiffs on ethnic cuisine? Think I’m off base? Let’s talk.
Everything Tastes Better When It's Served On A Stick! | https://siemachtsewingblog.com/2011/10/cooks-illustrated-challenge-grilled/ |
The trend reversal point is the stumbling block of any trader. Dozens, if not hundreds, of various indicators and candlestick patterns have been created to attempt to precisely determine it, because opening or closing a position as close as possible to the trend reversal point is the key to maximum profitability. The weakening of pressure from the bulls or the bears is most effectively shown by the MACD (Moving Average Convergence and Divergence) indicator.
From this article you will learn:
- How to trade with MACD indicator
- How to interpret MACD indicator
- How to use MACD indicator in day trading
- What are MACD settings.
What is MACD and how it is interpreted on MACD charts
The MACD indicator appeared on exchanges in the 70s and served to identify the direction of the trend and momentum, or the intensity of the price movement along the trend. This technical indicator has two varieties:
- the MACD line indicator: trend (lagging) indicator;
- the MACD histogram: an improved version of the line indicator, designed to be ahead of the signals given by the MACD line. It can be called an oscillator and used to make trading decisions.
On most modern exchanges, these two indicators are combined on one chart:
The value of the MACD indicator (blue line) represents the difference in values between the fast-moving (period 12) and the slow-moving average (period 26). This difference indicates the intensity of the trends. When the moving averages intersect, the MACD becomes zero. If the MACD is above the zero line, the trend is considered to be upward, and if it’s below, then it is downward.
The second line on the MACD graph (the red one) is the exponential moving average of the MACD line itself, with a step of 9. It is also called the signal line. It provides an earlier signal to trend reversal compared to the zero level of the MACD line. MACD histograms are constructed based on the interaction of the MACD with the signal line, but we should not use the histograms to analyze stock prices, since they are derived from the linear MACD.
In pursuit of discrepancies: MACD divergence and convergence
The discrepancies between the MACD indicator and the price on the chart are called divergence and convergence, depending on whether the trend is bullish or bearish. They act as a powerful and reliable MACD signal for opening or closing a position.
The most accurate are the divergences and convergences of class A. As a rule, they are followed by a steep reversal. Divergence A is formed when the rate updates the price maximum but the next indicator’s maximum is lower than the previous one. The reverse situation indicates a convergence of A, or a change in trend from bearish to bullish. This constitutes a signal to open a long position.
Divergence B indicates a weakening of the bull trend and its immediate correction. This signal is less reliable, since the price may have a reserve for further movement in the same direction.
In markets with high volatility, one can often observe class C divergence and convergence. This discrepancy suggests that there is only a slight drop in momentum, and such signals should not be given significant attention.
As a rule, both vertices are analyzed to detect discrepancies. But in some cases, the price confirms its trend at the next extreme, and the indicator shows the opposite. Such a situation is considered to be an even more reliable signal for opening or closing a position.
It is also possible to track discrepancies directly inside the MACD index, as they are an indicator of the intensity of the development of a trend. Thus, the divergence of moving averages occurs when the distance between the moving averages increases and the price increases rapidly. Then, the trend develops with greater speed. In this case, the MACD line is moving away from zero. The convergence of the moving averages, on the contrary, occurs when the moving averages approach each other. The impulse then subsides, and the trend slows down. The MACD line is thus nearing zero.
Signals based on MACD in the Xena Exchange terminal
Divergence is considered one of the most powerful signals, and high-grade trading strategies are built on its basis. In the Xena Exchange terminal, the signals to buy or sell an asset based on the MACD index are reflected directly on the MACD divergence chart for the convenience of the trader.
Nevertheless, before drawing conclusions based on divergence or convergence, it’s necessary to make sure that there’s a clear trend developing on the market, since a large number of false signals may appear during flat periods. The more obvious the difference traced on the market, the greater the number of traders who will react to it, which increases the likelihood of a correct forecast. The probability of error always exists, and we recommend that you limit risks by using stop orders. | https://xena.exchange/blog/seize-the-chance-trend-reversal-signal-on-the-macd-indicator/ |
The Gulf of Maine Research Institute (MRI) and Maine Aquaculture Association (Project Partners) required the services of a consulting team to develop an objective and fact-based Statewide Training Strategy (The Workforce Development Strategy) for Maine’s growing and evolving aquaculture industry.
The intended outcomes for the Workforce Development Strategy were:
1. to serve as a strategic roadmap for educators, institutions, and thought leaders/decision makers to understand: current workforce needs/challenges; future workforce needs/challenges; and strengths and weaknesses of existing programming.
2. to provide short-term and long-term recommendations for developing a robust and cohesive aquaculture training pipeline including, but not limited to, supplementing existing programs or creating new programs.
3. to provide a comprehensive assessment of existing educational and training programs.
Specific tasks performed by Imani Development included:
• Qualitative sector-specific growth scenarios (low, medium, high) using methodology agreed to by the Scottish Team, GMRI, & MAA.
• Analysis and basic modelling of sector-specific supply-chains including growth scenarios, required skills and job types
• Finalized interview questionnaire/topic guide and associated data collection template.
• Summary of current workforce needs by sector
• Descriptions with accompanying infographics of current and projected (based on growth scenario projections) aquaculture job types by company size and sector.
• Mapped current and projected workforce skills needs by company size and sector
• Additional written discussion/commentary on the above deliverables to highlight nuances and influencing factors as necessary.
• Development of report and presenting findings. | https://imanidevelopment.com/maine-aquaculture-workforce-development-strategy-2018-2019/ |
Healthy margins are a telling signal of a healthy business. But what’s considered a good net profit margin can vary depending on the industry, and depending on the year.
In my mind, it’s difficult to understand what constitutes a good net profit margin (also called “net margin”, or “net income margin”) when you have no context.
So in this post, I’ll do three things:
- Explain the basics of net profit margins
- Show the average net profit margin for the S&P 500 over the last 20 years
- My favorite part: Reveal a shocking truth about net margins
There are all sorts of profitability margins which describe pretty well how a company is controlling its costs and making a profit. My colleague Dave Ahern already wrote an excellent post on the 3 main margin ratios, which can be summarized as the following:
- Gross margin
- Operating margin
- Net margin
If you are a beginner, I highly recommend going through that article first. As someone with more experience with financial statements and accounting, I’d like to offer a quick shortcut that really helps me understand each of the ratios, and recall them.
Each of these margin ratios can be calculated using a company’s income statement.
First, let’s separate the main expenses that every company has to face as a part of doing business.
- COGs (cost of goods) = What it takes to create a product or service
- SG&A (selling, general, & administration) = marketing and corporate
- R&D (research and development) = your engineers and research team
- Interest, taxes, depreciation, amortization = the “ITDA” in EBITDA
Now that we have those definitions, let’s group them into the 3 main profitability/margins ratios:
Top-line = sales
-COGs
Gross margin
-SG&A
-R&D
-D&A
Operating margin (also EBIT)
-Int exp
-Taxes
Net profit margin (Net Income)
= the bottom line
Hopefully that was easy enough, I recommend doing what I did. Put a sticky note of that breakdown next to your computer and soon enough you’ll have it memorized.
So now that we know what constitutes the net margin, let’s uncover the pros and cons of using it.
Pros
- Shows you where (or when) a company needs to do a better job at cutting costs (low comparable margins)
- Shows you companies that are excellently managed and efficient (high net margin)
- Gives you a good estimate of how much in sales a company will need to make how much profit
Cons
- Will fluctuate as Net Income fluctuates. Especially pronounced if there’s a large tax benefit or charge
- Can be misused if an investor doesn’t compare the ratio to the correct context (apples to apples)
Alright, now that we know what a net profit margin is and how it is sourced from an income statement, let’s decide what constitutes a good net profit margin.
Like all smart analyses, this requires data.
The Average Net Profit Margin of the S&P 500 over the Last 20 Years
Since I have access to excellent datasets and love to dive into this stuff, I’ll provide two of them:
- For the entire S&P 500
- By industry (of the S&P)
Here’s a table using the current 500 S&P constituents, with their historical net profit margins from 2001- 2020:
I included the MEDIAN of the industries to find the S&P 500 middle point per year since a few industries had averages into the extremes, which distorts the true average.
Over this entire time period (2001-2020), the average (median) net profit margin by year was 8.9%.
So, we can surmise that a good net profit margin is anything 10% or above, and really is dependent on the year and economy as much as the individual companies.
For example, you can see that the S&P 500 had good net profit margins during the 2014-2020 period, with below average net profit margins in 2009-2010.
Now there is some survivorship bias in this data as it doesn’t update with each S&P 500 change over the years, and so you have some companies which were in a growth phase during the first decade and became more profitable in the second decade. And you had some companies with great net profit margins (like some of the FANGs) which were included in the S&P 500 in later years.
But overall, the dataset provides a good representation of how profit margins have looked across the S&P 500 historically, and gives us good context on what separates a good net profit margin from a subpar one.
How Small Improvements in Margins Can Lead to HUGE Growth in EPS and FCF
In breaking down the ramifications of margins, I guess like an engineer would tear down a device, I had an epiphany about just how powerful small improvements in margins can be.
It really was best illustrated for me by using a hypothetical example on a spreadsheet.
Let’s assume for the purposes of this example that a company has a 10% net profit margin, which we’ve established is pretty reasonable across the universe of stocks. Our company might have the following statistics then:
- Sales = $500
- Gross = $200
- EBITDA = $100
- Net Income = $50
So, what would an improvement of 1% in margins do to our financials?
Honestly, a 1% improvement didn’t seem like a lot to me at first, maybe that’s intuitive. After all, 1% of $500 is just $5, which is a pittance to this company, right?
Well actually, if the company was able to save 1% in costs at any point of that margin picture, and it flowed all the way down to the bottom line and they now have $5 more in profits, that means…
Our Net Income just jumped 10%, or from $50 to $55, just from a 1% increase in margins!
It gets better. Say we had a 3% improvement in margins, or just $15 of cost savings. Our Net Income would increase from $50 to $65, which represents a 30% increase.
And it becomes even more significant as you examine lower margin businesses! Let’s use an example of a company with an 8% net profit margin. Similar example here:
- Sales = $500
- Gross = $175
- EBITDA = $75
- Net Income = $40
The same 1% improvement in margins, $5, would turn $40 in Net Income into $45, which represents an instant 12.5% increase in Net Income!
It’s all because of the numbers, and how the percentages work!
How to Think About Cost Savings and Margins
The thing about these margin improvements too is that most cost savings plans should flow directly down to a company’s bottom line, at least in general.
For example, a savings in Cost of Goods from a margin perspective would flow most of the way through.
If a laptop manufacturer was able to find a cheaper source of electronics components which saved on costs with every laptop unit produced, that would be an example of COGs savings which is a margin improvement.
Since it’s on every item produced/sold, that 1% improvement increases Gross Margin by 1% without the company having to increase any other employment related costs like SG&A or R&D. So that 1% increase in Gross Margin becomes a similar 1% increase in Operating Margin, which flows down to Net Income (and Net Profit Margin) except for the small increase in taxes from the extra profits.
But we need to make sure that we’re not confusing nominal cost savings with percentage based, margin savings.
For example, lower COGs because less items were produced because of less demand may decrease costs, but that would mean that revenues were also decreased by a similar amount, which keeps the gross margin the same even though costs have decreased.
You can use the same logic of improving gross margins to increase net profit margin for improvements in operating margins too, if a company has operating leverage—meaning they can increase revenues without having to increase operating costs (like employment related to SG&A and R&D) in a proportional amount.
That’s where the real magic in margins lies, when a company has high operating leverage and can expand those gross or operating margins by increasing revenues while keeping operating costs suppressed.
Examples of companies with a high operating leverage would be Hershey’s or Netflix; they both have pricing power and can increase revenues by raising prices while keeping costs the same.
Companies might not want to admit publicly when they have these advantages as it can irritate customers, but high operating leverage often comes from competitive advantages, which allow for pricing power or other features of the business that allow for margin expansion.
Example: Margin Improvement and Long Term Growth
Margin expansion is where I want to focus next, because not only does it have a potential multiplicative effect in the short term, it can also contribute significantly to long term growth—which is extremely relevant in growth estimates for valuation.
Let’s go back to a simple example to illustrate just how powerful that can be.
Take Hershey’s again, $HSY.
If I pull up the long term financial data of the company, you can make calculations which show that over the last 10Y, revenue grew by 4.2% CAGR while EPS grew by 11.1% CAGR.
How can a company grow profits faster than revenues to this extent?
The answer lies in the company’s ability to increase its net profit margin.
Since stock buybacks also helped contribute to the company’s 11.1% CAGR in EPS, we’ll use a comparison between Net Income and Revenue to ignore the effects of shares outstanding for a moment. In the same 10 year time period, Net Income was increased by 10.2% CAGR compared to that 4.2% CAGR of revenue.
Let’s calculate the net profit margin for 2009, which is the initial date for our 10Y period.
Revenue = $5,299 million
Net Income = $436 million
Net profit margin = Net Income/ Revenue = 8.2%
Now we’ll make the same calculation for the ending period, or fiscal year 2019.
Revenue = $7,986 million
Net Income = $1,250 million
Net profit margin = Net Income/ Revenue = 14.4%
You can see that in this same 10Y time period, Hershey’s was able to improve their net profit margin by 6.2%, and herein lies the secret to a company growing profits faster than revenues.
In fact, outside of using buybacks to reduce shares outstanding, it is the only possible way to grow earnings faster than revenues.
With this example, we can make a very interesting observation.
Notice how a 6.2% improvement in net margin led to a 6% higher growth in Net Income than the 4.2% growth in revenue (10.2% 10Y CAGR in Net Income – 4.2% 10Y CAGR in Revenue = 6%, similar to the improvement in net profit margin we just calculated, 6.2%).
That’s a significant contribution long term CAGR growth over 10 years, from those 6% of percentage points of net margins improvement.
That means that for valuation models, we can bake margin improvements into our growth estimates, and if a company at any point improves its net margin by a certain amount, the company will see a superior long term EPS and Net Income growth to the extent that the margins are improved).
Suddenly, those comments about cost savings of $20 million for a $1.5B company perk up my ears a lot more, as even small percentages of sales mean significant long term growth of earnings.
Limitations, Analyses, and Takeaways
The limitations of using net profit margin improvements in valuation are inherent in the problems with the net profit margin ratio itself.
Since net margin can fluctuate so wildly from year to year, I actually like to use operating margin as a better long term proxy of a company’s margins.
This might seem counterintuitive, but I prefer a company with lower operating margin today but a history of higher operating margin in the past.
What this signals to me is a company with a great future growth catalyst, achievable simply by reaching profitability and efficiency levels that it was previously able to achieve. As long as the profitability of the industry itself has not changed much, or the company’s competitive advantage has not eroded, it’s generally safe to bake a few points of margin improvements into a valuation.
As we know, even a couple of percentage points added to a growth estimate can make a big difference in a company’s intrinsic value, which can uncover additional value opportunities among companies.
You always want to incorporate a margin of safety into valuations, and be conservative with growth estimates and margin improvements.
But if a company has had a good net profit margin in the past, and seems like it can grow back into those margins in the future, I think it’s a fantastic signal and a great way to evaluate the long term growth potential of future cash flows. | https://einvestingforbeginners.com/good-net-profit-margin-dataset/ |
The Brexit and its effect on a cross-border Innovation Alliance
The Cross-Border alliance at the UK / Ireland border potentially faces a new set of barriers which are more of a legal and historical nature. With the United Kingdom having voted for leaving the European Union, a large consortium of border stakeholders sees their efforts for acquiring funding for intensifying the research and innovation collaborations endangered.
Just over a few months ago, a working group comprised of Intertrade Ireland, NMEA/Louth LEO, representatives of the University of Ulster, Dundalk Institute of Technology, Sligo Institute of Technology and Letterkenny Institute of Technology, along with the recent addition of Scottish Enterprise & Highlands and Islands Enterprise submitted the SME Innovation support program ‘Co-Innovate’. The program aims to increase cross-border research and innovation collaboration of Northern Ireland, Republic of Ireland, and the west of Scotland, targeting a 10% increase in the joint innovation activities by the year 2023.
As much as the other businesses in Britain, the possibility the UK leaving the European Union after the Brexit vote raised concerns among the project stakeholders during the development of the ‘Co-Innovate‘ project submission. The partners called for a meeting to discuss the implications of a potential Brexit decision on the United Kingdom / Ireland border region, subsequently reaching to the consensus that Brexit would severely affect cross-border knowledge transfer through which HEI research and innovation is nurtured. This was followed by a high profile lobbying campaign taken up by the university, government, and the local development agency representatives of the initiative, in efforts to display the firm stand of local authorities for the Remain vote in the Brexit debate.
Despite the majority of stay votes in Northern Ireland, the UK voted for leave, paving the way for the alliance partners to plan the ‘Economic and Political Stability Symposium’ to be held in September 2016 with the prospective attendance of government and social representatives across Ireland to discuss the significant changes ahead and how to protect the interests of the region from Brexit aftershocks. | https://uiin.org/2016/09/08/the-brexit-and-its-effect-on-a-cross-border-innovation-alliance/ |
The Foundational Knowledge of Agricultural Production Systems program supports plant research to advance our knowledge for the wide range of agricultural production systems found across the rural-urban continuum, from conventional open-fields to protected built environments. Research addresses critical or process-limiting dynamics that occur among and within the various management components of a production system using experimental manipulations of system components, technological interventions, system analyses, modeling, or agro-ecological approaches. Results are expected to lead to the development of innovative sustainable solutions to challenges limiting or threatening the productivity, profitability, and good stewardship of natural resources, environment, and human capital.
2021 Project Highlights:
- The Ohio State University will use funds from this program to identify plant growth promoting rhizobacteria that can benefit crop performance in various production systems. This innovative technology will help develop more sustainable production systems by increasing the availability and plant uptake of essential nutrients, thereby reducing nutrient leaching and environmental contamination.
- Oklahoma State university will tackle the issue of declining water table in the Ogallala Aquifer region. They will integrate cotton (a low water demanding crop) into the traditional grain rotations and investigate the long-term environmental and economic impact of the new production system.
- The Pennsylvania State University will investigate effects of weather variability on crop performance and agroecosystem processes and how that knowledge could help assist farmers with adaptive management strategies. The research team will use open-top chambers and snow removal to manipulate climate within the field and examine how warmer temperatures and increasing winter weather variability associated with climate change affect perennial forage crops and weedy plant communities. A separate team from the same institution will optimize biological nitrogen fixation by alfalfa, a legume cover crop widely used in both conventional and organic production systems. | https://www.nifa.usda.gov/about-nifa/announcements/nifa-invests-over-6m-support-foundational-knowledge-ag-production-systems |
1. Introduction {#sec1-molecules-22-00532}
===============
*Dichapetalum* Thouars (Dichapetalaceae) is a rich source of triterpenoids and several species of the genus have produced a variety of this class of secondary metabolites. Although the genus was initially noted for being lethal to livestock and even humans, recent research has focused on the less toxic plant species and has led to the discovery of a novel class of phenylpyranotriterpenoid compounds, the dichapetalins. This unique class of triterpenoids in which a 2-phenylpyrano moiety is annellated to ring A of a 13,30-cyclodammarane-type triterpenoid is believed to be biogenetically derived from the condensation of the triterpenoid with a C~6~--C~2~ moiety, which is probably derived from the shikimic acid pathway. The main distinguishing feature of the dichapetalins is the nature of the side chain on the cyclopentane ring D which may comprise a lactone, methyl ester, spiroketal, lactol, acetyl and furan moieties. Originally known for their cytotoxic activity, dichapetalins with a spiroketal side chain have exhibited the most potent antineoplastic properties. Moreover, they have also been reported to have antioxidant, antihelminthic, antifeedant, nematicidal, antifungal, anti-HIV, nitric oxide-- and acetylcholinesterase-inhibitory activities \[[@B1-molecules-22-00532],[@B2-molecules-22-00532],[@B3-molecules-22-00532],[@B4-molecules-22-00532],[@B5-molecules-22-00532],[@B6-molecules-22-00532],[@B7-molecules-22-00532]\].
*Dichapetalum pallidum* (Oliv.) Engl. is distributed in west and central Africa. It has hitherto not been examined, neither for its chemical constituents nor for bioactivity. The main documented ethnobotanical applications are the use of the seeds as food in Togo and the leaves in the treatment of diarrhea \[[@B8-molecules-22-00532]\]. As part of our on-going studies on the less common and less toxic species of the genus, in our search for new and more potent cytotoxic dichapetalins, we report the isolation and characterization of three dichapetalins from the roots of *D. pallidum*, namely 7-hydroxydichapetalin P (**1**), dichapetalin A (**2**) and the recently reported dichapetalin X (**3**) from *D. filicaule* \[[@B7-molecules-22-00532]\]. Also isolated were friedelin-2,3-lactone (**4**), the dipeptide aurantiamide acetate (**5**), friedelan-3-one (**6**), friedelan-3β-ol (**7**) and pomolic acid (**8**) ([Figure 1](#molecules-22-00532-f001){ref-type="fig"}). Although dichapetalin P has been reported from *D*. *zenkeri* \[[@B5-molecules-22-00532]\], its 7-hydroxy derivative (**1**) has hitherto not been reported as a naturally occurring compound. The dichapetalins exhibited better anti-proliferative activity against the human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines than curcumin. The results further substantiate this class of dammarane-type triterpenoids as potential antitumor agents.
2. Results {#sec2-molecules-22-00532}
==========
2.1. Characterization of Compounds {#sec2dot1-molecules-22-00532}
----------------------------------
Repeated silica gel column chromatographic separation of the ethyl acetate extract of the roots of *D. pallidum* afforded a total of seven triterpene derivatives and a dipeptide, aurantiamide acetate (**5**). Among the triterpenoids were dammarane-type 7-hydroxydichapetalin P (**1**), which is reported for the first time, dichapetalin A (**2**) and the recently reported dichapetalin X (**3**) from *D. filicaule* \[[@B7-molecules-22-00532]\]. The remaining triterpenoids were the friedelane-type compounds friedelin-2,3-lactone (**4**), friedelan-3-one (**6**) and friedelan-3β-ol (**7**), and the ursane-type pomolic acid (**8**).
Compound **1** was obtained as a white crystalline solid. Five methyl protons were identified in the ^1^H-NMR spectrum within the range δ~H~ 0.92 to δ~H~ 2.03, the latter being assigned to an acetoxymethyl. The ^1^H-NMR spectrum exhibited signals due to five aromatic protons resonating at δ~H~ 7.24 (m, H-4″), δ~H~ 7.33 (m, H-3″, 5″) and δ~H~ 7.35 (m, H-2″, 6″). The ^13^C-NMR spectrum showed 38 signals. Two ester carbonyl functionalities were inferred by chemical shifts at δ~C~ 173.9 and δ~C~ 170.4 and supported by absorptions at 1780 and 1745 cm^−1^ in the IR spectrum. The intensity of the olefinic/aromatic signals at δ~C~ 125.8 and δ~C~ 128.4 appeared to be twice that of the other signals, indicating the presence of two sets of equivalent carbons. The HSQC data revealed 11 quaternary carbons interspersed within both the sp^2^- and sp^3^-hybridized regions, nine methylene, 13 methine and five methyl carbons. Thus, the expected total number of carbons present in **1** was 40.
Six ^1^H-^1^H COSY spin systems were observed ([Figure 2](#molecules-22-00532-f002){ref-type="fig"}), while some key HMBC correlations enabled the complete assignments of the ^1^H and ^13^C resonances of **1** which were consistent with previously accumulated data in our compound library of a dichapetalin carbon arrangement. For example, the 2-phenylpyrano moiety was corroborated from a mono-substituted phenyl ring comprising the four sp^2^ carbon signals C-1″ (δ~C~ 142.6), CH-2″, 6″ (δ~C~ 125.8, δ~H~ 7.35, m), CH-3″, 5″ (δ~C~ 128.4, δ~H~ 7.33, m) and CH-4″ (δ~C~ 127.5, δ~H~ 7.24, m), together with HMBC correlations from H-2″, 6″ to C-6′ (δ~C~ 81.8) and H-2′ to C-6′ and C-3 (δ~C~ 140.0) ([Figure 2](#molecules-22-00532-f002){ref-type="fig"}). The presence of the cyclopropane moiety, comprising C-13, -14 and -30, was supported by HMBC correlations from H-12 and H-17. The positions of the two isolated double bonds (C-2/C-3 and C-11/C-12), arising from four sp^2^ carbon signals at δ~C~ 117.8 (C-2), δ~C~ 124.1 (C-11), δ~C~ 129.1 (C-12), δ~C~ 140.0 (C-3) with corresponding olefinic proton multiplets at δ~H~ 5.42 (1H, dd, *J* = 1.8, 7.1 Hz, H-2), δ~H~ 5.46 (1H, dd, *J* = 2.6, 10.2 Hz, H-11), and δ~H~ 6.20 (1H, dd, *J* = 3.1, 10.2 Hz, H-12), were assigned based on HMBC correlations, for example from H~2~-1, H-2′ and H-9. In addition to an acetal at δ~C~ 111.3 (C-23), compound **1** revealed a spiroketal side chain at C-17 bearing an acetoxy group identical to those of dichapetalins M \[[@B4-molecules-22-00532]\] and P \[[@B5-molecules-22-00532]\] ([Figure 3](#molecules-22-00532-f003){ref-type="fig"}). However, the parent structure of the compound differed from those of both compounds, evident from an obvious absence of a C-7 ketocarbonyl in the ^13^C-NMR. This was replaced with a 7-OH group, supported by HSQC cross-peaks of C-7 (δ~C~ 72.3) to H-7 (δ~H~ 3.95), the ^1^H-^1^H COSY spin system involving H-5, H~2~-6 and H-7, and HMBC correlations to C-7 (δ~C~ 72.3) and C-8 (δ~C~ 36.4) from the methine proton H-5.
Thus, compound **1** was unequivocally identified as 7-hydroxydichapetalin P, the reduced form of dichapetalin P, which has hitherto not been reported as a naturally occurring dichapetalin. Moreover, **1** exhibited peaks in its IR spectrum and characteristic chromatographic profile with respect to its reaction with vanillin reagent as previously reported for the dichapetalins \[[@B5-molecules-22-00532]\]. Based on the close similarity of its NMR data to previously reported congeners, compound **1** is most likely to share a relatively similar stereochemistry as its congeners.
Compounds **2** and **3** were identified as dichapetalins A and X, respectively, by comparison of their physico-chemical and spectroscopic data with published results \[[@B1-molecules-22-00532],[@B7-molecules-22-00532]\] as well as by co-TLC with authentic samples in several solvent systems. Similarly, compounds **6**--**8** were also characterized respectively as friedelan-3-one, friedelan-3β-ol and pomolic acid on the basis of their physic-chemical and spectroscopic properties and comparison of the data with published data \[[@B7-molecules-22-00532],[@B9-molecules-22-00532],[@B10-molecules-22-00532]\].
Compound **4** was isolated as a white crystalline solid. Eight methyl groups were confirmed by the following signals in the ^1^H-NMR spectrum: (δ~H~ 0.83, s, Me-25), (δ~H~ 0.89, s, Me-24), (δ~H~ 0.95, s, Me-26), (δ~H~ 0.99, s, Me-27), (δ~H~ 0.99, s, Me-30), (δ~H~ 1.00, s), (δ~H~ 1.17, s, Me-28) and (δ~H~ 1.20, d, *J* = 6.5 Hz, Me-23). The ^13^C-NMR indicated the presence of 30 carbons, the signal at δ~C~ 18.6 integrating for two carbons. Together with the DEPT and HSQC assignments, eight methyls, 11 methylenes, four methines and seven quaternary carbons including a carbonyl (δ~C~ 175.6) were identified, suggesting a triterpenoid skeleton. Further analyses of the NMR data showed a good comparison with the literature \[[@B11-molecules-22-00532]\] for friedelin-2,3-lactone (**1**), ([Figure 1](#molecules-22-00532-f001){ref-type="fig"}). The HMBC correlations of C-4 (δ~C~ 84.9) to Me-23 (δ~H~ 1.20) and Me-24 (δ~H~ 0.89), and C-10 (δ~C~ 64.9) and C-3 (δ~C~ 175.6) to H-2a (δ~H~ 2.52) and H-2b (δ~H~ 2.63) supported the position of the lactone. Although the related compounds friedelan-3-one and friedelan-3β-ol are replete in the genus, this is the first report of the isolation of the lactone from the genus.
Compound **5** was obtained as a white amorphous solid. Its IR spectrum exhibited bands typical of an amide (3314 and 1661 cm^−1^), an acetoxy (1726 and 1261 cm^−1^), a monosubstituted phenyl (745 and 695 cm^−1^), and methyl, methylene and methine (2961, 2919, 2858 cm^−1^) groups, respectively. The presence of an acetoxymethyl was confirmed by a 3H singlet at δ~H~ 2.03 in the ^1^H-NMR spectrum. Signals for two amide NH groups were observed at δ~H~ 6.75 and δ~H~ 5.98. The ^13^C-NMR spectrum showed signals for three carbonyls, that is an acetoxy (δ~C~ 170.7), an aliphatic amide (δ~C~ 170.2) and an aromatic amide (δ~C~ 167.1), two benzylic methylenes and an oxymethylene signals at δ~C~ 37.8, δ~C~ 38.4 and δ~C~ 64.4, respectively, while two methines were found at δ~C~ 49.4 and δ~C~ 54.9, including the acetoxymethyl at δ~C~ 20.8. There were nine aromatic methines and three quaternary carbons within the range δ~C~ 126.7--δ~C~ 136.7, suggesting the presence of three mono-substituted phenyl rings. This was corroborated by 15 aromatic protons (δ~H~ 7.12--7.78) in the ^1^H-NMR spectrum. Comparison of the data with literature \[[@B12-molecules-22-00532]\] led to the identification of compound **5** as the dipeptide aurantiamide acetate ([Figure 1](#molecules-22-00532-f001){ref-type="fig"}), previously isolated from red algae and several families of higher plants \[[@B13-molecules-22-00532]\], but reported for the first time in the Dichapetalaceae.
2.2. Effect of Compounds ***1***--***5*** on Cell Proliferation of Leukemia Cancer Cell Lines {#sec2dot2-molecules-22-00532}
---------------------------------------------------------------------------------------------
Human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines were employed in the assay of the anti-proliferative activities of compounds **1**--**5**. Dichapetalins A and X were more active against CEM and HL-60 cells than 7-hydroxydichapetalin P and curcumin.
In the initial screening of compounds **1**--**5** towards Jurkat cell lines, the dichapetalins strongly inhibited the growth of the Jurkat cells. The inhibitory activities (IC~50~ values) of 7-hydroxydichapetalin P (**1**), dichapetalin A (**2**) and dichapetalin X (**3**) were 2.66, 2.97 and 1.80 μM, respectively, while that for standard curcumin was 2.54 μM. On the other hand, friedelin-2,3-lactone (**4**) and aurantiamide acetate (**5**) showed rather weak inhibitory activities (IC~50~ \> 100 µM) ([Figure 4](#molecules-22-00532-f004){ref-type="fig"}).
Further testing of the dichapetalins in HL-60 and CEM cells revealed weaker inhibitory potency compared to those in Jurkat cells. In HL-60 cells, measured IC~50~ values were 29.72, 11.19 and 5.56 μM, respectively, for the dichapetalins and 16.76 μM for curcumin ([Figure 5](#molecules-22-00532-f005){ref-type="fig"}). This result confirms a previous assay in which the chemosensitivity of dichapetalin A on HL-60 was reported as 11.0 µM^5^. The CEM cells were slightly more sensitive to the dichapetalins than HL-60 cells, with IC~50~ values of 23.92, 9.62 and 3.14 μM, respectively, for 7-hydroxydichapetalin P, dichapetalin A and dichapetalin X, but more resistant to curcumin (IC~50~ = 19.96 μM) ([Figure 6](#molecules-22-00532-f006){ref-type="fig"}).
Overall, dichapetalin X (**3**) showed the strongest and broadest cytotoxic activities against all the leukemic cell lines tested, exhibiting even stronger activities than curcumin. Although 7-hydroxydichapetalin P (**1**) was in all cases a weaker inhibitor than curcumin, their IC~50~ values were comparable, indicating that the dichapetalins isolated in this study are cytotoxic to all the leukemia cell lines tested. This suggests that the compounds are potential anticancer agents, corroborating earlier studies that have indicated that the dichapetalins have anticancer properties \[[@B2-molecules-22-00532],[@B3-molecules-22-00532],[@B5-molecules-22-00532],[@B6-molecules-22-00532]\]. So far, dichapetalins M and P, which contain an intact lactone in the side chain and a ketocarbonyl group at C-7, have exhibited the most potent anti-proliferative activities, with dichapetalin M exhibiting nanomolar cytotoxicity towards human colorectal carcinoma (HCT-116) \[[@B5-molecules-22-00532]\]. These two structural features have therefore been implicated in the pharmacological action of this class of compounds. Dichapetalin X and 7-hydroxydichapetalin P have the intact lactone but lack the 7-carbonyl, while both moieties are absent in dichapetalin A. Thus, structurally, 7-hydroxydichapetalin P and dichapetalin P are identical, with the exception of the substituent at the 7 position. Dichapetalin M is 6-hydroxydichapetalin P. Dichapetalin X, on the other hand, has a different side chain where the acetoxy group in the dichapetalin P derivatives is replaced with a butyloxy substituent. These findings suggest the need to carry out further studies to confirm the proposed structure-activity relationship and to determine the mechanisms of action of this intriguing class of triterpenoids.
3. Conclusions {#sec3-molecules-22-00532}
==============
The identification of dichapetalins in *D. pallidum*, hitherto unexamined for its chemical constituents, is of chemotaxonomic significance. All the isolated dichapetalins exhibited micromolar anti-proliferative activity towards three leukemia cancer cell lines, namely the Jurkat, HL-60 and CEM cell lines. Dichapetalin X, recently isolated as a novel dichapetalin from *D. filicaule* with potential antihelminthic activity, but not assayed for its anti-proliferative activity, was the most potent cytotoxic agent against all the leukemic cell lines tested. It exhibited even stronger activity towards these cell lines than the standard compound used, curcumin. The presence of a spiroketal moiety in its side chain further supports the suggested relationship of this structural feature to the potent anti-proliferative activity in this class of compounds.
In order to establish the identity of the pharmacophores, it is important to investigate the mechanisms underlying the observed anti-proliferative properties of the dichapetalins and possibly incorporate these pharmacophores onto smaller scaffolds as a means of synthesizing simple but potent anticancer agents.
4. Materials and Methods {#sec4-molecules-22-00532}
========================
4.1. General Experimental Procedures {#sec4dot1-molecules-22-00532}
------------------------------------
TLC was performed on aluminum foil slides pre-coated with silica gel (thickness 0.2 mm, type Kiesegel 60 F~254~ Merck (Merck KGaA, Darmstadt, Germany) using petroleum ether/Me~2~CO mixtures, petroleum ether/Me~2~CO/CHCl~3~ (7:5:5); petroleum ether/Et~2~O (3:7); petroleum ether/EtOAc (10:3); toluene/EtOH mixtures; CHCl~3~ (100%). Detection: I~2~ vapor, anisaldehyde spray reagent, and H~2~SO~4~ spray reagent. All chromatographic separations were carried out by column chromatography (CC) on Fluka silica gel 60 (Sigma-Aldrich, Buchs, Switzerland). Melting points (uncorrected) were determined on a Stuart Scientific Melting Point Apparatus (Cole-Parmer, Staffordshire, UK). IR spectra were recorded in KBr discs on a Shimadzu IR-408 spectrophotometer (Shimadzu, Burladingen, Germany). ^1^H-NMR was either run at 600 MHz on a Brüker Avance 600 Spectrophotometer (Bruker, Billerica, MA, USA) or at 500 MHz on a Brüker Ascend^TM^ 500 Spectrophotometer in CDCl~3~ with TMS as the internal standard.
4.2. Plant Material {#sec4dot2-molecules-22-00532}
-------------------
Whole roots and stem of *Dichapetalum pallidum* were collected from Asenanyo Forest Reserve (Ashanti Region, Ghana) in July 2013 and identified by Mr. John Ntim-Gyakari, formerly of the Forestry Commission, Kumasi. A voucher specimen (DPA001) was deposited at the National Herbarium, Botany Department, University of Ghana, Legon.
4.3. Extraction and Isolation {#sec4dot3-molecules-22-00532}
-----------------------------
The air-dried pulverized whole root of *D.* *pallidum* (1786 g) was extracted with EtOAc (4 L, 24 h) by soxhlet. After concentration under reduced pressure, the dark brown crude extract (38.7 g) was chromatographed on a silica gel column, eluting with petroleum ether/EtOAc (10:1 to 0:10, *v*/*v*) to obtain fractions F1--F5. Fraction F1 (2.14 g) was re-chromatographed with petroleum ether/EtOAc (15:0.5) to yield three oily subfractions, F11--F13. Subfraction F12 (942 mg) on trituration in petroleum ether followed by further CC with CHCl~3~/petroleum ether (3:1, *v*/*v*) gave friedelan-3-one (**6**) (240 mg), friedelan-3β-ol (**7**) (20 mg) and a mixture of the two compounds. Fraction F2 (4.54 g) yielded nine subfractions, F21--F29, when chromatographed with petroleum ether/EtOAc (5:1). Subfractions F23 to F25 (933 mg) were combined and triturated with petroleum ether to afford an impure solid (280 mg) which on further chromatography in CHCl~3~ afforded friedelin-2,3-lactone (**4**) (64 mg) and β-sitosterol + stigmasterol (20 mg). Subfraction F29, on trituration with petroleum ether/EtOAc (4:1) precipitated pomolic acid (**8**) (37 mg). Seven subfractions (F31 -- F37) were obtained when fraction F3 (1.35 g) was further separated by CC eluting with petroleum ether/EtOAc (5:1). Subfractions F33 and F35 to F37 were separately triturated with Et~2~O to yield aurantiamide acetate (**5**) (80 mg), 7-hydroxydichapetalin P (**1**) (20 mg), dichapetalin A (**2**) (25 mg) and dichapetalin X (**3**) (130 mg). Fraction F4 (1.15 g) was subjected to CC to yield subfractions (F41 -- F45) while F5 precipitated a solid, F5S1. No further analysis could be carried out on these due to paucity of material.
*7-Hydroxydichapetalin P* (**1**): White crystals (20 mg); m.p.: 249--251 °C; IR ν~max~ cm^−1^ (KBr): 3551, 3370 (OH hydrogen bonded), 2973, 2919 (methyl), 1782 (\>C=O lactone), 1746 (\>C=O ester), 1246, 1094, 947, 700 (C~6~H~5~ bending). ^1^H-NMR and ^13^C-NMR, see [Table 1](#molecules-22-00532-t001){ref-type="table"}.
*Dichapetalin A* (**2**): White crystals (25 mg); m.p.: 224--226 °C (Lit.: 228--230 °C, \[[@B4-molecules-22-00532]\]); IR ν~max~ cm^−1^ (KBr): 3573, 3536, 3360, 2957, 2931, 1745, 1602, 1449, 1191, 1071, 1050, 766, 701 (Lit.: 3573, 3535, 3369, 2957, 2932, 1713, 1654, 1449, 1191, 1071, 1050, 767, 701 \[[@B7-molecules-22-00532]\]); Co-TLC with authentic sample in petroleum ether/CHCl~3~/Me~2~CO (7:5:5), *R*~f~ = 0.82; petroleum ether/EtOAc (10:3), *R*~f~ = 0.46; CHCl~3~ (100%); *R*~f~ = 0.58, anisaldehyde: purple. ^1^H-NMR and ^13^C-NMR, see [Table 1](#molecules-22-00532-t001){ref-type="table"}.
*Dichapetalin X* (**3**): White crystals (130 mg); m.p.: 244--246 °C (Lit.: 246--248 °C, \[[@B7-molecules-22-00532]\]); IR ν~max~ cm^−1^ (KBr): 3549, 3367, 2973, 2921, 1784, 1743, 1167, 699 (Lit.: 3577, 3368, 2973, 2921, 1782, 1743, 1602, 699 \[[@B7-molecules-22-00532]\]); Co-TLC with authentic sample in petroleum ether/CHCl~3~/Me~2~CO (7:5:5), *R*~f~ = 0.82; petroleum ether/EtOAc (10:3), *R*~f~ = 0.46; CHCl~3~ (100%); *R*~f~ = 0.58, anisaldehyde: purple. ^1^H-NMR and ^13^C-NMR, see [Table 1](#molecules-22-00532-t001){ref-type="table"}. The values are agreeable to those reported by Chama et al. \[[@B7-molecules-22-00532]\].
*Friedelin-2,3-lactone* (**4**): White crystals (64 mg); m.p.: 285--288 °C (Lit.: 288--290 °C, \[[@B11-molecules-22-00532]\]); ^1^H-NMR (500 MHz, CDCl~3~) δ~H~: 0.83 (3H, s, Me-25), 0.89 (3H, s, Me-24), 0.95 (3H,s, Me-26), 0.99 (6H, s, Me-27, Me-30), 1.00 (3H, s, Me-29), 1.17 (3H, s, Me-28), 1.20 (3H,d, Me-23), 1.93 (1H, m), 2.52 (1H,td, H-2), 2.63 (1H,ddd, H-2), 4.22 (1H,q, H4). ^13^C-NMR (150 MHz, CDCl~3~) δ~C~: 18.6 (CH~2~, C-1), 34.4 (CH~2~, C-2), 175.6 (C, C-3), 84.9 (CH, C-4), 40.8 (C, C-5), 38.4 (CH~2~, C-6), 18.0 (CH~2~, C-7), 52.7 (C, C-8), 38.2 (C, C-9), 63.9 (CH, C-10), 35.3 (CH~2~, C-11), 30.6 (CH~2~, C-12), 39.3 (C, C-13), 38.4 (C, C-14), 32.4 (CH~2~, C-15), 35.4 (CH~2~, C-16), 30.0 (C-17), 42.7 (CH, C-18), 36.0 (CH~2~, C-19), 28.2 (C, C-20), 32.7 (CH~2~, C-21), 39.2 (CH~2~, C-22), 13.5 (CH~3~, C-23), 16.2 (CH~3~, C-24), 17.9 (CH~3~, C-25), 18.6 (CH~3~, C-26), 20.2 (CH~3~, C-27), 32.1 (CH~3~, C-28), 31.8 (CH~3~, C-29), 35.0 (CH~3~, C-30).
*Aurantiamide acetate* (**5**): White powdery/amorphous, (80 mg); m.p.: 177--180 °C (Lit.: 184 °C, \[[@B13-molecules-22-00532]\]). IR in KBr; ν~max~ cm^−1^: 3314 (NH), 1661 (-CON), 1726 and 1261 (OAc), 745 and 695 (monosubstituted phenyl), methyl (2961), methylene (2919) methine (2858). ^1^H-NMR (600 MHz, CDCl~3~) δ~H~: 7.07--7.73 (15H, aromatic protons), 6.75 (1H, d, *J* = 7.7 Hz, N-H), 5.98 (1H, d, *J* = 8.4 Hz, N-H), 4.78 (1H, dd, *J* = 5.6 Hz, H-7), 4.35 (1H, m, H-4), 3.93 (1H, dd, *J* = 11.9, 4.9 Hz, H-3b), 3.83 (1H, dd, *J* = 11.9, 4.2 Hz, H-3a), 3.22 (1H, dd, *J* = 13.3, 6.3 Hz, H-10b), 3.07 (1H, dd, *J* = 13.3, 8.4 Hz, H-10a), 2.75 (2H, m, H-11), 2.03 (3H, s, AcCH~3~). ^13^C-NMR (600 MHz CDCl~3~) δ~C~: 170.7 (C-2, ester), 170.2 (C, C-6, aliphatic amide), 167.1 (C, C-9, aromatic amide), 136.7 (C, C-1′′′), 136.6 (C, C-1z), 133.7 (C, C-1′), 131.9 (CH, C-4′), 129.3 (CH, C-4″), 129.1 (CH, C-4′′′), 128.7 (CH, C-2′′′/C-6′′′), 128.6 (CH, C-2′/C-6′), 128.6 (CH, C-3′/C-5′), 127.1 (CH, C-3″/C-5″), 127.0 (CH, C-2″/C-6″), 126.7 (CH, C-3′′′/C-5′′′), 64.6 (CH~2~, C-3), 54.9 (CH, C-7), 49.4 (CH, C-4), 38.4 (CH~2~, C-11), 37.4, (CH~2~, C-10), 20.8 (CH~3~, C-1).
*Friedelan-3-one* (**6**). White needles (240 mg); m.p.: 255--257 °C (from EtOH) (Lit.: 258--259 °C, \[[@B9-molecules-22-00532]\]); IR ν~max~ cm^−1^ (KBr): 2972, 2927, 2870, 1716, 1462, 1389 (Lit.: 2971, 2926, 2869, 1715, 1463, 1389 \[[@B9-molecules-22-00532]\]). Co-TLC with authentic sample in petroleum ether/Me~2~CO (12:0:5), R~f~ = 0.80; toluene/EtOH (14:0.1), *R*~f~ = 0.94; CHCl~3~ (100%); *R*~f~ = 0.83, anisaldehyde: yellow, darkens with time.
*Friedelan-3β-ol* (**7**). White crystals (20 mg); m.p.: 276--278 °C (from EtOH) (Lit.: 274--276 °C \[[@B7-molecules-22-00532]\]); IR ν~max~ cm^−1^ (KBr) 3621, 3480, 2915, 1451, 1385 (Lit.: 3619, 3474, 2911, 2870, 1448, 1385, \[[@B7-molecules-22-00532]\]); Co-TLC with authentic sample in petroleum ether/Me~2~CO (12:0:5), *R*~f~ = 0.51; toluene/EtOH (14:0.1), *R*~f~ = 0.76; CHCl~3~ (100%); *R*~f~ = 0.67, anisaldehyde: purple.
*Pomolic acid* (**8**): White powder (37 mg); m.p.: 289--292 °C (from absolute EtOH) (Lit.: 286--289 °C \[[@B10-molecules-22-00532]\]); Anisaldehyde: purple; IR ν~max~ cm^−1^ (KBr) 3569, 3413, 2875, 1687, 1462, 1388, 1269, 1073 (Lit.: 3569, 3413, 2875, 1687, 1461 \[[@B7-molecules-22-00532]\]); Co-TLC with authentic sample in petroleum ether/Me~2~CO (10:3), *R*~f~ = 0.48; petroleum ether/Et~2~O (3:7), *R*~f~ = 0.78; toluene/EtOH (8:1), *R*~f~ = 0.47, anisaldehyde: purple.
4.4. Cytotoxicity Assay {#sec4dot4-molecules-22-00532}
-----------------------
The cytotoxic activities of the compounds towards Jurkat, HL-60, CEM and MCF-7 cancer cell lines were determined using the MTT assay \[[@B14-molecules-22-00532]\]. The cells were cultured in RPMI supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. The cells were then seeded in a 96-well plate at 1 × 10^4^ cells/well and treated with varying concentrations of the compounds (0--100 µg/mL) and maintained in a humidified incubator at 37 °C in the presence of 5% CO~2~ incubated for 72 h. Twenty microliters of 2.5 mg/mL MTT solution in phosphate buffered saline (PBS) was added to each well and incubation was continued for 4 h. Acidified isopropanol containing 1% Triton-X was added to each well, and subsequently the plates were kept in the dark at room temperature to dissolve any formazan crystals formed. Absorbance readings of wells were measured at 570 nm with a microplate reader (Tecan Infinite M200, Grödig, Austria). All experiments were performed in triplicate.
The authors acknowledge the Chemistry Department and the Noguchi Memorial Institute for Medical Research, University of Ghana, for provision of laboratory space, solvents and reagents in support of the research work. They also wish to thank Fred Kumah, graduate student of the Chemistry Department, University of Ghana, for laboratory assistance. This research has not received any funds for covering the costs to publish in open access.
**Sample Availability:** Samples of the compounds **2**--**8** are available from the authors.
######
Click here for additional data file.
Supplementary materials are available online. Scheme S1: Isolation of compounds **1**--**8**, Figure S1: The structures of compounds **1**--**8**, Figures S2--S11: Spectroscopic data for compounds **1**--**3**, Tables S1--S3: Biodata for compounds **1**--**3**.
I.A.-M., D.O.-S. and M.A.C. conceived and designed the experiments; G.A.D., D.O.-S. and M.A.C. isolated the compounds; R.W., R.A., G.A.D., D.O.-S. and M.A.C. performed the structure elucidation and characterization of all the compounds; R.A.-O. and I.T. performed the biological assay experiments and analyzed the results; D.O.-S., G.A.D. and R.A.-O. wrote most of the manuscript; All authors contributed to the manuscript.
The authors declare no conflict of interest.
{#molecules-22-00532-f001}
{ref-type="app"}).](molecules-22-00532-g002){#molecules-22-00532-f002}
{#molecules-22-00532-f003}
{#molecules-22-00532-f004}
{#molecules-22-00532-f005}
{#molecules-22-00532-f006}
molecules-22-00532-t001_Table 1
######
NMR spectroscopic data for 7-hydroxydichapetalin P (**1**), dichapetalins A (**2**) and X (**3**).
No. 1 (in CDCl~3~, 600 MHz) 2 (in CDCl~3~, 600 MHz) 3 (in CDCl~3~, 500 MHz)
------------ ------------------------- ----------------------------- ------------------------- ---------------------------- ------------- -----------------------------
**1a** 1.68, m 1.66, m 1.69, m
**1b** 40.1, CH~2~ 2.03, dd (7.1, 16.1) 40.1, CH~2~ 2.10, dd (7.0, 16.2) 40.1, CH~2~ 2.11, dd (7.1, 16.2)
**2** 117.8, CH 5.42, d (7.1) 117.7, CH 5.40, d (6.9) 117.8, CH 5.43, ddd (1.8, 1.8, 7.1)
**3** 140.0, C 140.1, C 140.0, C
**4** 38.3, C 38.3, C 38.3, C
**5** 43.7, CH 2.01, m 43.8, CH 2.00, m 43.8, CH 2.04, m
**6a** 1.62, ddd (2.4, 13.8, 13.8) 1.62, m 1.67, m
**6b** 24.1, CH~2~ 1.85, ddd (3.0, 3.0, 13.8) 24.2, CH~2~ 1.85, dd (10.5, 12.7) 24.2, CH~2~ 1.86, ddd (3.0, 3.0, 13.8)
**7** 72.3, CH 3.95, dd (2.4, 3.0) 72.3, CH 3.94, m 72.3, CH 3.97, dd (2.4, 3.0)
**8** 36.4, C 36.4, C 36.4, C
**9** 45.7, CH 2.01, m 45.7, CH 1.98, m 45.7, CH 2.02, m
**10** 35.7, C 35.2, C 35.7, C
**11** 124.1, CH 5.46, dd (2.5, 10.2) 124.1, CH 5.45, dd (2.1, 10.0) 124.0, CH 5.48, dd (2.6, 10.2)
**12** 129.1, CH 6.20, dd (3.1, 10.2) 129.0, CH 6.14, dd (2.9, 10.0) 129.1, CH 6.21, dd (3.1, 10.2)
**13** 29.9, C 30.1, C 30.0, C
**14** 36.2, C 36.2, C 36.3, C
**15a** 1.73, m
**15b** 24.8, CH~2~ 2.05, m 24.9, CH~2~ 2.05, d (12.2) 24.8, CH~2~ 2.08, m
**16a** 1.27, m
**16b** 23.2, CH~2~ 1.78, ddd (9.6, 15.6, 19.2) 22.8, CH~2~ 1.12, m 23.2, CH~2~ 1.78, ddd (9.6, 15.6, 19.2)
**17** 40.3, CH 2.63, m 41.0, CH 2.62, m 40.3, CH 2.64, m
**18** 17.5, CH~3~ 0.92, s 17.4, CH~3~ 0.90, s 17.5, CH~3~ 0.92, s
**19** 18.2, CH~3~ 1.08, s 18.1, CH~3~ 1.08, s 18.2, CH~3~ 1.11, s
**20** 47.1, CH 3.01, dd (5.1, 10.0) 42.1, CH 3.08, ddd (4.9, 8.3, 12.9) 47.0, CH 3.05, dd (5.1, 10.0)
**21** 173.9, C 178.2, C 173.9, C
**22** 71.9, CH 4.18, t (9.6) 31.4, CH~2~ 2.37, m 72.1, CH 4.19, d (9.5)
**23** 111.3, C 75.1, CH 5.12, m 111.4, C
**24a** 2.51, d (15.1) 2.53, d (15.2)
**24b** 45.7, CH~2~ 2.84, d (15.1) 122.0, CH 5.52, dd (8.3, 1.0) 45.8, CH~2~ 2.91, d (15.2)
**25** 85.0, C 141.7, C 86.0, C
**26a** 4.09, d (10.2) 4.09, d (10.2)
**26b** 78.9, CH~2~ 4.32, d (10.2) 67.2, CH~2~ 4.05, s 78.3, CH~2~ 4.37, d (10.2)
**27** 22.0, CH~3~ 1.70, s 14.1, CH~3~ 1.74, s 21.6, CH~3~ 1.74, s
**28** 23.8, CH~3~ 1.33, s 23.8, CH~3~ 1.32, s 23.8, CH~3~ 1.36, s
**30a** 0.93, d (5.3) 0.78, d (5.2) 0.96, d (5.3)
**30b** 15.4, CH~2~ 1.29, m 15.0, CH~2~ 1.18, d (4.6) 15.5, CH~2~
**2′a** 3.62, d (10.5) 3.59, d (10.6) 3.63, d (10.5)
**2′b** 72.5, CH~2~ 3.80, d (10.5) 72.5, CH~2~ 3.76, d (10.6) 72.5, CH~2~ 3.80, d (10.5)
**5′a** 2.20, dd 2.19, dd (2.4, 13.4) 2.23, dd (2.7, 13.7)
**5′b** 40.7, CH~2~ 2.63, m 40.7, CH~2~ 2.62, m 40.8, CH~2~
**6′** 81.8, CH 4.28, dd (2.5, 9.1) 81.8, CH 4.26, dd (2.3, 11.6) 81.8, CH 4.29, dd (3.6, 11.6)
**1″** 142.6, C 142.6, C 142.6, C
**2″,6′′** 125.8, CH 7.35, m 125.8, CH 7.37, m 125.8, CH 7.36, m
**3″,5″** 128.4, CH 7.33, m 128.3, CH 7.33, m 128.4, CH 7.40, m
**4″** 127.5, CH 7.24, m 127.5, CH 7.25, m 127.5, CH 7.28, m
**1′′′** 170.4, C 172.1, C
**2′′′a** 21.8, CH~3~ 2.03, s 2.40, dd (9.2, 16.2)
**2′′′b** 43.7, CH~2~ 2.47, dd (3.6, 16.2)
**3′′′** 64.6, CH 4.20, m
**4′′′** 22.7, CH~3~ 1.26, d (6.1)
[^1]: Present address: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
| |
To the editor: The League of Women Voters of Alaska strongly supports the For the People Act, a bill that has recently passed the U.S. House (H.R.1) and is now in the Senate (S.1). The League supports this bill because it establishes safeguards for the voting public and makes our democracy stronger.
The For the People Act addresses many aspects of our voting and campaigning processes, and fair elections are at the top of the list of improvements. Improved access to the ballot box, the restoration of the voting rights act, automatic registration, restoration of felon rights and an adequate number of polling places to reduce long lines are just a few of the changes needed across the country. The status of these voting issues varies across the states. This bill would help equalize voting processes in all states so that all eligible voters have equal access to the voting process. Currently there are an estimated 253 state voting bills that would in a variety of ways limit voting access and are making their way through 43 state legislatures. It is the federal government’s responsibility to stop voter suppression so that all eligible citizens have access to the voting process.
Money in politics is another area the For the People Act addresses, particularly the existence of dark money where large-dollar donors’ identities are shielded. The bill also sets up a small-donor public campaign finance system paid for by a nominal surcharge on penalties assessed against corporate wrongdoers. This system allows candidates to focus on their constituents rather than on big dollar donors and increases the voice of small donors. And in addition, the Federal Election Commission would be reorganized to prevent the political gridlock that has recently hampered it. The bill would give the FEC strengthened powers to investigate campaign complaints.
The League of Women Voters sees the For the People Act as a piece of legislation that will strengthen our democracy at a time when many feel that democracy has been weakened. Democracy can thrive with honest and fair laws and citizens who are informed voters.
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Prince Rupert RCMP officers Bob Killbery and Jennifer Collins surpassed their Cops for Cancer fundraising goal on August 25, after holding jail and bail in front of Atlin Terminal during Cow Bay Day.
Approximately $9,400 was raised at the event, which surpassed the pair’s fundraising goal of $8,000.
“We couldn’t have done it without the help from the community. We had building supplies donated from Home Hardware, Rona, General Paint and Jim West Signs and food donated from Safeway and Overwaitea. They definitely helped with our success,” said Killbery, mentioning that a number of businesses also donated prizes to be given away.
12 locals were put in jail including MLA Gary Coons, Dr. Jeffrey Simons, School District 52 superintendent Lynn Hauptman, Tyler O’Halloran from EZ Rock, constable Matt Ericson from the Prince Rupert RCMP, Shaun Thomas from the Prince Rupert Northern View, Re/max real estate agents Mike Morris and Jeff Clarke, Scott Kehn from the DFO, Scott Farwell from the Crest Hotel, Homework and Sea Horse Trading owner David Smook and Kris Schumacher from the Prince Rupert Port Authority.
Jailed individuals had to call family, friends, co-workers and whoever else they knew would pay a fee to help bail them out. Over $8,000 in bail was collected, with just under $700 being raised from the barbecue that was held outside of the jail.
This was the final fundraising event the father and daughter riding pair will hold, however there are still raffle tickets available for purchase at the Crest, the RCMP detachment, Traylings Tackle, Seasport and Northwest Fuels. | https://www.thenorthernview.com/news/rcmp-tour-de-north-riders-hold-jail-and-bail-surpass-fundraising-goal/ |
Purpose:
Provide SQL and SSIS expertise to project teams in the design and development of data extraction and transformation (ETL) processes.
Responsible for the design, build and run of data pipelines to efficiently move operational data from primary source systems to various targets and reporting platforms using SSIS and other related technologies
Responsibilities:
- SSIS package development – including testing, configuration, automation, and operation.
- Database Development: SQL, TSQL, unit testing, analysis, design, technical document writing, logical database design, physical data modelling, automation scripting, and performance tuning
- Experience in data migration, cleansing, extracting and integrating across systems
- Interacting with multi-platforms and languages; specifically – Microsoft/Azure stack, Dynamics CRM, DES, Oracle, C# .NET, XML
- Formulation of SSIS source management guidelines and standards, and alignment with DevOps practices
- Assess, select and integrate any data tools, components, and frameworks
- Measure, evaluate, and performance tune pipeline performance.
- Assist with production and operational support – defect resolution, session monitoring, data fixes, data quality issues, performance issues. Assist with project release preparatory planning.
- Work collaboratively with other IT functions, business units, external contractors, consultants and vendors. Demonstrated interpersonal skills.
- Understanding data and how it is used in target systems and business context
- Compliance: Ensure that all the activities and deliverables comply with the requirements, coding standards, CLIENT policies, architectural principles, and current application design.
- Timely delivery: Deliver tasks on the agreed delivery times and the quality.
- Participate in identifying process, quality and system improvements, continuously learn new techniques, methodologies and technologies, look for and initiate improvement initiatives.
- Record and report all the activities as instructed by management.
- Optimising, debugged and maintained the load SSIS packages
- Rotational L1, L2 and L3 on call 24x7x365 support for system. Must be flexible to work weekends & evenings and shift schedules as pertains to on call rotations
- Other responsibilities as directed by the management
Qualifications
- Tertiary qualification in an IT discipline
- Relevant tertiary qualification at degree level
- 3+ years’ experience in SSIS and related technologies
Ideal experience & delivered Performance
- Microsoft Dynamics CRM, Azure/cloud technology, C# NET, DES,
- Attunity, KingswaySoft Adaptor (KWS)
- Oracle experience and skills
Highly desirable
- Microsoft Dynamics CRM, Azure/cloud technology, C# NET, DES,
- Attunity, KingswaySoft Adaptor (KWS)
- Oracle experience and skills
Key Challenges:
- Large Transformation Programmer – ability to work effectively across a large programme in various technologies (Oracle, SQL, Azure)
- Mixed Technology landscape – Oracle/Cobol/.NET heritage systems with expansion into Microsoft, Azure and cloud
- Communication – Effective use of communication channels in interactions with customers, vendors, management and team.
- Picking up new skills and technologies
Key Relational-Internal
- Database Team (DBA and Application Development)
- CRM Platform Team
- Testing Services
- Business SMEs
- Incident & Problem management team
- Change Management Team
How to apply:
Please apply using the link below or call Ricky on 03 8506 6521 for further details. Applications closes based on the volume of applications received. Only short-listed candidates will be contacted.
Adaps is an equal opportunity employer that actively embraces diversity in its workforce through accurate community representation of gender, culture; thought and work arrangements.
Connect with Adaps: | https://www.adaps.com.au/job/ms-sql-server-ssist-sql-programmer/ |
After wins at the Ultramook 50k and the McKenzie River 50k, it is time to take a look back at some of Asher’s training leading up to both races.
7/7 Ultramook 50k
9/7 McKenzie River 50k
April
Average weekly mileage = 85 (102, 114, 50, 75)
Key workouts: 12 x 40s hills, 30 minute threshold, 23 minute threshold, 10 x 3/1 (10k/jog)
Long runs: 90 min w/1900′, 95 min w/2500′, 14.9 miles in 2hr 30.
Asher generally did a speed development workout per week, and everything else was very easy running. Sometimes on the trails, sometimes on the road.
May
Races = Mt Spence 50k, 6th place in 4:24
Average weekly mileage = ?
Key workouts: 12 x 40s hills, 8 mile tempo in 46 minutes
Long runs: 90 min, 95 min, 13.5 mile run
June
Key workouts: 8×3/1 (10k/jog), 10 mile tempo in 60 minutes,
July
Key workouts: 11 x 50′ hills, 10 mile progression in 62:15, 10×800 averaging 2:39 w/45s rest,
Long runs: 2 hours, 22.25 in 3 hours w/2474′
August/September
Races: McKenzie River 50k
Key workouts: 11 mile progression, 15 x 50′ hills, 8x1k + 4×200 (10k/1500 effort), 12×50′ hills, 6xmile + 4 x 30s (10k/”distance smooth”)
Long runs: 12 miles up Stanley peak x 2
Above, I tried to include some spark notes from the spreadsheets. To get a better idea of Asher’s training, you’ll want to take a look at his log day to day. There is a lot that is not included, including his speed development, and what his easy days look like.
Although I write Asher’s training, looking back at his log is still a huge way for me to reflect on what he did. Going through I’m asking myself and him – what do we think worked? What didn’t? What did you need more of? What do we need to do less?
With this, it is a reminder that everyone should have two things, a log and a coach. If you take running serious, but find that your training is mostly whimsical, consider our personal coaching services. | https://ultimooktrackclub.oregoncoastalflowers.com/2019/10/09/ashers-50k-training/ |
When screenwriter Tehran Von Ghasri was a child, he never saw himself represented on the big or small screen. As a Persian, Black Jewish person, Von Ghasri felt alone in his identity and, at first, alone in the world.
"It wasn't easy," Von Ghasri said. "And the reason is that you feel like you don't really belong anywhere. I'm mixed. I am Black, but people didn't see me as Black. I am Persian, but people didn't see me as Persian. I am Jewish, and they didn't see me as Jewish."
"I think it influenced me to want a career in entertainment."
Von Ghasri has worked as a stand-up comedian and screenwriter for the better part of a decade. Currently, he is making people laugh at Netflix Is a Joke and every Thursday at The Laugh Factory. He also recently sold a script for a television show and is working on another.
The majority of his content explores what it's like being a Black and Persian Jew. And his recent scripts, including the feature that sold, have main characters who identify as BIPOC and Jewish.
"I want to show the world we exist," he said.
From Jewish diaspora to the big screen
According to World Population Review, as of 2021, 15.2 million people worldwide identify as Jewish -- less than .2% of the global population. This group includes a diversity of cultures and ethnicities that evolved since the "Jewish diaspora." The Jewish diaspora is the historical dispersion of Jews throughout the world due to exile and persecution, originally from their homeland in Judea, or modern-day Israel, centuries ago.
Since, Jews have classified themselves into subgroups, depending on where their families settled. Those subgroups include Ashkenazi, or descendants of Jews who traveled north and settled in France, Germany, and Eastern Europe at the time of their exile. Currently, there are roughly 10 million people worldwide who identify as Ashkenazi Jewish. In addition, there are 4.6 million Mizrahi Jews, or Jews who settled not far from Israel, in Southwest Asia, and parts of Northern Africa. And there are approximately 900,000 Sephardi Jews around the globe, or Jews whose ancestors initially settled in Iberia (Spain and Portugal).
Most of the Jews in the United States are Ashkenazi. The reason is that between 1945 and 1952 after World War II ended, more than 80,000 Jewish Holocaust survivors immigrated to the United States under the terms of the Displaced Persons Act, many with the aid of Jewish relief organizations.
And since the beginning of the movie industry, the Jewish stories depicted on television and in movies have been mostly, if not all, Ashkenazi Jewish stories. (Think Steven Spielberg's Schindler's List, Norman Jewison's Fiddler On The Roof, or Roman Polanski's The Pianist.)
"Most of this tiny minority happens to be white presenting people," Von Ghasri said. "And that's not only confusing for me; it's also confusing at times for the public because they see Jewish people as white when that is not the entire story."
Jewish Impact on Hollywood
The movie industry began in the late 1800s, but according to Vincent Brook, a retired lecturer and scholar in American film and television, with a particular emphasis on Jewish issues, Hollywood and the movie & television industry began thriving in the early 20th century thanks to Jewish immigrants.
In the early 1900s, antisemitism worldwide was arguably at its peak. Jews faced persecution, intense antisemitism that led to restrictions on Jewish marriage, business and professional life, and even pogroms, leading to WWII and the Holocaust. (A pogrom is an organized massacre of a particular ethnic group, particularly that of Jewish people in Russia or eastern Europe.) Jews who began to flee -- specifically Europe -- mostly ended up in Mandatory Palestine (Israel) and America.
When they arrived in America, according to Brook, although they found more freedom, they weren't treated kindly, as antisemitism was raging here too. Across America, antisemites periodically seized on Jewishness to justify blame and violence. They faced quotas in education, discrimination in the professional sphere, restriction from residential and recreational communities, and continued acts of physical violence. Jews were even denied membership at universities, clubs, and other parts of American society.
According to Brook, Jews were also kept out of reputable, established, and thriving industries at the time and instead given professional scraps viewed as going nowhere -- including the movie industry. Brook said Jews took what they could get and ran with it. By 1920, all the major studios (Warner Bros., Paramount, etc.) were almost exclusively Jewish-owned -- specifically -- owned by Jewish immigrants escaping persecution.
"When these immigrants came here, they got the crumbs and they went with it, made it a big industry, and all of a sudden the movies were a big business and making a lot of money," Brook said. "So, of course, the antisemites were up in arms. They thought this was this lousy industry that the Jews could have because it was going nowhere. And suddenly, it was this huge industry. And they were pissed."
"Jews didn't create the movie industry, but they made it what it's become."
Jewish Stereotypes and Struggles
Despite Jewish influence in Hollywood, since movies and television began, the depictions of Jews on screen have often been full of false and offensive Jewish stereotypes. Some of those stereotypes include Jewish obsession with money, Jews as outsiders, the overbearing Jewish mother, the cheap Jew, and the Jewish American princess.
Jewish stereotypes in media can be blatant or subtle and are even found in tentpole productions, including the infamous Harry Potter series. The goblins in Harry Potter, for instance, are a group of tiny, untrustworthy bankers with long noses who control the wizarding economy.
So how is it possible that stereotypes of Jewish people exist in the media when Jewish people have had an influence?
"That's easy, antisemitism," Brook said. "When Jews came here, they changed their names; they often changed their looks. And they did not want to rub their Jewishness into the audience's face on the screen."
"Even in Jewish movies and shows, you often have Jews assimilating, kind of losing their Jewishness -- that has become a major theme."
It wasn't until the late 1960s, Brook said, that a "Jewish new-wave" began, where Jewishness started to become more accepted in film, specifically because actors like Barbara Streisand began embracing their Jewishness versus hiding it. After that, Brook said it took longer for television to catch up, but in the late 80s and early '90s, shows like NBC's Seinfeld and people like Jerry Seinfeld and Larry David began to change the game for Jews in the medium.
Although Jewish stories and Jewish people started to become more accepted in Hollywood, most of the stories portrayed were of the Ashkenazi Jewish experience, leaving Jewish people like Von Ghasri and fellow writer Stephen Nolly, a Japanese-American Jew, feeling unseen.
"Jewish culture is so incredibly rich and complex," Nolly said. "There are African Jews, Chinese Jews; our culture is not a monolith."
"And when you talk about it, the Jewish community has so many different expressions, but the one that's most common, and the one that most non-Jews are familiar with, is this Ashkenazi white Jewish experience...specifically this Ashkenazi, Jewish New York experience and they aren't even aware of these other varietals."
Jewish Hollywood Bureau
While there has been some positive Jewish representation on-screen despite old stereotypes that continue to rear their heads, the orthodox Jewish community has objectively experienced the most negative portrayals in film and television. From Netflix's Unorthodox, and My Unorthodox Life, to The Awakening of Motti Wolkenbruch, the orthodox Jewish community is constantly portrayed as extremist, overbearing, and the main characters in these shows are shown as "escaping" their realities.
Because of this, in 2007, Allison Josephs created "Jew In The City," a nonprofit to confront the negative feelings that some people have towards orthodox Jews. Josephs said she launched the nonprofit with the goal of using social media to tell the stories and perspectives of orthodox Jews and Judaism that are rarely depicted in traditional media.
Since it began, her organization has grown tremendously, and in March of this year, Josephs launched an official Hollywood bureau to combat Jewish stereotypes in the media. Josephs said the bureau began with conversations with other bureaus fighting for better representation for their communities and discussions with the diversity, equity, and inclusion leadership at NBC, CBS, and Disney.
And already, Josephs said, NBC and CBS have asked her and her team to train their executives and serve as consultants.
Josephs said the Jewish Hollywood bureau would conduct minority impact studies, provide training and consulting, speak on panels at media conferences, host media awards, and build writers labs.
"We also intend to do policy work, as many other bureaus do," Josephs said. "It's 2022, and in the realm of sports, entertainment, and media, despite accommodations being made in historic ways for marginalized groups in these industries, Jews who observe Shabbat and holidays don't count."
While at first Josephs intended the Hollywood bureau to focus on orthodox Jewish depictions, she's since branched out to work to improve all Jewish representation.
"Although there are Jews in the writer's rooms, the ones who were reaching out to us are not happy with how they're being depicted. They're sick of the caricatures and perpetuated antisemitic tropes on the screen by Jews and non-Jews. In addition, they've noticed an absence of Jews of color," Josephs said.
"They asked us to broaden our mission, and we realized that the Muslim bureau doesn't differentiate between secular and religious Muslims. At only 15 million people worldwide, we realized we can't do that for Jews either."
According to the Anti-Defamation League, in 2021, antisemitism in the United States reached an all-time high, with more than 2,700 incidents recorded last year. Much of the violent and physical antisemitism is directed towards orthodox Jews since they are easily identifiable. Josephs believes much of this has to do with how orthodox Jews are portrayed in the media. With the new bureau, she hopes she can influence Hollywood to create more well-rounded, whole, and human orthodox and non-orthodox Jewish characters to develop more acceptance of the Jewish community.
"[What] we want to see are Jews who comfortably and proudly rest in their Jewishness. We want to see Jewish traditions depicted with authenticity and positivity so that Jewish viewers can watch with pride and non-Jewish viewers can be exposed to the beauty of our heritage. We want to see a diverse set of Jewish backgrounds - both religious and ethnic," Josephs said.
"We're looking for proud Jews to be able to tell their stories. Jews who don't feel they need to be in hiding. Jews who don't feel that they need to apologize or erase their Jewishness to meet the expectations of the rest of the world."
Hollywood Victories And Future of Jewish Representation
Brook, who has been studying Jews in the media for decades, said Jews have had some victory in Hollywood regarding on-screen representation, especially since Jews went from hiding to very often celebrating their Jewishness. But there is still much work to be done, especially when it comes to highlighting the beauty and diversity within the Jewish community.
Von Ghasri hopes through his work that the public becomes more familiar with what it truly means to be Jewish -- and specifically learns more BIPOC Jewish stories.
"There are basically no victories for Jews of color in the media," Von Ghasri said. "Thankfully, there are some that are on the way. And that's what I'm so excited about. I am excited for this new generation, who is speaking up and speaking out and showing the diversity in the world and inclusiveness, even in the Jewish population."
"I hope that one day, I will have children, and then you will have children, and these children will be Jews of color, and they will be able to turn on the TV, and they will be able to say, "Mommy, daddy, that person looks like me!"
Written by: Allison NorlianAllison Norlian is a three-time, Emmy-nominated journalist who has worked as a television reporter and anchor in markets around the country. She has covered a variety of stories from the riots in Charlottesville, Virginia to President Trump’s travel ban in the fourth circuit court of appeals. Allison has also won AP awards for her work and a Catalyst For Change award from the Arc of Virginia for her reporting on the disabled community. Allison just moved to Los Angeles with her screen writer husband and two cats and is excited for all LA has to offer! | https://blog.finaldraft.com/jewish-american-heritage-month-history-and-hopes-for-future-hollywood |
This is the first article in a new series detailing key elements of the systems the Jets run. The articles will appear on an irregular schedule based on events that deserve closer examination.
One of the biggest influences on Robert Saleh through his rise as a defensive coach in the NFL has been Pete Carroll. Saleh worked an entry level job for Carroll as a Seahawks defensive quality control coach from 2011 through 2013. His tenure coincided with the rise of Seattle’s iconic Legion of Boom.
The Jets cannot run the exact same defense at the exact same level as those Seattle teams. They lack the star power throughout the roster at the moment and don’t have a secondary full of Hall of Fame talent.
Still you can see broad philosophical similarities in some ways. One in particular seemed on display in Sunday’s season opener in Carolina as detailed by an ESPN article on Carroll from a few years back.
Limiting explosive plays
It’s not unusual during a Seahawks game to see defensive players give one another high fives after a quarterback completes a 6- or 8-yard pass.
Why? Because they don’t think most offenses can score a lot of points that way over the course of an entire game. They’ll limit yards after the catch and deliver punishing hits. They’ll find a way to create turnovers. Or their pass rush will force the quarterback into negative plays.
Even if those things don’t happen, forcing the offense to string together long drives will likely keep the game within reach in the fourth quarter. That’s why Carroll emphasizes finishing.
Carroll’s greatest Seattle teams dominated playing this way. They were willing to allow the opposing quarterback to dink and dunk and complete short passes all day. The Seahawks defense rallied to the ball, minimizing gains and delivering hits that added up over the course of the game, wearing out and weakening the will of the opponent over four quarters. Frequently the opposing quarterback lost patience by throwing short and would make a game changing turnover trying to force the ball into traffic.
The Jets had their own experience with this last year as they put together a number of long drives against Saleh’s 49ers defense but couldn’t finish them. Adam Gase refuted the notion his offense had been shut down, but his comments only proved that he didn’t understand how touchdowns happen in the NFL. When the defense prevents big plays, it’s difficult for the offense to execute. Over the course of a long play drive, something eventually is likely to go wrong. Somebody might jump early on a false start or commit a holding penalty. A receiver might slip, or the quarterback might miss a read.
It’s easy to say the defense got lucky when Sam Darnold misses a red zone pass on an 11 play drive, but the whole point of preventing the big play is forcing the offense to execute 11 straight times. It’s a very difficult thing to do.
Over the course of Week 1, the Jets pass defense was focused on trying to wall off the deep part of the field and force shorter, less productive completions.
Even on plays where the Jets were making aggressive calls up front, they were willing to surrender completions and rally to the ball. Here are how a couple of blitzes looked.
When blitzing many defenses will play tight coverage at the line of scrimmage to close off passing lanes since the quarterback will likely need to get the ball out quickly under pressure. This is the opposite approach. The Jets are almost trying to bait these throws.
It can be effective if you are confident in your defenders’ ability to tackle in space. There also must be awareness and commitment from everybody on the defense to make this work. In the top clip you see Brandin Echols leave the man he was covering to deliver a tackle.
Through the first week of the season, I think you could argue the approach worked reasonably well for the Jets. Crunching the numbers with Stathead I found that one-third of Sam Darnold’s completions on Sunday netted five yards or less, the sixth highest figure in the NFL.
According to Next Gen Stats, Darnold’s average completion traveled 4.8 yards through the air, ninth lowest of any quarterback in Week 1. Meanwhile his average attempt traveled 7.5 yards. That 2.7 yard difference between the length of his average attempt and completion was the sixth highest of any quarterback in the opening week. It’s a sign the Jets did a relatively good job conceding the short completions while protecting down the field.
It isn’t clear that Carolina’s plan was just a bunch of quick hitting passes either. Darnold’s average time to throw was a middle of the pack 2.61 seconds.
Of course the Jets weren’t perfect. It might be frustrating to watch your defense surrender a bunch of moderate gains through the air, but a primarily reason the Jets lost might have been the big play they did allow, the touchdown pass from Darnold to Robby Anderson.
In any event, don’t be surprised if this approach sticks around. And if you get angry with the defense for allowing quarterbacks easy completions, keep in mind it might be part of a bigger plan. | https://www.ganggreennation.com/2021/9/15/22676449/jets-system-primer-preventing-big-plays |
The Dolphins Threw Eight Players Into A Blitz. Were They Trying To Lose?
When the Miami Dolphins sent eight pass rushers at the Steelers on Monday, Pittsburgh’s Diontae Johnson scored an easy touchdown.
Justin Berl / Getty Images
On Monday night, the winless Miami Dolphins were headed toward halftime with a surprising two-touchdown lead. But for a Miami team that is widely believed to be tanking, leading the heavily favored 2-4 Pittsburgh Steelers may not have been a cause for celebration. Beating the Steelers might have boosted short-term morale among the players and coaching staff, but with the hapless Cincinnati Bengals also winless on the season, a victory could have potentially derailed the Dolphins’ plans for landing the No. 1 overall pick in next year’s draft. So with 26 seconds left before halftime, Miami general manager Chris Grier may have felt some small sense of relief after the defensive play that his head coach, Brian Flores, dialed up on third and 20 for the Steelers.
The Steelers lined up with three wide receivers and sent two out to the right side of the formation. Miami blitzed with eight pass rushers, leaving just three defenders in the secondary to cover the three receivers. With no help from a fourth defender, the defensive backs played well off the line of scrimmage to protect against deep routes. After the snap, right cornerback Xavien Howard and safety Nik Needham failed to switch responsibilities for the crossing receivers on the strong side of the formation. In the slot, JuJu Smith-Schuster ran a vertical route upfield and slightly toward the sideline, while Diontae Johnson, who was lined up further behind the line of scrimmage at flanker, ran a shallow slant toward the wide-open middle of the field. The result was an easy pitch and catch for a touchdown.
The defensive play call is uncommon enough, and the result so bad, that some commentators on Twitter immediately accused the Dolphins coaches of being complicit in the tank. After reviewing the tape, others disagreed, arguing that cover-zero blitzes — plays on which there is one coverage defender per receiver, and the rest of the defense rushes the quarterback — are poor evidence of tanking since they’re occasionally employed by successful teams. Who is right? Was sending eight rushers on third and long a viable strategy, or was it a questionable call made by a Miami team that should be under suspicion of in-game tanking?
The evidence suggests that the call was of dubious value if a team is attempting to win a football game. Rushing eight or more is actually quite rare in the NFL. Teams rushed eight players just 110 times on all downs and distances during the regular season from 2016 through Week 8 of 2019. On third-down passing plays over that same period, teams rushed eight or more just 33 times. And on third and 11 or greater — the situation most similar to the one the Dolphins faced — there have been just two plays called with eight or more pass rushers. And that’s counting the play run by Miami on Monday night.
Regardless of the call’s frequency, we can say with confidence1 that dialing up an eight-man rush on third down is the worst play that defensive coordinators can call if they want to prevent their opponent from scoring.
Third down is typically advantageous to the defense. On average, plays called with any combination of three to seven defenders rushing the passer cause the opposing offense to accrue negative expected points added.2 Only when defenses decide to rush eight and drop three into coverage does the offense regain the advantage. On those plays, the script gets flipped, and offenses net nearly a point per snap over expected.
To force short throws, drop eight — don’t rush eight
Average depth of target by opposing offenses according to number of pass rushers in all regular-season pass plays since 2016
Number of rushers
air yards per pass attempt
8 or more
8.32
7
9.58
6
9.13
5
8.35
4
8.03
3 or fewer
6.56
Through Week 8 of the 2019 season.
Sources: ESPN Stats & Information Group, Nfl ngs
Some have argued that the Miami play was sound based on the theory that an all-out blitz forces the quarterback to get rid of the ball more quickly, leading to shorter passes. But that’s not what we find. It turns out that if you want to minimize an offense’s depth of target, it’s better to drop eight or more into coverage than to rush eight.
Fans and analytics-minded observers, in particular, often scream and yell for NFL teams to be more aggressive, but in this case, conservatism appears to be the better choice. Especially on a third and long like the Steelers faced against the Dolphins, who were up two scores with less than 30 seconds remaining in the half, calling a high-risk, low-reward play doesn’t make a whole lot of sense. Unless, of course, the goal wasn’t actually to win. In that case, it was the perfect call. | |
Cross-border money transfers have always been important to Southeast Asia. Now, a sector-wide push towards digitalisation is changing the landscape.
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My fig leaves,
On silver sand I dance
In silence,
Ask my mother wind for
Guidance,
Across an uncertain sea,
Her moon-tide melody
Calls within water and wave,
She tells me time turns
To the Rise of Empaths,
To a world led by healers,
Wound relievers,
Ego leavers,
And soul believers.
Sister, Brother,
Mother Nature
Has been crying for years,
Her face is honey-combe
Caves of fears,
She tells me to turn
To the poet souls
With painter hearts,
Find self between
Berry, beetle, and lark,
Heal her wounds with
Birdsong balm
Found in the lullabies left
In June.
Some strange nights,
I walk beneath free skies,
Measuring the stars in years,
Below full moon,
I remove
My fig leaves,
And bathe the
Silver sand
In tears. | https://brizomagazine.com/2020/03/29/some-strange-nights/ |
The present invention relates to golf putters.
When a golf ball is struck by a putter, there is a certain amount of backspin or skid during the first part of the putt after the ball is impacted by the putter.
It is generally acknowledged that, the shorter the skid distance of a putted golf ball, the better its performance. This result is due, in part, to the coefficient of rolling friction which is generally much less than that of sliding friction, often as low as a very small fraction thereof. Thus, a rolling ball will be less affected by surface irregularities of the green or impediments in the grass than a sliding ball. Reduction of skid minimizes the consequences of shortcomings in accuracy of alignment, errors in allowance for distance, the adverse effects of grain (direction of grass growth), and minor impediments which may be in the path of the ball in the first few inches of a putt.
In the prior art, when a golf ball is struck in its centre by traditional putters being swung squarely in-line with the horizontal, the golf ball first skids without rolling for some distance before friction between the golf ball and the ground slows the golf ball's translational motion and induces a rolling action. This distance in which the golf ball skids before beginning to roll varies with the details of the prior art putter designs as well as the force of impact of the putter striking the ball. Efforts to minimize this skid condition in design and utilization of prior art putters have introduced other problems. For example, if the golf ball is struck above its horizontal centre line, a forward spin will result, but the ball will momentarily be driven slightly downward, thereby increasing the normal or perpendicular force on the putting green. This downward force can significantly increase the undesirable effects of grain and other irregularities in the putting surface. Correspondingly, if the golf ball is struck much below the centre line by a putter (without regard to the degree of loft build into the putter head), the golf ball will generally be lifted off the putting green, thereby reducing or eliminating the frictional force. However, in this latter case, the disadvantage is that, as the ball is being lifted, a significant amount of backspin may be introduced; this backspin will be present in the motion of the ball toward the target, producing skid which adversely affects control and predictability.
Prior art putters and golf clubs of which the applicants are aware include the following US patents: 5098103; 4508349; 4869508; 4725062; 4521022; 4471961; 3989257; 3759527; 3625518; 3368812 and 2023885. The applicants are aware of various other designs which may or may not be patented, such as the HMI II putter by Slotline and the PING putter by Karsten Solheim. In all prior art designs of which the applicants are aware, including those mentioned above, the configuration of the striking face of the putter head is a continuous geometric shape, usually either flat or curved. US-A-4508349 has three curved grooves on the striking face of a golf club.
According to the present invention there is provided a golf putter head comprising a horizontal lower face and a front driving face, characterised in that the driving face includes a planar striking surface, which is angled rearwardly and upwardly from a vertical plane, in that said striking surface has a substantially horizontal bottom edge which is forward of substantially all other portions of the putter head and in that said bottom edge is positioned a vertical distance from the lower face in a range less than the radius of a target golf ball and more than half said radius.
The putter of the present invention has been designed with a front face which has been shaped to present to the ball a narrow impact surface, or striking surface, at an impact point on the ball slightly below the centre line. The base of the putter head is positioned at an appropriate distance from the narrow striking face to provide the golfer with a convenient reference that enables him or her to strike the ball consistently at this point below the centre line. The striking surface of the putter protrudes or extends in front of the main body of the putter head such that the putter will strike the ball at the desired point below the centre line even in the case of minor variations of alignment of the putter with respect to the desired horizontal stroke in hitting the ball. The rearwardly inclined striking surface also minimizes the effects of any tendency to scoop under the ball which, as noted earlier, imparts excessive lift, backspin and skid, with undesirable effects. The position of the protruding striking surface along the putter head, along with the distance from the bottom edge of the striking surface to the base, providing a convenient ground reference, allows for the consistent imparting of forward momentum with a small amount of lift and without imparting backspin or skidding to the ball; all of this combines to provide a significantly improved golf putter than is found in prior art.
1. The putter provides a narrow striking surface conveniently referenced to the bottom or base surface of the putter. This placement of the striking surface gives the golfer a great measure of control in striking the ball at a consistent point just below the ball's centre line.
2. The striking surface is slanted or lofted rearwardly away from the ball such that the putter, when striking the ball, has a tendency to give a small amount of lift to the ball, thereby minimizing frictional interaction between the ball and the grass surface for the first part of the ball's travel toward its target.
3. The controlled striking of the ball at a point slightly below the centre line avoids the tendency to introduce significant backspin into the motion of the ball.
4. The forward protrusion of at least a part of the lofted striking face of the putter and the vertical position of this striking surface relative to the putter bottom or base insure that the ball will be struck at a point slightly below the centre line when used in a normal putting stroke with the base barely skimming the grass on the green. This optimal impact point will be hit even if the golfer's stroke is such that the shaft of the putter is not precisely vertical at the time the putter impacts the ball. This putter thus virtually eliminates undesirable downward motion or excessive lift associated with the performance of prior art putters when the golfer is not properly positioned above the ball at the time of the putt. If a right-handed golfer (using the fuller faced prior art putter design) stands with the ball too far forward of his left foot when putting, there is a tendency to strike the ball in a manner which imparts too much lift with backspin. Conversely, if the ball is positioned too far back of the right foot, a prior art putter will produce more of the downward motion on impact, as discussed earlier. The situations would be reversed for a left handed golfer. The design of the present invention compensates for such variations so that the point of impact on the balls remains very close to the desired point below the centre line, regardless of maintenance of vertical alignment during the putting process.
5. While not a requirement of the invention, the putter head optimally may be relatively massive compared with prior art putters. Such larger mass in a range 300 to 500 grams for a shorter backswing and a slower, more controlled putting motion with correspondingly increased accuracy in consistently striking the ball in line with the target or golf hole.
The putter head of the invention involves a design in which:-
The present invention overcomes common problems associated with prior art putters by incorporating into the design the rearwardly angled or lofted striking surface which is placed forward of the putter's centre of mass. This enables a golfer consistently to strike the ball just below the centre line, providing slight lift to the ball without inducing significant backspin or skidding. The forward location of the striking surface combines with the rearward angle of loft to provide a compensating mechanism to assist with problems associated with putter alignment at the time of impact with the golf ball. Finally, the lowest part of the putter provides a convenient reference surface at the exact distance from the centre of the narrow striking face to further assist the golfer in setting the height of the stroke as the putt is lined up.
Figure 1 is a perspective view of a putter according to the present invention;
Figure 2 is a front plan view of the putter head;
Figure 3 is a side plan view of the putter head;
Figure 4 is a side plan view of the putter, a golf ball and the ground, just prior to the putter impacting the golf ball; and
Figure 5 is a side plan view of the putter, a golf ball and the ground, just after the putter has impacted the golf ball.
In order that the present invention may more readily be understood, the following description is given, merely by way of example, reference being made to the accompanying drawings in which:-
Referring to Figure 1, a golf club putter 10 is illustrated having a shaft 11 with a grip 12, attached to a putter head 20 at the opposite end thereof. The putter head 20 has a top side 21 and a bottom side 22, a rear side 23, a right side 24, a left side opposite the right side 24, and a front driving face 30. In the preferred embodiment, the bottom side 22 will have slightly rounded edges in the front and rear so as to minimize any tendency of the putter to catch the grass or other objects during the back or forward swing of the putter motion. However, this is not a necessary or limiting feature of the design. The shaft 11 is attached to the putter head 20 rearwardly of the front driving face 30.
Referring to the enlarged inset of Figure 1, as further shown in Figures 2 and 3, the front driving face 30 consists of an upper surface 31, a protruding striking surface 32, and a lower surface 33. The bottom edge 34 of striking surface 32 is generally horizontal. The texture of the striking surface 32 is not intended to be a limitation of the present invention as it can be smooth or it can be textured in various fashions, including lined, grooved, crisscrossed, or other textures or patterns. The actual dimensions of the putter head 20 and its elements are not intended to limit the present invention. Even so, in the optimal configuration of the putter certain relationships are of importance, including the locations of the bottom edge of the striking surface 32. It is anticipated that a typical golfer of reasonable skill will be capable of operating the putter in such a fashion during the putting motion as to consistently cause the bottom side 22 of the putter head 20 to come very close to, if not slightly brush, the surface of the putting green without having the motion of the putter head 20 interrupted by making excessive direct contact with the green. By operation in such a fashion, the bottom side 22 of the putter head 20 will brush along the blades of grass of the green as a stroke is made with the invention. The ability of the golfer to operate the putter in this fashion, coupled with the dimensions of the putter head, will cause the centre striking section 32 to make contact with the golf ball, and for said contact to be made very close to, but just below the centre line of said golf ball.
For example, referring to Figure 4, for a golf ball 50 of diameter 1.68 inches or 4.27 cm, the width of the striking surface 32 of the putter head 20 could range from a line of infinitesimal width to a surface of 1.3 cm width, and the distance from the lowest point 22 of the putter and the bottom of the striking surface 32 would be in the range of 1.3 cm to 2.0 cm. The striking surface 32 is also angled from the vertical at an angle of loft 40 from 0° to 40° measured from the perpendicular, said angle of loft preferably being about 0° to 20° as shown in Figure 4. The specific angle of loft is not intended to limit the present invention. The mass of the putter head 20 is not intended to limit the present invention. It is anticipated that golfers will have varying preferences with regard to the mass of the putter head 20. In the preferred embodiment, the putter head 20 is of significant mass, preferably approximating 300 to 500 grams. It is well understood in the field of putting that the shorter the backswing the less likely the typical golfer will make an error in aim or control on the forward swing of the putter. With a putter of mass approximately 300 to 500 grams, the typical golfer may find that a relatively greater mass aids in terms of achieving the required momentum of the putter during the putting motion using a shorter backswing thereby providing for a more consistent putting motion.
Referring to Figure 5, during the putting motion, the putter head 20 will be drawn by the golfer closer to the golf ball 50 and its movement will preferably contain initially only a horizontal component of momentum. As the putter head 20 moves toward the golf ball 50, only the striking surface 32 makes contact with the golf ball 50 and imparts momentum to the golf ball 50 at an angle 41 to the horizontal as shown in Figure 5. At this point the golf ball 50 has a larger component of horizontal momentum and a small vertical component of momentum. Correspondingly, after the impact, the putter head 20 will have a decreased horizontal forward momentum and will have a small component of vertical momentum directed downward.
One aspect of the invention is that the putter is deflected downward slightly upon impact and, through operation of the law of conservation of angular momentum, that downward deflection compensates for backspin which would otherwise be imparted to the golf ball by prior art putters, thus substantially reducing or eliminating backspin in the case of the invention.
A number of calculations have been made on a model of the invention configured as described in the drawings where angle 40 in Figure 4 is 20°, with consideration given to the principles of conservation of linear and angular momenta. Various parameter choices were made to simulate as accurately as possible true field conditions.
As an example of the results, consider the case of a putt with an initial speed of 7 ft/s (2.13 m/s) which corresponds to a relatively short putt. Using the invention, the velocity of the putter as it strikes the ball would be approximately 1.27 m/s. Immediately after the impact, the putter would have a velocity of approximately 1.08 m/s directed downward at an angle of approximately 1.78° from the horizontal. The significance of this deflection of the putter becomes apparent when the matter of angular rotation of the golf ball is considered. Taking the centre of the golf ball as the reference origin, one can see that the initial angular momentum of the putter with respect to that reference is 2.31 x 10³ kg m²/s. This small difference in angular momentum will be compensated for by spin induced in the ball, which in this case would be a very slight forward spin. For other parameter choices, the results were not always this positive, but in every case the downward deflection of the putter in the collision greatly reduced any tendency to impart backspin to the ball when struck.
These calculations have been made in reference to the idealized model described above. A number of factors are difficult to quantify, including, in particular, the effect of frictional forces between the ball and the green. This frictional force between the ball and the green would however, tend toward the imparting of forward spin to the ball at the time of impact, and, therefore, has a positive effect on the putting process.
A number of field tests have been performed on the invention. These have included still frame video pictures that graphically illustrate the performance of this putter in the manner described. In this video study, it is apparent that, upon impact, the ball is lifted slightly. It was also clearly demonstrated by viewing the video pictures that the ball generally had little or no tendency to skid and no tendency to develop a backspin.
Distance in Feet
Number of Balls Struck
% Putts Made Using Prior Art Putter
%Putts Made Using Subject Putter
3
400
85
90
5
400
64
85
10
400
49
54
15
400
31
52
20
400
31
49
Totals:
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Other tests including the employment of four different experienced golfers to putt hundreds of times each at various specified distances from the hold on the same putting green, using prior art putters for half the putts and the subject invention for the other putts. The subject invention showed consistently better results for all distances as shown on the table below:-
Additional field tests by three golf professions also showed significantly superior results for the subject invention than prior art putters used by the same professionals under comparable conditions.
It will be appreciated that the bottom side 22 of the putter head need not necessarily be a flat surface but could, as is conventional be angled and or curved. Thus the lower edge shown in Figure 2 as a straight edge could be angled or curved. The bottom edge 34 of the striking face is, however, preferably a horizontal straight edge when the putter is used correctly. | |
Do you believe that Jesus is the Messiah? Can you prove it either way? Is the testimony of Jesus the Spirit of prophecy? Do you know that there are over 200 statements/prophecies from the Old Testament that the New Testament shows that Jesus fulfilled? Are you willing to be shown, with certainty, that Jesus is the prophesied Messiah? How did Jesus and the Apostles prove Jesus was the Messiah? Should Christians even refer to the Hebrew prophets to prove that Jesus was the prophesied Messiah? Dr. Thiel addresses these questions and more in the first part of a multi-part sermon intended to prove with certainty that Jesus is the Messiah.
Here is a link to the sermon: Proof Jesus is the Messiah: Certainty.
Proof Jesus is the Messiah This free book has over 200 Hebrew prophecies were fulfilled by Jesus. Plus, His arrival was consistent with specific prophecies and even Jewish interpretations of prophecy. Here is a link to a related sermon: Proof Jesus is the Messiah: Certainty. | http://ccog.nz/proof-jesus-is-the-messiah-certainty/ |
If there is one easy side dish that I love, it is oven-roasted broccoli! This is a recipe that I remember both my mother and grandmother making very regularly. It was the only way I would eat my broccoli! It is a quick and easy veggie side dish that adds a bit of freshness to every meal.
Delicious Oven-Roasted Broccoli For Dinner!
I make many side dishes to go with my main recipes (like these baked sweet potatoes), but oven-roasted broccoli has to be one of my favorites.
It is an easy and healthy side dish that pairs perfectly with just about any entree. I much prefer this roasted broccoli to steamed broccoli ANY DAY! The only other way I really like to eat it is in my favorite broccoli salad. So yummy!
This recipe is the perfect way to get your family to eat more vegetables without feeling like they are eating vegetables! Even picky children like this broccoli and are tempted to eat it at dinner time.
It’s really simple to make, whether you spend a lot of time in the kitchen or don’t have that kind of time to spare. It can be thrown together in a few minutes and left alone to cook.
It is one of my favorite go-to’s when I am having a busy day or just have other priorities than spending an hour whipping up dinner. I make this at least once a week!
Ingredients Needed to Make Roasted Broccoli
To make this roasted broccoli recipe, you will need the following ingredients:
- Fresh Broccoli: This fresh veggie is the star of the show and tastes amazing once it has been roasted to perfection. You can use other vegetables as well.
- Salt: Salt is an important seasoning ingredient to bring out the bright flavor of fresh broccoli.
- Pepper: Pepper is that classical seasoning that brings a bit of spice to the table without being overpowering or too spicy.
- Olive Oil: Olive oil helps the broccoli to roast and become nice and crispy. It also makes it easier to coat the broccoli in salt and pepper thoroughly.
Additions and Substitutions
- Other Vegetables: You can make this recipe with your favorite vegetable if you aren’t a fan of broccoli. You will just need to adjust the cooking times according to the vegetable that you decide to use.
- Garlic: For an even more flavorful side dish, you can add a bit of minced garlic or some garlic powder before you cook the broccoli. This will make the broccoli even more bright and flavorful!
Note:
- If I’m feeling fancy, I’ll sprinkle the broccoli with a little parmesan cheese and squeeze some fresh lemon on it after it comes out of the oven. So good!
What To Serve with Oven Roasted Broccoli
Some of my favorite things to serve with this roasted broccoli are dishes that need an added vegetable or some more freshness. That usually includes:
- Fried Chicken
- Grilled Cheese Sandwiches
- Classic Lasagna
- Creamy Mac and Cheese
These are all dishes that go very well with a side of freshly roasted broccoli!
I especially like to pair this side dish with my recipe for creamy chicken fettuccine alfredo. It adds a much-needed element of freshness to cut through the richness of the pasta dish. Sometimes I mix the broccoli in with my pasta!
Frequently Asked Questions About Broccoli
Whenever I share this recipe, I get some of the same questions. Here are the most popular ones that people ask!
If you have a question that isn’t listed here, please leave them in the comments, and I’ll answer them as soon as I possibly can.
Why is my roasted broccoli still tough?
If your oven-roasted broccoli came out of the oven still feeling tough and slightly undercooked, it might need more time in the oven.
Every oven is different, and some are slightly cooler than others. Your stalks of broccoli might also be thicker, which would require more cooking.
One guaranteed way of getting nice and tender roasted broccoli is to steam the broccoli before roasting in the oven lightly. Steam them until a fork can just penetrate the broccoli stem, then season the broccoli and put it in the oven to roast.
This will give you perfectly tender and deliciously roasted broccoli without fail!
Is roasted broccoli as healthy as steamed broccoli?
Both roasted and steamed broccoli is healthy. The only thing that might set them apart is the olive oil.
But, roasted broccoli is still just as healthy as steamed broccoli since butter would normally be added to the latter. Olive oil is a healthy fat and makes this broccoli even more filling and tasty while still remaining healthy.
As far as side dishes go, this broccoli recipe is a very healthy side dish and can help you to feed your family more vegetables with their meals!
Can I roast frozen broccoli?
Yes, you can definitely roasted frozen broccoli as well!
The secret to roasted frozen broccoli and getting the same results as fresh broccoli is a very hot oven and preheated pan.
Making sure the oven is nice and hot and putting the broccoli onto a hot pan will help the water to evaporate quickly. This will help your broccoli not become soggy and will allow it to begin browning.
By following these two tips, you can still make deliciously crispy roasted broccoli even when using frozen broccoli. This is perfect for when you are running out of fresh ingredients but still have some frozen vegetables on hand.
More Grandma Approved Recipes to Try
If you enjoyed this recipe for roasted broccoli, you might like these other savory dishes. These are some of my favorite home-cooked recipes.
- The Best Broccoli Salad Recipe
- How to Make Baked Sweet Potatoes
- Cheesy Broccoli and Rice Casserole
- Bisquick Sausage Balls Recipe with Cheese
- The Best Chicken Pot Pie Recipe
Oven Roasted Broccoli
Equipment
- Baking Sheet
Ingredients
- 12-16 oz. fresh broccoli
- salt, to taste
- pepper, to taste
- 1 Tbsp. olive oil
Instructions
- Preheat oven to 400 degrees.
- Cut the broccoli in bite sized pieces and spread over a baking sheet.
- Drizzle olive oil on top of the broccoli.
- Sprinkle with salt and pepper, to taste.
- Toss the broccoli around to coat with the seasonings and oil.
- Bake in the oven on 400 degrees for 20-25 minutes, flipping it in the middle of the baking time.
- Serve hot!
Notes
- If I’m feeling fancy, I’ll sprinkle the broccoli with a little parmesan cheese and squeeze some fresh lemon on it after it comes out of the oven. So good! | https://comfortfoodathome.com/easy-oven-roasted-broccoli/ |
Now comes the news, in a statement released by Clark, that he has been diagnosed with amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease.
“ALS is a devastating disease,” said Dr. Scott Vota, chairman of the Department of Neurology at VCU School of Medicine and director of the neuromuscular and ALS clinics at VCU. “We can slow it down, but we don’t have great treatments right now to make a meaningful impact.” Click here to read more. | https://www.vcuhealth.org/news/image-of-dwight-clark-and-the-catch-soon-to-change-and-not-for-better |
Fiber intake should be slowly increased over several weeks to decrease adverse effects. The next step in the treatment of constipation is the use of an osmotic laxative, such as polyethylene glycol, followed by a stool softener, such as docusate sodium, and then stimulant laxatives.
Dehydration is one of the most common causes of chronic constipation . The food you eat makes its way from your stomach to the large intestine, or colon. If you don’t have enough water in your body already, the large intestine soaks up water from your food waste.
In the elderly , chronic constipation can lead to fecal impaction and fecal incontinence. Fecal impaction is the accumulation of hardened feces in the colon or rectum. 18 Liquid stools from the proximal colon can bypass the impacted stool, causing overflow incontinence, often mistaken for diarrhea.
If you experience constipation , you should treat it promptly. Otherwise, stool can back up in the intestinal system, making it harder to poop and causing you to feel sick. There isn’t a defined amount of time — such as one week or one month — that a person could technically go without pooping.
Although it’s probably ideal to have a bowel movement every day, it’s generally considered acceptable to have them every 2-3 days, provided they aren’t hard, painful, or difficult to pass.
Urinary and bowel changes As your appetite decreases, your bowel habits may also change. The stools, or feces, may become hard and difficult to pass ( constipation ) as your fluid intake decreases and you become weaker.
The following quick treatments can help induce a bowel movement in a few hours. Take a fiber supplement. Eat a serving of high-fiber food. Drink a glass of water. Take a laxative stimulant. Take an osmotic. Try a lubricant laxative. Use a stool softener. Try an enema.
“For some people, drinking warm liquids, especially in the morning, can help unblock them,” Dr. McCall said. Exercising most days of the week can also help relieve your constipation. “Physical activity can increase the muscle activity in your intestines , helping move things along easier and faster,” Dr.
Treatment options for bowel obstruction can include: Medication. Opioids can lead to constipation. If this occurs, laxatives and stool softeners will help.
As we age , this process sometimes slows down, and this can cause food to move more slowly through the colon. When things slow down, more water gets absorbed from food waste, which can cause constipation .
Causes include consuming a diet that is too low in fibre and fluid, insufficient physical activity, medication side effect (e.g., opiates, tricyclic anti-depressants, calcium channel blockers), certain supplements (calcium and iron), irritable bowel syndrome, intestinal obstructions or strictures from surgery, diabetes
Causes of constipation in the elderly Some of the reasons for this propensity include poor diet, lack of adequate fluids in diet, lack of exercise, the use of certain drugs to treat other medical conditions, and poor bowel habits.
It’s a good idea to have a daily routine where your older adult at least “tries” to go at the same time every day. 2. Regularly eat (and drink) foods like: Beans. Whole grains, especially bran. Vegetables. Fresh and dried fruit. Nuts. High-fiber foods. Water — softens stool and stimulates the bowel .
If in addition to constipation , you experience a combination of any of these four symptoms—severe abdominal pain, an inability to pass gas, vomiting, and stomach bloating— you might actually have a bowel obstruction. This is a serious issue that definitely warrants a trip to the ER , says Chutkan.
Juices and dosage Prune juice. The most popular juice to relieve constipation is prune juice. Apple juice. Apple juice may provide you with a very gentle laxative effect. Pear juice. Another great option is pear juice, which contains four times more sorbitol than apple juice. | https://agefriendlyinnovators.org/elderly/dehydration-and-constipation-in-the-elderly.html |
One of the most common and abundant fish found at Karachi fish harbour, Queenfish is readily available throughout the year at a stable price.
Saram can be cooked in variety of methods including grills, curries, shallow frying and baking as it carries firm flesh and good flavour.
Disclaimer: We weigh the fish first and then carry out cleaning process in which on average there is a loss of 35-40% of whole weight including head and tail. Therefore end weight delivered to the customer will be around 600-650 gm.
Note: Fish rates are defined with respect to their weights. For instance, queen fish weighing greater than 2 kgs costs different to what a less than 2 kg piece costs.
Additional information
|Weight||1000 g|
Reviews
There are no reviews yet. | https://alsudais.co/product/saram-queenfish/ |
two out of three teens spend an average of two hours a day on social media.
Most teenagers could not last more than a day without using social media or smartphones, according to new research.
A survey of 2,000 youngsters found that two out of three spend an average of two hours a day on social media, and more during school holidays.
A similar number admitted they had sent a text to a member of their family while sitting in the same house.
Travel rewards firm Avios said its study found that family time was more likely to consist of watching TV than eating a meal together at the table.
Three out of four teenagers said they could not last a day without using social media, with one in seven admitting they would not last an hour. | https://www.scotsman.com/news-2-15012/teens-can-t-live-without-smartphones-and-social-media-1-3929363 |
At the NATO Advanced Research Workshop on Computers and Exploratory Learning (see diSessa, Hoyles and Noss, 1995) the organizers proposed several mathematical challenge problems. One problem that caught my attention was drawn from a British mathematics textbook and involved the game of rugby: (Italicized text is verbatim from the textbook, non-italicized comments in brackets are the author's).
In rugby, after a try has been scored, the scoring team has the opportunity to gain further points by "kicking a conversion." [i.e. Kicking the ball into the goal - the segment AB in the figure].The kick can be taken from anywhere on an imaginary line [line CK in the figure] that is perpendicular to the try line [line CB in the figure] and goes through the point that the try was scored [C in the figure]. Where should the kick be taken from to maximize the chance of a score? (In other words, where should we place the point K, so as to maximize the angle AKB?).
The authors of the textbook intended for the problem to be solved as a calculus problem. One was to maximize the angle AKB subject to the constraints. Some of the people at the workshop solved the problem in this way. Others used plane geometry or dynamic geometry environments to come to a solution. Seeing through the lens of "object-based parallel modeling languages" such as StarLogo (Resnick, 1994; Wilensky, 1995), I saw it, not as a calculus problem, but rather as a problem in discrete probability. A colleague (M. Resnick) saw this as well and we decided to construct a solution using StarLogo.
We imagined several rugby players standing in each patch along the perpendicular line, CK, with each player kicking thousands of balls in random directions. To find the best kicking point, we simply needed to determine which rugby player scored the most conversions. It was quite easy to write the StarLogo program that would implement this strategy. The basic idea is to setup players at each patch on the kicking line. Let each player kick balls randomly. When a ball scores, update a counter in the patch from which it originated. When all balls have either scored or missed, reset the balls and kick again. At the end of the snapshot, I have included a listing of the StarLogo program (translated into the new version of Macintosh StarLogo). As in object-based parallel languages, the balls are kicked simultaneously and check themselves at each step to see whether they have scored or gone out of bounds.
Thousands of kicked balls. To the left of the try line is a histogram of the successful kicks.
The technology of StarLogo facilitated our seeing the problem as amenable to probabilistic methods. Indeed, the most important piece of mathematics that can be garnered from this example is not the numerical solution to the particular problem, but the transformation of the problem from one of calculus or geometry to one of discrete probability. It is in making the connection between these different ways of seeing the problem, these different ways of measuring angles, that the powerful mathematics lies . The contribution of the StarLogo technology is in facilitating connections to stochastic mathematical processes whose relevance was much less obvious without such an object-based parallel modeling technology. This is a special case of the more general point that mathematics itself is a cognitive technology and the areas of mathematics we explore (or construct) are greatly constrained by the supporting technologies we possess. The application of probabilistic methods to the measurement of angles is not a natural operation without the availability of powerful computational tools. This lack of tools which allow intuitive probabilistic judgments is one important reason why probability has been a neglected area of mathematics education and why probabilistic thinking is so uncommon in our culture.
According to common mathematical wisdom, the StarLogo solution is not satisfying because it is less general, it gives us a numerical answer to a particular problem, not a general formula for line segment, CK, in terms of the variables CA and AB.
Note, however, that the notion of mathematical generality itself is relative both to the underlying supporting technologies, the potential contexts of application and the social purpose accorded the mathematics education.
In a computation rich world, is an algebraic formula more general than an algorithm? Is an analytic solution more general than a probabilistic approach?
Seeing this problem as a school mathematics problem (embedded in the social context of school mathematics) causes us to immediately ignore the real world conditions of the problem. We reflexively transform the problem from one about rugby to one about measuring angles. We implicitly assume that the kick is equally hard from any distance, in the real world an absurd assumption. We also assume that the grain of the grass is uniform and has no effect on the ball's trajectory and that the wind similarly has no effect. For this newly conceived, suitably transformed problem, the technology of plane geometry or calculus is adequate. These assumptions make the problem tractable using traditional school methods, but they also remove its connections from the world of our experience. The analytic solution is brittle, it works only under the idealized conditions of the problem. In contrast, the modeling solution can be easily modified to take account of differing conditions. We can experiment with the patches' grass rules letting them have different grains and seeing the differing results. We can introduce a wind of some velocity in some direction and see the results and we can introduce human factors such as the kicking ability of the player into the model.
By engaging in computational modeling -- this trialogue between the symbolism, the program output and the real world -- and, then, reflecting on the feedback obtained, learners can make meaningful connections. They can make both intra-mathematical connections -- connections within the sub-disciplines of mathematics such as calculus, geometry and probability -- as well as inter-domain connections -- connections between mathematical ways of knowing and everyday knowledge of sports, weather and human physiology.
It would be a mistake to interpret the above anecdote as demonstrating the superiority of object-based parallel modeling to traditional mathematical approaches. Indeed, used as another exercise in a traditional mathematics classroom, the StarLogo solution could facilitate inter-domain connections, but might serve to prevent making intra-mathematical connections. To facilitate these latter connections, modeling languages must be embedded in a "Connected Mathematics"-like environment (Wilensky, 1993; 1995), in which the pursuit of longer term investigations and wide connectivity are fostered and modeled. In the rugby example, many such avenues for connection are easily pursued. What are the level curves of constant "viewing angle" to the goal? What is the shape of these curves? What is their spacing, i.e. how fast does the viewing angle decline with distance from the goal? If kicking strength is to be modeled, what function governs the decay of the ball's velocity? What is the local effect of the grass grain and air resistance on the ball's trajectory? What probability distribution could be associated with a real kicker's kicking accuracy? By pursuing these questions and other questions of their own, learners can connect sub-disciplines of mathematics usually taught in isolation, allowing them to see and make mathematics not as a disconnected set of techniques to be memorized, but as a coherent and meaningful way of making sense of their experience.
As in object-based parallel languages, the procedures "kick" and "reset-balls" are executed at each clock tick by each ball kicked. The procedures "mon" and "update-stats" are executed once at each clock tick by the "observer" . Text after semi-colons are non-executable comments.
turtles-own [stopped scored orig-y px py] ;;; the balls' state variables
patches-own [pscored lang rang gang slope] ;;; the patches' state variables
globals [done curmax dist clock col ang ] ;;; global variables
;; rugby player kicks a ball, run this procedure forever
to kick
if stopped = 0 [fd 1] ;; at each clock tick the ball moves forward one unit
if out-of-bounds? [setstopped 1 stop] ;; no goal, try again
if goal? [setstopped 1 setscored scored + 1 tsetpscored-at (perp-line - xcor) (orig-y - 50)
(pscored-at (perp-line - xcor) (orig-y - 50)) + 1 stop]
;;; kick scored, increment the running total (pscored) for the patch from which the ball was kicked
end
;;; update the statistics and reset when needed, run this forever
to mon
update-stats ;; show a histogram of the number of scores from each patch on the kicking line
if done [stop-buttons show-results stop]
if ((total "stopped) = number) [reset-balls]
;;; if all the balls are stopped, set up new balls for the kickers
end
;; after all balls are determined, start over
to reset-balls
setclock clock + 1 ;;; update the number of times the players have kicked
setstopped 0 ;;;; all of the balls are back in play
setxy perp-line -50 + (who mod 100) ;;; each ball moves to its place on the kicking line
setorig-y ycor ;;; each ball remembers where it started
seth random 90 ;;; each ball gets a random heading
end
;;; creates the histogram of number of scores per kick site
to update-stats
setcurmax max "pscored
if pscored = curmax [psetdist (50 - ycor)]
graph-scores ;;;; draw the histogram
end
;;;; patch procedure to draw the histogram
to graph-scores
if (pc = blue) or (pc = pink) [setpc white] ;;; white out the histogram
if (xcor < perp-line) and ((perp-line - xcor) < ((pscored-at (perp-line - xcor) 0) * (perp-line + 50) / curmax)) [setpc blue] ;;; set the blue bars
if (xcor < perp-line) and ((pscored-at (perp-line - xcor) 0) = curmax) and ((perp-line - xcor) < ((pscored-at (perp-line - xcor) 0) * (perp-line + 50) / curmax)) [setpc pink] ;;;; color the maximum bar pink
end
; The following StarLogo code produces colorful curves of constant viewing angle:
;; calculate angle between patch and goal
to calc-gangle
setlang towards-patch left-goal 50 ;;; calculate angle with left goal post
setrang towards-patch right-goal 50 ;;; calculate angle with right goal post
setgang (rang - lang) mod 360 ;;;; calculate viewing angle
end
;;; draw a level curve of constant viewing angle
to level-curve :ang :col
if :ang = gang [setpc :col] ;;;; color yourself if your viewing angle is equal to the given angle
end
diSessa, Hoyles and Noss (1995). Computers and Exploratory Learning. Springer.
Papert, (1996). An Exploration in the Space of Mathematics Educations. International Journal of Computers for Mathematical Learning, Vol. 1. No. 1. Kluwer Academic.
Resnick, M. (1994). Changing the Centralized Mind. in Technology Review . v97, n5.
Wilensky, U. (1995). Paradox, Programming and Learning Probability: A Case Study in a Connected Mathematics Framework, Journal of Mathematical Behavior, Vol. 14, No. 2.
Wilensky, U. (1993). Connected Mathematics: Building Concrete Relationships with Mathematical Knowledge. Doctoral dissertation. Cambridge, MA: MIT. | http://ccl.northwestern.edu/papers/rugby/ |
The Paradigm of the Common Law
The common law is a complex phenomenon, having various aspects, each of which conditions and depends on the other aspects. It has a supranational dimension, as the law that stands over sovereignty and conditions it; it has a national dimension, as the law of the polity, the expression of its sovereignty in a general and indiscriminate way; and it has the dimension of spontaneous generation, as being court-evolved (“judge-made” law, a common but inadequate formulation).
All of these dimensions are various aspects of what at bottom is a unified entity.
The common law is the law of nations
Common law finds expression, first and foremost, in an overarching law-order, a sort of natural law providing the principles undergirding all positive law-orders. This common, universal law-order does not exist in a vacuum, or as a sort of Platonic idea transcending the legal systems of the nations, but in greater or lesser degree is interwoven into each of them. In this sense the common law is the same thing as what Stahl referred to as the doctrine of law and state. (1)
Sovereignty and law
This common law stands above sovereignty and conditions sovereignty. All sovereign polities are called to implement it in the positive legal orders they shape and maintain. (2)
The opposite of the common law is the civil law, which is formed by absolute law-creating sovereignty, and is the creature of sovereignty. In the common-law order, sovereignty is the servant of the law and exists to implement the law. In the civil-law order, sovereignty is the creator of the law; law exists to implement the will of the sovereign, and in fact is the will of the sovereign. (3)
Two kinds of sovereignty
There are thus two polar-opposite forms of sovereignty, corresponding to the two forms of law. Limited sovereignty recognizes a society of pluralistic authority structures, and mediates the relationships between them. Its goal is the formation and promotion of a society of independent groupings and associations. Absolute sovereignty recognizes no authority structures it does not itself create and control. It strives to create, not a society, but an organization.
The common law so conceived inspired the law-order developed over the course of centuries by Western Christendom as the corollary of limited sovereignty. It was once shared, in greater or lesser degree, by all Western polities. Especially since the French Revolution, this law-order on the European continent has been superseded by the civil law, the product of absolute sovereignty and its lawmaking effort of codification. This has led to the formation of two Western legal traditions, the common-law and the civil-law traditions, the common-law tradition carried on by the Anglo-Saxon countries, the civil-law tradition carried on in the continent, the vehicle being the French Revolution.
This development is therefore a product of the 18th and 19th centuries. Previously, there was a fundamental unity among the legal systems of the Anglo-Saxon and continental countries of Western Europe, a unity the sight of which has been lost by reading back into history these later developments. Certainly, there were major differences, but those differences cannot be used as an excuse to ignore the fundamental unity. (4)
Sovereignty is national
As the common law calls for limited sovereignty, it calls for multiple sovereignty. The basis of this order of multiple sovereigns is the nation. (5) Nations have the calling to establish positive legal orders, each incorporating the principles of the common law. In so doing, each nation establishes its own branch of the common law, and this national law is thus also its common law. Therefore, there is no contradiction between the universal law-order and national sovereignty. A truly universal law-order in fact requires multiple sovereigns, because only then can it retain the criteria necessary to that universality. A universal sovereign, on the other hand, of necessity subordinates all independent activity to its own will, and cannot abide by any independent authority; it therefore can never submit to an all-encompassing order which it itself does not control – and, since it can never subject everything to its will, there will always be unresolved conflict, never unanimity. Today this tendency is evident in the quest to establish global jurisdiction for international organizations – universal jurisdiction. Such is the fulfillment of the civil-law tradition.
But the common law, which stands over sovereignty, conditions it and restricts it to the maintenance of an order of freedom and equality for non-sovereign, private entities. It is thus universally integrating. In this law-order, sovereignty serves to implement the principles of universal law in the particular legal order of the nation.
Private law is common law within a particular society
The expression of the common law in the life of the nation is the regime of private law. Private law is the law of liberty and equality. In it, legal persons are equals; with it, there is no respect of persons. It does not subordinate legal persons to a higher order or purpose, but allows them to pursue their own purposes; it integrates these persons as equals, coordinating them over against each other rather than subordinating the one to the other or treating them as subordinates of a greater whole. It thus strives not for an order of monolithic organization but one of a plurality of associations.
In a common-law society, there are therefore a plethora of legal persons – associations, and individuals through associations – pursuing independent goals, coordinated in terms of the integrating private law. Each of these associations in turn has an internal order governed by the principle of distributive justice, in which distributions are made rather than transactions, in which the members are apportioned shares and responsibilities, rights and duties, in accordance with the administrative will.
These associations are both private and public, ranging from the family to corporations, clubs, foundations, and then also to public communities such as towns, cities, and states. They all are governed by internal laws. Outwardly, they are coordinated and integrated with other associations in terms of private law. The common law qua private law integrates these activities in terms of the principle of commutative justice.
The two kinds of justice
It is of the utmost importance to realize both the difference between distributive and commutative justice, and the mutuality thereof. The besetting sin of left and right in the modern age has been to subordinate and even subsume the one principle to the other, leading to collectivism on the one hand and individualism on the other.
The concept of justice is fundamental here, and requires closer attention. The classic definition is “rendering to each his due,” ensuring that what one has coming to him, one actually receives. The Roman jurist Ulpian’s celebrated definition is: “Iustitia est constans et perpetua voluntas ius suum cuique tribuens” (Justice is the constant and perpetual will to render to each his due) – but this would seem to define the just will rather than justice in itself.
Aristotle went further, first making the important point that justice always concerns outward dealings with others rather than internal states of mind or mood – justice therefore always involves relations. He then took the decisive step of dividing justice into the two forms of distributive and commutative. Distributive justice is “exercised in the distribution of honor, wealth, and the other divisible assets of the community, which may be allotted among its members in equal or unequal shares.” Commutative justice, on the other hand, “supplies a corrective principle in private transactions.”
The important thing to notice here is that commutative justice is transactional justice. It focuses on the act, not the actors; as such, it is “no respecter of persons.” It strives to abstract the thing from the person and focus simply on the justice involved in the transaction at hand. It is commutative justice that is being referred to when we say, “Justice is blind.” It does not play favorites, “it calls them like it sees them.”
Distributive justice, on the other hand, does not concern transactions but commands: it is realized when the command takes the person into account in an appropriate manner, looking to the need or merit of the various actors. Commutative justice concerns the thing; distributive justice concerns the person.
Yet Aristotle’s distinction does not quite get to the bottom of the issue. Which is, that what really is being distinguished here is two dimensions of association, the outside and the inside, or the internal and the external. In other words, distributive and commutative justice are correlative; they are not alternative approaches to justice, but complementary approaches to it. The regime of distributive justice pertains to relations within a particular association, while the regime of commutative justice pertains to relations between particular associations.
Two kinds of justice, two regimes of enacting them
These two functionalities have two different methods of accomplishment. As H.B. Acton pointed out, (6) distributive justice requires a distributing agency to be set over the persons involved in the distribution. So the parties are subordinate to a higher decision-making authority. In commutative justice, the parties are coordinated over against each other in independence, are equal rather than being subordinated in terms of a higher relation.
This understanding corrects the impression given by an exclusive emphasis on the principle of methodological individualism. For there is no isolated individual standing over against society, in all his autonomous glory. There is rather the citizen, whose functioning within the associationalism of the common-law order makes it go. The individual’s relationships are mediated, precisely through the associations of which society is composed. The citizen is the natural individual taking on the guises provided by the various associations of which he forms part. The key to properly-functioning citizenship is responsible membership in the various associations, some of which are natural and/or obligatory. One such example is the family, into which all are born. Another is the state, of which all are members (citizenship strictly speaking), with rights and responsibilities corresponding to that membership. For an association to remain healthy, its members must recognize its authority over them, recognize their place in it, and pursue the shared interest of that association.
The state: an association among associations
The state is not an all-embracing community; it is one association among many, albeit a primus inter pares, the pre-eminent association in the nation. That is because it is the means by which the nation’s various and disparate elements are integrated into a coherent whole. It does this in two ways: directly, through the functionality of public law (expressive of distributive justice); and indirectly, through private law.
Public law serves to integrate the citizenry in terms of its shared, common interests. This is the common good, the public interest, the salus publica. Such integration is limited by the common good, which needs to be understood in opposition to particular interests. In other words, the various elements in society are not to pursue their particular interests through the state, but only weigh in on the public interest, in pursuit of the common good. Of course, this requirement is scarcely honored in this day and age.
The other form of integration is through private law, which, as we have seen, integrates and coordinates the various activities in society through the institutions of property, contract, pledge, credit and debt, tort, and the like. Private law thus provides the tools for citizens to provide for themselves and arrange their own affairs, in coordination with and in synergetic cooperation with other citizens, through the various institutional and organizational formats available in a functioning differentiated society.
The state is necessary not only for public law and the common good, but also for private law. For more on this, see Dooyeweerd and the Common Law.
Common law as spontaneous growth
Since the sovereign does not impose the law but receives it, the common law in its guise of external private law is not imposed but rather issues forth, precisely as a function of the relations of the differentiated society. The state does not administer distributive justice over society, precisely because society is not an all-inclusive association. The state is entrusted with the peculiar function of sovereign mediation of civil relations, and hence acts as arbiter over society, not as manager over it.
In this process, law evolves rather than is promulgated. Law results from the interaction of the independent loci of authority which are allowed to arise when sovereignty is exercised as oversight rather than command. This issues forth in common law; common law therefore grows with society; it expands as society differentiates. A primitive society lacks much in the way of a common law because most relations are internal to the associations of which it is composed; these associations are monolithic. It is therefore no accident that primitive societies stand in isolation and have difficulty in maintaining open communications with the outside world. They have little concept of a universal law governing such relations.
The reach of common law
Directly, the common law governs the relations between associations, and between individuals to the degree that they act as legal persons outside of the boundaries of any particular association. Within associations it governs relations only indirectly, that is, to the degree that internal affairs impinge on the functioning of the broader legal order. For example, contracts establishing arrangements contrary to the institutions of the universal common law (e.g., polygamy, same-sex marriage) are impermissible.
Being a function of commutative justice, these relations are of the order of transactions. Since associations pursue independent goals, they do not attempt to subordinate other associations, but only to obtain from those other associations resources which they might need the better to attain their own goals. These transactions can take on numerous forms, and can have numerous objects; they can however be summarized in the term obligation – commitments to performance.
The institutions of common law: property and contract
Although there are two basic forms of obligation, contract and tort (Aristotle characterized these as voluntary and involuntary, respectively), contract is its example par excellence. (7) Contract establishes a commitment to some duty or performance. Contracts mainly involve the transfer either of goods or of services. In the case of goods, either a sale or some form of lease is contemplated; in the case of services, a commitment to do something or abstain from doing something.
Such obligation calls the concept of private property into existence. Private property only comes about in connection with these relations between legal persons. The contracts which arrange for a transfer of goods require the concept of property as a presupposition. Property, in turn, presupposes the existence of entities outside the owning group. The concept of property has no significance within the holding community, only outside of it – for everything within is held in common or in trust and is subject to the regime of distribution rather than exchange. Further, property is all the goods and services at the disposal of the group, thus not only material things but also the “human capital,” the capacities of members capable of being put to profitable use and in demand on the part of those outside. All of these can be leveraged. In the chapter on common-law economics this will be explored more thoroughly.
The key role of the judiciary
The common law as external private law develops in terms of these inter-group arrangements, reciprocally influencing their development and being influenced by it. The point of contact of this development is the judiciary, the adjudicative branch of government. This is one of the main instruments through which sovereignty affects the social order. By rendering decisions in cases of dispute, the judiciary establishes and confirms valid forms of relation, and of the components of relation. These “jural relations” as they are sometimes known are rights, involving both the legal persons (individuals and associations) and the legal objects (goods and services).
The common law as a universe of burgeoning rights thus develops in the service of a spontaneous order. It facilitates relations between groups by bringing to bear the legal institutions which can mediate those relations. These institutions include property, contract, tort or delict, due process of law, legal personality. They are not imposed, but rather grow out of custom as sanctioned by the courts. However, they are implicit in the logic of the common law. Such relations will always be conducted through such legal institutions, wherever such relations arise.
Court-evolved law
In this process, the courts are determined by precedent and thus follow a given trajectory, although such determination is not rigid; they are guided forward by the inner logic of the common law as entailed in its capacity as a universal, integrating legal order showing itself no respecter of persons. Here the common law reveals itself as general equity. Therefore, courts operating in terms of custom and equity as so defined act, in the issuing of decisions, as determinators of value, of the norms by which society is ruled. They do so not by prescribing a law but by providing an interpretation which then gives to law and custom its boundaries and indicates its path forward into the future. Decisions and precedents are the framework through which the common law takes shape in a particular society.
The values of society are therefore fundamentally influenced by the decisions issued by the courts. The legal system takes shape upon this basis, and legislation, if it is to maintain the legal order of the common law, must respect this legal system and build upon it. In the civil-law approach, legislation becomes omnipotent and takes it upon itself to replace this customary order. In so doing it interrupts the continuity of a society with its past and introduces an artificiality and an uprootedness which has a thoroughly pernicious effect on societal mores.
The process of valuation
This is the process by which, in a common-law order, valuation takes place which is valid across the society. Valuation occurs through a process in which an appeal is made to sovereign (or the sovereign’s representative) to adjudicate on a point of uncertainty. It is this decision which is decisive because it then becomes binding on society at large; it becomes law. And the law, as Stahl has noted, “is the primary, most immediate ethical measure for the actions of men;” (8) as such, it has a ripple effect throughout society, influencing its very moral fiber, for better or for worse.
The basic theorem of the common law
We can therefore establish as the fundamental theorem of the common-law order the following formula: the sovereign confirmation, under the leading of justice and in line with precedent, of (external) social value, in response to request, at the margin.
- Sovereign confirmation: a binding decision made by the public authority, enforced by the power of that authority, that cannot be gainsaid.
- the leading of justice: this decision is arrived at in strict consultation with the principle of justice.
- in line with precedent: this decision is correlated with previous decisions pertaining to the matter at hand; it must be shown to follow those decisions, or, if necessary, to derogate from them, and how; such derogation carries the burden of proof.
- social value: valuation which is “current,” i.e., which is valid for society at large, and not just within a particular family or other group; as such, it is imparted to all, and all are held accountable to it.
- in response to request: decisions are arrived at by appeal to authority, they are not handed down by decree. As such, they spring from the grass roots, from living reality, and capture the spontaneous development of society.
- at the margin: decisions are made only regarding a fraction of conflicts and other situations of doubt, and provide guidance to actors as to how to conform future behavior.
This process implements and generates the integrating universal value structure upon which civilization rests, which is the common law.
It integrates the universal with the particular, the top-down with the bottom-up.
The common law therefore brings down the higher law, which is God’s will for human society, into the life of the nation by means of the instrumentality of sovereignty, which through a process of spontaneous ordering overseen by the state generates the pluralist, differentiated, associationalist order characterized by liberty under law, and upheld by individuals dedicated to the citizen ideal.
Notes
- “The standards of law and the institutions of the state differ across different countries and times and, being the work of man, everywhere and of necessity contain bad as well as good. There is indeed however something higher, something universal, at work in all creations of law and the state, which purposes to be consummated in all of these, the consummation or lack thereof amounting to the superiority or poverty of the same: that inward unchanging essence of law and state. Now jurisprudence is the science of law and state as it exists in a particular time under a particular people. From this stems the requirement for a higher science, having as its object this inner unchanging essence of law and state. It may be called the doctrine of law and state.” Stahl, Principles of Law, p. 1.
- “Common law (lex communis) has been naturally implanted by God in all men.… It is commonly called the moral law (lex moralis).… In this common law (jus commune) is set forth for all men nothing other than the general theory and practice of love, both for God and for one’s neighbor.…. Christ set forth two headings of this common law. The first heading pertains to the performance of our duty immediately to God, and the second to what is owed to our neighbor.… Proper law (lex propria) is the law that is drawn up and established by the magistrate on the basis of common law (lex communis) and according to the nature, utility, condition, and other special circumstances of his country. It indicates the peculiar way, means, and manner by which this natural equity among men can be upheld, observed, and cultivated in any given commonwealth. Therefore, proper law (jus proprium) is nothing other than the practice of this common natural law (jus naturale) as adapted to a particular polity. It indicates how individual citizens of a given commonwealth are able to seek and attain this natural equity. Whence it is called the servant and handmaiden of common law (jus commune), and a teacher leading us to the observance of common law.” Johannes Althusius, Politica, §§. 19, 20, 22, 30.
- This is the theme of my book A Common Law: The Law of Nations and Western Civilization.
- This theme calls for a book-length exposition. In the meantime, regarding the relationship of Roman and English law one may consult Bryce’s Studies in History and Jurisprudence, Leoni’s Freedom and the Law, McIlwain’s “English Common Law” (cf. also his Constitutionalism: Ancient and Modern), for starters.
- Stahl, Principles of Law, ch. 4: “The Popular Character of Law,” pp. 79ff.
- The Morals of Markets and Related Essays, p. 103.
- Stahl, Private Law, p. 100.
- Stahl, Principles of Law, p. 39. | https://alvamail.synology.me/commonlawreview/the-paradigm/a-general-theory-of-the-common-law-2/ |
PROCEEDINGS VOLUME 1772Optical Information Processing Systems and Architectures IV
*This item is only available on the SPIE Digital Library.
Volume Details
Volume Number: 1772Date Published: 12 January 1993
Table of Contents
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Multiclass optical correlation filters for alphanumeric field recognition
Author(s): David P. Casasent; Srinivasan Gopalaswamy; Anand K. Iyer
Author(s): David P. Casasent; Srinivasan Gopalaswamy; Anand K. Iyer
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We consider the use of new distortion-invariant optical correlation filters for machine-printed OCR. Our work is unique in its treatment of a large set of different fonts, printer types, plus rotations and scale (point size) variations, and various practical issues such as printing artifacts and background noise. We detail their use in the locations and recognition of alphanumeric fluids (digits) in destination address blocks (DABs).
Synthetic discriminant functions for implementation on arbitrarily constrained devices
Author(s): Daniel W. Carlson; Bhagavatula Vijaya Kumar
Author(s): Daniel W. Carlson; Bhagavatula Vijaya Kumar
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The conventional Synthetic Discriminant Function (SDF) filters are complex-valued and thus cannot be accommodated on spatial light modulators that can represent only a subset of all possible values in the complex plane. Here, we compare the performance of different SDF filters designed to satisfy certain device restrictions.
Dynamically reconfigurable optical morphological processor and its applications
Author(s): Tien-Hsin Chao
Author(s): Tien-Hsin Chao
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An innovative optically implemented morphological processor is introduced. With the use of a large space-bandwidth-product Dammann grating and a high-speed shutter spatial light modulator, effective structuring element with large size and arbitrary shape can be constructed with dynamic reconfigurability. This reconfigurability is a major improvement over the conventional correlator-based morphological processor in which fixed holographic filters are used as structuring elements (Casasent and Botha, 1988). A novel two-dimensional thresholding photodetector array, capable of performing parallel thresholding and feedback, is utilized in this system and makes possible the implementation of many complex morphological operations requiring iterative feedbacks and full programmability. The optical architecture and the principle of operation are presented. Experimental demonstration of binary image morphological erosion, dilation, opening, and closing are also demonstrated. A technique for extending this technique to gray-scale image using thresholding decomposition technique is also discussed.
Real-valued composite filters for optical pattern recognition
Author(s): Anushia Balendra; P. Karivaratha Rajan
Author(s): Anushia Balendra; P. Karivaratha Rajan
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The design of real-valued composite filters for optical pattern recognition and classification is considered. A procedure to design a real-valued minimum average correlation energy (MACE) filter is developed. Also, the design of a real MVSDF-MACE filter that minimizes the output variance due to input noise while maintaining a sharp correlation peak is developed. Computer simulation indicates that the performance of these real filters is almost as good as that of the complex filters.
Computer sumulations of the nonlinear joint transform correlator performance for disjoint signal and scene noise
Author(s): Bahram Javidi; Jun Wang; Amir H. Fazlolahi
Author(s): Bahram Javidi; Jun Wang; Amir H. Fazlolahi
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The correlation performance of nonlinear joint transform correlator for input signals containing a target in the presence of the input scene noise that is disjoint with the signal is investigated. It is shown that the binary joint transform correlator outperforms other types of nonlinear joint transform correlator for lowpass scene noise. Correlation tests using computer simulations are presented. The nonlinear joint transform correlator performance is determined for various degrees of nonlinear transformations and different input scene noise parameters. The investigations indicate that the correlation performance is sensitive to the bandwidth variation of the small bandwidth noise and is less sensitive to that of the wide band noise.
Effects of nonlinear parameters in feedback joint transform correlator (I)
Author(s): Nobuyuki Kasama; Yasuyuki Mitsuoka; Tadao Iwaki; Shuhei Yamamoto
Author(s): Nobuyuki Kasama; Yasuyuki Mitsuoka; Tadao Iwaki; Shuhei Yamamoto
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We report that nonlinear parameters effect the characteristics of the optical pattern recognition of a feedback joint transform correlator (FJTC) which is based on a joint transform correlator (JTC). This system incorporates the optically addressed ferroelectric liquid crystal spatial light modulator named LAPS-SLM. Nonlinear parameters in the FJTC are a threshold level of the LAPS-SLM to record the binary joint power spectrum (JPS), and a feedback transfer function from the correlation plane to the input plane. It is important to control the threshold level of the binary JPS. But the FJTC does not always need the optimum condition where the FJTC recognizes the signal image correctly at the initial recognition.
Optoelectronic neural network utilizing a joint transform correlator
Author(s): Marc J. Paquin; Jonathan S. Kane
Author(s): Marc J. Paquin; Jonathan S. Kane
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Adaptive Resonance Theory provides a neural network architecture for self-organizing arbitrary input patterns into stable categories. In our work we utilize a model of ART known as ART2-A, which is capable of processing both analog and binary patterns. Our model is adapted to handle 2-D images for input patterns, and to allow for translation invariance. The computation of image patterns is assisted by a joint transform correlator (JTC), providing a fast, real-time, translation-invariant method of initial comparison. The JTC has an advantage over other optical correlator architectures in that a separate matched filter for each input need not be constructed. In this paper, we present a brief overview of the ART2-A algorithm and our optoelectronic implementation of this neural network model. This paper is based on work by Kane and Paquin submitted to IEEE Transactions on Neural Networks entitled 'POPART: Partial Optical ImPlementation of Adaptive Resonance Theory 2'.
Optoelectronic implementation of quasi phase-correlation-based processor
Author(s): Christophe Gorecki; Corinne Bournizien; Katarzyna Chalasinska-Macukow
Author(s): Christophe Gorecki; Corinne Bournizien; Katarzyna Chalasinska-Macukow
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We present a new optoelectronic quasi phase processor based on a conventional joint transform correlator architecture and using a liquid crystal SLM. The phase information is extracted from a joint transform spectrum producing a good correlation performance in terms of noise tolerances and peak sharpness. Several characteristics of the used SLM improving the correlation function are investigated. Computer simulations of the correlator performances and experimental results of an application on tool recognition are presented and discussed.
Tracking speckle patterns with optical correlation
Author(s): Natalie Clark; Michael K. Giles; Sarah H. Harrison; Chris P. Hofer
Author(s): Natalie Clark; Michael K. Giles; Sarah H. Harrison; Chris P. Hofer
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It has been shown that tracking small particle motion can be accomplished by tracking the speckle pattern is produces. This paper describes various methods of real-time tracking of speckle patterns obtained from ultrasonic flow imaging of blood and tissue motion using optical correlation. Results obtained from a gray scale joint transform correlator utilizing a twisted nematic liquid crystal spatial light modulator and from Sandia Lab's acousto-optical correlator are presented. The experimental results demonstrate the feasibility of real-time tracking with accuracy comparable to that of template matching algorithms currently being implemented in digital hardware.
Optimization of joint transform correlation
Author(s): Dong X. Yu; Don A. Gregory
Author(s): Dong X. Yu; Don A. Gregory
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The joint transform correlation can be optimized by subtracting the constant terms (Fourier transform power spectra) in the filter plane. Computer simulations for three approaches to optimization have been performed and have shown that the contrast of joint transform power spectrum can be maximized to produce optimal correlation signal.
Problems facing optical correlators
Author(s): Gregory O. Gheen; Edward R. Washwell; Chao H. Huang
Author(s): Gregory O. Gheen; Edward R. Washwell; Chao H. Huang
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Some of the problems in realizing a practical optical correlator based ATR system are discussed. Two factors play a key role in the discussion: (1) the system and component issues of optical correlators, and (2) the processing potential of digital processors. The lack of an appropriate Filter SLM is identified as a major problem area for optical correlators, both now and in the future at the current rate of development and emphasis.
Optimal introduction of optical efficiency for pattern recognition filters
Author(s): Philippe Refregier
Author(s): Philippe Refregier
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Optimal trade-off filters for the Signal-to-Noise Ratio, the sharpness of the correlation peak and the optical efficiency are discussed. A unified formalism is introduced for Circular Harmonic (CH) and Synthetic Discriminant Function (SDF) filters. With this formalism, new solutions for CH and SDF filters are derived.
Reduction of aliasing in correlation using a pixelated spatial light modulator
Author(s): Steven B. Heddle; David G. Vass; Richard M. Sillitto
Author(s): Steven B. Heddle; David G. Vass; Richard M. Sillitto
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Replication in the output plane of an optical correlator, due to pixelation of the Fourier plane filter, can lead to false correlation signals. This paper suggests randomization of the pixel positions of the Fourier plane filter as a solution, and demonstrates its effectiveness through computational simulations and optical correlation experiments using a custom made SLM.
Application of a hybrid digital-optical cross-correlator as a semiautonomous vision system
Author(s): Marija S. Scholl
Author(s): Marija S. Scholl
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We describe a complex optical system consisting of a 4f optical correlator with programmable filters under control of a digital on-board computer that operates at video rates for filter generation, storage, and management. It gives intelligent vision to a semi-autonomous vehicle, with ability to recognize immediate danger to its survival in the near term and ability to pursue navigational goals on the basis of tracking the previously identified features.
Fabrication of a character recognition system by a multiplexed matched spatial filter by feature-extracted patterns
Author(s): Shun-ichi Kamemaru; Jun-ichi Yano
Author(s): Shun-ichi Kamemaru; Jun-ichi Yano
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In a conventional pattern recognition system with a matched spatial filter (MSF), the system is based on a template matching which is the comparison of the test pattern with a number of stored patterns until an exact match is found. Therefore, sometimes, the system has not been able to distinguish some similar patterns. In this paper, we propose to apply a concept of feature extraction to matched spatial filtering to improve performance of the MSF for distinction of some closely similar patterns. The synthesis of the MSF with partial patterns of unknown input objects to be recognized enables filtering operation to extract desired features from some input patterns. Using this technique and a hybrid pattern recognition system with the MSF synthesized by nine feature extracted patterns, we could perfectly recognize a page of unknown 25 alphabets. The recognition result was given not by conventional peaks but by character symbols on a CRT display.
Nonlinear distortion-invariant filter performance with false targets, noise, and clutter
Author(s): David P. Casasent; Gopalan Ravichandran
Author(s): David P. Casasent; Gopalan Ravichandran
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We provide insight into the disadvantages of various non-linear distortion-invariant optical correlation filters. From this, guidelines for improved optical correlation filters emerge including: filters for intra-class recognition, filters for clutter rejection and the different types of clutter that arise, hierarchical inference filters, remarks of Fourier vs. image domain synthesis, filter space-bandwidth product (SBWP), techniques to reduce correlation plane energy and filter performance measures and issues.
Iterative algorithm for designing binary phase-only composite filters
Author(s): Charles D. Hendrix; Bhagavatula Vijaya Kumar
Author(s): Charles D. Hendrix; Bhagavatula Vijaya Kumar
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Use of the Magneto-Optic Spatial Light Modulator (MOSLM) in the filter plane of optical correlators is attractive because it is capable of high frame rates. This has led to the design of several different types of Binary Phase-Only Filters (BPOFs) and Ternary Filters matched to a single reference. To further increase the throughput of an optical correlator employing the MOSLM, attempts at designing Binary Phase-Only Composite Filters have been made. In this paper, we introduce a new iterative technique to design such Composite Filters in which we simultaneously maximize the peak sharpness and minimize the deviation of the actual correlation peak intensities from their desired values.
Optical experiments on kth-law nonlinearly transformed matched filters
Author(s): Bahram Javidi; Guanshen Zhang
Author(s): Bahram Javidi; Guanshen Zhang
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Experiments on kth law nonlinearly transformed matched filters for optical correlation are provided. Experimental results for the images tested indicate that nonlinear matched filters produce good correlation performance in the terms of correlation peak intensity, signal-to- noise ratio, and peak-to-sidelobe ratio. The sensitivity of the kth law nonlinearly transformed filter to rotational changes of the input signal is investigated. It is shown that for the images presented here, up to a certain degree of input signal rotation, a highly nonlinearly transformed matched filter may produce a larger peak-to-sidelobe ratio than a conventional matched filter.
Performance of mixed-metric optimized ternary correlation filters on realistic binary and gray-scale imagery
Author(s): David L. Flannery; William Earl Phillips III; Dennis H. Goldstein
Author(s): David L. Flannery; William Earl Phillips III; Dennis H. Goldstein
Show Abstract
The ternary phase-amplitude filter (TPAF) is by definition restricted to the modulation values -1, 0, and 1, thus comprising a binary phase-only filter (BPOF) multiplied by a binary- amplitude pattern, i.e., a region of support. The TPAF offers an attractive combination of real-time implementation with available devices and good correlation performance. Smart (optimized distortion-invariant) TPAF formulations have been developed. The TPAF enables filter implementation with magneto-optic devices and these devices also can be used for image input if gray scale scenes can be binarized while preserving good correlation performance. We provide simulation results addressing the comparative performance of mixed-metric smart TPAF's using gray scale, edge-enhanced and binary images derived from identical original scenes. The variation of filter performance with training set background intensity level is examined.
Distortion-invariant correlation using nonlinear feature-based binary phase-only filters
Author(s): Samuel Peter Kozaitis; Wesley E. Foor
Author(s): Samuel Peter Kozaitis; Wesley E. Foor
Show Abstract
In an optical correlator, binary phase-only filters (BPOFs) that recognize objects that vary in a nonrepeatable way are essential for recognizing objects from actual sensors. An approach is required that is as descriptive as a BPOF yet robust to object and background variations of an unknown or nonrepeatable type. We developed a BPOF that was more robust to unknown variations than a binary version of a synthetic discriminant function (fSDF) filter. We compared the values of spatial frequencies of a training set and compared them in terms of their similarity. Then, we grouped them into a cluster by forcing some values to zero. In this way, we retained the invariant spatial frequencies of a training set and generated a ternary filter. Our filter offered a range of performance by adjusting a parameter. At one extreme, our filter offered similar performance to that of a fSDF filter. As the value of the parameter was changed, correlation peaks within the training set became more consistent and broader as the filter became more robust. In addition, the feature-based filter was potentially useful for recognizing objects outside the training set. Furthermore, the feature-based filter was more easily calculated and trained than an fSDF filter.
Optical Gabor, wavelet, and morphological filters for image processing
Author(s): David P. Casasent; John Scott Smokelin; Anqi Ye
Author(s): David P. Casasent; John Scott Smokelin; Anqi Ye
Show Abstract
We consider wavelet and Gabor transforms for detection of candidate regions of interest in a 2-D scene. We generate wavelet and Gabor coefficients for each spatial region of a scene using new linear combination optical filters to reduce the output dimensionality and to simplify post-processing. We use two sets of wavelet coefficients as indicators of edge activity to suppress background clutter. The Gabor coefficients are found to be excellent for object detection and robust to object distortions and contrast differences. We provide insight into the selection of the Gabor parameters.
Optical wavelet transforms using spatial light rebroadcasters
Author(s): Alastair D. McAulay; Junqing Wang; Jian Tian Li
Author(s): Alastair D. McAulay; Junqing Wang; Jian Tian Li
Show Abstract
The advantages of a wavelet transform over a short time Fourier transform are explained using 1-D synthetic data in a computer simulation. An optical set up is described in which an electronic analog sensor signal drives an acoustooptic cell that controls the intensity of an Argon laser. A mechanical scanner writes the information as a line onto a spatial light rebroadcaster (SLR) module containing an optical liquid crystal light valve. A lens system expands the line into a 2-D array. A wavelet transform filter is placed in the Fourier transform plane of a 4f correlator. An optical demonstration shows the formation of a wavelet transform and an inverse wavelet transform to reconstruct the original waveform.
Optical wavelet processor for producing spatially localized ring-wedge-type information
Author(s): Mark O. Freeman; Adam S. Fedor; Brett D. Bock; Kenneth A. Duell
Author(s): Mark O. Freeman; Adam S. Fedor; Brett D. Bock; Kenneth A. Duell
Show Abstract
Ring-wedge detectors are known to produce a useful feature set for certain types of pattern recognition. Their major shortcoming is that they measure global features. We present an optical processor, based upon the computation of a two-dimensional wavelet transform, which overcomes this limitation. By using wavelet functions that are essentially compact in the space domain we generate an output that consists of a mosaic of spatially localized bandpass components. Consistent with the nature of wavelets, the radial (ring) frequency components, are organized into constant-Q (f0/(Delta) f) bands. The angular (wedge) frequency content is divided into a number of equal-width bands which cover the full 0 - 180 degree(s) range. The radial information is obtained by using a feedback iteration loop which scales the input image by a fixed factor for each time around the loop. By introducing a tilt in the Fourier plane of the feedback loop, we arrange for the space-domain representations of each scaled input to be spatially separated without altering the position of their Fourier transforms. In this way, all of the radial frequency bands can be extracted with a single wavelet filter. A diffraction grating is introduced into the optical path after the scaling loop to replicate the Fourier information M times. The angular information is extracted using M filters in parallel-- one for each wedge component. The filter outputs are minified consistent with Nyquist theory for their reduced bandwidths to produce an output whose space-bandwidth product is roughly the same as that of the input image. We present the design of the optical system along with some initial experimental results.
Particle characterization using a holographic ring-wedge detector and an optical neural network
Author(s): Martin S. Marshall; Robert E. Benner
Author(s): Martin S. Marshall; Robert E. Benner
Show Abstract
Digital and optical implementations of the holographic ring detector directly coupled into an optical neural network are studied as a means of increasing the speed of the decision process for particle characterization. A single holographic optical element which performs the same function as a ring detector and a simple two-layer, feedforward optical neural network is fabricated and evaluated.
One-dimensional hologram technology for optical computing
Author(s): Andrei L. Mikaelian
Author(s): Andrei L. Mikaelian
Show Abstract
One-dimensional hologram technology for parallel information recording on a continuously moving carrier in both thin and thick photolayers is considered. The possibility of superposing 1-D holograms allowing the information capacity to be increased up to several Gbytes on one side of the disk is shown. A high-speed holographic disk memory is disclosed. The application for designing neural nets with serial- parallel processing is discussed. For a two-layer neural net, the effective number of neurons is of order 105 with 16 real neurons in each layer.
Optical feature extraction using the Radon transform and angular correlation
Author(s): Oodaye B. Shukla; Bradley G. Boone
Author(s): Oodaye B. Shukla; Bradley G. Boone
Show Abstract
This paper describes two processing algorithms that can be implemented optically: the Radon transform and angular correlation. These two algorithms can be combined in one optical processor to extract all the basic geometric and amplitude features from objects embedded in video imagery. We show that the internal amplitude structure of objects is recovered by the Radon transform, which is a well-known result, but, in addition, we show simulation results that calculate angular correlation, a simple but unique algorithm, which extracts object length, width, area, aspect ratio, orientation and boundary from suitably thresholded images. In addition to being insensitive to scale and rotation, these simulations indicate that the features derived from angular correlation algorithm are relatively insensitive to tracking shifts and image noise. Some optical architecture concepts, including one based on micro-optical lenslet arrays, have been developed to implement these algorithms. We will discussed these architectures, stressing the micro-optical approach. Test and evaluation using simple synthetic object data will be described. We will also describe the results of a study that uses object boundary (derivable from angular correlation) to classify objects using a neural network.
Calculating potential fields using microchannel spatial light modulators
Author(s): Max B. Reid
Author(s): Max B. Reid
Show Abstract
We describe and present experimental results of the optical calculation of potential field maps suitable for mobile robot navigation. The optical computation employs two write modes of a microchannel spatial light modulator (MSLM). In one mode, written patterns expand spatially, and this characteristic is used to create an extended two dimensional function representing the influence of the goal in a robot's workspace. Distinct obstacle patterns are written in a second, non-expanding, mode. A model of the mechanisms determining MSLM write mode characteristics is developed and used to derive the optical calculation time for full potential field maps. Field calculations at a few hertz are possible with current technology, and calculation time vs. map size scales favorably in comparison to digital electronic computation.
Design of digital optical processors
Author(s): John Fraser Snowdon; Alex Kashko; Brian S. Wherrett
Author(s): John Fraser Snowdon; Alex Kashko; Brian S. Wherrett
Show Abstract
Optical cellular logic and extended-interconnect cellular logic processor architectures are described. Simulations, tolerance studies and circuit construction are used to advance both device technology and architectural thinking. Benchmarking against electronic distributed array processors leads to an optical non-locally interconnected, off-chip scheme with local electronic connections between smart pixels, unless ultra-low switching energy all-optical components can be fabricated. Fundamental limits to optical bistability do not rule out the latter possibility.
Optical parallel selectionist systems
Author(s): H. John Caulfield
Author(s): H. John Caulfield
Show Abstract
There are at least two major classes of computers in nature and technology: connectionist and selectionist. A subset of connectionist systems (Turing Machines) dominates modern computing, although another subset (Neural Networks) is growing rapidly. Selectionist machines have unique capabilities which should allow them to do truly creative operations. It is possible to make a parallel optical selectionist system using methods describes in this paper.
Microchannel-plate-based electro-optical A-D conversion
Author(s): Mohamed C. Zatet; Robert Y. Levine
Author(s): Mohamed C. Zatet; Robert Y. Levine
Show Abstract
A novel microchannel plate (MCP) based electrooptical A/D converter is proposed for signal bandwidths in excess of 100 MHz. The signal forward-biases an electron flux through 500 impedance matched transmission lines deposited on an MCP. The backbiasing of the gap between adjacent MCPs provides a voltage threshold for the signal triggering of an electron cascade in the second MCP. The second MCP is biased by a square wave timing pulse in order to measure the time at which the signal exceeded the backbias threshold. It is shown that reasonable MCP operating parameters result in 100 psec time resolution. The Nyquist criteria is applied to determine the least bit size for voltage sampling of a transient pulse.
Novel synchronous detection method for obtaining directional gradients of images
Author(s): Mark Storrs; David J. Mehrl
Author(s): Mark Storrs; David J. Mehrl
Show Abstract
We describe an optical, scanning-based imaging system for directly acquiring the directional gradient of an image. We later discuss a modification to the system which enables it to track contours of moving objects. We present results of proof-to-principle experiments and discuss applications of the system to the identification of objects.
Random phase errors and pseudorandom phase modulation of deformable mirror spatial light modulators
Author(s): Robert W. Cohn
Author(s): Robert W. Cohn
Show Abstract
Piston-only spatial light modulators, such as the flexure-beam deformable mirror device, hold great promise for real-time optical processors because of their ability to accurately match the phase of arbitrary laser images. Non-ideal devices may have uncontrolled phase errors which can limit performance. A statistical analysis has been developed which models the effect of random piston and tilt errors on the diffraction pattern of phase-only SLMs. A slight modification of these equations describes the performance of these SLMs in the phase-only correlator and the phase-only correlator modulated by pseudo-random sequences. Results on correlator diffraction efficiency versus amount of phase error are presented. For the specific case of a binary phase-only matched filter a diffraction efficiency of 40.5% is found.
Modified signed-digit to binary conversion using symbolic substitution
Author(s): Mir Mojtaba Mirsalehi
Author(s): Mir Mojtaba Mirsalehi
Show Abstract
An efficient method based on the symbolic substitution technique is proposed for the conversion of modified signed-digit numbers to binary numbers. As a specific example, the conversion of the output of an 8-bit adder with the proposed method is investigated and compared with a previous method.
Index interferometer
Author(s): Jacques E. Ludman; Juanita R. Riccobono
Author(s): Jacques E. Ludman; Juanita R. Riccobono
Show Abstract
The Index Interferometer is a novel instrument being developed by Northeast Photosciences. The instrument is a breakthrough in the high-accuracy measurement of the index of refraction, the dispersion, and the index profile of materials. The instrument accurately measures the index of refraction of materials to one or two more significant figures than previous instruments. Material slices polished moderately flat are sufficient, without any requirement for special or complicated material shapes, such as prisms. The index profile at any chosen wavelength can be measured using a simple color filter. No special laser sources or carefully collimated parallel beams are required. The index profile over an entire sample can be directly obtained at any desired wavelength. This instrument is remarkable in that it greatly increases the accuracy of measurement, eliminates the need for high-quality, extremely narrow sources and for fabrication of special-geometry samples, and adds additional features, such as index profile measurements. The technique compares the fringe pattern from the top surface with that from a reference mirror to determine the thickness. Then, with the aid of a filtered white light source, the interference pattern from the back surface is compared with that from the front to yield the optical thickness of the sample. The combination of the two measurements gives the index. The back surface fringe pattern itself gives the index profile.
Analysis of speckle interferometry images
Author(s): David H. Tofsted
Author(s): David H. Tofsted
Show Abstract
Speckle interferometry provides a basis for analyzing the dynamic motions of materials through differencing of the field scattered from objects at two different times. Phase differences in the signals measured at different times, inferred from fringe patterns, indicate the degree of deformation present. Automatic analysis of differences images requires significant preprocessing to enhance the contrast of fringe regions. Often fringes that are evident to the human eye cannot be perceived automatically because the fringes usually consist of widely separated high intensity spikes. Median or averaging filters are ineffective at enhancing these patterns. Adaptive filtering similar to that used in SAR image analysis is capable of enhancing the fringe area contrast. A two step process is detailed. In a first phase a filter based on window mean and variance suppresses noise and generates a greater cohesion of high intensity points in the fringe areas. In a second phase the image is average filtered to smooth the intensities in the fringes. An auxiliary routine used to count fringes is discussed. Comparisons with median filtered results show the greater ability to automatically count fringes using this two step method.
Optimal filters: a unified approach for SNR and PCE
Author(s): Richard D. Juday
Author(s): Richard D. Juday
Show Abstract
A unified approach for a general metric that encompasses both the signal-to-noise ratio (SNR) and the peak-to-correlation (PCE) ratio in optical correlators is described. In this approach, the connection between optimizing SNR and optimizing PCE is achieved by considering a metric in which the central correlation irradiance is divided by the total energy of the correlation plane. The peak-to-total energy (PTE) is shown to be optimized similarly to SNR and PCE. Since PTE is a function of the search values G and beta, the optimal filter is determined with only a two-dimensional search.
Dynamic photorefractive self-amplified angular-multiplex 2D optical beam-array generation
Author(s): Shaomin Zhou; Pochi Yeh; Hua-Kuang Liu
Author(s): Shaomin Zhou; Pochi Yeh; Hua-Kuang Liu
Show Abstract
A real-time 2-D angular-multiplex beam-array holographic storage and reconstruction technique using electrically-addressed spatial light modulators(E-SLM's) and photorefractive crystals is described. Using a liquid crystal television (LCTV) spatial light modulator (SLM) for beam steering and lithium niobate photorefractive crystal for holographic recording, experimental results of generating large and complicated arrays of laser beams with high diffraction efficiency and good uniformity are presented.
Imaging spectrometer based on white-light interferometry
Author(s): David J. Lanteigne
Author(s): David J. Lanteigne
Show Abstract
Many applications of imaging systems require information about the spectrum of light that forms the scene. One way of deriving spectral information from a source is by calculating the Fourier transform of the temporal coherence function, as measured by a Michelson interferometer. This is the basis of Fourier transform infrared spectroscopy (FTIR). With a phase-shifting spatial light modulator, it should be possible to construct a two-dimensional array of Michelson interferometers in order to derive independent spectral estimates for each pixel in a natural light image. Realistic constraints on the range of motion of mirror pixel elements will limit the spectral resolution of such a system, but these limits also allow the use of wide aperture imaging optics, and assure that the data processing burden is within the range of current digital technology. | https://spie.org/Publications/Proceedings/Volume/1772?SSO=1 |
Although at first glance it seems Chinese, this free and open source tool is so multifunctional that once you learn how to use it, you will not want to use anything else. R is a flexible programming language designed to make it easy to explore data analysis with high-level graphics. It has a large number of libraries, which makes it a very powerful ally for statistics, data mining and web analytics . Index of contents Its growing popularity is not the only reason to learn R. If you want to truly learn data science, you need to have the basic skills to understand it: knowledge of data manipulation, visualization, and machine learning. It is necessary to select a language that is capable of taking full advantage of these abilities, as well as that this language has resources to be able to learn to handle it completely. You have to learn to think about solving problems , and all this with R is much simpler.
Although there are many voices that indicate that R is becoming the lingua franca for data science , it is not for all audiences. Keep in mind that at first it is very difficult to understand and some basic knowledge is required to get started, in addition to the large number of packages and functions that make it up, the number of which is increasing, make it seem extremely complex. learn R Learn to program in R It is almost always recommended to start using this tool with RStudio , to handle a nicer and more understandable environment. Apart from all the information that can number list be obtained through the internet, three basic points are also recommended: know statistics (something obvious in this case), have basic knowledge of programming (something that not many people think of at first) and a good user manual. reference to always have at hand -not to be read from beginning to end, but to open when a doubt arises or to see if some operations are possible-. And most importantly: stop using any other programs and start using R , since troubleshooting is the best way to prepare.
There are thousands of ways to get to know this program on the internet, such as through manuals, specialized blogs, videos on YouTube or even examining other people's codes to understand how it works. It's also a good way to try to understand how the different features work. You can write the name of these, without the parentheses, hit enter and analyze the code to see what it does. The debug() function can also help you understand how things work. Previous knowledge to program in R If you already know other systems like SPSS or SAS , the best advice is to dive straight into R every time you want to do some work, even if you have to force yourself to do so. It is true that it will be hard, but asking google and even comparing the result with SPSS or SAS , little by little one will be taking control of the environment and handling it faster and faster. Reading specialized blogs can also help you learn the tricks and improve your knowledge of this tool, and there are even some dedicated to the relationship between R and these other programs. Although these are not programming languages like R, it is advisable to repeat problems that have already been solved in them with these tools. | https://www.cdpmcs.com/forum/medical-forum/background-knowledge-number-list |
William H. Belden, III is a managing director and head of product development at Guggenheim Investments. Mr. Belden has direct oversight for mutual funds, closed end funds, exchange-traded funds, variable annuities and product strategy. Prior to his current role, he was responsible for the overall operations of Guggenheim Investments ETF business line, which included product development, distribution and marketing activities.
Mr. Belden earned his MBA from the University of Chicago’s Booth School of Business and has a B.S. in finance from Miami University. He is series 7, 24 and 63 registered. Here are excerpts from his conversation with Research magazine.
The Guggenheim S&P 500 Equal Weight ETF (RSP) celebrates its 10-year anniversary in April 2013. Do you think equal weighted portfolios have gotten the recognition they deserve?
Launched in 2003, RSP was Guggenheim Investments’ first ETF as well as the first alternatively weighted ETF—a milestone in the industry. As you mentioned, the fund will celebrate its 10th anniversary later this year, which is a tremendous milestone specific to Guggenheim Investments.
Alternative weighting methodologies, such as equal weighting, have garnered significant attention during the past several years, however we still do not feel that equally weighted portfolios have received the recognition they deserve. Cap weighting is the more traditional and commonly used investment methodology, while equal weighting takes some explanation to understand its many benefits, including outperformance and diversification potential. As it relates to diversification, equal weighting has the ability to provide broad exposure across market segments and sectors, which may reduce concentration risk and result in a more balanced portfolio. Furthermore, a systematic quarterly rebalance serves the purpose of reallocating from index constituents that have appreciated the most, and have potentially become over-valued, to those that have decreased in value, and are potentially undervalued.
Those investors who have taken the time to educate themselves on the potential benefits of equally weighted strategies may have realized significant outperformance over the traditional cap-weighted approach. For example, over the past five years, RSP has offered more than 1,400 basis points of outperformance when compared to SPY, while exposing the investor to only slightly higher levels of volatility with 5-year annualized volatility levels of 23% and 19% respectively.
It is important to note that equal weighting will not outperform during all market cycles. Historically, this weighting methodology has lagged during periods of mega-cap outperformance. However, it should be considered as part of the core equity holdings discussion alongside the market-cap weighted products.
Emerging markets still have higher economic growth rates compared to developed markets and many of these countries even have less debt. What kind of opportunities do you see?
Emerging market ETFs represented the fastest growing ETF segment in January of 2013 with $5 billion in net inflows. We see exciting opportunities in a number of emerging market locales including Latin America and China. Taking a top down approach, what happens in the U.S. affects emerging markets. Per the U.S. Department of Commerce, and despite the slight contraction in Q4 2012, the U.S. economy has been expanding since Q3 2009. This drives export demand and presents growth opportunities for emerging markets. As China continues to import materials to fuel its export machine, emerging nations rich in natural resources, such as Chile and Peru, tend to benefit.
Chile and Peru fall into a somewhat grey area with many index providers. Both have developed just enough to be included as emerging nations with some providers, thus giving them a very small percentage allocation within the index. As an alternative, the benchmark index for the Guggenheim Frontier ETF (FRN), is maintained by BNY Mellon, and includes Chile and Peru. As such, both receive larger allocations within that index. FRN is a simple way to get exposure to this region without having to assume significant single country risk.
The Guggenheim China Real Estate ETF (TAO) gained 58.73% and was a top performing ETF in 2012. How important is China to the global economy?
China has been, and continues to be, incredibly important to the global economy. It is the largest exporting nation in the world, the most populous, and the largest foreign holder of U.S. government debt. For the U.S. and European nations, the historical difficulties that manufacturers have had in entering China have put them at a competitive disadvantage. For China, a downgrade in the U.S. credit rating could devalue their Treasury holdings.
As you mentioned, TAO has been performing well and is currently the only China real estate ETF in the market. Over its five year history, it has outperformed during periods of strong markets in China and conversely underperformed during more challenging periods. For broader exposure to the Chinese equity markets, we offer investors the Guggenheim China Small Cap ETF (HAO) and the Guggenheim China All-Cap ETF (YAO).
In addition to equity based ETFs, several products have launched in the past year providing access to the Dim Sum bond market including the Guggenheim China Yuan Bond ETF (RMB). The Dim Sum bond market is comprised of renminbi denominated bonds issued in Hong Kong. The availability of these products signals the continued liberalization efforts by China to open portions of its markets to outside investment.
The BulletShares ETFs take a unique approach to bond fund investing. What’s their strategy?
Fixed income ETFs have become an important access point to bonds for many investors. And similar to their equity counterparts, fixed income ETFs offer a low-cost, fully transparent alternative to bond mutual funds as well as individual bonds. Until recently, strategies such as setting up a bond ladder, or targeting a specific point on the yield curve, have been difficult to replicate through ETFs.
Guggenheim created BulletShares ETFs as a way to offer investors solutions to these problems. BulletShares ETFs are structured to track an index comprised of bonds, as well as to mature in a targeted year. Unlike traditional ETFs, which have a perpetual life, defined-maturity ETFs have a specified maturity date established when the ETF is launched. When the fund reaches that maturity date, the fund’s final net asset value (NAV) is returned to the current shareholders. This pre-defined maturity date allows investors to create portfolios that can do the following:
- Ladder a portfolio
- Fill maturity gaps in an existing portfolio
- Obtain targeted yield-curve exposure/manage interest rate exposure
- Manage future cash flow needs
These benefits are in addition to the low-cost, fully transparent, tax efficient, and tradable structure provided by ETFs in general. The Guggenheim BulletShares suite is comprised of eight investment grade corporate bond ETFs and six high yield ETFs with maturities spanning 2013 to 2020.
As of this interview, three BulletShares products (BSCB, BSCC, BCJC) have reached successful maturity, demonstrating that defined maturity ETFs can be a powerful and effective way to manage to specific investment goals. As proof of their usefulness to investors, the BulletShares lineup has enjoyed explosive growth of over 127% for the twelve months ended 02/15/2013, with now over $2 billion in assets. | https://www.thinkadvisor.com/2013/04/01/enthused-about-innovation/ |
Paramount Digital Entertainment has announced that a new Star Trek game will be coming to PC, Xbox 360 and PlayStation 3 sometime in Summer 2012, and will take place after the events of the JJ Abrams film, and developed by Digital Extremes.
The only information regarding the plot is that Kirk and Spock must work together to stop a legendary enemy race bent on conquering the galaxy. The story is an original story by Marianne Krawczyk, a BAFTA award winner and the author of the God of War games, in collaboration with the writer/producers of the new Star Trek films, Bob Orci and Alex Kurtzman.
Tom Lesinski, President of Paramount Digital Entertainment stated:
“Star Trek challenges the boundaries of co-op gameplay with a galactic adventure that gamers and fans have never experienced. Working closely with the Star Trek filmmaking team throughout development, the game is sure to deliver AAA production values, a wide variety of gameplay and all the action you would expect from the hit franchise. This will be the definitive Star Trek gaming experience.”
The game will be shown off at E3 2011.
Jonah Falcon is a blogger for TMRzoo and GameStooge.com and covers all gaming consoles and platforms including Sony Playstation 3, Microsoft XBOX 360, Nintendo Wii, Sony PSP and computer games designed for Mac OS, Microsoft Windows and Linux operating systems. Jonah provides his readers with reviews, previews, release dates and up to date gaming industry news, trailers and rumors.
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Kessler, Ian, Undy, Roger and Heron, Paul (2004) Employee perspectives on communication and consultation: Findings from a cross-national survey. The International Journal of Human Resource Management, 15 (3). pp. 512-532.
Abstract
Highlighting the ongoing significance of national models of employment relations, this paper examines whether variation in communication and consultation practices between countries is reflected in employee perceptions. Drawing upon a survey of around 3,500 employees in four European countries – France, Germany, Italy and the UK – the paper explores whether workers' views on various aspects of communication and consultation are similar or different. It finds that there are certain similarities, with particular types of information and forms of communication being valued across the countries. However, differences are also identified. It is suggested that national institutions may well shape employee expectations about the nature of communication and consultation, feeding through to how satisfied they are with these processes. | http://eureka.sbs.ox.ac.uk/1884/ |
Nathaniel Hepler joined the Baltimore Symphony Orchestra as Second Trumpet in 2013. Growing up in Malvern, a suburb of Philadelphia, Nate began playing trumpet in his school band program at age 9 and began private instruction with Kenneth Laudermilch at age 11. He attended Philadelphia’s prestigious Curtis Institute of Music, earning a Bachelor of Music while studying with Frank Kaderabek and David Bilger. He then attended the Manhattan School of Music, studying with Mark Gould and earning a Master of Music degree.
Before joining the Baltimore Symphony, Nate enjoyed an active schedule as a freelancer and teacher primarily based out of Philadelphia, while serving as Principal Trumpet of the Sarasota Opera and Second Trumpet of Symphony in C (formerly the Haddonfield Symphony). He has performed with many orchestras, including the Utah Symphony, the Grand Park Orchestra, the IRIS Orchestra, the New World Symphony, United States Military Academy Band at West Point, and numerous Pennsylvania based groups such as the Opera Company of Philadelphia, the Chamber Orchestra of Philadelphia, Pennsylvania Ballet, and the Harrisburg Symphony. He has attended numerous music festivals including three years with the Spoleto Festival USA, the Festival Dei Due Mondi (Spoleto Festival Italy), the Music Academy of the West, the National Repertory Orchestra, the Aspen Music Festival, invited as Co-Principal Trumpet of the Santo Domingo Music Festival, three years as Principal Trumpet of the Artosphere Music Festival, and five summers with the Verbier Festival in Switzerland, including three with the Festival Chamber Orchestra. As a soloist, Nate has performed Tartini’s Concerto in D, Copland’s Quiet City, Fasch’s Concerto in D, and Bach’s Brandenburg Concerto No. 2.
Nate is currently adjunct faculty at Temple University and continues to enjoy an active schedule of teaching, performing chamber music, and arranging music for his own company, Valley Music Press. | https://www.bsomusic.org/musicians/musician/nathaniel-hepler/ |
Why is the Moon orange tonight 2022?
The orange color of a moon near the horizon is a true physical effect. It stems from the fact that when you look toward the horizon you’re looking through a greater thickness of Earth’s atmosphere than when you gaze up and overhead.
Is the Moon turning red 2022?
The total lunar eclipse of 2022 will take place on the night of May 15 to early morning of May 16. It will be the first total lunar eclipse since May of 2021, according to NASA. The red moon or blood moon will be visible for about 1 and a half hours, one of the longest totalities of the decade.
Why is the Moon red in Australia?
The moon reflects light. During an eclipse the only light hitting the moon is sunlight filtered through the earth’s atmosphere. A colour shift known as Rayleigh scattering occurs and in turn, the moon looks red.
What is tonight’s full moon called 2022?
The September full moon in 2022 is also the Harvest Moon, so named as it coincides with the annual crop harvest in the Northern Hemisphere. is also known as the Full Sturgeon Moon. The full moon shows its face to Earth about once a month. Well, sort of.
Why is the Moon so big tonight and red?
Why Does the Moon Appear Orange When Low in the Sky? When the Moon appears extra-large near the horizon, you may also notice that it seems to be more orange or red in color. This is where Earth’s atmosphere comes into play. When the Moon is low in the sky, it is farther away from you than when it is directly overhead.
How often is there a blood moon?
The cause of the red coloring is just the way in which light scatters and how we see it as humans. Blood Moons happen about twice a year. While this may be exciting to most, you may not be able to see the Blood Moon.
What do red moons mean?
Blood moons bring chaos, disruption, and change in astrology. Because they require a full moon and total lunar eclipse to occur, blood moons amplify the already strong powers of the lunar cycle. The full moon symbolizes sudden illumination, hidden information rising to the surface, and shifts in your inner life.
Why did the moon look red?
As for why the moon looks red, it has to do with the way that light scatters. A phenomenon called Rayleigh scattering causes some wavelengths of light to scatter more than others. Specifically, wavelengths of light scatter the most off teensy particles that are about one-tenth the wavelength of the light or smaller.
Is there really a red moon?
As with most lunar eclipses, the moon appeared red during the April 15, 2014, eclipse. The red color is caused by Rayleigh scattering of sunlight through the Earth’s atmosphere, the same effect that causes sunsets to appear red.
Is there a Blood Moon tonight 2022?
May 1516, 2022 Total Lunar Eclipse (blood moon).
Can you see the Blood Moon in Australia 2022?
The next one will take place on Nov. 8, 2022 (opens in new tab). It will be visible at least partially from Asia, Australia, North America, parts of northern and eastern Europe, the Arctic and most of South America, according to TimeandDate.com.
What time is the Blood Moon in Australia 2022?
|Global Event:||Total Lunar Eclipse|
|Begins:||Tue, Nov 8, 2022 at 7:19 pm|
|Maximum:||Tue, Nov 8, 2022 at 9:59 pm 1.359 Magnitude|
|Ends:||Wed, Nov 9, 2022 at 12:56 am|
|Duration:||5 hours, 37 minutes|
What should you do on a full moon?
- Cleanse your mental and physical space. The full moon tends to mark a big build-up of energyboth light and dark. …
- Charge your crystals. …
- Learn to meditate. …
- Dance to release energy. …
- Let go of emotional baggage. …
- Check your to-do list. …
- Chill out for a bit.
What is the pink moon?
What Is A Full Pink Moon? So, what exactly is a Full Pink Moon? Well, the astronomical offering is named after a pink wildflower, also known as Creeping Phlox or Moss Phlox, hence the nickname ‘pink moon’. The plant itself blooms in early spring all over the United States and symbolises rebirth and renewal.
What is a Strawberry Moon 2022?
Looking to the east at dusk on Tuesday, June 14, 2022 was what you should have been doing to get eyes-on with the Strawberry Moonthe final full Moon of spring and also the year’s biggest, brightest and best supermoon.
Why is the moon orange right now?
In certain areas, the atmosphere can be filled with air pollution, dust, and even smoke from wildfires. These particles scatter light in the same way described above, leading to an orange or red Moon high in the sky.
Is there a blood moon tonight 2022?
May 1516, 2022 Total Lunar Eclipse (blood moon).
What does it mean when the moon is orange?
An orange moon means the shorter wavelengths of light are being filtered away. This could be due to the low position on the horizon causing the light to go through more atmosphere, smoke in the air, or pollution.
Why does the moon turn orange?
When the moon is near the horizon, its light has to travel through more atmosphere to reach our eyes, compared to when it is directly above us. This causes blue light to scatter so much that more of the reds and yellows reach us. This is why the moon sometimes has an orange color. | https://hello-newman.com/2022/09/10/why-is-the-moon-red-tonight-2022-australia/ |
Why Consider the Lighthouse a Public Good?
International Review of Law and Economics, vol. 60, 2019, pp.
43 Pages Posted: 7 Jan 2019 Last revised: 23 Oct 2019
Date Written: January 5, 2019
Abstract
Was the lighthouse ever a public good? The lighthouse is presented as the quintessential public good as it was inherently non-excludable and non-rivalrous. Since the work of Ronald Coase (1974) on the lighthouse, economists have used debated the extent to which the private provision of public goods is possible. In this work, we highlight recent findings in the history of lighting services (especially private provision of said services) in order to argue that it may be incorrect to consider the lighthouse as a public good. First, we argue that lighthouses are probably better seen as a complement to other maritime services (e.g. pilotage, docking, ballastage). The lighthouse could have been bundled with these complements, which were excludable and rivalrous, in ways that would have permitted its provision. Second, we argue that organizations in charge of providing lighthouses were aware of this bundling possibility and lobbied hard to monopolize these other aspects of the trade in ways that limited entrepreneurial opportunities. | https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3310619 |
For Gianna Reisen, a classically trained ballet dancer who now performs with L.A. Dance Project, the process of finding music for her choreography is everything. "If I'm not 100 percent inspired by the music, the movement just doesn't come out," she says. Following this natural creative spirit, though, wasn't always the driving force behind her artistry.
While in her graduating year at the School of American Ballet in 2016, the ultimate goal for Reisen, like most of her peers, was to join the New York City Ballet as a dancer—not to be a choreographer. But when Peter Martins, the company's director at the time, noticed her work at a student workshop, he was so impressed that he commissioned her to set a piece for that year's fall gala, making the then 18-year-old the company's youngest choreographer to date.
Now, in her second season as a company member with LADP, led by Benjamin Millepied, Reisen is continuing her dual path as dancer and choreographer. Her work Rising Waters, with music by Andrew Bird, premiered last September.
As a choreographer, Reisen is drawn toward neoclassical composers. "They have a natural human quality to their work that makes me feel emotional and curious," she explains. "My music has to be dynamic in some kind of way—a fast section and a slow section—otherwise it feels monotone or repetitive," she says.
She typically sorts through piles of music files and saves those that spark an emotional response. Once the music's selected, she'll study the dynamics of the composition and the patterns until she can sing every note. "When I hear a piece I like," says Reisen, "I tend to see or feel the choreography."
Playing with movement alone in a studio with music she loves has been a valuable tool that's enriched her musicality. She encourages all ballet dancers and teachers to explore this as an exercise. "It allows dancers to feel freer in their dancing," she says, "and ultimately be more unique."
Andrew Bird - Echolocations: River (10/6/17) www.youtube.com
Artist: Andrew Bird
Album: Echolocations: River
"The way he composes cuts through deeper than hearing it with just your ears, his music hits a nerve, and I can't help but see dances when listening to his instrumental pieces."
Adams: Judah to Ocean www.youtube.com
Artist: John Adams
Song: "Judah to Ocean"
Album: John's Book of Alleged Dances
"I used this for the second piece I choreographed for New York City Ballet, Judah. Adams uses a unique structure and unconventional sounds to create beautiful end results."
Lukas Foss: Three American Pieces (1944) www.youtube.com
Artist: Lukas Foss
Song: "Three American Pieces: Composer's Holiday"
Album: Foss Plays Foss
"Foss is a dynamic American composer, originally from Germany. He uses modern phrases in classical sounding music."
Moondog ― Lament I, "Bird's lament" www.youtube.com
Artist: Moondog
Album: Moondog
"In addition to being a composer, Louis Thomas Hardin (aka Moondog) was a poet and an inventor, which is clearly heard in his music, like poetry for the ears."
Sky Quartet: I. Sky Rising www.youtube.com
Artist: Jennifer Higdon
Album: Sky Quartet
"I love Higdon's classicism, but she puts a twist on a lot of her music, which intrigues me. I love this album in particular." | https://www.dance-teacher.com/gianna-reisen-is-drawn-to-neoclassical-music-for-her-choreography-2641516767.html |
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The growing importance of China in the 21st century has increased public interest in the history of China and its complex political, economic and cultural entanglement with other regions in modern times. “Modern” here broadly refers to the period of growing encounters and interactions between China and the world, especially since the 19th century. This new series aims at offering fresh scholarly perspectives at both domestic and international developments during this period. It explicitly calls for proposals that trace processes of transformation, adaption or continuity within Chinese society, which often cross well-established political boundaries such as the 1911 or 1949 divides. Emphasis will be placed on works that explore novel questions and theoretical approaches or that utilize previously neglected sources.
If you are interested in submitting your manuscript to the editors, please write to: [email protected]
Jennifer Altehenger, Kings College London; Sebastian Veg, EHESS Paris; Dong Guoqiang, Univ. Nanjing; Eugenia Lean, Columbia Univ., Daniel Leese/Nicola Spakowski, Univ. Freiburg
What does it mean to be a conservative in Republican China? Challenging the widely held view that Chinese conservatism set out to preserve traditional culture and was mainly a cultural movement, this book proposes a new framework with which to analyze modern Chinese conservatism. It identifies late Qing culturalist nationalism, which incorporates traditional culture into concrete political reforms inspired by modern Western politics, as the origin of conservatism in the Republican era. During the May Fourth period, New Culture activists belittled any attempts to reintegrate traditional culture with modern politics as conservative. What conservatives in Republican China stood for was essentially this late Qing culturalist nationalism that rejected squarely the museumification of traditional culture. Adopting a typological approach in order to distinguish different types of conservatism by differentiating various political implications of traditional culture, this book divides the Chinese conservatism of the Republican era into four typologies: liberal conservatism, antimodern conservatism, philosophical conservatism, and authoritarian conservatism. As such, this book captures – for the first time – how Chinese conservatism was in constant evolution, while also showing how its emblematic figures reacted differently to historical circumstances.
The book is a systematic study of the China-Britain relationship during the 1942–1949 period with a particular focus on the two countries’ discussions over both the 1943 Sino-British treaty and the discarded Sino-British commercial treaty, the future of Hong Kong, and the political status of Tibet. These were dominated by two underlying themes: the elimination of the British imperialist position in China and the establishment of an equal and reciprocal bilateral relationship. The negotiations started promisingly in 1942–1943, but, by 1949, had failed to reach a satisfactory settlement. Behind the failure lay a complex set of domestic considerations and external factors, including the powerful infl uence of the United States. Even after seven decades, the failure still has a contemporary impact. Recent Sino-British disputes over the Hong Kong Anti-Extradition Law Amendment Bill Movement and incessant Indo-Chinese confl icts and skirmishes over their unsettled borders all attest to the enduring legacy of the years 1942–1949 as setting the scene for subsequent Sino-British and Sino-Indian relations. From this perspective, the history has never left us.
The year 1919 changed Chinese culture radically, but in a way that completely took contemporaries by surprise. At the beginning of the year, even well-informed intellectuals did not anticipate that, for instance, baihua (aprecursor of the modern Chinese language), communism, Hu Shi and Chen Duxiu would become important and famous – all of which was very obvious to them at the end of the year.
Elisabeth Forster traces the precise mechanisms behind this transformation on the basis of a rich variety of sources, including newspapers, personal letters, student essays, advertisements, textbooks and diaries. She proposes a new model for cultural change, which puts intellectual marketing at its core. This book retells the story of the New Culture Movement in light of the diversifi ed and decentered picture of Republican China developed in recent scholarship. It is a lively and ironic narrative about cultural change through academic infi ghting, rumors and conspiracy theories, newspaper stories and intellectuals (hell-)bent on selling agendas through powerful buzzwords. | https://www.degruyter.com/serial/tmc-b/html |
At Bristol Myers Squibb, we are inspired by a single vision – transforming patients’ lives through science. In oncology, hematology, immunology and cardiovascular disease – and one of the most diverse and promising pipelines in the industry – each of our passionate colleagues contribute to innovations that drive meaningful change. We bring a human touch to every treatment we pioneer. Join us and make a difference.
Cell Therapy is one of the most groundbreaking new forms of cancer treatments being studied today. With therapies only in their infancy and BMS’s continued investment in our Cell Therapy capabilities, the growth potential of this science, your career, and the ability to help patients are incredible.
The Associate Director or Director, CMC Team Leader will lead the development of the CMC strategy for one or more programs and drive the development and execution of the CMC strategy with focus on late-stage assets within Cell Therapy Development & Operation (CTDO) organization. The individual will lead a cross functional CMC team across vector, drug product, analytical, quality, regulatory, supply chain, manufacturing operations and clinical supplies. CMC Team Lead is accountable for developing and delivering the Integrated CMC development plan and will work with cross-functional stakeholders to drive alignment and achievement of CMC development and manufacturing milestones in accordance with program timelines. As a member of the global Product Development Team (DPT), this role will ensure full alignment of the CMC and manufacturing plans with the clinical development, business and regulatory strategies and work with the Global Operation team (GO-CT) for commercial launch plans. In addition, the individual may also serve as project management interface between our internal functions, external business partners, and CDMO/CRO/CMO’s project teams.
Responsibilities
Requirements for Associate Director:
Requirements for Director:
If you want to challenge yourself, accelerate your career, and give new hope to patients, there’s no better place than here with our Cell Therapy team. Full of incredible and dedicated team members, those working on CAR-T and other forms of Cell Therapy are transforming patients’ lives through science. From studying individualized cell lines to making brand new discoveries, this bold and personal discipline allows you to grow your career while making a lasting impact on the field of medicine. Join us today.
BMSCART
Around the world, we are passionate about making an impact on the lives of patients with serious diseases. Empowered to apply our individual talents and diverse perspectives in an inclusive culture, our shared values of passion, innovation, urgency, accountability, inclusion and integrity bring out the highest potential of each of our colleagues.
Bristol Myers Squibb recognizes the importance of balance and flexibility in our work environment. We offer a wide variety of competitive benefits, services and programs that provide our employees with the resources to pursue their goals, both at work and in their personal lives.
Physical presence at the BMS worksite or physical presence in the field is an essential job function of this role which the Company deems critical to collaboration, innovation, productivity, employee well-being and engagement, and enhances the Company culture.
To protect the safety of our workforce, customers, patients and communities, the policy of the Company requires all employees and workers in the U.S. and Puerto Rico to be fully vaccinated against COVID-19, unless they have received an exception based on an approved request for a medical or religious reasonable accommodation. Therefore, all BMS applicants seeking a role located in the U.S. and Puerto Rico must confirm that they have already received or are willing to receive the full COVID-19 vaccination by their start date as a qualification of the role and condition of employment. This requirement is subject to state and local law restrictions and may not be applicable to employees working in certain jurisdictions such as Montana. This requirement is also subject to discussions with collective bargaining representatives in the U.S.
Our company is committed to ensuring that people with disabilities can excel through a transparent recruitment process, reasonable workplace adjustments and ongoing support in their roles. Applicants can request an approval of accommodation prior to accepting a job offer. If you require reasonable accommodation in completing this application or if you are applying to a role based in the U.S. or Puerto Rico and you believe that you are unable to receive a COVID-19 vaccine due to a medical condition or sincerely held religious belief, during or any part of the recruitment process, please direct your inquiries to [email protected]. Visit careers.bms.com/eeo-accessibility to access our complete Equal Employment Opportunity statement.
Any data processed in connection with role applications will be treated in accordance with applicable data privacy policies and regulations. | https://jobs.factoryfix.com/jobs/associate-director-or-director-late-stage-cmc-lead-cell-therapy--warren--nj--677169488--V2 |
The State Of The IBM i Installed Base, Part 2
In the first half of our analysis of the IBM i installed base, we looked at the number of machines and the number of logical partitions that respondents of the IBM i Marketplace Survey for the 2020 report gave last fall when they took the poll. We did some math and analysis on this to show that there is a large block of customers with lots of machines and lots of partitions that are just as important to Big Blue as those with big, fat NUMA servers.
In the second half of this series about the state of the IBM i base, we are going to get down to brass tacks and look at the vintage of the iron and operating systems in use at IBM midrange shops at least as far as the survey done in late 2019 is concerned. Thanks in part to the encouragement of the late Dan Burger, our executive managing editor for nearly two decades here at IT Jungle, and our assistance in encouraging people to take the survey, IBM i systems software provider HelpSystems has been doing a survey of the IBM i market for the past six years.
The sixth annual IBM i Marketplace Survey report was released by HelpSystems in mid-January, and it was based on a survey that had more than 500 respondents, which is a pretty good number. I participated in the webcast going over the survey results along with people from HelpSystems and IBM, as I have done for the past several years. Tom Huntington, the executive vice president of technical solutions at HelpSystems, hosted the webinar last Thursday, and we were joined by Alison Butterill, IBM i product offering manager, Ian Jarman, who had that job before and is now an executive in the IBM Lab Services division, and Brandon Pederson, who is worldwide IBM i product marketing manager. You can get a copy of the survey report and also listen to a replay of the webcast at this link. We have been interpreting the report results in a series of stories, and we already covered the plans that people have to upgrade their Power Systems hardware and IBM i software in 2020 and of course the system and partition analysis from last week. This week we want to see how the Power9 ramp and IBM i 7.3 and 7.4 ramps look compared to prior generations of hardware and software technology.
Let’s start with the hardware distribution by processor generation from the survey:
In the webinar going over the results, I said that I would have expected that the Power9 ramp would be a little bit stronger given the historical trends for the Power8 iron. That was a misstatement, and I will explain why.
The entry Power9 machines that could run IBM i were launched in February 2018 and the high-end boxes supporting IBM i got Power9 motors in August 2018, so you would have expected that at the end of 2018 when the survey was done for the 2019 report, customers would have some Power9 iron. And indeed, 14 percent of those polled said they had Power9 iron, and at the end of last year for the 2020 report, that share rose to 31 percent of the base. The entry Power8 machines made their debut in April 2014, and the high-end boxes based on Power8 rolled out in October 2014, so we would have expected for the Power8 to make its debut in the IBM i Marketplace 2015 report. And it did. But only 8 percent of customers said they had Power8 iron in the 2015 report, and that only rose to 22 percent in 2016. Now, to be fair, the Power9 machines were in the field three months longer, so that helped the ramp some, but based on this data, the initial Power9 ramp in year one was 1.75X steeper than the initial Power8 ramp, and in year two, the ramp was 1.4X percent steeper.
The Power8 ramp took longer than and built up to the point where close to 60 percent of customers report having at least one Power8 machine, and for the past two surveys (which are really about 2017 and 2018 data), it has been holding steady. This mirrors the long life that the Power7, launched in April 2010, and the Power7+, launched in July 2012, had in the field and as you can see, it is only now that the combined Power7 and Power7+ base is starting to wane, with only 38 percent of customers reporting having these older systems installed.
By the way, no one is trying to suggest that customers have only one machine or only one hardware level installed. The data shows that customers have a mix of iron, and if you add up the percentages, it is a very tight range that is consistent across the six years of the survey at right around an aggregate of 140 percent. The diversity is very consistent as iron comes and goes in the datacenters over the course of five or six years.
The other thing to note here is that machines using Power5, Power5+, Power6, and Power6+ processors, which date from 2004 through 2009, are still represented in the installed base as 2020 was rolling around. Collectively, these machines still were in use at 15 percent of customers.
The one thing we do not know from this data, of course, is the distribution of machines by Power chip make. Survey respondents are only telling you what they have, not how much they have. So, for instance, the response is the same for a shop that has one Power5 machine as one that has 50 machines; both count as one customer with a Power5 machine. We can’t just take the distribution of processors across the more than 500 people who took the survey for the 2020 report, representing their companies, and apply it to the 2,285 machines we think were represented in the survey based on the machine count per customer that we calculated in last week’s story. There is no way to calculate a finer level of granularity out of this data, and there is no way of getting it except by asking each customer to tell about their precise machines and their configurations across the entire company.
Still, this is a good indicator that Power9 had a good year, and it also suggests that, despite the overall downturn we are seeing with the Power Systems business, the IBM i portion is only halfway through its upgrade cycle. So maybe there is reason for optimism on this front even if it looks like some of the “upgrades” coming in 2020 will not be new systems and a switch to Power9 chips, but a move up to Power8 iron or an activation of latent capacity on an existing Power7, Power7+, or Power8 machine or a swap of processing cards perhaps. As we pointed out three weeks ago, our interpretation of the upgrade plans of IBM i shops for the survey done by HelpSystems for the 2020 report depends in large part on what the term “upgrade” means to the customers answering the question. Given all of the data we see, we would not be surprised if the IBM i portion of the Power Systems business does as well in 2020 as it did in 2019, although it probably won’t do as well as it did in 2018. But it is hard to say for sure, given how little data IBM gives out about this business.
What we can say for sure is that IBM has made it a lot easier to get current on iron and stay current thanks to Technology Refreshes without having to move to each release. And from what IBM told us a little more than a year ago, it looks like plenty of customers are skipping every other release and just using Technology Refreshes to get the new features and hardware support as it becomes available.
Now, let’s talk about operating systems. Here is the chart from the 2020 IBM i Marketplace Survey report:
We have to be careful about this operating distribution, too, based on the wording of the question. It asks about the primary operating system level in use at the customer, not for all operating system releases in use at the customer. These are very different questions, and we suspect that some people answered them one way and some the other way. In fact, after looking at all of the past survey reports put out by HelpSystems, I didn’t hear the question clearly myself until just now, and I was reading it as the latter rather than the former. (Sometimes, it is amazing that human beings are communicating at all, and I wonder that we really are with the precision that we think we are.)
What we can see here is that i5/OS 5.4 and older releases have dropped out of the picture, no matter which way you want to answer it, with the 2020 report, and the aggregate of 6.1 or older releases is on the decline. Mysteriously, use of these older releases rose from 2015 to 2016 by a factor of 1.6X and declined in 2017 and held steady for the follow two reports in 2018 and 2019 before falling by nearly half in 2020.
You can see the effect of the skip releasing by some customers in the data. IBM i 7.1 rises and holds to a nice smooth bell curve, IBM i 7.2 is kinda choppy in its adoption and also more muted albeit still very substantial, and IBM i 7.3 is on a smooth curve ramping up nicely. IBM i 7.4 is just getting started, and unless and until IBM makes Db2 Mirror clustering priced for low-end machines, it may have a distribution as the primary operating system similar to IBM i 7.2 over the next few years. We shall see.
What we would really like to see is the distribution of operating systems across machines and logical partitions. As far as we know, PowerVM will not let a machine run more than three different IBM i release levels at any particular release level of its own. But even still, the mix of operating systems could be a lot richer than this chart above implies. And, as I am apt to point out, given that I believe that the people who respond to surveys are also the ones who are most active in the customer base and therefore more likely to be current on hardware and software (as well as read The Four Hundred), this whole dataset could not be representative of anything but what it says: the primary operating system level in use at IBM i shops, not the total distribution of operating system levels in use. They could be very much the same, or not. We can’t know from the way this question was asked. The percents always add up to 100 percent in every year and that is a giveaway that people answered the question the way it was asked, not in the way that would be even more useful.
And it is on me as much as anyone else for not noticing that before now.
We do expect for the overall operating system distribution to be wider than the data for the primary operating system, given that there is a new release every 18 months to 24 months and new Power processors and hardware every 36 months to 42 months and that you can run new releases on older hardware for many, many years. The Technology Refreshes allow the skipping of releases, too, which mitigates against such operating system diversity, so it is hard to figure what forces are working harder on the base here.
All in all, what Big Blue is doing with IBM i is working pretty well, and it sure beats having a slew of shops stuck at V5R3, V5R4, or 6.1. | |
The aims of this article are to assess injury characteristics and risk factors in the Iowa Certified Safe Farm (CSF) program and to evaluate the effectiveness of CSF for reducing injuries. This intervention program includes a health screening, on-farm safety review, education, and monetary incentives. Cohorts of farmers in an intervention group (N = 152) and control group (N = 164) in northwestern Iowa were followed for a three-year period. During the follow-up, there were 318 injuries (42/100 person-years), of which 112 (15/100 person-years) required professional medical care. The monetary cost of injuries was $51,764 ($68 per farm per year). There were no differences in the self-reported injury rates and costs between the intervention and control groups. Raising livestock, poor general health, and exposures to dust and gas, noise, chemicals and pesticides, and lifting were among risk factors for injury. Most injuries in this study were related to animals, falls from elevation, slips/trips/falls, being struck by or struck against objects, lifting, and overexertion. Machinery was less prominent than generally reported in the literature. Hurry, fatigue, or stress were mentioned as the primary contributing factor in most injuries. These findings illustrate the need for new interventions to address a multitude of hazards in the farm work environment as well as management and organization of farm work. | http://nasdonline.org/2255/d002117/injuries-in-the-iowa-certified-safe-farm-study.html |
It is a fact that people across geographical and cultural boundaries believe in some sort of God. All civilizations have had a belief in the supernatural. The ontological argument is digging behind that belief to the question of why? Why is this belief seen in our world?
Let’s do an experiment. Let’s think of an original thought. Something that no one has ever thought before. Be imaginative. Let your mind work and think of a picture or event or scene. Try hard.
I’m not sure what you thought about, but this I know, it is nothing original. At best it is a combination of events, colors, shapes, and scenes in our world. For instance maybe you got outrageous and thought of a blue giraffe with the teeth of a crocodile. Or a robot shaped like a trashcan talking to you. As cool and imaginative as they might be they are not original. Instead they are simply a conglomerate of stuff that we all see. It might be an imaginative image, but it is still putting together what you have already interacted with. Even the complex machines that we use today are putting together technologies that we are discovering.
Now lets use this fact to think about the existence of God. All people groups believe in a creator. If we all can “imagine” a creator, and we cannot imagine an original (made up from scratch and not just rearranging things in our world) idea, then the creator must truly exist. Since true perfection does not exist in our world, yet we can think of a God who is truly perfect, then this God must really be true. And not only must he exist but the creator must have revealed himself to all people at some point.
I know this is a difficult argument to grasp. And it might not be one you are convinced of. Just remember this is not the only argument for God’s existence. Also ask questions on this topic and make comments as I know this is difficult to grasp and I’m sure others have questions as well. | http://www.studyyourbibleonline.com/apologetics/unpacking-the-ontological-argument/ |
Demonstrating and delivering value is crucial at a time when government decisions are under scrutiny and economic and environmental challenges continue to mount. But when it comes to making better decisions, value can be hard to tie down.
In this edition we unpack the practical tools and techniques we use to help our clients identify and deliver valued outcomes for society.
We also invite you to join Associate Director Martijn and Senior Consultant Sarah Leck as they share their insights in a webinar on economic analysis for coastal adaptation on Wednesday 31 March.
Accounting for value leads to better decisions
Understanding value reveals the costs and benefits of different actions – or inaction – and how these are distributed across users, uses, time and space. It supports better decision making, from the household level to decisions that affect industries, communities and environments. And it helps bring about positive change.
Taking the value into account requires work, including engagement and analysis, that can add time and costs to decision making. But if we don’t identify and assess the value of desired outcomes we risk wasting everyone’s time. In our experience, a lot of effort is spent working towards outputs not outcomes, or on outcomes that are unrealistic or without a clear value proposition.
If we don’t know the real value of different outcomes to individuals, industries, communities and governments, it’s impossible to weigh up priorities and trade-offs. It’s hard to secure buy-in or satisfy people when the outcomes being sought do not reflect the values of those affected. It also becomes impossible to know whether government interventions are working.
Including value in government decision making is therefore integral to improving how we deal with complex and contested topics, including water and environmental management.
Some practical ways we can embed value in decision making
Value is never fixed or easily measured. The real world is complex and imperfect, the future is uncertain, and data is often limited.
But we can bring outcomes and value-based decision making to the fore. In line with our purpose of helping our clients make better decisions, recent projects we’ve led show how value can be incorporated.
Some of our recent projects look beyond financial value to include environmental, social, and cultural values. Consistent with the theme of World Water Day 2021, our insight piece discusses How valuing water can help improve decisions.
In Enhancing value through outcomes-based monitoring and evaluation, Clare Ferguson describes how insights from effective monitoring and evaluation can improve planning, delivery, and adaptive management, and enhance overall value.
In The value of communicating economics in coastal adaptation decision-making, Martijn Gough and Sarah Leck explain how combining robust economic analysis with clear communication of value, risk and uncertainty builds stakeholder confidence in value-based solutions.
Martijn and Sarah will share some of their insights from multiple adaptation assessments in a webinar on Wednesday 31 March. Please register and join us if you can.
These are some of our recent experiences with using value to improve decision making and outcomes. They underscore our experience with approaches to help make better decisions, and we continue to work to this end.
Please continue to share your own ideas and work, or reach out to us for a discussion. | https://aither.com.au/aither-quarterly-letter-q3-fy2020-21-2 |
Due to the pandemic, more patients with complex needs are being discharged directly home, which can cause challenges for healthcare facilities and patients. Home care and home access are part of the solution to help those with limited mobility remain in their homes safely and on parallel path to help minimize readmission.
According to Kristine Lajeunesse, Owner of Always Best Care of Central CT, Inc., “We are seeing hospitals discharging fewer patients to skilled nursing facilities and more patients directly to the home. This results in patients with more complex needs going home. Home Care services are needed for more hours because the person needs more assistance.”
An accessibility assessment of the home environment followed by modifications such as grab bars, ramps, stair lifts, and tub cut-outs, can make the discharge-to-home process safer, reduce the risk of readmission, and make economic sense as well.
Patients Want to Go Home
According to AARP, 3 out of 4 adults age 50 and older want to stay in their homes and communities as they age. Many patients are resisting skilled nursing facilities upon hospital discharge and opting for in-home care, both for fear of COVID-19 and the impact that increased safety precautions will have on their social and emotional well-being. While it is too soon to predict the permanent impact of COVID on the trend for patient direct discharge home, currently this is the more prevalent choice.
When asked about hospital discharge patterns, Adriana Leon, Care Continuum Liaison at Manchester Memorial Hospital in Connecticut, states: “Our objective is to keep the patient safe. We advise the patient that if there is not enough support at home they will need to go to short-term rehab. We are finding that patients do not want to go to short-term rehab, they want to go home.”
Hospitals Working with Accessibility Providers
For those patients discharged directly home from the hospital setting, one concern is the increased risk of a falling, and as a result, increased risk of readmission. According to the Centers for Disease Control and Prevention, one out of every four older adults (age 65+) fall each year in the United States. Older adults are at a high risk of a fall after hospital discharge, and many homes do not match the physical needs of individuals with limited mobility. But many falls are preventable.
While hospital leadership continues to be focused on patient safety, the additional challenge of COVID has led to a modified approach to discharge. According to Dan Woloszyn, CEO of the Rehabilitation Hospital of Indiana, “the goal is always for the patient to go home. However, during the past year, the discharge plan was modified in ways to prevent community exposure and decrease emotional complications. This included shying away, as appropriate, from another transition to any long-term care facility. So, we needed to make the discharges to home meaningful and successful...Our Team at the Rehabilitation Hospital of Indiana used technology to virtually train proper techniques and provide education, while we would rely on our outside vendors to then supply equipment to make the transition home safe and successful.”
Home accessibility experts, with credentials such as CAPS and CEAC along with years of experience in the field, can make a valuable contribution to the process. Health care professionals are looking to Home Care and Home Access Solutions to help those at risk remain in their homes safely, and to reduce the risk of readmission.
Evaluations – Key to Preventing Falls at Home
“A home safety assessment with individualized safety modifications in conjunction with an exercise program can reduce the likelihood of a fall and keep people at home,” says Tracy VanOss, clinical professor of Occupational Therapy at Quinnipiac University in Hamden, CT.
Combining a clinical evaluation of the patient along with a home evaluation by a home access expert can provide valuable information on the available home modification options. Choosing to go this route can be a cost-effective way to make the discharge-to-home process safer.
“Access ramps, stairlifts, grab bars and tub cut-outs are just a few examples of modifications that can increase safety and decrease fall risk for the patient at home,” according to Lifeway Mobility Chairman Tim Burfield. “Research is indicating that the benefits of home accessibility modifications may well exceed the cost.”
One example is the CAPABLE trial. Looking at an interdisciplinary program using a team of nurses, occupational therapists and home modifications, the effect of roughly $3,000 in program costs yielded more than $30,000 in savings in medical costs, driven by reductions in both inpatient and outpatient expenditures. (Source)
Hospital discharge planners and clinicians working together with home modification experts and home care professionals can make a big difference in increased safety, and therefore decreased risk of readmission for patients. Learn more about modifications to assist with:
About the Author & Lifeway Mobility
Amy Finke, CAPS, CEAC
VP of Business Development Lifeway Mobility
E-mail: [email protected]
Lifeway Mobility is an accessibility solutions company serving individuals and businesses in Southern New England, Western Pennsylvania, the Midwest and California. Lifeway Mobility offers a full selection of accessibility and safety equipment to improve mobility and independence, including stairlifts, wheelchair lifts and ramps, home elevators, transfer lifts, and bath safety solutions. | https://www.lifewaymobility.com/minneapolis/accessibility-solutions-help-discharged-patients-remain-safe-at-home/ |
The unwarranted assumption in your article that "Selection 'leads to lower standards'" (TES May 25) was based on unsubstantiated claims by Professor David Jesson on work that he has not yet published.
Last year similar premature pronouncements were made by your newspaper and taken up by leading politicians, prior to the publication of Professor Jesson's work.
But Professor Sig Prais, of the National Institute of Economic and Social Research, has shown that Professor Jesson's data actually proves the opposite of what he had claimed - ie grammar schools do add more value to the top ability group than comprehensives.
Professor Jesson agreed with this and accepted that there was no statistical basis for his conclusions.
So to print more unsubstantiated and contentious statements on unpublished work is perverse in the extreme. Where is the balanced reporting your readers expect? | https://ngsa.org.uk/news-2001-03.php |
Why was geography important to the development of humans?
Why was geography important to the development of humans?
Human geography is a wide-ranging discipline that draws together many of the strands important for understanding the world today. It examines human societies and how they develop, their culture, economy and politics, all within the context of their environment.
How do geography affect human development?
These features include vegetation, climate, the local water cycle, and land formations. Geography doesn’t just determine whether humans can live in a certain area or not, it also determines people’s lifestyles, as they adapt to the available food and climate patterns.
How did geography and environment impact the development of civilization?
Geography and the environment play a monumental role in the establishment and success of a nearly every civilization. For example, rivers bring water and allow for agricultural development, while mountains or deserts provide for protection and create a barrier.
Why is location important in geography?
Location is an important term in geography, and is usually considered more precise than “place.” A locality is a human settlement: city, town, village, or even archaeological site. Relative location can help analyze how two places are connected, whether by distance, culture, or even technology.
What is place in the 5 themes of geography?
Place describes the human and physical characteristics of a location. Physical characteristics: Includes a description of such things as mountains, rivers, beaches, topography, climate, and animal and plant life of a place.
What does location mean in the 5 themes of geography?
The Five Themes are as follows: Location: Position on the Earth’s Surface (Absolute/Relative). Geographic study begins with the location of places on the earth. Places have absolute locations that pinpoint them on the earth, and relative locations that place each location in respect to other locations.
Why are the five themes of geography important?
The Five Themes of Geography started out as a framework for making geography accessible to kids from kindergarten to high school. They describe an easy, effective means for parents and educators to teach children about the concept of geography, and how it applies to nature, civilization, and more.
What are the basic elements of geography?
The six essential elements are The World in Spatial Terms, Places and Regions, Physical Systems, Human Systems, Environment and Society, and The Uses of Geography.
What are natural systems?
natural system. An open system whose elements, boundary, and relationships exist independently of human control. ( Created for SEBoK)
What is strongest muscle in human body?
The strongest muscle based on its weight is the masseter. With all muscles of the jaw working together it can close the teeth with a force as great as 55 pounds (25 kilograms) on the incisors or 200 pounds (90.7 kilograms) on the molars. The uterus sits in the lower pelvic region.
What is the weakest muscle in your body?
stapedius
What is the second strongest muscle in the human body?
So here are the top five strongest muscles in the body based on these different ways to measure strength:
- Heart. The heart, which consists of cardiac muscle, is said to be the hardest working muscle in the body.
- Masseter.
- Soleus.
- Gluteus Maximus.
- Uterus.
What is the hardest animal to kill?
tardigrades
Can a gorilla kill a lion?
However, a gorilla is a mighty foe with more stamina and fearsome strength. It’s the will to fight will last much longer than a male lion’s and if it gets its hands upon a solid branch, it can put a beating on its feline combatant. | https://color-newyork.com/why-was-geography-important-to-the-development-of-humans/ |
Anton Jörgen Andersen, born in Kristiansand on 10 October 1845 and died in Stockholm on 9 September 1926, was a cellist and composer who worked mainly in Stockholm. He studied composition with Johan Lindegren and cello performance with Andreas Gehrmann at the Royal Conservatory of Music from 1866 to 1868. He worked as a teacher at the conservatory from 1876 to 1911, advancing to rank of professor in 1912. He was a cellist in the Royal Court Orchestra between 1871 and 1905 and was a long-time member of the Aulin Quartet.
(Svenskt Porträttarkiv)
A successful career as a cellist
Anton Jörgen Andersen was born in Kristiansand in the southern-most part of Norway on 10 October 1845 and was the son of master gardener John Andersen and Karen Andrea Gundersen. His broad music education began with the organist and violinist Ferdinand Rojahn. He later continued in Sweden taking composition studies with Johan Lindegren and cello lessons with Andreas Gehrmann at the Musikkonservatoriet (the Royal Conservatory of Music). While still young, Andersen’s cello career advanced quickly with employment at Norwegian theatres in both Trondheim (1864) and Christiania (later renamed Oslo) in 1865, as well as being employed by the Hovkapellet (the Royal Court Orchestra) in Stockholm in 1871.
Andersen was appointed as a teacher of both cello and double bass at the Musikkonservatoriet in 1876, only a few years after he had fully completed his own studies, which is proof of the acknowledgement that Andersen had already received as a performing musician. In addition to these commitments, Andersen was a member of the popular Aulin Quartet for several years. The group was founded by Tor Aulin who was of great importance in the establishment of a classical quartet repertoire in Sweden. With all of these obligations, it was remarkable that Andersen also had time to compose a number of more extensive works.
Andersen was married in 1868 to Maria Augusta Vilhelmina Anstrin (1842−1910). They had two daughters, Astrid and Ingrid Maria, who both went on to work as pianists.
A large symphonic production
Andersen’s compositions were mostly ensemble and orchestral works (often in unusual or extensive formats), songs and works for his own instrument, the cello. No fewer than six symphonies are mentioned by contemporary sources and at least four of those were performed during his own lifetime: the Symphony in E-flat major was performed in 1888 by an orchestra composed of 100 musicians in the large hall of the Kungliga Musikaliska akademien (Royal Swedish Academy of Music), and led by Andersen himself; another symphonic work was performed in 1884, likely his Symphony in B minor. Stockholm audiences also heard two symphonies in D major in 1891 and in 1906, and the latter of the two works had additionally been published in 1903 in a version for two pianos.
A contemporary critic wrote in the journal Svensk Musiktidning that one could hear some of Bruckner, as well as ‘many beautiful ideas’ in Andersen’s symphonies, and as composer and author Lennart Hedwall noted in the publication Den svenska symfonin (the Swedish symphony) the symphonies seem to have been well accepted. That they have not found a place in the standing symphony repertoire is, according to Hedwall, ‘because they lack substantial content and are not stylistically convincing’. Hedwall is most favourable toward the first symphony in B minor in which he sees a ‘lively’ structure and ‘skilfully combined’ elaborative sections. He was also enthusiastic about the third symphony in D major, performed in 1891. He highlights the balance in ‘both the form and instrumentation’ and adds that in many ways, the work can ‘measure up to the B minor symphony and is also, from the musicianship’s perspective, more full of life than the maiden work'.
In addition to those symphonies, one can add Élégie Sinfonique for no fewer than nineteen cellos and four double basses, which garnered a great deal of interest at the Swedish music festival in Stuttgart in 1913.
A renowned composer with a penchant for darker tone qualities
The work that brought Andersen the greatest amount of recognition among Swedish composers was his Concert piece for five violins and three double basses which was performed at Första svenska musikfesten (the first Swedish music festival) in 1906 and was generally spoken of in positive terms. Andersen’s participation in this nationalistic event shows his total integration into the circle of Sweden composers, which is rather remarkable given the fact that the political separation of his homeland, Norway, from Sweden had only recently come about. The concerto piece is just one among several ensemble works that displays Andersen’s love for combining several cellos and double basses (aside from the larger elegy). At least five more works develop this special instrumental combination; of these, the most often mentioned is the Adagio, which besides three cellos and one double bass also includes two horns. Andersen taught double bass at the Musikkonservatoriet and so his interest in the instrument was natural, but it also appears that he was generally attracted to the deeper tonal textures. The tonal focus in Andersen’s instrumental opus lies quite clearly with instruments that have a darker tonal register, and he also arranged a large number of songs for male quartet.
Andersen’s ensemble chamber music works in a smaller form are dominated by pieces written for cello and piano, as well as songs. The most extensive work written for his own instrument is a cello sonata, published by the Musikaliska konstföreningen (the Swedish Art Music Society) in 1876. It is a lyrical piece, inspired by Brahms’s chamber music with folkloric themes, and contains references to Bach, as well as an intensively melancholic second movement.
Among his vocal works, besides the aforementioned arrangements for male quartet, are songs for mixed choir as well as a number of pieces for solo voice. These sometimes include lute or guitar accompaniment in place of the more usual piano accompaniment. Several of the songs for solo voice have texts in Norwegian, and it was the well known author Bjørnstjerne Bjørnson’s opus, Digte og Sange, that most often inspired Andersen. ‘Over de höje fjælde’, ‘Venevil’ and ‘Dulgt kærlighed’ are examples of songs based on Bjørnson’s texts.
Andersen ended his career in the Hovkapellet in 1905, retired in 1911 from the Musikkonservatoriet and earned the title of professor in 1912. Already in 1882 he received his membership in the Musikaliska akademien.
Gabrielle Kaufman © 2015
Trans. Jill Ann Johnson
Bibliography
Andersen, Rune J: Anton Jörgen Andersen, in Store norske leksikon.
Anton Andersen, in Svensk musiktidning, no. 1, 1907, p. 1.
Den första svenska musikfestens program, in Svensk Musiktidning, no. 11, 1906, p. 83.
Lärareombyte vid Musikkonservatoriet, in Svensk Musiktidning, no. 2, 1912, p. 10.
Teater och Musik, in Idun, no. 9, 1888, p. 61.
Castegren, Nils: Franz Berwalds kompositionselever vid Musikkonservatoriet 1867−1868, in Svensk tidskrift för musikforskning, 1974, pp. 19−30.
Hedwall, Lennart: Den svenska symfonin, Stockholm: AWE/Geber, 1983, pp. 179−183.
Norlind, Tobias: Svensk musikhistoria, Stockholm: Wahlström och Widstrand, 1918, pp. 311−312.
Tegen, Martin: Instrumentalmusiken, Orkesterverken, in Leif Jonsson (ed.), Musiken i Sverige, Stockholm: Fischer, 1992, pp. 435−436.
Vretblad, Patrik: Anton Andersen, in Svenskt biografiskt lexikon, vol. 1, 1918, pp. 664.
Sources
Musik- och teaterbiblioteket, Uppsala universitetsbibliotek
Summary list of works
6 symphonies, works for ensemble (Élégie Sinfonique, Konsertstycke, 4 adagios, and more), chamber music (cello sonata, small pieces for cello and piano etc.), songs and other vocal music.
Collected works
Orchestral works
Adagio and Scherzo for orchestra.
Symphony in B minor, ca 1884.
Symphony in E-flat major, 1888.
Symphony in D major for large orchestra, 1891. [Version for two pianos, published by Musikaliska konstföreningen 1903.]
Symphony in G major.
Symphony »Hardanger» for large orchestra and mixed choir.
Chamber music
Adagio cantabile for 3 violoncellos.
Adagio for 3 violoncellos, 2 horns and double bass.
Adagio for 4 violoncellod and 2 double basses.
Adagio [A major] for 4 violoncellos and 4 double basses.
Allegro moderato for violin, cello and piano.
Andantino religioso.
Élégie sinfonique [B minor] for 19 violoncellos and 3 double basses.
Fantasy piece, Vårstämning for 10 violoncellos and 3 double basses.
Concert piece for 5 violoncellos and 4 double basses.
Norwegian rapsody for violoncello and piano.
Serenade for 4 violoncellos or 4 double basses.
Sonata in D minor, for violoncello and piano. Published by Musikaliska konstföreningen 1877.
Strin quartet (incomplete?).
Voice and piano/lute
Den hvide, röde rose for voice and piano (B. Bjørnson).
Dulgt kaerlighed for voice and piano (B. Bjørnson).
Elegi for soprano, cello and piano.
Ingerid Sletten for voice and piano (B.Bjørnson).
Synnöve Solbakken for voice and piano (B. Bjørnson).
Two songs to lute/piano. 1. Tunga droppar, 2. Kosimaja.
Var min vän, for voice and lute/guitar.
Digte og sange af Björnstjerne Björnson, for voice and piano. Stockholm: Elkan & Schildknecht, 1880. 1. Over de höje fjælde ('Undrer mig på, hvad jeg får att se'), 2. Venevil ('Hun Venevil hopped på lette fod sin kaerest' imod').
Mixed choirr
Når du vil på fjeldesti (B. Bjørnson) fo mixed choir.
Digterens vise (Henrik Ibsen) for mixed choir.
Male quartet/choir
Adagio (Bo Bergman).
Dalmarsch (Erik Axel Karlfeldt).
En fin vise.
Flugsurr.
Foglalåt.
Fylgia.
Fädrelandssang.
Herr Olof.
Här dansar Fridolin (Erik Axel Karlfeldt).
I valet och kvalet.
Intet är som väntans tider (Erik Axel Karlfeldt).
Midsommar.
Sagan om Rosalind (Erik Axel Karlfeldt).
Sogenfjorden.
Sorgebudet (Gustaf Fröding).
Säf, säf, susa (Gustaf Fröding).
Under fanan.
Vallarelåt (Gustaf Fröding). | https://swedishmusicalheritage.com/composers/andersen-anton/ |
Q:
Is stock price priced in the uncertainty?
Consider a one step binomial tree model for stock price. The classical setup is as below:
At time $t=0$, the stock price is $S_0$.
At time $t=1$, the stock has probability $p$ to jump up to price $S_1^u = uS_0$ (define $u:=S_1^u/S_0$); and probability $q=1-p$ to jump down to price $S_1^d = dS_0$ (define $d:=S_1^d/S_0$).
Let the risk free interest rate as $r$. Normally, $1+r < pu + qd$, so
$$\frac{1}{1+r} \mathbb{E}[S_1] = \frac{pu+qd}{1+r}S_0 > S_0$$
, or, at time $0$ the stock is priced as $S_0$, lower than the discounted value of stock price expectation at time $1$.
Now, my question is , can we interpret the underbid of the stock price, $\frac{1}{1+r} \mathbb{E}[S_1] - S_0$, as the risk premium, or the cost because of uncertainties?
If so, is there any related formula? For example, an equation linking the stock price and its volatility $\sigma$?
Ps. in the risk neutral world, the probabilities are $\tilde p=\frac{1+r-d}{u-d}$ and $\tilde q = 1-\tilde p=\frac{u-1-r}{u-d}$, and we have $S_0 = \frac{1}{1+r} (\tilde p S_1^u + \tilde q S_1^d) = \mathbb{\tilde E}\left[\frac{S_1}{1+r}\right]$
, in other words, the stock price $S_t$ is a martingale, under numeraire $(1+r)$ and risk neutral measure. These are all smart and classic, but not related to my question.
A:
I'm not sure if I understand you perfectly, but basically, you have:
$$\mathbb{E}(S_1)= p S_0 u + (1-p) S_0 d = S_0\left[p (u-d) +d \right]$$
This is simply the expectation (i.e. there is no pricing here).
Notice that this means that:
$$\mathbb{E}\left[\frac{S_1}{S_0}\right]=p (u-d) + d$$
So the expected rate of return is $1+R_S=p (u-d) + d$.
If the investment was risk-free, it should yield $1+R_f$. So, you can say that the risk premium in there is $(1+R_S)-(1+R_f)=R_S-R_f=p (u-d) + d -1 -R_f$.
Notice that the volatility of the stock price here is determined by the choice of the $u$ and $d$ parameters.
| |
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Abstract
Objective
The Arabidopsis thaliana Niederzenz-1 genome sequence was recently published with an ab initio gene prediction. In depth analysis of the predicted gene set revealed some errors involving genes with non-canonical splice sites in their introns. Since non-canonical splice sites are difficult to predict ab initio, we checked for options to improve the annotation by transferring annotation information from the recently released Columbia-0 reference genome sequence annotation Araport11.
Results
Incorporation of hints generated from Araport11 enabled the precise prediction of non-canonical splice sites. Manual inspection of RNA-Seq read mapping and RT-PCR were applied to validate the structural annotations of non-canonical splice sites. Predictions of untranslated regions were also updated by harnessing the potential of Araport11’s information, which was generated by using high coverage RNA-Seq data. The improved gene set of the Nd-1 genome assembly (GeneSet_Nd-1_v1.1) was evaluated via comparison to the initial gene prediction (GeneSet_Nd-1_v1.0) as well as against Araport11 for the Col-0 reference genome sequence. GeneSet_Nd-1_v1.1 contains previously missed non-canonical splice sites in 1256 genes. Reciprocal best hits for 24,527 (89.4%) of all nuclear Col-0 genes against the GeneSet_Nd-1_v1.1 indicate a high gene prediction quality.
Keywords
Introduction
Eukaryotic genes are transcribed as a primary transcript that is subsequently converted to a mature mRNA through several processing steps including splicing. During splicing, introns [1–3] are removed from the primary transcript while exons are retained. The process is catalyzed by a RNA protein complex called a spliceosome, which exists in several variants. Based on the spliceosome variant that acts on a given intron, eukaryotic introns are classified as U2-type introns [4] that appear very frequently, or rare U12-type introns [5], respectively [6]. The highly conserved sequences at the termini of introns are not sufficient to distinguish between both types, since the U12-spliceosome can remove AT-AC introns, some other non-canonical intron variants, as well as some introns of the canonical GT-AG type [6–9]. Canonical GT-AG and non-canonical intron variants including AT-AC introns can coexist within the same gene, potentially with an effect on gene expression due to the slow removal of U12-type introns [10]. Several extremely rare terminal intron sequences were discovered and often discussed as potential artifacts, e.g. introns with GT-GG or TT-AG termini [11–14]. Further details regarding exceptional splicing events have recently been reviewed [15, 16].
Splicing processes were investigated intensively in the plant model system Arabidopsis thaliana [17–22], resulting in very well annotated splice sites throughout the reference genome sequence [23]. Despite attempts to annotate non-canonical splice sites automatically [24, 25], ab initio gene prediction without experimental support from e.g. RNA-Seq data (“external hints”) does not support the detection and annotation of non-canonical splice sites on genome sequence assemblies at a satisfying level [26–28]. By generating high quality gene prediction hints based on the recently released Araport11 annotation of the Col-0 sequence [29, 30], we improved the gene set generated by ab initio gene prediction based on the A. thaliana Niederzenz-1 (Nd-1) sequence [31].
To correlate and compare gene structures from related genomes, the first step is to define “orthologous” gene couples. Such couples can efficiently be determined by evaluating reciprocal best BLAST hits (RBHs) [32–35]. Each RBH couple consists of two genes, one from each of the two genome sequences (or genomes) to compare, which display the highest scoring hit in the other data set in a reciprocal manner [36]. RBH couples are the basis for gene-centric comparative genomics [32–35] and can also be used for synteny analysis or as guidance in a genome assembly [31].
Main text
Methods
Analysis of candidate genes
In total, 45 randomly selected Col-0 genes with non-canonical splice sites were manually inspected in a RNA-Seq read mapping produced with STAR [37] based on Araport11 data sets (listed in [30]). Reads were required to map with at least 90% of their length and 95% similarity. The number of selected cases was a compromise between the required accuracy of the results and a manageable amount for individual manual inspection. Corresponding loci in the Nd-1 sequence were identified via tblastn [38]. Gene structures around non-canonical splice sites in the Nd-1 assembly sequence [31] were annotated manually for further investigation.
Primer combinations for RT-PCR included one primer bridging an exon–exon junction with 100–500 nt distance to the other primer (Table 1). Oligonucleotides were purchased from Metabion (http://www.metabion.com/). Total RNA was isolated as described before [39]. DNAse I (M0303L, New England Biolabs) digestion was performed according to the suppliers’ protocol. cDNA synthesis was carried out using 1 µg of total RNA and ProtoScript II Reverse Transcriptase (M0368L, New England Biolabs) based on the suppliers’ protocol. Q5 High-Fidelity DNA polymerase (M0491L, New England Biolabs) was employed according to the suppliers’ recommendations (including PCR cycling conditions) for generation of amplicons. The size of the amplicons was checked by agarose gel electrophoresis. Samples were purified for sequencing by ExoSAP-IT (78201.1.ML ThermoFisher Scientific) treatment as described [40]. Sanger sequencing on ABI3730XL was applied to reveal the entire sequences as described [41]. Finally, the correct annotation of the non-canonical splice sites in the candidate genes was inspected via sequence alignments generated with MAFFT [42].
Hint-based gene prediction
All representative transcript sequences of protein coding genes in the Col-0 nucleome within the Araport11 annotation, as well as the first transcripts of At4g01800 and At3g10350, were mapped to the Nd-1 genome sequence via BLAT [43]. Perl scripts provided in the AUGUSTUS package filterPSL.pl and blat2hints.pl (http://bioinf.uni-greifswald.de/augustus/binaries/scripts/) were used to convert the BLAT output into valid hints. AUGUSTUS 3.2.1 [44, 45] was run on the Nd-1 genome sequence incorporating these hints.
Comparison of gene predictions
Calculation of gene prediction statistics as well as comparison to the Col-0 annotation via identification of RBHs was carried out by custom Python scripts as previously described [31]. ParsEval [46] was applied to compare the GeneSet_Nd1_v1.0 and GeneSet_Nd1_v1.1 in more detail.
Results and discussion
When analyzing the protein coding genes predicted in the recently released A. thaliana Nd-1 genome sequence [31], we observed complete absence of introns with non-canonical splice sites in the initially predicted gene set (GeneSet_Nd-1_v1.0). The structural annotation was performed ab initio using AUGUSTUS 3.2. By comparing the GeneSet_Nd-1_v1.0 with the Araport11 gene set for the Col-0 reference genome sequence [23, 29, 30], we identified several loci with gene structures showing mis-annotated introns or even a lack of gene prediction for the Nd-1 case. For the present study, we focused on protein encoding genes in the nuclear genome sequence since this gene set was previously predicted ab inito. The annotation update provided here will further support A. thaliana pan-genomic research by redefining the gene set for the accession Nd-1. Moreover, researchers interested in single genes and their Nd-1 alleles will be able to access a high quality annotation for comparison to Araport11 for the Col-0 reference sequence.
In total, the Araport11 gene set contains 1267 genes which display non-canonical splice sites to generate the respective representative transcript. This ‘representative transcript’ has been defined as the transcript isoform containing the longest protein coding sequence (CDS) [30]. We established a set of well investigated genes consisting of At1g79350 (FGT1) [47–49], At4g01800 (AGY1) [47, 50–52] and At4g27500 (PPI1) [53–57] as examples for genes containing confirmed introns with non-canonical slice sites in their main transcript isoform. Despite high sequence conservation between Col-0 and Nd-1, the gene structures predicted at these loci in GeneSet_Nd-1_v1.0 did not match the Araport11 annotation [29, 30], indicating that bona fide genes were missed by ab initio annotation of the Nd-1 genome sequence because they contain introns with non-canonical splice sites (Fig. 1).
Fig. 1
Representative gene structure of missed non-canonical splice sites in ab initio gene prediction on the Nd-1 genome sequence. Gene structures of At1g79350.1 and the corresponding reciprocal best BLAST hit (RBH) of the ab initio gene prediction in Nd-1 (GeneSet_Nd-1_v1.0) are displayed. The non-canonical splice sites were missed leading to a difference at exon 20 (blue arrows). Despite this deviation, the structure of At1g79350Nd−1 was predicted very well by AUGUSTUS [44, 45]
When analyzing the Araport11 data set of Col-0 protein coding nuclear genes, which is based on very high coverage RNA-Seq information, we identified 39 different pairs of splice donor and splice acceptor sites (i.e. intron types) that need removal in order to generate the representative transcript isoforms. In total, the Araport11 structural annotation dataset contains 119,097 splice site pairs (introns) in nuclear protein coding genes that are spliced out of the primary transcript to produce the representative transcript. Of these, 117,732 (98.9%) were canonical GT-AG splice site pairs, while 1196 (1.0%) were GC-AG pairs and 81 (0.1%) were AT-AC pairs. In addition, diverse and less frequent splice site pairs sum up to 88 (0.1%) cases. These less frequent splice site pairs occur with very low frequencies and case numbers between one and nine.
When considering all transcript isoforms of all genes annotated in Araport11, 125 different splice site pairs are annotated. Obviously, non-protein coding genes contribute a huge proportion to splice site variation. Despite the very high quality of the A. thaliana Col-0 reference sequence, sequencing errors or collapsed gene sequences [58] could explain at least a fraction of the very rare splice site pairs [11].
Representative structures of protein encoding genes from Araport11 were used to produce gene prediction hints for the Nd-1 genome sequence (see "Methods"). This information transfer was done to harness the improvement potential of 1267 annotated protein encoding genes in the Col-0 reference sequence containing various non-canonical splice sites in their representative transcript. Gene prediction on the Nd-1 genome sequence using these hints revealed 30,834 genes (GeneSet_Nd-1_v1.1, Additional file 1) exceeding the number of predicted genes in the GeneSet_Nd-1_v1.0 by 2164. Detailed comparison revealed a match of 91.2% in respect to predicted CDS features and a match of 50.2% concerning UTR features, respectively. Vast changes in the UTR prediction could be explained by the incorporated hints, since the ab initio prediction of these regions is error-prone. A slight reduction in the average CDS length from 1086 bp (median) in the GeneSet_Nd-1_v1.0 compared to an average length of 1041 bp (median) in the GeneSet_Nd-1_v1.1 was observed. There are 135,356 introns with 30 different pairs of donor and acceptor splice sites in the GeneSet_Nd-1_v1.1 (Additional file 2), supporting the assumption that some minor splice sites in the Araport11 annotation might be due to sequencing errors [11]. Splice site pairs were distinguished into 134,004 (99.0%) GT-AG splice site pairs, 1080 (0.8%) GC-AG splice site pairs, 66 (0.05%) AT-AC splice site pairs and 206 (0.15%) diverse and less frequent splice site pairs. In total, 1256 genes within the GeneSet_Nd-1_v1.1 contain introns with non-canonical splice sites. Their average transcript length is 2003 bp (median) consisting on average of ten protein encoding exons. Compared to the average number of four annotated exons in all genes of GeneSet_Nd-1_v1.1, we see a clear accumulation of non-canonical splice sites in exon-rich transcripts. This overrepresentation of exon-rich transcripts among the non-canonically spliced transcripts is supported by the Araport11 annotation where the average exon number of protein encoding transcripts with non-canonical splice sites is also ten. Manual inspection identified At4g01800 and At3g10350 as genes where the representative transcript in Araport11 does not require processing of non-canonical splice site pair, but another strongly expressed isoform does. Therefore, we expect the number of genes with non-canonical splice sites in Col-0 to be slightly higher than 1267 as deduced from the representative transcript data set.
Reciprocal best BLAST hit (RBH)-based comparison of the new GeneSet_Nd1_v1.1 and the Araport11 annotation revealed 24,527 gene couples (Additional file 3). The number of RBHs within the hint-based GeneSet_Nd1_v1.1 is strongly increased compared to the ab initio predicted GeneSet_Nd1_v1.0. We expect a further increase in prediction accuracy if the underlying sequence would be available with enhanced continuity, as for example possible if generated by SMRT sequencing, and if incorporation of additional hints from RNA-Seq data would be possible. High sensitivity mapping of Col-0 exon sequences to the Nd-1 genome sequence might discover small matches leading to further prediction improvements. Gene duplications are a special challenge in this process, because exon sequences might map to only one copy in the Nd-1 genome sequence. This might explain a part of the observed difference between the Col-0 annotation and the Nd-1 gene prediction concerning the number of transcripts with non-canonical splice sites.
Non-canonical splice sites in the reciprocal best hits (RBHs) of the three candidate genes FGT1, AGY1 and PPI1 in the GeneSet_Nd1_v1.1 were confirmed by Sanger sequencing of amplicons generated from cDNA. FGT1 contained 31 exons and displayed a GC-CT splice site pair in intron 20 (Fig. 2). AGY1 contained 20 exons and displayed a GA-AG splice site pair in intron 4. PPI1 contained 7 exons and displayed a GA-AG splice site pair in intron 6.
Fig. 2
Representative gene structure of missed non-canonical splice sites in ab initio gene prediction in Nd-1. Gene structure of the At1g79350 RBH in the hint-based gene prediction (GeneSet_Nd-1_v1.1) on the Nd-1 genome sequence is displayed (a). The non-canonical splice sites were missed in the ab initio gene prediction leading to a skipping of exon 20 (highlighted in yellow) (b)
Limitations
Allowing an increased number of alternative splicing possibilities deviating from the GT-AG rule would render ab initio prediction of gene structures almost impossible. Since the number of non-canonical splice sites is low, the ratio of false positive predictions would strongly increase. Incorporation of evidence from RNA-Seq experiments or high quality annotations of related genome sequences into a gene prediction process with AUGUSTUS [44, 45] or a combination of AUGUSTUS and GeneMark [59] within BRAKER1 [60] is most probably the best way to achieve high quality gene predictions. Annotating new genome sequences via transfer of annotations from model species and adding additional expression data derived hints was successfully carried out several times before and has recovered many non-canonical splice sites [61–65]. Other promising approaches are completely based on homology to predict gene structures [66]. Nevertheless, the accurate prediction of non-canonical splice sites remains a challenge. Anyway, it will be a general contribution to accuracy to pay attention to non-canonical splice sites when applying ab initio gene prediction.
Declarations
Authors’ contributions
BP, DH and BW conceived and designed research. BP conducted experiments. BP, DH and BW interpreted the data. BP, DH and BW wrote the manuscript. All authors read and approved the final manuscript.
Acknowledgements
We are grateful to Katharina Kemmet for her help with the validation of non-canonical splice sites in Nd-1 genes. In addition, the authors wish to thank the members of the Genome Research Team at Bielefeld University as well as the Bioinformatics Resource Facility for their excellent assistance and support.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
All data generated during this study are included in this published article and its additional files.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
Funding
We acknowledge the financial support of the German Research Foundation (DFG) and the Open Access Publication Fund of Bielefeld University for the article processing charge.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Additional files
13104_2017_2985_MOESM2_ESM.xlsxAdditional file 2. Non-canonical splice sites in Nd-1. All occurrences of the different splice site pairs within the first transcript of predicted Nd-1 genes in GeneSet_Nd1_v.1.1 are listed.
13104_2017_2985_MOESM3_ESM.txtAdditional file 3. Reciprocal Best Hits. Gene couples with reciprocal best hits between the Araport11 annotation of Col-0 and the GeneSet_Nd1_v1.1 are listed.
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Fans of the vertical mattress suture, consider this relatively straightforward modification of the technique: shorthand it.
You were probably taught in medical school, as I was, that the vertical mattress suture typically follows a far-far then a near-near pattern of suture placement. But this doesn’t necessarily have to be the rule. Since the suture material ultimately forms a continuous loop, the pattern can simply be reversed and a near-near bite can then precede the far-far bite.
The obvious technical problem is readily apparent: how can that far-far bite be performed effectively once the margins of the wound have already been approximated by the near-near bite? Don’t you need to exit in the center of the wound to achieve the far-far bite?
Herein lies the crux of the shorthand technique: after the near-near bite is placed, roughly 3 mm from each wound edge, the operator then retracts upward on the suture material with the non-dominant hand in order to place the far-far bite, about 6 mm from each wound edge. This aids not only in traversing the tissue effectively to attain that far-far bite, but also has the desired effect of placing the suture material at differential depths–as you raise the tissue near the wound edge, it exaggerates the depth differential between the two throws.
The technique is not without a few disadvantages:
- it is technically a little more challenging to master than the traditional vertical mattress suture.
- since the deeper far-far throw is now placed in a blinded fashion, there is a risk (albeit small) of damaging underlying vascular and nerve structures.
That said, this is a relatively simple modification of a tried-and-true technique that, with a little practice, can actually help you to place your next vertical mattress suture better.
References:
- Jones JS, Gartner M, Drew G, Pack S. The shorthand vertical mattress stitch: evaluation of a new suture technique. Am J Emerg Med.1993;11(5):483-485.
- Snow SN, Goodman MM, Lemke BN. The shorthand vertical mattress stitch–a rapid skin everting suture technique. J Dermatol Surg Oncol. 1989;15(4):379-381.
- Kantor, J. Atlas of Suturing Techniques. Chapter 5.17. | https://lacerationrepair.com/techniques/advanced-wound-closure-techniques/the-shorthand-vertical-mattress-suture/?shared=email&msg=fail |
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Q:
Put data into Matrix
I'm using Matlab and i have this big vector representing time from 5 to 55 seconds sampled at 512 Hz,so each sample is aprox. 0.0020 sec.
I want to fill a matrix in order that each row represents 10 sec. interval.
i.e row1 5-15,row2 15-25,row3 25-35,row4 35-45 and row5 45-55 seconds.
So i created a matrix 5 by 5121 elements,and i created this loop
Matrix=ones(5,5121)
tmp=1;
for row=1:5
for column=1:5121
Matrix(row,column)=t(tmp);
tmp=tmp+1;
end
end
The problem is that when i go to a new row i want that the last values of the previous row is repeated in the new row.
i.e
5-5.0020-5.0039...15
15-15.0020 and so on.
With this loop that i created i have this situation
5-5.0020-5.0039...15
15.0020-15.0039
Hope you can help me
Thanks
A:
n_rows = 5;
n_cols = 5121;
overlap_size = 10;
t = rand(n_rows*n_cols,1);
matrix = nan(n_rows,n_cols);
i_t = 1;
for i_row = 1 : n_rows
for i_col = 1 : n_cols
matrix(i_row,i_col) = t(i_t);
i_t=i_t+1;
end
end
matrix = [matrix(1:end-1,(end-overlap_size+1):end),matrix(2:end,:)];
of course, if this is the whole code, and you don´t have other operations in it, this is a far better solution:
matrix = reshape(t,[n_cols,n_rows])';
matrix = [matrix(1:end-1,(end-overlap_size+1):end),matrix(2:end,:)];
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Just as we, humans, need vitamins and nutrients in order for us to be healthy and strong, other living beings need the same as well. And plants are also living beings, so they are not excluded. If there is plant nutrients deficiency, plants will not be healthy and may wither and die.
Therefore, you need to use proper nutrient mixtures and solutions so that wouldn’t happen.
In this text, I will explain what plant nutrients deficiency exactly is, how it can hurt the plant and what are possible solutions to dealing with this problem. So stick with me and let’s start!
Contents
- What Does Plant Nutrients Deficiency Mean?
- How To Identify Plant Nutrients Deficiency?
- What Types Of Nutrients Exist?
- How To Treat Plant Nutrient Deficiency?
- FAQ
What Does Plant Nutrients Deficiency Mean?
When you hear the word “nutrients”, the first thing that comes to your mind is probably nutrients for the people. But, that is not the case here because plants, of course, require different nutrients than us, so before you try to treat your plants, you need to know exactly what nutrients they need.
Plants require nutrient minerals, which are the common elements that can be seen in the periodic table. Plants consume these elements, turning it into raw energy, which is used to keep the plant healthy.
Now, when those minerals are missing from the plant’s system, that means the energy that comes with them is missing as well. That leads to the plant’s diminishing health. And that is exactly what plant nutrients deficiency means.
Just as people get sick when they lack some nutrients or vitamins, the same goes for plants. That is why you should take great care of your plants.
Now, before you start pumping all nutrients to the plant’s body, you should first get to know what nutrients it needs and what is the percentage of used nutrients. It is very important to keep this in mind.
Giving it too many or too little can be as counter-productive as not giving it the required nutrients at all.
With that comes the understanding of the environment in which the plant lives. Knowing what affects the plant’s everyday life and how it contributes to its welfare is as important as everything else.
1. Watering
One of the crucial environmental effects to look out for is the watering process, where you need to make sure you don’t use too much or too little water.
2. Lighting
Then we have the lighting. You should learn what type of light your plants need, so you know how much to expose them to it. Whether to put them closer to the window or not, whether to use more natural light or not, and so on.
3. Soil
Soil types and its temperature is also a very important factor to look out for. Different plants require different soil type and different soil temperature. Therefore, it is crucial for you to learn about those characteristics of your plant as well.
4. Pests
Of course, apart from all of this, one more danger to keep in mind are pests that can really damage your plant and diminish all your hard work. You should definitely look into what types of pests attack certain plants and what are the ways to deal with them.
How To Identify Plant Nutrients Deficiency?
Identifying symptoms of plant nutrients deficiency is not an easy task. There are a lot of nutrients and each carries a different symptom to show. So it is very important to get to know the most important plant nutrients and the symptoms that plants would show in case of their deficiency.
Even though there are a lot of symptoms that may occur, there are several of them that are most common:
- Scrubby growth – if you notice that your plant hasn’t grown enough, that may be one of the symptoms of plant nutrients deficiency;
- Dried leaves – if you notice that leaves have been a bit dried out and look like they have been burned, you might want to look into the symptom and find out what nutrient deficiency might have caused it;
- Chlorosis – this is the situation where plants lose their green color;
- Necrosis – this means that plant’s cells are dying, which can turn the tissue color to very dark. This is usually the sign of a fungus.
What Types Of Nutrients Exist?
In order for plants to stay healthy and grow as they should, they need a proper mixture of nutrients. They consume it through the root, so it is very important to have a good soil composition and to water the plant as much as needed, no more, no less.
There are two main groups of nutrients:
- Macronutrients – these are nutrients that have to be consumed in large amounts or let’s say, the nutrients plants need the most;
- Micronutrients – these are secondary nutrients, which are also important, but don’t have to be consumed in such large amounts as macronutrients.
Macronutrients
As mentioned above, macronutrients are the nutrients that need to be consumed in a fairly large amount. I will mention the most important ones and the symptoms their deficiency could cause.
1. Calcium
Important for: Maintaining the cell walls healthy to ensure steady growth;
Source: Gypsum and any other product that has a calcium label;
Deficiency symptoms: Yellow spots on leaves and deformed looks of the leaves, which are shaped like a hook.
2. Nitrogen
Important for: Ensures that stem and leaf grow healthy. It is the most important nutrient, not just for plants, but for everyone else as well;
Source: Fertilizer;
Deficiency symptoms: Slower growth and yellowed leaves, mostly at the bottom of the plant itself.
3. Magnesium
Important for: It is crucial for the process of photosynthesis and formatting the proteins;
Source: Some mixtures that contain “Mg” label, such are the Epsom Salts (I love this product, it can do wonders!);
Deficiency symptoms: Slower growth and brown, yellow leaves on the outside part of the plant.
4. Phosphorus
Important for: Maintaining the right root growth and flowering;
Source: Greensand (I use this organic version of green sand; it is all natural and it really promotes the plant’s growth and health);
Deficiency symptoms: Leaves can be very small with a distinctive red or purple color. Also, the tip of the leaf can seem dead, with black or dark brown color.
5. Potassium
Important for: Defense against pests and cold weather. Apart from that, it is important for growing healthy new leaves;
Source: Mixtures with “potash” or “potassium” label;
Deficiency symptoms: Chlorosis
Micronutrients
Now that we are done with all the most important macronutrients, let us also mention the most important micronutrients you should keep in mind.
1. Boron
Important for: Creating and maintaining the way root and leaves grow, and it is used to move the sugar through the plant;
Source: Mixtures with the label “borax” or “borate”;
Deficiency symptoms: It can cause the formation of witches brooms and can affect root growth;
2. Iron
Important for: It is crucial for creating chlorophyll;
Source: Mixtures labeled with “Fe”
Deficiency symptoms: Slower growth, interveinal chlorosis
How To Treat Plant Nutrient Deficiency?
When treating the plant nutrient deficiency, it is important to know exactly what kind of deficiency your plant has, so you could act in a proper way.
It is crucial to use the right tool to deal with this problem. Know that some deficiencies can spread and cause other deficiencies, which would only cause you more problems.
The best solution in a short term is the use of proper nutrient mixtures in order to give the missing nutrients to plants. In that case, you should observe the symptoms closely and see what kind of deficiency your plant has and then look for the right mixture to help you with that.
Since some deficiencies can show similar symptoms, sometimes it can be a bit harder to exactly pinpoint the cause of the particular plant nutrients deficiency. If you made a mistake and the mixture you had used didn’t work, then you need to look for another mixture. So, basically, a trial and error system.
Of course, this comes easier when you get more experienced in recognizing the symptoms for each plant nutrients deficiency, so you will be able to do it properly much faster.
FAQ
1. Nutrient mixture from the store isn’t working. What to do?
As mentioned above, if a specific mixture is not working, try a different one. It could be that you didn’t use the right one for the right plant nutrients deficiency.
2.Young leaves are growing healthy, but the older ones are still sick. What to do?
If the new growth seems fine and healthy, that usually means the problem is solved. What you should do is remove the old damaged parts.
How do you deal with plant nutrients deficiency? Do you have a cheat sheet to determine what is the cause of a plant’s problem to share with us? | https://todaysgardener.com/plant-nutrients-deficiency-identification-and-solutions/ |
All stakeholders, from patients to health-care professionals and regulatory agencies, agree to promote “proper drug use” and to fight against “misuse” (Garfinkel and Bilek, 2020; Nothelle et al., 2017). Misuse is a concept covering different situations which are summarized in Figure 1, including unintentional medication errors, poisoning, or recreational use. Such situations will not be considered in our discussion. For intentional prescriptions with therapeutic goals, defining the boundary between appropriate and inappropriate use could be challenging. Intentional off label use for therapeutic purposes can be appropriate in a specific clinical context if supported by a recommendation, consensus, or scientific data. Inappropriate use is therefore defined as unjustified intentional use, and this situation is one of the main concerns tackled by the ANSM (the French drug agency) and calls for collective action.
The appropriateness of medication use should be considered as a continuum from the conditions with the most favorable benefit–risk balance to conditions with an unfavorable balance. Yet, the more the drug use deviates from the profile defined by the summary of product recommendations, the less it is expected to benefit the individual’s health status and the more it exposes the patient to unacceptable adverse effects. From a medical point of view, a case-by-case assessment is required, taking into account all the individual patient characteristics requiring treatment and assessing comedications and comorbidities. For these reasons, medical practice requires that experimental and evidence-based data be applied to the uniqueness of the patient. This is a challenging situation explaining why the appropriate use of a drug, even with the best intention, remains a difficult choice, especially in frail populations.
Inappropriate medication use is an important source of adverse effects (Eguale et al., 2016). Very rare (<1/10,000) or rare (<1/1,000) undesirable effects, which are barely identified in clinical trials and almost impossible to detect at an individual level, are heavily represented as a health problem in the population as millions of patients are exposed to these medications over the years.
The gray area of inappropriate use is then difficult to perceive at an individual level. It is not limited to an abrupt switch between right and wrong prescriptions but could also be linked to a progressive drift in practices, leading to new risks for certain populations, in certain clinical contexts or with certain associations. It is also in this reflection that self-medication must take place. It is a direct source of inappropriate use or a factor that favors it indirectly through the risk of interactions that may not be perceptible to the prescribers.
In this context, fighting against inappropriate use and its adverse consequences is a matter of the individual relevance of the medical prescription, but global actions are also required to control them. The needs and wishes of the patient, the physician’s experience, and the population expertise of the authorities should not be opposed. Based on recent experiences, the ANSM and its expert group of advisors are advocating for a more integrated vision between the individual scale and the population approach.
In recent years, several risky health situations linked to inappropriate use of drugs have been highlighted. Consequently, health organizations such as the ANSM endorsed recommendations to limit inappropriate uses of medications. For instance, the third and fourth generations of oral contraceptives have been massively prescribed despite their higher relative risk of thromboembolic accident than the 1st and 2nd generations (Emmerich et al., 2014). This has led the ANSM to warn against the former and to recommend the latter as the first line contraceptives. Valproic acid, which has a well-known risk of teratogenicity, was commonly used by women at a childbearing age, forcing the ANSM to ban its use in certain cases (Casassus, 2017). Paracetamol is hugely used with prescriptions of high doses in France (Hider-Mlynarz et al., 2018), increasing the risk of liver toxicity. This situation led to specific measures to provide information on the dosage and to control the availability of the product in pharmacies. Inappropriate prescription of antibiotics was tackled by several awareness campaigns in France and other countries but is still a major concern for health authorities, with the emergence of extensively drug-resistant bacteria (World Health Organization, 2017).
Other initiatives have been launched by health authorities to limit the risks caused by inappropriate use of specific drugs. They are commonly based on communication strategies or regulatory action toward laboratories, but few are focused on the global issue. Some initiatives suggest focusing on particular medications and offering toolkits for prescribers (Hodgson, 2015). The most frequently selected medications according to practitioner opinions included antibiotics, proton pump inhibitors, opioids, statins, cholinesterase inhibitors, and non-steroidal anti-inflammatory drugs (Hazard et al., 2020).
These initiatives are of major importance, but may a common perception of issues related to inappropriate use still be lacking between patients, health-care professionals, and authorities? How could we build a long-term strategy beyond specific topics and crisis situations?
New perspectives should be implemented now:
Better anticipation. It involves the early identification of situations where inappropriate use would lead to health risk. Such situations are characterized by the expected level of exposure in the population, the context of use and the patient profile (e.g., vulnerable populations, patients exposed to polymedication, etc.), and the pharmacological characteristics of the drug (pharmacodynamic effects, adverse effects, therapeutic margin, variability of effects, drug interactions, etc.). Taking into account these characteristics should make it possible to map risks linked to inappropriate drug use for the purpose of prevention. Detection of inappropriate use should involve all actors. Benchmarking on the use of drugs within different countries will also be a valuable tool to tackle potential misuse of drugs.
Better collective commitment including educational programs and co-construction of action plans with stakeholders. Because it could be difficult to immediately assess whether the use of a particular drug is inappropriate or not, each actor needs to be responsible for its rational use. Discussion between patients and health professionals (prescribers and pharmacists) and use of prevention tools should help to identify and limit uncertain situations to decreased risks. A public debate with all the stakeholders should foster exchanges on the different perceptions and the co-construction of prevention tools in order to sensitize the entire population. The debate could lead to the development of tools to promote prevention such as computerized systems, institutional communication, or guidelines (Dalton et al., 2018; Monteiro et al., 2019). The need for new communication channels is already evident, and the best options should be chosen based on the recipients’ opinions. We can then plan specific prevention and information strategies for the known situation of inappropriate use and launch nonspecific pedagogical programs. Helping patients and professionals to understand the risks associated with the use of a drug also involves training and education (Foucaud et al., 2013). The ANSM wishes to involve academics and patient partners to co-construct training programs, in particular for patients with chronic diseases or professionals and future health professionals. The main goal of such programs should be to change patients’ and health-care professionals’ perception on the appropriate and inappropriate use of health products.
The ANSM now integrates these different perspectives in its strategy of transparency and openness to health-care professionals and the general population. In particular, patients participate as ex officio members in all expert committees, and the ANSM has integrated advisor groups including physicians and patient partners into its organization to improve co-construction of health policies on health products. Even if dialogs already existed, of course, between the agency and the stakeholders, the aim is now to organize an entanglement throughout all our reflections. This sharing of experiences and points of view, from bedside to institution, will be the cornerstone of the collective culture of appropriate use that we all wish to promote.
Author Contributions
All authors: conceptualization, analysis, writing (review and editing), and validation. SV and PM: additional writing (original draft) and supervision. All authors agree to be accountable for the content of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Casassus, B. (2017). France bans sodium valproate use in case of pregnancy. Lancet 390 (10091), 217. doi:10.1016/s0140-6736(17)31866-4
Dalton, K., O’Brien, G., O’Mahony, D., and Byrne, S. (2018). Computerised interventions designed to reduce potentially inappropriate prescribing in hospitalised older adults: a systematic review and meta-analysis. Age Ageing 47 (5), 670–678. doi:10.1093/ageing/afy086
Eguale, T., Buckeridge, D. L., Verma, A., Winslade, N. E., Benedetti, A., Hanley, J. A., et al. (2016). Association of off-label drug use and adverse drug events in an adult population. JAMA Intern. Med. 176 (1), 55–63. doi:10.1001/jamainternmed.2015.6058
Emmerich, J., Thomassin, C., and Zureik, M. (2014). Contraceptive pills and thrombosis: effects of the French crisis on prescriptions and consequences for medicine agencies. J. Thromb. Haemost. 12 (9), 1388–1390. doi:10.1111/jth.12661
Foucaud, J., Balcou-Debussche, M., Gautier, A., and Debussche, X. (2013). Training in therapeutic patient education of French primary care physicians: practices and perceived needs. Educ. Ther. Patient/ther Patient Educ. 5 (1), 123–130. doi:10.1051/tpe/2012021
Garfinkel, D., and Bilek, A. (2020). Inappropriate medication use and polypharmacy in older people. BMJ. 369, m2023. doi:10.1136/bmj.m2023
Hazard, A., Fournier, L., Rossignol, L., Pelletier Fleury, N., Hervé, C., Pitel, T., et al. (2020). A top 5 list for French general practice. BMC Fam. Pract. 21 (1), 161. doi:10.1186/s12875-020-01235-5
Hider-Mlynarz, K., Cavalié, P., and Maison, P. (2018). Trends in analgesic consumption in France over the last 10 years and comparison of patterns across Europe. Br. J. Clin. Pharmacol. 84 (6), 1324–1334. doi:10.1111/bcp.13564
Hodgson, H. (2015). Choosing wisely - choosing tactics. Clin Med (Lond). 15 (4), 315–316. doi:10.7861/clinmedicine.15-4-315
Monteiro, L., Maricoto, T., Solha, I., et al. (2019). Reducing potentially inappropriate prescriptions for older patients using computerized decision support tools: systematic review. J. Med. Internet Res. 21 (11), e15385. doi:10.2196/15385
Nothelle, S. K., Sharma, R., Oakes, A. H., Jackson, M., and Segal, J. B. (2017). Determinants of potentially inappropriate medication use in long-term and acute care settings: a systematic review. J. Am. Med. Directors Assoc. 18 (9), 806.e1–806.e17. doi:10.1016/j.jamda.2017.06.005
World Health Organization (2017). WHO campaign. Stop overuse and misuse of antibiotics: combat resistance Available at: https://www.who.int/westernpacific/news/detail/10-11-2017-stop-overuse-and-misuse-of-antibiotics-combat-resistance (Accessed November 30, 2020)
Keywords: drug misuse, collegiality, anticipation, collective commitment, regulatory science
Citation: Vignot S, Daynes P, Bacon T, Vial T, Montagne O, Albin N, Emmerich J, Ratignier-Carbonneil C, Martin D and Maison P (2021) Collaboration Between Health-Care Professionals, Patients, and National Competent Authorities Is Crucial for Prevention of Health Risks Linked to the Inappropriate Use of Drugs: A Position Paper of the ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Front. Pharmacol. 12:635841. doi: 10.3389/fphar.2021.635841
Received: 30 November 2020; Accepted: 16 March 2021;
Published: 28 April 2021.
Edited by:Francisco J. DeAbajo, University of Alcalá, Spain
Reviewed by:Chieko Kurihara, National Institutes for Quantum and Radiological Science and Technology, Japan
Copyright © 2021 Vignot, Daynes, Bacon, Vial, Montagne, Albin, Emmerich, Ratignier-Carbonneil, Martin and Maison. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | https://www.frontiersin.org/articles/10.3389/fphar.2021.635841/full |
The practice-based PhD is aimed at practitioners operating within or across the broad range of disciplines represented in the school, from architecture and design to planning and construction. Early and mid-career, and senior practitioners, will have the opportunity to apply the knowledge, skills and methodologies they've developed in the field within a broader framework of critical and rigorous scholarly enquiry. The expanded range of interrogative, analytical and evaluative skills developed during their candidatures should directly enhance their own practice.
A practice-based PhD is available across all disciplines represented in the School of Built Environment:
architecture
city planning
computational design
construction management and property
industrial design
interior architecture
landscape architecture.
The primary aim of the practice-based PhD is to contribute new knowledge to the field through systematic investigation. A candidate will apply the research value of the knowledge, skills and methodologies developed as a practitioner within a broader framework of critical enquiry and analysis. It's expected that the candidate will generate a new body of ideas-based, creative work (the project) and a written work (the dissertation) that will make an original contribution to knowledge within the field.
The project may take one of a number of different forms, such as architectural design, urban design and planning, construction methods and technologies, industrial design, interior design, and landscape design. It could also cross a number of disciplines. The chosen medium can also vary, for example, it might take the form of objects, drawings, plans, prototypes, models, creative text, digital fabrication, film, virtual reality, or a combination of these. The requirement, however, is that the project can be fully documented in electronic form for the purposes of examination.
The dissertation is a substantial research-based academic essay that bears a direct relationship to the project. Together the dissertation and the project comprise the PhD thesis.
To assist commencing students in developing an appropriate research methodology, candidates are required to undertake a course in their first session - BENV7020 Research Seminar.
Candidates undertaking a practice-based PhD will also be required to undertake a specialised Thesis Writing Workshop run by UNSW Learning Centre.
For information on the structure of the program, please refer to the UNSW Online Handbook.
For information on how a practice-based PhD is examined, please refer to Notes For Examiners.
Are you an established and passionate practitioner operating within or across the broad range of disciplines represented in the School of Built Environment like architecture and urban design, city planning, computational design, construction management and property, industrial design, interior architecture and landscape architecture?
Are you interested in developing rigorous critical thinking and knowledge creation to improve your practice and the industry?
Based on your direct experience as an established practitioner in the built environment industry, you will generate a project through robust critical research.
The research project would result from historically and scientifically broadening and contextualising the field of enquiry.
Reflection, experimentation and testing boundaries within your field will narrow the PhD topic to a sharp, focused and manageable research project.
Research projects will affect, benefit and reward industry by improving and expanding your services to clients.
Discipline and interdisciplinary oriented research projects will shape the future of our cities and allow you, as a practitioner, to become a global leader in your field.
Your research project will encourage, promote and support collaboration between academia and industry.
Your close working relationship with the industry can potentially lead to funding, where the research topic is aligned with the industry’s future visions. (For example, design-construction-developer companies, construction material industries/associations)
Project aim: the broader aim is to contribute to the growing discourse on community development and social agency in vulnerable communities. The history of humanitarian concerns in development delivery stem from colonisation and top-down practices. Practice-based PhD candidate Renate Carius’ research project focuses on participatory design processes set within the context of post-disaster reconstruction in Nepal. Current fieldwork serves as a case study to explore how reflexive design can contribute to local agency in informal settlements.
Project findings: Findings from the process could contribute to future knowledge on co-design strategies and policy in vulnerable communities for social agency.
Project aim: by integrating the building to the city and its urban landscape, the aim of the practice-based PhD in architecture and the urban condition is to question the role of architecture in responding with contemporary and progressive design of volumes, spaces, public/private human activities and use of materiality to the existing urban fabric.
Project findings: research findings from critical forward-thinking and imaginative practitioners will enhance research about ‘urban contiguity’ - how considering the existing urban context and envisioning a new project complement each other; how rethinking and integrating urban high-density and public infrastructure with multigenerational/affordable housing, public activities and educational institutions will create a more liveable community.
Project aim: Diane Jones’ PhD proposal looks at the cultural shift and interest in urban settings which are not age or otherwise segregated for integrated communities embedded within the existing urban context. This intersects with the perceived benefits and realities of high density living in a compact city. The aim is to understand the architectural design attributes of wellbeing for people who are aging within purposefully designed high rise living settings- in an integrated (across generations and uses) community within an urban context. How do architectural design decisions in practice align with people’s experiences of wellbeing?
Project findings: the proposal will work towards the development of a suite of principles that are evidence-based - that can be organised as an evaluative matrix, which can be used to brief, design and evaluate the spatial experiences that contribute to people’s wellbeing and continuing vitality and vibrancy as they grow older.
Project aim: despite its contribution to the global and national economies, the construction industry is notorious for being unsafe. In such an environment, project management personnel play an important role in leading safety task implementation and creating positive safety climate in construction projects. This, subsequently, leads to accident prevention through the efforts of eliminating unsafe acts and conditions. To do so, project management personnel need to possess sufficient skills. Therefore, this present research has investigated the role of project management personnel’s skills (comprising conceptual, human, political and technical skills) in implementing safety management tasks and developing safety climate.
Project findings: this research has identified four essential skills and 15 skill components of project management personnel to manage construction safety. Visioning, self-awareness and apparent sincerity are the foundation skills; scoping and integration, and self-management are the first-tier mediator skills; whilst social awareness, social astuteness and relationship management are the second-tier mediator skills. A significant contribution of this research to construction safety practice is the development of a model that portrays skill applications and development processes for project management personnel to implement safety management tasks and develop safety climate. The model recommended assists construction organisations to identify skill shortages and make decisions on their human resource development strategies and plans.
Project aim and findings: computational design is moving from promise to practice. Where PhD research in the early years of computational design often engage with provocative form finding and experiments in computation and computing, a practice-based PhD in Computational Design aims to tackle problems in the industry. The Computational Design degree and its HDR extensions sees itself as the research and development department for local, national and international firms investigating third horizon challenges spanning from Machine Learning / AI, to bio-mimicry, to AR/VR, robotic and digital fabrication, to smart cities and responsive environments and performance and optimisation of design, architecture, structure and cities.
As established practitioners, PhD applicants can bring firm-specific third horizon challenges into the PhD investigation and answer the research question through academic supervision within the school, but also, depending on the topic, within the university. The PhD student can further make use of the Design Futures Lab with its extensive range of collaborative and industry robots, AR/VR and sensing and capturing facilities, as well as conventional making.
Project aim and findings: a practice-based PhD in Industrial Design is aimed at mid-career and senior practitioners operating within the field of industrial design. Candidates will contribute new knowledge to the field through critical and rigorous self-reflection, systematic investigation, scholarly enquiry and analysis of their own design practice; including the knowledge, skills and methodologies they developed as a practitioner.
The aim is to document, make explicit and voice this research knowledge, which is otherwise inherent and implicit in their ongoing design practice. In return, the candidates’ own practice will be enhanced with the expanded range of interrogative, analytical and evaluative skills developed during the practice-based PhD. Outcomes of a practice-based PhD are expected to be in the form of a combined project, generating a new body of ideas-based/creative work and a written dissertation that together will make an original contribution to knowledge, enabling the candidate to become a recognized authority within the field.
Project aim: the development of affordable housing in mixed-tenure neighbourhoods is frequently meant with opposition from local residents, planners, politicians and the media. This opposition can lead to costly construction delays and amendments for affordable housing developers and, in some cases, may even force the abandonment of projects. In the most high-profile cases, the opposition threatens to undermine political and public support for affordable housing provision. There has been much research on the phenomenon of community opposition to affordable housing development in the USA, but there is almost no equivalent research in Australia.
Project findings: Gethin Davison’s PhD research found that most affordable housing proposals are not controversial, but a small number of high-profile cases undermine political and public support for affordable housing provision. This project also contributes to understanding the NIMBY (Not In My Backyard) movement in Australia. Levels of opposition to affordable housing tend to be greater in relatively wealthy areas, especially where there is no precedent for multi-unit development or affordable housing. In particular, opposition to affordable housing is highly localised, with most submissions made against affordable housing proposals coming from people living close to the site. Planning assessment processes can generate or exacerbate community opposition to affordable housing, especially where community involvement is limited.
Project aim: in recent years, the planning, design and installation of “green infrastructure” at the local and city level have been identified as a best practice and nature-based solution to achieving greater urban sustainability and resilience. This project aims to develop an indicator-based model using a mixed-method approach to evaluate the performance of urban green infrastructure. This model is composed of a set of sixteen key indicators within four subcategories: ecological; health and wellbeing; sociocultural; and economic. Each represents key interactions between human health, ecosystem services and ecosystem health. This model is tested, validated and verified through a case study in Sydney, Australia.
Project findings: the significance of the research is that the derived indicator-based model provides an opportunity to understand the complex relationships of the multidimensional structure of urban green spaces. It provides a useful insight for urban designers and decision-makers in monitoring various aspects of the urban ecosystem, and it also allows for early warnings regarding any undesirable changes in sustainability levels.
Appropriate undergraduate degree with first or upper second-class honours or a completed Masters by Research degree, or academic qualification(s) considered equivalent.
Candidates may be admitted to the PhD program after one year's full-time enrolment in a Masters by Research program with the approval of the School Higher Degree Research Committee.
In exceptional cases, an applicant who submits evidence of such other academic and professional qualifications, as may be approved by the School Higher Degree Committee, may be permitted to enrol for the degree. English language requirements apply. Please refer to UNSW’s English Requirements Policy.
Postgraduate Research Scholarships (RTP, UPA, TFS): allow at least eight weeks from the time of submitting your application to the School HDC to the closing date for the university’s scholarship rounds. For more information, please see the Graduate Research School website. See deadlines for UNSW apply online applications and scholarships. | https://www.unsw.edu.au/arts-design-architecture/study-with-us/postgraduate-research/doctor-of-philosophy-phd/built-environment-practice-based-phd |
The Falls and Syncope Service (FASS) based at the RVI is the largest unit of its kind in Europe. With an international reputation for its research and clinical work our staff here have received several national awards for their innovative work in the field of falls and blackouts.
Founded in 1991, the FASS investigates, diagnoses and helps manage syncope (blackouts / loss of consciousness) and falls, particularly, but not exclusively, in older patients.
Patients are referred to us by local GPs and consultants from within the Trust or from other hospitals throughout the country. In 2006 we established the first Rapid Access facility in the UK to allow direct referrals from the North East Ambulance Service, as well as from Accident and Emergency and wards within our Trust.
Our patients present with a range of problems such as: balance disorders; dizziness; low blood pressure; gait and balance problems; or unspecified lack of co-ordination and falls. New patients undergo a series of investigations to establish the cause of their condition and we assess, identify and treat risk factors for falls, blackouts, dizziness and osteoporosis.
We continually monitor our standards of care and foster innovation through ongoing education and training for all our staff.
unspecified lack of co-ordination and falls.
All new patients we see undergo a series of highly specialist investigations to help us find out the cause of their condition and we can also assess, identify and treat risk factors for falls, blackouts, dizziness and osteoporosis. Once we know the root of the problem, you can start the right treatment or receive advice to help resolve the problem.
If you are attending the Falls and Syncope Service and it is felt appropriate for your care you will be referred to the Falls and Syncope Service Physiotherapist.
The majority of people referred to the Falls and Syncope Physiotherapist will be experiencing balance problems, unsteadiness, or dizziness.
On your initial appointment the Physiotherapist will ask you about your falls, unsteadiness and dizziness. She will look at the movement in your joints, muscle strength, balance and walking. This initial assessment will take approximately 45 minutes. From this the Physiotherapist will identify whether her assistance is the most appropriate, and if so, areas in your health that require assistance; these can include strength and balance exercises, coping strategies in the event of any future falls, any requirements you may need at home, walking aids, and mutual goal setting. If necessary the Physiotherapist will also refer you to our Occupational Therapist for a home assessment to identify any assistance that can be given.
A “plan of action” will be agreed between yourself and the Falls and Syncope Service Physiotherapist and a further appointment will be given at your convenience.
Your physiotherapy appointment will go at your pace however it is usual to be seen in clinic approximately every 4 – 6 weeks. The Physiotherapist is also happy to answer any questions you may have.
The Falls and Syncope Service is a day unit that is open from 9am – 5pm.
If you have difficulty getting to the unit an Ambulance can be arranged to collect you from home and return you after your appointment.
All new patients will have an ECG, an active stand test, and a blood test. The tests are done by the nursing staff in the unit.
The doctor will take a full medical history and a thorough physical examination in accordance with our care pathway. | http://www.newcastle-hospitals.org.uk/services/falls-syncope.aspx |
A classification essay is a type of college essay that classifies different items with the same characteristics into specific classes or groups. It is assigned to paper writing service and students at different academic levels. In this essay type, the writer must carefully conduct research and collect data carefully.
At first glance, this essay might seem very simple, but as a matter of fact, this essay involves finding a group of things that have something in common and then dividing them into groups. The division is done on the basis of one or more factors that differentiate them. Yet another difficult thing that an essay writer faces while writing this essay is finding a good topic. Not just for a classification essay but a good topic is important for any other essay type. It helps the writer to write my essay and attain the attention of the reader and also it helps in making the overall process of writing easy.
In this article, you will find some very interesting topics for your classification essay. Once you select a good topic, make sure that you conduct enough research on it, and analyze it. The topics mentioned below are carefully picked and are researchable as well. Hopefully, after going through these topics, you will not need any assistance regarding the topic selection.
Easy Topics For Classification Essay
- Types of different mental disorders.
- Types of phobias people face.
- Types of student behavior in class.
- Different types of obsessive-compulsive disorders.
- Types of behavior in the workplace.
- Different types of weight-loss diets.
- The most common allergy types.
- Types of home treatments for migraines.
- Types of self-help strategies for depression
- Ways arthritis sufferers can get relief from joint pain.
- Factors increasing the risk of heart disease.
- Types of hair loss treatments.
- Types of social networks these days.
- Types of mobile applications.
- Types of smart devices for kids.
- The most widely used search engines these days.
- Types of school systems in North American countries.
- Different ways to pay for your college education.
- Types of extracurricular activities that schools offer.
- Accommodation options for college students.
- Types of study resources available on the internet.
- Types of teaching techniques applied in elementary school.
- Types of energy sources in the United States.
- Theories explaining how life started on Earth.
- Modern monarchies around the world.
- International organizations that the US participates in.
- Types of strategies applied in political debate.
- Different factors are essential for a healthy relationship.
- Types of family gatherings around you.
- Dictators of the 20th century in Europe.
- World leaders during World War II.
- Wars led by the United States before the start of the 20th century
- Different countries involved in World War I.
- Types of skills that managers should have.
- Types of job applicant assessment tests.
- Different funding options for new businesses.
- Types of strategies for making a good business decision.
- The major stock exchanges in the world.
- Different types of real estate investment strategies.
- Different types of surveys in market research.
- Different types of economic theories.
- International economic organizations.
Interesting Classification Essay Topics
It is very important that the topic you choose is interesting. Along with that, it should also be easy and unique. To make this sure, you need to conduct detailed research or also hire an online essay writer. Nevertheless, the following is a list of some very catchy classification essay topics.
- Different art movements of the 20th century.
- Ways to say that you are embarrassed.
- Types of jobs that students can get on campus.
- Ways to make a home eco friendly.
- Types of sources for essay writing.
- The most popular tools students use these days.
- Colors and their meaning in the paintings.
- The evolution of rock-music types.
- Standard methods students use to prepare for tests.
- Public speakers that have influenced the world.
- Unique factors to determine a successful relationship.
- How to improve child-parent relationships.
- Main motives to start a political career
- Learning techniques for college students
- Types of TV comedy shows you get to see.
- The major types of mobile applications.
- Different communication possibilities available online.
- Strategies for making good decisions in business.
- Leadership and leader types.
- Conflicts at the job and effective ways to get away with them.
- The motivation for doing sports and exercise.
- Bowling is categorized as an Olympic sport.
- Women playing on men’s sports teams.
- Illustrated chapter books: comic books vs. graphic novels
- The enforcers of sports rules: referee vs. umpire vs. official
- Different types of modern outdoor sports.
- Elements of the U.S. constitution that are now considered outdated.
- Rules for teens moving into separate housing.
- Holistic medicine covered by health insurance.
- Different types of teasing done on living things.
Hopefully now must have understood what should a classification essay topic look like. But still, if at any point you feel the need for professional help, hit up an essay writer with your “write essay for me” query.
- Types of snacks called “chips” that are not actually potato chips.
- Caffeinated drinks categorized as energy drinks.
- Different earbuds are categorized as a type of headphones.
- Movies with different types of graphics.
- Reality shows that should be considered scripted or pre-planned.
- Types of social media posts.
- Different types of democratic parties.
- Calming techniques that work.
- Places that haven’t been explored by humans yet.
- Different types of inventions.
- Extracurricular activities for schools.
- Occupational fields that can never be outdated.
Hopefully, these topics will help you with the topic selection of your classification essay. In addition to that, you need to write my essay for me and make sure that you are using the right data for the right type of audience. In case you are not able to manage the time for your essay writing assignment, you may hit an essay writing service. Such services will help you not just write an essay but also get a good grade on that assignment.
More Resources: | https://webyourself.eu/blogs/5568/Creative-Classification-Essay-Topics |
Listing Provided Courtesy Of:
SoCal Real Estate Consultants
Data Source:
San Diego Regional MLS (SDMLS) - 32 - CA
Property Description
Variance granted Detached. Nicely maintained 2 on 1 on the border of San Diego and La Mesa. Street of well kept homes. Front house is a 3/1 with a detached 2 car garage and large yard. Rear house is a 2/1 that is accessed from the alley in back and has off street parking and a private yard. Both homes have their own laundry. Front house has real hard wood floors, three bedrooms, all with ceiling fans, nice kitchen with slider to back yard. Bath has tub and separate shower. Live in one home, have rental income to help pay the mortgage with the second house. There is lots of parking for front house. Room for 5 or 6 cars, RV, boat. etc. Home has a lot of charm, Rear house is a two bedroom with large kitchen, and living room, nice outside living space and privacy. All tenants are month to month and know property is for sale. Rents are low. One block south of I-8. West of 70th street. Approximately 2 miles east of SDSU campus. Close to Lake Murray. Property can be delivered vacant or occupied. | https://www.pemberleyrealty.com/property/32-210028491-6937-39-Saranac-St-San-Diego-CA-92115 |
The information they provide is similar to that provided by medical screening tests. Compare different sources books, movies, art, songs, poems about an event and talk about how they treat one topic or moment differently. Push-ups are one measure of upper body strength. It may not be the vacation of Peter's dreams, but as millions of Judy Blume fans know, it won't be dull.
As mentioned before, if she needs some inspiration, she can use a real newspaper as a guide. Talk about the books as you read them, reviewing main ideas and plots and expressing your opinions on the book. Do this for a few problems and keep score. A Individualized Education Program.
The average child completed 10 push-ups. The highest scoring child completed 19 push-ups. In our sample, the Y axis represents the number of children who earned a specific score number of push-ups completed. Help your child see things from different perspectives.
Here's how you can tell the difference between a news story and a feature story. Were black and white students separated. The next most frequently obtained scores were 9 and 11, followed by 8 and When you attend your next IEP or Eligibility meeting, you will be glad you did your homework.
If you believe that you "can't" understand your child's testing, it's time to change your beliefs. As we continue to analyze the children's scores, we see patterns: As we analyze the data in our sample, we can compare the performance of any individual child with that of the entire group. Be sure your interviewee knows he is being recorded.
A score may measure only one variable or it may accurately reflect all of the above. Related learning resources Worksheet Zombie News Story Imagine you are a reporter in the midst of a zombie outbreak. She would progress from the 5. Student Two Opinion Four Square. Half of the children completed ten push-ups or more.
Identifies, compares, and contrasts different perspectives from which texts are written.
Man bites dog and not passive verbs for example: Eventually, the teacher sent Mike's "case" to a special education committee. Fourth graders also use technology to research both past and current events. When he starts asking questions about his ancestors, he is startled to discover a black sheep in the family tree.
Instead, she plans to send Elsie to boarding school. In other words, after a full year of special education to remediate her learning disabilities, Shannon was expected to make only four months of progress in reading and math.
Back to Top Statistics: Where will you find the information you need.
The Basic Story Outline The best way to structure a newspaper article is to first write an outline. We will measure the children's progress on one or more occasions as they progress through the class.
Oct 20, · How to Write a News Article. Four Parts: Sample Articles Planning Your Article Writing Your News Article Proofing Your Article Community Q&A. Writing a news article is different from writing other articles or informative pieces because news articles present information in a specific way%(91).
It's bad writing. It's always been bad writing. With the Common Core Standards designed to shift the way we teach students to think, read, and write, this outdated writing tradition must end. If. 4 Lesson Plan Let's Write a Newspaper Story!
Goal: Students will be transformed into reporters who write newspaper stories that can be pasted up into a class newspaper.
STEP 2: Now, using your research and notes, write an outline for your own article. Remember, your first version of a story is a first draft, not a finished article. Here a few good tips for turning in a quality story to your editor/teacher. Read the story at least one time for comprehension.
Our subscribers' grade-level estimate for this page: 4th - 5th Newspaper Glossary. Graphic Organizers: Newspaper Worksheets for writing newspaper articles and for analyzing existing newspaper articles: Fact/Opinion News Article T-Chart Printout (4. | https://konilukilu.clientesporclics.com/how-to-write-a-newspaper-article-4th-grade-33423bi.html |
After a tumultuous few years, the psychological impact of the Covid-19 pandemic is still emerging but experts fear that we are heading into a mental health pandemic.
It’s believed that the pandemic has hit certain demographics harder including the unemployed, those with existing long-term physical or mental health conditions, women, people from minority ethnic communities and the LGBTQ+ community.
With mental health cases on the rise, we take a look at 10 shocking statistics which every employer needs to know.
822,000 workers suffered from work-related stress, depression or anxiety (new or long-standing) in 2020/21.
An estimated 449,000 reported that this was caused or made worse by the effects of the coronavirus pandemic.
Source: hse.gov.uk
In 2020/21 stress, depression or anxiety accounted for 50% of all work-related ill health cases.
Source: hse.gov.uk
According to the Mental Health Foundation, 74% of UK adults have felt so stressed at some point over the last year they felt overwhelmed or unable to cope.
Source: stress.org.uk
Evidence suggests that 12.7% of all sickness absence days in the UK can be attributed to mental health conditions.
Source: mentalhealth.org.uk
Better mental health support in the workplace can save UK businesses up to £8 billion per year.
Source: mentalhealth.org.uk
One in six adults experienced some form of depression in summer 2021, compared with one in five in early 2021
Source: ons.gov.uk
In summer 2021, the most commonly reported impacts of the pandemic on life by adults experiencing some form of depression were well-being (74%), lack of freedom and independence (44%) and access to healthcare and treatment for non-coronavirus related issues (40%).
Source: ons.gov.uk
Poor mental health is also cited as a factor that impacts productivity for 1 in 5 employees, contributing to costly levels of presenteeism (on both a personal and business level).
Source: championhealth.co.uk
Almost 35% of employees report that the stress they experience at work is having a negative impact on them.
Source: championhealth.co.uk
As a result of the pandemic, in 2021, 57% of organisations placed mental health as a focus area.
Source: cipd.co.uk
With such startling statistics, paying attention to workplace mental health has never been more important. It’s believed that good mental health at work and good management go hand in hand and there is strong evidence that workplaces with high levels of mental wellbeing are more productive.
Wellness programmes, additional paid leave and private health insurance are all tools which savvy employers are utilising to support their employees during what is considered a mental health crisis.
Do you need inspiration on how to improve the wellbeing in your workplace? Why not check out our blogs?
21 Wellness Benefits to Help Your Employees Thrive
How To Support Mental Health in the Workplace
Who is Spencer Clarke Group?
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We currently specialise in 8 sectors:
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Corporate Functions
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Employers
If you’re struggling to fill a role, why don’t you give us a call on 01772 954200 to see how we can help?
One of our Recruitment Consultants will be happy to listen to the challenges which you are facing and advise on the best possible solution for you. | https://www.spencerclarkegroup.co.uk/blog/2022/03/10-mental-health-statistics-every-employer-should-know |
A Maryland tax exempt organization is also referred to as a nonprofit organization. Such businesses are generally formed in the same way as other types of business structures. There are similar requirements for most businesses when forming, such as choosing a name, choosing a business structure, filing an organizational document, obtaining an Employer Identification Number (EIN), and obtaining applicable licensing and permits.
However, every state has unique requirements for different types of businesses; nonprofit organizations are especially different in that they are formed not to make a profit, but rather have a charitable purpose to assist a certain population, whether it is assistance for children, those suffering from a substance abuse disorder, animals, wildlife, the elderly, or another category.
Choosing a Maryland Nonprofit Structure
In every state, there are categories of nonprofits that a business can be categorized in. The State of Maryland has three categories as follows:
- Religious
- Tax-exempt nonstock
- Nonstock
A religious nonprofit is one that is formed for a religious purpose. It could be a religious organization to help a particular Catholic church, synagogue, or mosque. The second category is a nonprofit organization that qualifies as a 501(c)(3) organization. You will be categorized as a 501(c) only if you apply for the federal tax exemption. The third category is the typical nonprofit organization – one that doesn’t qualify as a 501(c), but isn’t formed for religious purposes.
Prepare and File the Articles of Incorporation
You must have one of the officers or directors draft the Articles of Incorporation, which will include information regarding the business as follows:
- Name
- Address
- Purpose
- If the business is going to request to be treated as a 501(c)
- Category that the nonprofit falls into
- Number of directors, including their names, addresses, and responsibilities
You can choose to submit the form by mail, in person, fax, or online. There is a $100 filing fee, along with a $20 organization fee and a $50 development center fee if you also plan on requesting 501(c) status. If you want to expedite your submission, you can pay an additional $50 fee.
The State of Maryland takes roughly 10 weeks to process your submission. If you pay the expedited fee, you can expect a response within approximately 7 business days.
Obtain an EIN
You’ll need to obtain an EIN, or Employer Identification Number, for your nonprofit. All nonprofits are required to obtain this 9-digit identification number, even if the business doesn’t hire employees. You will need this ID number to open a business bank account, apply for 501(c) status, and to submit Form 990 to the IRS. There is no fee for obtaining an EIN, and it can be done quickly online.
Draft Policies and Procedures
While not required, it is highly advisable to create some sort of policy and procedure document. This will be a governing document for your nonprofit that can be used for future reference. It will essentially be the manual that all directors, employees, and officers can look to when they are unsure of something. If an issue comes along and there is nothing identified in the policy, the document should be amended to include such information.
Obtain Maryland State Identification Number
Any new business in Maryland is enrolled in Maryland property tax. You will need to register for a state ID number, (which is done on the Comptroller of Maryland’s website). You will need to submit form CRA (Combined Registration Application). You can submit it online or by mail. There is no fee associated with this form.
Apply for 501(c)
While this might seem like a difficult task, applying for 501(c) status can be incredibly beneficial for your nonprofit. You’ll be able to apply for grants, benefit from tax exemptions, and more. In order to apply for such status, you will fill out Form 1023 or 1023-EZ, which can be found on the IRS website.
After submitting your application, the IRS will then send you a determination letter identifying whether or not your application was successful.
Keep in mind that not all nonprofits qualify for this status, and it is best to have a professional assist in this application.
If you need help with learning about a Maryland tax exempt organization, or how to register your Maryland nonprofit organization, you can post your legal need on UpCounsel’s marketplace. UpCounsel accepts only the top 5 percent of lawyers to its site. Lawyers on UpCounsel come from law schools such as Harvard Law and Yale Law, and average 14 years of legal experience, including work with or on behalf of companies like Google, Menlo Ventures, and Airbnb. | https://www.upcounsel.com/maryland-tax-exempt-organizations |
MTN Nigeria – The leader in telecommunications in Nigeria, and a part of a diverse community in Africa and the Middle East, our brand is instantly recognisable.
It is through our compelling brand that we are able to attract the right talents who we carefully nurture by continuously improving our employment offerings even beyond reward and recognition.
We are recruiting to fill the position of:
Job Title: Strategic Accounts Manager
Location: Nigeria
Job Description
- Ensure full compliance with regulatory, legal and commercial requirements.
- Manage a direct sales Enterprise sales account team
- Consistently meet and exceed sales and revenue targets, monthly, quarterly and yearly.
- Build and maintain relationship with Internal suppliers/stakeholders
- Liaise with all ES staff and other relevant Divisions within MTN Group
- Review market and internal conditions and develop aggressive sales strategy that grows MTNN’s revenue streams and exceeds individual targets and objectives and assist department in planning and developing budgets for the upcoming year.
- Capture sales data, monitor sales performance and trends and generate assessment reports and analysis for management review.
- Supply relevant decision support and management information data to ensure that sales performance conform to investors’expectations.
- Ensures efficient use of the resources assigned to Strategic Accounts to profitably meet the agreed needs of all customers.
- Identify sales training and development needs and manage skills enhancement programmes for Strategic Account partners to ensure enterprise sales targets are fully met.
- Review performance of individual team members and complete appraisals in accordance with the employee performance appraisal procedures and time schedules.
- Identify and develop a robust pipeline of opportunities within the strategic accounts which are systematically qualified, whilst managing the decision-making process within the account to ensure sales opportunities are closed.
- Develop compelling business cases for investment within relevant verticals, to assist in clearly identifying return on investment and risk.
- Provide guidance and manage relationship with allocated Customer Service Officers and Debt Collection Officers to ensure maximum support for all Strategic Accounts.
- Integrate quality management processes within all business processes within the department to ensure effectiveness, efficiency and quality services to customers.
Job Condition
- Normal MTNN working conditions
- May be required to work extended hours
- Maybe required to travel out of station (10%)
Experience & Training
Experience:
- 8 years’ work experience which includes:
- Minimum of 5 years’ experience in Sales or Business development organization
- At least 2 years in sales management will be an advantage
- Strong sales planning, negotiation and analytical skills
- Outstanding sales target achievement record will be a consideration
- Sales experience in OEM, ICT, Telecom or Banking environment will be an advantage
- Excellent oral and written communication skills, plus a good working knowledge of Microsoft Office Suite is required
Training:
- Sales Management
- Relationship Management
- Leadership Management
- People Management
- Business Development
Minimum Qualification
- BA, B.Ed, B.Sc, HND or B.Tech.
How to Apply
Interested and qualified candidates should:
Click here to apply
Application Deadline 17th November, 2015. | http://joblanda.com/mtn-nigeria-job-vacancy-for-a-strategic-accounts-manager/ |
Voynich Meadow Part 4: Sunflower
This work was inspired and adapted from the "Voynich Manuscript," a 15th century codex hand-written in an unknown writing system, which may have been composed in Northern Italy during the Italian Renaissance. The mystery of the meaning and origin of the manuscript has excited the popular imagination, making the manuscript the subject of novels and speculation.
Sunflowers symbolize adoration, loyalty and longevity. Much of the meaning of sunflowers stems from its namesake, the sun itself. These flowers are unique in that they have the ability to provide energy in the form of nourishment and vibrancy—attributes which mirror the sun and the energy provided by its heat and light. | https://elainegleason.com/products/voynich-meadow-part-4-sunflower |
Inventory Executive SAP (B-1) APPLY NOW
Zuria Dor is looking for an Inventory Executive. This person will be responsible for ensuring inventory operational excellence, overseeing multiple key functions in the business, and driving both top and bottom-line growth relevant to inventory, warehouse and SAP ERP. This person is a strategic thinker, capable of quickly assessing scenarios and translating strategy into action plans. They must be a strong leader who is able to inspire others to take positive action without being prescriptive. This person has experience honing their operational, strategy, and management skills in a fast-paced environment and is well-versed in how to manage complex inventory-based operations at scale. This person will be critical touch point for multiple teams, including activities related to product development, product documentation, supply chain, SKU planning, vendor management, people operations, quality and compliance to ensure the entire business is operating efficiently. They will report to the CEO and Creative Director. This role will put in place processes for operational tasks and run their day-to-day. The ideal candidate will be a key player in enabling the team to support rapid growth and drive efficiencies in the company's back-end operation. As the brand grows, this role's responsibilities will expand.
How you will contribute:
- Assist the CEO in setting and driving inventory strategy
- Ensuring purchase order processing information is kept up to date on SAP Business One
- Supporting third party supplier relationships and attending supply chain meetings
- Liaising with purchasing lead to monitor stock levels
- Updating SAP Business One for delivery information received from suppliers
- Providing booking information for warehouses when goods arrive
- Organising transportation from warehouses
- End to end inventory management including daily issuances and production fulfilments
- Managing and keeping up to date Master Item Data and relevant product catalogues
- Managing inward and outward movement of stock
- Managing all relevant issuances
- Training other SAP users
- Managing daily and monthly stock reports
- Monitoring production runs, creating and maintaining WIP report
- Drive the inventory and planning to optimise for stock levels, speed, and margin
- Coordinate with internal design teams on product development issuances as well as maintain accurate product documentation
- Oversee order flow and logistics
- Help coordinate the transportation of goods along the production process
- Propose best path forward to balance growth and profitability
- Provide calendar management
- Develop reports and analysis
- Supporting initiatives for data integrity and normalisation
- Generating reports from single or multiple systems/databases
- Troubleshooting the reporting database environment and reports
- Evaluating changes and updates to source
- Create data dashboards, graphs and visualisations
- Carry out all duties and functions as directed by the CEO
- Approach every day with a continuous improvement mindset; consistently identifying areas for improvement and putting forward recommendations
- Provide continuous improvement methodology and formal problem-solving techniques, enabling departments to drive better business results
- Adhere to company, federal, and local business requirements, enforcing compliance and taking action when necessary
Ideal Candidate: | https://zuriador.com/pages/inventory-executive-sap-b-1 |
The 2021 Electoral Program is a 2-month long paid direct voter contact field program for fellows that provides the skills, financial compensation, and long term infrastructure to support door-knocking efforts through Planned Parenthood Virginia PAC on behalf of our endorsed candidates in Virginia.
General Description
Planned Parenthood Virginia PAC is seeking fellows to engage in grassroots outreach to members in their community about the 2021 election and our endorsed candidates. Each fellow will work directly with the fellows manager and the community organizer responsible for their region to develop and execute campaign plans in their assigned area.
What the fellow will gain from working with the Electoral Fellowship Program:
Opportunity to craft and implement campaign plans with Planned Parenthood Virginia PAC
Build deep and intentional relationships with the local community, organizations and leaders who can support campaign efforts
Engage, educate, and mobilize local communities on reproductive health and rights, and electing supportive champions to statewide office and the House of Delegates
Experience recruiting, training, and managing volunteers to participate in canvassing, campaign actions, and other community events
Develop an understanding of how data is a vital component to track and analyze advocacy campaigns by using Voter Activation Network (VAN)
Manage logistics, planning, and implementation of efforts for canvassing outreach
Special qualifications include: | https://jobs.feminist.org/job/planned-parenthood-advocates-of-virginia-fellowship-paid-electoral-fellowship/ |
This course introduces applications and algorithms for linear, network, integer, and nonlinear optimization. Topics include the primal and dual simplex methods, network flow algorithms, branch and bound, interior point methods, Newton and quasi-Newton methods, and heuristic methods. Students will gain experience in formulating models and implementing algorithms using MATLAB. No previous experience with the software is required. Prerequisite(s): Multivariate calculus, linear algebra. Comfort with reading and writing mathematical proofs would be helpful but is not required. Course Note(s): Due to overlap in subject matter in EN.625.615 and EN.625.616, students may not receive credit towards the MS or post-master’s certificate for both EN.625.615 and EN.625.616.
Course Goal
This course covers fundamental methods of optimization. Emphasis in this course will be on formulating optimization problems, understanding the methods available to address them, and solving them using appropriate means.
Course Objectives
Learn how to convert real world scenarios involving optimization into mathematical problems.
- Use the Simplex Method, and some of its variants to numerically solve problems that can be stated as linear programs.
- Apply classical methods of optimization to problems that may be formulated using nonlinear functions.
- Address special topics such as multi-objective optimization, dynamic programming, non-derivative optimization methods, and optimization heuristics.
When This Course is Typically Offered
This course is typically offered online in the fall and spring semesters.
Syllabus
- Optimization Applications
- Formulation of Optimization Models
- Graphical Solution of Linear Programs
- Simplex Method
- Linear Programming Duality and Sensitivity Analysis
- Nonlinear Optimization Theory
- Steepest Descent and Conjugate Gradient Methods
- Newton and Quasi-Newton Methods
- Quadratic Programming
- Network Models
- Dynamic Programming
- Multi-objective Programming
- Optimization Heuristics
Student Assessment Criteria
|Homework||30%|
|Midterm Exam||30%|
|Final Exam||30%|
|Discussions||10%|
All homework is due within one week of its assignment. Late homework will not be accepted without the prior permission of the instructor. The two lowest homework scores will be dropped.
Timely feedback on students' performance is an established learning tool, so we will endeavor to grade and return to you, as quickly as possible, all material that you submit.
Homework will normally be graded and returned via the website before the next assignment is due. If you do not receive a grade on homework that you have turned in, please ask of its whereabouts; it may need to be resubmitted.
A grade of A-/A/A+ indicates achievement of consistent excellence and distinction throughout the course—that is, conspicuous excellence in all aspects of assignments and discussion in every week.
A grade of B-/B/B+ indicates work that meets all course requirements on a level appropriate for graduate academic work.
These criteria apply to both undergraduates and graduate students taking the course.
All external sources of information used by the student must be appropriately referenced. Students should be fully aware of JHU's policy on academic integrity.
Computer and Technical Requirements
Students will use Matlab to complete assignments. Students are not expected to be proficient with the software although some experience with it would be beneficial. Examples on how to use the software will be provided in the lectures and through handouts.
Participation Expectations
Homework is expected to be turned in on the website as indicated in the assignment tool; it will be considered late if it is received after that time. Special circumstances (e.g., temporary lack of internet access) can be cheerfully accommodated if the student informs us in advance. Homework that is unjustifiably late will have the grade reduced for lateness.
We generally do not directly grade spelling and grammar. However, egregious violations of the rules of the English language will be noted without comment. Consistently poor performance in either spelling or grammar is taken as an indication of poor written communication ability that may detract from your grade.
Students are expected to participate in any class discussions. Discussions are used to review concepts from the lectures.
Textbooks
Textbook information for this course is available online through the MBS Direct Virtual Bookstore.
Course Notes
There are no notes for this course.
Final Words from the Instructor
The optional course text is Engineering Optimization: Theory and Practice, by Singiresu S. Rao, John Wiley and Sons. You can reference the 4th edition or higher:
* 4th edition (2009). ISBN: 978-0-470-18352-6
* 5th edition (2019) ISBN: 978-1-119-45471-7
To be successful in this course, the student should have a good understanding of multivariable calculus and proof techniques. Specifically, from multivariable calculus, you should be familiar with:
1. limits
2. derivative definition as a limit
3. product rule for differentiation
4. L'Hopital's rule
5. chain rule for differentiation
6. integration by parts
7. integration via substitutions
8. partial derivatives
From Linear Algebra, you should be familiar with:
1. Taking a word problem and converting it into a system of linear equations and/or linear inequalities.
2. Finding the set of feasible solutions for a system of linear inequalities in 2 variables graphically.
3. Matrix arithmetic (add, subtract, multiple by a constant; multiplying two matrices)
4. Solving systems of linear equations using Gaussian or Gauss-Jordan elimination.
5. Finding the inverse of a matrix using Gauss-Jordan elimination
6. Finding the determinant of a matrix
7. Finding eigenvalues and eigenvectors for a matrix
8. Linear independence and dependence of vectors
9. Linear combinations of vectors
While students will generally be walked through any proofs, it will also help students are familiar with basic proof techniques:
1. Direct proof of if-then and if-and-only-if statements.
2.Indirect proof (i.e., by contradiction or contrapositive)
3.Proof by weak and strong induction. | https://apps.ep.jhu.edu/course-homepages/3022-625-615-introduction-to-optimization |
CROSS REFERENCE TO RELATED APPLICATIONS
FIELD
This application is a U.S. National Phase application under 35 U.S.C. § 371 of International Application No. PCT/EP2020/073808, filed on Aug. 26, 2020, and claims benefit to European Patent Application No. EP 19194447.9, filed on Aug. 29, 2019. The International Application was published in German on Mar. 4, 2021 as WO 2021/037885 A1 under PCT Article 21(2).
The invention relates to a method and a computer program product for automated defect detection during borescoping of an engine.
BACKGROUND
Engines, in particular jet engines of aircraft, have to be regularly inspected in order to check compliance with the technical safety requirements and to recognize any possible damage at an early stage. Particularly for inspections while the jet engine is mounted on the aircraft (on-wing), lateral flaps on the jet engine are opened and/or individual components are removed, so that an inspector can look into the interior of the jet engine directly or with the aid of a borescope in order to inspect the engine blades. In this case, the task of the inspector, directly at the eyepiece of the borescope or—in the case of a video borescope—at the video monitor connected thereto, is to assess the engine blades and reliably identify defects on the engine blades, such as e.g. notches or indentations, in the tenths of a millimeter range.
In this case, for inspecting the engine blades of an individual rotatable engine stage of the jet engine, it is known to guide them, by rotation of the engine stage, past an observation opening of the jet engine or past a borescope inserted into the jet engine in such a way that one after another all the engine blades of the engine stage of the jet engine can be assessed in the observation opening or the field of view of the borescope.
The inspection of all the engine stages of a jet engine requires a number of hours; for example, four hours have to be estimated just for the inspection of the nine stages of the high-pressure compressor of a CFM56 engine. The outcome of this is then an evaluation by the inspector, which represents the inspector's visual impression, but regularly does not satisfy the requirements in respect of a standardized appraisal.
SUMMARY
In an embodiment, the present disclosure provides a method that automatically detects defects during borescoping of an engine. In the method, a video borescope is inserted into the engine in such a way that, during rotation of an engine shaft, engine blades of an engine stage which are secured to the engine shaft are moved successively through the image region of the video borescope. A possible defect on an engine blade is identified by image recognition on the basis of a frame generated by the video borescope. The movement of the engine blades in the image region of the video borescope is detected by comparing in each case two successive frames. The possible defect on the video image along the detected movement is tracked by optical image recognition on the basis of the successive frames used for detecting the movement. In a condition where a trace of the possible defect on the video image corresponds to the detected movement in terms of direction and speed over a predefined length, the possible defect is identified as an actual defect.
BRIEF DESCRIPTION OF THE DRAWINGS
Subject matter of the present disclosure will be described in even greater detail below based on the exemplary figures. All features described and/or illustrated herein can be used alone or combined in different combinations. The features and advantages of various embodiments will become apparent by reading the following detailed description with reference to the attached drawings, which illustrate the following:
FIG. 1
shows an arrangement configured for carrying out the method according to the invention;
a
b
FIGS. 2and 2
FIG. 1
show two series of successive frames recorded by the video borescope of the arrangement in accordance with ;
FIG. 3
shows an exemplary illustration of the segmentation of frames; and
a
b
FIGS. 4and 4
show an exemplary illustration of the movement recognition and determination of the relative position of engine blades on the basis of segmented frames.
DETAILED DESCRIPTION
In an embodiment, the present invention provides a method with which the inspection of the engine blades of rotatable engine stages of a jet engine is improved.
Identifying a possible defect on an engine blade by image recognition on the basis of a frame of the video borescope;
Detecting the movement of the engine blades in the image region of the video borescope by comparing in each case two successive frames;
Tracking the possible defect on the video image along the detected movement by optical image recognition on the basis of the frames used for detecting the movement;
If the trace of a possible defect on the video image corresponds to the detected movement in terms of direction and speed over a predefined length: identifying the possible defect as an actual defect.
An embodiment of the present invention relates to a method for automated defect detection during borescoping of an engine, in which a video borescope is inserted into an engine in such a way that, during rotation of an engine shaft, the engine blades of an engine stage which are secured to the engine shaft are moved successively through the image region of the video borescope. The method includes:
An embodiment of the present invention furthermore relates to a computer program product comprising program parts which, when loaded in a computer, are designed for carrying out a method according to an embodiment of the invention.
Some terms used in association with the invention are explained below.
A “video borescope” is a borescope which provides a continuous analog or digital video image of the image region of the borescope for further processing. In this case, the image recorded by an optical unit at the free end of the borescope can be guided via an optical line to a camera at the other end of the borescope and there it can be converted to the desired video image. However it is also possible for the recorded image to be converted into a video image by a suitable chip (e.g. charge-coupled device (CCD) or complementary metal oxide semiconductor (CMOS) chip) directly at the free end of the borescope, the video image then being communicated via a data line to the other end of the borescope and being available there for further processing.
The “video image” is a continuous sequence of “frames” in which the temporal spacing between the recording of the frames is generally constant, for which reason it is also possible to have recourse to the image refresh rate as a measure of the number of frames per predefined time segment.
“Two successive frames” are two temporally successive frames. They need not necessarily be two directly successive images of the video image. It is also possible for the video image also to comprise intermediate images between the two successive frames, but the intermediate images are not taken into account at least in the determination according to the invention of the movement of the engine blades in the image region of the video borescope.
An embodiment of the present invention provides a method which makes it possible at least partly to automate the demanding, but also monotonous activity of individual assessment of the multiplicity of engine blades of an aircraft engine. In order that this (partial) automation of the inspection of the engine can be taken into consideration at all, a high reliability of the defect detection is required. This is achieved with the method according to an embodiment of the invention since both false negative and false positive results can be reduced to such a great extent that the error rate of the method according to an embodiment of the invention is comparable to, if not even lower than, that in the case of manual inspection.
The method according to embodiments of the invention is based here on an arrangement which is in the context of borescoping of an engine and in which a video borescope is inserted through a suitable opening into an aircraft engine and is oriented such that at least one engine blade of the engine stage to be examined is situated in the image region of the video borescope. Consequently, by rotation of that engine shaft to which the engine blades of the engine stage to be examined are secured, the individual engine blades of the engine stage can be moved successively through the image region of the video borescope.
Even if hereinafter, for reasons of clarity, it is assumed that the image region of the video borescope is large enough, in principle, to capture the entire blade length of the engine blades, the method according to embodiments of the invention is also suitable for assessing individual longitudinal sections of the engine blades. By means of sufficient repetition of the method for the individual longitudinal sections, it is then possible to carry out a complete inspection of the engine blades of an engine stage over the entire blade length thereof.
On the frames of the video image or at least one portion thereof, possible defects on the engine blade(s) situated in the image are identified with the aid of image recognition. What are involved at this stage are initially only “defect candidates”, i.e. those distinctive features on the engine blades which are identifiable by the image recognition and which may possibly represent a defect.
By virtue of the fact that the video borescope does not just record frames as necessary, but rather provides a continuous video image, a possible movement of the engine blades can be detected by comparing in each case two successive frames. Such a movement can regularly be achieved only by rotation of the engine shaft to which the engine blades observed by the video borescope are secured. By virtue of the fact that, according to an embodiment of the invention, the movement of the engine blades is detected solely on the basis of the video image, it is unimportant how the rotational movement of the engine shaft is actually achieved. Even manual rotation of the engine shaft remains possible, as a result of which the method according to an embodiment of the invention is usable in a flexible way.
If a movement of the engine blades is detected, the possible defect identified previously is tracked on the video images along the detected movement. For this purpose, an optical image recognition is applied to those frames of the video image which are actually used for detecting the movement. It is possible here to apply the image recognition in each case to the entire frames, in order thus, e.g., also to be able to identify newly possible defects in the image region of the video borescope (see above), or else to restrict the image recognition to those regions of the frames in which the possible defect would have to be situated in accordance with the detected movement, which can result in a considerable saving of computing power. A combination of the two possibilities is also conceivable; by way of example, every fourth frame is supplied in its entirety to the image recognition, while only the regions in which possible defects identified previously would have to be situated are analyzed in each case for the intervening frames.
If a possible defect identified initially is repeatedly identified by the image recognition on a plurality of successive frames, this gives rise to a trace of the possible defect across the frames. If this trace corresponds, in terms of direction and speed, to the movement of the engine blades detected on the basis of the same frames, and if the trace furthermore has a predefined length as well, the defect previously classified only as a possible candidate can be identified as an actual defect.
By virtue of the fact that the method according to embodiments the invention does not rely on the image recognition of frames for identifying defects, incorrect results—e.g. on account of light reflections, shadow casting, contamination, dust, etc.—can be avoided. Only if a possible defect, across a plurality of frames in which the possible defect is situated at a different location on account of the movement of the engine blades, is in each case identified and thus confirmed as a possible defect is it possible to assume with very high probability that a defect is actually involved. Conversely, it holds true that if a possible defect is identified only on individual frames that are not temporally successive, it is possible to assume with very high probability that an actual defect is not involved.
It has been found that with the method according to embodiments of the invention it is possible to achieve a defect recognition accuracy at least comparable to that of manual inspection. Often it is even possible to achieve a better result.
Inter alia, in order that the defects identified in accordance with the method according to embodiments of the invention can be checked in a simple manner, it is preferred if the detection of the movement of the engine blades is used to identify the position of the individual engine blades vis-à-vis an arbitrarily chosen initial engine blade. By way of example, if the engine blade situated the most fully in the image region of the video borescope upon the first identification of a possible defect on the basis of the video image is assumed as the initial engine blade, the other engine blades can be unambiguously determined in their relative position vis-à-vis the initial engine blade by means of the detected movement correspondingly being taken into account. For example, it is thus possible to “consecutively number” the individual engine blades proceeding from the initial engine blade. As a result, by means of suitable rotation of the engine shaft with detection of the movement, a specific, already analyzed engine blade can be moved into the image region of the video borescope in order that in this way e.g. an inspector can check the defect detected by the method on the engine blade in question, which is unambiguously identifiable on the basis of the numbering, once again on the basis of a live video image in order thus to confirm or reject the defect detection. In the course of numbering the engine blades it is possible to take account of the direction of rotation of the engine shaft, such that the numbering e.g. is ascending in the clockwise direction, in principle.
In a preferred embodiment, the method comprises controlling the rotational movement. The rotational movement can be controlled, e.g., by suitable driving of the air starter of the aircraft engine or of an external drive arranged temporarily on the aircraft engine. Even if, solely on the basis of corresponding control, it is not regularly possible to accurately determine the movement of the engine blades in the image region of the video borescope, nevertheless at least the presence of such a movement per se and in particular the basic direction of the movement can be taken into account in the comparison of two successive frames for the purpose of detecting the movement, wherein in particular the predefinition of the direction can simplify the ultimate detection of the movement. Furthermore, suitable control of the rotational movement makes it possible to ensure that the engine blades move only at a sufficiently low speed through the image region of the borescope in order that their movement can still be detected on the basis of the frames and optionally also the position of the individual engine blades vis-à-vis an arbitrarily chosen initial engine blade can be identified.
For the detection of the movement of the engine blades, in a preferred embodiment, the frames are segmented into regions which exactly reflect the contours of the individual engine blades, wherein the remaining region can then be identified as non-blade region. In comparison with image capturing methods which involve determining a bounding box around specific objects contained in an image, the segmentation yields the exact contour of the visible part of e.g. an engine blade. This enables a more accurate assignment of the individual image regions to individual engine blades. The segmentation can be effected e.g. by a convolutional neural network, such as the mask-region-based convolutional neural network (RCNN) method, for example, preferably comprising an inception feature extractor as described by He, Gkioxari, Dollar and Girshick in the article “Mask R-CNN” (arXiv.org, document number 1703.06870v3). The movement detection can then be effected by altering the segmentation of two temporally successive frames. All that is necessary for this purpose is that the movement of the engine blades is sufficiently slow, that the positions of the individual engine blades do not change too much from one frame to the next, and in particular that a specific engine blade is imaged on more than two successive frames used for detecting the movement. This last can be ensured by a suitable choice of the image refresh rate of the video borescope, a suitable choice of the number of intermediate images—not to be considered—between two frames and/or the speed of the movement of the engine blades in the image region of the video borescope.
In order to reduce the required computing power for the segmentation of frames, in a preferred embodiment, exclusion regions are defined in which the frames are not segmented. If the video image contains, e.g., regions which do not change even during movement of the engine blades—such as e.g. stator blades or stationary walls—these can be excluded by the predefinition of suitable exclusion regions prior to the segmentation, such that the segmentation need only be carried out for a section of the frames.
Irrespective of whether the detection of the movement is effected by way of the described segmentation and the subsequent comparison of successive frames or any other method, in a preferred embodiment, a direction of movement of the engine blades in the image region of the video borescope is predefined, which direction of movement is then actually complied with during the actual movement. If a direction of movement is predefined, this reduces the computational complexity of the assignment of the individual engine blades or of the individual engine blade segments during a movement. In this case, the predefinition of the direction of movement of the turbine blades in the image region of the video borescope corresponds, in principle, to a predefinition of the direction of rotation for the rotation of the engine shaft to which the turbine blades in question are secured.
The actual identification of defects on the engine blades, such as, e.g., notches or indentations, is preferably effected with the aid of a convolutional neural network, e.g. a Faster-RCNN method, as described inter alia by Ren, He, Girshick and Sun in the article “Faster R-CNN: Towards Real-Time Object Detection with Region Proposal Networks” (arXiv.org, document number 1506.01497v3). The method is fast enough to be used in addition to the initial defect identification also for tracking a possible defect during the movement of the engine blades.
Both the Mask-RCNN method and the Faster-RCNN method are based on convolutional neural networks. However, it is also possible, in principle, to have recourse to other deep learning methods. In particular, the deep learning method ultimately used for the defect identification can continue to be improved by the above-described confirmation or rejection of the defect detection by an inspector. Moreover, the deep learning methods used are trained prior to their first use by means of suitable manually edited or evaluated training data sets each comprising frames on which the regions or features to be recognized later in an automated manner are marked. Depending on the deep learning method used, the training complexity or the complexity for creating training data sets can be reduced by a frame that forms the basis of a training data set being converted into a further data training set by mirroring, rotation or adaptation of contrast and/or brightness, wherein the ultimate complex marking of the frames—if appropriate with comparable mirroring and/or rotation—can be adopted without manual rework being required.
For the elucidation of the computer program product, reference is made to the explanations above.
FIG. 1
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shows, by way of example, an exemplary arrangement configured for carrying out the method according an embodiment of the invention during use for borescope inspection of an aircraft engine .
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The aircraft engine is a turbofan engine with a low-pressure compressor stage comprising the fan , this stage being connected to a low-pressure turbine via a first shaft , and also a high-pressure compressor stage , which is connected to a high-pressure turbine stage via a second shaft . The combustion chamber is arranged between the high-pressure compressor stage and high-pressure turbine stage .
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FIG. 1
For the inspection of the engine blades of the individual stages , , and , the engine cowling has been opened (and is therefore illustrated using dashed lines), with the result that access to the core engine is free. Various borescope openings are provided on the core engine and a video borescope can be selectively inserted into them. shows by way of example two borescope openings , into each of which a borescope can be inserted in order thus to assess the engine blades of a specific turbine stage—either the high-pressure compressor stage or the high-pressure turbine stage in the example illustrated—by means of the borescope . By means of rotation of that shaft , to which the engine blades to be assessed are secured—i.e. the second shaft in the example—all engine blades of the engine stage situated in the image region of the borescope can be assessed successively. A direction of rotation, indicated by the arrow , is predefined for this purpose. The actual rotation of the second shaft is effected by a drive unit integrated into the aircraft engine .
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The video borescope is connected to a computer unit configured for the processing—described below—of the video image originating from the video borescope . Furthermore, the computer unit also comprises an output for linking to the control unit of the aircraft engine in order by way thereof to control the drive unit for the second shaft . A terminal is furthermore connected to the computer unit , via which terminal the video image or frames therefrom can be assessed by an inspector.
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FIG. 2
FIG. 1
FIG. 2
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shows by way of example from left to right three temporally successive frames of the video image of an individual stage of the high-pressure turbine stage , the video image having been recorded by the video borescope in accordance with . Between the frames shown there are also two intermediate images in each case, which are not taken into account, however, in the processing described below and can therefore also be omitted in the illustration in
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On account of a rotation of the second shaft in the direction of rotation shown in , the rotation being initiated by the computer unit via the output , the engine blades of the engine stage move through the image field of the video borescope . Consequently, the engine blade shown moves from left to right in the frames in
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For each of the frames in accordance with , an image recognition is carried out in order to recognize possible defects. For the defect recognition, recourse is made to a suitably trained Faster-RCNN method trained in particular for recognizing notches and dents. All possible defects on the frames in accordance with are marked by a box .
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The frames in accordance with are also used to determine the movement of the engine blades in the image region of the video borescope .
FIG. 3
FIG. 3
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As shown by way of example in on the basis of other frames ′ of a video image recorded by a borescope , each frame ′ is segmented into individual engine blade regions ′ with the aid of a Mask-RCNN method with an inception feature extractor (, bottom).
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In this case, an exclusion region indicated by dash-dotted lines is defined, in which the frames ′ need not be segmented since a stationary element is situated in this region of the video image and the possibility that an engine blade will be able to be seen in this region is thus excluded. The computing power required for the segmentation can be reduced by the definition of an exclusion region .
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Since the computer unit has initiated rotation of the second shaft in the direction via the output , as a result of which the basic direction of movement of the engine blades in the image region of the borescope is known, the speed and direction of the movement of the engine blades ′, which is indicated by the vector ′ in , can be ascertained in a simple manner on the basis of the engine blade regions ′.
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The envisaged segmentation of the frames ′ also makes it possible, in addition to the detection of the movement of the engine blades , to determine the relative position of the individual engine blades vis-à-vis an arbitrarily chosen initial engine blade ″, which will be explained in greater detail below with reference to and
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As illustrated in , a frame ″ is firstly segmented in accordance with , wherein—if a corresponding selection has not yet been made—one of the engine blade segments ′ is defined as the initial engine blade ″. The engine blades or the engine blade segments ′ can then be numbered consecutively proceeding from the initial engine blade ″.
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Afterward, taking account of the detected movement of the engine blades , each engine blade segment ′ can be assigned a unique number corresponding to counting through the individual engine blades or engine blade segments ′ (cf. ). By virtue of the position of the individual engine blades that is detected in this way, it is possible to move individual engine blades whose position was detected in a targeted manner by means of corresponding driving of the drive of the shaft via the output of the computer unit and simultaneous checking in accordance with in order thus to enable e.g. the rechecking of a specific possible defect identified on the corresponding engine blades on the basis of a live video image via the terminal .
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Already on the basis of the movement of the engine blades that is detected in accordance with , the possible defects identified in can be tracked on the video image, more precisely on the frames used for the movement detection. For this purpose, an optical image recognition is carried out in each case for the frames in question, wherein—as in the present case—it is possible to have recourse to the image capturing described in association with for identifying possible defects or the results thereof. In combination with the detected movement, for the individual possible defects, provided that they are found on all of the frames, it is possible to determine a trace over the video image such as illustrated in . If one of the traces determined in this way has a length that is above a predefined length, the possible defect forming the trace can be identified as an actual defect, which can be documented suitably in a standardized manner.
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If a continuous trace of sufficient length cannot be determined for a possible defect, e.g. because no defect assignable to a specific trace was able to be identified on a frame , the possible defect is with high probability not an actual defect. Such a possible defect can nevertheless be documented and, in particular, as discussed above, by means of a process of moving in a targeted manner to the engine blade with the possible defect, can be assessed once again by an inspector via the terminal in order to verify the appraisal determined in an automated manner. The same also applies, of course, to the defects identified as actual defects.
The results of the verification by an inspector can be used for optimizing the image recognition of possible defects.
While subject matter of the present disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. Any statement made herein characterizing the invention is also to be considered illustrative or exemplary and not restrictive as the invention is defined by the claims. It will be understood that changes and modifications may be made, by those of ordinary skill in the art, within the scope of the following claims, which may include any combination of features from different embodiments described above.
The terms used in the claims should be construed to have the broadest reasonable interpretation consistent with the foregoing description. For example, the use of the article “a” or “the” in introducing an element should not be interpreted as being exclusive of a plurality of elements. Likewise, the recitation of “or” should be interpreted as being inclusive, such that the recitation of “A or B” is not exclusive of “A and B,” unless it is clear from the context or the foregoing description that only one of A and B is intended. Further, the recitation of “at least one of A, B and C” should be interpreted as one or more of a group of elements consisting of A, B and C, and should not be interpreted as requiring at least one of each of the listed elements A, B and C, regardless of whether A, B and C are related as categories or otherwise. Moreover, the recitation of “A, B and/or C” or “at least one of A, B or C” should be interpreted as including any singular entity from the listed elements, e.g., A, any subset from the listed elements, e.g., A and B, or the entire list of elements A, B and C. | |
Flashcards in AFC Arthritis Deck (30)
Loading flashcards...
1
Where do bones grow from?
Growth plate (epiphyseal plate)
2
State Hueter-Volkmann’s Law?
Increased compression at the growth plate slows down longitudinal growth
Increased tension at the growth plate speeds up longitudinal growth
3
Give an example of where this can be used to correct an abnormality.
Eight Growth Plate – if there is abnormal growth on one side of the distal tibial physis you can inset a metal plate with pins on either side of the growth plate to prevent further growth on that side and allow the other side to catch up
4
What are the three different types of knee alignment?
Normal/Neutral
Varus – bowed legs
Valgus – knocked knees
5
What types of athletes get varus alignment?
Footballers
6
Which part of the knee joint would be loaded most in varus alignment?
The inner part
7
What are the consequences of this?
It will wear out the cartilage and cause osteoarthritis
8
What surgical intervention can be performed before the onset of osteoarthritis to realign the knee joint?
Osteotomy – this involves taking a wedge out of the tibia to realign the knee joint
9
State Wolff’s Law.
Bone in a healthy person will adapt to the loads under which it is placed
10
Give an example that illustrates Wolff’s law.
Surfer’s knots
11
What are the two surfaces of the cortical bone?
Periosteal surface
Endosteal surface
12
Load on the bones causes an increase in cortical thickness – how is this response to loading different in children compared to adults?
Children – have an active periosteum and endosteum so they get increased bone growth at BOTH surfaces
Adults – their periosteum is less active – so the response to increased loading is mainly at the endosteal surface
13
A lot of problems to do with body shape occur in utero. Give an example of such a problem that is associated with 9-10% of cases of osteoarthritis
Developmental Dysplasia of the Hip (DDH)
14
Describe the appearance of the hip joint in someone who had DDH.
The hip joint may be higher than normal
The acetabulum is shallow and it doesn’t cover much of the femoral head
This leads to increased load and wear
15
Why is it important to spot these deformities early?
If these deformities are caught early, they could realign them and cause a remodelling of the joint to allow normal stance
16
Name and describe two abnormalities of the hip joint.
Cam – bump on the neck
Pincer – the acetabulum tries to capture the hip joint so it is much deeper than normal (mainly seen in females)
17
What are the negative consequences of Cam abnormality?
Deep flexion will cause repeated impact between the bump on the femoral neck and the acetabular rim leading to the wearing away of thecartilage --> osteoarthritis
18
What are the negative consequences of Pincer abnormality?
The femoral neck will impact with the deepened acetabular labrum and cause compacting of the femoral head posteriorly (this will cause a contre-coup type erosion of the cartilage on the posterior acetabular surface)
19
Name the two cruciate ligaments of the knee joints and state their roles with regards to sliding at the knee joint.
Anterior cruciate ligament – stops the tibia from sliding forwards
Posterior cruciate ligament – stops the tibia from sliding backwards
20
What is a synovial joint?
A joint covered with hyaline cartilage or fibrocartilage that is surrounded by a fibrous capsule with a synovial membrane on the inside producing synovial fluid to lubricate the joint
21
What is the structural difference between the medial and lateral menisci?
The lateral meniscus has a much tighter C shape
22
What are the two main functions of cartilage?
Shock absorption
Low friction
23
Which type of collagen is found in cartilage?
Type 2
24
Describe the arrangement of collagen in the superficial layer andexplain why they are arranged like this.
Horizontally – resists shear forces
25
Describe the arrangement of collagen in the deep layer and explain why they are arranged like this.
Vertically – resists compressive forces
26
What provides the nutrition to the tissue above the tidemark?
Synovial fluid
27
What is the downside to the lack of blood supply above the tidemark?
This means that if the cartilage superficial to the subchondral bone is damaged, it can’t really heal itself
28
What is the name given to the pattern of fibres that form the collagen network in bone?
Arcades
29
What happens to your tibia when the ACL snaps and what other structures will try to hold it in place? | https://www.brainscape.com/flashcards/afc-arthritis-7508008/packs/12343027 |
Representative Ro Khanna, a Democrat from California, speaks during a House Oversight and Reform Committee hearing in Washington, D.C. Bloomberg/Bloomberg via Getty Images
There were tense moments in a House Oversight Committee hearing Thursday, where executives from the world's biggest oil and gas companies took questions about their role in the climate crisis. It's the first time all were testifying together.
Rep. Carolyn Maloney, D-N.Y., who chairs the oversight committee, compared the hearing to the one in 1994 when the CEOs of all the large tobacco companies appeared under oath and answered questions about industry practices. During that hearing the witnesses argued smoking wasn't addictive, but admitted publicly the harmful health effects of nicotine.
Maloney ended the hearing by saying that she had subpoenas at hand for the executives after she said they failed to comply with a request for documents that could show where and how the companies are spending their money on ads and lobbying. Rep. James Comer, R-Ky., the top Republican on the panel, objected to the idea.
Thursday's hearing was also part of the committee's investigation into what Maloney called the industry's decades-long "climate disinformation" efforts about the impact of fossil fuels on global warming.
"It's time for the American people to hear directly from the top fossil fuel executives about how they manufactured and concealed a global emergency while reaping trillions in corporate profit," Maloney told NPR.
The case Democrats made throughout the day is one they've made for a long time. Oil and gas companies — much like tobacco — knew that their product was harmful for years and did nothing. Moreover, Democrats demanded the witnesses take some blame, not just for their inaction but for pushing misinformation and for lobbying against legislation that would reduce carbon emissions — claims that they rejected.
The CEOs — Darren Woods of ExxonMobil, David Lawler of BP America, Michael Wirth of Chevron, Gretchen Watkins of Shell — as well as Mike Sommers from the American Petroleum Institute, the industry's trade association, and Suzanne Clark from the U.S. Chamber of Commerce, each made their case saying that climate change was real and that they were taking steps to address how their companies can move towards renewable and clean energy. But the witnesses — and Republicans at the hearing — also tried to make the case of how much oil and gas played in day-to-day life.
"I don't think people understand this isn't about just starting the car everyday," said Rep. Yvette Herrell, R-N.M. "Anybody who's gotten a vaccination or is going to get one, thank you to the oil and gas industry because I would bet that almost every single one of these syringes has been touched by petroleum products."
BP's Lawler recognized that "the world's carbon budget was finite" and said a carbon-neutral future was imperative but would take time.
"This doesn't mean BP is getting out of the oil and gas business," Lawler said. "As we transition, our oil and gas business will continue providing the energy the world needs, while funding our investments in wind, solar, and other renewable energy sources."
The time of a transition away from carbon pollution was at the heart of the hearing, as well as the case that oil and gas companies weren't doing enough to stop misinformation and lobbying against legislation from Congress.
Rep. Ro Khanna, D-Calif., who chairs the environment subcommittee, asked if the CEOs would ask API's Sommers if his organization would stop running ads attacking the methane tax and electric cars. (They side-stepped the question.)
Maloney also asked the executives if they would pledge to stop spending money to oppose efforts that would reduce emissions. Lawler from BP said that his company had stopped "all reputational advertising" but side-stepped the pledge. Watkins of Shell said she would "continue spending money on climate policy advocacy" but also side-stepped.
House Democrats cited a report released Thursday morning showing that the American Petroleum Institute, Exxon, BP, Chevron, Shell spent $452.6 million on lobbying the federal government since 2011. The executives also made the case throughout the day that they support measures like the Paris Agreement but the report found that almost "none of Big Oil's lobbying on legislation since 2015 was devoted to the Paris Agreement or related legislation."
Democrats focused on climate disinformation
Maloney and Khanna sent letters to all the oil companies and business organizations in September seeking information about marketing, lobbying, communications and research efforts related to climate policy. But Maloney said they have not complied. "They have provided documents but they're not the documents we requested."
At least one company pushed back on that assertion. Casey Norton, spokesperson for ExxonMobil, said they've been communicating with committee staff "for months and have cooperated with the request for documents."
What Democratic lawmakers want to uncover in this investigation is how the industry spent money on lobbyists and public relations efforts to influence lawmakers and the public by sowing doubts about climate science and the consequences of climate change.
Khanna said the committee has other public records and research that can helplay out the industry's record.
And he adds that he wants to press the executives on public campaigns indicating they are taking steps to use cleaner technologies while they are still pushing for leases to expand drilling.
"What they're doing in expanding oil development is totally inconsistent with what they're claiming they're going to do. And the hearing will expose both. They knew things and they lied about it and they continue to deceive," Khanna said.
Democrats also pressed ExxonMobil's Woods about comments from a lobbyist for the company, Keith McCoy, made to undercover activists that Greenpeace released this summer. McCoy talked about efforts to undermine any move to introduce a carbon tax and other regulations. He also boasted about his influence over Sen. Joe Manchin, D-W.Va., and other lawmakers. Woods condemned McCoy's comments after the video was circulated. Woods also reiterated the company's support for the goals in the Paris climate accord.
ExxonMobil's Norton said the company "has long acknowledged that climate change is real and poses serious risks." He pointed to the company's investments in new technologies. He added, "as the scientific community's understanding of climate change developed, ExxonMobil responded accordingly."
Comer objected to the hearing, arguing the panel is ignoring other pressing issues like immigration enforcement at the U.S. Southwest border or the president's decision to withdraw all U.S. troops from Afghanistan. The Republican suggested Cabinet officials should be asked to appear, not oil company CEOs.
In his opening statement shared with NPR, Comer was blunt about why Democrats had called the hearing.
"The purpose of this hearing is clear: to deliver partisan theater for primetime news," Comer said, according to his prepared remarks.
As for the Greenpeace video, Comer plans to say McCoy's comments were "deceptively edited."
Will Democrats be able to deliver on climate?
The hearing comes as Democratic leaders in Congress are struggling with intraparty divisions about policies to include in a broad domestic spending bill to combat climate change. President Biden and most Democrats pushed what's called the Clean Energy Performance Program to give utility companies incentives for switching to greener technologies and impose fees for those that failed to reduce emission targets.
Opposition from Manchin forced leaders to scuttle that approach, and they are working on a new mix of tax incentives and research and development grants to try to meet the president's target to cut greenhouse emissions by 50% by 2030.
The president, as well as a congressional delegation, are headed to a climate summit in Scotland this weekend, and many hope there will at least be an agreement on a framework on the climate programs to discuss, even if there is no vote on any package.
Maloney indicated that there would be more hearings on the issue, and that she hoped the companies would "work with us and come clean."
"Our committee members will not be satisfied with the executives paying lip service to renewable energy and climate change measures while they're investing in fossil fuels and signing contracts well into the future," she said.
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Earlier in the week, I wrote about the importance of identifying one’s time frame when trying to win in Ms. Market’s game. As I opined, trying to use a long-term approach to succeed from a short-term perspective can cause a great deal of both emotional and financial pain. As such, it is critical to know which of the three major time frames you are focusing on: Short-, Intermediate-, or Long-term. And it is for this reason that every couple of weeks, we attempt to succinctly summarize the outlook for all three.
So let’s review. From a short-term perspective, I’ve written that the trend is clearly a friend to the bulls right now. However, stocks are indeed overbought, sentiment has become too upbeat/complacent, and the seasonal cycle becomes a headwind from next week into early October. As such, I’ve suggested that investors plan accordingly and be prepared to buy the dip (or to put money to work in their portfolios for the long-term).
Looking out over the next 3-6 months, we believe the keys include the outlook for both earnings and the economy as well as the state of Fed policy. So, given that (a) the recent economic data (including this week’s LEI) has been decent and supports the prospects for further growth, (b) earnings are expected to perk up during the next reporting season (remember, oil has been a major reason for the earnings recession and oil is now moving higher), and (c) that global central banks continue to implement their QE programs, it is hard to be overly negative on the market.
From a longer-term point of view, we contend that stocks embarked on a new cyclical bull market on February 12, 2016. And as we’ve discussed, this new cyclical bull is occurring within the context of the secular bull trend that began on March 9, 2009. If we let history be our guide, this means that the cyclical bull should be stronger and longer than average and any cyclical bears that occur along the way (such as those we saw in 2011 and from August 2015 through February 11, 2016) should be shorter and shallower than average.
However, the bears contend that valuations are a big problem (the goal from our furry friends here is to conjure up memories/fears of 2000) and that we should be worried about the election.
On the first score, there is really no denying the fact that the absolute valuation metrics such as Price-to-Earnings/Dividends/Cash Flow/Book Value are at very high levels.
Yet it is important to note that when interest rates and the economic backdrop are taken into account, valuations are not at extreme levels. In fact, when considering the “relative valuation” of stocks and interest rates, the current levels are actually quite bullish.
Then when you consider the fact that the economy is growing and earnings are improving, even the absolute valuation picture doesn’t look so bad. And unless we see a 1999-style surge in prices or a very large spike in interest rates, we are of the opinion that valuations are not a reason to avoid stocks – even at these lofty levels.
For me, the bottom line here is the issue of valuation lies in the eyes of the beholder. So, you can either take defensive action now on the assumption that this won’t end well -or- decide to ride the bull train until there are signs that valuations matter to the market (such as when the economy weakens, inflation perks up, or the Fed gets aggressive).
As for the much ballyhooed election worries, I believe it is important to keep in mind that Wall Street really doesn’t care which side wins the White House in November. No, from a stock market perspective, presidential elections are really about expectations and/or uncertainty. And with Clinton leading in the polls of many key battle ground states, there doesn’t appear to be much fear or uncertainty in the market at this time. However, if the race tightens or if candidates start to talk about implementing pans that would be considered anti-growth, this situation could change in a hurry.
So for investors, I will suggest that one should pay more attention to the outlook for earnings and economic growth than the election – as far as investing in stocks and bonds are concerned, that is!
The literal bottom line is that while things may get sloppy in the near-term, there doesn’t seem to be a reason to be defensive from a longer-term perspective. However, I will be sure to alert you if things appear to be changing. | https://www.smarteranalyst.com/bloggers-corner/markets-outlook-things-may-get-sloppy-near-term-long-term-bullish-perspective-remains-intact/ |
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