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So, it has been about two years since I posted my wedding blog. We did have two other events but I never came back to write about the remaining. I do have a bunch of reasons for not posting about it but to cut a long story short, that year was a very overwhelming year for me. I had thought about writing it after I launched my website properly. But things got really busy with my PhD and a new job. The other reasons are rather dramatic and long so I will spare you the details.
As we were in January, I had social media and family reminding me of the events that happened two years ago. I couldn’t help but reminisce the past. I started wondering whether I should post the blog or if it is too late. I pretty much spent the last few weeks thinking about it and told myself that I’m just going to do it. So here it goes!
We had our pre-wedding function a week before our wedding. This event is a chance to put haldi / holud (turmeric paste) on the bride and groom. Applying turmeric paste to the bride and groom is seen as an act of blessing. Traditionally, haldi (Hindi) or holud (Bengali) holds a special place of honour as the colour is thought be auspicious and provides a natural glow.
Prior to the event
There was a lot of gift wrapping that needed to be done as this event also included a gift exchange from both parties. My family spent the whole day preparing the foods and presents, as per tradition. I wanted to help out but I was told to rest and enjoy being a bride.
I could have used that time to start getting ready earlier. But I was a hell of an enthusiastic bride who also wanted to wear a photographer hat. Here are some shots I took:
At the event
The theme for our event was yellow, green and red. The guests were asked to wear these colours. The venue was at Wright’s Road Function Centre in Castle Hill.
We had several dance performances by our family and friends. But we also had a local Bengali band come in to perform live music. The stage and table setting
The entrance song I chose for myself was Teri Ore (an all-time fav). The groom’s entrance was performed by a Punjabi
Some of the other
The Instagram frame for the DIY
Wedding favours were saved for the final event. We had initially planned to order on Etsy but we realised the products we liked had long shipping periods or did not have enough in supply (we needed ~200). In the end, we decided to keep it local by purchasing candles from Ikea and ordering customised labels on Vistaprint.
That’s pretty much it. Here are some shots captured by BV photography: | http://www.anikarouf.com/category/personal-stories/ |
In today’s reading (13:24-32), Jesus describes what lies ahead using words and phrases from many Old Testament prophecies. His reference to cosmic fireworks (“the sun will be darkened, and the moon will not give its light”) is not a literal description. The prophets frequently used these phrases to describe God’s judgment on and the downfall of powerful pagan nations (see Isa 13:9-10; 34:4; Ezek 32:7-8; Joel 2:10, 31; Amos 8:9). The coming judgment on Jerusalem for refusing to believe in the Messiah and for emptying the covenant of its true meaning was going to be a world-shaking event.
The destruction of the Temple, however, was not just the end of a beautiful building. It brought to a conclusion the long history of animal sacrifice for sin in Israel’s worship. When Jesus made His own sacrifice on the Cross and rose victorious over death, He became the fulfillment of all that had come before Him. To emphasize this, Jesus says that at the conclusion of the cosmic upheaval (the judgment on Israel and the destruction of the Temple), the disciples will see “the Son of Man coming in the clouds with great power and glory.” These are words from the prophet, Daniel, who had seen in a vision the ascendancy of “one like a Son of Man” over defeated earthly powers. After the tumultuous defeat of a succession of pagan kingdoms, the Son of Man was seen coming “with the clouds of heaven” to receive an eternal kingdom from “the Ancient of Days” (see Dan 7:13). Jews listening to Jesus that day would have been very familiar with Daniel’s vision and terminology. It was a prophecy of God’s ultimate victory over all earthly powers and the establishment of a new, everlasting kingdom of God’s people. That is precisely what began when the Temple in Jerusalem was destroyed. The “Son of Man,” Jesus, is God’s newTemple. He is the new and definitive meeting place of God and man. The “beautiful stones” in this Temple are believers, “the elect from the four winds, from the end of the earth to the end of the sky” (see 1 Pet 2:5).
This reading helps us put the destruction of the Temple and the reign of the Son of Man into biblical perspective. The author of Hebrews shows us the shortcomings of the sacrificial system of the Old Covenant. The blood of animals “can never take away sin.” The ritual practice of animal sacrifice was always meant to be a “tutor” for God’s people (see Gal 3:23-29), preparing them for its fulfillment. Jesus made “one sacrifice for sins,” Himself. Now, He is at God’s right hand as “He waits until His enemies are made His footstool.” We are nowin that time. As the Gospel spreads out to all the nations, conquering sin and death, Jesus’ enemies are being vanquished. At some point, this work will be completed, and Jesus will return to usher in the life of the world to come, where we will find that “by one offering He has made perfect forever those who are being consecrated.” May we wait with patience and joy. | http://corardens.com/blog/2018/11/11/thirty-third-sunday-in-ordinary-time-year-b-november-18-2018/ |
One of the most important WWE wrestlers of the whole company but also the most important of the whole world pro-wrestling scene, is undoubtedly WWE Champion Brock Lesnar, one of the Superstars of the McMahon-owned company with one of the highest star power ever, so much so that he managed to defeat The Undertaker at Wrestlemania 30, something that no one had succeeded in over 21 years of in-ring activity.
Since the beginning of his second stint in WWE, then, Lesnar has managed to reach heights never seen or reached before, conquering titled kingdoms over titled kingdoms, alongside thick characters such as Seth Rollins, Roman Reigns, Triple H, The Undertaker and many other holy monsters of the company.
In the last period, moreover, Lesnar has also let himself go to some answers to questions and questions that the fans of the WWE Universe have always asked themselves, with the WWE Champion who has appeared in several interviews, which has not happened for years, with the fighter who wanted to respond to these arguments that fans have been asking for a long time, but against which they have always and only found silence on the part of Beast Incarnate.
Brock Lesnar is a wrestling legend
Shortly before his match at MSG, Brock Lesnar appeared on The Michael Kay Show. He predicted that Roman Reigns could come out as a replacement for Bobby Lashley and challenge him for the belt.
Lesnar also added that he would have to keep an eye out for Reigns and Heyman. "I'm ready to be at the Garden. It's exciting to me. I don't know who I'm fighting yet, like, my opponent, Bobby Lashley, got injured.
I got a hunch, maybe, that Roman Reigns and Paul Heyman are gonna show up. I'm gonna have some eyeballs at the back of my head tomorrow," said Lesnar. In his latest and unusual interview released for the Newsday site, the WWE Champion of Monday Night Raw wanted to talk about how he managed to achieve a very large and wide success in the rings of the McMahon-owned company, also making a comparison with the Chairman himself of the federation and other important figures.
Regarding this argument, Brock Lesnar in fact stated: "I just have a work ethic that no one else has and it shows. If you follow me for seven days, you'll understand why I am who I am. And the people who have made such a huge success like Dwayne Johnson and Vince McMahon and Pat McAfee.
they are simply people who go there and take, refusing to say no." According to Lensar, therefore, the main secret would be to never stop or give up, continuing to work as workaholics day after day, to achieve all the set goals, however far they may be, they will never be unattainable. | https://www.wrestling-world.com/news/news/wwe/13968/brock-lesnar-still-has-a-lot-of-goals-to-achieve-/ |
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Rye Bread (Reduced Calorie)
Other common serving sizes
1 slice, thin
1 slice
1 oz
1 slice thick
100 g
Calories
203
Fat
2.9 g
Carbs
40.5 g
Protein
9.1 g
There are 203 calories in 100 grams of Rye Bread (Reduced Calorie).
Nutrition Facts
Serving Size
100 g
Amount Per Serving
Calories
203
% Daily Values*
Total Fat
2.9g
4%
Saturated Fat
0.368g
2%
Trans
Fat
-
Polyunsaturated Fat
0.752g
Monounsaturated Fat
0.672g
Cholesterol
0mg
0%
Sodium
405mg
17%
Total Carbohydrate
40.5g
14%
Dietary Fiber
12g
48%
Sugars
2.29g
Protein
9.1g
Vitamin D
-
Calcium
76mg
8%
Iron
3.10mg
17%
Potassium
98mg
3%
Vitamin A
4IU
0%
Vitamin C
0.4mg
1%
* The % Daily Value (DV) tells you how much a nutrient in a serving of food contributes to a daily diet. 2,000 calories a day is used for general nutrition advice.
Last updated
04 Feb 08 05:08 AM
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Calorie Counter 100% Free
Other common serving sizes
Serving Size
Calories
1 slice, thin
41
1 slice
47
1 oz
58
1 slice thick
65
100 g
203
Related types of Rye Bread
Reduced Calorie High Fiber Rye Bread
Toasted Rye Bread
Marble Rye and Pumpernickel Bread
Toasted Marble Rye and Pumpernickel Bread
Rye Bread
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This introductory course considers what is distinctively religious about religions. Using a combination of in depth case study and cross-cultural comparison, it introduces the student to recurrent themes, forms and structures of religion, considering such topics as: the nature of myth and ritual; sacred time and sacred space; gods, spirits and ancestors; as well as the roles of shaman, prophet, and priest.
001 Tu, F 11:10-12:25 Sproul
156 Tu, F 15:45-17:00 Raver
051 Tu, Th 20:25-21:40 Adluri
REL 111 Approaches to Religion
A modern critical study of religion using a variety of methods to further understanding of the role of religion in personal and social life. Approaches include those of philosophy, psychology, the arts, history, sociology, and anthropology. Readings are from a variety of differing religious traditions.
001 Tu, F 08:10-09:25 O’Neil
002 Tu, F 14:10-15:25 Cerequas (Room 205W)
051 M, W 20:25-21:40 Raver
REL 204 Experience of Religion
Here the emphasis is not on doctrines of religion, but on central experiences that underlie the institutions of religion. Readings are drawn from a variety of cultures: from ancient writings to contemporary ones; from religious traditions and from outside religious systems as such. Most of the readings concern the experiences themselves, in material such as the Australian initiation rites, Islamic and Native American rituals, The Epic of Gilgamesh, biblical narratives, the enlightenment of the Buddha, mystical experiences, the journals of Etty Hillesum. Work by several theorists will also be read. Questions will include: What is the experience like? What is "religious" experience? How does the experience affect people and their lives?
051 M, W 17:35-19:50 Raver
REL 206 Ideas of God
How does contemporary Western theology understand faith in God? What is meant--or ought to be meant--by the word "God"? How does the reality of evil figure into faith? Answers to these questions will be our primary focus as we read works by representative Jewish, Christian, and heterodox religious thinkers since World War II. Examples will be drawn from liberal, process, feminist, and radical perspectives, among others.
001 M, Th 13:10-14:25 Long
REL 207 Religious Sources for Morality
Ethics has been defined as the tension between that which "is" and that which "ought" to be. This course will focus on the origin of the "ought": How do we decide what is good and evil? What are the sources of our understanding of what ought to be? Are these sources religious? Have they to do with belief in God? (What do we mean by "religion" and by God"?) Reading will be in Buber, The Book of Job, Genesis, Psalms, The Gospel of Matthew, Wiesel, Kant, Kierkegaard, and Tillich.
001 Tu, F 12:45-14:00 Sproul
REL 208 Religion and Social Justice
While all religions agree that securing a socially just world is a 'constant occupation,' they disagree as to the concrete nature of that vocation. This course is designed to examine contemporary religious reflection on four social issues: war, race, the economy, and gender relations. The issues will be approached from as many sides as possible, examining them in light of the attitudes they reveal about God, society, and justice. The course will focus primarily on readings from a range of different traditions, in large part to illustrate the plurality of perspectives that exist.
001 Tu, F 11:10-12:25 Huffman (Room 205W)
REL 251 Eastern Religions
In an age of increasing encounter between very different cultures, it is critical that we attempt to understand religious traditions that are not historically our own. In this course we will encounter primarily the religious traditions of India (Hinduism and Buddhism) and China (Confucianism and Taoism). Readings are in sacred texts and secondary sources.
001 M, Th 11:10-12:25 Rhodes (Room 205W)
REL 252 Ancient Near Eastern Religions
This course is a survey of the basic history and of the most significant aspects of the religions of the major Near Eastern peoples in the Bronze Age (8000BCE-3000 BCE), including the Egyptians, Sumerians, Babylonians, Hittites, Canaanites, and Israelites. The magnificent civilizations that they built had an enormous influence on subsequent human culture. This course is based on primary material, of both archeological and literary natures, and will discuss the most important texts produced by religious and secular sources.
051 M, W 19:00-20:15 Raver
REL 253 Western Religions
Introduction to fundamental religious ideas in Judaism, Christianity, and Islam, focusing on the essential sacred texts in the Bible and the Qur'an. Attention is given to the influence of dualistic thought from Zoroastrianism and Gnostic systems, and to some mystical and contemporary interpretations.
001 Tu, W, F 9:10-10:00 Tirana
REL 254 Tribal Religions
An examination of the traditional religions of Australia, the Pacific Islands, and North America. Study of the theological implications of myths and rituals (ideas of God, good and evil, humanity and the world), consideration of social values and the role of the individual in relation to the group, discussion of the meaning found in life and in death in traditional cultures.
001 Tu, F 14:10-15:25 Sproul
REL 261.55 The Sacred Sky: Astrology in World Religion
Different cultures have varied beliefs about the sacred nature of the sky and how astronomical movement relates to lives and events on Earth. Viewing astrology as the vernacular used to describe the effect of astronomical cycles on terrestrial cycles, this course examines how those patterns were interpreted and understood to have meaning. The emphasis of the course is on Western astrology, from its origins in Mesopotamia to its current popularity, but also includes a look at Chinese, Native American, Mesoamerican, and Vedic astrology.
001 M, Th 8:10-9:25 Finn
REL 262.54 Religions of Early Europe
Both Greek and Roman classical authors described the peoples north of the Danube River as “barbarians,” tribes uncultured and illiterate, warlike and unmatched in their banality. We know from what they left behind, however, that this was far from true. We know very little about the tribes of ancient Europe, and even less about their religious systems, but what we do know through archaeology and text provides us with a belief system that does not necessarily correspond to what the Greeks and Romans, and later, the Christians, believed. We examine early religions systems found in Europe from prehistoric, Celtic, Germanic, Balkan and Nordic cultural remains and reconstruct their belief systems based on the primary sources at hand.
051 Tu, Th 17:35-18:50 Raver
REL 270 Religion and Psychology
"Every statement about God is a statement about the human person, and every statement about the human is a statement about God." This course will examine the complementarity between religion and psychology in many aspects of the human person through the media of selected text, film, and story.
001 M, Th 16:10-17:25 Haltenberger (Room 205W)
REL 310 Religious Meaning of Death
The fact of death is at the center of the study of religion. The meaning one gives to death often determines the direction of one's life. This course will explore the various meanings which different cultures in different historical periods have discovered in the reality of death. Attention will also be given to contemporary formulations. Material studied will be cross-cultural and interdisciplinary. Discussion will center on the assigned readings.
051 M, W 19:00-20:15 Adluri
REL 312 Religion and Politics
This course examines the interplay between religion and politics: how religious beliefs influence politics and how historical, cultural, and social factors affect religious views. Examined are contemporary situations in which religion is playing a visible role in the aims and understandings of political purposes. Included are "fundamentalist" movements in Islam, Judaism, and Christianity, and theologies of liberation in Latin America, U. S. Black Churches, and the feminist movement. The religious foundations and historical backgrounds of each movement will be considered, as will the present religious perspectives and interpretations of tradition that underlie specific political positions.
001 Tu, W, F 10:10-11:00 Tirana
REL 313 Spirit and Nature
The religious traditions of the world give expression to--and are frequently the supports for--many of our attitudes towards the natural world; both conscious and unconscious. The religious traditions treated in the course are chosen to present a typology of the different ways religions have conceptualized and thereby evaluated nature and animal life; whether, for example, the human is conceptualized as being kin to nature (as among Australian Aborigines and Native Americas), or part of nature (e.g., Taoism and Buddhism), or indeed "above" nature (e.g., the Abrahamic faiths, Judaism, Christianity, and Islam). At the same time, the course is rounded out by an exploration of religious grounds for and against vegetarianism.
001 M, Th 14:45-16:00 Long
REL 315 The Problem of Evil
Is it possible to say that we are living in an "age of evil," that the events of our time reveal the presence of a "spirit of evil" in our midst? What does religion have to say about such a phenomenon? How does religion think about and define evil? Who or what is responsible? Can anything be done about it? These are the questions this course will address by way of Eastern and Western religious materials.
001 M, Th 9:45-11:00 Bruinius (Room 205W)
REL 321 Buddhism
Study of Buddhism, its development, literature, and religious practices. Since Gautama Buddha is the outstanding figure in the history of Indian religions, we will explore the myths about him in order to understand his life and teachings. The emphasis will be Indian Buddhism. Whenever possible, we will compare this Eastern tradition with the traditions of the West in order to better understand our own faiths.
001 M, Th 13:10-14:45 Rhodes (Room 205W)
REL 322 Islam
An introduction to the major concepts, practices, and texts of Islam, as well as an examination of the life and faith of the prophet Mohammed. A study of Islam's origin in its own sociocultural framework, its ideologies, ethos, and ethics, as well as its adaptive changes and reinterpretations in the course of history, including its status in the modern world as one of the most populous and wide-spread religions.
001 M, W, Th 12:10-13:00 Weinfield (Room 409W)
REL 324 Islam and Buddhism
A constructive study of Buddhism and Islam, two dynamic world religions propagating differing world views. In the past, they have had historical interactions with one another. This course is an examination of their founders, their development, their major texts, their beliefs and rituals. Special attention is given to their historic collisions and to the manner in which they have met the challenges posed by the different cultural and geographic contexts they have encountered. Their contrasting appeals for contemporary Americans are considered.
001 M, Th 9:45-11:00 Breiner (Room 205W)
REL 323 Christianity
An upper level introduction to the liturgical, doctrinal, and spiritual
heritage of the various forms of Christianity.
001 M, F 09:45-11:00 Cole
REL 334 Mysticism
A critical analysis of the patterns and nature of mystical experiences. Analyzing mystical reports and writers from a variety of traditions and eras, we will explore the nature of the transition processes which lead to these experiences and the experiences themselves. We will also ask of the commonalities and differences of the thoughts of mystics, and explore several typologies of them. Finally, we will look at the very lively contemporary debate about these experiences, focusing on the question of the role of language, background, and expectations in mystical experiences.
051 Tu, Th 17:35-18:50 Adluri (Room 205W)
REL 340 Homosexuality in World Religions
This course surveys and analyzes typical ways in which homosexuality has been understood, evaluated and, in some cases, institutionalized in a variety of religious traditions, attending especially to implicit constructions of gender.
001 M, Th 16:10-17:25 Long
REL 361.53 Atheism
What does it mean today to consider oneself an atheist? Is being an atheist a matter of preferring a particular set of values, or is more the absence of those values? Do atheists have a coherent belief-system? In answering this question, it helps to observe the historical moment when “atheism” changed from being simply an insult to a defended philosophical position. Studying this evolution yields some surprises: we are used to thinking of atheism as the antithesis of all that religion is. But in fact, atheism as we know it in our world today has many important roots that lie inside of different religious traditions. This course will explore some of these origins and challenge students to rethink and refine their concepts of what is involved in “not believing in God.”
001 M, Th 11:10-12:25 Weinfield
REL 361.56 Religion and Science
An exploration of the ways in which Science and Religion have related historically as well as in modern times. As a class we will agree on a definition of both Science and Religion and work to discover their place in the human experience both historically and in modern times, exploring the relation between Science and Religion historically, theoretically, philosophically, and theologically. | http://www.hunter.cuny.edu/religion/course-offerings/by-semester/10c?None&month:int=10&year:int=2012&orig_query=None |
Not every child in poor communities will take summer school classes. Community members must support summer programs that engage parents and families.
By Don Allen, Publisher – Our Black News
In this modern world filled with thousands of technological distractions, it is becoming very difficult for students to focus in their educative processes without falling for the temptations of using free wifi or instant messaging. What can we do to help students keep their attention on the important things and contents that will be essential for them in the future in an attractive way? How can we incorporate meaningful activities during summer breaks in order maintain their interest and mindset around their education?
First of all, we need to acknowledge the fact that learning should be a cyclical process based on scaffolding. Most teachers and professional trainers become inefficient to some degree because they fail to recognize this basic truth, and do not apply the right procedures that will help them avoid the classic forgetting curve, which is a fundamental truth in memory theory. The key element to make sure the retention of knowledge happens successfully in our students by applying constant revision in regular doses to consolidate their memories.
Second of all, we must make sure students keep contact with at least some of the most important part of every subject during summer time. Let’s be honest: it’s very difficult for most kids to even open a book in their free time, so it seems impossible to make this happen. How do we proceed under these difficult conditions? If we want to make a difference here, there must be a shift in our approach on the situation: instead of giving students lots and lots of boring and difficult material they have to do, let’s give them small spaced doses of knowledge over a period of time to elaborate and allow deep processing to fix long-term memories. If we do this, they won’t feel the pressure of the assignments and the increase in the productivity of learning will be gigantic.
The other main aspect to consider is the fact that during summer, students are on their own: they won’t have a teacher that will be guiding them or helping them with their doubts, (or to act as a positive role model and supervise the kids during the summer months-keeping them out of danger and away from crime) so we must prepare students and give them the right strategies that will allow them to ensure their own learning. This is a very beneficial measure to take: it will help them to gain control over their own learning process, which will benefit them not only during the summer, but in every educational task they undertake in the future. The most important step we must follow is teaching students these strategies during the school year and give them the right opportunities to put them to practice during their free time. Some of the best strategies we can teach them are: Self-rehearsal, Blogging, and Games pedagogy.
Self-rehearsal gives students changes to go over the information many times and create a pattern of reinforcement. Besides, everyone can adapt it to their own needs or schedules, so it’s very approachable for most people. Blogging will let students share information with other students and even their teacher while they are away, so the flow of the learning process never gets broken. This is also a way to include the new technologies in education that is becoming more and more popular in online courses, and with good reason: it conveys a repeated consolidation and feedback which promotes retention. Games pedagogy is a must, if we want students to use their time to learn during the summer. Good games that allow for repetition and let you progress according to your proficiency level of the subject, while being fun are probably the best way to include those modern tools that sometimes we consider enemies, as our best allies.
The benefits promoted by all these constructivist and modern methods in retention work together, so the more chances students get to manipulate, develop, understand and practice with their own methods, the more and better results they will obtain. Long term memory is built by experiencing something many times, familiarizing with it and creating emotional ties with it, so let’s show every single child and teenager the right way to make the best of their summer and still have fun. | http://ourblacknews.com/2015/06/12/summer-here-school-out-k-12-learners-retain-knowledge-summer-break/ |
By Teachers, For Teachers
Whether you’re new to teaching or a seasoned veteran, there’s a very good chance that you have heard of Project-Based Learning. Much like STEM education is an integral part of our children’s future, Project-Based Learning builds on students’ competencies in order for them to be successful in the 21st century.
In order for our youth to be able to live in this new digital age, and compete with the other industrialized nations, we must give them the right tools. Project-Based Learning is a teaching method that can do just that. Students gain knowledge and skills by investigating and responding to complex questions and real-world problems. With Project-Based Learning, students build 21st century skills like critical thinking, problem solving, and using technology, all of which will help them in the workplace and as well as their lives.
What Does Project-Based Learning Research Say?
So many teachers are trying this new approach out in their classrooms because there has been a ton of research that confirms what an effective and enjoyable way to learn PBL is. Teachers love how PBL:
The Essential Elements of Project-Based Learning
Before we get into the elements that make Project-Based Learning so essential, let’s first discuss what it is not.
Remember when you were in school and had to make a diorama or a poster to correlate with your book report? Back then these menial tasks were considered your school project. Not only were they not creative, they made it really hard for anyone to stay engaged or even motivated.
Since then, we have learned that the process that students take while working on a project is much more important than the end result. When students understand a project’s educational purpose, it becomes more meaningful to them, which in turn leads to student engagement.
Now that we know what Project-Based Learning is not (a simple menial task that doesn’t include any cognitive engagement), we can talk about what the essential elements of PBL include. Here are the eight essential elements presented from the Buck Institute of Education.
1. Significant Content.
2. 21st-Century Skills.
3. In-Depth Inquiry.
4. A Driving Question.
5. A Need to Know.
6. Student Voice and the ability to Choose.
7. Reflection and Revision.
8. An Audience.
Taking a concept that you want students to learn and turning it into Project-Based Learning takes some effort. First you must find significant content (may be derived from the Common Core Standards). Then you must determine how you will build 21st century experiences where students will use skills like creative thinking, problem solving, innovation, and collaboration.
Next you must find a driving question that is open-ended to get students intrigued. It mustn’t be a question that students can easily look up on the Internet. Students will need to know that they will be challenged, and they need to know the reason for undertaking this project. The question needs to be crafted in a way that students will use in-depth inquiry to ask innovative questions and find solutions.
Once you pique your students’ interest, give them a voice and a choice. Make the project meaningful for students by giving them the opportunity to choose how they will present their project, or what technology they will use. Allow them to choose who they will work with or how they will create their project. In order to find a solution to the driving question, students will have to reflect and revise throughout the project.
The final element is presenting their project to a public audience. This is where they use their 21st century skills of communication to present their project through either (a) the use of technology, or (b) a formal presentation.
Although implementing Project-Based Learning into your classroom may seem like a challenge, just remember all of the benefits that are backed by science. When teachers create an environment that gives students a voice and a choice, as well as keeps them engaged while using important 21st century skills, then you know it is all worth it.
What do you think about Project-Based Learning? Is a new fad or so you think it is here to stay? Share with us in the comment section below, we would love to hear your thoughts.
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Justice Souter, with whom Justice Stevens, Justice Ginsburg, and Justice Breyer join, dissenting.
I
Kansas’s capital sentencing statute provides that a defendant “shall be sentenced to death” if, by unanimous vote, “the jury finds beyond a reasonable doubt that one or more aggravating circumstances … exist and … that the existence of such aggravating circumstances is not outweighed by any mitigating circumstances which are found to exist.” Kan. Stat. Ann. §21–4624(e) (1995). The Supreme Court of Kansas has read this provision to require imposition of the death penalty “[i]n the event of equipoise, [that is,] the jury’s determination that the balance of any aggravating circumstances and any mitigating circumstances weighed equal.” 278 Kan. 520, 534, 102 P. 3d 445, 457 (2004) (case below); see also State v. Kleypas, 272 Kan. 894, 1016, 40 P. 3d 139, 232 (2001) (stating that the language of §21–4624(e) “provides that in doubtful cases the jury must return a sentence of death”). Given this construction, the state court held the law unconstitutional on the ground that the Eighth Amendment requires that a “ ‘tie g[o] to the defendant’ when life or death is at issue.” Ibid. Because I agree with the Kansas judges that the Constitution forbids a mandatory death penalty in what they describe as “doubtful cases,” when aggravating and mitigating factors are of equal weight, I respectfully dissent.1
II
More than 30 years ago, this Court explained that the Eighth Amendment ’s guarantee against cruel and unusual punishment barred imposition of the death penalty under statutory schemes so inarticulate that sentencing discretion produced wanton and freakish results. See Furman v. Georgia, 408 U. S. 238, 309–310 (1972) (per curiam) (Stewart, J., concurring) (“[T]he Eighth and Fourteenth Amendment s cannot tolerate the infliction of a sentence of death under legal systems that permit this unique penalty to be … wantonly and … freakishly imposed” on a “capriciously selected random handful” of individuals). The Constitution was held to require, instead, a system structured to produce reliable, Woodson v. North Carolina, 428 U. S. 280, 305 (1976) (plurality opinion), rational, Jurek v. Texas, 428 U. S. 262, 276 (1976) (joint opinion of Stewart, Powell, and Stevens, JJ.), and rationally reviewable, Woodson, supra, at 303, determinations of sentence.
Decades of back-and-forth between legislative experiment and judicial review have made it plain that the constitutional demand for rationality goes beyond the minimal requirement to replace unbounded discretion with a sentencing structure; a State has much leeway in devising such a structure and in selecting the terms for measuring relative culpability, but a system must meet an ultimate test of constitutional reliability in producing “ ‘a reasoned moral response to the defendant’s background, character, and crime,’ ” Penry v. Lynaugh, 492 U. S. 302, 319 (1989) (quoting California v. Brown, 479 U. S. 538, 545 (1987) (O’Connor, J., concurring); emphasis deleted); cf. Gregg v. Georgia, 428 U. S. 153, 206 (1976) (joint opinion of Stewart, Powell, and Stevens, JJ.) (sanctioning sentencing procedures that “focus the jury’s attention on the particularized nature of the crime and the particularized characteristics of the individual defendant”). The Eighth Amendment , that is, demands both form and substance, both a system for decision and one geared to produce morally justifiable results.
The State thinks its scheme is beyond questioning, whether as to form or substance, for it sees the tie-breaker law as equivalent to the provisions examined in Blystone v. Pennsylvania, 494 U. S. 299 (1990) , and Boyde v. California, 494 U. S. 370 (1990) , where we approved statutes that required a death sentence upon a jury finding that aggravating circumstances outweighed mitigating ones. But the crucial fact in those systems was the predominance of the aggravators, and our recognition of the moral rationality of a mandatory capital sentence based on that finding is no authority for giving States free rein to select a different conclusion that will dictate death.
Instead, the constitutional demand for a reasoned moral response requires the state statute to satisfy two criteria that speak to the issue before us now, one governing the character of sentencing evidence, and one going to the substantive justification needed for a death sentence. As to the first, there is an obligation in each case to inform the jury’s choice of sentence with evidence about the crime as actually committed and about the specific individual who committed it. See Spaziano v. Florida, 468 U. S. 447 , and n. 7 (1984). Since the sentencing choice is, by definition, the attribution of particular culpability to a criminal act and defendant, as distinct from the general culpability necessarily implicated by committing a given offense, see Penry, supra, at 327–328; Spaziano, supra, at 460; Zant v. Stephens, 462 U. S. 862, 879 (1983) , the sentencing decision must turn on the uniqueness of the individual defendant and on the details of the crime, to which any resulting choice of death must be “directly” related. Penry, supra, at 319.
Second, there is the point to which the particulars of crime and criminal are relevant: within the category of capital crimes, the death penalty must be reserved for “the worst of the worst.” See, e.g., Roper v. Simmons, 543 U. S. 551, 568 (2005) (“Capital punishment must be limited to those offenders who commit ‘a narrow category of the most serious crimes’ and whose extreme culpability makes them ‘the most deserving of execution’ ” (quoting Atkins v. Virginia, 536 U. S. 304, 319 (2002) )). One object of the structured sentencing proceeding required in the aftermath of Furman is to eliminate the risk that a death sentence will be imposed in spite of facts calling for a lesser penalty, Penry, supra, at 328–329, and the essence of the sentencing authority’s responsibility is to determine whether the response to the crime and defendant “must be death,” Spaziano, supra, at 461; cf. Gregg, supra, at 184 (joint opinion of Stewart, Powell, and Stevens, JJ.). Of course, in the moral world of those who reject capital punishment in principle, a death sentence can never be a moral imperative. The point, however, is that within our legal and moral system, which allows a place for the death penalty, “must be death” does not mean “may be death.”
Since a valid capital sentence thus requires a choice based upon unique particulars identifying the crime and its perpetrator as heinous to the point of demanding death even within the class of potentially capital offenses, the State’s provision for a tie breaker in favor of death fails on both counts. The dispositive fact under the tie breaker is not the details of the crime or the unique identity of the individual defendant. The determining fact is not directly linked to a particular crime or particular criminal at all; the law operates merely on a jury’s finding of equipoise in the State’s own selected considerations for and against death. Nor does the tie breaker identify the worst of the worst, or even purport to reflect any evidentiary showing that death must be the reasoned moral response; it does the opposite. The statute produces a death sentence exactly when a sentencing impasse demonstrates as a matter of law that the jury does not see the evidence as showing the worst sort of crime committed by the worst sort of criminal, in a combination heinous enough to demand death. It operates, that is, when a jury has applied the State’s chosen standards of culpability and mitigation and reached nothing more than what the Supreme Court of Kansas calls a “tie,” Kleypas, 272 Kan., at 1016, 40 P. 3d, at 232 (internal quotation marks omitted). It mandates death in what that court identifies as “doubtful cases,” ibid. The statute thus addresses the risk of a morally unjustifiable death sentence, not by minimizing it as precedent unmistakably requires, but by guaranteeing that in equipoise cases the risk will be realized, by “placing a ‘thumb [on] death’s side of the scale,’ ” Sochor v. Florida, 504 U. S. 527, 532 (1992) (quoting Stringer v. Black, 503 U. S. 222, 232 (1992) ; alteration in original).
In Kansas, when a jury applies the State’s own standards of relative culpability and cannot decide that a defendant is among the most culpable, the state law says that equivocal evidence is good enough and the defendant must die. A law that requires execution when the case for aggravation has failed to convince the sentencing jury is morally absurd, and the Court’s holding that the Constitution tolerates this moral irrationality defies decades of precedent aimed at eliminating freakish capital sentencing in the United States.
III
That precedent, demanding reasoned moral judgment, developed in response to facts that could not be ignored, the kaleidoscope of life and death verdicts that made no sense in fact or morality in the random sentencing before Furman was decided in 1972. See 408 U. S., at 309–310 (Stewart, J., concurring). Today, a new body of fact must be accounted for in deciding what, in practical terms, the Eighth Amendment guarantees should tolerate, for the period starting in 1989 has seen repeated exonerations of convicts under death sentences, in numbers never imagined before the development of DNA tests. We cannot face up to these facts and still hold that the guarantee of morally justifiable sentencing is hollow enough to allow maximizing death sentences, by requiring them when juries fail to find the worst degree of culpability: when, by a State’s own standards and a State’s own characterization, the case for death is “doubtful.”
A few numbers from a growing literature will give a sense of the reality that must be addressed. When the Governor of Illinois imposed a moratorium on executions in 2000, 13 prisoners under death sentences had been released since 1977 after a number of them were shown to be innocent, as described in a report which used their examples to illustrate a theme common to all 13, of “relatively little solid evidence connecting the charged defendants to the crimes.” State of Illinois, G. Ryan, Governor, Report of the Governor’s Commission on Capital Punishment: Recommendations Only 7 (Apr. 2002) (hereinafter Report); see also id., at 5–6, 7–9. During the same period, 12 condemned convicts had been executed. Subsequently the Governor determined that 4 more death row inmates were innocent. See id., at 5–6; Warden, Illinois Death Penalty Reform, 95 J. Crim. L. & C. 381, 382, and n. 6 (2005).2 Illinois had thus wrongly convicted and condemned even more capital defendants than it had executed, but it may well not have been otherwise unique; one recent study reports that between 1989 and 2003, 74 American prisoners condemned to death were exonerated, Gross, Jacoby, Matheson, Montgomery, & Patil, Exonerations in the United States 1989 Through 2003, 95J. Crim. L. & C. 523, 531 (2006) (hereinafter Gross), many of them cleared by DNA evidence, ibid.<footcall num="3"> Another report states that “more than 110” death row prisoners have been released since 1973 upon findings that they were innocent of the crimes charged, and “[h]undreds of additional wrongful convictions in potentially capital cases have been documented over the past century.” Lanier & Acker, Capital Punishment, the Moratorium Movement, and Empirical Questions, 10 Psychology, Public Policy & Law 577, 593 (2004). Most of these wrongful convictions and sentences resulted from eyewitness misidentification, false confession, and (most frequently) perjury, Gross 544, 551–552, and the total shows that among all prosecutions homicide cases suffer an unusually high incidence of false conviction, id., at 532, 552, probably owing to the combined difficulty of investigating without help from the victim, intense pressure to get convictions in homicide cases, and the corresponding incentive for the guilty to frame the innocent, id., at 532.
We are thus in a period of new empirical argument about how “death is different,” Gregg, 428 U. S., at 188 (joint opinion of Stewart, Powell, and Stevens, JJ.): not only would these false verdicts defy correction after the fatal moment, the Illinois experience shows them to be remarkable in number, and they are probably disproportionately high in capital cases. While it is far too soon for any generalization about the soundness of capital sentencing across the country, the cautionary lesson of recent experience addresses the tie-breaking potential of the Kansas statute: the same risks of falsity that infect proof of guilt raise questions about sentences, when the circumstances of the crime are aggravating factors and bear on predictions of future dangerousness.
In the face of evidence of the hazards of capital prosecution, maintaining a sentencing system mandating death when the sentencer finds the evidence pro and con to be in equipoise is obtuse by any moral or social measure. And unless application of the Eighth Amendment no longer calls for reasoned moral judgment in substance as well as form, the Kansas law is unconstitutional.
Notes
1 The majority views Walton v. Arizona, 497 U. S. 639 (1990) , as having decided this issue. But Walton is ambiguous on this point; while the Court there approved Arizona’s practice of placing the burden on capital defendants to prove, “by a preponderance of the evidence, the existence of mitigating circumstances sufficiently substantial to call for leniency,” id., at 649 (plurality opinion), it did not quantify the phrase “sufficiently substantial.” Justice Blackmun clearly thought otherwise, see id., at 687 (dissenting opinion), but he cried a greater foul than one can get from the majority opinion. Stare decisis does not control this case.
2 The Illinois Report emphasizes the difference between exoneration of a convict because of actual innocence, and reversal of a judgment because of legal error affecting conviction or sentence but not inconsistent with guilt in fact. See Report 9 (noting that, apart from the 13 released men, a “broader review” discloses that more than half of the State’s death penalty cases “were reversed at some point in the process”). More importantly, it takes only a cursory reading of the Report to recognize that it describes men released who were demonstrably innocent or convicted on grossly unreliable evidence. Of one, the Report notes “two other persons were subsequently convicted in Wisconsin of” the murders. Id., at 8. Of two others, the Report states that they were released after “DNA tests revealed that none of them were the source of the semen found in the victim. That same year, two other men confessed to the crime, pleaded guilty and were sentenced to life in prison, and a third was tried and convicted for the crime.” Ibid. Of yet another, the Report says that “another man subsequently confessed to the crime for which [the released man] was convicted. He entered a plea of guilty and is currently serving a prison term for that crime.” Id., at 9. A number were subject to judgments as close to innocence as any judgments courts normally render. In the case of one of the released men, the Supreme Court of Illinois found the evidence insufficient to support his conviction. See People v. Smith, 185 Ill. 2d 532, 708 N. E. 2d 365 (1999). Several others obtained acquittals, and still more simply had the charges against them dropped, after receiving orders for new trials. At least 2 of the 13 were released at the initiative of the executive. We can reasonably assume that a State under no obligation to do so would not release into the public a person against whom it had a valid conviction and sentence unless it were certain beyond all doubt that the person in custody was not the perpetrator of the crime. The reason that the State would forgo even a judicial forum in which defendants would demonstrate grounds for vacating their convictions is a matter of common sense: evidence going to innocence was conclusive.
3 The authors state the criteria for their study: “As we use the term, ‘exoneration’ is an official act declaring a defendant not guilty of a crime for which he or she had previously been convicted. The exonerations we have studied occurred in four ways: (1) In forty-two cases governors (or other appropriate executive officers) issued pardons based on evidence of the defendants’ innocence. (2) In 263 cases criminal charges were dismissed by courts after new evidence of innocence emerged, such as DNA. (3) In thirty-one cases the defendants were acquitted at a retrial on the basis of evidence that they had no role in the crimes for which they were originally convicted. (4) In four cases, states posthumously acknowledged the innocence of defendants who had already died in prison . . . .” Gross 524 (footnote omitted). The authors exclude from their list of exonerations “any case in which a dismissal or an acquittal appears to have been based on a decision that while the defendant was not guilty of the charges in the original conviction, he did play a role in the crime and may be guilty of some lesser crime that is based on the same conduct. For our purposes, a defendant who is acquitted of murder on retrial, but convicted of involuntary manslaughter, has not been exonerated. We have also excluded any case in which a dismissal was entered in the absence of strong evidence of factual innocence, or in which—despite such evidence—there was unexplained physical evidence of the defendant’s guilt.” Ibid., n. 4. | https://www.law.cornell.edu/supct/html/04-1170.ZD1.html |
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abstract: 'The goal of this paper is to present a systematic method to compute reference dependent positively invariant sets for systems subject to constraints. To this end, we first characterize these sets as level sets of reference dependent Lyapunov functions. Based on this characterization and using Sum of Squares (SOS) theory, we provide a polynomial certificate for the existence of such sets. Subsequently, through some algebraic manipulations, we express this certificate in terms of a Semi-Definite Programming (SDP) problem which maximizes the size of the resulting reference dependent invariant sets. We then present the results of implementing the proposed method to an example system and propose some variations of the proposed method that may help in reducing the numerical issues of the method. Finally, the proposed method is employed in the Model Predictive Control (MPC) for Tracking scheme to compute the terminal set, and in the Explicit Reference Governor (ERG) scheme to compute the so-called Dynamic Safety Margin (DSM). The effectiveness of the proposed method in each of the schemes is demonstrated through a simulation study.'
address:
- 'Service d’Automatique et d’Analyse des Systèmes (SAAS), Université Libre de Bruxelles (ULB), Brussels, Belgium'
- 'Department of Electrical and Systems Engineering, Washington University in St. Louis, Missouri, USA'
- 'Departmento de Ingeniería de Sistemas y Automática, Escuela Técnica Superior de Ingeniería, Universidad de Sevilla, Seville, Spain'
author:
- Andres Cotorruelo
- Mehdi Hosseinzadeh
- 'Daniel R. Ramirez'
- Daniel Limon
- Emanuele Garone
bibliography:
- 'ref.bib'
title: 'Reference Dependent Invariant Sets: Sum of Squares Based Computation and Applications in Constrained Control'
---
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Invariance ,Control of Constrained Systems ,Sum of Squares ,Tracking ,Reference Dependence.
Introduction
============
The relevance of positively invariant sets lies in their numerous applications [@blanchini1999set]. More precisely, given an autonomous dynamical system, a subset of the state space is said to be *positively* invariant if, assuming it contains the state of the system at some time, it will also contain it in the future.
Invariance is particularly important in the control of dynamical systems subject to constraints. In particular, in Model Predictive Control (MPC) [@Mayne2000], the use of an invariant set as a terminal constraint is typically used to ensure stability and recursive feasibility. Additionally, invariant sets are at the basis of Reference Governor (RG) [@garone2017reference] approaches, of the recently introduced Explicit Reference Governors (ERG) [@Nicotra2018], and of multimode regulators for constrained control [@kolmanovsky1997multimode].
The computation of positively invariant sets has been the object of many research works. In [@haimovich2010componentwise], the authors compute polyhedral invariant sets for switched linear systems. In [@pluymers2005efficient], a method to compute a polyhedral invariant set for linear systems with polytopic uncertainty is presented. For what concerns input saturated systems, in [@alamo2005improved] the authors present a method to compute invariant ellipsoids, and in [@alamo2006new] a novel concept of invariance for saturated systems is introduced. For an extensive survey on research in invariant sets and their usage in control, the reader is referred to [@Blanchini2008].
The majority of the work present in the literature focuses on finding domains of attraction for a single point of equilibrium. However, in the realm of reference tracking, the required invariant sets need to be centered around any admissible point of equilibrium, and thus become parameterized in the reference. These sets are much less straightforward to be computed explicitly.
To the best of our knowledge, the first instance of this concept dates to the Maximal Output Admissible Sets [@gilbert1991linear]. These sets are defined as the set of pairs of initial states and references such that the trajectory of the system fulfills the constraints when said reference is kept constant. For discrete time systems, some polyhedral representations of these sets can be computed for linear [@kolmanovsky1995maximal] and nonlinear systems [@hirata2008exact], or characterized using Lyapunov arguments [@gilbert1999set].
Due to the link between the Maximal Output Admissible Sets and the Dynamic Safety Margin (DSM) in the ERG framework, this line of research has seen a recent increase in activity. In [@garone2018explicit], a closed form solution of the optimal DSM for linear systems subject to linear constraints is provided. In [@Hosseinzadeh2018], the authors present a method to estimate the DSM implicitly in the case of convex Lyapunov functions and concave constraints. A method able to work with unions and intersections of concave constraints has been presented in [@Hosseinzadeh2019Letter].
A promising tool to tackle the computation of reference dependent invariant sets is Sum of Squares (SOS) programming [@parrilo2000structured]. In recent years the SOS framework has been used extensively to tackle invariance-related problems. For example, it was shown that it is possible to compute estimations of the basin of attraction of polynomial systems [@tan2008stability] and non-polynomial systems [@chesi2005domain].
In this paper we propose to employ the SOS framework to compute reference dependent invariant sets for constrained systems. The main idea is to fix a polynomial Lyapunov function parameterized in the reference, and through SOS arguments compute the largest level set fully contained in the constraints. The effectiveness of the proposed methods is showcased with two applications: a discrete time system controlled with an MPC for Tracking, and a continuous time system controlled with an ERG.
The rest of this paper is organized as follows. Section \[sec:PS\] states the problem. In Section \[sec:method\] we provide a polynomial certificate for the existence of reference dependent invariant sets, along with an optimization problem to compute them. In Section \[sec:practical\] some practical considerations that might aid in reducing the possible numerical issues are discussed. Two applications are presented in Section \[sec:app\]: (i) characterizing the terminal set in the MPC for Tracking framework in Subsection \[sec:appMPC\], and (ii) providing a measure of safety in the ERG framework in Subsection \[sec:appERG\]. Some simulation results are also provided to show the effectiveness of the proposed method. Finally, in Section \[sec:conclusion\] some conclusions and possible future research lines are presented.
#### Notation: {#notation .unnumbered}
The set of polynomials with variables $x_1,\ldots,x_n$, whose coefficients belong to $\mathbb{R}$, is denoted by $\mathbb{R}[x_1,\ldots,x_n]$. We denote the set of all positive reals plus zero, and the set of all positive integers plus zero as $\mathbb{R}_{\geq0}$ and $\mathbb{Z}_{\geq0}$, respectively. For polynomials $p_j$, $j=1,\ldots,N$, we will use $\{p_j\}_{i=1}^N$ to denote the set $\{p_1,\ldots,p_N\}$. The set of all Sum of Squares polynomials with variables $x_1,x_2,\ldots,x_n$ is denoted by $\Sigma[x_1,x_2,\ldots,x_n]$. We denote the degree of a polynomial $p$ by $\partial p$. The $n$-dimensional identity matrix is denoted by $I_n$. The Jacobian matrix of a vector valued function $f$ is denoted by $\nabla f$. The gradient of a scalar function $V$ is denoted as $\nabla V$. For two sets $\mathcal{A},\mathcal{B}\subseteq \mathbb{R}^n$, $\mathcal{A}\ominus\mathcal{B}$ denotes the Pontryagin difference. We denote the $n$-dimensional ball of radius $\varepsilon$ by $\mathcal{B}_n(\varepsilon)\triangleq \{x\in\mathbb{R}^n : x^Tx\leq \varepsilon^2 \}$.
Problem Statement {#sec:PS}
=================
Let the system $$\label{eq:system_open_loop}
\delta x=\phi(x,u),$$ where $\delta x$ is the successor state in discrete time or the time derivative in continuous time, $x\in\mathbb{R}^n$ is the state, and $u\in\mathbb{R}^m$ is the input. The system is subject to constraints in the following form: $$x\in\mathcal{X}\,,~u\in\mathcal{U}\,,$$ where $\mathcal{X}\subseteq\mathbb{R}^n$ and $\mathcal{U}\subseteq\mathbb{R}^m$ are simply connected sets with nonempty interiors.
As often done in reference tracking problems, it is assumed that a control law $u=\kappa\left(x,r\right)$ is used to stabilize[^1] the system, where $r\in\mathbb{R}^p$ is the reference signal. System then becomes $$\label{eq:system}
\delta x=f\left(x,r\right),$$ where $f\left(x,r\right)\triangleq \phi\left(x,\kappa\left(x,r\right)\right)\in\mathbb{R}[x,r]$ and the pair $\left(x,r\right)$ is constrained in the set $\mathcal{D}\triangleq\left\{\left(x,r\right):x\in\mathcal{X}\right.$, $\left.\kappa\left(x,r\right)\in\mathcal{U}\right\}$. Typically, this set can be expressed through a set of inequalities as $$\label{constraint}
\mathcal{D}=\{(x,r):c_i(x,r)\geq0,~i=1,\ldots,n_c\}.$$ In this paper we assume that these inequalities are polynomial, *i.e.* $c_i(x,r)\in\mathbb{R}[x,r],~i=1,\ldots,n_c$ (see \[fig:GeoInt1\]). For reasons that will be clearer later on, we also define the set of admissible references $$\label{eq:r_admissible}
\mathcal{R}\triangleq\{r\in\mathbb{R}^p:\overline{c}_i(r)\geq0,~i=1,\ldots,n_c\},$$ where $\overline{c}_i(r)\triangleq c_i(\overline{x}_{r},r)$, with $\overline{x}_r$ as the equilibrium point of associated with a constant reference signal $r$ , *i.e.*, $f(\overline{x}_r,r)=0$ in continuous time, and $f(\overline{x}_r,r)=\overline{x}_r$ in discrete time. Furthermore, $\mathcal{R}$ is assumed to be connected.
The purpose of this paper is to solve the following problem.
[(Safe Reference Dependent Positively Invariant Sets)]{} Consider system where the pair $(x,r)$ is constrained in the set $\mathcal{D}$ as in . Compute a family of sets parameterized in the reference $\mathcal{S}(r)$ such that
- $\mathcal{S}(r)$ is invariant for system for any constant $r\in\mathcal{R}$, *i.e.*, every trajectory of with initial condition $x(t_0)\in\mathcal{S}(r)$ and a constant reference $r\in\mathcal{R}$ is such that $x(t)\in\mathcal{S}(r)$ for all $t\geq t_0$,
- $\mathcal{S}(r)$ is fully contained in the constraint set $\mathcal{D}$ for every $r\in\mathcal{R}$.
![Geometric illustration of the class of constraints under study.[]{data-label="fig:GeoInt1"}](Figures/GeoInt1.pdf){width="7cm"}
Contrary to regulation problems where a single invariant set centered around the origin is computed, in reference tracking we need to compute invariant sets centered around all possible points of equilibrium $\overline{x}_r$ associated with $r\in\mathcal{R}$.
It is well known that one way to determine invariant sets is using Lyapunov level sets. In this paper we will assume, without loss of generality, that for each reference $r$, the corresponding equilibrium point of system denoted by $\overline{x}_r$ is globally asymptotically stable (see Remark \[rem:local\] for local stability). We will also assume that a polynomial Reference Dependent Lyapunov Function (RDLF) $V(x,r):\mathbb{R}^n\times\mathbb{R}^p\rightarrow\mathbb{R}_{\geq 0}$ is known such that: $$\label{eq:Lyap_def}
\Bigg\{
\begin{aligned}
V(x,r)&>0\ \forall x\in\mathbb{R}^n\setminus \{\overline{x}_r\},\,V(x,r)=0 \Leftrightarrow x=\overline{x}_r\\
\delta V(x,r)&<0\ \forall x\in\mathbb{R}^n\setminus \{\overline{x}_r\},\, \delta V(x,r) = 0\Leftrightarrow x=\overline{x}_r
\end{aligned}.$$ where $\delta V(x,r)$ denotes $\nabla V(x,r)f(x,r)$ in the continuous time case, and $V(f(x,r),r)-V(x,r)$ in the discrete time case.
It is easy to see that if the level set $\mathcal{S}_\Gamma(r)=\{x\in\mathbb{R}^n:V(x,r)\leq\Gamma(r),\,\Gamma(r)>0\},\,\ \forall r\in\mathcal{R}$ is fully contained in $\mathcal{D}$, then $\mathcal{S}_\Gamma(r)$ is a safe positively invariant set.
Typically it is useful to determine the largest possible safe invariant set. In the case of invariant sets based on Lyapunov functions, this corresponds to finding the largest bound $\Gamma^\ast(r)$ corresponding to the solution of the following optimization problem: $$\label{eq:optGammaStar}
\Gamma^\ast(r)=\left\{
\begin{array}{ll}
&\max\Gamma \\
\text{s.t.}& \\
& \left\{x\in\mathbb{R}^n:V(x,r)\leq\Gamma\right\}\subseteq\mathcal{D}
\end{array}
\right.,$$ for every $r\in\mathcal{R}$. Note that this optimization problem is parameterized in $r$ and that, except in a very simple case [@garone2018explicit], its closed form parametric solution might be hard to compute and/or to handle.
In this paper we propose a systematic method to compute a good polynomial approximation of $\Gamma^\ast(r)$, denoted by $\hat\Gamma(r)\in\mathbb{R}[r]$ such that $\hat\Gamma(r)\leq\Gamma^\ast(r),\ \forall r\in\mathcal{R}$. Note that for any lower bound $\hat{\Gamma}(r) \leq \Gamma^\ast(r)$, the set $\mathcal{S}_{\hat{\Gamma}}(r)$ is a safe reference dependent invariant set.
For the sake of simplicity, in the sequel we will compute one $\hat{\Gamma}(r)$ at a time. This is without loss of generality, since the multi constraint case can be expressed as the composition of single constraint cases as follows: $$\label{eq:multiconstraint}
\Gamma^\ast(r) = \min_i \{\Gamma^\ast_i(r)\},~i=1,\ldots,n_c,$$ where $\Gamma^\ast_i(r)$ is the value of $\Gamma^\ast(r)$ if only the $i$-th constraint $c_i(x,r)$ is considered.
\[rem:local\] In the case of local stability, it is possible to impose the additional constraint $\delta V(x,r)<0$ in , which will yield the largest safe level set of the local RDLF.
Approximating the Largest positively Invariant Set via SOS Techniques {#sec:method}
=====================================================================
In this paper we propose a method to compute a parameterized solution for using SOS programming. This framework is able to tackle convex relaxations of non-convex optimization problems through polynomial optimization [@jarvis2005control].
As usually done when working with the Krivine–Stengle Positivstellensatz (P-satz) [@papachristodoulou2005tutorial], the first step is to express the conditions for an admissible solution of problem in terms of set emptiness. In the case at hand, the condition that an admissible $\hat{\Gamma}_i(r)$ must fulfill is $$\label{eq:emptyset0}
\left\{(x,r):V(x,r)\leq\hat{\Gamma}_i(r)\right\}\subseteq \mathcal{D}, ~\forall r \in \mathcal{R},$$ where $V(x,r)$ is an RDLF as in . It is straightforward to reformulate as the following set emptiness condition $$\label{eq:emptyset1}
\begin{aligned}
\left\{(x,r):r\in\mathcal{R},\,c_i(x,r)=0,\,V(x,r)>\hat{\Gamma}_i(r)\right\}=\emptyset.
\end{aligned}$$ The next step is to apply the Krivine–Stengle P-satz [@tan2008stability]. Since in this formulation of the P-satz (See Appendix) the semialgebraic set required to be empty is described in terms of *greater-than-or-equal-to*, *not-equal-to*, and *equals* operators, the set must be rewritten as[^2]: $$\label{eq:emptyset}
\begin{aligned}
\left\{(x,r):\hat{\Gamma}_i-V\geq 0,\,V-\hat{\Gamma}_i\neq 0,\,c_i=0,\,\{\overline{c}_j\}_{j=1}^{n_c}\geq0\right\}.
\end{aligned}$$ Note that, although we consider only one constraint for the computation of $\hat{\Gamma}_i$ (*i.e.* $c_i(x,r)=0$), we still limit $r\in\mathcal{R}$ through $\overline{c}_1(r)\geq0,\ldots,\overline{c}_{n_c}(r)\geq0$.
At this point, using the Krivine–Stengle P-satz and some standard algebraic manipulations, it follows that the set is empty if there exist SOS polynomials $s_1,\ldots,s_{n_c+1}\in\Sigma[x,r]$, a polynomial $\bar{q}\in\mathbb{R}[x,r]$, and a non-negative integer $k$, such that $$\begin{gathered}
\label{eq:SOSconditions0}
-s_0\cdot(V-\hat{\Gamma}_i)+(V-\hat{\Gamma}_i)^{2k}+\bar{q}\cdot c_i\\
-(V-\hat{\Gamma}_i)\sum_{j=1}^{n_c}s_j\cdot\overline{c}_j+s_{n_c+1}=0.\end{gathered}$$ If we impose $k=1$, $s_{n_c+1}=0$, and $\bar{q}=q(V-\hat{\Gamma}_i)$ where $q\in\mathbb{R}[x,r]$ it follows that, is fulfilled if $$\label{eq:SOSconditions1}
(V-\hat{\Gamma}_i)(-s_0+(V-\hat{\Gamma}_i) +q\cdot c_i-\sum_{j=1}^{n_c}s_j\cdot\overline{c}_j)=0,$$ which allows us to formulate the following sufficient condition $$\label{eq:SOSconditions2}
s_0=V-\hat{\Gamma}_i+q\cdot c_i-\sum_{j=1}^{n_c}s_j\cdot\overline{c}_j.$$ Since $s_0$ is a SOS polynomial, implies that $\hat{\Gamma}_i$ is a lower bound of $\Gamma^\ast_i$ if there exist SOS polynomials $s_1,\ldots,s_{n_c}$ and a polynomial $q$ such that $$\label{eq:SOSconditions}
V-\hat{\Gamma}_i+q\cdot c_i-\sum_{j=1}^{n_c}s_j\cdot\overline{c}_j\in\Sigma[x,r].$$ Once the structure of polynomials $\hat{\Gamma}_i$, $q$, and $s_j,\,j=1,\ldots,n_c$, are fixed, can in turn be expressed as a Linear Matrix Inequality (LMI) feasibility problem, where the decision variables are the coefficients of these polynomials, as proven in [@parrilo2000structured].
As previously mentioned, in this paper we are interested in computing level sets of RDLFs fully contained in $\mathcal{D}$ that are as large as possible. A possible way to do so is to maximize the integral of $\hat{\Gamma}_i(r)$, as $$\label{eq:Gammahat}
\left\{
\begin{array}{rl}
& \max\int\limits_{r\in\mathcal{R}_d}\hat{\Gamma}_i(r)\,\text{d}r\\
\text{s.t.}&\\
&V-\hat{\Gamma}_i+q\cdot c_i -\sum_{j=1}^{n_c}s_j\cdot\overline{c}_j\in\Sigma [x,r]\\
& \{s_j\}_{j=1}^{n_c}\in\Sigma [x,r]\\
& q \in\mathbb{R}[x,r]
\end{array}
\right..$$ where $\mathcal{R}_d\subseteq\mathcal{R}$ is a compact domain, chosen so as to avoid improper integrals in the case where $\mathcal{R}$ is unbounded. Additionally, $\mathcal{R}_d$ can be chosen so as to prioritize the accuracy of $\hat{\Gamma}_i(r)$ in a certain region of interest of $\mathcal{R}$, *e.g.*, around likely operation points of the system.
Note that whenever $\mathcal{R}_d$ is a normal domain [@calculus] described by polynomials, $\int_{r\in\mathcal{R}_d}\hat{\Gamma}_i(r)\,\textnormal{d}r$ can easily be computed in closed form and is polynomial [@algebra], which implies that the objective function of remains linear in the coefficients of $\hat{\Gamma}_i$. When this is not the case, a practical approach is to randomly select a (possibly large) number of points in $\mathcal{R}_d$, $p_1,\ldots,p_{n_w}$, and use the following objective function $$\label{eq:objfun2}
\frac{1}{n_w}\sum_{w=1}^{n_w} \hat{\Gamma}_i(p_w).$$ Note that for a sufficiently large $n_w$, optimizing over is equivalent to optimizing over $\int_{\mathcal{R}_d}\hat{\Gamma}_i(r)~\textnormal{d}r$.
Example and practical considerations {#sec:practical}
====================================
It is widely known that the LMI problems that arise from SOS theory can become exceedingly sparse [@kojima2005sparsity] and numerically ill-conditioned. This may limit the applicability of the method presented in Section \[sec:method\]. In this section we propose two techniques that might aid in mitigating numerical issues in the proposed methodology. The first technique is based on exploiting the structure of the problem at hand to utilize some *a priori* knowledge in the structure of $\hat{\Gamma}(r)$. The second technique is based on a division of the domain $\mathcal{R}_d$.
In order to show the practical improvements due to the application of these two techniques, we introduce a numerical case study consisting of a continuous time double integrator controlled with a PD control law $$\label{eq:sys_example}
\dot{x}=\begin{bmatrix}
0 & 1\\
-\omega^2 & -2\zeta\omega
\end{bmatrix}x + \begin{bmatrix}0\\ \omega ^2
\end{bmatrix}r,$$ where $\omega=10$ is the angular frequency and $\zeta=0.2$ is the damping ratio. This system is subject to the following constraint $$\label{eq:const_1}
c(x,r)=x_2-x_1^3+3x_1^2+10\geq0.$$ Since $\overline{x}_r=[r\quad\!\!\!0]^T$, constraint defines $\mathcal{R}$ as $\mathcal{R}=\{r:r\leq3.721\}$. The domain $\mathcal{R}_d$ is chosen as $\mathcal{R}_d=\{r:-1.5\leq r \leq 3.721\}$. For every equilibrium point, stability can be proved using a quadratic RDLF in the following form $$\label{eq:LF}
V(x,r)=\left(x-\overline{x}_r\right)^\top \left[\begin{matrix}
12.6450&-0.005\\
-0.005&0.1263
\end{matrix}\right]\left(x-\overline{x}_r\right).$$
![Visual representation of the case study. The set of possible points of equilibrium of system is depicted as a grey dashed line, the set of points where $c(x,r)<0$ is represented by a solid dark red shaded area, and the set of points within $\mathcal{R}_d$ are encapsulated by black square brackets. For a given $r=\tilde{r}$, the set of points such that $V(x,\tilde{r})=\Gamma^\ast$ is represented as a solid blue ellipsoid, and the steady state associated to $\tilde{r}$, $\overline{x}_{\tilde{r}}$, is represented by a blue cross-shaped marker.[]{data-label="fig:visual_representation"}](Figures/case_study_visual_representation.pdf){width="\linewidth"}
![Approximation of $\Gamma^\ast$ for different values of $\partial\hat{\Gamma}$.[]{data-label="fig:gamma_1poly_several_d"}](Figures/gamma_one_poly_several_degrees.pdf){width="\linewidth"}
The problem is depicted in \[fig:visual\_representation\]. In \[fig:gamma\_1poly\_several\_d\] we show the results obtained by solving for constraint for several values of $\partial\hat{\Gamma}$. The obtained results are compared with $\Gamma^\ast(r)$ which was computed using a brute force approach. As expected, the accuracy of the approximation increases with the degree of $\hat{\Gamma}$. However, as it can be seen, a relatively high value of $\partial\hat{\Gamma}$ is required to get a fairly good approximation.
Exploiting the structure of $\Gamma^\ast(r)$
--------------------------------------------
A first way to reduce the required degree of $\hat{\Gamma}_i(r)$ consists in exploiting the fact that the set $\{r: \Gamma^\ast_i(r)=0\}$ coincides with the set $\{r : \overline{c}_i(r)=0\}$. This is proved by the following lemma.
\[lemma:signs\] Consider system , subject to the constraint $c_i(x,r)\geq0$, and whose global stability can be proved through an RDLF $V(x,r)$. Then for any $r\in\mathcal{R}$, $\overline{c}_i(r)>0$ implies that $\Gamma_i^\ast(r)>0$, and $\overline{c}_i(r)=0$ implies that $\Gamma^\ast_i(r)=0$.
Let $r'\in\mathcal{R}$ be such that $\overline{c}_i(r')>0$ (*i.e.*, $r'$ is in the interior of $\mathcal{R}$) and $\overline{x}_{r'}$ its associated steady-state. The definition of $\Gamma^\ast_i(r)$ in implies that $$\label{eq:lemma1}
\exists x' \in \{x:V(x,r')=\Gamma^\ast_i(r')\} \textrm{, such that } c_i(x',r')=0.$$ Since from the definition of RDLFs $V(x',r')>0$ if $x\neq\overline{x}_{r'}$, it follows from that $\Gamma^\ast_i(r')>0$, and finally that $\overline{c}_i(r')>0\Leftrightarrow\Gamma^\ast_i(r')>0$. Using the same logic, it follows that $\Gamma^\ast_i(r'')=0\Leftrightarrow \overline{c}_i(r'')=0$ (*i.e.*, $r''$ is on the border of $\mathcal{R}$). $\hfill\blacksquare$
We can use the results of Lemma \[lemma:signs\] to our advantage by assuming the following structure for $\hat{\Gamma}_i$ $$\label{eq:cbar}
\hat{\Gamma}_i=\overline{c}_i^k\cdot\tilde{\Gamma}_i,$$ where $k\in\mathbb{Z}_{\geq0}$ and $\tilde{\Gamma}_i\in\mathbb{R}[r]$. Intuitively, the use of this term may require a lower $\partial\tilde{\Gamma}_i$ to achieve a higher accuracy, since assuming that $\hat{\Gamma}_i$ is factorized in $\overline{c}_i$ automatically sets $\hat{\Gamma}_i$ to 0 wherever $\overline{c}_i$ vanishes.
![Approximation of $\Gamma^\ast$ for different values of $\partial\tilde{\Gamma}$, assuming $\hat\Gamma=\tilde{\Gamma}\cdot\overline{c}$.[]{data-label="fig:gamma_1poly_several_d_cbar"}](Figures/gamma_one_poly_several_degrees_cbar.pdf){width="\linewidth"}
![Approximation of $\Gamma^\ast$ for different values of $\partial\tilde{\Gamma}$, assuming $\hat\Gamma=\tilde{\Gamma}\cdot\overline{c}^2$. Note that the curve corresponding to $\partial\tilde{\Gamma}=2$ overlaps with $\partial\tilde{\Gamma}=3$, and $\partial\tilde{\Gamma}=5$ overlaps with $\partial\tilde{\Gamma}=7$.[]{data-label="fig:gamma_1poly_several_d_cbar2"}](Figures/gamma_one_poly_several_degrees_cbar2.pdf){width="\linewidth"}
![Accuracy of $\hat{\Gamma}=\overline{c}^k\cdot\tilde{\Gamma}$ with respect to the degree of $\tilde{\Gamma}$ for $k\in\{0,1,2\}$.[]{data-label="fig:bargraph"}](Figures/bargraph.pdf){width="\linewidth"}
In \[fig:gamma\_1poly\_several\_d\_cbar\] and \[fig:gamma\_1poly\_several\_d\_cbar2\] we show the results of applying this notion to our case study, assuming that $\hat{\Gamma}$ is factorized in $\overline{c}$ and $\overline{c}^2$, respectively. As it can be seen in \[fig:bargraph\], when assuming $\hat{\Gamma}=\tilde{\Gamma}\cdot\overline{c}$ the required degree to obtain an accuracy of more than 80% is $\partial\tilde{\Gamma}=5$, compared to the required degree of $\partial\hat{\Gamma}=7$ if this assumption is not made. The required degree is further decreased to $\partial\tilde{\Gamma}=2$ if we assume $\hat{\Gamma}=\tilde{\Gamma}\cdot\overline{c}^2$.
Piece-wise polynomial approach {#sec:practical_div}
------------------------------
In some cases the Semi-Definite Programming (SDP) solver may not arrive at a sensible approximation of $\Gamma^\ast_i$ due to the high dimensionality of the system, to the high degree of the involved polynomials, or to the resulting optimization problem being ill-conditioned. To tackle this, a possible approach is to divide $\mathcal{R}_d$ in several subsets $\mathcal{R}_\ell,~\ell=1,\ldots,n_r$ such that $$\mathcal{R}_d=\bigcup_{\ell=1}^{n_r} \mathcal{R}_\ell.$$ These subsets are described by the additional constraints $\overline{c}^\ell_j(r)$, with $j=1,\ldots,n_\ell$. Subsequently the polynomial approximation of $\Gamma^\ast$ associated with the $\ell$-th subset $\mathcal{R}_\ell$, denoted by $\hat{\Gamma}_{i,\ell}$, can be computed through the following SOS condition $$\label{eq:gamma_Rd}
V-\hat{\Gamma}_{i,\ell}+q\cdot c_i - \sum_{j=1}^{n_\ell} s_j \cdot \overline{c}_j \in \Sigma [x,r],$$ Once the $\hat{\Gamma}_{i,\ell}$s have been computed, $\hat{\Gamma}_i(r)$ can be recovered as follows: $$\hat{\Gamma}_i(r)=\max_\ell\{\hat{\Gamma}_{i,\ell}(r)\},$$ where $\hat{\Gamma}_{i,\ell}=0~\forall r \notin \mathcal{R}_\ell$. By dividing $\mathcal{R}_d$, not only we reduce the size of the domain over which we compute each $\hat{\Gamma}_{i,\ell}$, but also the term $\sum_{j=1}^{n_\ell} s_j \cdot \overline{c}_j$ becomes simpler since typically $n_c>n_\ell$. A possible approach for the division of $\mathcal{R}_d$ is the Delaunay tessellation [@watson1981computing; @lawson1986properties], which divides the space into $p$-simplices. It is well known that a $p$-simplex requires $p+1$ inequalities to be described, therefore, this tessellation achieves the minimal amount of inequalities describing a given inner $\mathcal{R}_\ell$ for a polyhedral division of $\mathcal{R}_d$.
We show the results of applying this approach to the case study in \[fig:several\], for $n_r=9$, $\partial\hat{\Gamma}_{1,\ell}=\partial s_j=4$. As it can be seen, $\hat{\Gamma}$ and $\Gamma^\ast$ overlap, thus yielding a very good approximation for this case study.
![Piece-wise polynomial approach for the case study, using $\partial\hat{\Gamma}_\ell=4,~ \ell\in \{1,\ldots,9\}$. $\Gamma^\ast$ is depicted as a solid black line, each of the divisions is marked as a yellow circular marker, and every $\hat{\Gamma}_\ell$ is depicted as a dashed colored line.[]{data-label="fig:several"}](Figures/gamma_several_polys.pdf){width="\linewidth"}
It should be noted that the two techniques presented in this section are not mutually exclusive and can be used at the same time.
Applications in constrained control {#sec:app}
===================================
In this section we will discuss two different applications of the proposed reference dependent positively invariant sets in constrained control problems. The first application is in discrete time and allows us to compute the terminal set in the MPC for Tracking framework for discrete time systems. The second case shows that continuous time positively invariant sets can be used to calculate the dynamic safety margin in the ERG framework.
Safe Invariant Sets As Terminal Conditions In the MPC for Tracking Framework {#sec:appMPC}
----------------------------------------------------------------------------
In the last two decades, MPC schemes have been widely used to address constrained control problems [@Mayne2000; @Camacho2007]. These schemes have the remarkable feature of being able to drive the system state to a fixed set-point while optimizing the control performances and satisfying the constraints of the system.
However, classical MPC schemes might lose feasibility under sudden set-point changes [@bemporad1997nonlinear]. To tackle this, the MPC for Tracking scheme was presented in [@limon2008mpc]. This control scheme solves at every time step $t$ the following optimization problem
[lCr]{} \_[**u**,v]{} J\_[N\_p,N\_c]{}(x,r;**u**,v), \[eq:MPC\_first\]\
\
x(0)=x(t),\
x(j+1)=(x(j),u(j)),j=0,…,N\_c-1,\
(x(j),u(j)),j=0,…,N\_c-1,\
x(j+1)=(x(j),(x(j),v)), j=N\_c,…,N\_p-1,\
(x(j),(x(j),v)),j=N\_c,…,N\_p-1,\
\_v=g\_x(v),\
\_v=g\_u(v),\
(x(N\_p),v), \[eq:MPC\_last\]
with objective function
[lCr]{} J\_[N\_p,N\_c]{}(x,r;**u**,v)=\_[j=0]{}\^[N\_c-1]{}J\_s(x(j)-\_v,u(j)-\_v)\
+\_[j=N\_c]{}\^[N\_p-1]{}J\_s(x(j)-\_v,(x(j),v)-\_v)\
+J\_f(x(N\_p)-\_v)+J\_o(v-r)
where $N_p$ and $N_c$ are the prediction and control horizons, respectively, $\kappa:\mathbb{R}^n\times\mathbb{R}^p\rightarrow\mathbb{R}^m$ is a stabilizing control law as in Section \[sec:PS\], $\mathcal{Z}=\mathcal{X}\times\mathcal{U}$, $v\in\mathcal{R}$ is the auxiliary reference, $g_x:\mathcal{R}\rightarrow\mathbb{R}^n$ and $g_u:\mathcal{R}\rightarrow\mathbb{R}^m$ are two locally Lipschitz functions that map the auxiliary reference to its corresponding steady state and input $(\overline{x}_v,\overline{u}_v)$ (*i.e.*, $\overline{x}_v=\phi(g_x(v),g_u(v)$), $J_s:\mathbb{R}^n\times\mathbb{R}^m\rightarrow\mathbb{R}$, $J_o:\mathbb{R}^p\rightarrow\mathbb{R}$, and $J_f:\mathbb{R}^n\rightarrow\mathbb{R}$ are convex positive definite functions that represent the stage, offset, and terminal costs, respectively (see [@limon2018nonlinear] for more details). $\Omega$ is an invariant set for tracking which can be defined as follows:
\[def:invset4t\] For a given set of constraints $\mathcal{Z}=\mathcal{X}\times\mathcal{U}$, a set of admissible references $\mathcal{R}$, and a local control law $u=\kappa(x,v)$, a set $\Omega\subset\mathbb{R}^n\times\mathbb{R}^p$ is an (admissible) invariant set for tracking for system if for all $(x,v)\in\Omega$, we have $(x,\kappa(x,v))\in\mathcal{Z}$, $v\in\mathcal{R}\ominus\mathcal{B}_p(\varepsilon)$, and $(\phi(x,\kappa(x,v)),v)\in\Omega$.
This set represents the MPC for Tracking counterpart of the classical terminal set used in MPC schemes to guarantee stability and recursive feasibility. The computation of such a reference dependent set is one of the most challenging problems when designing an MPC for tracking.
To approximate these sets, in [@limon2018nonlinear] the authors resort to a partition of the set of points of equilibrium paired with linearization of the system for each partition based on a Linear Time Varying characterization [@wan2003efficient; @wan2003efficient2]. However, this *ad-hoc* technique is conservative and has a solution only for limited classes of constraints.
Note that once a control law $\kappa(x,v)$ acting as a terminal control law has been fixed [@Schmid2010; @Ntogramatzidis2016], terminal sets for this scheme can be characterized as safe level sets of RDLFs, meaning that the proposed method in Section \[sec:method\] can be employed to compute these sets. In the rest of this subsection we will show an example where an invariant set for tracking is computed using the methodology proposed in this paper.
#### Example: {#example .unnumbered}
Consider the following model of a ball-and-plate system in discrete time $$\begin{aligned}
\label{eq:sys_sim_MPC}
x(t+1)=&\left[\begin{matrix}
1 & 0.5 & 0 & 0\\
0 & 1 & 0 & 0\\
0 & 0 & 1 & 0.5\\
0 & 0 & 0 & 1
\end{matrix}\right]x(t)+\left[\begin{matrix}
0.125 & 0\\
0.5 & 0\\
0 & 0.125\\
0 & 0.5
\end{matrix}\right]u(t).\end{aligned}$$ The positions of this system are constrained as follows $$\label{eq:mpc_const}
c(x,v)=x_1^4+x_3^4-10x_1^2+x_3^2-0.1\leq0,$$ which describes the *bow tie* set depicted in \[fig:domain\_mpc\]. In order to build the MPC for Tracking, we chose the following stabilizing terminal control law $$\kappa(x,v)=\begin{bmatrix}
-4 & -2.73 & 0 & 0\\
0 & 0 & -4 & -2.73
\end{bmatrix}
x+\begin{bmatrix}
4 & 0\\
0 & 4
\end{bmatrix}v.$$ When the system is controlled with this law and $v$ is kept constant, for every equilibrium point $\overline{x}_v=[v_1\ 0\ v_2 \ 0]^T$, it admits the following Lyapunov function $$\label{eq:LyapunovExample}
V(x,v)=(x-\overline{x}_{v})^TP(x-\overline{x}_{v}),$$ with $$P=\left[\begin{matrix}
5.3933 & 0.8668 & 0 & 0\\
0.8668 & 1.1946 & 0 & 0\\
0 & 0 & 5.3933 & 0.8668\\
0 & 0 & 0.8668 & 1.1946
\end{matrix}\right].$$ To compute $\hat{\Gamma}$, we used the approach presented in Section \[sec:practical\_div\]: we divided $\mathcal{R}$ into 16 subsets (see \[fig:domain\_mpc\]), and we did not assume any parameterization on $\overline{c}$ (*i.e.*, $k=0$ in ). For what concerns the maximal degrees of the decision polynomials, we set $\partial q_\ell=6$, $\partial s_{j,
\ell}=4$ and $\partial \hat{\Gamma}_\ell=8$, where $\ell\in\{1,\ldots,16\}$.
![Representation of $\mathcal{R}$ and its division used in the example at hand.[]{data-label="fig:domain_mpc"}](Figures/domain_mpc.pdf){width="\linewidth"}
Since the set described by is non-convex, we used the results in [@cotorruelo2018tracking] to ensure convergence. For what concerns the MPC for Tracking design parameters, the control and prediction horizons were set to $N_c=1$ and $N_p=2$, respectively. The stage and offset cost functions in the objective function of the MPC optimization problem are
[lCr]{} J\_s(x-\_v,u-\_v)=(x-\_v)\^TQ(x-\_v)+\
(u-\_v)\^TR(u-\_v),\
J\_o(v-r)=(v-r)\^TT(v-r),\
J\_f(x-\_v)=(x(N\_p)-\_v)\^TP(x(N\_p)-\_v),
with weights $Q=I_4$, $R=0.1I_2$, and $T=10I_2$.
In \[fig:mpc\_phase\_plot\] and \[fig:subplots\] we report the simulation results of the resulting MPC scheme assuming the initial state $x_0=[-2\ 0\ 1.75 \ 0]^T$, and setting the reference to $r=[2\ 1]^T$. As it can be seen in \[fig:subplots\] (which shows only for some time steps) the MPC is able to drive the system in $N_p$ steps to the terminal invariant set, whose size allows for a large domain of attraction of the MPC for Tracking.
![Simulation results; state trajectory of the system when controlled with a MPC for Tracking scheme. The state trajectory is depicted as a solid blue line with cross markers. The initial and steady state associated to the desired reference are depicted in green circular and cross-shaped markers, respectively.[]{data-label="fig:mpc_phase_plot"}](Figures/mpc_phase_plot.pdf){width="\linewidth"}
![Simulation results; previous state trajectory, its predicted evolution and terminal set at different time steps. The previous state trajectory is depicted in a solid yellow line, the predicted trajectory for the first $N_c$ steps is depicted in a solid blue line, the last $N_p-N_c$ steps is depicted in a solid orange line, and the terminal invariant set is outlined in a solid black line. The initial point is marked with a green circle, and the steady state associated to the auxiliary reference is represented with a green cross.[]{data-label="fig:subplots"}](Figures/mpc_multiplot.pdf){width="\linewidth"}
Reference Dependent Positively Invariant Sets in the ERG Framework {#sec:appERG}
------------------------------------------------------------------
The ERG [@Nicotra2018] is an add-on unit that is able to provide constraint satisfying capabilities to prestabilized continuous time systems (see \[fig:ERG\]). The main idea behind the ERG is to feed the precompensated system with a filtered version of the desired reference $r$, $v\in\mathbb{R}^p$, computed such that if $v$ remains constant, the system will not violate any constraints. In particular, the ERG [@Hosseinzadeh2018] manipulates the time derivative of the auxiliary reference $v$ as $$\label{eq:ERG}
\dot{v}=\Delta(x,v)\cdot\rho(r,v),$$ where $\rho(r,v)$ and $\Delta(x,v)$ are the two fundamental components of the ERG, called the Navigation Field (NF) and the Dynamic Safety Margin (DSM), respectively.
The NF is a vector field such that for any two steady-state admissible references $v$ and $r$, the trajectory of system $\dot{v}=\rho(r,v)$ goes from $v$ to $r$ through a path of strictly steady-state admissible references. This problem can be addressed using standard path planning algorithms (*e.g.*, [@latombe2012robot]).
The DSM is a measure of the distance between the constraints and the system trajectory that would emanate from the state $x$ for a constant reference $v$. A possible way to construct a DSM [@Nicotra2018; @Hosseinzadeh2018] is by using an RDLF $V(x,v)$ and a bound $\hat{\Gamma}$ such that $\mathcal{S}_{\hat{\Gamma}}$ is a safe invariant set as follows: $$\label{DSM_formula}
\Delta(x,v)=\lambda\cdot(\hat{\Gamma}(v)-V(x,v)),$$ where $\lambda>0$ is a tuning parameter. Note that this implies that $\Delta(x,v)>0$ whenever $x$ is in the interior of $\mathcal{S}_{\hat{\Gamma}}(v)$, and $\Delta(x,v)=0$ when $x$ is on the border of $\mathcal{S}_{\hat{\Gamma}}(v)$.
Accordingly, the methodology presented in this paper can be applied directly to compute the bound $\hat{\Gamma}(v)$ in the DSM within the ERG framework.
![The general structure of the ERG scheme.[]{data-label="fig:ERG"}](Figures/ERG_Scheme.pdf){width="\linewidth"}
#### Example: {#example-1 .unnumbered}
Consider a ball-and-plate system in continuous time stabilized with a PD control law $$\dot{x}=\begin{bmatrix}
0 & 1 & 0 & 0\\
-100 & -4 & 0 & 0 \\
0 & 0 & 0 & 1\\
0 & 0 & -100 & -4
\end{bmatrix}x + \begin{bmatrix}
0 & 0\\
100 & 0\\
0 & 0\\
0 & 100
\end{bmatrix}v,$$ whose positions are constrained to lie within the *bow tie* set . For every equilibrium point $\overline{x}_v=[v_1\ 0\ v_2 \ 0]^T$, stability can be proved using the quadratic RDLF $$V(x,v)=(x-\overline{x}_v)^TP(x-\overline{x}_v),$$ with $$P=\left[\begin{matrix}
12.645 & 0.005 & 0 & 0\\
0.005 & 0.1263 & 0 & 0\\
0 & 0 & 12.645 & 0.005\\
0 & 0 & 0.005 & 0.1263
\end{matrix}\right].$$ We computed $\hat{\Gamma}$ by dividing $\mathcal{R}$ and by setting the degrees of the polynomials in the same manner as in the example presented in Section \[sec:appMPC\].
For what concerns the NF, since $\mathcal{R}$ is non-convex[@Nicotra2018], it is enough to choose it as $$\rho(r,v)=\frac{\nabla\Phi(v)^{-1}(\Phi(r)-\Phi(v))}{\max\{\nabla\Phi(v)^{-1}(\Phi(r)-\Phi(v)),\theta\}},$$ where $\Phi:\mathcal{R}_d\rightarrow\mathcal{R}_c$ is a diffeomorphism that maps the interior of $\mathcal{R}$ to a convex set $\mathcal{R}_c$ and $\theta=0.01$ is a smoothing factor. A possible choice for $\Phi$ is $$\Phi(r)= \begin{bmatrix} r_1\\\displaystyle\frac{r_2}{\sqrt{\displaystyle\frac{1}{2}\sqrt{- 4r_1^4 + 40r_1^2 + \displaystyle\frac{7}{5}} - \displaystyle\frac{1}{2}}}
\end{bmatrix}.$$ Simulation results are shown in \[fig:result1\] for an initial state $x_0=[-2\ 0\ 1.75 \ 0]^T$, and a desired reference $r=[2\ 1]^T$. As it can be seen, the proposed ERG is able to steer the system state to the desired reference point while fulfilling the constraints at all times. The reader is referred to <https://www.youtube.com/watch?v=25yPHpviR18> for a video containing extra material.
![Simulation results; state trajectory of the system when controlled with an ERG. The trajectory of the system is depicted in solid blue line, the trajectory of the auxiliary reference,$v$ , is depicted as a black dashed line. The initial and steady state associated to the desired reference are depicted in green circular and cross-shaped markers, respectively.[]{data-label="fig:result1"}](Figures/erg_phase_plot.pdf){width="\linewidth"}
Conclusions {#sec:conclusion}
===========
In this paper we proposed a systematic method to approximate safe reference dependent positively invariant sets parameterized for systems that are subject to general polynomial constraints.
To do so, first, we demonstrated that such sets can be determined through an optimization problem. It was then shown that we can approximate a parameterized solution of this optimization problem by making use of SOS techniques. We later showed that it is possible to alleviate some of the numerical issues that the SOS framework presents if the underlying structure of the largest safe level set is exploited, and if the overall optimization problem is broken down into several, smaller better numerically conditioned problems.
The proposed method has relevant applications in constrained control schemes. In particular, the proposed method can be used in the MPC for Tracking framework to determine the terminal set, and in the ERG framework to determine the Dynamic Safety Margin. Corresponding formulations in the context of the mentioned applications were discussed, and a numerical simulation for each of the mentioned applications were presented in order to evaluate the effectiveness of the proposed method.
We believe that the proposed methodology can be applied to systems subject to polynomial constraints such as robotic manipulators or the aging-aware charge of Li-ion batteries [@romagnoli2017computationally]. Possible future research lines include simultaneously computing the RDLF and its largest safe level set and generalizing the methodology beyond polynomials, *e.g.* for rational functions.
Krivine–Stengle Positivstellensatz {#sec:psatz}
==================================
Before presenting the Krivine–Stengle Positivstellensatz, a few definitions need to be introduced. For the sake of simplicity, the following concepts will not be explained in depth, and will rather be mathematically characterized. For further information on the matter, the reader is referred to [@parrilo2000structured; @bochnak2013real; @stengle1974nullstellensatz] and the references therein.
[(Multiplicative Monoid)]{} The multiplicative monoid generated by a set of polynomials $P=\{p_i\}_{i=1}^m$, $p_i\in\mathbb{R}[x_1,\ldots,x_n],~ i=1,\ldots,m$ is the set of finite products of the $p_i$, including the unity: $$\textnormal{Monoid}(P)=\left\{\prod_{i=1}^m p_i^{k_i},\ k_i\in\mathbb{Z}_{\geq 0},~ i=1,\ldots,m\right\}.$$
[(Cone)]{} The cone generated by a set of polynomials $P=\{p_i\}_{i=1}^m$ , $p_i\in\mathbb{R}[x_1,\ldots,x_n],~i=1,\ldots,m$ is the sum of the elements of $\textnormal{Monoid}(P)$ multiplied by some sum of squares polynomials $s_i$: $$\begin{gathered}
\textnormal{Cone}(P)=\left\{ s_0 + \sum_i s_i g_i : s_i \in \Sigma[x_1,\ldots,x_n], \right. \\ g_i \in \textnormal{Monoid}(P) \Bigg\}.\end{gathered}$$
[(Ideal)]{} The ideal generated by a set of polynomials $P=\{p_i\}_{i=1}^m$, $p_i\in\mathbb{R}[x_1,\ldots,x_n],~i=1,\ldots,m$ is the sum of the products of the $p_i$ and some polynomials $t_i$: $$\textnormal{Ideal}(P)=\left\{\sum_{i=1}^m t_i p_i: t_i\in\mathbb{R}[x_1,\ldots,x_n],~i=1,\ldots,m \right \}.$$
At this point, the Krivine–Stengle Positivstellensatz can be expressed as follows:
[(Krivine–Stengle Positivstellensatz)]{} Let $f_i(x)$, $i\in\mathcal{I}$, $g_j(x),\ j\in\mathcal{J}$, $h_k(x),\ k\in\mathcal{K}$ be finite sets of polynomials in $\mathbb{R}[x]$, $C=\operatorname{Cone}(f_i)$, $M=\operatorname{Monoid}(g_j)$, and $I=\operatorname{Ideal}(h_k)$, then the set $$\{x : f_i(x)\geq 0,i \in \mathcal{I},g_j(x)\neq\ 0,j \in \mathcal{J}, h_k(x)=0, k \in \mathcal{K}\}$$ is empty if and only if $$\exists f\in C,\,g\in M,\,h\in I\ :\ f+g^2+h=0.$$
[^1]: The stabilization of unconstrained nonlinear systems is the subject of an extensive literature (*e.g.*, [@Schmid2010; @Ntogramatzidis2016]), and can be approached using a variety of available control tools.
[^2]: For brevity, we will omit the arguments of functions whenever there is no risk of confusion.
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Central mechanisms for thermoregulation in a hot environment.
Homeothermic animals regulate body temperature by autonomic and behavioral thermoeffector responses. The regulation is conducted mainly in the brain. Especially, the preoptic area (PO) in the hypothalamus plays a key role. The PO has abundant warm-sensitive neurons, sending excitatory signals to the brain regions involved in heat loss mechanisms, and inhibitory signals to those involved in heat production mechanisms. The sympathetic fibers determine tail blood flow in rats, which is an effective heat loss process. Some areas in the midbrain and medulla are involved in the control of tail blood flow. Recent study also showed that the hypothalamus is involved in heat escape behavior in rats. However, our knowledge about behavioral regulation is limited. The central mechanism for thermal comfort and discomfort, which induce various behavioral responses, should be clarified. In the heat, dehydration affects both autonomic and behavioral thermoregulation by non-thermoregulatory factors such as high Na+ concentration. The PO seems to be closely involved in these responses. The knowledge about the central mechanisms involved in thermoregulation is important to improve industrial health, e.g. preventing accidents associated with the heat or organizing more comfortable working environment.
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The paper written by John E. Edlund “Let’s do it again: A call for replications” in Psi Chi Journal of Psychological Research examines the importance of replication in science, particularly psychology. For so many years replication has been difficult to execute due to fabricated data, selective analyses, and manipulations of degrees. As stated in the paper, “Early career researchers in the field are pressured to publish early and often” which in turn can direct them towards “taking steps to drive up their publication counts”. Direct and conceptual replications alike are incredibly important in psychology. For without subsequent research supporting a study, there is no evidence supporting that the study was producing accurate data. In turn, this means the study is not contributing to the growth of psychological knowledge.
Christopher A. Wolters & Maryam Hussain’s paper, Investigating grit and its relations with college students’ self-regulated learning and academic achievement, discusses the effect of grit in relation with college students’ success in school. Essentially, a study showed that grit was a predictor for indications of self-regulated learning (SRL). Grit, while associated with the tendency to be academically successful, is not consistently linked “specifically to students’ academic achievement”. SRL, however, is reinforced by convincing evidence in being linked with academic achievement. The study has shown that grit and SRL could truly be major factors in a student’s academic success. Without studies to make important connections like this, psychological knowledge would be left with many gaps. Relating two traits is important in cultivating psychology.
Psychology is the study of the mind and its functions, especially those affecting behavior. This essentially means that the contributions of the study of psychology are virtually unlimited and ever-changing. As the importance of mental health continues to grow in our society, psychology will continue to be useful and important in our general knowledge. People are increasingly more aware of behaviors and what conditions may affect them. Psychology highlights the importance of understanding others and their actions. It provides a ‘why’ to many questions people ask in their everyday lives. For example, touching on the study done by Wolters & Hussain, instead of assuming someone is successful in school by pure luck or just ‘being smart’ we now can understand that they most likely encompass a personality trait that encourages them to work harder and focus more, otherwise known as grit.
While there are many contributions psychology provides to our general knowledge, there are also many limitations. Psychology is not like any other science. The study of the mind is complex and can be different for many people. Replications can pose a challenge, and replication is a key part of the scientific method. Without the ability to be accurately replicated, some may argue the study of psychology is not considered to be a science. Another limitation is that many people believe they know just as much about psychology as a trained and experienced psychologist. People tend to believe their common sense and life experience are enough to make them psychologists.
Future psychological research will be different than it is today, just as it is different today compared to the past. Psychology has much controversy surrounding it due to the fact that it is, and always will be varying. This is due to the environment and culture in which people live. My prediction is that in the future psychology will be proven more reliable and accurate due to evolving technology and the increasing focus on mental health. Psychology has not been taken seriously by many people in the past, but that is changing- and the future looks bright.
With mental health becoming so prevalent in today’s world, and continuing to grow, psychology faces some obstacles. Tying back in what was previously stated about people believing their own experiences provide enough evidence to make judgements on psychology, this could prove to be a serious issue in the future of psychological research. With everyone believing they truly understand psychological behavior, it will make it difficult for actual psychological studies to be executed and trusted. In a sense, it could end up giving the study of psychology a bad reputation because people will associate it with those who falsely claim to be knowledgeable on the subject. | https://eduzaurus.com/free-essay-samples/the-importance-of-replication-in-science-in-lets-do-it-again-a-call-for-replications-by-john-e-edlund/ |
After receiving his undergraduate degree in occupational therapy from Hong Kong Polytechnic University, Wing (Alex) Wong worked for several years as a therapist in a rehabilitation hospital.
As he cared for patients using the protocols he had learned as a student, he found himself often ruminating over larger philosophical questions: Why do we choose a certain kind of treatment? Is there another type of treatment that could provide better outcomes? Is this treatment the best option for this patient, or just a general approach that benefits most people?
Determined to find solutions, he contacted his former advisor, who shared his intrigue and interest in scientific research. Wong returned to Hong Kong Polytechnic University to complete doctoral work in rehabilitation science. While working as a Graduate Assistant, he discovered his knack for solving clinical questions using principles from applied science. “I was motivated by the excitement of discovery that I felt in the lab, even if such discovery is tiny,” he remembers.
Wong’s fascination with asking questions and trying to solve clinical problems stayed with him. He earned two Doctors of Philosophy: one in Rehabilitation Sciences from Hong Kong Polytechnic University, and another in Community Health from the University of Illinois at Urbana-Champaign. He later completed post-doctoral research in Health Services and Outcomes Research at the Rehabilitation Institute of Chicago, now the Shirley Ryan AbilityLab.
Currently a Research Scientist at the Shirley Ryan AbilityLab and Associate Professor of Physical Medicine & Rehabilitation and Medical Social Sciences at Northwestern University, Wong was one of four recipients to receive funding from the inaugural C-STAR pilot project program. (Editor’s note: When Wong applied, he was an Assistant Professor at Washington University School of Medicine in St. Louis.)
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Alex Wong, PhD, DPhil, OT, CRCResearch Scientist | Associate Professor, Physical Medicine & Rehabilitation and Medical Social Sciences, Northwestern
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For his project, Wong and his team are developing mobile cognitive tests that can be quickly and easily administered via a smartphone app. He hopes that these tests will complement traditional neurocognitive assessments and provide clinicians with a better picture of a patient’s overall status and recovery.
“Cognition is an important function in intervention studies, but conducting traditional assessments in these studies is not possible due to the high costs associated with the nature of in-person evaluations,” he says.
In addition, traditional testing is often administered in a controlled setting, such as a private office that is free from noise, potentially creating a disconnect between what the patient can do in a controlled setting compared to the real world.
“This tool can supplement traditional neurocognitive assessments by supporting our clinicians to know their patients’ cognitive recovery after transitioning to home,” he explains.
The C-STAR project will allow Wong to validate these mobile assessments and test how well they can be implemented in home environments.
Wong was especially interested in C-STAR because of its focus on applying emerging technologies, such as sensors and mobile health, in rehabilitation medicine. “C-STAR is the place that provides the opportunity to learn and grow your research to make a significant contribution to people with disabilities using technologies,” he says.
Some of the valuable resources that have helped him hone his project so far have included direct mentorship at meetings with senior scientists and multidisciplinary clinicians (Idea Labs or Buzz Labs) where he has received candid feedback from multiple points of view.
Using the knowledge he gains from participating in C-STAR, he hopes to establish a research program focused on the effective implementation of technology-enabled assessments and treatments in rehabilitation settings and communities. “I hope that this program will have a direct impact on our hospital to improve patient outcomes,” he says.
Fun facts: As a child, Wong often attended photography courses, joined photography clubs, and participated in photographic field trips – and his dream was to one day become a professional photographer! Currently on weekends, he brings a DSLR camera everywhere he goes. His favorite subject is his smiley 11-month-old son. | https://www.sralab.org/research/labs/cstar/news/c-star-pilot-project-awardee-spotlight-alex-wong-phd |
Rein Chemical Company A quick read through the case shows that Rein Chemical has a task on hand and Garrison needs to correct the issue before it blows out of proportion. What is more concerning is that some of the management’s reactions have been to push this under the carpet and move on. This points to a fundamental ethics issue in the firm on what is acceptable and what is not. The problem of providing inferior chemicals instead of the one ordered arises due to a bunch of issues. The major ones 1.
2) Had you been advising Mr. Cathy, what would you have counseled him? If I had the job of advising Mr. Cathy after making the comment he did I would’ve done everything I could to make him realize the impact his statement truly had. After he was aware of what it is he was doing to his and the company’s reputation I would’ve continued to discuss how he planned on handling the situation. I believe that things got out of control on both ends of the spectrum with the Appreciation Day and the Kiss-In. I believe it is important for people to stay true to who they are, their beliefs, and their values, but it is also just as important to be considerate, professional,
INTRODUCTION This case is about the unethical decisions and activities that are instructed by Phil Bailey, supervisor of Empress Luxury Line. The case also describes the ethical decision that is taken by Kevin and his refusal to follow an unethical decision of his supervisor Phil Bailey by denying making fraud with the insurance adjustor. This report will highlight the ethical dilemma faced by Antonio during following unethical orders of his superiors. Additionally, from the point of view of Antonio suitable and effective strategy will be also suggested that will be beneficial for the organization and for the employees without compromising their ethics. 1) Analyze the ethical dilemma faced by Antonio In the case, when Phil Bailey told to Kevin to charge high amount of money over the insurance company for the damage of wires and computer circuits, Kevin disagreed to do this unethical activity due to having high morality and standards.
An ethical dilemma is defined as a morally problematic situation in which you must choose between two or more alternatives that aren’t equally acceptable to different groups. Ethics in business have gained much attention over the years. Some ethical dilemmas are fairly straight forward; meanwhile others can be a bit more complex. Based on the scenario for Angela at WellCare USA, the suggested course of action will be discussed. Angela’s ethical dilemma is that of adhering to the confidentiality requested of her by her firm vs. listening to her moral compass and looking out for her friend by warning him.
According to Pierce Hollingsworth (2004), the parents and school should not blame the food marketing for being the main cause of obesity rather than teaching and helping the kids to have good habit of eating. He thought that the responsibilities of the parents and schools were important for educating childhood obesity. However, there are so many problems with his arguments. He did not think about the bad effects of advertising on kids. For example, the food marketing companies usually uses the attractive poster about fast food to get the attention of the kids.
Re-building the trust of our customers is not worth the potential gains of sharing their personal information and there would have to be negative repercussions for anyone who attempted that type of unethical behavior. Like any other company, we would also have to maintain awareness of the ethical integrity of our marketing strategy. We would not want to put off a negative public image by promoting any negative stereotypes. It would also be our social responsibility to aware of the culture of the people we were marketing to. It would be unethical to market our mobile app as something only a "higher quality" of people should use.
These pro and cons will have to be measured by risk and how it will effect the company. After the weight of the risk is measured the company will then need to decide on what strategy will be most beneficial and less risky. 1. Analyze the ethical dilemma faced by Antonio. In this case study Antonio work in the Empress Luxury Lines and he faced dilemma regarding the ethic in the work place.
He needs this contract to keep his job but not “coming clean” is jeopardizing his sense of ethics. What should he do? An ethical dilemma is a situation where there is no right and wrong in relation to a decision and therefore a solution is not quickly achieved (Shaw, Barry, Sansbury, 2009). Ethical dilemma can also be defined by a sense of moral obligation. Kent’s situation does consist of several ethical dilemmas as his accomplishments since joining Dura- Stick have been mediocre at best and he fears that his time at Dura-Stick might be limited unless he starts closing big accounts such as the project proposed from Spray-On.
The true need for sound ethical behavior is the cornerstone to the foundation of a person’s character. Character is ethical behavior combined with choices and that is what defines us as individuals. Our character is tested when a paper is due, you run out of time and there is an option to cheat. Character plays a major role in team effort when collusion can be prevalent. A university is a vast consortium and it creates a challenge to your ethical standpoint and ethics must be exercised regularly.
It should focus on results and find the underlying cause of the problem to resolve this from excelling over time. Carefully make sure that they are not getting in over their heads and take smaller steps before jumping into to something that can ruin them. By the company, admitting nationally any fault of their own this will help to gain the public trust once again. By informing investors and consumers of this wrongdoing, this is the first step to fixing the problem at hand. Making sure that all involved in this wrongdoing are reprimanded for their actions and noting that to investors and the public. | https://www.antiessays.com/free-essays/Mt-140-Unit-8-Asignment-638062.html |
Radiology in the era of personalised medicine: is radiology personalised enough?
To select the right treatment at the right time for your patient is a common slogan used to describe personalised medicine (PM): a new vision of healthcare which is already becoming a reality today. Different “omics” approaches such as genomics, proteomics or metabolomics allow patients’ predispositions to certain diseases or treatment response to specific medication to be predicted.
What is the role of radiology and radiologists in PM?
In the recent white paper, published by the ESR Working Group on Personalised Medicine (Insights Imaging (2015) 6:141–155), the authors emphasise the key roles medical imaging plays in PM. The authors clearly specify all areas and give examples of the unique and personalised information provided with medical imaging technologies.
In a substantial number of diseases, the first step leading from clinical symptoms to a diagnosis relies on imaging. Imaging has played this role for decades: assessing the location and extent of a disease in individual patients and characterising structural abnormalities and physiological environment, thus providing crucial information for the choice of the right treatment. | https://blog.myesr.org/tag/personalised-radiology/ |
Health care decisions are never easy to make, especially when the decisions are complex such as considering a new therapy or participating in a clinical trial. Many health care professionals recognize this and are encouraging patients to play a more active role in making treatment decisions based on balancing evidence based options with a patient’s personal health outcome goals, preferences and values.
Shared decision-making is when patients, caregivers and health care professionals work together to make the health-related decisions that are best for the individual patient. This is an approach to decision making that considers input from patients as part of the planning process and works best when a patient wants to be part of their own treatment team. | https://www.fabrynetwork.org/2021/09/16/understanding-the-importance-of-shared-health-care-decisions/ |
ST. PAUL — Even before the city of St. Paul increased the citywide minimum wage last year, some restaurants and retailers began dropping jobs and shedding hours.
Full-service restaurants — those with wait-staff and sit-down service — saw jobs decline by 16%. Limited-service restaurants, such as fast-food eateries, saw a 27% decline.
Minneapolis, which began hiking its minimum wage two years earlier, lost nearly 3,000 restaurant jobs during the same time, according to two new analyses from the Federal Reserve Bank of Minneapolis and the University of Minnesota.
But some St. Paul retailers and food service employers actually raised wages in 2018 and 2019, apparently in anticipation of the mandate, or in competition for workers with higher-paying jobs across the river. And a tight labor market in the months since has raised wages further.
Impact of $15 minimum wage
With the goal of gradually moving toward a $15-an-hour citywide minimum wage over the next few years, St. Paul rolled out a wage schedule that requires most low-wage employers to institute annual increases, which began at $9.25 to $11.50 an hour as of July 1, 2020, depending upon business size.
Officials in both St. Paul and Minneapolis promised they would contract economists to analyze the impact on jobs, earnings and employment hours. It's a task complicated by the COVID-19 pandemic, the recession, rioting and arson following the death of George Floyd, federal relief checks, a labor shortage, inflation and other curveballs of the past several years.
"This needs to be interpreted with caution," said Anusha Nath, a research economist who worked on the analyses for the Minneapolis Fed.
Nevertheless, the researchers were able to glean some "baseline" data from pre-COVID employment numbers, and they spotted some sizable "anticipation effects" in St. Paul. In short, restaurants, retail and food services apparently braced for the minimum wage hike by cutting jobs or reducing hours in 2018 and 2019, even before the new law rolled out, though the overall low-wage sector showed little net effect.
Drops in jobs, hours, earnings
St. Paul restaurants in particular saw large drops in jobs, hours and total earnings.
"The estimates of job loss in the restaurant industries of both St. Paul and Minneapolis are particularly large compared with other studies of minimum wages, implying that at least some businesses in the Twin Cities were quite sensitive to the actual or imminent increases in labor costs," reads a study summary by Lisa Camner McKay, a writer-analyst with the Opportunity and Inclusive Growth Institute at the Minneapolis Fed.
Most other low-wage sectors studied in St. Paul, such as social assistance and administrative support, showed no deep changes in the studies. A hodge-podge of jobs falling into the "other" category — such as repair shops, barber shops and personal care services — actually increased in number, for reasons that aren't entirely clear.
"In that sector, we saw an increase in total jobs," Nath said. "This could partly be driven by if there's a loss in restaurant jobs, these workers could be getting jobs elsewhere. ... These are the types of channels we want to study in future reports."
How much did St. Paul's initial minimum wage increase impact St. Paul businesses after July 1, 2020?
Given that the increase took effect in the early months of the pandemic, shortly after riots rocked St. Paul's Midway, it's probably too soon to tell.
"Isolating the impact of the minimum wage during ... unprecedented times poses a significant challenge and raises questions about how to interpret data from 2020," reads the study summary from the Minneapolis Fed.
Given the scramble to attract workers during a labor shortage, some call it unlikely that boosting the minimum wage has had deep impact.
Andy Remke, co-owner of the Black Dog Cafe in St. Paul's Lowertown, said the restaurant industry used to attract many casual workers who wanted to pick up a shift here or there for extra spending cash.
"The pandemic pushed a lot of those people out of the industry," said Remke. "We're paying probably easily 20% more than we were for cooks, and probably more."
He added: "Minimum wage is certainly not a factor. The only people we have working here making the minimum wage are servers, and that's before tips, after which they make substantially more. Everybody else — food runners, kitchen staff — they're all making more, because that's the labor environment we're in."
Minneapolis impacts
The Minneapolis wage law began in 2018, offering more pre-pandemic data to work with.
The researchers found that through early 2020, the total number of jobs declined by 12% more than they otherwise might have at full-service Minneapolis restaurants, and 18% more at limited-service restaurants. That's roughly 2,900 Minneapolis restaurant jobs lost over the 27 months analyzed.
At the same time, wages increased about 4% more for Minneapolis full-service restaurant workers, and 9% more for limited-service restaurant workers, than they otherwise might have.
The analyses are the first in a series of annual reports planned from the Minneapolis Fed through 2028, and they've already garnered pushback from advocates for the $15 minimum wage. A written critique published by the Economic Policy Institute, a left-leaning think tank based in Washington, D.C., calls the Minneapolis changes in employment "implausibly large" and likely attributable to other factors, given that the Minneapolis minimum wage last year increased by only 75 cents at small employers and $1 at large employers.
"The data and methodology used in the study are simply not sufficient to distinguish between the effects of the minimum wage increases and other changes in employment happening around the same time," it states.
Full effect might not be known for years
It will be a few more years before the full effect of a $15 minimum wage in the Twin Cities can be studied in retrospect.
That's because the mandated increases roll out on different schedules for large or small employers in Minneapolis, and micro, small, large, and macro businesses of more than 10,000 employees in St. Paul. It won't go into effect for all city businesses until 2024 in Minneapolis and 2028 in St. Paul.
For their findings, researchers with the Minneapolis Fed and the University of Minnesota used administrative data from the Minnesota Department of Employment and Economic Development, which provides quarterly earnings and hours worked for each employee of businesses that file unemployment insurance reports with the state.
The DEED data was combined with information from the U.S. Bureau of Labor Statistics' Quarterly Census of Employment and Wages, allowing researchers to identify the specific establishment, industry, ZIP code and city where each individual works. | https://www.grandforksherald.com/business/restaurants-and-bars/7296097-St.-Pauls-15-minimum-wage-Some-restaurants-were-shedding-jobs-before-it-took-effect |
Short abstract:
India is a privileged context for building social, cultural, religious, political and historical places. At the same time, India is a starting point for building Indian places outside its territorial matrix. Diaspora phenomena illustrate these multi-sited and multi-belonging experiences.
Long abstract:
In and outside India diverse negotiations coexist in the way in which people shape their lives and places, starting from the different historical and colonial pathways that differentiate Goa, Daman and Diu, previously under Portuguese administration, from the rest of India, formerly British. The different uses of history must be seen in relation to memory and daily life: caste, religion, symbols and localities imply social, cultural and historical approaches.
Residential clusters inhabited by South Asian groups all over the world's greatest urban areas originate interesting interactions between people and spaces which, in turn, does not inhibit multiple processes of localization, driven by Diaspora dynamics and, by the same token, as an outcome of ambivalent belonging emotions towards extremely different national sites such as India and Portugal. Different life experiences, itineraries and memories all contribute to constructing real and imaginary spaces, which in turn act as strong identity features in present.
South Asians' quotidian and trajectories in cosmopolitan sites show that India and Asian societies in general act as a permanent inspiration, nourished by the media and contemporary consumption society. Therefore, we may raise several questions: what strategies do people use to shape their lives and places, in India and abroad? How is memory construction embodied? What differences and similarities can we, as researchers, observe, whether from the perspectives of individuals, groups or policy makers? | https://nomadit.co.uk/sief/sief2011/panels.php5?PanelID=768 |
Project Roadmaps: What Are They?
A project roadmap depicts a strategic, high-level overview of every key component involved in a project. This form of business roadmap marks your official reference to look at the bigger picture of any future project such as each project milestone, objective, timeframe, deliverable, or risk. And project roadmaps are the best communication system when it comes to sharing with the whole team how projects should turn out as planned.
According to a project management survey, 70% of projects tend to fail.
Why Is a Project Roadmap Important?
Project roadmaps are the key to visualizing project tasks and objectives within a feasible timeframe. But why else is it important or needed in any project in the first place? In this section, you will learn the many essential reasons for having a project roadmap.
Connection to Project Goals
There are times when a project management workflow plan works exactly as planned, but it may not always align with your organization’s goals and objectives. Hence, project roadmaps exist to help you ensure that your project objectives are met during the project’s outcome. As the project information is presented visually, stakeholders and team members get a proper understanding of why there is a need to deliver that project successfully.
Step-by-Step Mapping Tool
You will appreciate project roadmaps for showing you every single step needed to carry out the project successfully. Thus, this is a mapping tool that highlights your project’s task list. It answers what must be done from start to finish until the benefits from the project are acquired in the long run. So the next time any project team member loses track of what to do next, simply let the member refer to the roadmap for reference.
Reliable Timeline View
Project roadmaps don’t simply deal with what to do as it also tackles when to do such project tasks. Refer to the roadmap to view the timeframe of the project. This is helpful, particularly when setting a timeline for deadlines. Because without a deadline, who knows how long the project could be completed? Ensure to provide an agile project schedule on the roadmap to boost the project team’s productivity.
Dependable Progress Tracker
Want a thorough understanding of your project’s progress? The project roadmap can be a useful tool in creating your project tracking sheet. This explains why you can monitor the project’s milestones and progress because you can report for observations on a timely basis. Without a tracker, there would be no assurance as to how near or far your project is to completion.
High Success Rate for Projects
A project roadmap is linked to your project plan. So you are guaranteed that your entire strategic plan will reach a successful turn in the future. As all project members follow the requirements and instructions in the roadmap, projects do not have to fail. Take this opportunity to improve the success rate of every project instead.
What Makes a Standard Project Roadmap?
Project roadmaps don’t have to be the same for every organization. In fact, projects are different from one application to another as a project could be related to healthcare, construction, school, or any other aspect. However, there is a similar format for standard project roadmaps. And they often contain the following elements:
How to Make a Stellar Project Roadmap
Project roadmaps are a dynamic tool for your next potential project, especially when you now know its definition, importance, and elements. So are you prepared to create an excellent project roadmap of your own? Without further ado, here are the steps in building a proper project roadmap:
Step 1: Download a Sample Project Roadmap Template
You need not go through the hassle of creating roadmaps from scratch. Simply choose and download from any of the 33+ sample project roadmaps listed above in this post. Each project roadmap example is editable and printable so you can design how the project roadmap presentation goes anytime. And you may even check out more roadmap examples such as a product roadmap, marketing roadmap, and many more. Customize a template now!
Step 2: Define the Project and Its Key Elements
It is standard that developing the project roadmap should happen first before even formulating the project plan. But as much as possible, you should be able to define the general data of your project first, including its key components. This includes the project scope statement, level of expectations, and other objectives. When you have a clear vision of the project, writing the rest of the project roadmap gets easier.
Step 3: Assign Project Roles and Responsibilities
Indeed, recognizing the tasks needed to achieve in a project is essential to a project roadmap. But you have to make sure you have enough staff to work on those duties. In fact, part of making the roadmap is to assign the project responsibilities and roles ahead. Start by identifying the project manager, team members, and external and internal stakeholders. Be sure to set up a meeting with the rest of the team ahead to introduce the task assignments promptly.
Step 4: Complete the Project Roadmap Components and Classify
As discussed earlier on what makes a basic project roadmap, there are six standard elements from the project overview to the notes. Be sure to put them on your roadmap and classify each. Don’t just collate all the information without visual organizers or your document will end up being hard to read. You can make use of tables, organizational charts, graphs, and other examples to compartmentalize your data. Also, you can add more elements besides the six basic components as long as they are necessary for your project.
Step 5: Set a Communication Plan
It is expected that you will evaluate and correct the content of your project roadmap. And once you are confident with the results, your next concern is how to present the information to the entire project team. A proper communication plan shall definitely do the trick. Maybe your team members do not understand the symbols used or that the instructions were too technical. Also, take this opportunity to discuss with the team in determining the project risks and analyzing the quality of the project. The more informed the members are, the better the outcome.
Step 6: Update the Project Roadmap Regularly
You can refer to the project roadmap from time to time. But its data can be changed anytime too. Last-minute decisions might come up. Or perhaps, you need to highlight some details in the roadmap for your project’s progress report. So don’t ignore the content of the project roadmap after making it because it can be edited in the aftermath. And you need to outline what project changes were made in a dashboard or software to inform other members that there were alterations.
FAQs
What is the difference between a project roadmap and a project plan?
The project-roadmap-vs-project-plan debate has been talked about for years. Although they are linked to one another, there is also a polarity between the two. Project roadmaps are more on the visual overview of a project whereas a project plan is more detailed by mentioning the project requirements, activities, and other project data reports. So if you want to see the big picture of your project, use a project roadmap. And if you want in-depth information on a project, the project plan has your back.
What types of projects benefit from project roadmaps?
All sorts of projects can make use of a project roadmap. But generally, project roadmaps are appropriately used for marketing plans, IT strategies, business development projects, sales projects, technology projects, and project portfolio management.
What is a project charter?
A project charter is a useful tool to ensure the team members of the project and its stakeholders are in the loop. That means the project charter guides everyone to work on common goals. It is simply a short document, typically a one-page sheet, that talks about the entirety of a project.
Project managers often feel pressure since a single project can deal with numerous deadlines, tasks, resources, budget, and decisions. Nonetheless, they will continue to do their best to lead the whole team and reach project completion as soon as possible. And a well-made project roadmap can promise you just that. Optimize a sample project roadmap template and reach your project goals now! | https://www.sample.net/maps/project-roadmap-report/ |
Today a lot of big and small organizations are using Google Workspace for work. And their users are wondering does Google have a Kanban board?
13 November 2021 0
Does Google Have A Gantt Chart?
Currently, Google Workspace is an online productivity tool with lots of apps related to organization and team management. The three main components are Gmail, Docs, and Sheets. Correct me if I am wrong but, many project managers seem to be successfully using Google Apps for their tasks. This can be on the basis of featuring several tools. Or the ability to work on all devices on which you have this app installed. Or on the basis of its cloud storage facility, collaboration feature with which you can work on projects with your team members, and so on. But many project managers ask for a Gantt chart solution. That’s why their search history contains the question: does Google have a Gantt chart?
What Is A Gantt Chart?
The Gantt chart is one of the most popular project management tools used in project planning. Basically, it is a graphical representation of tasks involved in a project, and how these tasks are scheduled into time periods. Gantt charts are very useful in project forecasting the actions, risks, timeline, and phase-by-phase completion. Moreover, these charts also help to simplify complex projects with multiple critical tasks, resources, due dates, and dependencies. It is typically used to document resource dependence and duration relationships of the tasks in a project schedule.
Gantt charts were invented by the Swedish engineer and management consultant, Henrik Emil Gantt. They are often used for scheduling specific activities and tasks over time and visualizing the time frame of single or multiple projects. This can be helpful for tracking complex projects to adjust them as per schedule, budget, and plan. Used by professionals, it provides all the necessary information so that project managers can make real-time decisions.
Whenever we’re working on a big project, we can always use a Gantt chart to see how the different parts of an event or project fit together. It’s like holding it all in your hand. The first implementation is very nice and includes several different views. I would say it’s the best tool for tracking projects or tasks that you need to follow up on regularly.
The Importance Of Using Gantt Charts
The importance of Gantt charts is huge for any project. That is why it’s advisable to learn to use them at least a little bit. Some people see Gantt charts as complicated and unnecessary tools. But if you choose the right one for your needs, you can achieve all your project management goals.
In addition, the Gantt chart gives you a much clearer overview of your tasks and project activities. By seeing everything laid out in front of the user, it aids the person responsible for the project to assess the needs of the project and their ability to reach their established deadlines. They are crucial in finding out any possible bottlenecks that can affect your project’s completion agenda. They can alleviate the common problem of tracking progress in a project with lots of different interrelated tasks.
Generally, Gantt charts represent your project schedule, with all events and tasks represented visually on the chart. They allow you to see how various sub-projects relate to each other, as well as their relationship to the whole project, the milestones they cross, and the outcomes they generate. All this information is invaluable in determining your future success or failure.
Does Google Have A Gantt Chart?
Creating a Gantt chart is a perfect way to take control of your project management efforts. And Google lacks it, unfortunately. Although Google Workspace apps pack has spreadsheets to organize, schedule, and run tasks, there is no way to make a Gantt chart in these tools.
I would say, there are two types of people in this world: those that love spreadsheets, and those that love Gantt charts. I’m definitely in the latter group. I’ve always flinched at the thought of using a spreadsheet to organize complex projects. At first glance, the spreadsheet seems to contain all the necessary functionality, there are sheets with tasks, filters, comments, dates. But if you try to do something more complex for several users at once, then it turns out that any significant data operation takes place manually or too slowly.
Gantt Chart Solution For Google Workspace
Until Google actually decides to offer a Gantt chart tool on their website, many users will be looking for an alternative that is available on the web. And Kanbanchi app is the solution for Google Workspace users. It offers a Gantt chart for project managers with all the features they might need. Gantt Chart in Kanbanchi is used to visually present the tasks and their durations. This makes it possible to find out whether the planned main activities match the envisioned duration, otherwise, it is possible to rearrange the scope of the project or cut down on it.
Kanbanchi’s Integration With Google Apps
Kanbanchi is a project management tool that has a difference. It is a project management tool that allows you to create Kanban boards, Gantt charts, and use different tools for everyday workflow. Kanbanchi is built to integrate with Google Workspace Apps (such as Calendar, Drive, Sheets, etc.) and can work with Google Drive. All you need to start working with Kanbanchi is your Google account.
Using Kanbanchi, you can manage your tasks, create timelines for your projects or events, track their progress with beautiful dashboards and also assign tasks to others on your team. Sign up today and try it out yourself. | https://www.kanbanchi.com/does-google-have-a-gantt-chart |
A patent is a limited duration property right relating to an invention, granted by the United States Patent and Trademark Office in exchange for public disclosure of the invention. Patentable materials include machines, manufactured articles, industrial processes, and chemical compositions.
When it comes to intellectual property and the rights and laws associated with it, people tend to confuse patents, copyrights, and trademarks. Intellectual property is one of the assets that can boost …
Trademark Copyright And Patent Likewise, a subsection proposed for the copyright act prohibiting enforcement against … The Section also commented on the proposal within Bill C-86 to create a College of Patent Agents and Trademark … creative ideas and expressions of the human mind that may have commercial value and are protectable under patent, trademark, copyright or trade secret
Nov 10, 2018 · The process for getting a copyright, trademark, or patent varies by country, as do the requirements for registration. Registration is not always required for copyrights and trademarks, although in both cases, there may be benefits to doing so.
(Excerpted from General Information Concerning Patents, U.S. Patent and trademark office website) Need a patent form? Try these: Exclusive Patent License Nonexclusive Patent License Assignment of Patent Application. Some additional differences between a copyright and a trademark are as follows: 1. | https://wcpinstitute.org/difference-between-patent-and-copyright-and-trademark/ |
Van Alen’s Book Club is taking a break starting August 2020. During our hiatus, we’ll think fondly about all the great books we’ve read, and all the engaging, informative discussions we’ve had the past few years. It’s your curiosity, enthusiasm, and participation that makes our Book Club great.
We wish you all the best, and many thanks for your past support of Book Club.
Van Alen Book Club meets the last Tuesday of every month (except December) in our street-level space. Our discussions, moderated by some of our favorite urbanists, use the urban experience in fiction and non-fiction as a springboard to ask how we experience cities, and how we want to make them in the future. Meetings are open to all, and include pizza, wine, and beer. | https://past.vanalen.org/projects/van-alen-book-club/ |
I am a professional with an extensive background in project management, event execution and process solutions. I use an approach that includes creativity, practical experience and collaboration to forge a path to business and team improvements.
I specialize in collaborating with small to medium organizations, working to develop immediate, actionable solutions that include successful, impactful execution of developed thoughtful plans.
I am passionate about fostering and nurturing positive relationships both professionally and personally. The art of friendship is important in every aspect of your life! If you are seeking to evaluate your professional or personal interactions with friends and colleagues, I can offer coaching to enhance those relationships and offer insights about cultivating new ones!
I am experienced in nonprofit governance, fundraising and media strategies as well as private financial management and accounting. During my professional career I have supported multiple profit and nonprofit organizations in numerous capacities, including serving as a member of the Board for the Albany Berkshire Ballet and as a member of the community impact board with Berkshire Farm. I have worked to raise tens of thousands of dollars for health, community, and national nonprofits, and committed to continuing these efforts in the future. In 2018, I began coaching high school students in philanthropic pursuits including event planning, marketing and fundraising. I started my career in the field of accounting and finance working for a number of companies including Wm. Wrigley Jr. Company and TransWorld Entertainment.
I hold a Bachelor’s in Accounting and Computer Science from Russell Sage College. | https://www.sdroussin.com/about |
Taking the step for counseling is the most important decision you can make for YOU! My encouraging client centered, solution focused approach will provide support for you to explore your issues of concern. I am dedicated to providing a safe, non-judgmental and caring environment so that each client feels comfortable and understood.
I counsel clients for any issue that is causing a distraction or distress in life. Some of my specialty areas include depression, relationship disturbances, life transitions, addictions, and stress management. I utilize a variety of therapy modalities based on the individual needs of each client.
Together, we will set goals which will encourage you to move forward in life. My goal is that you will leave each session feeling renewed, with a plan to look forward to addressing in the coming week. I encourage you to call now and take an important step for YOU! | https://www.psychologytoday.com/us/therapists/joan-oconnor-kings-park-ny/203217 |
INTRODUCTION: Due to the anti-inflammatory, antioxidant and anti-apoptotic properties of minocycline, clinical trials have evaluated the potential of this drug to treat several psychiatric and neurological disorders, including major depressive disorder, schizophrenia, bipolar disorder, stroke and amyotrophic lateral sclerosis. This protocol proposes a systematic review (and potential meta-analysis) that aims to identify and critically evaluate randomised controlled trials of minocycline for treating psychiatric and neurological disorders.
METHODS AND ANALYSIS: PubMed, Embase, Cochrane Central Register of Controlled Clinical Trials, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be used to identify randomised controlled trials that used minocycline to treat psychiatric and neurological disorders. Double-blind, randomised, controlled, clinical trials of participants aged 18 years or older and written in English will be included in the review. Data will be extracted by two independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed and the Cochrane Collaboration's 'Risk of Bias' tool will be used to assess the risk of bias in all studies included in the systematic review. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to access the overall quality of the level of evidence of the studies. If sufficient evidence is identified, a meta-analysis will be conducted using the standardised mean difference approach and reported with 95% CIs. Heterogeneity of evidence will be evaluated using the I2 model.
ETHICS AND DISSEMINATION: This systematic review will evaluate only published data; therefore, ethical approval is not required. The systematic review will be published in a peer-reviewed journal and presented at relevant research conferences.
TRIAL REGISTRATION NUMBER: CRD42020153292. | https://research.bond.edu.au/en/publications/minocycline-for-the-treatment-of-mental-health-and-neurological-c |
Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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Due date: The date on which a payment is due under this agreement. The plenipotentiary is the person designated by a party in his or her statements or any person who, in accordance with this agreement, is replaced as an authorized official. An author should also refrain from filling recitals with additional non-key definitions (e.g., actions. B, company or product) or a multiple of references » (as defined in Article 1) immediately after each defined term. In order to ensure the inclusion of key definitions in the legally binding contract, a better approach might be to include the text «as defined below» just before the term defined in the recitals and, therefore, to implicitly draw the reader`s attention to the section of the definition contained in the treaty arrangement. However, in practice, it is unlikely that a court will not take into account all references to terms defined in the recitals when interpreting the agreement. Considerations can be useful in defining the «transaction» (in non-legal terms). However, do not use popular or loose language to describe an object that is otherwise well defined in a definition, as this creates ambiguity. From this point on, the core of the contract, which contains legally binding rights and obligations between the parties, is established. Whether or not there is clear language in this regard, it is important to pay attention to the interpretive clauses which, as a general rule, must be found immediately after the definition clause, which should determine which parts of the treaty are part of the legally binding agreement or are excluded from it.
Contract plans (which generally contain other key terms of the contract) are often explicitly designated as components of the contract and therefore have legal value. Considerations of transaction structure – these are atypical and complex transactions that have experienced the implementation of the contract. An example would be a succession of events. The data provided is information provided by a party on page 1 of this agreement or a specific amendment notified by the party by notification in accordance with this agreement. The guarantee for the payment of a debt, any other monetary obligation or the performance of another obligation and includes any agreement to grant or create any of the aforementioned commitments. Zone IV: the territory of rental properties and any other rental property covered by Schedule 2 that has been requested or acquired for the purposes of this agreement, or any other area agreed in writing by all joint ventures. The preamble to a contract usually consists of one to five paragraphs that identify the entire transaction. For most relatively standard types of contracts, the list of recitals is limited to a few. On the other hand, highly customized (complex) transaction agreements and agreements may have a dozen or more considerations that list any fact or event, the uncertainty to be settled or each party`s position on a dispute.
preamble. The preamble is usually given the title considerations, during or background, probably written in all-caps or bold. They address some of the key features of the agreement, the associated transaction or the parties` transactions and help the reader understand the background before looking at the Definitions section. «total,» the percentage of funds that must be made available to a joint venture to the pure enterprise under this agreement to finance joint venture activities under an approved program and budget. Recitals can play a useful role in helping third parties conclude or re-examine the contract at a later date in order to understand the intent of the original parties. The reality is that the commercial intent of a written contract does not always appear easily in the material provisions. | https://unsuspectedband.com/legal-agreement-recitals/ |
mirror(redirected from Mouth mirror)
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mirror,in optics, a reflecting surface that forms an imageimage,
in optics, likeness or counterpart of an object produced when rays of light coming from that object are reflected from a mirror or are refracted by a lens. An image of an object is also formed when this light passes through a very small opening like that of a pinhole
..... Click the link for more information. of an object when light rays coming from that object fall upon it (see reflectionreflection,
return of a wave from a surface that it strikes into the medium through which it has traveled. The general principles governing the reflection of light and sound are similar, for both normally travel in straight lines and both are wave phenomena.
..... Click the link for more information. ). Usually mirrors are made of plate glass, one side of which is coated with metal or some special preparation to serve as a reflecting surface. The junction of this reflecting surface and the plate glass is called the mirror line. Highly polished metal and other materials serve also as mirrors; fused quartz is used for applications that require high precision because of its very low thermal expansion. Three common types of mirror are the plane mirror, which has a flat, or plane, surface; the convex mirror; and the concave mirror.
The Plane Mirror
In a plane mirror the rays of light falling on it are reflected with little change in their original character and their relationship to one another in space. The apparent position of the image is the same distance behind the mirror as the actual object is in front of the mirror; the image is the same size as the object and is called a virtual image (i.e., the rays of light from the object do not actually go to the image, but extensions of the reflected light rays appear to intersect behind the mirror).
Convex and Concave Mirrors
Convex and concave mirrors are known collectively as spherical mirrors, since their curved reflecting surfaces are usually part of the surface of a sphere. The concave type is one in which the midpoint or vertex of the reflecting surface is farther away from the object than are the edges. The center of the imaginary sphere of which it is a part is called the center of curvature and each point of the mirror surface is, therefore, equidistant from this point. A line extending through the center of curvature and the vertex of the mirror is the principal axis, and rays parallel to it are all reflected in such a way that they meet at a point on it lying halfway between the center of curvature and the vertex. This point is called the principal focus.
The size, nature, and position of an image formed by a concave spherical mirror depend on the position of the object in relation to the principal focus and the center of curvature. If the object is at a point farther from the mirror than the center of curvature, the image is real (i.e., it is formed directly by the reflected rays), inverted, and smaller than the object. If the object is at the center of curvature, the image is the same size as the object and is real and inverted. If the object is between the center of curvature and the principal focus, the image is larger, real, and inverted. If the object is inside the principal focus, the image is virtual, erect (right side up), and larger than the object. The position of the object can be found from the equation relating the focal length f of the mirror (the distance from the mirror to the principal focus), the distance do of the object from the mirror, and the distance di of the image from the mirror: 1/f=1/do+1/di. In the case of the virtual image, this equation yields a negative image distance, indicating that the image is behind the mirror. In the case of both the real and the virtual image, the size of the image is to the size of the object as the distance of the image from the mirror is to the distance of the object from the mirror.
In a convex spherical mirror the vertex of the mirror is nearer to the object than the edges—the mirror bulges toward the object. The image formed by it is always smaller than the object and always erect. It is never real because the reflected rays diverge outward from the face of the mirror and are not brought to a focus, and the image, therefore, is determined by their prolongation behind the mirror as in the case of the plane mirror.
History and Development
The mirror of the ancient Greeks and Romans was a disk of metal with a highly polished face, sometimes with a design on the back, and usually with a handle. Glass mirrors date from the Middle Ages. They were made in large quantities in Venice from the 16th cent., the back being covered with a thin coating of tin mixed with mercury; after 1840 a thin coating of silver was generally substituted. The introduction of plate glass for mirrors (17th cent.) stimulated the use of large stationary mirrors as part of household furniture. Small bits of silvered glass were much used in the East to adorn articles of dress and of decoration. The metal trench hand mirror of World War I revived the manufacture of mirrors of this type. More recently, aluminum was introduced as the reflecting material because it is almost as efficient as silver but is more resistant to oxidation. Mirrors play an important part in the modern astronomical telescopetelescope,
traditionally, a system of lenses, mirrors, or both, used to gather light from a distant object and form an image of it. Traditional optical telescopes, which are the subject of this article, also are used to magnify objects on earth and in astronomy; other types of
..... Click the link for more information. .
mirrorAn optical element designed to reflect light or other radiation, normally consisting of a glass or glasslike substrate on which is deposited a thin but uniform coating of highly reflective material. Aluminum is now usually used in telescope mirrors (see aluminizing). A very high quality reflecting surface can also be made from a multilayered stack of very thin films. The films have alternately high and low refractive indices and are of such a thickness and spacing that almost all the incident light is reflected.
Mirrors may be planar, i.e. flat. Alternatively the shapes may be concave (converging) or convex (diverging) and are generally spherical or paraboloid in form. The mirror base must be accurately ground and the surface polished to within one quarter of the wavelength used, i.e. to about 0.1 micrometer for optical wavelengths, if good quality images are to be produced. Paraboloid mirrors do not suffer from spherical aberration but for wide fields have severe coma. Spherical mirrors are free of coma and astigmatism if a suitable stop is used; they do, however, suffer from spherical aberration. See also grazing incidence; primary mirror.
Mirror
Mirror(religion, spiritualism, and occult)
Mirrors have been associated with magic in many stories, myths, and legends. It was once believed that one's reflection in a mirror, or any reflective surface, was a vital part of one's soul. Mirrors were therefore regarded as "soul catchers," and were therefore draped with black cloth in the sick room of a dying person. Today's superstition that breaking a mirror causes bad luck stems from these old beliefs. Walker points out that the ancient Egyptian word for "mirror" is also the word for "life." Buddhists claim that all existence is like a reflection in a mirror.
In Witchcraft, mirrors are mainly used for divination, the user gazing into the reflective surface as into a crystal ball. Some such mirrors are blackened to cancel out any extraneous sights, while some are made with concave glass to help draw the eyes into the image.
The murals on the walls of the Initiation Room in the Villa of Mysteries at Pompeii include a scene of the initiate gazing into a polished copper mirror held aloft by a priest. In it, the initiate sees and relives the death of Dionysus. Leonardo da Vinci drew a picture (now in the library of Christ Church, Oxford) of two witches using a magic mirror to see the future. A similar illustration is found in the miniature from the eighteenth-century manuscript attributed to the Comte de Saint-Germain, La Très Sainte Trinosophie.
De Givry suggests that Catherine de Medici possessed a magic mirror in which she studied the future of France. Queen Elizabeth I's astrologer, Dr. John Dee, owned a magic mirror made of polished obsidian, a black volcanic glass. This mirror, or speculum, is preserved in the British Museum. Dee and his assistant, Edward Kelley, toured sixteenth-century Europe using the mirror in the service of various rulers and aristocrats.
Old grimoires for Ceremonial Magic give recipes for the paint used to turn a piece of clear glass into a black gazing mirror. Ingredients include turpentine and multiple coats of asphaltum. Some suggested inscribing the edge of the glass with the words "S. Solam S. Tattler S. Echogordner Gematur." Others say the mirror should be standing within a triangle whose three sides are marked with the words "Alpha— Omega—Tetragrammaton" (others say "Adonay—Eloy—Tetragrammaton").
The Roman god Vulcan had a magic mirror that showed past, present, and future. Al-Asnam, in the Arabian Nights, had a similar mirror. Other magic mirrors appear in fairy stories and folk tales around the world.
Mirror(religion, spiritualism, and occult)
The mirror can be a useful tool for developing clairvoyance. It also features in much ancient folklore. In American lore, if an unmarried woman looks into a mirror by the light of a candle at midnight on Hallowe’en night, she will see the reflection of her future husband looking at her over her left shoulder. An older legend from Europe has it that by gazing into a reflection of the moon in a hand mirror, a young woman can tell how many years will pass before she marries, based on the length of time before either a cloud passes before the moon or a bird flies across it.
In earliest times, Chinese sages, together with wise men and women of ancient Greece and Rome, believed that to dream of seeing your own reflection—be it in water, polished brass or copper, or wherever—was an omen of death. The death was not necessarily yours but was of a person close to you. Seeing your reflection at various times of the day also had meaning. This was all brought together in what was known as catoptromancy, or enoptromancy, divination by mirror. Hydromancy, divination by water, was but a small part of it.
Catoptromancy, as an aspect of mirror-gazing, is referred to by Sir Thomas Urquhart in The Third Book of the Works of Mr. Francis Rabelais (London, 1693), which reads, “Catoptromancy is held in such account by the emperor Didius Julianus,” implying that it was practiced in ancient Rome. The (London) Annual Register of 1758 says, “He understands all the mysteries of catoptromancy, he having a magical glass to be consulted upon some extraordinary occasions.” Pausanius, the fifth century BCE Spartan regent of the Greek forces and admiral of the Greek fleet, described how this form of divination was performed, “Before the Temple of Ceres, at Patras, there was a fountain, separated from the temple by a wall, and there was an oracle, very truthful, but not for all events—for the sick only. The sick person let down a mirror (of bronze or silver), suspended by a thread, till its base touched the surface of the water, having first prayed to the goddess and offered incense. Then looking in the mirror, he saw the presage of death or recovery, according as the face appeared fresh and healthy or of a ghastly aspect.” The Romans and the Egyptians also used this form of divination.
Mirror gazing is one of the many forms of scrying, of divining by looking into a reflective surface. The mirror is used much like a crystal ball in crystal gazing, being gazed into with the diviner or medium seeing scenes from the past, present, or future. The Roman god Vulcan had a magic mirror in which he was able to see all things. England’s Merlin had one that warned him of treason. In Chaucer’s Canterbury Tales, the mirror of Cambuscan told of misfortunes to come. In Goldsmith’s Citizen of the World, Lao’s mirror reflected pure thought. In the Arabian Nights, there is the all-seeing mirror of Al-Asnam, and in Snow White and the Seven Dwarfs there is the magic mirror of the wicked Queen, in which she can see Snow White. A drawing by Leonardo da Vinci now in the Library of Christ Church, Oxford, England, shows a woman holding up a mirror to a seeress as part of a ritual. In the mirror can be seen the face of an old man.
In Étienne Pasquier’s Recherches de la France (1560), he speaks of a magic mirror owned and used by Catherine de Médicis (1519–1589). She supposedly could clairvoyantly see the future of France, especially as it pertained to the de Médicis family. According to Grillot de Givry, Père Cotton used that same mirror to show Henri IV all the plots that were being hatched against him.
All types of mirrors have been used over the ages, with polished metal faces, glass, crystal, and obsidian. The mirror may or may not be enclosed in a frame. If it is, the frame is usually engraved or marked in some way with sigils to help generate and amplify the images seen. In Francis Barrett’s book The Magus (1801), there is shown a mirror set in a frame of “pure gold” with the sacred names MICHAEL, GABRIEL, URIEL, and RAPHAEL inscribed around it, inside a double circle. These are the angels ruling over the Sun, Moon, Venus, and Mercury. Above the name Michael is drawn a six-pointed star. On the other side of the frame there is also a circle engraved, inside which (next to the glass) is a six-pointed star together with a five-pointed star and a Maltese-style cross. These are followed by the word TETRAGRAMMATON. The glass, Barrett says, should be “of a lapidary good clear pellucid crystal … about one inch and a half in diameter.” There are also instructions for the preparation and inscribing of the table on which the glass should stand. Other authorities give other instructions and suggestions as to what would be appropriate to mark around the frame, though some leave the frame unmarked.
Many diviners say that a black mirror is far superior to any other. Similarly, a concave mirror is an advantage. One way to make a mirror that follows both these suggestions is to obtain one of the old framed pictures, from around the turn of the previous century, which has an oval, convex glass. Reversing the glass and painting what then becomes the back of it with black paint produces a convex black mirror that is perfect for mirror gazing. Old books of magic state that the glass should be painted three times with asphaltum. To make the asphaltum stick to the glass, it first needs to be cleaned with turpentine. The asphalt should be laid on with a camel-hair brush. However, using modern black enamel from a spray can seems to work just as well. As with all magical practices, while making the object you should be concentrating on its purpose, on it being good for projecting scenes from past, present, and future.
The Revue Archéologique of 1846 contains an illustration and description of a magic mirror that belonged to a Spanish family at Saragossa in the seventeenth century. It was a metal, convex mirror decorated with figures and with the words MUERTE, ETAM, TETECEME, and ZAPS. It was said that images appeared on the surface of any liquid reflected in the mirror’s surface.
Some people training to become Spiritualist mediums will begin their exercises with scrying, using either a crystal ball or a mirror. It can be an effective way to get started so long as the medium does not come to rely solely on the object but merely uses it as a tool for further development.
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Mirror
(or speculum, Russian zerkal’tse), in biology.
(1) The shiny pigmented membrane of the eye in some animals that reflects light on the retina and thereby intensifies the light stimulation of the visual cells. It causes the apparent luminosity of the eye in almost complete darkness. In vertebrates (some fish, reptiles, and birds and almost all predatory and aquatic mammals) it is located on the internal surface of the vascular tunic of the eye; in many fish and some reptiles it is in the cells of the pigmented epithelium of the retina (in the form of crystals of a shiny pigment). In invertebrates with lens eyes (some mollusks, annelid worms, and arthropods) it is formed of pigmented cells of the reflecting layer.
(2) [Usually “speculum.”] Areas of brightly colored plumage, sometimes with a mirror-like gleam, on the wings in the area of the secondaries in male birds, especially in many species of ducks. They serve as signals, for example, in mating games.
(3) [In English, “wax plate.”] Organs of wax secretion in worker bees (two wax mirrors for each four to seven sternites of the abdomen). They consist of a layer of hypodermal cells and a transparent cuticle that covers them, through which the wax secreted by the gland cells of the hypodermis is exuded.
(4) Part of the sound (stridulating) organs in the males of some crickets. It is a thin, smooth, transparent plate with edges inflated in the form of a ridge and is located on the surface of the right wing, which is covered with the left one. It serves as a resonator that intensifies sounds arising during stridulation from rubbing the left wing on the ridge of the right one.
Mirror
a body that has a polished surface and is capable of forming optical images of objects (including light sources) by reflecting light rays.
The first mention of the use of metal mirrors (made of bronze or silver) in daily life dates to the third millennium B.C. In the Bronze Age mirrors were known chiefly in the countries of the ancient East; in the Iron Age they were used more extensively. The face of metal mirrors was smoothly polished, and the reverse side was covered with engraved or raised designs or images. The mirrors were usually round, with a handle (among the ancient Greeks the handle was often in the form of a sculptured figure). Glass mirrors with a tin or lead backing began to be used by the Romans in the first century A.D.; they disappeared in the early Middle Ages and reappeared only in the 13th century. In the 16th century the backing of glass mirrors with tin amalgam was discovered.
The diversity of the shapes and types of mirrors, from pocket mirrors to very large cheval glasses, began to increase in the 17th century. Mirror frames became more ornate. Mirrors often served as a finishing touch on walls and mantles in court interiors during the baroque era and the period of classicism. In the 20th century, with the development of functionalist tendencies in architecture, mirrors have almost lost their decorative role and are now usually manufactured according to their domestic function (in a simple metal frame or unframed).
Optical properties. The closer the shape of a mirror’s surface to a mathematically regular shape, the higher the quality of the mirror. The maximum permissible size of microscopic surface irregularities is determined by the intended purpose of the mirror: for astronomical mirrors and some laser mirrors it must not exceed 0.1 of the shortest wavelength λmin of the radiation incident on the mirror, but for searchlight or converging mirrors it may be as high as 10λmin.
The position of the optical image produced by a mirror can be determined according to the laws of geometric optics. It depends on the shape of the mirror surface and the position of the represented object.
A flat mirror is a natural optical system that produces a wholly aberration-free image (always a virtual image) for any light beams incident on it. This property of flat mirrors is responsible for their extensive use for various design purposes (rotation of a light beam, autocollimation, image reversal, and so on). Such mirrors are also used in high-precision measuring instruments, such as interferometers.
Concave and convex mirrors are also used in optical systems. Their reflecting surfaces are spherical, paraboloidal, ellipsoidal, or toroidal; mirrors with surfaces of more complex shapes are also used. Concave mirrors usually (but not always) concentrate the energy of a light beam by collecting it; convex mirrors scatter it. Nonflat mirrors have all the aberrations inherent in optical systems, except chromatic aberrations. The position of the image of the object created by a mirror whose surface has an axis of symmetry is related to the radius of curvature r of the mirror at its apex O (Figure 1) by the ratio
l/s + l/s’ = 2/r
where s is the distance from the apex O to the object A and s’ is the distance to the imaged’. This formula is strictly valid
only in the extreme case of the infinitesimal angles formed by the light rays with the axis of the mirror; however, it is a good approximation even at finite but sufficiently small angles. If the object is located at a distance that may be considered infinitely large, s’ is equal to the focal distance of the mirror: s’ = f’ = r/2.
Properties of reflecting surfaces. A mirror must have a high reflection coefficient. Smooth metal surfaces, such as aluminum in the ultraviolet, visible, and infrared bands, silver in the visible and infrared bands, and gold in the infrared band, have high reflection coefficients. The reflection from any metal depends strongly on the wavelength of the light A: as A increases, the reflection coefficient Rλ rises to 99 percent or more for some metals (Figure 2).
The reflection coefficients of dielectrics are much smaller than those of metals (only 4 percent for glass with an index of refraction n = 1.5). However, by using light interference in multilayer combinations of transparent dielectrics it is possible to obtain (in a relatively narrow region of the spectrum) reflecting surfaces with reflection coefficients of over 99 per-cent not only in the visible band but also in the ultraviolet, which is impossible with metallic surfaces. Dielectric mirrors consist of a large number (13–17) of alternating layers of dielectrics with high and low n. The thickness of each layer is such that the optical length of the light’s path in it is one-fourth of the wavelength. Odd layers are made of a material that has a high n (such as sulfides of zinc and antimony and oxides of titanium, zirconium, hafnium, and thorium), and even layers are made of a material that has a low n (fluorides of magnesium and strontium; silica). The reflection coefficients of dielectric mirrors depend not only on the wavelength but also on the angle of incidence of the radiation.
Production of mirrors. In antiquity, polished metal plates were used as mirrors. As glassmaking developed, metal mirrors gave way to glass mirrors, whose reflecting surfaces were thin layers of metals applied to the glass. Originally small mirrors of irregular shape were produced by pouring into a spherical glass vessel a molten metal which, upon hardening, formed a reflective layer (after cooling, the vessel was cut up). The first glass mirrors of significant size were manufactured by coating the glass with a mercury-tin amalgam. This method, which is harmful to the health of workers, was later replaced by chemical silvering, which is based on the ability of some compounds that contain the aldehyde group to recover silver from saline solutions in the form of a metallic film. The most widely used industrial process for producing mirrors by silver-plating consists in the removal of impurities and corrosion products from the surface of the glass, the application of silver deposition centers, silvering, and the application of protective coatings to the reflecting layer. The thickness of the silver film usually varies from 0.15 to 0.30 microns (μm). To provide electrochemical protection of the reflecting layer, it is coated with a copper film of thickness comparable to that of the silver film. Paint and varnish materials such as polyvinyl-butyral, nitroepoxy, and epoxy enamels, which prevent physical damage to the protective coating, are applied to the copper film. Mirrors intended for technical use are manufactured with reflecting films consisting of gold, palladium, platinum, lead, chromium, or nickel.
Mirrors are also manufactured by plating glass by cathode sputtering and vacuum vaporization. Thermal vaporization of aluminum in a vacuum at a pressure of 6.7 x 102to l.3 x 10-3 newtons per sq m (N/m2), or 5 x 10-4 to 10-5 mm of mercury (mm Hg), is becoming particularly widespread. The aluminum is vaporized from braids made of tungsten wire or from a fireproof crucible. The preparation of the glass surface for aluminum coating is performed even more carefully than before chemical silvering; it includes dehydration and treatment by electrical discharge in a vacuum of 13.3 N/m2 (10”1 mm Hg). To produce a mirror with maximum reflectance, the thickness of the aluminum coating should be at least 0.12 μm. Because of their increased chemical stability, aluminum-coated mirrors are sometimes used as external reflecting sur-faces protected by optically transparent layers of A12O3, SiO2, MgF2, or ZnS. Usually the layer of aluminum is covered with the same opaque paints and varnishes used in silvering. A certain nonuniformity over the spectrum and the reflectance of aluminum-plated mirrors, which is lower than that of silver-plated mirrors, are justified by the significant saving of silver in the mass production of mirrors.
Mirrors with coatings of most metals, as well as dielectrics, can be produced by the methods of cathode sputtering and thermal vaporization.
Use in science, technology, and medicine. The ability of concave mirrors to focus light beams parallel to their axis is used in reflecting telescopes. The operation of searchlights is based on the reverse phenomenon—the transformation in a mirror of a beam of light from a source located at the focal point into a parallel beam. Mirrors used in combination with lenses form a broad group of catadioptric systems. In lasers, mirrors are used as components of optical cavities. The lack of chromatic aberrations brought about the use of mirrors in monochromators (especially of infrared radiation) and many other devices.
In addition to measuring and optical devices, mirrors are also used in other fields of technology—for example, in solar concentrators, solar power plants, and zone melting apparatus (the operation of these devices is based on the ability of concave mirrors to concentrate the energy of radiation in a small volume). A frontal reflector—a concave mirror with an aperture in the middle that is used to direct a narrow light beam into the eyes, ears, nose, throat, and larynx—is the most widely used mirror in medicine. Mirrors of diverse design and form are also used for research in stomatology, surgery, and gynecology.
REFERENCESSliusarev, G. G. Melody rascheta opticheskikh sistem. Moscow-Leningrad, 1937.
Sonnefeld, A. Vognutye zerkala. Moscow-Leningrad, 1935. (Translated from German.)
Maksutov, D. D. Astronomicheskaia optika. Moscow-Leningrad, 1946.
Vinokurov, V. M. Khimicheskie melody serebreniia zerkal. Moscow, 1950.
Tudorovskii, A. I. Teoriia opticheskikh pribomv, part 2. Moscow-Leningrad, 1952.
Rozenberg, G. V. Optika tonkosloinykh pokrytii. Moscow, 1958.
Danilin, B. S. Vakuumnoe nanesenie tonkikh plenok. Moscow, 1967.
Gluck, I. /vse eto delaiut zerkala. Moscow, 1970. (Translated from English.)
L. I. BORISOVA and V. N. ROZHDESTVENSKII
What does it mean when you dream about a mirror?
The mirror reflects oneself from the inner depths. If the mirror is clear, one is gazing upon one’s true self. This may be a shocking or a pleasant experience, depending upon how many shortcomings or false images the dreamer presents in the real world. A cracked or cloudy mirror reflects the distortions that are projected into the world.
mirror[′mir·ər]
mirror
mirror
mirror
MirrorAlasnam’s mirror
mirror(hardware, storage)
Several operating systems support software disk mirroring or disk-duplexing, e.g. Novell NetWare.
See also Redundant Array of Independent Disks.
Interestingly, when this technique is used with magnetic tape storage systems, it is usually called "twinning".
A less expensive alternative, which only limits the amount of data loss, is to make regular backups from a single disk to magnetic tape. | https://encyclopedia2.thefreedictionary.com/Mouth+mirror |
The Children of Refugees
Virtually every country in the world today makes educating its children a societal goal, and considers education essential in meeting national and individual aspirations. Educational philosophers, such as John Dewey and George Counts, argue that the primary purpose of education and schooling is not just to prepare students to live a useful life, but also to teach them how to live pragmatically and independently as participants in society. Today, however, there are unprecedented numbers of refugee children for whom education is at best inadequate and cursory. As refugee and resettlements camps become more overcrowded, some children receive no formal schooling, presaging a crisis of enormous magnitude. The reality of the Syrian refugee crisis is staggering. Syria is the world’s top source country of refugees. The UNHCR estimates that more than twenty percent of all refugees, or four million refugees, are Syrian, an increase of one million refugees in the last ten months. Another 7.6 million Syrians have been displaced within their own country. Together this represents the largest forced migration since World War Two. It is particularly alarming that over half of the four million Syrian refugees are children under eighteen years old. Syrian refugee children face particular educational challenges, as many of them were internally displaced before they became refugees., and thus have experienced multiple disruptions in their education.
Data indicates that as internal conflict has continued for so long, Syrian schools have failed to provide an adequate education to their children, even before they become refugees. From 2014 to 2015, for example, the number of students enrolled in basic and secondary schools within Syria decreased by 2 million, to 3.4 million. Syrian refugee children, then, never have the chance to develop societal values that promote social cohesion.
The Organization for Economic Cooperation and Development (OECD) defines a cohesive society as one that “works towards the well-being of all its members, fights exclusion and marginalization, creates a sense of belonging, promotes trust, and offers its members the opportunity of upward mobility.” Societal well-being depends on schools’ success in conveying and embedding this premise in children. The OECD report asserts that societies lacking social cohesion “are unlikely to be sustainable.” Thus, the need for schools to promote social cohesion continues, even when schools are disrupted, closed, or destroyed, and arguably increases as school disruptions increase.
However, today, the children’s physical and geographic dislocations, the schools’ inability to maintain a permanent faculty, and the absence of out-of-classroom activities all inhibit refugee schools’ success in promoting social cohesion in dislocated and refugee children. This is equally true for both the refugee children living in camps in many different countries, as well as for those who remain displaced in Syria.
The physical condition of Syrian refugee children’s schools is disheartening. “External” refugees (those who have left Syria) are taught in makeshift structures, some just in tents or semi-enclosed facilities, and “internal” refugees (those displaced from their communities and living elsewhere in Syria) are taught in buildings severely damaged by fighting and bombing. 4,500 of Syria’s 22,000 schools have been destroyed or are no longer being used as schools.
Data also indicates that Syria ranks sixth of eight countries in the Middle East with a literacy rate of 84 percent in 2011, with continuing declines as the civil war continues. The deplorable physical condition of schools attended by the refugee children in Syria and abroad, as well as the relatively low literacy rate, indicates a barely functioning system that does not provide children with skills or prepares them for futures as members and participants in a socially cohesive society.
Given the precarious nature of their situations as refugees, these Syrian children particularly need schools that provide the structure for them to develop social cohesion. These schools should deliver the tripartite functions of teaching literacy, preparing individuals for sustained economic livelihood, and developing a commitment to the values of social cohesion that enable refugee children to live as productive members of society. Another essential component of social cohesion is self-regulation, and Syrian schools must teach self-regulation by instilling tolerance for differences, promoting cooperation, and fostering altruism.
The future of Syria and its citizens is uncertain. Budgets to support refugees in the countries where they now reside are strained, and education has often taken a backseat to health, housing, and subsistence. Without schools and a commitment to schools’ transformative potential to create cohesion, civility, and comity, Syrian refugee children will be unable to develop a future commitment “to a common objective.”
The international community must support both short and long term opportunities for refugee children. It must first provide financial support for schools in refugee camps and other areas in the short term. This financial support must go to train teachers, so educators are equipped to help refugee children make educationally effective transitions that sustain learning continuity throughout their journeys as refugees. In the longer term, the international community must assist, when feasible, in returning return refugee children to their home countries, as well as in creating opportunities to make them immigrants, not refugees, to countries that will accept them.
Beyond these imperatives, there must also be unified international initiatives to create effective schools for children currently living in refugee camps. A well-funded, worldwide effort with strong international political and humanitarian support to build and maintain such schools must be the immediate next step. By definition, refugee camps are meant to be temporary. Schools within such camps, though, must teach enduring content and values. | https://www.georgetownjournalofinternationalaffairs.org/online-edition/the-children-of-refugees |
Adjacent to the company’s headquarters and its underground rail station, the two-building BellSouth campus was designed to offer employees using mass transit an attractive transition from the suburbs. Architectural precast concrete panels clad both structures in the complex.
The precaster worked closely with the designers from the early stages of the project to create an economical way to master the intricate base designs for the two buildings. Three different mixes were used to simulate various granites, while seven finishes were used on the towers.
Precast concrete provided design flexibility in color and form, plus a durable cladding material for the high rises, the designers said. Approximately 117,000 square feet of precast panels were used on the smaller building, while 126,000 square feet were used on the taller one. Architectural precast concrete spandrels were used to clad an adjacent parking structure as well, blending the look of the two projects. | http://gcpci.org/projects/project.cfm?articleID=07596BBF-F1F6-B13E-8AD521CBA8B96004&categoryIDs=8175C072-F1F6-B13E-8B93BA47BC10C018&searchString= |
China has outpaced the United States in the number of worldwide artificial intelligence-related patent applications, according to a new report issued by the China Industrial Control Systems Cyber Emergency Response team, a research unit under the Ministry of Industry and Information Technology.
China-based companies have applied for a total of more than 440,000 AI patents as of October. Internet search giant Baidu Inc. filed 5,712 AI-related patent applications, ranking first in China for the second consecutive year, followed by Tencent (4,115), Microsoft China (3,978), Inspur (3,755) and Huawei (3,656).
The report showed that Baidu is the patent application leader in several key areas of AI, including the deep learning (1,429), natural language processing (938) and speech recognition (933).
The report pointed out that AI is taken as an important direction for industrial upgrading, and the country’s strategic plan for AI offers a broad space for the research and development of AI technologies and related industries. Moreover, from the perspective of applicants, enterprises such as Baidu and universities have become the main force in driving AI technologies.
It suggested more efforts are needed to strengthen basic AI research and establish intellectual property systems related to AI, as well as introduce high-level talents, in an attempt to grasp the opportunities brought about by AI. | https://fairskylaw.com/news/nation-leads-the-world-in-applications-for-ai-patents/ |
FIFTEEN years after the traditional stool became vacant, people of Ajali town in Orumba North Local Government Area of Anambra, installed a new traditional ruler, Eze Emesinwa Nwosu VII, on Monday.
Nwosu is the first son of the immediate past traditional ruler, Eze Obinali Nwosu.
The Ogbuti-Oti dynasty is famed to be the founder of Ajali. The dynasty’s palace is home to the traditional stool of the community and succession to the throne is automatically transferred to the first son of the immediate past traditional ruler.
Past traditional rules of Ajali include Oji-Oti, Oti-Oji, Nwafor-Oti, Aniche-Oti, Nwosu Nwafor and Obinani Nwosu.
Eze Nwosu VII’s coronation was performed by Prince Patrick Nwosu, the “Akakpa Ofor’’ Ogbuti-Uti and eldest man of the ruling house.
The ceremony was witnessed by the heads of the four villages of Ajali – Amagu, Omuabiama, Umueve and Obinikpa.
Chief Austin Nwosu, a prince of the palace said the presentation of Eze Emesinwa Nwosu by the ‘Ime-Obi Ogbuti Oti’ was the climax of the Ajali traditional ruler succession process.
He said the plot to make the second son of the late Eze succeed him against Emesinwa who was abroad led to the delay of the succession process for 15 years.
Chief Nwosu said the matter had been determined by a competent court, which ruled in favour of Ajali tradition of non- rotation of the traditional ruler’s seat and automatic transfer of staff to the heir apparent of a deceased ruler.
“Normally in dynasty there are times when we have tussle over who should replace the Eze; there are people who would want to use money to subvert the process; that is what was going on until the case went to court.
“The High Court delivered judgment according to the customs and traditions of Ajali, having traced the history of Eze and declared that the stool rests in this palace and must go to the first son of the deceased ruler,’’ he said.
A palace chief, Chief Chukwunedum Enekwe, said he was happy that bad politics was not allowed to desecrate the succession process by allowing the true successor to ascend the throne.
Enekwe said the presence of the heads of the four villages signified the endorsement by the gods of Ajali and prayed that their spirits would bless the new king and give the town lasting peace and progress.
Mrs Ellion Gbinijie, a princess of the palace described the event as a pleasant end to long years of squabble.
Gbinijie said that Ajali community had a lot of crises during the days of vacuum because some matters which would have been resolved by the Eze-in-Council were either taken to court or to the Police.
“We are happy in this palace because we have been able to install the rightful successor. Since the father of the Eze died, Ajali had been in chaos because of the inability of the palace to have a traditional ruler.
“So for us, it is the beginning of peace and greater things to come. With a new king, there will be less court and police cases because the Eze-in-Council has a very efficient and acceptable way of resolving disputes,’’ she said.
In his acceptance speech, Eze Nwosu VII said he would continue in the same manner his ancestors ruled the community in their times, adding that he would yield himself to their spirit for guidance.
He called on the people of Ajali to support his reign and forgive one another for peace and progress of the community.
Eze Nwosu VII had his secondary education at Izzi High School, Ebonyi and studied Mass Communication at Western Cape University, South Africa, where he lived for 30 years. | https://realnewsmagazine.net/ajali-anambra-community-gets-traditional-ruler-after-15-years/ |
Many assns will spend tens of thousands of dollars and months of effort to select and implement a new assn management system, only to find that in a very short time, the system is not being used as effectively as had been hoped.
While there are many factors that affect long-term success of an AMS, one underlying factor is user adoption. User adoption reflects how well (or not) the staff takes to using the new database. That is, do they fully embrace the system, find workarounds to avoid using it, or even actively work against its success?
So what elements can affect user adoption? Here are five that are critical:
- User interface. This is what the software looks like to the user. It includes the navigation, design, icons and colors. Of the five elements here, this one might be the least under your control, but this is changing somewhat. Many software packages now allow users to configure their systems to only show information that is relevant to their job or function.
- Training. In order to have a successful experience with a database, users must have a proper understanding of how to use the system. Training is where this happens.
- Documentation. While training is critical for getting a user comfortable with using the system, long-term success is dependent on complete and thorough documentation that users can refer to while using the system.
- Continuous feedback loop. Database software is ever-evolving. New functionality and new needs are constantly being identified. So it’s critically important to have some type of feedback loop that allows users to talk with each other and to provide feedback to the database manager and developers. If staff is having problems with the database, they need to know that they’ve got an outlet for raising those issues and having them addressed. Without this, staff will quickly resort to workarounds and creating “shadow” databases outside the primary system.
- What’s in the user’s best self-interest? The single, most-effective way to get user adoption is to identify why it is in the user’s self-interest to use the system. Both carrots and sticks apply here. That is, the person’s job might require that they use the database. But carrots tend to work better, so identifying how the system will make the person more efficient, more effective, or more valuable to the organization will help with user adoption. But keep in mind that what might work for one person might not for another. Everyone has their own self-interest.
Finally, it should be noted that selecting the right system for your organization is absolutely critical for user adoption. It’s nearly impossible to improve user adoption of a tool that simply doesn’t do what the organization needs it to do.
User adoption is key to long-term success in your database. By addressing these five issues (and selecting the right system) you will greatly improve the odds of users adopting the database.
This article originally appeared in the May 15, 2009, issue of Association Trends. Reprinted with permission.
Did you like this article? If you’d like to receive notice of articles like these as they are posted in the future, click here. | https://effectivedatabase.com/getting-user-to-actually-use-the-database/ |
New Security Vulnerabilities: How Should You Respond?
- May 25, 2022
- Brad LaPorte
Cybercrime has exploded in growth over the past several years to levels that are stunning to contemplate. To put it into perspective, consider these facts:
With so much money at stake, it’s not surprising that there is a seemingly endless supply of news stories and updates about the latest threats, along with updates from cybersecurity agencies. On average, security researchers documented 55 common vulnerabilities and exposures on average each day of 2021 – more than 20,000 in total. In addition, the phenomenon of the “celebrity vulnerability” has become a trend of late, generating coverage not just in the trade publications but general interest news outlets such as the New York Times, USA Today, CNN, and CBS.
All of this demonstrates that organizations in all sectors need high-performing security teams. Such teams can keep on top of the attack vectors that threat actors are employing and cover up their infrastructure’s critical flaws before damage is done.
In theory, the reports of new threats would seem to be valuable in helping security teams keep abreast of the latest attack vectors to guard against. But it’s not so simple.
Let’s look at some of the reports from the time period of March and April of 2022. On April 25th, the Cybersecurity and Infrastructure Security Agency (CISA) listed seven new vulnerabilities to the Known Exploited Vulnerabilities Catalog and informed federal agencies that they needed to respond to these threats by a specified date. It also suggested that organizations of all sorts – not just federal agencies – add these vulnerabilities to their catalogs of vulnerabilities.
That report only gives a hint at the number of warnings about vulnerabilities that CISA gave during that time period. Besides the April 25th report, that month CISA provided a list of known and exploited vulnerabilities on April 4, 6, 11, 13, 14, 15, and 19. The previous month it alerted readers to vulnerabilities through updates provided on March 3 (95 such vulnerabilities on that date alone), as well as March 7, 15, 25, 28 and 31.
The total for the two-month period: 271.
But that is just one category of information that security teams are expected to absorb and react to. One of the others is a list of updates that vendors share that security teams may need to install as part of their vulnerability management system to safeguard their infrastructure.
For example, VMware announced on April 6th that it had found eight vulnerabilities across their products, three of which did not require authentication before exploitation and were assigned high vulnerability scores (CVSSv3 of 9.8). It provided patches to address the vulnerabilities and confirmed that at least one of the vulnerabilities had been exploited by April 13th. The vulnerability was such that the threat actors could bypass typical defenses such as antivirus (AV) and endpoint detection and response (EDR).
VMware warned that the patching was to be implemented as soon as possible. “This critical vulnerability should be patched or mitigated immediately per the instructions in VMSA-2021-0011. The ramifications of this vulnerability are serious,” the company wrote.
As important as that patch was to any organization using the affected VMware products, patching is also a never-ending activity. In fact, patching of vulnerabilities has been so commonplace for so long that Microsoft started something it called “Patch Tuesday” in 2003. Now many vendors have their own Patch Tuesdays – a once-a-month patch release for vulnerabilities of some concern. Emergency patches of more critical security vulnerabilities are released whenever they are available.
Perhaps the most perplexing vulnerability to address these days is the one that falls into the “celebrity” category. These are the ones that are deemed so significant that their existence is reported far beyond the trade publications, which means they get noticed by the top levels of an organization. Board members will not only be alarmed by such accounts; they’re also likely to want reassurance the vulnerability is addressed quickly and completely.
That can lead to a house-on-fire reaction by the security team, at least for a while. Celebrity vulnerabilities have the unfortunate tendency to draw too much attention initially – teams not affected by it may need to spend days proving to misinformed executives that they are not suffering the consequences.
Curiously enough, the celebrity vulnerabilities can overwhelm teams so they end up not fully addressing them. After a few months, the executives stop paying attention, so the vulnerability continues to be exploited, potentially causing significant damage. This can be due to simple fatigue, but it can also be due to inadequate resources to address the vulnerability, including tools and personnel.
And this leads us to our final article from this time period, one that appeared on April 26th on BleepingComputer.com with the title “Public Interest in Log4Shell fades but attack surface remains.” The article says that four months after Log4Shell was discovered, “the application of the available fixes is still way behind.” Data from Google’s Open Source Insights showed that of 17,840 open-source packages using Log4J, only 7,140 had upgraded to a fixed version. The problem may be due to several factors, the article says, including “proper vulnerability management processes and poor visibility.”
High-performing security teams are able to stay above the din of vulnerability alerts and focus on what matters. It’s not easy and never will be, but it should be the goal of every CISO and security team. To do this effectively requires a unified threat solution. NopSec helps security teams prioritize and manage their security vulnerabilities based on their unique environments. NopSec’s Unified VRM helps you remediate the risks that are most likely to be weaponized against your organization and cut through the noise around security vulnerabilities.
Don’t be distracted by the vulnerabilities that make a big splash in the news but don’t actually impact your organization. Watch Celebrity Vulnerabilities 101 here.
Answer: New security vulnerabilities are ones that are reported by agencies and news organizations on an almost daily basis. Because of the large number that accumulates over time, it is difficult to determine how to respond.
Answer: A celebrity vulnerability is one that is deemed significant enough to have its own special name (often provided by the threat actors themselves). Typically these vulnerabilities are highly dangerous and widely spread.
Answer: No. A new vulnerability is only clearly dangerous if it is known to be exploited by cybercriminals. Many are not. | https://www.nopsec.com/blog/responding-new-security-vulnerabilities/ |
Indistinguishability against adaptive chosen-ciphertext attacks (IND-CCA2) is usually considered the most desirable security notion for classical encryption. In this work, we investigate its adaptation in the quantum world, when an adversary can perform superposition queries. The security of quantum-secure classical encryption has first been studied by Boneh and Zhandry (CRYPTO'13), but they restricted the adversary to classical challenge queries, which makes the indistinguishability only hold for classical messages (IND-qCCA2). We extend their work by giving the first security notions for fully quantum indistinguishability under quantum adaptive chosen-ciphertext attacks, where the indistinguishability holds for superposition of plaintexts (qIND-qCCA2). This resolves an open problem asked by Gagliardoni et al. (CRYPTO'16). The qCCA2 security is defined in Boneh-Zhandry's paper using string copying and comparison, which is inherent in the classical setting. Quantumly, it is unclear what it means for a ciphertext to be different from the challenge ciphertext, and how the challenger can check the equality. The classical approach would either violate the no-cloning theorem or lead to perturbing the adversary's state, which may be detectable. To remedy these problems, from the recent groundbreaking compressed oracle technique introduced by Zhandry (CRYPTO'19), we develop a generic framework that allows recording quantum queries for probabilistic functions. We then give definitions for fully quantum real-or-random indistinguishability under adaptive chosen-ciphertext attacks (qIND-qCCA2). In the symmetric setting, we show that various classical modes of encryption are trivially broken in our security notions. We then provide the first formal proof for quantum security of the Encrypt-then-MAC paradigm, which also answers an open problem posed by Boneh and Zhandry. In the public-key setting, we show how to achieve these stronger security notions (qIND-qCCA2) from any encryption scheme secure in the sense of Boneh-Zhandry (IND-qCCA2). Along the way, we also give the first definitions of non-malleability for classical encryption in the quantum world and show that the picture of the relations between these notions is essentially the same as in the classical setting.
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- Preprint. MINOR revision. | https://eprint.iacr.org/2020/237 |
The Greenbeards Have Blue Throats In The Evolution Of Altruistic Behavior
A new study of side-blotched lizards in California has revealed the genetic underpinnings of altruistic behavior in this common lizard species, providing new insights into the long-standing puzzle of how cooperation and altruism can evolve.
The study, led by researchers at the University of California, Santa Cruz, offers the first evidence in vertebrates of an important theoretical concept in evolutionary biology known as "greenbeard" altruism.
"This reflects a major breakthrough in our understanding of how cooperative behavior arises from genes," said Barry Sinervo, professor of ecology and evolutionary biology at UCSC and first author of a paper describing the new findings. The paper will be published in the May 9 issue of Proceedings of the National Academy of Sciences (PNAS) and is currently available in the online early edition of PNAS.
The paper describes unrelated male lizards that form cooperative partnerships to protect their territories. These partnerships are often mutually beneficial, enabling both partners to father more offspring than they would on their own. Under some circumstances, however, one male in the pair may have few or no offspring as a result of protecting its partner from the aggressive intrusions of other lizards.
This type of cooperation, in which one individual bears all the costs and another unrelated individual receives the benefits, is called "true altruism." These lizards have an annual life cycle, so this behavior may spell the end of the altruistic male's lineage.
The evolution of cooperation is puzzling because cooperative systems are vulnerable to cheaters or defectors. Cheaters and defectors benefit from the cooperative behavior of others without paying the costs, so they ought to be favored under natural selection. But then cheater genes would spread in the population, and the cooperative system would collapse. The greenbeard effect is one way to get around this.
The concept originated with the British evolutionary theorist W. D. Hamilton and was popularized by Richard Dawkins in his book The Selfish Gene. Dawkins illustrated the concept with a hypothetical example in which a green beard serves as a marker enabling individuals with a gene for cooperation to recognize others with the same gene. The greenbeard gene (or genes) must do three things: establish a signal (the green beard), enable recognition of others that share the signal, and promote cooperative behavior towards other greenbeards.
In side-blotched lizards, the greenbeards have blue throats. This species comes in three different throat colors--orange, yellow, and blue--and throat color corresponds to different territorial behaviors in the males. Blue-throated males form partnerships in which two males cooperate to protect their territories; orange-throated males are highly aggressive and usurp territory from other lizards; and yellow-throated males sneak into the territory of other males to mate with females.
Previous research by Sinervo and his collaborators has demonstrated that these strategies result in a kind of "rock-paper-scissors" game in which orange defeats blue, blue defeats yellow, and yellow defeats orange. The lizard populations go through cycles in which one color after another increases its numbers at the expense of the others, but none are able to maintain dominance.
In the new paper, Sinervo's group investigated the genetic basis of the cooperative behavior in blue-throated males. They found that, in addition to the gene that controls throat color, there are at least three other genetic factors that determine the components of the greenbeard effect.
"Our study provides the first comprehensive genetic evidence of a greenbeard in vertebrates," Sinervo said. "Unlike Hamilton's idea and most modern views of greenbeards, we find that many genetic loci across the genome 'cooperate' to establish conditions for the greenbeard behaviors."
The cooperative behavior of blue-throated males plays out differently depending on the frequency of aggressive orange males in the population. In years when there are few orange males, cooperating blue males both benefit. But when orange males are common, one blue male ends up serving as a buffer for his territorial partner, bearing the brunt of the advances of aggressive orange males. Thus, the behavior of the blue-throated males cycles between mutualism and altruism, depending on where the population as a whole is in the rock-paper-scissors cycle.
"One of the big problems in the evolution of altruism is explaining how it gets off the ground in the first place," said Alexis Chaine, a graduate student in ecology and evolutionary biology at UCSC and a coauthor of the paper. "This is a situation that oscillates between mutualism and altruism, depending on the circumstances. Periods of mutualism give a much-needed boost at early stages in the evolution of altruistic genes and also provide long-term stability to the cooperative relationship."
"True altruism may be something that is evolutionarily fleeting, and what keeps it stable is the long-term payoff," Sinervo added. "The lizards are in a bind. They can't break up the partnership, because the success of the blue strategy depends on cooperation. Evolution has set them up so they can't cheat and turn on their partner."
The study is the culmination of two decades of laboratory and field research by Sinervo's lab to develop a deep pedigree of side-blotched lizards and their behavioral traits in the field. The researchers have tracked 18 generations of lizards so far and have mapped the locations of genes that coordinate reproductive behavior and throat color, as well as "genetic self-recognition"--the ability to recognize other individuals with the same gene complex.
The researchers used genetic tests to determine the paternity of all the lizards in each generation, and from this they could determine the "fitness" of each male in terms of the number of offspring he fathers. The fitness of altruistic blue males drops to nearly zero, while the protected partner is able to maintain high fitness. But in years when orange males are few, both blue males in a partnership have high fitness. Sinervo emphasized that the cooperative blue males are not even remotely related to one another.
"All other examples of greenbeards are found in invertebrates, such as ants, or lower taxa, such as slime molds, and in all these examples the researchers have not completely ruled out the confounding effects of kin selection," he said. "We establish that the greenbeard of the side-blotched lizard is not confounded by the effects of kin-helping behavior."
Interestingly, not all blue-throated males possess the complete set of genes required for greenbeard altruism. These "loner males" do not form partnerships with other blue-throated males. Their fitness is higher than that of altruistic males, but lower than that of the protected partner. And in years when blue-male partnerships are mutually beneficial, the fitness of loner males is lower than that of cooperating males.
The existence of loner blue males means that the genetic self-recognition required to establish a partnership involves more than the recognition of a blue throat in the other male. Cooperative males are able to recognize others that possess the complete set of genes for cooperative behavior.
"These are genes that cause lizards to recognize one another at the gene level and cause them to act in a certain way. The genes are driving the whole social system," Sinervo said. | https://phys.org/news/2006-05-greenbeards-blue-throats-evolution-altruistic.html |
- 'A shot of his own': the acceptability of a male hormonal contraceptive in Indonesia.
- A comparative qualitative analysis of stories of spousal caregivers of people with dementia: negative, ambivalent, and positive experiences.
- Accidental communities: race, emergency medicine, and the problem of polyheme.
- Adolescent/Young Adult Perspectives of a Therapeutic Music Video Intervention to Improve Resilience During Hematopoietic Stem Cell Transplant for Cancer.
- Brief treatment for PTSD: A non-inferiority trial.
- Coordinating assessment of spiritual needs: a cross-walk of narrative and psychometric assessment tools used in palliative care.
- Discussing life story, forgiveness, heritage, and legacy with patients with life-limiting illnesses.
- Dual-Task Effects on Story Retell for Participants With Moderate, Mild, or No Aphasia: Quantitative and Qualitative Findings.
- Dual-task effects of simulated lane navigation and story recall in older adults with and without memory impairment.
- Editor's note: Say "Yes!" to NO.
- Elementary, my dear readers.
- Eliciting recovery narratives in global mental health: Benefits and potential harms in service user participation.
- Enjoying and enduring: groups reading aloud for wellbeing.
- Experimental manipulations of the phenomenology of memory.
- Finding the stories: a novice qualitative researcher learns to analyse narrative inquiry data.
- Follow-Up of Young Adults With ADHD in the MTA: Design and Methods for Qualitative Interviews.
- HIV and tuberculosis in prisons in sub-Saharan Africa.
- How Responsiveness From a Communication Partner Affects Story Retell in Aphasia: Quantitative and Qualitative Findings.
- Narrative centrality and negative affectivity: independent and interactive contributors to stress reactions.
- Narratives that address affective forecasting errors reduce perceived barriers to colorectal cancer screening.
- Outcomes of physician job satisfaction: a narrative review, implications, and directions for future research.
- Parental perspectives on a behavioral health music intervention for adolescent/young adult resilience during cancer treatment: report from the children's oncology group.
- Perceived breast cancer risk: Heuristic reasoning and search for a dominance structure
- Recruitment strategies and rates of a multi-site behavioral intervention for adolescents and young adults with cancer.
- Religion in Organized Medicine: The AMA's Committee and Department of Medicine and Religion, 1961-1974.
- Rewriting the Microaggression Narrative: Enhancing Nursing Students' Ability to Respond.
- Scientific evidence versus outdated beliefs: A response to Brewin (2016).
- Serendipities leading to private practice.
- Story stimuli for creating false beliefs about the world.
- Stress at encoding, context at retrieval, and children's narrative content.
- Temporal-order iconicity bias in narrative event understanding and memory.
- The coherence of memories for trauma: evidence from posttraumatic stress disorder.
- The gift of voice.
- The period of untreated psychosis before treatment initiation: a qualitative study of family members' perspectives.
- The stories of nursing student repeaters: A narrative inquiry study.
- The two voices of Alzheimer's: attitudes toward brain health by diagnosed individuals and support persons.
- The use of critical reflection in clinical practice and health profession education.
- Use of qualitative methods to map job tasks and exposures to occupational hazards for commercial fishermen.
- What do medical students learn when they follow patients from hospital to community? A longitudinal qualitative study.
- Work-life balance in academic medicine: narratives of physician-researchers and their mentors. | https://scholars.duke.edu/display/meshD033262 |
In 1858, Gaspard-Felix Tournachon, also known as “Nadar,” flew a hot air balloon over Paris, taking the earliest known aerial photographs. Surveyors have used manned airplanes to capture data on the terrain below since the dawn of aviation. They will continue to do so for the foreseeable future because it enables them to cover large areas. For professionals across many industries, however, the explosion in unmanned aerial vehicles (UAVs) has greatly increased their options for surveying, photographing, measuring, and mapping a variety of spaces and places. It has also created great efficiencies and cost savings for organizations of all sizes, while challenging traditional workflows and expectations. Firms that require surveying now often wonder whether they should replace manned aircraft with UAVs. In some cases, one or the other is clearly the superior choice or the only possible one. More often, the two kinds of aerial platforms are complementary, just as UAVs and terrestrial scanners are.
Manned aircraft are the best choice to cover large areas quickly and/or to carry heavy sensors, because of their much greater endurance. Sometimes, a client’s RFP (requests for proposals) requires a manned aircraft. UAVs are the best choice for areas where manned aircraft cannot fly safely, such as very close to a building or a cell phone tower, and they are the only choice for areas where manned aircraft cannot fly at all, such as along narrow streets, under a bridge, or inside a covered stadium, and for those too far from airports. UAVs need only very small areas to take off and land—no more than a few square feet in the case of vertical take-off and landing (VTOL) models. They are also more cost-effective for repeated surveys of small areas, such as monitoring progress on construction sites.
In some cases, both manned aircraft and UAVs are used on the same project, such as for corridor mapping of power lines, with the former capturing the whole corridor and the latter inspecting specific towers. In fact, some manned aircraft surveyors are teaming with UAV operators to combine these technologies and create more useful data packages. Other times, a manned aircraft company will subcontract a job directly to a UAV company, or vice versa. These working relationships improve the process and the product for the client.
Manned helicopters combine some of the benefits of manned airplanes (endurance, payload capacity) with those of UAVs (ability to hover and get close to targets, small area for take-off and landing), but are very expensive per hour of operation.
Ultimately, the project should define the acquisition technique. Key considerations include:
Typical professional UAVs cost a few thousand dollars, while a Cessna 172 airplane, a model regularly used for aerial imaging, costs roughly $300,000 and a Bell 206 JetRanger helicopter costs more than three times as much. However, it is difficult to compare the hourly cost of manned flights with the equivalent cost of UAVs because there is not a standardized and accepted protocol for calculating costs per flight hour, which can be based on various metrics. Additionally, when end users switch from one aerial platform to another, they often also overhaul their whole operation. Furthermore, the UAV market is still in rapid growth, so the price per hour will continue to drop for the foreseeable future, while that of manned aircraft will likely remain stable.
Another consideration is the number of people required for a flight. Under the Federal Aviation Administration’s regulations for small unmanned aircraft (Part 107), it is legal for a single pilot to operate a UAV. However, in most cases it is still preferable to have a pilot in command (PIC) and a spotter on every project, with the former totally focused on the aircraft’s stability. For mapping missions with a manned aircraft, the pilot is often the only person required on board.
In the case of digital imaging, the much greater payload capacity of manned aircraft compared to UAVs enables them to carry much larger cameras with much greater resolution. UAVs compensate for this disadvantage by flying much lower. Typically, UAV imagery at 400 feet yields 5 cm resolution and at 200 feet it yields 2.5 cm resolution. However, not all surveys need the highest resolution for all the terrain to be covered.
Manned aircraft can carry much heavier sensors than UAVs can, such as bathymetric LiDAR. Moreover, they can carry a combination of sensors, such as a LiDAR sensor, a digital camera, and a hyperspectral imager. Some projects require collecting data with multiple sensors. A UAV that can carry only one sensor at a time would have to make multiple passes, thus increasing the flight time as well as the processing time, while a manned aircraft carrying multiple sensors could collect all the data in a single pass.
As UAVs continue to improve—fly longer, withstand higher wind speeds, and carry more sophisticated payloads—the overlap between their mapping capabilities and those of manned aircraft will increase. The next huge increase in the number of UAVs and in their applications will be when the FAA allows flight beyond line of sight (BVLOS) in controlled airspace. Continue reading about BVLOS and Applanix DG. | https://www.applanix.com/news/blog-analysis-manned-vs-uavs-for-mapping/ |
Bears Show a Physiological but Limited Behavioral Response to Unmanned Aerial Vehicles.
Unmanned aerial vehicles (UAVs) have the potential to revolutionize the way research is conducted in many scientific fields. UAVs can access remote or difficult terrain, collect large amounts of data for lower cost than traditional aerial methods, and facilitate observations of species that are wary of human presence. Currently, despite large regulatory hurdles, UAVs are being deployed by researchers and conservationists to monitor threats to biodiversity, collect frequent aerial imagery, estimate population abundance, and deter poaching. Studies have examined the behavioral responses of wildlife to aircraft (including UAVs), but with the widespread increase in UAV flights, it is critical to understand whether UAVs act as stressors to wildlife and to quantify that impact. Biologger technology allows for the remote monitoring of stress responses in free-roaming individuals, and when linked to locational information, it can be used to determine events or components of an animal's environment that elicit a physiological response not apparent based on behavior alone. We assessed effects of UAV flights on movements and heart rate responses of free-roaming American black bears. We observed consistently strong physiological responses but infrequent behavioral changes. All bears, including an individual denned for hibernation, responded to UAV flights with elevated heart rates, rising as much as 123 beats per minute above the pre-flight baseline. It is important to consider the additional stress on wildlife from UAV flights when developing regulations and best scientific practices.
| |
Brasserie Blanc is a chain of upscale restaurants offering an elegant dining experience. They serve a menu of fresh, seasonal modern and classic French fare by Raymond Blanc. They clearly label vegan and gluten-free options. Vegan dishes have included pea, broad bean and red pepper salad, hearty chilli pie, summer rolls and coconut rice with fresh mango.
Opening hours
|Sunday||07:00–21:00|
|Monday||06:30–22:30|
|Tuesday||06:30–22:30|
|Wednesday||06:30–22:30|
|Thursday||06:30–22:30|
|Friday||
06:30–22:30
|
(can vary during public holidays)
|Saturday||07:00–23:00|
Is the information outdated? Suggest an edit! | https://www.vanilla-bean.com/localities/5b325a9fb9051003585ab8c9 |
Swimming for Olympics
University of Edinburgh Swim Team members are competing for a place in the 2012 Olympics.
Eight men and four women from the team are swimming in the Olympic and Paralympic Trials this week, which take place in the London Olympic Pool.
Swimmers must finish either first or second in their race and achieve the Olympic qualifying time in order to qualify for the London Games.
The events are being televised on the BBC’s red button service at 6.25pm, or online at:
Qualifying for Olympic Trials is a big achievement in itself. The amount of swimmers from the University who are competing shows how far our Performance Swimming Team has come in recent years, and overall the future for the club looks extremely bright.
Going for gold
The University has an impressive record in swimming events.
In the 2011 Commonwealth Games, five University of Edinburgh Swim Team members competed in swimming events.
In those games, Michael Jamieson came second in the men’s 200m breaststroke event, missing out on gold by just 0.12 seconds.
In the same event, fellow University Swim Team member Kris Gilchrist finished fifth. Kris previously won a relay medal as part of the 2006 Commonwealth Games team.
Of this week’s competitors, Richard Schafers - a student in chemical physics who is competing in the 50m and 100m Freestyle - is the current Scottish record holder for the 50m event.
High performance programme
The University’s swimming team’s success is built on Edinburgh’s Performance Swimming Programme and a strong club structure. Launched in 2008, the programme has attracted several top swimmers to the University.
It combines swimming training with sports conditioning - weight and circuit training - as well as constant attention from physiotherapists.
The swimming team also works closely with the University’s Centre for Aquatics Research & Education, a centre for research into topics such as rhythm in swimming and drag in water.
The centre uses underwater cameras and other technology to analyse swimmers technique, aiding with the split-second improvements that can mean the difference between first and last place in top-level swimming events. | https://www.ed.ac.uk/news/all-news/swimming-070312 |
Introduction {#sec1}
============
Heterocyclic moieties are widely prevalent in bioactive natural products as well as in the marketed pharmaceuticals, agrochemicals, dyes, and many other application-oriented materials.^[@ref1]−[@ref5]^ Polyfunctionalized heterocycles, very particularly, occupy a dominating position in the drug discovery process, and recently, it has been estimated that approximately more than 70% of all enlisted pharmaceuticals and agrochemicals bear at least one heterocyclic ring.^[@ref6]^ Hence, research on the synthesis of polyfunctionalized heterocyclic compounds has gained special attention. Among N-heterocycles, pyrimidine and its derivatives have been studied for over a century because of their varying chemical and biological significance;^[@ref7],[@ref8]^ a good number of such heterocyclic scaffolds are reported for a wide range of biological profiles including antioxidant, anti-inflammatory, immunomodulating, antibacterial, antiviral, and antitumor activity.^[@ref9]−[@ref11]^ Categorically, barbituric/2-thiobarbituric acids, an important class of pharmaceutically promising pyrimidine derivatives, find potential applications as building blocks for a series of barbiturate/thiobarbiturate drugs used as hypnotics, sedatives, anticonvulsants, anesthetics, antioxidants, antifungal, and central nervous system depressants.^[@ref12]−[@ref14]^ Combination of barbituric/thiobarbituric acid moieties with other pharmacophoric groups, thus, may offer a possibility to synthesize numerous new types of other scaffolds with desired potential biological effects. With this view, a large number of endeavors were undertaken previously in fusing this important scaffold with other diverse molecular skeletons such as 1,3-diketones,^[@ref15],[@ref16]^ isatins,^[@ref17]−[@ref19]^ Meldrum's acid,^[@ref20]^ 4-hydroxycoumarin,^[@ref21]^ and many more under varying reaction conditions, involving the use of catalysts and additives, organic solvents, heating/refluxing, microwaves, electrolysis, and so forth.^[@ref22]^
Again, chromenes and related O-heterocyclic derivatives are a group of biologically promising molecular frameworks commonly found in natural and synthetic bioactive compounds exhibiting a broad spectrum of biological activities.^[@ref23]^ In addition to these two N- and O-heterocyclic scaffolds, 2-hydroxy-1,4-naphthoquinone (known as lawsone), a major chemical constituent of the medicinal plant *Lawsonia inermis* Linn., has been evaluated to possess many interesting biological and pharmacological activities so far, which motivated our group to explore this useful scaffold in synthesizing a series of novel bislawsone compounds with potent anticancer activity.^[@ref24],[@ref25]^ However, available reports on the novel scaffold developments with lawsone are still very limited.
Currently, molecular hybridization (MH)^[@ref26]^ is well-practiced in the process of rational drug design based on the recognition of pharmacophoric subunits in the molecular structure of two or more known bioactive derivatives which, through an adequate fusion of these subunits, leads to the design of new hybrid architectures with extended pharmacological potential.^[@ref27]^ Considering the success of MH techniques toward the design of various lead candidates coupled with the proven pharmaceutical potential of barbiturate/thiobarbiturate derivatives, functionalized chromenes, and 2-hydroxy-1,4-naphthoquinone (lawsone)-derived compounds, we felt excitement whether all of these privileged scaffolds could be bound together within one molecular framework so as to construct a novel series of polyfunctionalized heterocyclic architectures by designing an efficient protocol that would, at the same time, satisfy several green chemistry aspects. It has been a major challenge of modern drug discovery, indeed, to design highly efficient chemical reaction sequences that provide maximum structural complexity and diversity with a minimum number of synthetic steps to assemble compounds with interesting properties,^[@ref28],[@ref29]^ and multicomponent reactions (MCRs) have recently been proven to be an efficient and green method for the synthesis of structurally diverse and complex organic compounds from simple starting materials under one-pot condition with huge benefits, particularly in regard to a facile automation, operational simplicity, and reduction in the number of workup steps, thereby minimizing the extraction and purification processes as well as waste generation and saving energy and manpower.^[@ref30]−[@ref38]^ In addition, designing for room-temperature conditions coupled with other green aspects is also an area of current choice in synthetic organic chemistry.^[@ref39]^
From green chemistry perspective, water is considered as a safe and uniquely redox-stable green solvent which facilitates typical solvation and molecular assembly processes, leading to the remarkable modes of reactivity and selectivity of a wide variety of organic reactions.^[@ref40]−[@ref46]^ Apart from water, ethanol also already proved itself as a greener solvent for organic syntheses and an alternative to toxic organic solvents because of its solvation with most type of media and low toxicity.^[@ref47],[@ref48]^ Therefore, the combination of water and ethanol is receiving considerable attention as an important green solvent system in organic transformations with green procedure.^[@ref49]−[@ref55]^ Hence, the development of new synthesis methods keeping in view of all such recent trends has become a new research direction, which enables the simultaneous growth of both MCRs and green solvent systems toward ideal organic synthesis in drug discovery and materials science. As part of our ongoing research in the field of green synthesis,^[@ref56]−[@ref68]^ we herein wish to report a convenient, clean, facile, and catalyst-free practical method for the synthesis of a new series of functionalized 5-aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones (**4**) from the one-pot MCR between barbituric acid/*N*,*N*-dimethylbarbituric acid/2-thiobarbituric acid (**1**), aromatic aldehydes (**2**), and 2-hydroxy-1,4-naphthoquinone (**3**) in aqueous ethanol at ambient conditions (25--30 °C); the overall results are summarized in [Scheme [1](#sch1){ref-type="scheme"}](#sch1){ref-type="scheme"}. The key advantages of this newly developed protocol are the clean reaction profile, use of no catalyst and no toxic organic solvents, mild reaction conditions at room temperature, energy efficiency, use of commercially available low-cost starting materials, no need of column chromatographic purification, high atom economy (89.43--93.01%), and excellent yields.
![Catalyst-Free One-Pot Room-Temperature Synthesis of Diversely Functionalized 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones (**4**)](ao-2017-00791b_0001){#sch1}
Results and Discussion {#sec2}
======================
On the basis of the critical survey of the literature on catalyst-free organic transformations coupled with our own experience in performing this kind of organic synthesis,^[@ref69]^ we envisioned that such a 1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine scaffold might be constructed out of a one-pot MCR of its starting constituents such as barbituric acid, aldehyde, and 2-hydroxy-1,4-naphthoquinone without the aid of any catalyst in the presence of a suitable solvent. First, we checked our model reaction between barbituric acid (**1-1**; 1 equiv), benzaldehyde (**2-1**; 1 equiv), and 2-hydroxy-1,4-naphthoquinone (**3**; 1 equiv) in the absence of any catalyst in aqueous medium under ambient conditions, thereby isolating the desired compound, 5-phenyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-1**), in 61% yield at 20 h ([Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}, entry 1). Then, we performed the same reaction several times using either ethanol or ethanol--water mixtures in varying proportions (v/v) as solvents or no solvent at ambient conditions and observed that the reaction took place smoothly in aqueous ethanol (1:1 v/v), affording the desired product **4-1** in 99% yield at 12 h ([Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}, entry 3). Compound **4-1** was characterized by its analytical and spectral properties. The overall results are summarized in [Table [1](#tbl1){ref-type="other"}](#tbl1){ref-type="other"}.
###### Optimization of Reaction Conditions for the Synthesis of 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones (**4**)
{#GRAPHIC-d789e435-autogenerated}
entry solvent time (h) yield (%)[a](#t1fn1){ref-type="table-fn"}^,^[b](#t1fn2){ref-type="table-fn"}
------- --------------------------------- ---------- ------------------------------------------------------------------------------
1 H~2~O 20 61
2 EtOH 20 72
3 **EtOH/H**~**2**~**O(1:1 v/v)** **12** **99**
4 EtOH/H~2~O (2:1 v/v) 20 81
5 EtOH/H~2~O (1:2 v/v) 20 68
6 neat 20 trace
Reaction Conditions: barbituric acid (0.5 mmol), benzaldehyde (0.5 mmol), and 2-hydroxy-1,4-naphthoquinone (0.5 mmol) in 4 mL of water/ethanol/ethanol--water/neat at room temperature (25--30 °C) without any added catalyst.
Isolated yields.
Under the optimized conditions, we then carried out the reaction between barbituric acid, 4-methylbenzaldehyde, and 2-hydroxy-1,4-naphthoquinone and another reaction between barbituric acid, 4-methoxybenzaldehyde, and 2-hydroxy-1,4-naphthoquinone; both the reactions furnished the respective desired products, viz., 5-(*p*-tolyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-2**) ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 2) and 5-(4-methoxyphenyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-3**) ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 3), in 98 and 97% yield, respectively, within 12--16 h. To check the generality as well as the effectiveness of this newly developed protocol, a number of aromatic aldehydes with varying functionalities such as bromo, cyano, formyl, di- and trimethoxyls, and nitro were reacted with barbituric acid and 2-hydroxy-1,4-naphthoquinone using identical reaction conditions; all of these nine entries underwent the reaction smoothly, affording the corresponding 5-aryl-2-oxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones (**4-4--4-12**) ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entries 4--12) in excellent yields ranging from 92 to 99% at room temperature within 12--20 h.
###### Synthesis of Diversely Substituted 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones (**4**)
{#GRAPHIC-d789e632-autogenerated}
melting point (°C)
---- ------- --- -------------------------- ------------------ ---- ---- -------------------- ---
1 H O C~6~H~5~ **4** (**4-1**) 12 99 198--200
2 H O 4-CH~3~C~6~H~4~ **4** (**4-2**) 12 98 102--105
3 H O 4-OCH~3~C~6~H~4~ **4** (**4-3**) 16 97 140--141
4 H O 4-CF~3~C~6~H~4~ **4** (**4-4**) 12 96 188--190
5 H O 4-CNC~6~H~4~ **4** (**4-5**) 14 92 192--194
6 H O 3-BrC~6~H~4~ **4** (**4-6**) 16 97 162--165
7 H O 3-NO~2~C~6~H~4~ **4** (**4-7**) 14 97 165--167
8 H O 4-NO~2~C~6~H~4~ **4** (**4-8**) 13 99 176--178
9 H O 2,5-di-OCH~3~C~6~H~3~ **4** (**4-9**) 20 98 198--200
10 H O 3,4,5-tri-OCH~3~C~6~H~2~ **4** (**4-10**) 16 98 209--210
11 H O 3-CHOC~6~H~4~ **4** (**4-11**) 18 99 189--191
12 H O 4-CHOC~6~H~4~ **4** (**4-12**) 17 99 191--192
13 CH~3~ O C~6~H~5~ **4** (**4-13**) 16 97 152--154
14 CH~3~ O 4-CH~3~C~6~H~4~ **4** (**4-14**) 18 96 182--184
15 CH~3~ O 4-OCH~3~C~6~H~4~ **4** (**4-15**) 20 95 160--162
16 CH~3~ O 4-CF~3~C~6~H~4~ **4** (**4-16**) 12 98 158--160
17 CH~3~ O 4-CNC~6~H~4~ **4** (**4-17**) 14 98 188--190
18 CH~3~ O 3-BrC~6~H~4~ **4** (**4-18**) 16 99 209--210
19 CH~3~ O 4-BrC~6~H~4~ **4** (**4-19**) 15 99 178--181
20 CH~3~ O 3-NO~2~C~6~H~4~ **4** (**4-20**) 16 98 206--208
21 CH~3~ O 4-NO~2~C~6~H~4~ **4** (**4-21**) 15 98 178--180
22 CH~3~ O 2,5-di-OCH~3~C~6~H~3~ **4** (**4-22**) 20 97 130--132
23 CH~3~ O 3,4-OCH~2~OC~6~H~3~ **4** (**4-23**) 21 98 178--179
24 CH~3~ O 3-CHOC~6~H~4~ **4** (**4-24**) 19 99 180--182
25 CH~3~ O 4-CHOC~6~H~4~ **4** (**4-25**) 18 98 198--200
26 H S C~6~H~5~ **4** (**4-26**) 20 96 164--165
27 H S 4-OCH~3~C~6~H~4~ **4** (**4-27**) 22 97 174--176
28 H S 4-CF~3~C~6~H~4~ **4** (**4-28**) 16 95 168--170
29 H S 4-CNC~6~H~4~ **4** (**4-29**) 18 97 172--174
30 H S 3-BrC~6~H~4~ **4** (**4-30**) 18 98 193--195
31 H S 3-NO~2~C~6~H~4~ **4** (**4-31**) 18 91 188--190
32 H S 4-NO~2~C~6~H~4~ **4** (**4-32**) 18 92 168--170
33 H S 2,5-di-OCH~3~C~6~H~3~ **4** (**4-33**) 22 87 180--182
34 H S 3,4,5-tri-OCH~3~C~6~H~2~ **4** (**4-34**) 20 93 198--200
35 H S 3-CHOC~6~H~4~ **4** (**4-35**) 22 93 184--186
36 H S 4-CHOC~6~H~4~ **4** (**4-36**) 21 93 192--194
37 H S 2-furyl **4** (**4-37**) 22 96 162--166
Reaction Conditions: barbituric acids (**1**; 0.5 mmol), aldehydes (**2**; 0.5 mmol), and 2-hydroxy-1,4-naphthoquinone (**3**; 0.5 mmol) in 4 mL of aqueous ethanol (1:1 v/v) at room temperature (25--30 °C) in the absence of any catalyst.
Isolated yields.
Inspired by these results, we then replaced unsubstituted barbituric acid with *N*,*N*-dimethylbarbituric acid and carried out a similar set of three different reactions from the mixture of this substituted barbituric acid (1 equiv) and 2-hydroxy-1,4-naphthoquinone (1 equiv), separately treating with benzaldehyde (1 equiv), 4-methylbenzaldehyde (1 equiv), and 4-methoxybenzaldehyde (1 equiv) in aqueous ethanol (1:1 v/v) under the catalyst-free conditions just at room temperature. To our delight, all three reactions produced the expected products, 1,3-dimethyl-5-phenyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-13**), 1,3-dimethyl-5-(*p*-tolyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-14**), and 5-(4-methoxyphenyl)-1,3-dimethyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-15**), in 97, 96, and 95% yield, respectively, within 16--20 h ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entries 13--15). We then extended this methodology in synthesizing 11 more new 1,3-dimethyl-5-aryl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone derivatives (**4-16--4-25**) ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entries 16--25) from the one-pot reaction of *N*,*N*-dimethylbarbituric acid (**1**; 1 equiv) with a variety of functionalized aromatic aldehydes (**2**; 1 equiv) and 2-hydroxy-1,4-naphthoquinone (**3**; 1 equiv) using identical reaction conditions; all of them underwent the reaction in a facile manner, affording the desired products **4-16--4-25** ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entries 16--25) with excellent yields ranging from 97 to 99% within 12--21 h. However, aliphatic aldehydes were found reluctant to undergo the reaction; we observed that both butyraldehyde and isobutyraldehyde upon treating separately with the mixture of 2-hydroxy-1,4-naphthoquinone and barbituric acid/*N*,*N*-dimethylbarbituric acid under the identical reaction conditions produced only the desired products with 23--28% yield.
Encouraged by these results, we then planned to replace barbituric acid/*N*,*N*-dimethylbarbituric acid with 2-thiobarbituric acid so as to further extend the newly developed protocol in generating 2-thioxo-substituted analogues. For this purpose, we performed the reaction between 2-thiobarbituric acid (**1-26**; 1 equiv), benzaldehyde (**2-26**; 1 equiv), and 2-hydroxy-1,4-naphthoquinone (**3**; 1 equiv) in aqueous ethanol (1:1 v/v) under the same reaction conditions, and we were delighted to have the desired product, 5-phenyl-2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione (**4-26**) ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 26), in 96% yield at 20 h. We, furthermore, utilized the optimized reaction conditions to synthesize a series of new 5-aryl-2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione derivatives (**4-27--4-36**) ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entries 27--36) from the one-pot reaction of 2-thiobarbituric acid (**1**; 1 equiv) with a varying range of aromatic aldehydes (**2**; 1 equiv) containing different functionalities such as bromo, cyano, formyl, mono-, di-, and trimethoxyls, nitro, trifluoromethyl, and so forth as substituents and 2-hydroxy-1,4-naphthoquinone (**3**; 1 equiv) in aqueous ethanol (1:1 v/v) without the aid of any catalyst under ambient conditions. All reactions were successfully completed, furnishing the expected products **4-27--4-36** ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entries 27--36) with excellent yields ranging from 87 to 98% within 16--22 h. In addition, a heteroaryl aldehyde, furan-2-carbaldehyde (**2-37**), was also found to undergo the reaction with 2-thiobarbituric acid and 2-hydroxy-1,4-naphthoquinone under the identical reaction conditions to produce 5-(furan-2-yl)-2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione (**4-37**) in 96% yield ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 37). The overall results are summarized in [Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}.
With this successful background, we were motivated to study the present protocol whether capable to furnish the bis(2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione) scaffold upon reaction with biscarboxaldehyde such as phthalaldehyde, isophthalaldehyde, and terephthalaldehyde. Accordingly, we performed the reaction between biscarboxaldehyde (1 equiv), barbituric acid (2 equiv), and 2-hydroxy-1,4-naphthoquinone (2 equiv) in aqueous ethanol at ambient conditions and observed that both phthalaldehyde and isophthalaldehyde did not undergo any reaction (possibly because of the steric crowding), whereas terephthalaldehyde produced the desired bis-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine scaffold (**4′**) satisfactorily. To our delight, we were successful in synthesizing a set of three such new compounds, namely, 5,5′-(1,4-phenylene)bis(1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone) (**4′-1**), 5,5′-(1,4-phenylene)bis(1,3-dimethyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone) (**4′-2**), and 5,5′-(1,4-phenylene)bis(2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione) (**4′-3**), in 98, 92, and 94% yield, respectively, within 18--22 h, using this methodology ([Table [3](#tbl3){ref-type="other"}](#tbl3){ref-type="other"}).
###### Synthesis of Substituted 5,5′-(1,4-Phenylene)bis(2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione) Derivatives **4′** (**4′-1--4′-3**)
{#GRAPHIC-d789e2264-autogenerated}
melting point (°C)
--- ------- --- ------------------- ---- ---- -------------------- ---
1 H O **4′** (**4′-1**) 18 98 199--200
2 CH~3~ O **4′** (**4′-2**) 22 92 195--203
3 H S **4′** (**4′-3**) 20 94 250--252
Reaction conditions: barbituric acids (**1**; 1.0 mmol), terephthalaldehyde (**2**; 0.5 mmol), and 2-hydroxy-1,4-naphthoquinone (**3**; 1.0 mmol) in 5 mL of aqueous ethanol (1:1 v/v) at room temperature (25--30 °C) in the absence of any catalyst.
Isolated yields.
All products (**4-1--4-37** and **4′-1--4′-3**) were isolated pure just by washing with cold aqueous ethanol. All isolated products were new and were fully characterized based on their analytical data and detailed spectral studies including Fourier transform infrared (FT-IR), ^1^H NMR, ^13^C NMR, and distortionless enhancement by polarization transfer (DEPT)-135.
We herein propose a possible mechanism for the aqueous ethanol-mediated one-pot synthesis of 5-aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones (**4**) from the three-component reaction of barbituric acids (**1**), aromatic aldehydes (**2**), and 2-hydroxy-1,4-naphthoquinone (**3**) in [Scheme [2](#sch2){ref-type="scheme"}](#sch2){ref-type="scheme"}. For this purpose, we monitored the pH of the reaction media for a representative entry (entry 3, [Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}) throughout the progress of the reaction and studied this reaction based on the formation of possible condensation adducts as intermediates. We successfully isolated and characterized (see [Experimental Section](#sec4){ref-type="other"}) the chalcone derivative, 5-(4-methoxybenzylidene)pyrimidine-2,4,6(1*H*,3*H*,5*H*)-trione (**6-3**), from the reaction of barbituric acid (**1-3**) and 4-methoxybenzaldehyde (**2-3**) in aqueous ethanol (1:1 v/v) at ambient conditions, as an intermediate with 86% yield, having the physical and spectral data in full agreement with those reported in the literature.^[@ref70]^ In the next step, the isolated intermediate **6-3** produced the desired product, 5-(4-methoxyphenyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-3**), upon reaction with 2-hydroxy-1,4-naphthoquinone (**3**) under the same reaction conditions. In favor of our proposition, we also carried out a similar reaction between 4-methoxybenzaldehyde (**2-3**) and 2-hydroxy-1,4-naphthoquinone (**3**) in aqueous ethanol (1:1 v/v) under identical reaction conditions and observed that the rate of this condensation reaction was too slow and the reaction was not completed within a reasonable time frame in comparison to the former case.
![Proposed Mechanism for the Aqueous Ethanol-Mediated Three-Component One-Pot Synthesis of Functionalized 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione **4** at Ambient Conditions](ao-2017-00791b_0002){#sch2}
The results of pH monitoring throughout the progress of this representative entry 3 are quite logical with the proposed path---the mixture of barbituric acid (**1-3**; 0.5 mmol) and 4-methoxybenzaldehyde (**2-3**; 0.5 mmol) in aqueous ethanol (1:1 v/v; 4 mL) recorded a pH of 3.11, and under this acidic condition, a Claisen--Schmidt condensation takes place between the enolic tautomer (**1′**) of barbituric acid and the protonated aldehyde (**2**) to produce an aldol adduct **5** that eliminates one molecule of water, resulting in the formation of a chalcone intermediate **6** (**6-3** was isolated and characterized). In the next step, 2-hydroxy-1,4-naphthoquinone (**3**) (0.5 mmol of which recorded a pH of 3.92 in 4 mL of aqueous ethanol) undergoes Michael addition with the chalcone intermediate **6** to produce the nucleophilic adduct **7**, which subsequently takes part in a facile intramolecular ring closure via a 6-exo-trig process, generating the cycloadduct **8** that eventually furnishes the desired product **4** upon the elimination of water as a green waste ([Scheme [2](#sch2){ref-type="scheme"}](#sch2){ref-type="scheme"}).
It is worth noting that we successfully reused the reaction media containing the residual solvent and substrates obtained upon the filtration of the reaction mixture after the completion of the reaction up to the fourth run in the case of a representative entry ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 3), viz., reaction between barbituric acid, 4-methoxybenzaldehyde, and 2-hydroxy-1,4-naphthoquinone. The desired product, 5-(4-methoxyphenyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-3**), was isolated in almost identical yields (96--98%) in all runs. We also examined the feasibility of the present method for a slightly scaled-up (on the gram scale; 10 mmol scale) experiment with the same entry ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 3) at room temperature in ethanol--water (20 mL; 1:1 v/v): the reaction was found to proceed smoothly, affording the desired product **4-3** in 96% isolated yield, and the product yield of this large-scale reaction is almost similar to that of the 0.5 mmol scale entry ([Table [2](#tbl2){ref-type="other"}](#tbl2){ref-type="other"}, entry 3) in terms of yield and time. This experiment demonstrated the applicability of this catalyst-free room-temperature protocol for large-scale productions as well.
We evaluated the green chemistry credentials of this newly developed one-pot synthesis protocol by performing a series of green metrics calculations^[@ref71]−[@ref82]^ such as effective mass yield (EMY), atom economy (AE), atom efficiency (AEf), carbon efficiency (CE), reaction mass efficiency (RME), optimum efficiency (OE), mass productivity (MP), mass intensity (MI) and process mass intensity (PMI), *E*-factor, solvent intensity (SI), and water intensity (WI) for all synthesized compounds **4** (**4-1--4-37**) and **4′** (**4′-1--4′-3**) (see the [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.7b00791/suppl_file/ao7b00791_si_001.pdf)). The calculated AE and AEf for the method range from 89.43 to 93.01% and from 80.53 to 92.08%, respectively, and are less than 100% because of the formation of H~2~O as the byproduct. The calculated CE (79.60--99.00%) for this process is also quite good. As the RME includes all reactant mass, yield, and AE, it is the most useful metric to determine the greenness of a process. Calculations of EMY (83.83--91.86%) and RME (80.58--92.22%) also indicate the excellent green credential of the present method. Similarly, the evaluations of MI (7.32--10.15 g/g) and PMI (31.64--41.14 g/g) parameters also corroborate this fact. The calculated *E*-factors ranging from 0.09 to 0.19 are found to be very much supportive for the greenness of the present method. The other green parameters have also been found to be in order. Working formulas for green metrics, their calculations, and respective data for all entries are documented in the [Supporting Information](http://pubs.acs.org/doi/suppl/10.1021/acsomega.7b00791/suppl_file/ao7b00791_si_001.pdf); [Tables [4](#tbl4){ref-type="other"}](#tbl4){ref-type="other"} and [5](#tbl5){ref-type="other"} offer such data for three representative entries.
###### Green Metrics (EMY, AE, AEf, CE, RME, OE, and MP) for Three Representative Compounds (**4-1**, **4-15**, and **4-32**)[a](#t4fn1){ref-type="table-fn"}
entry product yield (%) EMY (%) AE (%) AEf (%) CE (%) RME (%) OE (%) MP (%)
------- ---------- ----------- --------- -------- --------- -------- --------- -------- --------
1 **4-1** 99 90.20 91.23 90.32 98.00 90.19 98.86 10.04
2 **4-15** 95 87.55 92.27 87.67 94.88 87.55 94.88 10.97
3 **4-32** 92 84.68 92.32 84.94 91.80 85.04 91.11 10.67
Higher is the value, greener is the process.
###### Green Metrics (PMI, MI, *E*-Factor, SI, and WI) for Three Representative Compounds (**4-1**, **4-15**, and **4-32**)[a](#t5fn1){ref-type="table-fn"}
entry product PMI (g/g) MI (g/g) *E* (g/g) SI (g/g) WI (g/g)
------- ---------- ----------- ---------- ----------- ---------- ----------
1 **4-1** 40.46 9.97 0.11 17.72 21.63
2 **4-15** 36.63 9.13 0.14 15.98 19.50
3 **4-32** 37.56 9.37 0.18 16.38 20.00
Lower is the value, better is the process.
Conclusions {#sec3}
===========
A simple, catalyst-free, energy-efficient, and conveniently practical method for easy access to a huge range of biologically interesting diverse and functionalized 5-aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones **4** (**4-1--4-37**) and substituted 5,5′-(1,4-phenylene)bis(2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione) derivatives **4′** (**4′-1--4′-3**) has been developed from the one-pot MCR between barbituric/2-thiobarbituric acids (**1**), aromatic aldehydes (**2**), and 2-hydroxy-1,4-naphthoquinone (**3**) in aqueous ethanol at room temperature. The salient features of this present protocol include mild reaction conditions at room temperature, avoidance of catalyst, operational simplicity and clean reaction profiles, and excellent yields with high atom economy. In addition, the use of commercially available inexpensive starting materials and the ease of product isolation/purification without the aid of tedious column chromatography are added advantages of this present method, thereby satisfying the triple bottom line philosophy of green and sustainable chemistry.^[@ref83]^ In addition, the reusability of the reaction media and the quite successful operation in gram-scale synthesis offer added advantages to this protocol. The present method satisfies green credentials at the best. Considering the synthetic importance of such biologically relevant multi-heterocentric organic scaffolds, the present catalyst-free green methodology with operational simplicity may thus also afford cost-effective and environmentally friendlier ways for large-scale syntheses of these useful molecules.
Experimental Section {#sec4}
====================
General Considerations {#sec4-1}
----------------------
Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) FT-IR spectrophotometer using a KBr disk. ^1^H and ^13^C NMR spectra were collected at 400 and 100 MHz, respectively, on a Bruker DRX spectrometer using CDCl~3~ and DMSO-*d*~6~ as solvents. Elemental analyses were performed with an Elementar Vario EL III Carlo Erba 1108 microanalyzer instrument. Melting point was recorded on a Chemiline CL-725 melting point apparatus and was uncorrected. Thin-layer chromatography (TLC) was performed using silica gel 60 F~254~ (Merck) plates.
General Procedure for the Synthesis of Functionalized 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-triones **4** {#sec4-2}
----------------------------------------------------------------------------------------------------------------------------------------------------------------
A magnetic stir bar, barbituric/2-thiobarbituric acid (**1**; 0.5 mmol), aromatic aldehyde (**2**; 0.5 mmol), 2-hydroxy-1,4-naphthoquinone (**3**; 0.5 mmol), and 4 mL of aqueous ethanol (1:1 v/v) were transferred to an oven-dried reaction tube in a sequential manner at ambient conditions, and the reaction mixture was then stirred vigorously for a stipulated time frame (12--22 h). The progress of the reaction was monitored by TLC. Upon the completion of the reaction, a solid mass precipitated out and was filtered off, followed by the purification of the crude product just by washing with cold aqueous ethanol. The structure of each purified compound was confirmed by analytical as well as spectral studies including FT-IR, ^1^H NMR, ^13^C NMR, and DEPT-135.
The spectral and analytical data of some selected compounds are given below:
### 5-Phenyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-1**) {#sec4-2-1}
Pale yellow solid; yield 99% (0.184 g, 0.5 mmol scale); mp 198--200 °C; IR (KBr) ν~max~: 3215 (NH), 3103, 2849, 1711 (CO), 1670 (CONH), 1648 (CONH), 1593, 1494, 1273, 1043 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.01 (br s, 2H, 2 × −N*H*), 7.97 (d, 2H, *J* = 7.2 Hz, Ar-H), 7.86--7.76 (m, 2H, Ar-H), 7.42 (br s, 2H, Ar-H), 7.23 (t, 2H, *J* = 7.2, 6.8 Hz, Ar-H), 7.15 (t, 1H, *J* = 6.8, 6.4 Hz, Ar-H), 4.88 (br s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.43 (CO), 181.45 (CO), 169.69 (2 × CO), 151.66, 135.49, 133.99, 132.50, 129.69, 128.35 (5C), 127.06 (4C), 126.65, 126.27, 43.61 (−*C*H) ppm. Elemental analysis: calcd (%) for C~21~H~12~N~2~O~5~: C, 67.74; H, 3.25; N, 7.52; found: C, 67.69; H, 3.24; N, 7.49.
### 5-(4-Methoxyphenyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-3**) {#sec4-2-2}
Yellow solid; yield 97% (0.195 g, 0.5 mmol scale); mp 140--141 °C; IR (KBr) ν~max~: 3299 (NH), 3085, 2980, 2840, 1709 (CO), 1648 (CONH), 1639 (CONH), 1588, 1512, 1270, 1040 cm^--1^. ^1^H NMR (400 MHz, CDCl~3~): δ 8.09 (d, 2H, *J* = 7.6 Hz, Ar-H), 7.76--7.67 (m, 3H, Ar-H), 7.19 (d, 1H, *J* = 8.4 Hz, Ar-H), 6.82 (d, 2H, *J* = 8.8 Hz, Ar-H), 6.16 (br s, 1H, −C*H*), 4.77 (br s, 2H, 2 × −N*H*), 3.77 (s, 3H, Ar-OC*H*~3~) ppm. ^13^C NMR (100 MHz, CDCl~3~): δ 184.90 (2 × CO), 181.34 (2 × *C*ONH), 154.83, 133.35 (2C), 132.85, 129.92, 129.76, 129.39 (2C), 127.33 (2C), 126.45 (2C), 122.87, 119.70, 113.91 (2C), 55.34 (Ar-O*C*H~3~), 37.16 (−*C*H) ppm. Elemental analysis: calcd (%) for C~22~H~14~N~2~O~6~: C, 65.67; H, 3.51; N, 6.96; found: C, 65.61; H, 3.52; N, 6.94.
### 5-(4-(Trifluoromethyl)phenyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-4**) {#sec4-2-3}
Reddish-yellow solid; yield 96% (0.211 g, 0.5 mmol scale); mp 188--190 °C; IR (KBr) ν~max~: 3234 (NH), 3190, 2979, 2869, 1711 (CO), 1691 (CO), 1670 (CONH), 1605, 1595, 1565, 1465, 1282, 1068 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 9.95 (br s, 2H, 2 × −N*H*), 7.97 (d, 1H, *J* = 7.2 Hz, Ar-H), 7.90 (dd, 1H, *J* = 7.6, 1.2 Hz, Ar-H), 7.78 (dt, 1H, *J* = 7.6, 1.2 Hz, Ar-H), 7.73--7.69 (m, 1H, Ar-H), 7.65 (t, 1H, *J* = 8.0, 6.0 Hz, Ar-H), 7.50 (d, 2H, *J* = 8.0 Hz, Ar-H), 7.27 (d, 1H, *J* = 8.0 Hz, Ar-H), 6.37 (br s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 183.84 (2 × CO), 172.59 (*C*ONH), 165.81 (*C*ONH), 151.55, 151.05, 148.96, 134.51 (2C), 132.91, 131.41, 130.76, 129.25, 128.04 (2C), 126.41, 126.28, 125.78, 125.13 (*C*F~3~), 125.10, 88.81, 49.04 (−*C*H) ppm. Elemental analysis: calcd (%) for C~22~H~11~N~2~O~5~F~3~: C, 60.01; H, 2.52; N, 6.36; found: C, 60.03; H, 2.51; N, 6.34.
### 5-(4-Nitrophenyl)-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-8**) {#sec4-2-4}
Creamy yellow solid; yield 99% (0.206 g, 0.5 mmol scale); mp 176--178 °C; IR (KBr) ν~max~: 3213 (NH), 3097, 2871, 1710 (CO), 1672 (CONH), 1645 (CONH), 1596, 1513, 1274, 1045 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.01 (br s, 2H, 2 × −N*H*), 8.08 (d, 2H, *J* = 8.8 Hz, Ar-H), 7.97 (t, 2H, *J* = 8.4, 7.6 Hz, Ar-H), 7.85--7.76 (m, 2H, Ar-H), 7.67--7.52 (m, 2H, Ar-H), 5.06 (br s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.84 (CO), 184.62 (CO), 184.52 (2 × CONH), 151.41 (2C), 135.43, 135.28, 133.87, 131.25, 130.75, 126.61 (2C), 126.27 (2C), 126.05, 123.40 (2C), 111.61, 103.30, 41.30 (−*C*H) ppm. Elemental analysis: calcd (%) for C~21~H~11~N~3~O~7~: C, 60.44; H, 2.66; N, 10.07; found: C, 60.40; H, 2.67; N, 10.04.
### 4-(2,4,6,11-Tetraoxo-2,3,4,5,6,11-hexahydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidin-5-yl)benzaldehyde (**4-12**) {#sec4-2-5}
Creamy yellow solid; yield 99% (0.198 g, 0.5 mmol scale); mp 191--192 °C; IR (KBr) ν~max~: 3205 (NH), 3090, 2846, 1709 (CO), 1676 (CHO), 1648 (CONH), 1600, 1580, 1461, 1275, 1045 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.09 (br s, 1H, −N*H*), 10.99 (br s, 1H, −N*H*), 9.93 (s, 1H, −C*H*O), 8.12--8.05 (m, 1H, Ar-H), 7.96 (q, 2H, *J* = 8.4, 7.2, 6.4 Hz, Ar-H), 7.85--7.80 (m, 2H, Ar-H), 7.77 (d, 2H, *J* = 8.0 Hz, Ar-H), 7.61 (br s, 1H, Ar-H), 5.03 (br s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 193.72 (CHO), 184.53 (2 × *C*O), 184.01 (*C*ONH), 181.70 (*C*ONH), 163.77, 162.06, 150.82, 140.32, 136.32, 135.30, 133.77, 132.72, 132.48, 130.61 (2C), 129.63, 129.21, 126.62, 126.24, 121.10, 31.39 (−*C*H) ppm. Elemental analysis: calcd (%) for C~22~H~12~N~2~O~6~: C, 66.00; H, 3.02; N, 7.00; found: C, 65.98; H, 3.03; N, 6.99.
### 4-(2,4,6,11-Tetraoxo-2,3,4,5,6,11-hexahydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidin-5-yl)benzonitrile (**4-17**) {#sec4-2-6}
Pale yellow solid; yield 98% (0.208 g, 0.5 mmol scale); mp 188--190 °C; IR (KBr) ν~max~: 3080, 2971, 2234 (CN), 1698 (CO), 1642 (CONCH~3~), 1598, 1526, 1508, 1491, 1271, 1037 cm^--1^. ^1^H NMR (400 MHz, CDCl~3~): δ 8.09--8.06 (m, 2H, Ar-H), 7.78 (dt, 1H, *J* = 7.6, 1.2 Hz, Ar-H), 7.71 (dt, 1H, *J* = 7.6, 7.4, 1.2, 0.8 Hz, Ar-H), 7.59 (dt, 4H, *J* = 8.8, 8.4, 2.8, 2.0 Hz, Ar-H), 5.06--5.04 (m, 1H, −C*H*), 3.22 (s, 6H, 2 × NC*H*~3~) ppm. ^13^C NMR (100 MHz, CDCl~3~): δ 184.08 (*C*O), 180.84 (*C*O), 167.06 (2 × *C*ONCH~3~), 153.37, 151.69, 143.77, 135.70, 133.65, 132.71, 132.56 (2C), 132.24, 129.91, 129.12, 127.64, 127.14, 126.64, 119.83 (*C*N), 118.79, 111.42, 43.45 (−*C*H), 29.02 (N*C*H~3~), 28.91 (N*C*H~3~) ppm. Elemental analysis: calcd (%) for C~24~H~15~N~3~O~5~: C, 67.76; H, 3.55; N, 9.88; found: C, 67.74; H, 3.54; N, 9.91.
### 5-(4-Bromophenyl)-1,3-dimethyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-19**) {#sec4-2-7}
Yellow solid; yield 99% (0.237 g, 0.5 mmol scale); mp 178--181 °C; IR (KBr) ν~max~: 3078, 2967, 1697 (CO), 1666 (CONCH~3~), 1589, 1517, 1276, 1038 cm^--1^. ^1^H NMR (400 MHz, CDCl~3~): δ 8.07 (dq, 2H, *J* = 7.6, 5.6, 0.8 Hz, Ar-H), 7.76 (dt, 1H, *J* = 7.6, 1.2 Hz, Ar-H), 7.68 (dt, 1H, *J* = 7.6, 7.4, 1.6, 1.2 Hz, Ar-H), 7.42--7.36 (m, 4H, Ar-H), 4.94--4.92 (m, 1H, −C*H*), 3.20 (s, 3H, −NC*H*~3~), 3.19 (s, 3H, −NC*H*~3~) ppm. ^13^C NMR (100 MHz, CDCl~3~): δ 184.00 (*C*O), 181.06 (*C*O), 167.49 (*C*ONCH~3~), 167.30 (*C*ONCH~3~), 153.24, 151.85, 136.73, 135.56 (2C), 133.49, 132.75, 131.62 (2C), 130.92 (2C), 129.17, 127.40, 126.52, 121.81, 120.40, 43.90 (*C*H), 28.94 (N*C*H~3~), 28.83 (N*C*H~3~) ppm. Elemental analysis: calcd (%) for C~23~H~15~BrN~2~O~5~: C, 57.64; H, 3.15; N, 5.84; found: C, 57.61; H, 3.14; N, 5.82.
### 5-(Benzo\[*d*\]\[1,3\]dioxol-5-yl)-1,3-dimethyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone (**4-23**) {#sec4-2-8}
Golden-yellow solid; yield 98% (0.218 g, 0.5 mmol scale); mp 178--179 °C; IR (KBr) ν~max~: 3097, 2992, 1705 (CO), 1673 (CONCH~3~), 1647, 1588, 1494, 1275, 1035 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 7.99--7.95 (m, 2H, Ar-H), 7.85--7.77 (m, 2H, Ar-H), 7.08 (d, 1H, *J* = 8.0 Hz, Ar-H), 6.79--6.78 (m, 1H, Ar-H), 6.74 (d, 1H, *J* = 8.0 Hz, Ar-H), 5.93 (s, 2H, OC*H*~2~O), 4.85 (br s, 1H, −C*H*), 3.01 (s, 6H, 2 × −NC*H*~3~) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.27 (2 × CO), 168.05 (*C*ONCH~3~), 165.37 (*C*ONCH~3~), 156.11, 152.24 (3C), 147.12 (2C), 135.29, 133.77 (2C), 126.48 (2C), 126.12, 107.97 (3C), 102.77, 101.18 (−O*C*H~2~O−), 43.62 (−*C*H), 29.07 (N*C*H~3~), 28.44 (N*C*H~3~) ppm. Elemental analysis: calcd (%) for C~24~H~16~N~2~O~7~: C, 64.87; H, 3.63; N, 6.30; found: C, 64.84; H, 3.61; N, 6.28.
### 3-(1,3-Dimethyl-2,4,6,11-tetraoxo-2,3,4,5,6,11-hexahydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidin-5-yl)benzaldehyde (**4-24**) {#sec4-2-9}
Dark yellow solid; yield 99% (0.212 g, 0.5 mmol scale); mp 180--182 °C; IR (KBr) ν~max~: 3077, 2986, 1700 (CO), 1667 (CHO), 1587, 1521, 1459, 1274, 1041 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 9.95 (s, 1H, −C*HO*), 8.00--7.95 (m, 2H, Ar-H), 7.86--7.77 (m, 4H, Ar-H), 7.72 (d, 1H, *J* = 7.2 Hz, Ar-H), 7.48 (t, 1H, *J* = 7.6, 7.2 Hz, Ar-H), 5.13 (br s, 1H, −C*H*), 3.04 (s, 6H, −NC*H*~3~) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 193.71 (2 × CO), 184.36 (−*C*HO), 181.13 (*C*ONCH~3~), 167.90 (*C*ONCH~3~), 152.24, 136.35, 135.63, 135.25, 135.15, 133.82, 132.39, 130.34, 130.24, 130.12, 129.01 (2C), 128.34, 126.52 (2C), 126.17, 42.51 (−*C*H), 28.50 (2 × N*C*H~3~) ppm. Elemental analysis: calcd (%) for C~24~H~16~N~2~O~6~: C, 67.29; H, 3.76; N, 6.54; found: C, 67.25; H, 3.77; N, 6.52.
### 5-(4-Methoxyphenyl)-2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione (**4**-**27**) {#sec4-2-10}
Bright yellow solid; yield 97% (0.203 g, 0.5 mmol scale); mp 174--176 °C; IR (KBr) ν~max~: 3149 (NH), 3075, 2934, 1696 (CO), 1656 (CONH), 1596, 1527, 1508, 1435, 1343 (C=S), 1270, 1214 (C=S), 1004 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.69 (br s, 2H, N*H*), 7.98--7.89 (m, 2H, Ar-H), 7.81--7.74 (m, 2H, Ar-H), 7.07 (d, 1H, *J* = 9.2 Hz, Ar-H), 6.99 (d, 1H, *J* = 7.6 Hz, Ar-H), 6.74 (dd, 2H, *J* = 7.8, 2.0 Hz, Ar-H), 6.16--6.15 (m, 1H, −C*H*), 3.67 (s, 3H, Ar-OC*H*~3~) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.96 (C=S), 181.90 (CO), 178.88 (CO), 164.59 (CONH), 163.56, 162.83, 160.57, 156.59, 156.33, 138.56, 129.87, 128.34, 126.56, 126.18, 125.89, 116.21, 114.72, 113.86, 113.61, 94.79, 55.52 (Ar-O*C*H~3~), 32.17 (−*C*H) ppm. Elemental analysis: calcd (%) for C~22~H~14~N~2~O~5~S: C, 63.15; H, 3.37; N, 6.70; found: C, 63.10; H, 3.36; N, 6.69.
### 4-(4,6,11-Trioxo-2-thioxo-2,3,4,5,6,11-hexahydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidin-5-yl)benzonitrile (**4-29**) {#sec4-2-11}
Reddish-yellow solid; yield 97% (0.200 g, 0.5 mmol scale); mp 172--174 °C; IR (KBr) ν~max~: 3237 (NH), 3041, 2231 (CN), 1671 (CO), 1666 (CONH), 1600, 1590, 1579, 1533, 1362 (C=S), 1277, 1226 (C=S), 1016 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.56 (br s, 2H, 2 × −N*H*), 7.96 (q, 2H, *J* = 7.6, 7.2, 4.8 Hz, Ar-H), 7.83--7.74 (m, 2H, Ar-H), 7.65 (d, 2H, *J* = 8.4 Hz, Ar-H), 7.30 (d, 2H, *J* = 7.6 Hz, Ar-H), 6.32 (br s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 186.94 (C=S), 184.08 (CO), 182.68 (CO), 173.72 (CONH), 163.76, 160.98, 148.75, 134.52, 133.18, 132.80, 132.22 (2C), 131.16, 129.28, 128.37, 126.39, 125.84, 123.83, 119.69 (*C*N), 108.28, 93.60, 33.20 (−*C*H) ppm. Elemental analysis: calcd (%) for C~22~H~11~N~3~O~4~S: C, 63.92; H, 2.68; N, 10.16; found: C, 63.87; H, 2.66; N, 10.14.
### 2-Thioxo-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione (**4-34**) {#sec4-2-12}
Golden-yellow solid; yield 93% (0.222 g, 0.5 mmol scale); mp 198--200 °C; IR (KBr) ν~max~: 3190 (NH), 3050, 2943, 1703 (CO), 1675 (CONH), 1648, 1592, 1513, 1432, 1331 (C=S), 1277, 1243 (C=S), 1047 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.68 (br s, 2H, 2 × −N*H*), 7.99--7.94 (m, 2H, Ar-H), 7.86--7.74 (m, 2H, Ar-H), 6.40 (br s, 2H, Ar-H), 6.18--6.17 (m, 1H, −C*H*), 3.63 (s, 3H, Ar-OC*H*~3~), 3.62 (s, 6H, 2 × Ar-OC*H*~3~) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.66 (C=S), 183.42 (CO), 182.50 (CO), 173.42 (CO), 163.40, 160.45, 152.81, 137.27, 136.16, 134.51, 133.21, 132.80, 131.05, 126.39, 125.81, 124.79, 122.54, 111.44, 105.04, 94.38, 60.34 (Ar-O*C*H~3~), 56.47 (Ar-O*C*H~3~), 56.28 (Ar-O*C*H~3~), 33.01 (−*C*H) ppm. Elemental analysis: calcd (%) for C~24~H~18~N~2~O~7~S: C, 60.25; H, 3.79; N, 5.85; found: C, 60.21; H, 3.81; N, 5.83.
### 4-(4,6,11-Trioxo-2-thioxo-2,3,4,5,6,11-hexahydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidin-5-yl)benzaldehyde (**4-36**) {#sec4-2-13}
Deep yellow solid; yield 93% (0.194 g, 0.5 mmol scale); mp 192--194 °C; IR (KBr) ν~max~: 3200 (NH), 3059, 2903, 1679 (CO & CHO), 1636 (CONH), 1603, 1548, 1429, 1364 (C=S), 1276, 1043 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.76--11.68 (m, 1H, −N*H*), 11.51 (s, 1H, −N*H*), 9.92 (s, 1H, −C*HO*), 7.97 (q, 2H, *J* = 8.0, 7.6, 6.8 Hz, Ar-H), 7.84--7.77 (m, 2H, Ar-H), 7.74 (d, 2H, *J* = 8.4 Hz, Ar-H), 7.33 (d, 1H, *J* = 7.6 Hz, Ar-H), 6.93 (br s, 1H, Ar-H), 6.36 (br s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 193.67 (*C*=S), 193.16 (*C*HO), 184.38 (CO), 182.87 (CO), 173.83 (CONH), 173.59, 163.84, 161.02, 134.75, 134.52, 133.37, 132.92, 130.59, 130.01, 129.88 (2C), 129.12, 128.12, 126.55, 126.00, 124.29, 33.50 (−*C*H) ppm. Elemental analysis: calcd (%) for C~22~H~12~N~2~O~6~: C, 63.46; H, 2.90; N, 6.73; found: C, 63.42; H, 2.89; N, 6.72.
### 5-(Furan-2-yl)-2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione (**4-37**) {#sec4-2-14}
Dark yellow solid; yield 96% (0.181 g, 0.5 mmol scale); mp 162--166 °C; IR (KBr) ν~max~: 3139 (NH), 3071, 1701 (CO), 1645 (CONH), 1555, 1523, 1352 (C=S), 1285, 1031 cm^--1^. ^1^H NMR (400 MHz, CDCl~3~): δ 8.11 (d, 4H, *J* = 7.6 Hz, Ar-H), 7.79 (dt, 2H, *J* = 7.6, 0.8 Hz, Ar-H), 7.72 (dt, 1H, *J* = 7.6, 7.0, 1.2 Hz, Ar-H), 7.45 (br s, 2H, 2 × −N*H*), 6.36 (s, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 185.14 (C=S), 182.09 (2 × CO), 167.49 (CO), 156.51, 152.87, 135.43, 133.29, 133.04, 129.57, 126.85 (2C), 126.65, 120.50, 117.16, 110.87 (2C), 107.34, 48.03 (−*C*H) ppm. Elemental analysis: calcd (%) for C~19~H~10~N~2~O~5~S: C, 60.31; H, 2.66; N, 7.40; found: C, 60.26; H, 2.65; N, 7.38.
### 5,5′-(1,4-Phenylene)bis(1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone) (**4′-1**) {#sec4-2-15}
Brownish-yellow solid; yield 98% (0.326 g, 0.5 mmol scale); mp 199--200 °C; IR (KBr) ν~max~: 3208 (NH), 3095, 2851, 1708 (CO), 1646 (CONH), 1589, 1506, 1275, 1043 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.67 (br s, 1H, −N*H*), 10.99--10.96 (m, 2H, 2 × −N*H*), 10.48 (br s, 1H, −N*H*), 8.10--8.06 (m, 1H, Ar-H), 7.97--7.91 (m, 4H, Ar-H), 7.78 (d, 2H, *J* = 6.8 Hz, Ar-H), 7.74 (d, 2H, *J* = 7.2 Hz, Ar-H), 7.31 (br s, 2H, Ar-H), 6.98 (br s, 1H, Ar-H), 4.81--4.78 (m, 1H, −C*H*), 4.51--4.49 (m, 1H, −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.06 (2 × *C*O), 181.25 (2 × *C*O), 169.45 (2 × *C*ONH), 163.59 (2 × *C*ONH), 161.88, 155.98 (2C), 153.43, 151.47 (2C), 150.62 (2C), 136.16, 135.20 (2C), 133.74 (2C), 132.31 (2C), 130.00 (2C), 129.01 (2C), 126.44 (2C), 126.05 (2C), 121.86, 92.28 (2C), 51.19 (−*C*H), 43.40 (−*C*H) ppm. Elemental analysis: calcd (%) for C~36~H~18~N~4~O~10~: C, 64.87; H, 2.72; N, 8.41; found: C, 64.81; H, 2.71; N, 8.39.
### 5,5′-(1,4-Phenylene)bis(1,3-dimethyl-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-2,4,6,11(3*H*,5*H*)-tetraone) (**4′-2**) {#sec4-2-16}
Light yellow solid; yield 92% (0.333 g, 0.5 mmol scale); mp 193--196 °C; IR (KBr) ν~max~: 3033, 2961, 2892, 1677 (CO), 1671 (CO), 1663 (CONCH~3~), 1645 (CONCH~3~), 1623, 1585, 1459, 1277, 1042 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 8.03--7.99 (m, 1H, Ar-H), 7.97--7.94 (m, 4H, Ar-H), 7.82--7.75 (m, 5H, Ar-H), 7.27 (br s, 2H, Ar-H), 4.90 (br s, 1H, −C*H*), 4.68 (br s, 1H, −C*H*), 3.19--3.16 (m, 3H, −NC*H*~3~), 3.06 (br s, 3H, −NC*H*~3~), 2.98 (br s, 6H, 2 × −NC*H*~3~) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 184.74 (CO), 184.29 (CO), 179.74 (CO), 173.29 (CO), 171.36 (2 × CONCH~3~), 168.48 (2 × CONCH~3~), 152.43 (2C), 152.40 (2C), 139.23, 135.09 (2C), 133.96 (2C), 133.87, 129.68 (2C), 128.96 (2C), 126.66 (2C), 126.64 (2C), 126.59 (2C), 126.56 (2C), 126.00 (2C), 84.80 (2C), 42.46 (2 × −*C*H), 29.21 (2 × N*C*H~3~), 28.59 (2 × N*C*H~3~) ppm. Elemental analysis: calcd (%) for C~40~H~26~N~4~O~10~: C, 66.48; H, 3.63; N, 7.75; found: C, 66.51; H, 3.62; N, 7.78.
### 5,5′-(1,4-Phenylene)bis(2-thioxo-2,3-dihydro-1*H*-benzo\[6,7\]chromeno\[2,3-*d*\]pyrimidine-4,6,11(5*H*)-trione) (**4′-3**) {#sec4-2-17}
Pale yellow solid; yield 94% (0.329 g, 0.5 mmol scale); mp 199--200 °C; IR (KBr) ν~max~: 3159 (NH), 3041, 2897, 1719 (CO), 1646 (CONH), 1590, 1544, 1444, 1336 (C=S), 1276, 1045 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.94 (br s, 4H, 4 × −NH), 7.99--7.92 (m, 4H, Ar-H), 7.81--7.73 (m, 4H, Ar-H), 7.34--7.26 (m, 1H, Ar-H), 6.95 (br s, 3H, Ar-H), 6.16--6.13 (m, 2H, 2 × −C*H*) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 194.65 (C=S), 193.01 (C=S), 185.16 (2 × CO), 182.06 (2 × CO), 173.42 (2 × CONH), 163.11 (2C), 159.84 (2C), 137.45 (2C), 134.64 (2C), 133.47 (2C), 132.59 (2C), 130.89 (2C), 126.84 (2C), 126.47 (4C), 125.93 (2C), 124.42 (2C), 94.75 (2C), 42.89 (−*C*H), 32.62 (−*C*H) ppm. Elemental analysis: calcd (%) for C~36~H~18~N~4~O~8~S~2~: C, 61.89; H, 2.60; N, 8.02; found: C, 61.86; H, 2.59; N, 8.00.
Isolation and Characterization of a Representative Chalcone Intermediate (Benzylidene Barbituric Acid) **6-3** {#sec4-3}
--------------------------------------------------------------------------------------------------------------
An oven-dried sealed tube was charged with a magnetic stir bar, barbituric acid (**1-3**; 0.5 mmol), 4-methoxybenzaldehyde (**2-3**; 0.5 mmol), and 4 mL of aqueous ethanol (1:1 v/v) in a sequential manner at ambient conditions, and the reaction mixture was then stirred for 5 h. The progress of the reaction was monitored by TLC. Upon the completion of the reaction, a yellow solid mass precipitated out, was filtered off, and was washed with cold aqueous ethanol to obtain pure 5-(4-methoxybenzylidene)pyrimidine-2,4,6(1*H*,3*H*,5*H*)-trione (**6-3**) having the physical and spectral data in full agreement with those reported in the literature.^[@ref70]^
### 5-(4-Methoxybenzylidene)pyrimidine-2,4,6(1*H*,3*H*,5*H*)-trione (**6-3**) {#sec4-3-1}
Bright yellow solid; yield 86% (0.106 g, 0.5 mmol scale); mp 271--274 °C; IR (KBr) ν~max~: 3207 (NH), 3079, 2986, 1682 (−CH=CCO−), 1672 (−CONH), 1658, 1548, 1509, 1461, 1272, 1047 cm^--1^. ^1^H NMR (400 MHz, DMSO-*d*~6~): δ 11.31 (br s, 1H, −NH), 11.18 (br s, 1H, −NH), 8.37 (d, 2H, *J* = 8.8 Hz, Ar-H), 8.25 (s, 1H, −C*H*=C−), 7.07 (d, 2H, *J* = 8.8 Hz, Ar-H), 3.88 (s, 3H, Ar-OC*H*~3~) ppm. ^13^C NMR (100 MHz, DMSO-*d*~6~): δ 164.38 (*C*ONH), 163.90 (*C*ONH), 162.64, 155.40 (−*C*H=C−), 150.67 (−NH*C*ONH−), 137.94 (2C), 125.62, 116.01 (−CH=*C*−), 114.41 (2C), 56.15 (Ar-O*C*H~3~) ppm. Elemental analysis: calcd (%) for C~12~H~10~N~2~O~4~: C, 58.54; H, 4.09; N, 11.38; found: C, 58.51; H, 4.08; N, 11.36.
The Supporting Information is available free of charge on the [ACS Publications website](http://pubs.acs.org) at DOI: [10.1021/acsomega.7b00791](http://pubs.acs.org/doi/abs/10.1021/acsomega.7b00791).Spectral and analytical data for all synthesized compounds (**4-1--4-37** and **4′-1--4′-3**) and the chalcone intermediate **6-3** including the scanned copies of the respective ^1^H NMR and ^13^C NMR spectra and working formulas for the calculations of green metrics and respective calculated data for all synthesized compounds ([PDF](http://pubs.acs.org/doi/suppl/10.1021/acsomega.7b00791/suppl_file/ao7b00791_si_001.pdf))
Supplementary Material
======================
######
ao7b00791_si_001.pdf
The authors declare no competing financial interest.
The authors are thankful to the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India, New Delhi, for generous financial support (grant no. EMR/2014/001220). They are also thankful to CDRI, Lucknow, and Department of Chemistry, Visva-Bharati University, for spectral measurements.
This paper is dedicated to Professor Basudeb Basu on the occasion of his 61st birthday.
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Though they have many different names, these committees generally have the same responsibilities.
What does an architectural committee do?
Every HOA is unique, but no HOA board is exempt from its fiduciary duty to care for and act in the best interests of the association. Having governing rules and bylaws in place (including established architectural rules) helps ensure that the HOA meets this duty.
Managing and maintaining an HOA is a lot of work, and although it is ultimately up to the board to ensure the community is properly cared for, committees can help ease the workload and minimize tasks for busy board members. Members of the architectural committee, for example, help maintain the aesthetic and structural integrity of the association. They are partially responsible for enforcing the CC&Rs, and any rules that deal with architectural issues.
The architectural committee reviews applications for modifications, additions, or architectural changes in the community, and may make recommendations to the board. However, the board may still have the final say about these types of requests.
When a homeowner wants to build a deck, paint their fence, or build a shed, or if a project that was already approved suddenly changes, detailed plans must be sent to the architectural committee first to make sure they are in compliance with the association’s design standards. The application may require the homeowner to include information such as the colour and brand of paint they intend to use, blueprints/sketches of the structure they intend to build, or the specific materials they intend to use for the project. The homeowner may also have to provide an estimated start and completion date, and agree to certain directives if the project is approved.
If the committee does find any issues with the application, they will let the homeowner know what the issues are, and will try to help them come up with other options.
Depending on the size of the association, the board may handle the duties of the architectural committee, or a separate group of members may operate as a committee. Some CC&Rs contain provisions that mandate the formation of an architectural committee separate from the board of directors, so check with your governing documents first to ensure your committee is following the rules.
Architectural committees are typically comprised of volunteer association members. Members meet regularly to make decisions about architectural change requests, discuss ways that application/approval processes could be improved, etc. The meetings of an architectural committee are not board meetings, and therefore are not subject to the requirements and restrictions contained in typical open meeting Acts. Many HOAs will require the architectural committee to keep and maintain minutes of its meetings though, and to make the minutes available for review by the association’s members within a certain amount of time.
The architectural committee looks out for the entire community. Aside from stopping residents from painting their homes bright pink, keeping Christmas lights up all year long, or paving over their front lawns with asphalt, the committee makes sure that the size and style of each project aligns with the overall look and feel of the community, and adheres to the association’s architectural requirements. Not only does this keep the development looking cohesive, it also helps to keep values of each home up by preventing individual structures from standing out.
Does every HOA need an architectural committee?
Before you make a decision about whether you need an architectural committee, check your governing documents to make sure you are not required to have one.
If you do have a choice, it may be worth it to create an architectural committee. Committees can be an invaluable resource to the board, and the entire community, because they perform work that would otherwise be hard for the board to take care of. That being said, the committee needs to be comprised of volunteers who are prepared to do the work, and these volunteers will still require some guidance from the board. Boards should fully understand the extent of the architectural committee’s authority, and the extent of liability the committee could potentially create for the HOA.
Play by the rules
For an architectural committee to be effective, the members need to have a strong understanding of applicable architectural rules and guidelines so that they can make informed decisions when they are reviewing requests and applications. They should be familiar with any provincial/state rules governing architectural and aesthetic reviews within associations, especially rules pertaining to time limits for responding to requests. This is very important because if the committee fails to act on applications within statutory guidelines, it can get sued and be forced to pay legal fees or penalties for not having reasonable guidelines in place for responding to architectural requests.
The committee also needs to base its decisions on solid reasoning, not arbitrary standards, and will need a system in place (likely the architectural guidelines) to help members make objective decisions.
Architectural guidelines
Architectural guidelines establish an association’s policies and procedures for changes and improvements to an owner’s home or property. Guidelines not only provide criteria for the current committee to make appropriate decisions, successive committee members can use the guidelines to make consistent decisions in the future. Without the guidelines, an application approved today may result in a project that is deemed unacceptable by new committee members after it is complete.
Guidelines are developed and approved by the board of directors, not the architectural committee.
Setting your committee up for success
A good committee can make life easier, and more enjoyable for the entire community. Here are some tips you can pass on to your architectural committee to set them up for success.
Provide a roadmap
Successful architectural committees provide homeowners with a roadmap for the application process. This could be something as simple as a step-by-step guide, or an easy-to-follow outline on the community website. Whatever the roadmap looks like, it should give clear and simple directions from start to finish.
Create an FAQ document
Instead of having to answer the same questions over and over again, create an FAQ document for homeowners. Attach this document to the roadmap, or include a section at the end of the architectural change request form.
Remove complicated language
If your application or request form contains language that the average person can’t understand without a dictionary, then it’s time for some editing. Get rid of unnecessary jargon and use simple language that your homeowners can actually understand. If there are terms that can’t be simplified, consider including a glossary with definitions.
Consider ways to digitize forms
Instead of distributing and managing stacks of papers, HOAs may want to consider digitizing architectural change request forms or applications. Condo Control Central has a convenient feature dedicated specifically to architectural change requests. Taking the approval process online makes it easier for HOAs to track, manage, and approve requests.
Bonus: Acknowledge the committee’s hard work
Finally, remember to thank your architectural committee. Don’t overlook the effectiveness of a simple thank-you note, an acknowledgment in the HOA newsletter, or a customized plaque. Committee members whose contributions are acknowledged are more likely to continue working hard and remain on the team. | https://www.condocontrol.com/blog/hoa-architectural-committee/ |
France's largest region, New-Aquitaine, lies in the South West and is a nature lover's destination par excellence. It boasts a variety of landscapes, moods and settings, from coastal to rural to mountainous, along with a clement climate year-round. The off-seasons are mild and sunny, ideal for nourishing needs for adventure, freedom and relaxation.
Four reasons to visit New-Aquitaine
- Wide, open spaces where nature rules, with a variety of environments to explore: 720 km of coastline, with some of the Atlantic's prettiest beaches (Lacanau, Hossegor, La Palmyre...); paradise islands (Ré, Oléron, Aix and Madame); well-known seaside resorts (Arcachon, Royan, Biarritz...); five Natural Parks with unique sites like the Great Dunes of Pilat, Europe's largest fine sandy beach, the Dordogne Valley, and more...
- 100% outdoor activities: on foot or horseback, by bike, boat or canoe. There are secret gardens for hikers, terrific terrain for cyclists with bike paths, sign-posted mountain bike trails, long-distance cycling circuits (La Vélodyssée®, La Scandibérique, Le Canal des 2 Mers, la Véloroute de la Vallée du Lot, La Vélo Francette®...). From the Basque coast to La Rochelle, and via Ré or Oléron Islands, this region (known in French as the Glissicon Valley) is the perfect playground for water sports enthusiasts.
- A large variety of quality accommodation, all in enchanting natural settings.
- A unique historical heritage, with the highest number of UNESCO World Heritage Sites in France.
Gironde
Create unforgettable memories in Gironde, from wine tastings on the Bordeaux Wine Route to strolls amongst the fortified towns and UNESCO Heritage Sites in Blaye, Bordeaux and Saint-Emilion. Ride along scenic bike trails, climb to the top of the Dune of Pilat on the Arcachon Basin, sail down the Gironde Estuary, the Garonne and Dordogne rivers, and hit the waves on the Atlantic. And don't forget to replenish in nature at the heart of the Landes de Gascogne Regional Natural Park, all the while indulging in a variety of unique local products...
Five reasons to visit Gironde
- A cycling destination, par excellence: Gironde has a number of bike paths around Bordeaux, along the Atlantic Coast and Arcachon Basin, and through the Médoc, Saint-Emilion, Graves, Sauternes and Entre-Deux-Mers vineyards...
- With its preserved natural environment and 126 km of fine, sandy beaches, the Gironde coast inspires absolute freedom. It's ideal for swimming and surfing, windsurfing on Médoc's great lakes, biking, hiking or horseback riding around the lakes, pine forests and dunes...
- Three major UNESCO World Heritage Sites: the Jurisdiction of Saint-Emilion, a "historic vineyard landscape"; Bordeaux's Port of the Moon, an "outstanding urban and architectural ensemble"; and Blaye's Citadel, a Vauban fortification and "Bolt of the Estuary."
- 400 km of navigable waterways on which to explore the Gironde, open to small sailboats and bigger cruise ships. Embark on a cruise, whether it's for a few hours, a day or several days, down the Estuary, the Garonne or Dordogne rivers.
- The Great Dune of Pilat is to the Arcachon Basin what the Eiffel Tower is to Paris: a must-see. Standing in at 110 metres tall, the Dune of Pilat is the tallest dune in Europe! It boasts an awe-inspiring panoramic view of the Ocean, the Arcachon Basin and Gascony's Landes forest. | https://ca.france.fr/en/news/article/welcome-bordeaux-and-its-surroundings |
Miliy Balakirev (1836-1910)
BALAKIREV, Miliy Alekseyevich (b. 21 December 1836 [2 January 1837], Nizhny Novgorod; d. 16 May 1910, St. Petersburg) — organizer and inspirational force behind the circle of Russian composers known as the “Mighty Handful”; in 1862, together with G. Ya. Lomakin, founded the Free Musical School in St. Petersburg, conducted its vocal-symphonic concerts, and worked with its choir. From 1883 to 1894 was the Administrator of the Imperial Court Chapel; from 1881 to 1908 again headed the Free Music School, which he had left in the 1870s. The main sphere of Balakirev’s compositional activity was instrumental music (symphonic and piano); his works also include compositions for vocal chamber ensembles, songs, secular choruses a cappella, arrangements for chorus of solo and instrumental compositions. Despite close ties with the field of church music and a personal religiosity, Balakirev composed only nine sacred works, of which five are free compositions and four are arrangements of chants. | http://www.musicarussica.com/composers/miliy-balakirev?tracks_order=title&tracks_sort_mode=desc |
This Description may be from another edition of this product.
Fichte's thought marks a crucial transitional stage between Kant and post-Kantian philosophy. Foundations of Natural Right, thought by many to be Fichte's most important work of political philosophy, applies his ideas to fundamental issues in political and legal philosophy, covering such topics as civic freedom, right, private property, contracts, family relations, and the foundations of modern political organization. This volume offers the first complete translation of the work into English, by Michael Baur, together with an introduction by Frederick Neuhouser that sets it in its philosophical and historical context.
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CROSS-REFERENCE TO RELATED APPLICATION
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
TECHNICAL FIELD
BACKGROUND
SUMMARY OF THE INVENTION
DETAILED DESCRIPTION
Terminology and Definitions
EMBODIMENTS
EXAMPLES
st
1Set of Experiments
2nd Set of Experiments
3rd Set of Experiments
4th Set of Experiments
5th Set of Experiments
This nonprovisional application claims the benefit of U.S. Provisional Application No. 62/436,642 filed Dec. 20, 2017. The disclosure of the prior application is hereby incorporated by reference in its entirety.
This invention was made with government support under HL120404 awarded by the National Heart Lung Blood Institute of the National Institute of Health, and W81XWH-15-C-0173 awarded by the U.S. Army Medical Research and Materiel Command Fort Detrick. The government has certain rights in the invention.
The present disclosure relates to the field of cell, tissue and organ preservation, particularly new ice-free formulations (e.g., for vitrification) incorporating sugars, such as disaccharides (e.g., trehalose and sucrose), and protocols that improve sample material properties and biological viability, even as sample volumes are increased to greater than 4 mL. More specifically, the invention relates to a method for supplementing ice-free vitrification formulations for large samples containing cellular materials (e.g., having a volume greater than 4 mL, such as greater than 10 mL) with sugars, such as disaccharides (e.g., trehalose and sucrose), in an effort to enhance cell survival and tissue functions post-preservation.
Conventional approaches to ice-free cryopreservation have been successful for storage of relatively small sample sizes. For example, human oocyte storage where it has revolutionized clinical in vitro fertilization practice.
In order for the cells or tissues to be preserved, cryoprotectant solutions are typically used to prevent damage due to freezing during the cooling or thawing/warming process. For cryopreservation to be useful, the preserved sample should retain the integrity and/or viability thereof to a reasonable level post-preservation. Thus, the process of preserving the sample should avoid and/or limit the damage or destruction of the cells and/or tissue architecture.
g
Vitrification, cryopreserved storage in a “glassy” rather than crystalline phase, is an important enabling approach for tissue banking and regenerative medicine, offering the ability to store and transport cells, tissues and organs for a variety of biomedical uses. In ice-free cryopreservation by vitrification the formation of ice is prevented by the presence of high concentrations of chemicals known as cryoprotectants that both interact with and replace water and, therefore, prevent water molecules from forming ice. This approach essentially stops biological time during storage below the cryoprotectant formulations glass transition temperature (T), and has been used successfully to maintain the viability and function of small-scale cell and thin tissue samples due to diffusive (heat and mass transfer) and phase change limitations that preclude use in bulk systems such as organs and larger tissues. While previous vitrification techniques (and cryoprotecting agents used therewith, such as DSMO) employing conventional boundary convection warming techniques can sometimes be successful for samples up to 4-5 mL, ice-formation still occurs as the sample volume approaches 10 mL because conventional boundary convection warming in a bath does not provide fast enough warming rates. Ice formation results in cell and tissue destruction. The major limitations of vitrification for large tissue samples are potential cytotoxicity due to prolonged exposure to the cryoprotectants employed and ice-formation during rewarming.
It was found that supplementation of ice-free vitrification formulations employed for large volume cellular materials (e.g., having a volume greater than 4 mL, such as greater than 10 mL) with sugars, such as disaccharides (e.g., trehalose and/or sucrose), resulted in increased cell survival post-preservation and tissue functions.
The present application thus provides new methodology and new formulations for treatment of large volume cellular materials in which sugars, such as disaccharides (e.g., trehalose and/or sucrose) are added to ice-free vitrification cryoprotectant formulations. Supplementation with these sugars reduces both cryoprotectant-induced cytotoxicity and the risk of ice formation during cooling and most importantly during rewarming.
In the following description, numerous details are set forth to provide an understanding of the present disclosure. However, it may be understood by those skilled in the art that the methods of the present disclosure may be practiced without these details and that numerous variations or modifications from the described embodiments may be possible.
At the outset, it should be noted that in the development of any such actual embodiment, numerous implementation-specific decisions may be made to achieve the developer's specific goals, such as compliance with system related and business related constraints, which will vary from one implementation to another. Moreover, it will be appreciated that such a development effort might be complex and time consuming but would nevertheless be a routine undertaking for those of ordinary skill in the art having the benefit of this disclosure. In addition, the composition used/disclosed herein can also comprise some components other than those cited. In the summary and this detailed description, each numerical value should be read once as modified by the term “about” (unless already expressly so modified), and then read again as not so modified unless otherwise indicated in context.
As used herein, the term “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context. For example, it includes at least the degree of error associated with the measurement of the particular quantity. When used in the context of a range, the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the range “from about 2 to about 4” also discloses the range “from 2 to 4.”
Unless otherwise expressly stated herein, the modifier “about” with respect temperatures (° C.) refers to the stated temperature or range of temperatures, as well as the stated temperature or range of temperatures +/−1-4% (of the stated temperature or endpoints of a range of temperatures) of the stated. Regarding cell viability and cell retention (%), unless otherwise expressly stated herein, the modifier “about” with respect to cell viability and cell retention (%) refers to the stated value or range of values as well as the stated value or range of values +/−1-3%. Regarding expression contents, such as, for example, with the units in either parts per million (ppm) or parts per billion (ppb), unless otherwise expressly stated herein, the modifier “about” with respect to cell viability and cell retention (%) refers to the stated value or range of values as well as the stated value or range of values +/−1-3%. Regarding expressing contents with the units μg/mL, unless otherwise expressly stated herein, the modifier “about” with respect to value in μg/mL refers to the stated value or range of values as well as the stated value or range of values +/−1-4%. Regarding molarity (M), unless otherwise expressly stated herein, the modifier “about” with respect to molarity (M) refers to the stated value or range of values as well as the stated value or range of values +/−1-2%. Regarding, cooling rates (° C./min), unless otherwise expressly stated herein, the modifier “about” with respect to cooling rates (° C./min) refers to the stated value or range of values as well as the stated value or range of values +/−1-3%.
Also, in the summary and this detailed description, it should be understood that a range listed or described as being useful, suitable, or the like, is intended to include support for any conceivable sub-range within the range at least because every point within the range, including the end points, is to be considered as having been stated. For example, “a range of from 1 to 10” is to be read as indicating each possible number along the continuum between about 1 and about 10. Additionally, for example, +/−1-4% is to be read as indicating each possible number along the continuum between 1 and 4. Furthermore, one or more of the data points in the present examples may be combined together, or may be combined with one of the data points in the specification to create a range, and thus include each possible value or number within this range. Thus, (1) even if numerous specific data points within the range are explicitly identified, (2) even if reference is made to a few specific data points within the range, or (3) even when no data points within the range are explicitly identified, it is to be understood (i) that the inventors appreciate and understand that any conceivable data point within the range is to be considered to have been specified, and (ii) that the inventors possessed knowledge of the entire range, each conceivable sub-range within the range, and each conceivable point within the range. Furthermore, the subject matter of this application illustratively disclosed herein suitably may be practiced in the absence of any element(s) that are not specifically disclosed herein.
Unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by anyone of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
In addition, use of the “a” or “an” are employed to describe elements and components of the embodiments herein. This is done merely for convenience and to give a general sense of concepts according to the disclosure. This description should be read to include one or at least one and the singular also includes the plural unless otherwise stated.
The terminology and phraseology used herein is for descriptive purposes and should not be construed as limiting in scope. Language such as “including,” “comprising,” “having,” “containing,” or “involving,” and variations thereof, is intended to be broad and encompass the subject matter listed thereafter, equivalents, and additional subject matter not recited.
Also, as used herein any references to “one embodiment” or “an embodiment” means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily referring to the same embodiment.
As used herein, the term “room temperature” refers to a temperature of about 18° C. to about 25° C. at standard pressure. In various examples, room temperature may be about 18° C., about 19° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., or about 25° C.
As used herein, “cellular material” or “cellular sample” refers to living biological material containing cellular components, whether the material is natural or man-made and includes cells, tissues and organs, whether natural or man-made. Such terms also mean any kind of living material to be cryopreserved, such as cells, tissues and organs. In some embodiments, the cells, tissues and organs may be mammalian organs (such as human organs), mammalian cells (such as human cells) and mammalian tissues (such as human tissues).
As used herein, “large volume” as used in the phrase large volume cellular material” or “large volume sample” or “large volume cellular sample” refers to living biological material containing cellular components, whether the material is natural or man-made and includes cellular materials, tissues and organs, whether natural or man-made, where such living biological material containing cellular components has a volume greater than about 4 mL, such as a volume greater than about 5 mL, or a volume greater than about 10 mL, or a volume greater than about 15 mL, or a volume greater than about 30 mL, or a volume greater than about 50 mL, or a volume greater than about 70 mL, or a volume in a range of from about 4 mL to about 200 mL, such as a volume in a range of from about 4 mL to about 50 mL, a volume in a range of from about 4 mL to about 30 mL, or a volume in a range of from about 5 mL to about 100 mL, such as a volume in a range of from about 5 mL to about 50 mL, or a volume in a range of from about 5 mL to about 30 mL, or a volume in a range of from about 6 mL to about 100 mL, or a volume in a range of from about 6 mL to about 50 mL, or a volume in a range of from about 6 mL to about 25 mL, or a volume in a range of from about 10 mL to about 100 mL, or a volume in a range of from about 10 mL to about 50 mL, or a volume in a range of from about 10 mL to about 25 mL, or a volume in a range of from about 10 mL to about 20 mL. Such terms also include any kind of living material having such a volume to be cryopreserved, such as cellular materials, tissues and organs. In some embodiments, the tissues and organs having such a volume may be mammalian organs (such as human organs), mammalian cells and mammalian tissues (such as human tissues).
As used herein, the term “organ” refers to any organ, such as, for example, liver, lung, kidney, intestine, heart, pancreas, testes, placenta, thymus, adrenal gland, arteries, veins, lymph nodes, bone or skeletal muscle. As used herein, the term “tissue” or “tissues” comprises any tissue type comprising any kind of cell type (such as from one of the above-mentioned organs) and combinations thereof, including, for example, ovarian tissue, testicular tissue, umbilical cord tissue, placental tissue, connective tissue, cardiac tissue, tissues from muscle, cartilage and bone, endocrine tissue, skin and neural tissue. The term “tissue” or “tissues” may also comprise adipose tissue or dental pulp tissue. In some embodiments, the tissue or organ is obtained from a human such as a human liver, human lung, human kidney, human intestine, human heart, human pancreas, human testes, human placenta, human thymus, human adrenal gland, human arteries, human veins, human nerves, human skin, human lymph nodes, human bone or human skeletal muscle.
As used herein, the term “cell(s)” comprises any type of cell, such as, for example, somatic cells (including all kind of cells in tissue or organs), fibroblasts, keratinocytes, hepatocytes, cardiac myocytes, smooth muscle cells, stem cells, progenitor cells, oocytes, and germ cells. Such cells may be in the form of a tissue or organ. In some embodiments, the cells are from a mammal tissue or organ, such as a human tissue or organ described above.
As used herein, “preservation protocol” refers to a process for provision of shelf life to a cell containing, living biological material. Preservation protocols may include cryopreservation by vitrification and/or anhydrobiotic preservation by either freeze-drying or desiccation.
As used herein, the term “vitrification” refers to solidification either without ice crystal formation or without substantial ice crystal formation. In some embodiments, a sample to be preserved (e.g., such as a tissue or cellular material) may be vitrified such that vitrification and/or vitreous cryopreservation (in its entirety-from initial cooling to the completion of rewarming) may be achieved without any ice crystal formation. In some embodiments, a sample to be preserved (e.g., such as a tissue or cellular material) may be vitrified such that vitrification and/or vitreous cryopreservation may be achieved where the solidification of the sample to be preserved (e.g., such as a tissue or cellular material) may occur without substantial ice crystal formation (i.e., the vitrification and/or vitreous cryopreservation (in its entirety-from initial cooling to the completion of rewarming) may be achieved even in the presence of a small, or restricted amount of ice, which is less than an amount that causes injury to the tissue).
h
g
As used herein, a sample to be preserved (e.g., such as a tissue or cellular material) is vitrified when it reaches the glass transition temperature (Tg). The process of vitrification involves a marked increase in viscosity of the cryoprotectant solution as the temperature is lowered such that ice nucleation and growth are inhibited. Generally, the lowest temperature a solution can possibly supercool to without freezing is the homogeneous nucleation temperature T, at which temperature ice crystals nucleate and grow, and a crystalline solid is formed from the solution. Vitrification solutions have a glass transition temperature T, at which temperature the solute vitrifies, or becomes a non-crystalline solid.
As used herein, the “glass transition temperature” refers to the glass transition temperature of a solution or formulation under the conditions at which the process is being conducted. In general, the methodology of the present disclosure is conducted at physiological pressures. However, higher pressures can be used as long as the sample to be preserved (e.g., such as a tissue or cellular material) is not significantly damaged thereby.
As used herein, “physiological pressures” refer to pressures that tissues undergo during normal function. The term “physiological pressures” thus includes normal atmospheric conditions, as well as the higher pressures that various tissues, such as vascularized tissues, undergo under diastolic and systolic conditions.
As used herein, the term “cryoprotectant” means a chemical that minimizes ice crystal formation in and around a tissue/organ when the tissue is cooled to subzero temperatures and results in substantially no damage to the tissue/organ after warming, in comparison to the effect of cooling without cryoprotectant.
As used herein, the term “sugar” may refer to any sugar. In some embodiments, the sugar is a polysaccharide. As used herein, the term “polysaccharide” refers to a sugar containing more than one monosaccharide unit. That is, the term polysaccharide includes oligosaccharides such as disaccharides and trisaccharides, but does not include monosaccharides. The sugar may also be a mixture of sugars, such as where at least one of the sugars is a polysaccharide. In some embodiments, the sugar is at least one member selected from the group consisting of a disaccharide and a trisaccharide. In some embodiments, the sugar is a disaccharide, such as, for example, where the disaccharide is at least one member selected from the group consisting of trehalose and sucrose. In some embodiments, the sugar is a trisaccharide, such as raffinose. The sugar may also be a combination of trehalose and/or sucrose and/or raffinose and/or other disaccharides or trisaccharides. In some embodiments, the sugar comprises trehalose.
As used herein, the term “functional after cryopreservation” in relation to a cryopreserved material means that the cryopreserved material, such as organs or tissues, after cryopreservation retains an acceptable and/or intended function after cryopreservation. In some embodiments, the cellular material after cryopreservation retains all its indented function. In some embodiments, the cellular cryopreserved material preserved by the methods of the present disclosure retains at least 50% of the intended function, such as at least 60% of the intended function, such as at least 70% of the intended function, such as at least 80% of the intended function, such as at least 90% of the intended function, such as at least 95% of the intended function, such as 100% of the intended function. For example, along with preserving the viability of the cells, it may be important to also maintain/preserve the physiological function of the tissue/organ, e.g. for a heart the pumping function, and/or the ability of a tissue (e.g., those to be transplanted) to integrate with surrounding tissue.
As used herein, the term “sterile” means free from living germs, microorganisms and other organisms capable of proliferation.
As used herein, the term “substantially free of cryoprotectant” means a cryoprotectant in an amount less than 0.01 w/w %. In some embodiments, the methods of the present disclosure may use and/or achieve a medium/solution and/or cellular material that is substantially free of cryoprotectant, such as a cellular material that is substantially free of DMSO (i.e., the DMSO is in an amount less than 0.01 w/w %). In some embodiments, the methods of the present disclosure may use and/or achieve a medium/solution and/or cellular material that is substantially free of any cryoprotectant other than the sugar, such as sucrose and/or trehalose).
The present disclosure is directed to methods for preserving large volume living materials/samples/organ(s)/tissue(s) (The terms “materials,” “samples,”, “organ(s)”, and “tissue(s)” are used interchangeably and encompass any living biological material containing cellular components).
The methods of the present disclosure comprise bringing a large volume cellular material into contact with a cryoprotectant solution containing at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose). In some embodiments, this may comprise incubating a large volume cellular material in a cryoprotectant formulation/solution containing at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) (and optionally a further cryoprotectant), such as incubating (or bringing into contact) a large volume cellular material in a medium/solution containing at least sugar, such as a disaccharide (e.g., trehalose and/or sucrose) (and optionally a further cryoprotectant). In embodiments, the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), may be present in the cryoprotectant formulation/solution in an amount effective to provide an environment more conducive to survival of the cells of the large volume cellular material during cooling and rewarming.
For example, in some embodiments, the cellular cryopreserved material preserved by the methods of the present disclosure retains at least 50% of the intended function, such as at least 60% of the intended function, such as at least 70% of the intended function, such as at least 80% of the intended function, such as at least 90% of the intended function, such as at least 95% of the intended function, such as 100% of the intended function. For example, along with preserving the viability of the cells in tissues and organs, it may be important to also maintain/preserve the physiological function of the cell/tissue/organ, e.g. for a heart the pumping function, and/or the ability of a tissue/cell(s) (e.g., those to be transplanted) to integrate with surrounding tissue/cell(s).
In the methods of the present disclosure, the cells of the large volume cellular material (hereinafter referred to as “cells”) are protected during cryopreservation after being brought into contact with the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in combination with other cryoprotectants during cooling to the cryopreservation temperature and rewarming. In embodiments, being brought into contact with the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in combination with other cryoprotectants during cooling and rewarming means that the risks of ice formation is minimized such that the viability of the cells does not significantly deteriorate because the cryoprotectant solution has been stabilized/protected by the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in the cryopreservation formulation/solution/composition.
In embodiments, the solution, such as a known solution well suited for organ storage of cells, tissues and organs, may contain any effective amount of sugar that is effective to provide an environment more conducive to survival of the cells of the large volume cellular material during the preservation protocol.
In some embodiments, in the methods of the present disclosure a medium (the terms “medium” and “solution” are used interchangeably) containing the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in combination with other cryoprotectants may be combined with cellular materials, such as tissues and organs to prepare a cryopreservation composition. The medium (which may be an aqueous medium) can contain any suitable concentration of the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in combination with other cryoprotectants for these purposes.
In some embodiments, at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in combination with other cryoprotectants, is used in an amount in the methods of the present disclosure such that it results in an improved viability (post-cryopreservation) of the living cellular material/sample selected from the group consisting of organs, cells and tissues, such as mammalian organs, mammalian cells, and mammalian tissues (including those which may be subsequently transplanted). The phrases, “improved cell viability” or “improved viability,” refer, for example, to a cell viability (%) of at least 60%, such as 80% or more. The improved cell viability (%) may be 50% or more, 60% or more, 70% or more, 73% or more, 75% or more, 77% or more, 80% or more, 83% or more, 85% or more, 87% or more, 90% or more, 93% or more, 95% or more, 97% or more, 98% or more, or 99% or more.
In some embodiments, at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) (and optionally a further cryoprotectant) is used in an amount in the methods of the present disclosure such that it is effective to accomplish one or more of the following: inhibit ice nucleation, modify ice structure, decrease ice formation, prevent ice formation, decrease/prevent ice formation to an extent that would allow the use of more rapid cooling rates, decrease/prevent ice formation to an extent that would allow a reduction in the amount of cryoprotectant required providing an environment more conducive to cell survival.
In some embodiments, the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) represents from about 1 to about 50% of the total weight of the medium comprising the cells to be preserved, such as from about 2 to about 50%, or from about 4 to about 45%, or from about 5 to 20%, or from about 5 to about 12%, or from about 6 to 20%, or from about 6 to about 12%, or from about 6 to about 10% of the total weight of the formulation/solution/medium being used with the cells to be preserved.
In some embodiments, the formulation/solution/medium contains the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) at a concentration ranging from 0.01 M to 5 M, from 0.1 M to 4 M, from 0.1 M to 3 M, from 0.1 M to 2 M, from 0.2 M to 2 M, from 0.3 M to 2 M, from 0.4 M to 2 M, from 0.5 M to 2 M, from 0.6 M to 2 M, from 0.1 M to 1 M, from 0.2 M to 1 M, from 0.3 M to 1 M, from 0.4 M to 1 M, from 0.5 M to 1 M, from about 0.05 M to about 6 M, about 0.1 to about 3 M, about 0.25 to about 6 M, about 0.25 to about 1 M, about 0.25 to about 2 M, about 0.25 to about 3 M, about 0.25 to about 4 M, about 0.25 to about 5 M, about 1 to about 4 M, about 1 to about 3 M, about 1 to about 2 M, about 3 to about 5 M, about 2 to about 4 M, about 0.5 to about 6 M, about 0.5 to about 5 M, about 0.5 to about 4 M, about 0.5 to about 3 M, about 0.5 to about 2 M, or about 0.5 to about 1M, wherein any concentration occurring within the above ranges can also serve as an endpoint for a range.
In embodiments, the formulation/solution/medium comprising the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), may be contacted with the sample to be preserved for any desired duration, such as until a desired dosage (such as an effective dosage) of the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) is present on/in the cells or tissues to afford an improved viability (post-cryopreservation), and/or to prevent/protect against tissue damage and/or to accomplish one or more of the following: inhibit ice nucleation, modify ice structure, decrease ice formation, prevent ice formation, decrease/prevent ice formation to an extent that would allow the use of slower cooling and warming rates, decrease/prevent ice formation to an extent that would allow a reduction in the amount of cryoprotectant required to provide an environment more conducive to cell survival to preserve tissues.
In some embodiments, the cells to be cryopreserved may also be in contact with a freezing-compatible pH buffer comprised of, for example, at least a basic salt solution, an energy source (for example, glucose), and a buffer capable of maintaining a neutral pH at cooled temperatures. Well known such materials include, for example, Dulbecco's Modified Eagle Medium (DMEM). This material may also be included as part of the cryopreservation composition. See, e.g., Campbell et al., “Cryopreservation of Adherent Smooth Muscle and Endothelial Cells with Disaccharides,” In: Katkov I. (ed.) Current Frontiers in Cryopreservation. Croatia: In Tech (2012); and Campbell et al., “Development of Pancreas Storage Solutions: Initial Screening of Cytoprotective Supplements for β-cell Survival and Metabolic Status after Hypothermic Storage,” Biopreservation and Biobanking 11(1): 12-18 (2013).
In some embodiments, the cryoprotectant compounds (in total, including the sugars and any other cryoprotectant) may be present in the cryopreservation composition in an amount of from, for example, about 0.05 M to about 13 M, about 0.1 to about 13 M, about 0.25 to about 13 M, about 1 to about 13 M, about 2 to about 13 M, about 4 to about 13 M, about 6 to about 13 M, about 8 to about 13 M, about 0.25 to about 11 M, about 0.25 to about 9 M, about 0.25 to about 8 M, about 0.25 to about 7 M, about 0.25 to about 10 M, about 1 to about 7 M, about 1 to about 8 M, about 1 to about 9 M, about 3 to about 10 M, about 2 to about 10 M, about 0.5 to about 10 M, about 0.5 to about 9 M, about 0.5 to about 9 M, about 0.5 to about 8 M, or about 0.5 to about 7 M, or about 6.5 to about 11 M. In some embodiments, the cryoprotectant compounds may be present in the cryopreservation composition in an amount of from, for example, about 0.05 M to about 6 M, about 0.1 to about 3 M, about 0.25 to about 6 M, about 1 to about 6 M, about 2 to about 6 M, about 3 to about 6 M, about 4 to about 6 M, about 5 to about 6M.
In some embodiments, the cellular material to be preserved may be brought into contact with a cryoprotectant-containing solution/medium/formulation/composition before, during or after incubating the cellular material to be preserved in a solution/medium/formulation/composition containing at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose). The duration that the tissue may be contacted by immersion and or perfusion in such solution/medium/formulation/composition will be a function of the mass of the tissue. In embodiments, the cooling rates of such solutions/mediums/formulations/compositions may be adjusted to provide adequate tissue permeation (function of concentration and time) to prevent ice formation.
Suitable further cryoprotectants may include, for example, acetamide, agarose, alginate, alanine, albumin, ammonium acetate, anti-freeze proteins, butanediols (such as 2,3-butanediol), chondroitin sulfate, chloroform, choline, cyclohexanediols, cyclohexanediones, cyclohexanetriols, dextrans, diethylene glycol, dimethyl acetamide, dimethyl formamide (such as n-dimethyl formamide), dimethyl sulfoxide, erythritol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, formamide, glucose, glycerol, glycerophosphate, glyceryl monoacetate, glycine, glycoproteins, hydroxyethyl starch, inositol, lactose, magnesium chloride, magnesium sulfate, maltose, mannitol, mannose, methanol, methoxy propanediol, methyl acetamide, methyl formamide, methyl ureas, methyl glucose, methyl glycerol, phenol, pluronic polyols, polyethylene glycol, polyvinylpyrrolidone, proline, propanediols (such as 1,2-propanediol and 1,3-propanediol), pyridine N-oxide, raffinose, ribose, serine, sodium bromide, sodium chloride, sodium iodide, sodium nitrate, sodium nitrite, sodium sulfate, sorbitol, triethylene glycol, trimethylamine acetate, urea, valine and xylose. Other cryoprotectants that may be used in the present disclosure are described in U.S. Pat. No. 6,395,467 to Fahy et al.; U.S. Pat. No. 6,274,303 to Wowk et al.; U.S. Pat. No. 6,194,137 to Khirabadi et al.; U.S. Pat. No. 6,187,529 to Fahy et al.; U.S. Pat. No. 5,962,214 to Fahy et al.; U.S. Pat. No. 5,955,448 to Calaco et al.; U.S. Pat. No. 5,629,145 to Meryman; and/or WO 02/32225 A2, which corresponds to U.S. patent application Ser. No. 09/691,197 to Khirabadi et al., the disclosures of which are each hereby incorporated by reference in their entireties.
The cryoprotectant composition may also include at least one cyclohexanediol (CHD) compound, for example the cis or trans forms of 1,3-cyclohexanediol (1,3CHD) or 1,4-cyclohexanediol (1,4CHD), or racemic mixtures thereof, as a cryoprotectant compound.
The CHD compound may be present in the cryopreservation composition in an amount of from, for example, about 0.05 to about 2 M, about 0.1 M to about 1 M, about 0.1 to about 2 M, about 0.1 to about 1 M, about 0.1 to about 1.5 M, about 0.1 to about 0.5 M, about 0.1 to about 0.25 M, about 1 to about 2 M, about 1.5 to about 2 M, about 0.75 to about 2 M, about 0.75 to about 1.5 M, about 0.75 to about 1 M, about 0.05 to about 1 M, about 0.05 to about 0.75 M, about 0.05 to about 0.5 M, or about 0.05 to about 0.1 M.
The cryopreservation composition also may include (or be based on) a solution well suited for storage of cells, tissues and organs. The solution may include well known pH buffers. In some embodiments, the solution may be, for example, the EuroCollins Solution, which is composed of dextrose, potassium phosphate monobasic and dibasic, sodium bicarbonate, and potassium chloride, described in Taylor et al., “Comparison of Unisol with Euro-Collins Solution as a Vehicle Solution for Cryoprotectants,” Transplantation Proceedings 33: 677-679 (2001), or a “VS55” solution, which is an optimized cryoprotectant cocktail that has demonstrated successful vitrification of many biological systems. VS55 solution is composed of 3.1 M dimethyl sulfoxide (DMSO), 2.2 M propylene glycol, and 3.1 M formamide in a base Euro-Collins solution, for a total of 8.4M. Alternatively the cryoprotectant solution may be formulated in an alternative solution, such as Unisol.
Still further, the cryopreservation composition for use in the methods of the present disclosure may also include an anti-freeze glycolipid (AFGL), anti-freeze protein/peptide (AFP), “thermal hysteresis” proteins, (THPs) or ice recrystallization inhibitors (IRIs). Such materials may be present in the cryopreservation composition in an amount of from, for example, about 0.001 to about 1 mg/mL, about 0.05 to about 0.5 mg/mL, or about 0.1 to about 0.75 mg/mL of composition.
In some embodiments, the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), may act as a replacement for a cryoprotectant, such as, for example, DMSO, or as a supplement to such other cryoprotectants to reduce the concentration thereof, such as to non-toxic concentrations, at which the cryoprotectant achieves the same or better protective effects with regard to preserving as much functionality of the cryopreserved material/sample during the cryopreservation procedure. For example, in some embodiments, the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), may act as a replacement for a cryoprotectant, such as, for example, DMSO, in a solution known as “VS55”, which is an optimized cryoprotectant cocktail that has demonstrated successful vitrification of many biological systems (VS55 solution is composed of 3.1M dimethyl sulfoxide (DMSO), 2.2M propylene glycol, and 3.1M formamide in a base Euro-Collins solution, for a total of 8.4M). In this regard, the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), may act as a replacement for the cryoprotectant in the VS55 solution, to reduce the concentration thereof, such as to non-toxic concentrations, or as a supplement to the other cryoprotectants in VS55 at which the cryoprotectant achieves the same or better protective effects with regard to preserving as much functionality of the cryopreserved material/sample during the cryopreservation procedure.
In some embodiments, at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), is used in an amount in the methods of the present disclosure such that it is effective to act as a cryoprotectant for a living material/sample selected from the group consisting of organs, cells and tissues, such as mammalian organs, mammalian cells, and mammalian tissues (including those which may be subsequently transplanted).
The cells in the cellular materials that may be used in the methods of the present disclosure can be any suitable cell composition. In some embodiments, the cells can be skin cells, keratinocytes, skeletal muscle cells, cardiac muscle cells, lung cells, mesentery cells, adipose cells, stem cells, hepatocytes, epithelial cells, Kupffer cells, fibroblasts, neurons, cardio myocytes, myocytes, chondrocytes, pancreatic acinar cells, islets of Langerhans, osteocytes, myoblasts, satellite cells, endothelial cells, adipocytes, preadipocytes, biliary epithelial cells, and progenitor cells or combinations of any of these cell types.
In some embodiments, the cells used in the methods of the present disclosure may be from any suitable species of animal, for example a mammal, such as a human, canine (e.g. dog), feline (e.g. cat), equine (e.g. horse), porcine, ovine, caprine, or bovine mammal.
The formulation/composition used to prepare the cryopreservation solution can be combined with the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose), in a variety of ways. In some embodiments, a cellular material can be combined with an aqueous liquid medium, such as an aqueous solution, containing the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose). For example, a gradual combination, optionally with gentle agitation, can be conducted.
Once the cryopreservation composition has been prepared (and the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) and associated with the cellular material to be preserved), the cooling for ice-free vitrified cryopreservation may be conducted in any manner, and may use any additional materials to those described above. Protocols for preserving cellular material are described in the following patents and publications: U.S. Pat. No. 6,395,467 to Fahy et al.; U.S. Pat. No. 6,274,303 to Wowk et al.; U.S. Pat. No. 6,194,137 to Khirabadi et al.; U.S. Pat. No. 6,187,529 to Fahy et al.; U.S. Pat. No. 6,127,177 to Toner et al.; U.S. Pat. No. 5,962,214 to Fahy et al.; U.S. Pat. No. 5,955,448 to Calaco et al.; U.S. Pat. No. 5,827,741 to Beattie et al.; U.S. Pat. No. 5,648,206 to Goodrich et al.; U.S. Pat. No. 5,629,145 to Meryman; U.S. Pat. No. 5,242,792 to Rudolph et al.; and WO 02/32225 A2, which corresponds to U.S. patent application Ser. No. 09/691,197 to Khirabadi et al., the disclosure of which are each hereby incorporated in their entirety by reference.
The cryopreservation portion of the preservation protocol typically involves cooling cells to temperatures well below the freezing point of water, e.g., to about −80° C. or lower, more typically to about −130° C. or lower. Any method of cryopreservation known to practitioners in the art may be used. For example, the cooling protocol for cryopreservation may be any suitable type in which the cryopreservation temperature may be lower (i.e., colder) than about −20° C., such as about −80° C. or lower (i.e., colder), or about −135° C. or lower (i.e., colder). In some embodiments, the cryopreservation temperature may be in a range of from about −20° C. to about −200° C., or about −120 to about 200° C., or about −130° C. to about −196° C., or about −140° C. to about −190° C., or about −150° C. to about −190° C., or about −150° C. to about −180° C., or about −30 to about −175° C., or about −80° C. to about −160° C., or about −85° C. to about −150° C., or about −95° C. to about −135° C., or about −80° C. to about −180° C., or about −90° C. to about −196° C., or about −100° C. to about −196° C.
In some embodiments, the preservation protocol may include continuous controlled rate cooling from the point of initiation temperature (+4 to −30° C.) to −80° C. or any of the above disclosed cooling temperatures, with the rate of cooling depending on the characteristics of the cells/tissues being cryopreserved. For example, the cooling protocol for cryopreservation may be at any suitable rate, such as a rate (and/or average cooling rate, for example from the initial temperature of the sample to the cryopreservation temperature) may be greater than about −0.1° C. per minute, or greater than about −4.0° C. per minute, or greater than about −6.0° C. per minute, or greater than about −8.0° C. per minute, or greater than about −10.0° C. per minute, or greater than about −14.0° C. per minute, or greater than about −25.0° C. per minute, or greater than 50° C. per minute. The cooling rate (and/or average cooling rate), such as, for example, for continuous rate cooling (or other types of cooling), may be, for example, from about −0.1° C. to about −10° C. per minute or about −1° C. to about −2° C. per minute. The cooling rate may be about −0.1 to about −9° C. per minute, about −0.1 to about −8° C. per minute, about −0.1 to about −7° C. per minute, about −0.1 to about −6° C. per minute, about −0.1 to about −5° C. per minute, about −0.1 to about −4° C. per minute, about −0.1 to about −3° C. per minute, about −0.1 to about −2° C. per minute, about 0.1 to about −1° C. per minute, about 0.1 to about −0.5° C. per minute, about −1 to about −2° C. per minute, about −1 to about −3° C. per minute, about −1 to about −4° C. per minute, about −1 to about −5° C. per minute, about −1 to about −6° C. per minute, about −1 to about −7° C. per minute, about −1 to about −8° C. per minute, about −1 to about −9° C. per minute, about −1 to about −10° C. per minute, about −2 to about −3° C. per minute, about −2 to about −5° C. per minute, about −2 to about −7° C. per minute, about −2 to about −8° C. per minute, about −2 to about −20° C. per minute, about −4 to about −10° C. per minute, about −4° per minute to about −8° C. per minute, about −4 to about −6° C. per minute, about −6 to about −10° C. per minute, about −6 to about −9° C. per minute, about −6 to about −8° C. per minute, about −6 to about −7° C. per minute, about −7 to about −10° C. per minute, about −7 to about −9° C. per minute, about −7 to about −8° C. per minute, about −8 to about −9° C. per minute, about −9 to about −10° C. per minute, about −7 to about −30° C. per minute, about −10 to about −25° C. per minute, about −15 to about −25° C. per minute, about −20 to about −25° C. per minute, or about −20 to about −30° C. per minute. The preservation protocol may also be independent of cooling rate in some embodiments.
Once the samples to be preserved (e.g., cellular materials and/or tissues) are cooled to about −40° C. to −80° C. or lower by this continuous rate cooling, they may be transferred to liquid nitrogen or the vapor phase of liquid nitrogen for further cooling to the cryopreservation temperature, which is typically below the glass transition temperature of the freezing solution. The samples to be preserved (e.g., cellular materials and/or tissues) may be cooled to about −40° C. to about −75° C., about −45° C. to about −70° C., about −50° C. to about −60° C., about −55° C. to about −60° C., about −70° C. to about −80° C., about −75° C. to about −80° C., about −40° C. to about −45° C., about −40° C. to about −50° C., about −40° C. to about −60° C., about −50° C. to about −70° C., or about −50° C. to about −80° C. before further cooling to the cryopreservation temperature. However, it is anticipated that the outcome is independent of cooling rate because ice formation will not occur. The limiting factor for retention of cell viability will be the duration of cryoprotectant exposure at temperatures close to zero centigrade, the lower the temperature the less the risk of cytotoxic effects until storage temperatures are achieved at which no deterioration of viability is anticipated.
The cryoprotectant formulations supplemented with sugars (such as trehalose and or sucrose) have a reduced propensity for ice nucleation during exposure to temperatures above the glass transition temperature. Thus, cellular materials in these formulation will tolerate short term exposure to temperatures such as −80° C., for minutes or hours. The precise duration depending upon the cryoprotectant/sugar formulation. The duration tolerated at each temperature will depend upon the relative cytotoxicity of the cryoprotectant formulation employed at that temperature. Furthermore, it is anticipated that these cryoprotectant formulations can be used for storage of tissues, where cell viability is not desired (some heart valves, skin, tendons and peripheral nerve grafts for example), at temperatures ranging from liquid nitrogen to physiological temperatures below the denaturation temperature range of collagen (approximately 60° C.).
Some embodiments may comprise a stepwise cooling process, in which the temperature of the tissue is decreased to a first temperature in a first solution containing cryoprotectant at a first temperature between the glass transition temperature of the first solution and −20° C., then is further decreased to a second temperature in a second solution containing cryoprotectant at temperature between the glass transition temperature of the first solution and −20° C., and this process may be repeated with a third, fourth, fifth, sixth, seventh, etc., solution until the desired temperature is achieved.
In embodiments, the glass transition temperature of the first solution (such as a cryoprotectant formulation) may be in set at any desired level, such as, for example, in a range of from about −100° C. to about −140° C., such as about −110° C. to about −130° C., or −115° C. to about −130° C. In embodiments, the tissue may be cooled and subsequently stored at temperatures between the glass transition temperature and about −20° C., such as about −120° C. to about −20° C., such as between about −110° C. to about −30° C., or between about −90° C. and about −60° C.
After being immersed in an initial solution, the sample to be preserved (such as a cellular material or tissue) may be immersed in a solution containing cryoprotectant. The final cryoprotectant concentration may be reached in a stepwise cooling process in which the sample to be preserved (such as a cellular material or tissue) may be immersed in a first solution containing a first cryoprotectant concentration, then the tissue may be immersed in a second solution containing a second cryoprotectant concentration (which is higher than the first cryoprotectant concentration), and this process may be repeated with a third, fourth, fifth, sixth, seventh, etc., solution until the desired concentration is achieved. The cryoprotectant solution may contain any combination of cryoprotectants. In some embodiments, the final desired cryoprotectant concentration may be achieved at any suitable temperature that limits the growth of ice during cooling such that ice-induced damage does not occur, for example the final desired cryoprotectant concentration may be achieved at a temperature in the range of from 0° C. to about −30° C., such as about −5° C. to about −20° C., or about −7° C. to about −15° C., or −8° C. to about −12° C., or a temperature of about −10° C.
In embodiments, the sample to be preserved (such as a cellular material or tissue) may remain free from ice and/or free from ice-induced damage during the preservation protocol (e.g., the cooling protocol, storage, and warming protocol). For example, after completion of the cooling process, the sample to be preserved (such as a cellular material or tissue) may remain free from ice and/or free from ice-induced damage during the storage step/phase for a long period of time, such as a period of at least 3 days, or a period of at least 5 days, or a period of at least 7 days, or a period of at least 8 days.
In some embodiments, upon initiation of the cooling process, the sample to be preserved (such as a cellular material or tissue) may remain free from ice and/or free from ice-induced damage during the entire preservation protocol (i.e., during the cooling protocol, storage, and warming protocol), where the entire preservation protocol (e.g., the cooling protocol, storage step/phase, and warming protocol) has a duration in a range of from at least 3 days to up to about 3 months, or a duration in a range in a range of from at least 5 days up to about 2 months, or a duration in a range in a range of from at least 7 days up to about 1 month, or a duration in a range in a range of from at least 8 days up to about 21 days, or a duration in a range in a range of from at least 8 days up to about 14 days. Additionally, in embodiments, during such preservation protocols the sample to be preserved (such as a cellular material or tissue) will experience minimal cytotoxicity during the duration of the preservation protocol.
The warming protocol may involve a two-step warming procedure (such as that described by Campbell et al., Two stage method for thawing cryopreserved cells; see, for example, U.S. Pat. No. 6,596,531, the disclosure of which is hereby incorporated by reference in its entirety. In the two-step warming protocol, the cryopreserved cellular materials (cryopreserved at the cryopreservation temperature) may be removed from the storage freezer. The cryopreserved cellular materials are allowed to first slowly warm in a first environment in the first step of the two-step protocol. The environment is not required to undergo any special treatment or have any particular make-up, and any environment may be used. The environment may be a gaseous atmosphere, for example, air. To effect the slow warming of the first stage, the environment may be at a first warming temperature greater than the cryopreservation temperature. The first warming temperature may be below freezing temperature. For example, temperatures of −30° C. or, such as about −15° C. to about −30° C., about −20° C. to about −25° C., or about −20° to about −30° C. may be used. The advantage of warming in the first step to a sub-zero centigrade temperature is that the potential cytotoxic effects of the cryoprotectant formulation at warmer temperatures will be minimized.
The second step of the two-step warming procedure involves rewarming the cellular material rapidly in a second environment at a second warming temperature that is greater than the warming temperature used in the first warming step. The second warming temperature may be 32° C. or more, about 32° C. to about 50° C., about 35° C. to about 45° C., about 40° C. to about 50° C., about 45° C. to about 50° C., about 32° C. to about 40° C., about 35° C. to about 40° C., or about 37° C. Again, any suitable environment such as gas (air), liquid, or fluid bed may be used as the second environment. For example, a water or dimethylsulfoxide bath at the warm temperature may be used to effect this rapid rewarming. During this step dilution of the cryoprotectants can be initiated using warm diluent solutions that will also contribute to the warming step.
In some embodiments, the conventional heating methods that may be used to warm the samples include, for example, convection and microwave heating. Prior to the methodology of the present disclosure, conventional methodology including convection heating, which heats from the outer boundary, is effective for small vitrified samples but ineffective for large samples (e.g., having a volume greater than 5 mL) due to cytotoxicity and ice formation. In some embodiments, low radiofrequencies and inductive heating may be used to heat when combined with distributed biocompatible magnetic nanoparticles (mNPs). See, for example, U.S. Patent Application Publication No. 2016/0015025, the disclosure of which is hereby incorporated by reference in its entirety.
In embodiments, a majority or all of the cells of the sample (e.g., tissue or cellular material) to be preserved may remain viable after the preservation protocol as the majority or all of the cells of the sample will be exposed to minimal cytotoxicity. In other words, the methods of the present disclosure avoid the cytotoxicity of some conventional cryoprotectant solutions by avoiding exposure of the sample to be preserved to the increase of cytotoxicity of the cryoprotectant solution that occurs as the tissue (and solution) temperatures approaches 37° C. In embodiments, the methods of the present disclosure avoid exposing the sample to be preserved to any conditions and/or cryoprotectants (e.g., by exposure to the extreme conditions, such as severe osmotic stresses and/or chemical cytotoxicity) that may kill a majority or all of the cells (e.g., because of the increased level of cytotoxicity of the cryoprotectant solution at temperatures approaching 37° C.) of the tissue to be preserved. However, it should be noted that in embodiments where cell viability is not desired chemical toxicity or severe osmotic stresses may be employed to render the cellular materials essentially free of living cells.
In embodiments, the cryopreserved cellular materials preserved by the methods of the present disclosure may be put to any suitable use, including, for example, research or therapeutic uses. For example, regarding therapeutic uses, the cryopreserved cellular materials may be administered to a human or animal patient to treat or prevent a disease or condition such as aortic heart disease, degenerative joint disease, degenerative bone disease, colon or intestinal diseases, degenerative myelopathy, chronic renal failure disease, heart disease, intervertebral disc disease, corneal disease, spinal trauma and replacement of parts lost due to trauma, such as fingers, limb extremities, and faces.
The cryopreserved cellular materials can be administered to a patient in any suitable manner. In some embodiments, the cryopreserved cellular materials may be delivered topically to the patient (e.g. in the treatment of burns, wounds, or skin disorders). In some embodiments, the cryopreserved cellular materials may be delivered to a local implant site within a patient. Any of these or any combination of these modes of administration may be used in the treatment of a patient.
In a first aspect, the present disclosure relates to a method for preserving living large volume cellular material, comprising: exposing the cellular material to a cryoprotectant formulation/solution/medium containing at least one sugar, subjecting the cellular material to a preservation protocol in which ice-induced damage to the cellular material does not occur, and obtaining a cryopreserved cellular material. In a second aspect the method of the first aspect may be a method in which the cellular material has a volume greater than 4 mL. In a third aspect, the method of any of the above aspects may be a method in which the volume of the cellular material is greater than 10 mL. In a fourth aspect, the method of any of the above aspects may be a method in which wherein the cellular material is ice-free for at least 7 days upon subjecting the cellular material to the preservation protocol. In a fifth aspect, the method of any of the above aspects may be a method in which the preservation protocol includes a vitrification strategy that limits the growth of ice during cooling and warming such that ice-induced damage does not occur during the preservation protocol. In a sixth aspect, the method of any of the above aspects may be a method in which the at least one sugar is a disaccharide. In a seventh aspect, the method of any of the above aspects may be a method in which the at least one sugar is selected from the group consisting of trehalose and sucrose. In an eighth aspect, the method of any of the above aspects may be a method in which subjecting the cellular material to a preservation protocol comprises: stepwise cryoprotectant addition to the cryoprotectant formulation/solution/medium to achieve a final cryoprotectant formulation/solution/medium with a cryoprotectant concentration and/or at least one sugar concentration effective to avoid ice-induced damage to the cellular material, such as where the last cryoprotectant addition step that achieves the final cryoprotectant formulation/solution/medium is performed while the cryoprotectant formulation/solution/medium is being maintained at a temperature of about −10° C. In a ninth aspect, the method of any of the above aspects may be a method in which subjecting the cellular material to a preservation protocol comprises: immersing the cellular material in a series of solutions having increasing concentrations of the cryoprotectant and/or increasing concentrations of the at least one sugar to achieve immersion in a final solution with a cryoprotectant concentration and/or at least one sugar concentration effective to avoid ice-induced damage to the cellular material. In a tenth aspect, the method of any of the above aspects may be a method in which the cellular material is incubated in a cryoprotectant formulation, the cryoprotectant formulation containing from 0.1 to 1 M of the at least one sugar. In a eleventh aspect, the method of any of the above aspects may be a method in which the preservation protocol further comprises cooling the cellular material in a cryoprotectant formulation containing at least one sugar, such as where a further cryoprotectant is added to the cryoprotectant formulation prior or during cooling, the further cryoprotectant being different from the sugar, such as where the further cryoprotectant is selected from the group consisting of acetamide, agarose, alginate, alanine, albumin, ammonium acetate, anti-freeze proteins, butanediol, chondroitin sulfate, chloroform, choline, cyclohexanediols, cyclohexanediones, cyclohexanetriols, dextrans, diethylene glycol, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, erythritol, ethanol, ethylene glycol, ethylene glycol monomethyl ether, formamide, glucose, glycerol, glycerophosphate, glyceryl monoacetate, glycine, glycoproteins, hydroxyethyl starch, ice recrystalization inhibitors, inositol, lactose, magnesium chloride, magnesium sulfate, maltose, mannitol, mannose, methanol, methoxy propanediol, methyl acetamide, methyl formamide, methyl ureas, methyl glucose, methyl glycerol, phenol, pluronic polyols, polyethylene glycol, polyvinylpyrrolidone, proline, propanediol, pyridine N-oxide, raffinose, ribose, serine, sodium bromide, sodium chloride, sodium iodide, sodium nitrate, sodium nitrite, sodium sulfate, sorbitol, sucrose, trehalose, triethylene glycol, trimethylamine acetate, urea, valine and xylose, and, if desired, the cryoprotectant formulation may contain the further cryoprotectant at a concentration of from 0.1 to 13.0 M. In a twelfth aspect, the method of any of the above aspects may be a method in which said cellular material is a natural or man-made tissue or organ. In a thirteenth aspect, the method of any of the above aspects may be a method in which the cellular material is selected from the group consisting of mammalian organs and mammalian tissues. In a fourteenth aspect, the method of any of the above aspects may be a method in which the cellular material is selected from the group consisting of human organs and human tissues. In a fifteenth aspect, the method of any of the above aspects may be a method in which a cell viability (%) of the cellular material after completion of the preservation protocol is at least 60%. In sixteenth aspect, the method of any of the above aspects may be a method in which the medium does not contain DMSO. In a seventeenth aspect, the method of any of the above aspects may be a method in which the medium does not contain formamide. In an eighteenth aspect, the method of any of the above aspects may be a method in which wherein the medium does not contain propylene glycol. In a nineteenth aspect, the method of any of the above aspects may be a method in which the medium does not contain DMSO, formamide and/or propylene glycol.
In a further aspect, the present disclosure also relates to cryopreserved cellular material obtained by exposure of a living large volume cellular material to a cryoprotectant formulation containing at least one sugar, and optionally a further cryoprotectant, during a preservation protocol; wherein a cell viability (%) of the cellular material after the preservation protocol is at least 50%, and the cellular material has a volume greater than 4 mL, such cryopreserved cellular material may be obtained, for example, by a method of any of the above aspects, and may be administered to a patient.
In a further aspect, the present disclosure also relates to a method for increasing production yield of viable cryopreserved cellular material, comprising: exposure of a large volume cellular material to a cryoprotectant, the cryoprotectant containing at least one sugar, for a predetermined amount of time to form a cryopreservation formulation; subjecting the cryopreservation formulation to a preservation protocol comprising cryopreservation at a cryopreservation temperature of about −80° C. or lower; and after completion of the preservation protocol, recovering the cryopreserved cellular material; wherein a cell viability (%) of the recovered cryopreserved cellular material is at least 60% and the cellular material has a volume greater than 4 mL. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is selected from the group consisting of organs and tissues. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is selected from the group consisting of mammalian organs and mammalian tissues. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is selected from the group consisting of human organs and human tissues. In a further aspect, the method of any of the above aspects may be a method in which wherein the cell viability (%) of the recovered cryopreserved cellular material is at least 80%.
In a further aspect, the present disclosure also relates to a method for storing living large volume cellular material in which cellular viability is not desired, comprising: exposing the cellular material to a cryoprotectant formulation/solution/medium containing at least one sugar, subjecting the cellular material to a preservation protocol, which comprises storing the cellular material at temperatures ranging from the temperature of liquid nitrogen to physiological temperatures below the denaturation temperature range of collagen, and obtaining a cryopreserved cellular material. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is selected from the group consisting of heart valves, skin, tendons and peripheral nerve grafts. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is obtained from a mammal. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is obtained from a human. In a further aspect, the method of any of the above aspects may be a method in which the cellular material is stored at temperatures ranging from about −190° C. to about 60° C. In a further aspect, the method of any of the above aspects may be a method in which the cell viability (%) of the recovered cryopreserved cellular material is 0%.
The foregoing is further illustrated by reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the present disclosure.
FIG. 1
In the following ice-free cryopreservation formulation supplementation experiments, disaccharides (trehalose and sucrose) are added to various vitrification formulations (VS49, DP6, and VS55) in the amounts shown in and compared to a solution (without trehalose and/or sucrose) to access the effectiveness at inhibiting ice formation in various tissues.
FIG. 1
In particular, the shows that there are significant increases in tissue viability induced by trehalose and sucrose supplementation of vitrification formulations. Data shown in % of control VS55 results performed with the final cryoprotectant concentration added at 4° C., N=6, *p<0.05 by ANOVA or #T-test compared with no additive controls.
In this experiment, addition of either 600 mM trehalose or sucrose to VS49, DP6 and VS55 formulations was compared. The tissues were vitrified in 4 mL of solution. Trehalose supplementation increased leaflet viability in VS49 and VS55. Sucrose supplementation increased leaflet viability in all three formulations. These differences were significantly different, p<0.05 by ANOVA or T-test. DP6 consistently had the best muscle preservation in all treatment groups but did not achieve statistical significance in this experiment, however, this outcome suggested that cardiac muscle is more tolerant of ice formation than the other tissue types (leaflet and artery) and that formamide might be causing some cytotoxicity. This led to plans to test DP6 with sugars more thoroughly in later experiments. Repetitive experiments were performed using sucrose supplemented VS55 and obtained outcomes similar to those for supplemented VS55 shown here.
Methods
Heart Valve and Blood Vessel Procurement:
FIG. 1
Bonafide excess heart valves or blood vessels were obtained from animals employed in other IACUC approved research studies or from a food processing plant post-mortem. The tissues were dissected, rinsed and placed in sterile cups with ice-cold tissue culture medium containing antibiotics overnight and then allocated for in vitro studies. The heart valve tissues in each consisted of a piece of tissue consisting of pulmonary artery, leaflet and cardiac muscle. They were separated and individually assayed for viability using an assay that assesses metabolic activity that is described below.
Vitrification Method:
Tissues were gradually infiltrated with VS55 consisting of 3.10 M DMSO, 3.10M formamide, and 2.21 M propylene glycol in Euro-Collins solution at 4° C. using methods previously described for blood vessel vitrification, a dilution of VS55 to VS49 or DP6 consisting of 3 M DMSO, 3 M propylene glycol. Precooled dilute vitrification solutions (4° C.) are added in five sequential 15-min steps of increasing concentration on ice. The last cryoprotectant concentration with mNPs was added in a final sixth addition step in either precooled −10° C. or 4° C. full strength vitrification solution and kept in a −10° C. bath for 15 minutes or at 4° C. on ice in plastic tubes. The samples were then cooled in two steps, first rapid cooling to −100° C. by placing in a precooled 2-methylbutane bath at −135° C. and then by transfer to vapor phase nitrogen storage for slower cooling to below −135° C. Finally, the samples were stored below −130° C. in vapor phase nitrogen for at least 24 h before testing.
Warming:
Warming was performed by either convection warming or nanowarming. Convection warming is a two-stage process including slow warming to −100° C. and then as rapid as possible warming to melting. The slow warming rate is created by taking the sample to the top of the −135° C. freezer and the control warming rate is generated by placing the plastic container in the mixture of 30% DMSO/H2O at room temperature. After rewarming, the vitrification solution was removed in a stepwise manner on ice to keep the tissues cold and minimize cytotoxicity due to the presence of residual cryoprotectants.
Viability Assessment:
Metabolic Activity—An alamarBlue™ assay will be used to evaluate the metabolic activity of control and treated tissue samples. Tissues were incubated in 2 ml of DMEM+10% FBS culture medium for one hour to equilibrate followed by the addition of 20% AlamarBlue under standard cell culture conditions for 3 hours. AlamarBlue is a non-toxic fluorometric indicator based on detection of metabolic activity. Fluorescence was measured at an excitation wavelength of 544 nm and an emission wavelength of 590 nm. This evaluation was performed after rewarming (day 0) to demonstrate cell viability. Control and experimental tissues were dried at the end of each experiment, weighed, and results expressed as relative fluorescence units (RFU)/mg tissue dry weight.
The results of these experiments indicate that 0.6M of trehalose or sucrose prevents visible ice formation in both DP6 and VS49 formulations and increases post-vitrification viability in these solutions (DP6, VS49 and VS55) with leaflet viability demonstrating 2-3 fold increases. Notably, the VS49 or DP6 formulations are not effective at controlling ice formation using conventional convection warming, described in U.S. Patent Application Publication No. 2016/0015025. However, no ice formation was observed in the presence of either trehalose or sucrose during cooling and rewarming in these experiments with nanowarming.
FIG. 2
A further series of experiments was conducted with a 0.5M sucrose DP6 formulation with blood vessels using a device called a Cryomacroscope (used to visualize events during cryopreservation). The results are shown in (Contractile responses of fresh and vitrified rabbit carotid arteries, (top) Norepinephrine and Phenylephrine (lower) dose response curves).
FIG. 2
The above study was performed on 4 mL samples using convection warming without nanowarming. Preparation, vitrification and rewarming was performed as previously indicated. The blood vessels were cut into 2 mm rings for testing. The artery samples preserved with DP6 supplemented with 0.5M sucrose yielded greater than 90% viability by alamarBlue using methods described above in the first set of experiments (data not shown). The samples were also checked for smooth muscle function and excellent responses to two contractile drugs were observed, as seen in .
Methods
Blood Vessel Physiology:
Two-mm rings of fresh and ice free cryopreserved blood vessels were prepared for vascular physiology studies to document the function of rabbit femoral artery rings in a Radnoti organ bath system using a panel of constrictive drugs. Isometric contractile tensions were measured after addition of increasing concentrations of each drug using methods previously employed. The physiology results were expressed as grams tension/mg tissue dry weight.
FIG. 3
FIG. 4
Pig femoral artery cryopreservation was performed in VS55±0.6M sucrose at 4 and 10 mL cellular material volumes. Significant preservation was demonstrated in all formulations at 4 mL, whereas at 10 mL the VS55 without sucrose demonstrated low viability. In contrast, the sucrose supplemented formulations demonstrated preservation of viability by both the alamarBlue (; porcine femoral artery comparison of 4 and 10 mL samples of VS55±0.6M sucrose, where tissue rings were assessed using the alamarBlue metabolic assay) and physiology assays (; porcine smooth muscle relaxation induced by sodium nitroprusside after pre-contraction, where VS55 alone works well for a 4 mL sample, but fails at 10 mL sample, and sucrose supplementation preserves the functionality (relaxation) at 10 mL volume sample) employed. These results demonstrate that disaccharide supplementation results in tissue survival at large volumes (e.g., 10 mL volume) where unsupplemented VS55 solution (i.e., no disaccharide added) fails (due to ice formation with loss of tissue viability). Similar results were obtained for two contractile drugs.
The methods used here were the same as in the earlier examples using convection warming.
FIG. 5
Rabbit thoracic aorta samples were vitrified in 30 mL volumes of VS55 with or without 0.6M sucrose with or without nanoparticles for comparison of convection versus nanowarming. The results are set forth in (30 mL rabbit thoracic aorta results demonstrating improved outcomes with sucrose supplementation using either convection (middle bar) or nanowarming (far right bar)).
The methods were as described for earlier examples regarding addition of cryoprotectants and cooling. However, in this experiment we compared convection warming and nanowarming. Nanowarming was performed after at least 24 h at −130° C. The samples were vitrified with 7.69 mg/ml Fe nanoparticles (EMG-308, Ferrotec) and the samples were inserted into the coil of an inductive heater for rewarming. More specifically we employed a 6.0 kW terminal, 150-400 kHz, EASYHEAT 5060LI solid state induction power supply with a remote work head and custom multi-turn helical coil with 6-7 turns to create a 35 kA/m magnetic field in the center. Good results (just under 50% viability) were achieved with either convection heating or nanowarming (conducted as described in U.S. Patent Application Publication No. 2016/0015025) as long as sucrose was present in the vitrification solution. VS55 without sucrose performed poorly due to ice formation that was observed in the rewarming process.
FIG. 6A
FIG. 6B
In this series of experiments (the results of which are illustrated in and ), the viability of heart valve tissues in which intact heart valves were preserved in 30 mL cryoprotectant volumes and rewarmed by either convection or nanowarming methods are compared.
FIG. 1
FIG. 6B
Three tissue samples were taken from each leaflet and associated pulmonary artery and cardiac muscle for a total of 9 samples of each tissue type from each valve. The ice-free vitrification and rewarming procedures were performed as previously described except that a stepwise addition of DP6 was employed with sucrose or trehalose in the last step. In some cases the DP6+sugar step was followed by immersion in VS55+sugar at −10 C followed by immediate vitrification. It should be noted that in this experiment, as also observed in , DP6 alone results in good cardiac muscle cell viability in spite of the freezing that occurs with DP6, however in this experiment two cryopreservation groups achieved control values (, bottom) after addition of sucrose.
FIG. 6A
FIG. 6B
FIG. 6A
FIG. 6B
With respect to the data shown in and , individual porcine heart valves were loaded with DP6 and then cryopreserved in either DP6 alone, DP6 with either 0.6M trehalose, 0.6M sucrose or a mixture of 0.3M sucrose and 0.3M trehalose, or transferred at the last moment from DP6 with sugar to VS55 with the same sugar. The total volume of tissue and solution was at least 30 mLs. The results from top to bottom are for leaflet, then conduit and finally cardiac muscle. The results in are for convection warming and the results in are after nanowarming (n=9). The results are expressed as the mean±1 standard error in percent of untreated control heart valve tissues.
These results demonstrate that DP6 (3.0M dimethylsulfoxide plus 3.0M in EuroCollins Solution) with 0.6M sucrose results in excellent preservation of all three tissue components in heart valves, particularly after nanowarming. Several other treatment groups including loading with DP6 and then transferring to VS55 with either sucrose or trehalose also improved viability after either convection warming or nanowarming. There was a tendency for treatment groups with sucrose to be better than with trehalose.
FIGS. 1-6
FIG. 6
FIG. 7
The above results () combine to demonstrate that the use of sugars, such as disaccharides, e.g., sucrose and trehalose, with VS55 and more dilute cryoprotectant formulations (DP6, ) result in unexpected improved outcomes of ice-free vitrification. These sugars help during both convection and rapid warming with inductive heating of magnetic nanoparticles but it appears that high sucrose and trehalose formulations do not need rapid warming ().
The use of sugars, such as disaccharides, e.g., sucrose and trehalose, permits preservation of large volume samples and slow warming with less risk of ice formation and increased post-rewarming viability.
FIG. 7
Storage of VS55 with a range of trehalose and sucrose concentrations demonstrates freedom from ice formation at −80 C for 1 week. In this experiment 30 mL samples of VS55 with increasing concentrations of sugars were placed in 50 mL plastic tubes and stored in a −80 C mechanical storage freezer for 7 days. The tubes were checked daily for ice formation. The tubes demonstrated ice in a sugar concentration dependent manner with the highest concentrations (such as in a range of from 0.5-0.6M) not showing ice formation after 8 days, shows the tubes after 1 and 7 days of storage. After one day 0.4 to 0.6M trehalose and 0.5-0.6M sucrose were free of ice, while after 7 days 0.5-0.6M trehalose and 0.6M sucrose groups were free of ice. Lower concentrations of these sugars may still be used for ice-free vitrification but more rapid cooling and warming will be needed because the risk of ice formation will be greater and nanowarming rather than convection warming may be needed.
FIG. 7
Specifically, is photograph illustrating the ice formation in VS55 supplemented with sugars at −80° C.: Top left: VS55 with 0-0.6M sucrose at 24 hours; Top right: VS55 with 0-0.6M trehalose at 24 hours. At this time point the VS55 supplemented with either 0-0.4M sucrose or 0-0.6M trehalose demonstrated ice (white) formation. Higher concentrations were clear without ice. Bottom left: VS55 with 0-0.6M sucrose at 7 days; and Bottom right: VS55 with 0-0.6M trehalose at 7 days. After a week at −80° C. the highest concentrations of sugars are still free of ice.
Incorporation of sugars, such as disaccharides, e.g., sucrose and trehalose, in to such ice-free vitrification formulations permits relatively slow cooling and warming rates (such as on the order of hours or days) to be used without ice formation and loss of cell/tissue viability. Additionally, both convection warming and nanowarming methods may be used in the methods of the present disclosure with the formulations described herein. Rapid warming methods, such as nanowarming methods may still be desired because at rapid warming rates there is less opportunity for cryoprotectant exposure induced cytotoxicity. These observations also suggest that other cryoprotectant formulations with sugars can be developed that have even less risk of cryoprotectant cytotoxicity.
All literature and patent references cited throughout the disclosure are incorporated by reference in their entireties. Although the preceding description has been described herein with reference to particular means, materials and embodiments, it is not intended to be limited to the particulars disclosed herein; rather, it extends to all functionally equivalent structures, methods and uses, such as are within the scope of the appended claims. Furthermore, although only a few example embodiments have been described in detail above, those skilled in the art will readily appreciate that many modifications are possible in the example embodiments without materially departing from the disclosure of ICE-FREE PRESERVATION OF LARGE VOLUME TISSUE SAMPLES FOR VIABLE, FUNCTIONAL TISSUE BANKING. Accordingly, all such modifications are intended to be included within the scope of this disclosure as defined in the following claims. In the claims, means-plus-function clauses are intended to cover the structures described herein as performing the recited function and not only structural equivalents, but also equivalent structures. Thus, although a nail and a screw may not be structural equivalents in that a nail employs a cylindrical surface to secure wooden parts together, whereas a screw employs a helical surface, in the environment of fastening wooden parts, a nail and a screw may be equivalent structures. It is the express intention of the applicant not to invoke 35 U.S.C. § 112(f) for any limitations of any of the claims herein, except for those in which the claim expressly uses the words ‘means for’ together with an associated function.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1
is an illustration of the data obtained with respect to ice-free cryopreservation formulation supplementation experiments in which disaccharides (trehalose and sucrose) are added to various vitrification formulations (VS49, DP6, and VS55).
FIG. 2
is an illustration of the data obtained with respect to contractile responses of fresh and vitrified rabbit carotid arteries, (top) Norepinephrine and Phenylephrine (lower) dose response curves.
FIG. 3
is an illustration of the data obtained with respect to porcine femoral artery comparison of 4 and 10 mL samples of VS55±0.6M sucrose (alamarBlue assay).
FIG. 4
is an illustration of the data obtained with respect to porcine smooth muscle relaxation induced by sodium nitroprusside after pre-contraction (physiology assay).
FIG. 5
is an illustration of the data obtained with respect to rabbit thoracic aorta samples that were vitrified in 30 mL volumes of VS55 with or without 0.6M sucrose with or without nanoparticles for comparison of convection versus nanowarming.
FIGS. 6A and 6B
is an illustration of the data obtained with respect to a comparison of the viability of heart valve tissues in which intact heart valves were preserved in 30 mL cryoprotectant volumes and rewarmed by either convection or nanowarming methods.
FIG. 7
is an photograph showing the tubes after 1 and 7 days of storage and ice formation in VS55 supplemented with sugars at −80° C. (Top left: VS55 with 0-0.6M sucrose at 24 hours; Top right: VS55 with 0-0.6M trehalose at 24 hours; Bottom left: VS55 with 0-0.6M sucrose at 7 days; and Bottom right: VS55 with 0-0.6M trehalose at 7 days). | |
Advances in mixed reality and discoveries in perception science offer exciting possibilities of matching human perceptual strengths with vast distributed sensing, AI, and memory resources. In this sphere, audio-based techniques stand to lead the way, both with recent advances in non-occluding, head-tracking headphones and increasing evidence for ambient/peripheral stimuli influencing human mood, attention, and cognition.
In this talk, I present my doctoral research work moving this vision from the lab into a real-world testbed, focusing on a large-scale environmental sensing system, massive environmental audio dataset, and audio AR wearable devices I developed. In our 577-acre wetlands testbed, users are able to superimpose the past onto the present, observe distant effects of their actions, and explore events from different perspectives. An AI system perceiving sensor data and audio alongside human users can subtly direct user attention by weighting stimuli without explicitly interrupting. In studies, I found that certain digitally-produced illusions, caused by the melding of the digital sense media and the physical world, would resolve into qualitatively new perceptual experiences. Through HearThere, a bone-conducting AR system many users could not separate from their natural hearing, intuited discoveries ranged from self-evident seasonal variations to the intricate discovery of wildlife migration patterns.
Finally, I will touch on ongoing research here in Paris. We aim to create a human-in-the-loop feedback system with sensing and concatenative synthesis on a large corpus of field recordings, applied to sleep staging and meditation/mind-wandering. In its artistic format, this work was recently presented in the form of a live performance system at NIME 2021, and is due at Ars Electronica and other venues later this year. Through this talk and in conversation, I hope to intersect a broad array of IRCAM’s projects and aims: from auditory perception to concatenative synthesis, immersive and spatial audio; ability and access; and broad opportunities at the intersection of audio and human-centered AI. | https://medias.ircam.fr/x981600 |
Effects of Variety and Grape Berry Condition of Vitis vinifera on Preference Behavior and Performance of Drosophila suzukii.
Drosophila suzukii is an invasive fruit pest and represents a potential economic threat to viticulture. After first observations of D. suzukii in Europe in 2008, research mainly focused on the evaluation of the host range and infestation risk for fruit and berry crops. However, the risk assessment of D. suzukii in viticulture has only recently started. Understanding the factors influencing preferences of D. suzukii for host species and varieties as well as offspring performance is essential to improve management strategies. We investigated the field infestation of different grape varieties across Baden-Wuerttemberg, southwestern Germany, between 2015 and 2018. Moreover, we performed dual-choice assays in the laboratory to investigate whether adults show preferences for certain varieties and whether offspring performance differs between varieties. Furthermore, we studied the impact of grape damage on choice behavior. Field monitoring revealed that D. suzukii show preferences for red varieties, whereas almost no oviposition occurred in white varieties. The results of dual-choice assays confirmed that D. suzukii preference and performance are influenced by grape variety and that flies preferred damaged over intact "Pinot Noir", "Pinot Blanc", and "Müller-Thurgau" berries. Overall, these findings may have important implications for winegrowers regarding cultivated varieties, grape health, and insecticide reduction.
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Conventional spindle motor systems (e.g., including a spindle motor controller) are closed-looped systems that use feedback sources to regulate variations in the velocity of a spindle motor as it tracks a target velocity. The spindle motor systems can be used, for example, in hard disk drives. Servo sector timing marks and back-electromotive-force (BEMF) timing marks from spindle motor windings can be used as feedback sources for control loops (e.g., a frequency-locked-loop (FLL), a phase-locked-loop (PLL)) associated with the spindle motor controller. In conventional systems, servo sector timing marks are not available during a self-servo-write (SSW) process because the servo sector timing marks are not yet written. Therefore, during SSW processes feedback from BEMF pulses can be used to determine spindle motor speed characteristics.
Conventional control loops include low frequency electrical system poles. The low frequency electrical system poles limit the bandwidth of the control loop. Low bandwidth can result in low frequency non-repeatable errors and a slow transient response. A user might find it difficult to use the conventional control loops for high precision applications, such as accurate writing of servo marks on blank disk media in a SSW process. On the other hand, high bandwidth is particularly important for smaller form factor hard disk drives due to a smaller disk diameter and a resultant lower inertia of the rotating disk.
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5 edition of Waves and optics simulations found in the catalog.
Published
1995
by John Wiley in New York
.
Written in English
Edition Notes
|Statement||the Consortium for Upper-Level Physics Software ; Wolfgang Christian ... [et al.].|
|Contributions||Christian, Wolfgang.|
|Classifications|
|LC Classifications||QC157 .W385 1995|
|The Physical Object|
|Pagination||xiii, 257 p. :|
|Number of Pages||257|
|ID Numbers|
|Open Library||OL792257M|
|ISBN 10||0471548871|
|LC Control Number||95024813|
COVID Resources. Reliable information about the coronavirus (COVID) is available from the World Health Organization (current situation, international travel).Numerous and frequently-updated resource results are available from this ’s WebJunction has pulled together information and resources to assist library staff as they consider how to handle coronavirus. HTML5 Simulations. Updated 4/3/ - simulations of mine plus 4 others Beyond physics. Waves. A transverse wave; A longitudinal wave; A longitudinal wave on a spring; A wave movie and a graph; Geometrical Optics - Refraction and lenses.
Browse, download and run Java simulations on a wide range of topics. Learn to make your own simulations using Easy Java Simulations (Ejs) Physlet Physics. Run ready-made simple explorations in mechanics, fluids, waves, thermodynamics, electromagnetism, circuits and optics. Create your own simulations. Geogebra: Download the graphing calculator. Part II: Optics 1. Introduction to waves optics 2. Approximations of geometrical optics: ray model of light and analysis of the formation of images by assuming the light to travel in straight – line paths or rays. 3. Fermat’s principle: statement, derivation of the laws reflection and refraction; total internal reflection and applications. Size: KB.
The Physics Classroom Tutorial presents physics concepts and principles in an easy-to-understand language. Conceptual ideas develop logically and sequentially, ultimately leading into the mathematics of the topics. Each lesson includes informative graphics, occasional animations and videos, and Check Your Understanding sections that allow the user to practice what is taught. Fourier-optics course. This is why AFIT has separate courses on Fourier optics and wave-optics simulations. This book is intended for graduate students in programs like physics, electrical engineering, electro-optics, or optical science. The book gives all of the relevant equations from Fourier optics, but to fully understand and appreciate the.
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The Simulations being developed are: Astrophysics, Classical Mechanics, Electricity & Magnetism, Modern Physics, Nuclear and Particle Physics, Quantum Mechanics, Solid State, Thermal and Statistical, and Wave and : $ This is a direct link to PhET's 24 simulations relating to light, optics, and radiation.
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Whitham's extension of geometrical optics to nonlinear diffraction is applied to solitary waves of reference amplitudea 0 in water of uniform depthd 0 on the hypotheses thata 0≪d 0 and that the.
Oscillations, Waves and Optics book (rev) 6. OSCILLATIONS To find the velocity, we take the time derivative of the displacement, v = d dt File Size: 1MB. Try the new Google Books.
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There are two books by Eugene Hecht. The older one was edited in the Schaum collection, with the typical Schaum style: just the minimum theoretical notes, followed by tons of solved exercises.
This one is probably what you Waves and optics simulations book looking for. Another question is the book referenced above, by Hecht and Zajac. Workshop Tutorials for Biological and Environmental Physics WR2B: Waves. Qualitative Questions: 1. Sound is a longitudinal wave. The diagram below shows air particles, A to M, in their equilibrium positions in the top line.
The lower line shows the particles as a sound wave moves through the air. In optics, it is often convenient to represent electromagnetic wave phenomena as a superpo-sition of sinusoidal functions having the form Acos(x+), where xrepresents a variable, and Aand represent parameters.
The sine function is intrinsically present in this formula through the identity cos(x+) = cosxcos sinxsin (). The Simple Wave Simulator Interactive is shown in the iFrame below. There is a small hot spot in the top-left corner. Clicking/tapping the hot spot opens the Interactive in full-screen mode.
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Study Guide and Review Waves and Optics 41 Advanced Placement Physics Waves and Optics Energy: E Waves transport energy.
Vibration / oscillation: Something must be vibrating / oscillating in order to create a wave. Medium: Waves must travel in a medium with one important exception.
Electromagnetic waves are the only type of wave that do not require a medium at Size: KB. Waves and Optics Simulations The Consortium for Upper-Level Physics Software Wolfgang Christian, Andrew Antonelli, and Susan Fischer Department of Physics, Davidson College, Davidson, North Carolina Robin A.
Giles Department of Physics and Astronomy, Brandon University, Brandon, Manitoba, Canada Brian W. James. Geometrical Optics - Snell's law, total internal reflection, and examples; Imaging, the thin lens formula, and examples of optical instruments; Oscillations and Waves - Oscillations and simple harmonic motion; travelling waves; Doppler effect; linear superposition and beats; reflections; standing waves.
Books - Oscillation and Waves. For questions related to oscillations and waves you should, first of all, go through NCERT with giving attention to examples.
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Topics include wave properties, wave interference, standing waves, mirrors, lenses and refraction, diffraction, oscillators and. Numerical Simulation of Optical Wave Propagation is solely dedicated to wave-optics simulations. The book discusses digital Fourier transforms (FT), FT-based operations, multiple methods of wave-optics simulations, sampling requirements, and simulations in atmospheric turbulence.
This book will benefit optical scientists and engineers at all levels as a guide for FT-based data analysis, imaging system analysis, and wave-optics simulations. FREE DOWNLOAD!This book contains fundamentals of oscillations and waves and properties of electromagnetic waves.
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Dc pandey electricity and magnetism pdf. Best optics book for jee, jee mains, jee advanced. Optics Lecture Notes by Michigan State University.
This lecture note covers following topics: Nature of Light, Geometrical Optics, Optical Instrumentation, Dispersion, Prisms, and Aberrations, Wave Equations, EM Waves, Polarization, Fresnel Equations, Production of Polarized Light, Superposition of Waves Interference of Light, Coherence, Fraunhofer Diffraction, Fourier Optics, Characteristics.
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Math Tutorials: Finding the Mean, Median.wave simulations. However, with the Wave Optics Module you can do time-harmonic simulations of domains that are much larger than the wavelength. This situation is typical for optical phenomena, components and systems.
Due to the relatively weakFile Size: 1MB. Plus, Scattering of Electromagnetic Waves contains detailed discussions of both analytical and numerical methods, including cutting-edge techniques for the recovery of earth/land parametric information. The three volumes are entitled respectively Theories and Applications, Numerical Simulation, and Advanced Topics. | https://buwykubefonebopoc.gama-uk.com/waves-and-optics-simulations-book-17180wt.php |
Keeping up with customer demand and staying ahead of the competition requires fast releases and efficient code. This is where DevOps comes into play. Where DevOps is the practice, mindset, and culture of combining software development (i.e. Dev) and IT operations (i.e. Ops) to accelerate the development lifecycle and provide continuous delivery without compromising quality.
By focusing on applying practices that promote and nurture collaboration and communication, DevOps enables the building, testing, and releasing of applications faster, more frequently, and more reliably than ever, transforming traditional approaches to software development.
The actual set of practices that comprise the DevOps methodology is the DevOps pipeline. In this article, we’re going to be taking a closer look at what this pipeline actually is, what are its objectives, components, phases, and more.
What is a DevOps pipeline?
A DevOps pipeline is the set of tools, flows, and automated processes that enable teams to effectively and efficiently leverage various technologies in building and deploying software.
The primary objective of the pipeline is to keep the software development process well focused and continually organized.
The 6 components of a DevOps pipeline
The goal of the DevOps pipeline – that is, delivering clean, secure, and bug-free code to production, fast and frequently, is achieved through the pipeline’s main components, which include the following:
Continuous integration is the method of merging small pieces of code from multiple developers into a shared code repository as often as possible. This enables the automatic testing of code without having to wait for other team members to contribute their own piece.
By eliminating this wait, continuous integration also eliminates the risk of integration conflicts and, consequently, the deployment of bad code.
1. Continuous delivery
Encourages developers to release code to production incrementally. Any change made to an application is automatically tested for bugs and uploaded to a repository, from where it can be deployed to production by the operations team.
Through such an approach to releasing code, troubleshooting becomes much easier when compared with attempting to do so on all the changes at once.
2. Continuous deployment
Similar to continuous delivery, but differs in that it is all about automation. With continuous deployment, code updates are automatically released from the repository to end-users in live production without manual intervention.
3. Continuous testing
CT is about running automated tests at every stage of development, as often as possible. This enables teams to detect issues and any risks that may be involved before the code reaches production.
4. Continuous operations
Enables maximum availability of apps and environments. This approach prevents availability issues and downtime during the release process and assures that the constant release of code updates, bug fixes, and patches are transparent to users.
5. Continuous monitoring
(also sometimes called continuous control) enables DevOps teams to observe and detect security threats and compliance issues during each phase of development lifecycle. It is also leveraged by the services team in the production environment to confirm that applications are on track and are doing what they’re supposed to be doing.
6. Continuous feedback
An essential component of the DevOps pipeline, and involves evaluating the effect of releases on the user experience and reporting findings to the team charged with improving future releases.
The 6 phases of a DevOps pipeline
While DevOps teams often add or remove certain phases of the pipeline as based on specific workflows, the four that are included in almost every pipeline are develop, build, test, and deploy, with many others also including plan and monitor.
1. Plan
For planning the full workflow before anyone starts to code. This includes creating the development roadmap for guiding the team through the process, gathering feedback, and breaking down the workflow to specific tasks that are executed in sprints, which are typically done every two weeks.
2. Develop
This is when the coding starts, which should follow pre-defined standards to ensure uniformity. This makes it easier for other team members to understand their colleagues’ code.
3. Build
A crucial phase as it enables developers to detect issues and assure that only error-free code makes it down the pipeline. With this phase the team runs automated tests and if a problem with the code is detected, the build fails and the relevant developer is alerted.
4. Test
Happens only when the build passes, and entails running both manual and automated tests for further validating code integrity.
5. Deploy
At this stage, the code is ready to go to production. If only small changes were made to the code about to be deployed, then the process is automated. If, however, a major change has occurred, the code will first be deployed to a production-like environment for monitoring code behavior before it goes live.
6. Monitor
This is the final stage in the DevOps pipeline, which calls for teams to make sure that the infrastructure, systems, and applications are all running smoothly.
The 5 pillars of the DevOps pipeline
Now that we know what the components and stages of the DevOps pipeline are, we need to understand what are the main tools and services for optimal execution.
- The CI/CD environment which is where you will store the source code. The most popular repository is GitHub, with GitLab and BitBucket also serving as worthy alternatives. And a recommended CI/CD tool is the open source, Java-based Jenkins, which is considered to be the de-facto standard.
- Source control management when integrated with the CI/CD tool helps developers avoid merge conflicts as they share code modifications. Git is considered to be the standard, with other open source options including Subversion, Vesta, and Mercurial.
- Build server and automation tool: with Jenkinsand Travis-CI being the most popular. Jenkins is open-source (as noted) and free, while Travis-CI is a hosted solution and is also free, but only for projects that are open-source.
- Automated tests enable teams to reuse tests in a repeatable process and eliminate time-intensive, rote tasks. Among the testing tools that are considered to be the best are Ranorex, SoapUI, Katalon Studio, and others.
- Web application server for deployment enables the programming logic inside deployable packages to be detected. It also renders the interface and offers web services. Among the open source web application servers available are Tomcat, Jetty, WildFly, and more.
How to successfully implement your own DevOps pipeline
With tools in hand, it’s now time to implement your DevOps pipeline, and the three key steps that must be taken in order to ensure its success are:
Developing a DevOps strategy
As with any strategic initiative, it is critical to fully understand why you are embarking on this journey and to be able to clearly define and articulate this ‘why’ as well as to identify the resources required and potential limitations that may arise.
But DevOps is not just about workflows, tools, and processes. This is an approach to software development that requires a significant shift in mindset and culture – which requires a lot of communication, engagement, education, and evangelizing within the organization.
Monitoring EVERYTHING
Monitoring a project’s status from strategy to deployment is critical. There are so many tools being used to create a toolchain and pipelines, so many different pieces of code being pushed down the pipeline and so many sprints and team members involved throughout the lifecycle.
The only way to make sure that things are organized and under control is to monitor it all, including:
- Application performance
- Sprint progress and defects status
- The code repository
- Security test results
- Versioned artifacts
- And much more
Setting metrics
Monitoring goes hand-in-hand with metrics – which are critical for enabling a quantified understanding of progress and performance. Among what should be measured are:
- Deployment frequency over a given period
- Change lead time between when a change is planned and completed
- Mean time to recovery (MTTR) of the application after a failure
- Change fail rate regarding how many times changes cause a deployment to fail as compared with the number of deployments\
The accelerating popularity of DevOps is no surprise with the many benefits it brings – the agility of teams, the quality and reliability of code, and efficiency of operations.
While it may seem like a daunting task to make the DevOps vision a reality, with the right strategy, tools, and mindset – it is possible, and it does bring remarkable and measurable results.
To learn how Exigence can help you recover when something goes wrong in your DevOps pipeline, we invite you to reach out to us at [email protected]. | https://blog.exigence.io/build-devops-pipeline |
Turkey's relationship with Serbia at its best level, Erdoğan says
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President Recep Tayyip Erdoğan on Monday said relations with Serbia were at the best level in history.
Erdoğan's remarks came before his two-day visit to Serbia where he will mark the 140th anniversary of diplomatic ties between Turkey and Serbia.
Speaking to the Serbian newspaper "Politika," Erdoğan evaluated the diplomatic relations, and economic and cultural developments between the two countries.
Turkey wants to carry out activities that will contribute to the "welfare and stability" of the Balkan region and to strengthen the relations and cooperation with the region in every field, Erdoğan said.
"Serbia has a central and strategic position in the Balkans. We have deep-rooted, historical and cultural ties with Serbia, and we see Serbia as a neighboring country, even though we do not have common borders. Today, our relationship is at its best level. My dear friend (Serbian President Aleksandar) Vucic has a great role and support in this."
Turkey's investments in Serbia
Erdoğan pointed out that Turkey's investments in Serbia have risen for the last two years.
"I paid a visit to Serbia two years ago, almost on the same dates, which gave momentum to our relations. I will hold the second meeting of the High-Level Cooperation Council, which was established during that visit," Erdoğan said.
"We will have the opportunity to evaluate what we have done for the last two years and set new targets," he added.
Erdoğan said that he is proud to see that the Turkish Cooperation and Coordination Agency (TIKA) has implemented development aids in the protection of the countries' common historical and cultural heritage and development in different fields such as health and agriculture.
TIKA contributes to tourism through the restoration of Ram Fortress – a 15th century Ottoman castle – in Serbia and the historical monuments in Kalemegdan, he added.
"We also lay the foundation of the Belgrade-Sarajevo Highway, which we consider as a friendship project of great importance for the region," said Erdoğan, adding that Turkey attaches "great importance to the realization of this project."
"We see it not only as a project that will strengthen the relations but also as a friendship project that will contribute to regional peace and unite the hearts. I do not doubt that we will take our cooperation with the strong political will to the next level, and we attach great importance to the preservation of peace and stability throughout the Balkans," he said.
Turkey supports "Serbia's economic development efforts and the EU accession process," that if prosperity and peace continues in Serbia, this will have positive repercussions for the whole region, he added.
"Serbia plays a crucial role in maintaining regional peace and the development of the region. I get a chance to see this, even more, every time I visit Belgrade," Erdoğan said.
Referring to the economic development between the two countries, Erdoğan said that together with Vucic's partnership they have encouraged Turkish businessmen and investors to expand their business in Serbia.
Erdoğan pointed out that Turkish investments in Serbia have risen from only $1 million in 2011 to $200 million in 2018 and provided employment for approximately 8,000 people in the country.
"Our companies have investments in Serbia in many sectors such as textile and garment, automotive supplier industry, machinery, banking, tourism. The number of Turkish companies operating in Serbia was around 130 in 2015, and it has already exceeded 800," Erdoğan said.
Kosovo-Serbia relations
Erdoğan urged the continuation of the dialogue process of Belgrade-Pristina for reaching a permanent and comprehensive agreement.
"An agreement on the Kosovo issue that satisfies all parties, is vital for the long-term stability and peace in the Balkans, of whic Turkey is also a part," he said.
Turkey supports "the attainment of a lasting and comprehensive agreement based on the free will and consensus of the parties," said Erdoğan.
He said Turkey is ready to give its best efforts to solve the issue and to find a mutual agreement between the two countries.
"Relations between Turkey and Serbia are based on mutual understanding and respect. We are conducting a multi-layered cooperation that serves the interests of our countries. Our countries have mature foreign policy traditions that can turn different perspectives into areas of cooperation," he said.
Turkey's policy toward Balkan region is clear
Referring to Turkey's policy for the region, Erdoğan said that the country's policy toward the Balkans is not based on religion.
"While we attach great importance to our historical and cultural ties in the Balkans, we do not carry out our policy toward the Balkans on a religious basis. Regardless of (religion), we see all the peoples of this geography as our friends that we have lived together with for centuries, and we will cooperate in every field in the future without differentiating between Serbs, Bosniaks, Albanians and Croats. We want Serbia to be in unity, solidarity and peace, to successfully complete European integration and to become a prosperous country," said Erdoğan.
Erdoğan arrived in the Serbian capital Belgrade on Monday where he met with his counterpart Vucic. Together they are taking part in the second meeting of the bilateral High-Level Cooperation Council.
The presidents will also discuss bilateral issues and sign a range of agreements. | |
We are pleased to announce that Into the Black Box will organize a roundtable at next RC21 Conference in Delhi next 18-21 September “In and Beyond the City: Emerging Ontologies, Persistent Challenges and Hopeful Futures“.
Research Committee 21 (RC21) on Sociology of Urban and Regional Development of the International Sociological Association was established in 1970 to promote theory and research in the sociology of urban and regional development.
Our project is to work on a global mapping of platforms’ different geographical development and this Delhi event is the first step in this direction. So the first results of EU PLUS project will be presented together with other researches on platforms in India and Latin America.
Below you find the roundtable agenda and the abstracts.
Roundtable 3
“The global challenges of “platform economies”: a trans – urban perspective”
General Introduction (10 minutes):
- “The global challenges of “platform economies”: from the PLUS project to a global gaze”
Mattia Frapporti (University of Bologna – Italy)
Session 1 – Concept (20 minutes):
- “Conceptualizing Trans-Urbanism”
Niccolo Cuppini (The University of Applied Sciences and Arts of Southern Switzerland – Swiss)
- “Taxi Drivers In the Era of platform Economy”
Shahana Purveen (Tata Institute of Social Sciences – Mumbay, India)
Session 2 – Case studies (40 minutes):
- “Can Gurgaon become a Sustainable and Inclusive City? Analyzing the Role of Startups and Technology Platforms in urban India”
Archana Mohan (Binghamton University of New York – USA)
- “A new platform union: the case of Rappi in Mexico City
Federico De Stavola (Univerdidad Nacional Autónoma de México – Mexico)
(10 minutes’ video)
- “The case of the Uber driver in Monterreay”
Mariana Manriquez (University of Arizona – USA)
- “Platform capitalism, the entrepreneurship of urban condition and new forms of unionism: preliminary results from PLUS project research in Bologna”
Maurilio Pirone (University of Bologna – Italy)
Final Discussion (20 minutes)
Mattia Frapporti: “The global challenges of “platform economies”: from the PLUS project to a global gaze”
Adopting two main geographical scale, the roundtable we are proposing would like to face the global challenges of the so-called “platform capitalism” with a trans-urban approach. Platform economy, in fact, is undoubtedly a global phenomenon which is bursted since the last decade. All around the world this new type of economy is insinuating in the society imposing new opportunities as well as new challenges, especially for the cities inhabitants. This is the reason why, despite we will theoretically propose an analysis with a general overview on the platform economy, our focus will be on urban areas, where the effects of digital platforms are most apparent. Consequently, urban spaces are pivotal in this roundtable, even though we do not think of them as strictly bounded. We consider cities as a broad area that «surpass their own contours», integrated in a global network where social requests are developed by a multitude of actors. Starting from a wide reflection of such a kind of new economy generally considered part of the so-called “Industrial Revolution 4.0”, we will then focus on a specific case study composed by seven key European cities: Barcelona, Berlin, Bologna, Lisbon, London, Paris and Tallinn. On the one hand, we will face the «critical effects» of platforms in such cities both from an historical, theoretical and empirical point of views; on the other hand, we will concentrate on how «technological changes affect patterns of exclusions, the formation of social categories, or new and persistent inequalities».
Niccolò Cuppini: “Conceptualizing Trans-Urbanism”
Platforms are first of all urban technologies, impacting directly on metropolitan areas and radically changing and challenging their development. While the previous “industrial revolutions” have had different temporal implementation accordingly to the geopolitical location of the cities, the so called “industrial revolution 4.0” (digital platforms can be conceived as an icon of it) is defining an almost simultaneity of platforms “territorialisation” worldwide. Therefore, there is a need to conceptualize new analytical and theoretical tools to grasp this dynamic. The intervention will discuss the idea of “trans-urbanism” as a way to define the global emersion of platform capitalism in urban spaces. The elaboration of a trans-urban approach is under construction in a European research project called Platform Labour in Urban Spaces having 7 European cities as case studies, and will be also presented in historical terms.
Shahana Purveen: “Taxi Drivers In the Era of platform Economy”
The proliferation of digital platform and mobile application in recent year has been the primary source for the momentum in collaborative consumption in recent years. It is prevalent across the globe in the form of peer–to-peer ride-sharing, accommodation sharing and renting household items although it is a relatively new concept in India. In India Platform economy is penetrating in various sectors such as transportation, hospitality and food & beverages. However, it gained popularity with the penetration of Uber and Ola in taxi industry from past 6 or 7 years. Traditionally taxi industry was dominated by the famous Kaali and Peeli (Black and Yellow) taxi in Mumbai. Black and Yellow taxis always prove crucial in their role of providing last mile connectivity as well as safety. Yet the service providers (taxi drivers) always come under the ambit of apprehension and their integrity is always questionable. The entry of private aggregator companies like Uber and Ola have added more difficulties for drivers of Black and Yellow taxis. Therefore, the present paper try to explore how the more recently introduced digitally managed systems of service-provision affect taxi drivers’ experiences of work in Mumbai city. The paper also try highlights the need of new policy that can resolve the issue of drivers’ status being micro-entrepreneurs or self-employed in present scenario. Mixed methodology will be used to integrate both qualitative and quantitative methods in the research.
Archana Mohan: “Can Gurgaon become a Sustainable and Inclusive City? Analyzing the Role of Startups and Technology Platforms in urban India”
In order to cater to the demands of the global capital, satellite cities and towns in India have rapidly grown into major urban centers that are attracting migrants from all over the country for better employment opportunities and standard of living. However, these urban centers lack strong infrastructure and basic amenities and hence, access to resources is a daily struggle for all. This has enabled startups using technology platforms to provide services such as transport, waste management, and so on. Startups use technological efficiency and urban sustainability as tropes to offer innovative solutions to urban spaces. They are also redefining work available to people who are migrating to cities in large numbers. Based on two years of ethnographic fieldwork in Gurgaon, this paper analyzes the ways in which these tropes are used to rebuild it into a sustainable and inclusive city but may exclude those at the margins of urban economy.
Maurilio Pirone: “Platform capitalism, the entrepreneurship of urban condition and new forms of unionism: preliminary results form PLUS project research in Bologna”
The image of the platform generally indicates a new type of enterprise based on sharing, aggregation of offer and demand, horizontality of exchange. It is, generally, a business model that is radically transforming the labour market, the organisation of the production process and the forms of consumption.
We should also note the close relationship between many of the companies described as platforms and the urban dimension. On the one hand, the city is increasingly identified in a re-productive space in which activities linked to circulation, consumption and care are central. On the other hand, a new figure of productive subject seems to emerge, that of the urban entrepreneur who valorises some of his/her property related to his condition as a city user (the house, the means of transport) and his/her soft skills.
At the same time, however, it is clear that strong inequalities are created where platforms seem to be able to impose themselves as a winning business model, while digital workers often complain about a lack of protection in terms of rights and salaries. Food delivery expansion and riders’ unionism in the city of Bologna represent stimulating points of view on the role of urban spaces into capitalist accumulation, on new forms of labour immaterial control and workforce subjectivation. | http://www.intotheblackbox.com/events/the-global-challenges-of-platform-economies/ |
Mining time series has attracted an increasing interest due to its wide applications in finance, industry, biology, environment, and so on. In order to reduce execution time and storage space, many high level representations or abstractions of the raw time series data have been proposed including Discrete Fourier Transform (DFT), Discrete Wavelet Transform (DWT), Piecewise Aggregate Approximation (PAA) and Symbolic Aggregate approXimation (SAX). In this paper, we introduce a novel adaptive piecewise and symbolic aggregate approximation (APAA/ASAX) which creates segments of variable length in order to automatically adapts any segment length to its local condition of variability and difference to the average value of the current values in which the segment is defined. The average of each variable segment length from APAA is represented as a symbol from an ordered alphabet generating a modified version for SAX called adaptive SAX (ASAX). This straightforwardly allows to handle a more versatile definition for the event duration. The method APAA/ASAX was used for locating heat waves patterns in a real-world time series datasets of daily temperature information, from the year 1970 until 2009. The experimental results show that APAA/ASAX representation was able to locate heatwave events in a huge databases. Advantages of APAA regarding traditional PAA are mainly based on being constrain-free of fixed schemes of segment length. It also highlights the ability of self-tuning this length depending on local time series characteristics. This means that for flat time series APAA proposes a lower number of segments to reduce dimensionality than in the case to deal with time series of high variability. The approach will be of use to those looking extreme events in any time series.
|Original language||English|
|Pages||354|
|Number of pages||362|
|Publication status||Published - 4 Jul 2018|
|Event||Computing Conference 2018 - London, UK United Kingdom|
Duration: 10 Jul 2018 → 12 Jul 2018
http://saiconference.com/Computing
Conference
|Conference||Computing Conference 2018|
|Country||UK United Kingdom|
|City||London|
|Period||10/07/18 → 12/07/18|
|Internet address|
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Keywords
- Mining time series
- Piecewise Aggregate Approximation
- Symbolic Aggregate approXimation
- Extreme weather events I
Cite this
Ferreira, A. A., Herrera, M., Rameh Barbosa, I., de Aquino, R. R. B., Natarajan, S., Fosas, D., & Coley, D. (2018). Adaptive Piecewise and Symbolic Aggregate Approximation as an Improved Representation Method for Heat Waves Detection. 354. Paper presented at Computing Conference 2018, London, UK United Kingdom. | https://researchportal.bath.ac.uk/en/publications/adaptive-piecewise-and-symbolic-aggregate-approximation-as-an-imp |
Should You Be Worried About Fitting Your Music Into One Genre?
As musicians break down barriers and blend different styles to create previously unheard kinds of music, there's been a lot of talk around the topic of genre. Is this a concept that even matters anymore? Back in the day, people used to identify themselves as a rock fan or a member of the hip-hop community, but these days, almost all music lovers are fluid. Trying new things is expected for most artists, and fans seem to love good music, no matter what it sounds like.
As you progress in your career, should you worry about assigning you and your music to one genre? That’s a decision for you to make, but here is a look at the good and bad associated with both sides.
Letting people know what genre your music is before they’ve even listened is important because it gives them an idea of what they are about to get themselves into, and that’s valuable in many situations.
As a writer, I can say that I hate when press releases or artists themselves won’t say what kind of music they make. I have always focused on covering pop and electronic, and though I like other genres, it’s not what I write about. You can imagine, then, that it’s very frustrating when I am speaking with a musician I’ve just met, and when I ask “What genre is your music?” they answer with some version of “It’s too tough to describe,” or “It doesn’t really fit into a genre.” That’s nice and all, but if you were to say that it’s more hard rock, I’d be able to tell you that it isn’t in my wheelhouse, and we could settle that matter right there.
The same situation pops up for other writers, those creating playlists for streaming, radio programmers, booking agents, and the like. While we’d all like to think that people would only send dance music to a radio show that only plays that one style, that’s not the case. Don’t waste someone’s time by giving him or her something that isn’t a fit by avoiding the genre question. It’s not a clever way to get your music heard, it’s just obnoxious.
While music fans may have moved on from the idea of specific genres, much of the industry has not, and you’re going to run into scenarios where you’ll be forced to choose a genre, even if you don’t like it. At the end of the day, you can decide that you don’t want to start by sharing what genre your music is, but you should actually know the answer. You might be charting some new territory with your songs, but it still likely fits into some broad category, like “rock” or “pop,” and you can explain yourself dizzy after starting off there.
While knowing and sharing what genre of music you create can certainly come in handy, there are negative aspects to going that route as well.
First of all, it boxes you in to a certain extent. If you make it well known that you’re a hip-hop artist, and you build a fanbase with that, those people could be somewhat upset when you decide to try your hand at something different. If you let the music speak for itself, people may assign you a style, and you can ignore it and just keep putting out the art you love.
Drake does a good job of not sticking to just one style, but doing so in a way where nobody seems to be upset when he bounces between hip-hop, rap, R&B, and even pop. He started out like that, and he’s been able to make it work for years now. The same can’t be said for some other acts, which have been roasted for trying new things after establishing themselves as one kind of act.
As I mentioned, we're now living in a time when genre is starting to matter less and less, so perhaps you don’t need to really worry about it anyway, especially if you're just starting out. If you’re going to ignore these kinds of labels, at least make sure that you really aren’t creating some kind of easily identifiable music. Try new things and create something truly innovative; don’t just say you are. Nothing is worse than an artist exclaiming that his or her music can’t be assigned a label, but then after one quick listen, it becomes quite clear that that was an obvious lie. | http://blog.sonicbids.com/should-you-be-worried-about-fitting-your-music-into-one-genre |
The utility model discloses a crosslinked polyethylene insulated low-smoke halogen-free environment-friendly cable for a ship. The cable comprises six alloy conductors, wherein the outer sides of the six alloy conductors are respectively wrapped with fireproof layers, each fireproof layer is formed by a plurality of layers of mica tapes through overlapping and wrapping, the overlapping rate is not lower than 46 percent, the outer side of each fireproof layer is sequentially wrapped with an inner wrapping tape layer and an insulation layer, the inner side of the insulation layer is provided with a polyurethane elastomeric hollow pressure-resistant body, the cross section of the hollow pressure-resistant body is in a hexagon with six edges respectively and inwards concaved into an arch shape, an outer wrapping tape layer and a sheath layer are respectively wrapped outside the six alloy conductors wrapped with the insulation layer, and a tensile tape with the arc-shaped cross section is arranged in the sheath layer. The cable has the advantages that the hollow pressure-resistance body is arranged at the center of each conductor, the pressure resistance performance of the cable is improved, the structure after the cable formation becomes more compact, meanwhile, through the structure design of the fireproof layers and the inner and outer wrapping layers, the fireproof performance of the cable is enhanced, in addition, the smoke generated during the cable combustion is little, and the cable has good shielding performance and excellent external electromagnetic field interference capability. | |
Long, strong and durable, sisal can be spun into a fine textured yarn. Sisal Rugs tend to be fairly suitable for household for their anti-static, flame retardant, and sound absorbing properties of Sisal. Our sisal rugs are very exclusive in quality & appeal, and need more care that other rugs.
Can i help you? | https://www.tradebrio.com/product/sisal-rugs-rugsandcarpets.html |
Single cell phenotypic heterogeneity studies reveal more information about the pathogenesis process than conventional bulk methods. Furthermore, investigation of the individual cellular response mechanism during rapid environmental changes can only be achieved at single cell level. By enabling the study of cellular morphology, a single cell three-dimensional (3D) imaging system can be used to diagnose fatal diseases, such as cancer, at an early stage. One proven method, CellCT, accomplishes 3D imaging by rotating a single cell around a fixed axis. However, some existing cell rotating mechanisms require either intricate microfabrication, and some fail to provide a suitable environment for living cells. This thesis develops a microvorterx chamber that allows living cells to be rotated by hydrodynamic alone while facilitating imaging access. In this thesis work, 1) the new chamber design was developed through numerical simulation. Simulations revealed that in order to form a microvortex in the side chamber, the ratio of the chamber opening to the channel width must be smaller than one. After comparing different chamber designs, the trapezoidal side chamber was selected because it demonstrated controllable circulation and met the imaging requirements. Microvortex properties were not sensitive to the chambers with interface angles ranging from 0.32 to 0.64. A similar trend was observed when chamber heights were larger than chamber opening. 2) Micro-particle image velocimetry was used to characterize microvortices and validate simulation results. Agreement between experimentation and simulation confirmed that numerical simulation was an effective method for chamber design. 3) Finally, cell rotation experiments were performed in the trapezoidal side chamber. The experimental results demonstrated cell rotational rates ranging from 12 to 29 rpm for regular cells. With a volumetric flow rate of 0.5 µL/s, an irregular cell rotated at a mean rate of 97 ± 3 rpm. Rotational rates can be changed by altering inlet flow rates. | https://keep.lib.asu.edu:443/items/149887 |
Arc Atlantique 3 is made up of 65 projects relating to improving the efficiency, safety and sustainability of the European primary road network. This can be achieved with more wide-ranging use of so-called Intelligent Transport Systems (ITSs).
The aim of this is to harmonise European traffic and transport systems where possible. This project is in line with Rijkswaterstaat's mission: promoting safety, accessibility and quality of life in the Netherlands. ITS is seen as a resource that can be used to address the ever-growing demand for capacity on roads, without the immediate need for building new roads or widening existing ones. The objectives listed above can be achieved at less expense, in a shorter time-frame and with less space required.
Project Arc Atlantique 3
The project started in 2013 and involves 17 partners. Plans are currently being implemented in 7 European countries that form a corridor crossing Ireland, the United Kingdom, the Netherlands, Belgium and France to Spain. The current phase of the project deals primarily with implementation in greater depth, and integration of traffic management and traffic-information systems, along with increased knowledge sharing.
In addition, the project offers opportunities to experiment with innovative technologies, such as smart cameras, and new ways of collecting and storing data. Contacts with our fellow road managers in neighbouring countries offer the opportunity of sharing knowledge (innovation). In addition, participation in European projects means the potential of being able to influence European Commission policy to a certain degree. Moreover, grants may allow a project to be brought forward in time, or be used to extend the project in question. | https://www.rijkswaterstaat.nl/english/mobility/projects/arc-atlantique-3/index.aspx |
Business Insider compiled surveys from five reputed sources-- Republic-C -Voter, NDTV - Hansa, Today's Chanakya, India Today-Axis, and TimesNow - VMR – amongst many others and the final number is an average of these five polls.
Uttar Pradesh spans over an area of 243,290 square kilometers and this is the fourth largest state in India approximately comparable to the United Kingdom in its size. In terms of population, Uttar Pradesh is the largest state in India. The number of eligible voters in the state of Uttar Pradesh as per the electoral rolls is 14,43,16,893 which comprises of 7,81,88,467 males, 6,61,20,052 females and 8,374 third gender voters.
In 2014 Lok Sabha elections, the BJP won from 71 seats, SP from 5 constituencies, AD from 2 seats and other candidates got 2 places. In 2009 Lok Sabha elections, SP got 23 places, INC bagged 21 constituencies, BSP won from 20 seats and other candidates got 15 seats. In 2004 Parliamentary elections, SP got 35 places, BSP won from 19 seats, BJP got 10 seats and other won from 16 places.
Uttar Pradesh has the highest number of Lok Sabha seats in India numbering 80. Among them, 17 are reserved for scheduled castes. The state sends 31 Rajya Sabha members from here. The total number of assembly constituencies in Uttar Pradesh is 404 and the latest assembly elections were held in Uttar Pradesh in March 2017. The state polled for the Lok Sabha elections 2019 during all the seven phases.
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I just finished a video tutorial that demonstrates the use of the Lighting controls in Snap Art 4. Normally I use Snap Art for painterly looks, but this is a little different. My goal was to emphasize the texture.
The lighting controls are a powerful tool when used in combination with thicker paint. In the video, I use Impasto, which is a very thick style of painting. In Snap Art, this characteristic is mainly controlled with the Paint Thickness slider. If the value is high, the brush strokes will have stronger highlights and shadows, which can give the painting a sculptural quality, adding expressiveness.
The Lighting parameters provide a simple way of modifying the feel of thick brush strokes. In this case, they enhanced the texture without having the painting effect overpower the photo.
If you’ve ever wanted to add a little bit of Texture to an image, this is an easy way to do it. Check out the video, below.
Image provided by Dylan and Sara Howell. | https://exposure.software/blog/2014/lighting-for-textures-in-snap-art-4-video/ |
PINPOINTING the cause of paddock-yield variability using large data sets and innovative machine-learning models is the focus of a project led by the University of Adelaide and funded by the Grains Research and Development Corporation (GRDC).
South Australian Research and Development Institute (SARDI) agriculture scientist Rhiannon Schilling gave an update of the project at ABARES Outlook online this week.
Ms Schilling said the research looked at the challenge of working out what is behind variability in crop growth and yield across paddocks.
“Often there has been a focus on improving grain yields of our varieties; but when we drive around and have a look at our paddocks, we can see that we are not always achieving uniform crop growth and yield across our paddocks,” Ms Schilling said.
“What we are wanting to do is use some of those historic mapping layers, such as, the soil, climate, topography and remote-sensing information to see if we can shift away from just zoning paddocks from low and high-yielding zones to really try to understand what was causing that variability in yield.”
Ms Schilling said the team collaborated with experts from the Australian Institute of Machine Learning to create a model which could interpret a large amount of data taken from a specific paddock and give the producer an insight on what is causing yield issues at a particular location.
“What we were able to do as part of the project was bring together our growers, agronomists and researchers to share data at that paddock scale and be able to use that to develop a relevant machine learning model,” she said.
“We have used those outputs from the machine learning to develop a demo app where we can now showcase what we have been able to observe.”
Ms Schilling said the app gives the user a visual depiction of multiple traits measured on the paddock and shows which ones have the most impact on yield.
“To take it one step further, what we can do with this information is to start to look through time at how important…traits were across growing seasons, how they vary, which ones were always important and which ones vary between seasons.”
She said the app can delve into a high level of detail from looking at specific values of a nutrient in the soil, at a particular soil depth and in a defined year.
Ms Schilling said the overall goal of the project is showcase how machine learning technology can be used to increase crop yields.
“If we can understand what is causing that variability in yield, we can then inform different management decisions and help to achieve a more uniform yields across those paddocks.
“We want to show what we can do with the machine-learning model and how it can be used by growers, agronomists and researchers going forward.”
Reduce data burden on farmers
Ms Schilling said researchers understood that growers were gathering large quantities of data, which takes up their time and resources.
As an example, she said the machine-learning model used 150 soil traits which highlighted the amount of information that can be captured from a paddock.
“With the model, we can identify the ones that are reoccurring as being important, so we can start focusing on them going forward and, with the others, not monitor them every year, but monitor them every now and then going forward.
“That will help reduce the time and investment and also that curation and storage of that data.”
Ms Schilling said deciding which trait or mapping layer was important varies paddock to paddock.
“Once you know what is driving that yield in those paddocks, then you can start to tailor which mapping layers you should be collecting more than others.”
She said it is still early days with the app and the model and researchers are now looking into how it can be better adapted to suit different soil types and regions. | https://www.graincentral.com/news/machine-learning-presents-opportunities-to-boost-paddock-yield-abares/ |
Where does a squirrel keep its winter clothes? is a very interesting question right now. Below is the best answer to the Where do squirrels live in winter? that we assembled. we will definitely make you satisfied!
Brodie Brickey
Votes: 2211
Squirrels build big nests and line them with feathers and fur and leaves up in the trees, and live in those during the Winter. Periodically a squirrel will leave its nest to forage for the acorns and pine nuts it has buried in the ground. They are really quite good about finding their caches, but do not get all of them which the ponderosa pines can thank their lucky stars for. Aeberts squirrel is the main reason that we have so many pine trees here where I live. The little gray devils plant them.
George Rix
Votes: 9282
Actually, the same place as the rest of the year, their dreys or their burrows, it depends on whether we are talking about tree or ground squirrels. In winter they spend a great deal more time in their dreys, after all, the days are shorter and colder. There are nocturnal squirrels like the siberian flying squirrel. They rely heavily but not entirely on food stashed away in caches.
Votes: 684
It is one of the few mammals which can climb head first down a tree. Grey squirrels do not hibernate, so may be seen at all times of the year. However, in winter they are far less active, sleeping for long periods, sometimes several days at a time, and they are less frequently spotted during this season.
Of course, if you live in south Florida, you will see them more frequently in the winter than most parts of the country.
Nancy Allaire
Votes: 8829
It would depend on the species of squirrel. The ones in the Northeast US live in trees. They make nest of leaves that help insulate them against the cold and snow.
Bonnie Wingate
Votes: 3325
Same place they live in the summer. Squirrels make nests in trees. Their nests are easy to spot because they are larger than birds and often their construction is more haphazard and messy. But with a little engineering they can and do construct some fairly serviceable nests. And the bjshy tail is used not just for balance when leaping from limb to limb but also serves as an umbrella in rain and snow and can make a blanket for added warmth. While squirrels are usually solitary several will bundle into a nest during cold weather and snuggle together. If the nest is big enough there can be seven to eight squirrels together.
Patricia Snyder
Votes: 3920
How do squirrels manage to keep their nest of leaves together in high winter winds?
Well, first of all they usually make two nests just in case one is destroyed by a storm. A summer house is high up in the thin, top branches and a winter nest is usually in a fork or hollow. They make their nests out of larger leaves and branches, cut when they are green and easily woven on the outside, graduating to smaller, softer leaves, dried grass, moss, found feathers and their own fur, on the interior. This makes them cozy and snug.
Deck Travis
Votes: 2286
Do squirrels really gather nuts for winter?
In high school in central Missouri I helped renovate an old house out in the country. The house was surrounded by black walnut trees out by itself on a hill. An upstairs dormer window had a crack in it with a piece of glass out of it that was big enough to slip your hand through. The squirrels in the area had picked the walnuts and slipped through the broken window and found an upstairs floor board that was warped from the rain that came through that window. They packed the area between the floor joists and ceiling below with black walnuts. From one end of the house to the other. They had chew
Daksha Sunil
Votes: 2389
What do squirrels eat in the winter?
Even when it’s cold out, squirrels need to eat. They look to communal stores of mast — nut fruits such as acorns — for calories and fat to see them through the winter. Squirrels can also eat bugs, bird eggs, soil, mushrooms and animal bones, and may find some of this food in winter
Deck Travis
Votes: 2285
Do squirrels need water in winter?
Absolutely. Squirrels need water in both summer and winter. In the summer, squirrels can be found drinking out of containers laying around your yard or even bird baths. And in the winter, they will eat snow to stay hydrated. Some people like to put out heated water bowls or place a container of warm water outside for them. However, If you live in Canada, like me, warm water only lasts for so long and will freeze pretty quickly. We may not see them doing it often, but squirrels actually drink a fair amount!
The overhead is the best answer to where does a squirrel keep its winter clothes? that we researched. Follow us for more interesting answers! | https://dotheduty.org/where-does-a-squirrel-keep-its-winter-clothes/ |
Remote Sensing of the Environment
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Abstract
The SSM/I microwave satellite radiometer and its predecessor SMMR are primary sources of information for global sea-ice and climate studies. However, comparisons of SSM/I, LANDSAT, AVHRR and ERS-1 SAR have shown substantial seasonal and regional differences in their estimates of sea ice concentration. To evaluate these differences, we compared SSM/I estimates of sea ice coverage derived with the NASA Team and Bootstrap algorithms to estimates made using RADARSAT, and OKEAN-01 satellite sensor data. The study area included the Barents, Kara Sea, Laptev Sea, and adjacent parts of the Arctic Ocean, during October 1995 through October 1999. Ice concentration estimates from spatially and temporally near-coincident imagery were calculated using independent algorithms for each sensor type. The OKEAN algorithm implemented the satellite's two-channel active (radar) and passive microwave data in a linear mixture model based on the measured values of brightness temperature and radar backscatter. The RADARSAT algorithm utilized a segmentation approach of the measured radar backscatter, and the SSM/I ice concentrations were derived at National Snow and Ice Data Center (NSIDC) using the NASA Team and Bootstrap algorithms. Seasonal and monthly differences between SSM/I, OKEAN, and RADARSAT ice concentrations were calculated and compared. Overall, total sea ice concentration estimates derived independently from near-coincident RADARSAT, OKEAN-01 and SSM/I satellite imagery demonstrated mean differences of less than 5.5 % (SD < 9.5%) during the winter period. Differences between the SSM/I NASA Team and the SSM/I Bootstrap concentrations were no more than 3.1 % (SD < 5.4%) during this period. RADARSAT and OKEAN-01 data both yielded higher total ice concentrations than the NASA Team and the Bootstrap algorithms. The Bootstrap algorithm yielded higher total ice concentrations than the NASA Team algorithm. Total ice concentrations derived from OKEAN-01 and SSM/I satellite imagery were highly correlated during winter, spring, and fall, with mean differences of less than 8.1% (SD < 15%) for the NASA Team algorithm, and less than 2.8 % (SD < 13.8%) for the Bootstrap algorithm. Respective differences between SSM/I NASA Team and SSM/I Bootstrap total concentrations were less than 5.3% (SD < 6.9%). Monthly mean differences between SSM/I and OKEAN differed annually by less than 6%, with smaller differences primarily in winter. The NASA Team and Bootstrap algorithms underestimated the total sea ice concentrations relative to the RADARSAT ScanSAR no more than 3.0% (SD<9 %) and 1.2% (SD < 7.5%) during cold months, and no more than 12% and 7% during summer, respectively. ScanSAR tended to estimate higher ice concentrations for ice concentrations greater than 50%, when compared to SSM/I during all months. ScanSAR underestimated total sea ice concentration by 2 % compared to the OKEAN-01 algorithm during cold months, and gave an overestimation by 2% during spring and summer months. Total NASA Team and Bootstrap sea ice concentration estimates derived from coincident SSM/I and OKEAN-01 data demonstrated mean differences no more than 5.3 % (SD < 7%), 3.1 % (SD < 5.5%), 2.0% (SD < 5.5%), and 7.3 % (SD < 10%) for fall, winter, spring, and summer periods, respectively. Large disagreements were observed between the OKEAN and NASA Team results in spring and summer for estimates of the first-year and multiyear age classes. The OKEAN-01 algorithm and data tended to estimate, on average, lower concentrations of young or first-year ice and higher concentrations of total and multiyear ice for all months and seasons. Our results contribute to the growing body of documentation about the levels of disparity obtained when seasonal sea ice concentrations are estimated using various types of satellite data and algorithms.
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In November 2007 approximately 90 Catholic Inspired Non-Governmental Organizations (NGOs) with consultative status before intergovernmental institutions constituted a Forum. In so doing their intention was to identify and develop means of collaboration regarding international issues, in the hope to thereby achieve a more efficacious presence and action.
The Forum was conceived as a place of dialogue and exchange among Catholic Inspired NGOs in order to offer a strengthened Christian witness at the international level. This witness is at the service of the common good of humanity, the defense of human life and dignity, as well as the promotion of global peace in a spirit of communion and generosity.
The Forum invites organizations to consider the approach articulated in the papal encyclical Caritas in Veritate, namely, that new solutions are “to be found together in the light of an integral vision of man, reflecting the different aspects of the human person, contemplated through a lens purified by charity” (32).
The Forum Committee and Secretariat wish to warmly welcome you and thank you for visiting the website.
https://foruminternational.org/
FIAMC is member of the Forum. Dr José María Simón is the representative to Forum. | https://www.fiamc.org/vatican/website-of-the-forum-of-catholic-ngos/ |
Frances Rings new leader for Bangarra
Seldom have the words "end of an era" been so aptly chosen when Bangarra Dance Theatre announced this week that Stephen Page will step down as Bangarra Artistic Director in early 2023.
Page’s resignation marks the end of an incredible 32-year tenure as Bangarra’s Artistic Director. Over this time, he has developed an unique body of works that have become milestones in Australian performing arts history, while firmly establishing Bangarra as a critical part of the Australian cultural ecosystem and one of our most lauded dance institutions.
Stepping into his giant footsteps will be Kokatha woman, Frances Rings. She has a long association with Bangarra, originally as a dancer when she joined in 2002, then as Resident Choreographer and most recently as Associate Artistic Director.
"I didn’t arrive here without the mentorship and guidance from our current Artistic Director, Stephen Page," she said in the company's press release. "Stephen is an icon of our industry, a cultural leader and esteemed visionary. He is our national treasure. What I inherit is due to his incredible hard work, sacrifice and indominable belief in the power of our artform and its ability to create lasting change. His profound impact on our industry is a lasting legacy that will resonate for generations to come”.
For his part, Page is "delighted to now entrust the future of Bangarra to this deeply committed and community-connected cultural leader not only because of her sensational artistry but because her lived experience is that Bangarra is so much more than an arts organisation," he says. "Ceremonially I pass her this precious coolamon filled with all our truly unique First Nations dancers and administrators as well as our many valuable non-Indigenous supporters."
In 2022, audiences will have the special opportunity to experience Page’s largest major stage work as Bangarra’s Artistic Director, with the world premiere of Wudjang: Not the Past, as well as one of Rings’ most lauded works, Terrain, as the company embarks on a special 10th anniversary tour of the landmark production.
A new era begins for this precious Australian company.
– KAREN VAN ULZEN
See more here. | http://www.danceaustralia.com.au/news/frances-rings-new-leader-for-bangarra |
Terror is increasingly becoming a challenge each passing day. As the world changes so are the forms, which it takes and the victims it targets. As a result, counterterrorism efforts are facing new challenges to overcome by the day necessitating a shift in the approaches being used. Counterterrorism is thus adopting new trends with time for the sake of effectively combating the problem. The inflexible bureaucratic approach previously employed to counter terrorism had proved inefficient in tackling the problem. Throughout the world, there are calls for measures that are both flexible and adaptive to the undercurrents of the world around us.
As such, the new age mechanisms being developed to fight terror are designed to target very specific yet dynamic areas. There is an emphasis on the formulation of policies that are driven by gender-specific roles, the qualitative change in terror landscape of a variety of conflict areas as well as the changing tactics utilized by extremist groups.
A key trend is a need for intelligence sharing, cooperation and joint counter-terrorism measures across different countries and regions. Gone are the days when intelligence was guarded secretively. We are now learning that terrorism is a global threat that can potentially affect anyone. Countries sharing close geographical links are now forming regional task forces that cooperate with another with the aim of protecting the entire region. Moreover, international bodies such as the United Nations are also calling for coordination in fighting terrorism. Therefore the current trend involves joint efforts from countries that would not otherwise work together.
Also, new trends in the fight against terror are closely examining the role parents and their children play in the fight. The institutionalized indoctrination of young minds by people affiliated to the radical groups is emerging as a new problem. It is spreading the menace across generations. As a result, the participation of children in terror at the moment has become a widespread phenomenon. Furthermore, terror groups like the AlShabaab are recently reported to be recruiting children. Thus, counterterrorism efforts here are being designed to protect the children physically as well as ideologically.
Other measures introduced by the Kenyan government in countering terrorism include: Deployment of anti-terror police in North eastern region, increased border patrols to refrain terrorist influx and Nyumba Kumi initiative-which plays a vital role in enabling citizens report suspicious cases to security forces. Uganda and Tanzania have embraced citizen-led programs to encourage cohesion and good neighborliness. This makes their citizens less susceptible to militant recruitment.
Lastly, there are calls for a complementary approach to counter-terrorism. It is termed as preventing and countering violent extremism. Here, the new trend aims at preventing terror as opposed to fighting it. As mentioned earlier, this approach is not meant to replace counterterrorism in general. The method directly targets the disturbing yet lawful belief as well as actions that are conducted in the pre-criminal space. Accordingly, the trend strategically places emphasis on fighting the growing radicalization efforts that are responsible for the violence. The approach also combines some of the previously discussed trends in an effort to provide a global platform for preventing terror attacks without violence where possible.
Indeed, the dynamic nature of the world brings with it challenges in counterterrorism. New trends are thus emerging to address said issues. These include the development of policies that target the entire complexity of terrorism, joint efforts and intelligence sharing, protecting children from ideological indoctrination and preventing and countering violent extremism. | http://epukaugaidi.com/2019/02/06/emerging-trends-in-counterterrorism/ |
DNA Leak Test - Are You Completely Anonymous?
A VPN is often used to hide your IP address in order to surf anonymously on the Internet. However, a wrong configuration by the user or the VPN software can lead to a leak of the original IP address or other sensitive information. The EXPERTE.com DNS Leak Test checks whether your DNS requests are sent to a secure DNS server.
Note: For the test to produce meaningful results, you must be connected to a VPN.
What is a DNS Leak?
The Domain Name System (DNS) is responsible for resolving an Internet address like www.experte.com into the corresponding IP of the web server. Therefore, when you visit a website, your computer sends a query to a DNS server (name server), which responds with the appropriate IP address.
If your computer now sends the DNS queries to a DNS server that does not belong to the VPN provider, this DNS server will find out all the websites you have visited. Since the DNS protocol is also largely unencrypted, this data can also be monitored during transmission.
What Information Is Leaked?
A DNS leak tells the DNS provider which Internet addresses are contacting you. This way he knows
- which websites you visit
- which files you download
- which online services you use
How Does the DNS Leak Test Work?
To determine whether you are affected by a DNS leak, we carry out the following steps.
- We make a total of 5 requests from your browser to random subdomains controlled by us (e.g. r5ymkun1.experte.com).
- Your computer tries to determine the IP associated with these random domains and makes a request to its DNS server.
- We receive the DNS request and now know the IP address of your DNS server.
- We compare the owner of your IP address with the owner of your DNS server. If these data do not match, there may be a DNS leak. | https://www.experte.com/dns-leak |
I need your help for writing essay (4 pages not including the cover page and references page)
The topic as below:
Read through the Case Study entitled “Highline Financial Services, Ltd.” in Chapter 3 of your textbook. Examine the historical trends this company has experienced for the three products (A, B, C) discussed over the 2 years shown.
Address the following requirements:
Directions:
– Write an essay that includes an introduction paragraph, the essay’s body, and a conclusion paragraph to address the assignment’s guide questions. Do not address the questions using a question-and-answer format.
-APA style should be used
-Font will be: Times roman 12, and double space should be between lines
-At least 3-4 scholarly, peer-reviewed journal articles will be used as references (including the below two).
Recommended Reference:
Choudhury, D. K. (2018). Market demand forecast method selection and application: A case study in Hero MotoCorp Ltd. IUP Journal of Operations Management, 17(2), 7-22.
We confidently assure you high-quality work. We engage a number of strategies in order to guarantee top-level assignments. The projects go through a thorough system of control prior to being submitted to the customers. nerdyassignmenthelp.com guarantees that the assignments delivered are 100 percent plagiarism-free.
We never share or resell customer’s work. Therefore, once it is checked using our plagiarism software, the assignment will be original. In terms of assignment completion, we adhere to the guidelines given by you and assign the work to the most suitable writer. We assign our writers based on various factors such as academic qualification, previous customer feedback, etc.
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Our team of editors revises the assignments, checking them to ensure they comply with the standards of academic writings. Additionally, editing may entail refining the language, adding more reference material, and making sure the formatting part is properly done. The editors may also enhance papers completed by yourself in order to meet your needs.
We guarantee the following quality in our work to you:
We use the following tools to crosscheck our assignments: | https://usaelitewriters.com/critical-thinking-essay-forecasting/ |
In this lesson students choose a service project to take action for children's health in the poorest countries. Many ideas are suggested related to Save the Children's Newborn and Child Survival Campaign. The suggested projects are calendar events and can be found in the Service...
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Unit: Newborn and Child Survival (6-8)
Unit: Community Impact
In this three-day lesson, students analyze self-esteem in themselves and in fictional and nonfictional characters. They discuss the value of having a positive and realistic image of oneself and set goals for developing self-esteem in self and others by identifying strengths and personal talents/...
Unit: Bullying Prevention Plan
In this lesson, learners will explore and address the following questions: Who are the minority voices of the past and how has the civil society sector stepped in to protect their rights? What actions were effective? What public policies are in place to protect them? Who are the bullied today...
Unit: Food for Thought Middle School Unit by the Westminster Schools
To produce paintings or drawings that represent their “Dream of Peace” and that are submitted to an art competition.
A teacher using this lesson can look for art competitions locally or nationally that are sponsored by a museum, organization, or school district; a teacher might...
To help students understand how to use their voices to advocate for causes about which they care. ...
Unit: Writers as Activists
Students will recognize the linguistic strategies that Alice Walker uses in her introduction to Anything You Love Can Be Saved that persuade readers to believe in her causes, and thus begin to think about techniques that they can use in their own activist writing, which they will do in...
Unit: Mighty Pens: Writers for Positive Change
Through persuasive writing, the learners will build awareness and invite action for change in their school, the community or the world about an issue of concern. Typical forms may include essays, editorials, feature articles, or speeches.
Unit: We the Kids - The Three Branches and Me
In a kid-friendly approach, we look at the components of the U.S. Constitution and put early government-forming events in a context and timeline. Students learn the roles of the three branches of government, especially the structure and responsibilities of our judicial system. Students learn...
Unit: Social Reformer—Jane Addams
Jane Addams is used as a model to demonstrate a philanthropist in action, improving many situations, not only in the city of Chicago, but also at state, national and international levels.
Students learn about the philanthropic work of Jane Addams. | https://www.learningtogive.org/resources/lessons-units?search_api_views_fulltext_1=Voice&page=8 |
This summer, the United States experienced one of the worst droughts in history since the dustbowl. Farms went weeks on end without a drop of rain, particularly in the Midwest and, combined with high temperatures, resulted in a significant drop in harvest-ready plants. The drought affected numerous parts of the nation's industrial sector as well as countries outside of the U.S. The United States has ample agriculture, if one part of the U.S. is experiencing drought and crop loss problems, then the whole food industry suffers as a result. While droughts are not uncommon, this summer the drought conditions were felt all over the United States, leaving almost all farms affected. As the image shows, the majority of the United States experienced at least an abnormal dryness level. The Midwest and Southwestern parts of the United States were particularly hard-hit, experiencing severe to exceptional drought conditions.
The drought conditions were persistent and occurred during the maturing and harvesting periods of the country's most important crops- corn. The USDA estimated the drought damaged crops enough to lower corn production to by 13 percent when compared to 2011 crop numbers. Corn and its by-products, is used for wheat in food, fertilizer, ethanol, beverages, animal feed and biodegradable plastics. Director of the Agricultural Entrepreneurship Initiative at the University of Iowa and Agricultural Economist Kevin Kimle explained that "corn matures by about Labor Day, but what happens in dry conditions is it shuts down early if it doesn't get any moisture. When the cost of a base ingredient like corn goes up, it fundamentally affects everything."
The EPA mandates that 13.6 billion gallons of bio-fuels such as ethanol to be produced. At 26 pounds of corn per gallon of ethanol, the amount of corn necessary to meet the EPA's mandate of could exceed 40 percent of the total corn crop for 2012. The number of beef and dairy cattle also reached 90.8 million head according to the USDA. Cattle typically eat 8 pounds of supplemental feed, mainly corn, in addition to 20 pounds of hay per day. The drought will result in higher prices for both corn and hay up, and potentially force ranchers to cut the amount of feed, the resulting smaller animals. The overall scarcity of feed and beef will negatively affect the consumer beef and dairy market, bringing eventual price increases.
Farmers are at a slight advantage during the drought, being covered by federal programs and crop insurance. The livestock industry (beef, poultry and pork) was affected by the drought and subsequent higher feed prices and is not typically covered by insurance. Ranchers face being unable to feed their livestock for the coming winter, and may be forced to thin out herds, creating an excess of meats on the market and lowering prices. Brian Fuchs, a climatologist at the National Drought Mitigation Center acknowledges that this may seem like the one good thing to come out of everything, but he also warned that these tough decisions "create a glut of meat and force prices to go down in the short term," Fuchs says. "Once that glut is gone, prices spike from lack of supply, and it will take several calving seasons to build that supply up again."
The United States will not be the only country affected. Every year, the U.S. ships thousands of tons of grains as foreign aid to impoverished third world countries. These countries include Afghanistan, India, Congo, Nepal, and many more. The full list of countries that rely on U.S. food aid can be found at http://foodaid.org/food-aid-programs/food-for-peace/. While the U.S. has pledged not to decrease foreign aid foodstuffs, the increase of prices could have a devastating effect on countries with food stability issues that rely on purchasing grain from overseas. | http://www.neiuindependent.com/news/view.php/549387/Drought-Hits-US-Midwest-Hard |
Atonement: The Meaning and Message of the Cross
The atonement of Jesus Christ is a theme that runs throughout the entire Bible—it is at the very heart of God’s redemptive purpose for humanity. In secular usage, the word atonement refers to reparation for a wrong or injury; it is derived from Anglo-Saxon words meaning “making at one.” Atonement infers doing what is necessary to reconcile two alienated parties through making amends or providing compensation for a transgression, wrong, or injury. In effect, it levels out an imbalance created by wrongdoing.
In Christian theology, atonement refers to the substitutionary work of the incarnate Son of God, accomplished through the giving of His life at Calvary in payment for sin. In the Old Testament, the Hebrew word kaphar, translated atonement, literally means “to cover; cancel.” Figuratively, it carries the implication of appeasement, pardoning, and reconciling. In the New Testament, the Greek word katallage, is translated as atonement only in Romans 5:11. However, the same word is translated as reconciliation in numerous other instances. Both the Hebrew and Greek words indicate the reconciliation of man to God made possible by the death of the Perfect Sacrifice, Jesus Christ. Without the covering for sin provided through Jesus’ death, there could be no possibility of reconciliation. Thus, the atonement is fundamental to the Gospel message, as it makes forgiveness for sin possible.
The atonement is a provision of God’s love for humanity. The Apostle John made this vital truth clear in 1 John 4:10, where he wrote, “Herein is love, not that we loved God, but that he loved us, and sent his Son to be the propitiation for our sins.”
Why atonement is necessary
Sin is what made the atonement necessary. When God created the first man and woman, Adam and Eve, they enjoyed perfect fellowship with Him. However, God made them free moral agents—they had the ability and liberty to choose to obey or disobey Him. God gave them only one prohibition: they were not to eat of the Tree of the Knowledge of Good and Evil. In spite of knowing there was a penalty for disobedience (see Genesis 2:17), Adam and Eve chose to defy God’s directive. They ate from the forbidden tree, and as a result of this act of deliberate rebellion, sin entered into their hearts. Since God cannot tolerate sin, they were immediately estranged from Him.
Sin is not only a series of committed transgressions, but also the inbred condition or nature out of which acts of sin originate.
The descendants of Adam and Eve—every person born into this world—inherited the sinful nature of their ancestors. Romans 5:12 states that “by one man sin entered into the world, and death by sin; and so death passed upon all men, for that all have sinned.” Instead of being born with a desire to do right, every individual is born with an innate predisposition toward evil. Thus, sin is not only a series of committed transgressions, but also the inbred condition or nature out of which acts of sin originate.
Sins may be obvious or subtle, flagrant or hidden, but they always separate from God. The prophet Isaiah indicated this in Isaiah 59:2, “But your iniquities have separated between you and your God, and your sins have hid his face from you, that he will not hear.” Romans 1:18 states, “The wrath of God is revealed from heaven against all ungodliness and unrighteousness of men.” “Wrath” in this context does not refer to anger or fury, but to God’s absolute antipathy and holy revulsion toward sin. He cannot tolerate it in any degree, because God’s perfect moral nature can never be stained by complicity with or allowance for unrighteousness.
The immediate result of sin is spiritual death and separation from God, while the end result of sin is death and separation from God for eternity.
The immediate result of sin is spiritual death and separation from God, while the end result of sin is death and separation from God for eternity. Paul explained, “For the wages of sin is death”—physical death, spiritual death (separation from God), and eternal death (forever separated from God with no hope of ever experiencing His saving grace). However, he went on to add, “but the gift of God is eternal life through Jesus Christ our Lord” (Romans 6:23). In God’s infinite love and mercy, He provided salvation through the propitiatory sacrifice of His Son Jesus Christ as a way for humanity to escape sin’s awful consequences and be reconciled to God. Only a sinless sacrifice could avail, and because Christ was sinless, He could pay the atoning price. Christ willingly gave His life on the Cross, suffering an agonizing death so that we could be saved.
Foreordained and universal
The atonement was foreordained by God. We read in Revelation 13:8 that Jesus was slain “from the foundation of the world.” God, in His foreknowledge, was fully aware that Adam and Eve eventually would sin, and made provision for the redemption of fallen humanity. Before the world was created, Christ understood that He would take upon Himself the disobedience and rebellion of humanity, thus providing an atonement for sin.
The atonement of Christ is a universal provision—it is for all people everywhere. Some hold that Jesus died only for a select group of individuals, but the Word of God teaches otherwise. The unlimited nature of Christ’s atonement is evident throughout the New Testament. For example, Paul wrote, “the grace of God that bringeth salvation hath appeared to all men” (Titus 2:11). He asserted that God wills “for all men to be saved, and to come unto the knowledge of the truth” and that He “gave himself a ransom for all” (1 Timothy 2:4,6). We read in Hebrews 2:9 that Jesus tasted death for every man. Christ died to make atonement available to all, but receiving the benefits of the atonement depends upon each individual’s acceptance or rejection of God’s offer of forgiveness and reconciliation.
The nature of the atonement
The words redemption, substitution, propitiation, and reconciliation illuminate the nature of Christ’s atonement.
Redemption: The concept of redemption, as explained in Leviticus 25:47-49, has to do with the setting free of one who is enslaved, through the payment of a ransom price or penalty. Jesus Christ, through His death on the Cross, paid the price for all who were “sold under sin” (Romans 7:14). The Apostle Peter states that we are not redeemed with corruptible things, as silver or gold, but “with the precious blood of Christ, as of a lamb without blemish and without spot” (1 Peter 1:18-20). In Old Testament times, if a slave preferred to remain a slave, redemption was not forced upon him, and the same is true of the redemption offered by Jesus Christ. Individuals must choose to accept the provision Christ made for deliverance, or pay the penalty for sin.
Substitution: The death of Christ was substitutionary in nature. Although the words substitute and substitution do not appear in Scripture, the principle of replacement is clearly seen in what Christ did upon the Cross. There, as our Substitute, He bore the awful judgments of God against sin. Paul explains this in 2 Corinthians 5:21, “For he hath made him to be sin for us, who knew no sin; that we might be made the righteousness of God in him.”
Propitiation: The Apostle John wrote in 1 John 2:2, “And he is the propitiation for our sins: and not for ours only, but also for the sins of the whole world.” The word propitiation, translated from the Greek word hilasmos, expresses the concept of appeasement or reconciliation. A propitiatory sacrifice averts punishment for sin.
In New Testament writings, the word propitiation points to Jesus’ atoning sacrifice, as the means by which God’s judgment against sin is appeased or placated. God is eternally righteous and holy, so He cannot overlook sin or excuse the guilty—justice demands that a penalty be paid for an offense. The prophet Nahum reminds us that God does not acquit the wicked. A price must be paid for wickedness and sin (see Nahum 1:3). Christ paid the price for our sins through His death; this conciliation or appeasement made it consistent with God’s righteous nature to pardon sinners. The Innocent Blood was shed for the guilty, that we might be pardoned and made free.
Reconciliation: The concept of reconciliation is also a theme of the Atonement, and is closely related to propitiation in what it accomplishes. Adam’s sin alienated humanity from God, but Jesus’ death made reconciliation available and possible for all. Colossians 1:21-22 states, “And you, that were sometime alienated and enemies in your mind by wicked works, yet now hath he reconciled in the body of his flesh through death, to present you holy and unblameable and unreproveable in his sight.”
Old Testament sacrifices foreshadowed Christ’s sacrifice
Throughout the Old Testament, blood is set forth as the means of atonement. Leviticus 17:11 indicates why blood is necessary. “For the life of the flesh is in the blood: and I have given it to you upon the altar to make an atonement for your souls: for it is the blood that maketh an atonement for the soul.” That point is reiterated in New Testament teaching. Hebrews 9:22 states, “And without shedding of blood is no remission.” Since the wages of sin is death and life is in the blood, blood is required in order for the wages of sin to be paid.
This was first demonstrated in the Book of Genesis when God created a covering for Adam and Eve—a covering necessitated by their act of sin—based on the shedding of the blood of innocent animals. Later, God accepted Abel’s blood offering, while Cain’s offering of the fruit of the ground was rejected. Noah offered animal sacrifices when he came out of the ark after the Flood. Abraham was known for the many blood sacrifices he made unto the Lord.
The slaying of the Passover lamb looked ahead to the time when Christ, our Passover Lamb, would be “sacrificed for us” (1 Corinthians 5:7).
On the eve of the day the Israelites were released from Egyptian bondage, the blood of a lamb without blemish was applied to the door posts and lintels (top of door frame) of their houses (see Exodus 12:3-7). This exempted them from death when the Lord passed through the land that night to smite the Egyptians, slaying the eldest in every Egyptian home. God had told the Israelites, “When I see the blood, I will pass over you” (Exodus 12:13). If they had ignored God’s instruction to apply the blood, had ventured out from under the blood that night, or had substituted something for the blood on the doorways of their houses, the firstborn sons in their families would have perished as well. The slaying of the Passover lamb looked ahead to the time when Christ, our Passover Lamb, would be “sacrificed for us” (1 Corinthians 5:7).
Many of the ceremonies of the Tabernacle worship and commandments of the Levitical Law prefigured the death of Jesus Christ as the Perfect Sacrifice—they were “a shadow of good things to come” (Hebrews 10:1). Daily sacrifices reinforced that God could not tolerate uncleanness or impurity, and gave the Israelites an example of the blood of a pure, undefiled creature as a cleansing agent (see Hebrews 9:19-22). The scapegoat taken into the wilderness on the annual Day of Atonement represented Christ, who took the condemnation and curse of sin upon Himself when He suffered on the Cross outside the city (Hebrews 13:12). Before the High Priest went into the Holy of Holies, an offering was presented and killed at the brazen altar, and the blood carefully drained. That blood was then taken into the Holy Place and the Most Holy Place, where it was applied as directed by God.
The atonement in Old Testament prophecy
The Old Testament contains over one hundred distinct prophecies about Jesus, and a number of these deal with His atoning death. For example, verses 14-16 of Psalm 22 describe the Messiah’s suffering when He was crucified for the sins of mankind. “I am poured out like water, and all my bones are out of joint: my heart is like wax; it is melted in the midst of my bowels. My strength is dried up like a potsherd; and my tongue cleaveth to my jaws; and thou hast brought me into the dust of death. For dogs have compassed me: the assembly of the wicked have inclosed me: they pierced my hands and my feet.”
Zechariah is another Old Testament prophet who foretold Christ’s death. We read in Zechariah 12:10 that in the last days, all the people of Jerusalem “shall look upon me whom they have pierced, and they shall mourn for him, as one mourneth for his only son.” Zechariah 13:6 records, “And one shall say unto him, What are these wounds in thine hands? Then he shall answer, Those with which I was wounded in the house of my friends.”
The majority of Old Testament references to Christ’s atonement are found in the Book of Isaiah; Chapter 53 especially is known as the great prophecy of the Suffering Servant. Isaiah 53:8-12 prophetically described Christ’s death and the provision He made for atonement, stating, “he was cut off out of the land of the living: for the transgression of my people was he stricken. And he made his grave with the wicked, and with the rich in his death; because he had done no violence, neither was any deceit in his mouth. Yet it pleased the Lord to bruise him; he hath put him to grief: when thou shalt make his soul an offering for sin, he shall see his seed, he shall prolong his days, and the pleasure of the Lord shall prosper in his hand. He shall see of the travail of his soul, and shall be satisfied: by his knowledge shall my righteous servant justify many; for he shall bear their iniquities. Therefore will I divide him a portion with the great, and he shall divide the spoil with the strong; because he hath poured out his soul unto death: and he was numbered with the transgressors; and he bare the sin of many, and made intercession for the transgressors.”
All the types, shadows, and Messianic prophecies in the Old Testament culminated at Calvary when Christ “suffered for sins, the just for the unjust, that He might bring us to God” (1 Peter 3:18).
Accessing the atonement
The fact that Jesus died for the sins of humanity does not mean that individuals are no longer separated from God. Salvation is provisional: it is available for all, but each person must come to God personally in order to receive pardon from sin.
When repentant sinners come to God acknowledging their need, confessing their sins, and believing that Christ’s atoning work at Calvary avails for them, they will experience reconciliation with God.
The benefits of the atonement are appropriated through faith in the provision made by Christ’s death. When repentant sinners come to God acknowledging their need, confessing their sins, and believing that Christ’s atoning work at Calvary avails for them, they will experience reconciliation with God. Hebrews 11:6 tells us, “He that cometh to God must believe that he is, and that he is a rewarder of them that diligently seek him.” Ephesians 2:8-9 makes the same point, noting, “By grace are ye saved through faith; and that not of yourselves: it is the gift of God: not of works, lest any man should boast.”
Benefits of the atonement
The power of the atoning Blood is not limited to salvation; believers enjoy many other benefits through the Blood of Jesus. These benefits include the following:
Joy and freedom from guilt. Paul wrote in Romans 5:11, “And not only so, but we also joy in God through our Lord Jesus Christ, by whom we have now received the atonement.” In Romans 8:1 he stated, “There is therefore now no condemnation to them which are in Christ Jesus.” Sinners try many ways of soothing their guilty consciences, but the Bible says, “He that covereth his sins shall not prosper: but whoso confesseth and forsaketh them shall have mercy” (Proverbs 28:13). There is only one place sinners can go to find relief from guilt. That place is described in the words of an old hymn, “There is a fountain filled with Blood, drawn from Emmanuel’s veins, and sinners plunged beneath its flood, lose all their guilty stains.” The Blood of Jesus Christ can set one free from the bondage of sin and eliminate all condemnation and guilt.
Sanctification. The Atonement not only provides for justification and forgiveness of sins, but it also provides for entire sanctification, a second work of grace by which the inbred nature of sin is removed, making the saved individual pure and holy in heart and motive. The writer of Hebrews addressed this, stating, “Jesus also, that he might sanctify the people with his own blood, suffered without the gate” (Hebrews 13:12).
The Apostle John pointed to the two-fold remedy for sin provided in the Atonement when he wrote, “If we walk in the light, as he is in the light, we have fellowship one with another, and the blood of Jesus Christ his Son cleanseth us from all sin [singular, denoting the sin nature]. If we say that we have no sin [that we were not born with a sin nature], we deceive ourselves, and the truth is not in us. If we confess our sins, [plural, meaning committed sins] he is faithful and just to forgive us our sins [salvation], and to cleanse us from all unrighteousness [sanctification]” (1 John 1:7-9). We obtain both forgiveness for committed sins and cleansing for the sin nature through the Atonement.
Divine healing. Divine healing is provided by the atonement. We read in Isaiah 53:5 that by His stripes, endured at the Crucifixion, we are healed. Peter reinforced this truth when he said of Christ, “Who his own self bare our sins in his own body on the tree, that we, being dead to sins, should live unto righteousness: by whose stripes ye were healed” (1 Peter 2:24). This includes healing of physical ailments and disease (see Matthew 8:16-17). Whether our need is physical, spiritual, or emotional, we can find the remedy in Jesus’ Blood.
Gives power in prayer. The atoning Blood is of primary importance in intercessory prayer. When we are living in obedience to every known command of God and find ourselves in need of protection, deliverance, or strength, we have access to God through the Blood of Jesus. We read, “Having therefore, brethren, boldness to enter into the holiest by the blood of Jesus, . . . Let us draw near with a true heart in full assurance of faith” (Hebrews 10:19,22). In Romans 8:34, Paul stated, “It is Christ that died, yea rather, that is risen again, who is even at the right hand of God, who also maketh intercession for us.”
Enables victorious living. Christ’s death at Calvary dealt a crushing blow to the enemy of our souls. The writer of Hebrews stated that Christ took on the form of human flesh and blood “that through death he might destroy him that had the power of death, that is, the devil; and deliver them who through fear of death were all their lifetime subject to bondage” (Hebrews 2:14-15). Through the Blood and the word of our testimonies, Satan is a vanquished enemy, for we read in Revelation 12:11, “And they overcame him by the blood of the Lamb, and by the word of their testimony; and they loved not their lives unto the death.” Knowing and recounting what God has done for us protects us from Satan’s deceptions.
Eternal life. If we believe and receive salvation and remain faithful to God, we will have the joyful privilege of being united with Christ throughout eternity, and the Atonement is the means by which this is possible. One of the most familiar verses in Scripture, John 3:16, states, “For God so loved the world, that he gave his only begotten Son, that whosoever believeth in him should not perish, but have everlasting life.”
Clearly, any attempt to place a value on the Blood of Christ would be impossible. It is priceless! The Blood is essential and can never be set aside or replaced.
A question for you
Have you availed yourself of the benefits that are available through the atoning work of Christ? Have your sins been forgiven? Do you know what it means to have the Blood of Jesus applied to your heart? If not, you can find deliverance from sin and power to live a life without sin from now to eternity. There truly is wonder-working power in the Blood of Jesus! | https://www.apostolicfaith.org/the-apostolic-faith/atonement-the-meaning-and-message-of-the-cross |
Comparisons can indeed be odious especially if comparing ourselves to others!
Two weeks ago I posted about self-kindness and the related benefits of being lazy. It’s hard not to be attracted by that advice! In reading about what other advice is out there, one expert suggests that you should concentrate on self-compassion rather than self-esteem in being kind to yourself. Hmm, maybe. But doesn’t that depend on the health of your self-esteem, and how specifically you define these terms? Along with the extraordinary stresses most people are experiencing during this never-ending pandemic, many people of all ages add to their stress – and distress – every day by continuing to measure themselves against some arbitrary societal standard. Surely, developing the self-confidence to be your own person and learning to like that person are important aspects of self-kindness. How can they not be? | https://waynewoodman.net/2021/02/04/self-kindness-includes-self-esteem/ |
BACKGROUND
SUMMARY
DETAILED DESCRIPTION
Isotopic labeling is one of two techniques for using isotopes to observe biological samples, at various molecular or atomic levels. One technique uses radioactive isotopes. The other technique involves less abundant, non-radioactive, or stable, isotopes. Observations are made by measuring the relative abundance of stable isotopes using equipment, such as mass spectrometers, which are devices that determine the relative amounts of various stable isotopes in a biological sample being analyzed.
This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
In accordance with this invention, a method, a computer-readable medium, and a system are provided. One method form of the invention includes a method for finding paired features in biological samples. The method comprises forming a composite image from an experiment in which a control sample and a treated sample, which has a tracing relationship with the control sample, are brought together as a prepared sample without having to identify a nucleic acid sequence of features. The method further comprises finding pairs of features of interest from the composite image, a member of a pair of features of interest being associated with another member of the pair according to the tracing relationship, which describes a constraint to find both members of the pair on the composite image.
In accordance with another aspect of the invention, a computer-readable medium form of the invention includes a computer-readable medium having computer-executable instructions stored thereon for implementing a method for finding paired features in biological samples. The method comprises forming a composite image from an experiment in which a control sample and a treated sample, which has a tracing relationship with the control sample, are brought together as a prepared sample, without having to identify a nucleic acid sequence of features. The method further comprises finding pairs of features of interest from the composite image, a member of a pair of features of interest being associated with another member of the pair according to the tracing relationship, which describes a constraint to find both members of the pair on the composite image.
In accordance with another aspect of the invention, a system form of the invention includes a system for finding paired features of interest. The system comprises a collection of chromatography and mass spectrometry instruments for receiving a prepared sample in which a control sample and a treated sample are submitted together for processing. The system further comprises an image processing pipeline for creating and processing a composite image from the prepared sample on which features are extracted and characteristics are calculated. The system further comprises a paired feature processor for processing the features from the composite image to find pairs of features of interest that are associated with one another according to a relationship without having to first identify the nucleic acid sequences of the features.
As will be illuminated, various embodiments of the present invention recognize the problem of identifying features, such as determining the exact protein sequences, before discovering pairs of features that are associated due to an experimental or biological relationship. Also, various embodiments of the present invention use a composite image formed from multiple samples being submitted to LC/MS instruments as a prepared sample or from multiple replicates so as to better reduce noise and better detection of features that have weak expression. Furthermore, various embodiments of the present invention allow isotopic labeling to be reversed to inhibit or reduce biases connected with isotopic labeling processes.
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A system in which paired features of interest are discovered from biological samples is shown in . Generally, experiments can be reduced to a comparison between two things: that which is a control and that which is treated; that which is not diseased and that which is diseased; that which is well and that which is sick; and so on. In proteomic experiments, scientists desire to know whether proteins behave differently with respect to introduced conditions. In metabolic experiments, scientists desire to know whether metabolites behave differently with respect to introduced conditions. There are many other types of experiments that can suitably leverage various embodiments of the present invention to better understand drug treatments, therapeutic outcomes, and toxicity risks.
Various embodiments of the present invention allow paired features of biological samples to be found without at first having to identify the features. After pairing, various embodiments allow the features, be they differentially or non-differentially expressed, to proceed to targeted identifications. Those features, now paired, if not having been previously identified, can be sent to tandem mass spectrometry or other pieces of equipment for identification of the peptide (or protein) sequences or metabolites. After the peptide, protein, or metabolite identification (or other biological identification), these features may be annotated by the peptide, sequence, protein sequence or metabolite information (or other biological information).
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Returning to , a control sample A is set aside. A treated sample A is an instance of the control sample that has undergone a treatment condition. Furthermore, added to or recognized within the treated sample A is a trace that allows its relationship to the control sample A to be tracked. One suitable trace is the addition of a label using a suitable isotopic labeling technique, such as SILAC or ICAT. A selected number of atomic mass units, such as six daltons, is used to label the treated sample A. This selected number or label will be used later in the system to trace the relationship of the control sample A and the treated sample A when they are represented as pairs of features found on a composite image. One member of the paired features probably originates from the control sample A and the other member of the paired features probably originates from the treated sample A. As illustrated in , the label that is used to label the treated sample A has a nomenclature of “labeled A.”
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The control sample A and the treated sample A (labeled A) can be prepared as a prepared sample to be submitted as a single run to the system . By allowing both the control sample A and the treated sample A (labeled A) to come into the system as one prepared sample , various embodiments of the present invention inhibit or reduce equipment dependent variations, which can inject falsities into experiments. With equipment dependent variations inhibited or reduced, found features can be attributed to the control sample A and the treated sample A (labeled A). For example, if there is a difference in the expression level of the treated sample A (labeled) as compared to the control sample A, the difference can be attributed to the treatment condition and not necessarily to the equipment dependent variations.
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A number of isotopic labeling techniques, such as SILAC, add label dependent biases, which inject falsities into experiments. Various embodiments of the present invention inhibit or reduce label dependent biases by supporting label reversal experiment protocol. For example, the control sample A can be labeled (labeled A) by the selected number of atomic mass units, such as six daltons, used previously to label the treated sample A. The treated sample A, on the other hand, is not labeled. The labeled control sample is now referenced as the control sample B and the non-labeled treated sample is now referenced as the treated sample B. The control sample B (labeled A) and the treated sample B can be prepared together with the control sample A and the treated sample A (labeled A) as the prepared sample to be submitted as a single run to the system . By allowing both the control samples A, B (labeled A) and the treated samples A (labeled A), B to come into the system as one prepared sample , the label-reversal experimental protocol is executed and label biases are inhibited or reduced.
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The system can also accommodate additional experiments that may be collected together with control samples A, B (labeled A) and the treated samples A (labeled A), B to come into the system as one prepared sample . For example, in another experiment with using the same control sample, a control sample C is provided, which is identical to the control sample A. A treated sample C is a sample in which an instance of the control sample C has undergone another treatment condition different from the treatment condition to which the treated sample A (labeled A) was subjected. The treated sample C is labeled using similar isotopic labeling technique but using a different number of atomic mass units, such as 12 daltons (labeled B).
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To inhibit or reduce label dependent biases, the control sample C and the treated sample C (labeled B) may also be subjected to a label reversal experiment protocol. For example, the control sample C can be labeled (labeled B) by the selected number of atomic mass units, such as 12 daltons, used previously to label the treated sample C. The treated sample C, on the other hand, is not labeled. The labeled control sample is now referenced as the control sample D and the non-labeled treated sample is now referenced as the treated sample D. The control sample D (labeled B) and the treated sample D can be prepared together with the control samples A-C and the treated sample A-C as the prepared sample to be submitted as a single run to the system . By allowing both the control samples A-D and the treated samples A-D to come into the system as one prepared sample , the label-reversal experimental protocol is executed and label biases are inhibited or reduced.
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The prepared sample is submitted to LC/MS instruments . LC/MS instruments allow biological features, such as peptides, to be separated in two dimensions (retention time and mass/charge). For a given retention time, a one-dimensional continuum can be obtained in the interested mass/charge range. Biological features are shown as isotope peaks in the continuum. The peak intensity is assumed to be proportional to the relative abundance of non-radioactive, stable isotopes, which are associated with biological features of interest. Eventually, the sequentially collected one-dimensional mass-spectrometer continua form a two-dimensional data set, with retention time being referenced as the x axis and mass/charge being referenced as the y axis.
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An image processing pipeline produces a feature list from the two-dimensional data set obtained from the LC/MS instruments , which includes feature characteristics and expression profiles. The image processing pipeline facilitates feature extraction so that features that are associated with other features by some relationships are paired for further scientific research. Some of the components (not shown) of the image processing pipeline include a composite image producer, which performs image preprocessing (data interpolation, image alignment, image noise filtering, background correction, and forming a composite image); and a composite image processor, which performs image feature extraction (peaks, isotope groups, and charge groups) and computes feature characteristics. Outputs of the image processing pipeline include a list of features and their characteristics.
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The list of features and their characteristics are provided to a paired feature processor . Using isotopic labeling, the paired feature processor finds whether one member of a pair of features is related to the other member of the pair of features by the number of atomic mass units. (Of course, if other types of relationships are used, the relation may be found, not in the number of atomic mass units, but by other indicators.) In other words, for a given retention time, the pair of features should be found to be separated primarily by the number of atomic mass units and not necessarily in time. Given that the y-axis of the composite image references mass/charge, the pair of features can be found vertically along the y-axis for a given retention time. For example, if a given isotope peak represents the expression of a control sample, such as the control sample A, one would expect to find another isotope peak, which represents the expression of the treated sample A (labeled A), separated by the number of atomic mass units, such as six daltons. In the end, the paired feature processor collects pairs of features, performs characteristic calculations, such as determining ratios of intensities, for further differential or non-differential analyses. For example, the pairs of features and their characteristics can help to illuminate whether protein expressions under different drug dosages occur for different experiments of different treatment conditions A-D,A-D.
FIG. 2
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shows that the image processing pipeline is comprised of a composite image producer . The composite image producer produces a composite image . The art has failed to recognize that merging images together into a composite image reduces noise and retains features that are weakly expressed but may be biologically important. As previously discussed, on this composite image are regions of interest that may represent features from the control samples A-D, some of which are reverse-labeled (labeled A, B), and features from the treated samples , A-D, some of which are labeled (labeled A, B). A composite image processor processes the composite image to find a list of features, such as isotope peaks, isotope groups, and charge groups. The composite image processor also calculates characteristics and profiles of these features.
Previously, the art has attempted to identify all the features by determining the sequences of the features prior to finding paired features. The art has failed to recognize that the step of identifying features need not occur prior to finding paired features of interest. Sometimes it is not possible to identify those features which have a low level of expression or for which the treatment condition inhibits expression. Additionally, there may be thousands of features, and it is inefficient to identify all of them. For those features that are not a member of a pair and therefore may not have a relationship of biological significance, they need not be identified. Attempts to identify all features before pairing may slow scientific discovery.
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The paired feature processor is shown in greater details in . The paired feature processor comprises a feature ranker , which takes the list of features produced by the composite image processor and ranks the list of features. The ranking places the features in an order so that those features with characteristics of the strongest signal have priority processing. For example, the ranking may be in a descending order where features with the greatest peak intensities and/or the greatest mass/charge be listed first so that they can be processed first. In this way, various embodiments of the present invention focus initial resources to those features that are likely to point to pairs of features of interest and avoid noisy features that may lead the analysis astray.
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A paired feature detector receives the ranked list of features and finds paired features of interest. As previously discussed, each pair may be composed of a feature originating from a control sample A-D and another feature originating from a treated sample A-D. After pairs of features of interest are found, for those features that lack identifying information, such as protein sequences, targeted identification can proceed. Tandem mass spectrometers or other identifying instruments can be set to trigger upon certain features to cause a breakdown so as to obtain nucleic acid sequences or amino acid sequences for those features. Again, as previously discussed, for biological reasons, sometimes features that are biologically significant fail to show up in a run through the system . The use of the composite image to merge all runs together so that, even if the features fail to show up in a forward-labeled run but succeed to show up in a reverse-labeled run, these features may appear in the composite image allowing pairs of features of interest that are associated by some relationships to be found. It does not matter to various embodiments of the invention where the features show up as long as biologically significant features are captured for subsequent analysis.
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The feature ranker provides to the paired feature detector the strongest features to the weakest features in a list. The paired feature detector starts with the strongest features and parses through the list of features to determine corresponding features that are candidates for pairing because of a relationship, such as the number of atomic mass units (a relationship by weight). For example, if the number of atomic mass units is six daltons, candidate features for pairing should appear about six daltons, within a user definable tolerance, away from the strongest features for a given retention time, also within another user definable tolerance. In one embodiment, the retention time tolerance defaults to ten seconds. The user can adjust the retention time tolerance as well as the mass/charge tolerance to accommodate equipment variations.
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After finding a pair of features of interest, the paired feature detector removes the pair from the ranked list of features. The paired feature detector then focuses on the next strongest feature in the ranked list of features and attempts to find another feature that corresponds to the strongest feature to pair them up. It is possible that the paired feature detector may find a number of features that are candidates for pairing with the strongest feature. When this occurs, the paired feature detector selects a candidate feature from all other candidate features that has the largest mass and the closest retention time with respect to the strongest feature in the ranked list of features. To limit computing resources that the paired feature detector may use to find candidate features, the retention time tolerance defines the extent within which the paired feature detector may venture to find candidate features. Similarly, a mass/charge tolerance is used to define the extent within which the paired feature detector may find candidate features. In one embodiment, the default tolerance in the mass/charge direction is 0.1 part per million, and is dependent on the equipment and its operating mode.
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One type of feature received by the feature ranker is isotope group. There can be multiple isotope groups. One isotope group may have a number of isotope peaks, and another isotope group may have a different number of isotope peaks. There may be a large number of isotope groups. The paired feature detector limits the search for pairs of features of interest by a user selectable threshold, which defaults to four. In other words, after looking at the fourth isotope group for isotope peaks that may be candidates for pairing, the paired feature detector will not venture beyond to other isotope groups to find additional candidates.
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The paired feature detector determines a common number of isotope peaks between two isotope groups, focuses on the common number, and disregards extra isotope peaks that are not part of the common number of isotope peaks. For example, a first isotope group has three isotope peaks beginning with those isotope peaks with the lowest mass/charge; the paired feature detector may have found a paired feature in a second isotope group but this second isotope group has five isotope peaks. In one embodiment, to create a common number of isotope peaks, the paired feature detector may choose to use the three lowest mass/charge isotope peaks of the first isotope group and the three lowest mass/charge isotope peaks of the second isotope group while disregarding the highest mass/charge isotope peaks of the second isotope group. In another embodiment, the common number of isotope peaks can be chosen from those isotope peaks that have the greatest intensities. For example, the paired feature detector may choose to use the three isotope peaks with the greatest intensities in both the first and second isotope groups.
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Paired features of interest found by the paired feature detector are forwarded to a paired feature characteristic processor . One processed characteristic includes ratios of intensities. The paired feature characteristic processor takes the intensities of isotope peaks of one isotope group as members of a pair, which represent a treated sample, and sums the intensities into a dividend. The paired feature characteristic processor then takes the intensities of isotope peaks of another isotope group as members of the pair, which represent a control sample, and sums the intensities into a divisor. A ratio is created from the dividend and the divisor. The paired feature characteristic processor creates sets of ratios. From these ratios, the paired feature characteristic processor generates profiling parameters for allowing expression information to be searched. One profiling parameter is to take the common logarithm of a ratio after which the error of the common logarithm is calculated to obtain p-values for each pair of features.
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P-values are used for differential detection. A user can use a paired feature characteristic searcher to set a differential threshold. The paired feature characteristic searcher gathers those pairs with p-values that are less than the differential threshold and present those pairs to the user for further analysis. For example, in looking closer at a pair of features that is found by the paired feature characteristic searcher , the user may determine that a member of the pair may lack identifying information. The user may set a triggering mechanism at a particular retention time in a tandem mass spectrometry process to cause instruments to target the member of the pair to determine its nucleic acid or amino acid sequence. This avoids the need to identify all features and instead those features that have an experimental or biological relationship are brought to the fore as a focus for further discovery.
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As an aside, the paired feature characteristic processor may perform normalization. If a ratio of intensities is less than a normalization level, the ratio may not add knowledge and the ratio can be eliminated. One normalization technique includes summing all isotope peaks of a control sample and dividing by the number of isotope peaks to obtain an average of the control sample. Similarly, an average of the treated sample is obtained by summing all isotope peaks of a treated sample and dividing by the number of isotope peaks. If the averages of the control sample and the treated sample are not similar, a scaling process is executed to produce a normalization level to get rid of ratios that are not significant.
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FIG. 3
A graph visually explains a composite image that includes features of interest representing common samples and treated samples. See . The graph includes a y-axis, which is a reference for a mass/charge dimension, and an x-axis, which is a reference for a retention time dimension. At a particular retention time, three isotope group features appear. One of the three isotope groups includes a control isotope group , which represents a control sample. The control isotope group includes four isotope peaks . The four isotope peaks may be members of pairs that relate a control sample to a treated sample.
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Another of the three isotope groups includes a treated isotope group A that has three isotope peaks . The treated isotope group A appears along a similar retention time as the control isotope group and thus, the three isotope peaks may be candidates for pairing with the isotope peaks of the control isotope group . The treated isotope group A may represent a treated sample that has been labeled by a number of atomic mass units, which separate the treated isotope group A from the control isotope group by the amount of atomic mass units used in the isotopic labeling, such as six daltons. A common number of isotope peaks may be established by the paired feature processor given the differences in the number of isotope peaks and . For example, there are three isotope peaks in the isotope peaks whereas there are four isotope peaks in the isotope peaks . In this instance, the common number of isotope peaks may be designated as three given that the treated isotope group A has three isotope peaks .
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If another experiment was part of the same prepared sample submitted to the LC/MS instruments , a representation of another treated sample may appear on the graph , such as a treated isotope group B , which has five isotope peaks . If the same common sample was used, some of the five isotope peaks of the treated isotope group B may be paired with the isotope peaks of the control isotope group . A common number of isotope peaks is determined, which in this case is four. If a scheme for establishing common isotope peaks is based on the lowest isotope peaks of the isotope groups , , and , a line has three ticks. The bottom tick of the line indicates that the lowest isotope peak can be paired with the lowest isotope peak referenced by the middle tick, and furthermore, the lowest isotope peak can be paired with the lowest isotope peak as referenced by the top tick of the line . The remaining lines , , and shows other pairings.
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The graph shows that the focus on various embodiments of the present invention is to find pairs of features that are associated with each other according to some relationship. The graph shows isotope groups appearing at a similar retention time and these isotope groups are separated by a certain mass/charge, which may define the relationship. These relationships define constraints by which the paired feature processor can find pairs of features of interest. In some of the above examples, an isotopic label was added to a treated sample. In other examples (not shown), instead of using isotopic labels, the paired feature processor can find relationships that are based on other constraints, such as the presence of a particular molecule, and so on. In yet other examples (not shown), the paired feature processor can find relationships that are based on metabolites, such as the present of an acquired atom or the loss of an atom, and so on.
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FIGS. 4A-4C
Some experiments introduce bias, which is not desired. For example, in attaching an isotopic label to a treated sample, a bias may be introduced. Some peptides exhibit consistent label-dependent ratio biases. These biases may appear in up regulation, down regulation, or both. The resultant expression of the treated sample may also contain the same bias. The art has failed to recognize that this bias should be removed to enhance experimental results. Graphs - as illustrated in show a removal of biases after a reverse-label experimental protocol is implemented. In all graphs -, the y-axis references the natural logarithm of the ratios and the x-axis references the natural logarithm of the scaled intensities of the paired features. The graph (which displays features that are forward-labeled) and the graph (which displays features that are reverse-labeled) show biases away from the clusters. After executing a reverse-label experiment protocol, these biases disappear as shown by the graph .
FIGS. 5A-5K
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illustrate a method for finding paired features of interest in biological samples. From a start block, the method proceeds to a set of method steps , defined between a continuation terminal (“Terminal A”) and an exit terminal (“Terminal B”). The set of method steps describes the production of a prepared sample and its processing to produce a composite image for feature extraction and calculation of feature characteristics.
FIG. 5B
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From Terminal A (), the method proceeds to block where a control sample is set aside for an experiment. A treated sample is created from an experiment of a different phenotypical or treatment condition. See block . The treated sample is labeled so as to contain an isotopic tracer using non-radioactive, stable isotopes that composed of a particular number of atomic mass units, such as six daltons. See block . The method then continues to decision block where a test is performed to determine whether the protocol of the experiment requires label reversal. If the answer to the test at decision block is YES, the method proceeds to another continuation terminal (“Terminal A”). If the answer to the test at decision block is NO, the method proceeds to another continuation terminal (“Terminal A”).
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From Terminal A (), an instance of the control sample is labeled with the isotopic tracer composing the same number of atomic mass units as was used to label the treated sample. See block . An instance of the treated sample is set aside without being labeled with the isotopic tracer. See block . Next, at decision block , a test is performed to determine whether there is another experiment of a different phenotypical or treatment condition. If the answer to the test at decision block is NO, the method continues to another continuation terminal (“Terminal A”). If the answer to the test at decision block is YES, the method continues to block where a new isotopic tracer is chosen as a label using non-radioactive, stable isotopes composed of another number of atomic mass units (another label), such as 12 daltons. Steps - are repeated using the new isotopic tracer for the new experiment. See block . The method then continues to Terminal A.
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From Terminal A (), the method proceeds to block where prepared control and treated samples, labeled or non-labeled, from one or more experiments are collected together as a prepared sample for submission to the LC/MS instruments. A composite image is produced containing mass spectrometry spectra in three dimensions: mass/charge in the y-axis, retention time in the x-axis, and values of isotope peaks in the z-axis. The method then continues to the exit terminal B.
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From Terminal B (), the method proceeds to a set of method steps , defined between a continuation terminal (“Terminal C”) and an exit terminal (“Terminal D”). The set of method steps finds paired features, such as paired isotope peaks or other pairs that are associated by a particular relationship.
FIG. 5E
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From Terminal C (), the method proceeds to block where the features are ranked, in descending order, by the intensities of the isotope peaks. The intensity-ranked features are further ranked, in descending order, by the mass of the isotope peaks. See block . The method then selects the first isotope peak in the ranked list, which is the highest ranked isotope peak with the strongest intensity. See block . The method determines the isotope group (first isotope group) to which the first isotope peak belongs. See block . The method continues to another continuation terminal (“Terminal C”). The method searches the ranked list to find a labeled isotope peak in a second isotope group within retention time and mass/charge tolerances. See block . The method notes the found isotope peak, which is spaced from the first isotope peak by a number of atomic mass units, such as six daltons, as a potential candidate or member of a paired isotope group. See block . The method continues to another continuation terminal (“Terminal C”).
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From Terminal C (), the method proceeds to decision block where a test is performed to determine whether there are other labeled isotope peaks in the second isotope group. If the answer to the test at decision block is NO, the method proceeds to another continuation terminal (“Terminal C”). If the answer to the test at decision block is YES, the method proceeds to another decision block where another test is performed to determine whether the other labeled isotope peaks are within the retention time and mass/charge tolerances. If the answer to the test at decision block is NO, the method continues to Terminal C. If the answer to the test at decision block is YES, the method continues to Terminal C.
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From Terminal C (), the method proceeds to block where from all the candidates or potential members, the method selects one that is closest to the first isotope peak in retention time and is spaced closest to the number of atomic mass units (label). The selected member becomes a member of the paired isotope group and the other member is the first isotope peak. See block . The selected member, which is an isotope peak in the second isotope group and which corresponds to the first isotope peak in the first isotope group, is removed from the ranked list. See block . A test is performed at decision block to determine whether the limit for searching additional isotope groups has been reached. If the answer to the test at decision block is YES, the method continues to another continuation terminal (“Terminal C”). If the answer to the test at decision block is NO, the method continues to block where the method uses another number of atomic mass units to search for another isotopic group that may contain paired isotope peaks. The method then proceeds to Terminal C and skips back to block where the above processing steps are repeated.
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From Terminal C (), the method proceeds to block where the first isotope peak from the first isotope group is removed from the ranked list. A test is performed at decision block to determine whether the limit to seed further searches for paired isotope peaks has been reached. If the answer to the test at decision block is YES, the method proceeds to exit terminal D. If the answer to the test at decision block is NO, the method proceeds to block where the method selects another isotope peak in the ranked list, which is the highest ranked isotope peak with the strongest intensity. The method then continues to Terminal C and skips back to block where the above processing steps are repeated.
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From exit terminal D (), the method proceeds to a set of method steps , defined between a continuation terminal (“Terminal E”) and an exit terminal (“Terminal F”). The set of method steps describes the calculation of paired feature characteristics for searches to be performed to find paired features of interest.
FIG. 5I
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From Terminal E (), the method proceeds to block where the method has found a set of paired isotope groups, each group containing an isotope peak from a control sample and another isotope peak from a treated sample. A sum of intensities of all members of a pair that belong to one isotope group is calculated. For example, if there are three pairs, each pair including a member that originates from a control sample, the peak intensities of the three members that originate from the control sample are summed. The peak intensities of the remaining three members that originate from the treated sample are summed. A ratio is created for each pair by taking the sum of intensities of the isotope peaks from a treated sample as a dividend and the sum of intensities of the isotope peaks from a control sample as a divisor. See block . A common logarithm is taken for each ratio. See block . The error of each common logarithm of each ratio is calculated. See block . Other characteristics of paired isotope groups are calculated by the method. See block . The method proceeds to another continuation terminal (“Terminal E”).
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From Terminal E (), the method proceeds to block where p-values are generated for the common logarithms of the ratios of all paired isotope groups. For differential detection, a user specify a differential threshold. See block . A test is performed to determine whether there are p-values that are smaller than the threshold. See decision block . If the answer to the test at decision block is NO, the method proceeds to block where the experiment was not differentially expressed according to the threshold. The method continues to another continuation terminal (“Terminal E”). If the answer to the test at decision block is YES, the method proceeds to block where the list of features with p-values less than the threshold is presented to the user. The method continues to exit terminal F and terminates execution.
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From Terminal E (), the method proceeds to block where the method identifies features with no identification. A test is performed at decision block to determine whether the user wishes to execute a targeted analysis. If the answer to the test at decision block is NO, the method proceeds to exit terminal F and terminates execution. If the answer to the test at decision block is YES, the method proceeds to block where the user uses the generated feature list to select those features for targeted analysis. Tandem mass spectrometry technique is used to identify peptide sequences and other information from the selected features. See block . The method continues to exit terminal F and terminates execution.
While illustrative embodiments have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
DESCRIPTION OF THE DRAWINGS
The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
FIG. 1
is a block diagram illustrating an exemplary system for finding paired features of biological samples that have a relationship that defines their pairing;
FIG. 2
is a block diagram illustrating an exemplary paired feature processor for finding paired features of biological samples that have a relationship that defines their pairing;
FIG. 3
is a pictorial diagram illustrating an exemplary graph of isotope groups separated by labels with the x axis representing retention time and the y axis representing mass over charge;
FIGS. 4A-4C
are pictorial diagrams illustrating exemplary graphs that show bias connected with isotopic labeling and its elimination or reduction according to various embodiments of the present invention; and
FIGS. 5A-5K
are process diagrams illustrating an exemplary method for finding paired features of interest in biological samples according to a relationship. | |
The following article by Ruy Teixeira, author of The Optimistic Leftist and other works of political analysis, is cross-posted from his blog:
In my latest for The Liberal Patriot, I consider the Democrats’ ongoing problems with Hispanic voters.
“The Democrats are steadily losing ground with Hispanic voters. The seriousness of this problem tends to be underestimated in Democratic circles for a couple of reasons: (1) they don’t realize how big the shift is; and (2) they don’t realize how thoroughly it undermines the most influential Democratic theory of the case for building their coalition.
On the latter, consider that most Democrats like to believe that, since a relatively conservative white population is in sharp decline while a presumably liberal nonwhite population keeps growing, the course of social and demographic change should deliver an ever-growing Democratic coalition. It is simply a matter of getting this burgeoning nonwhite population to the polls.
But consider further that, as the Census documents, the biggest single driver of the increased nonwhite population is the growth of the Hispanic population. They are by far the largest group within the Census-designated nonwhite population (19 percent vs. 12 percent for blacks). While their representation among voters considerably lags their representation in the overall population, it is fair to say that voting trends among this group will decisively shape voting trends among nonwhites in the future since their share of voters will continue to increase while black voter share is expected to remain roughly constant.
It therefore follows that, if Hispanic voting trends continue to move steadily against the Democrats, the pro-Democratic effect of nonwhite population growth will be blunted, if not cancelled out entirely, and that very influential Democratic theory of the case falls apart. That could—or should—provoke quite a sea change in Democratic thinking.
Turning to the nature and size of recent Hispanic shifts against the Democrats—it’s not as bad as you think, it’s worse. Here are ten points drawn from available data about the views and voting behavior of this population. Read ‘em and weep.
1. In the most recent Wall Street Journal poll, Hispanic voters were split evenly between Democrats and Republicans in the 2022 generic Congressional ballot. And in a 2024 hypothetical rematch between Trump and Biden, these voters favored Biden by only a single point. This is among a voter group that favored Biden over Trump in 2020 by 26 points according to Catalist (two party vote).”
Read all ten at The Liberal Patriot. And subscribe! | https://thedemocraticstrategist.org/2021/12/teixeira-its-not-as-bad-as-you-think-it-is-its-worse/ |
Virtual Learning Code Conduct
All D. A. T. E., students receiving digital curriculum and direct instruction online are subject to any applicable District policies and this Student Virtual Learning Code of Conduct.
Students are responsible for proper behavior during online learning.
Students are expected to take integrity and use authenticity of their own work.
It is illegal to create harmful computer viruses.
Remote Learning correspondences are public under school’s records and subject to disclosure.
Internet Policy
Data that is composed, transmitted, accessed, or received via the Internet must not contain content that could be considered discriminatory, offensive, obscene, threatening, harassing, intimidating, or disruptive to any other person. Examples of unacceptable content may include, but are not limited to, sexual comments or images, racial slurs, gender-specific comments, or any other comments or images that could reasonably offend someone on the basis of race, age, sex, religious or political beliefs, national origin, disability, sexual orientation, or any other characteristic protected by law.
Disciplinary Action
Progressive discipline will continue to be utilized to create the expectation that the degree of discipline imposed will be in proportion to the severity of the behavior. Violations of the Code of Conduct will result in disciplinary action up to and including Districts policies and guidelines.
Curriculum, Instruction & Assessment
Dr. K. Taylor,
Dr. E. Wilson
Middle School Principal
Please have a very Safe Spring Break.
D. A. T. E.'s Motto: "Learning with Relationships, Relevance, and Rigor."
Dr. H. McCladdie,
These scholars are to be celebrated for their greatness and contribution to the world of Science, Technology, Engineering, and Mathematics.
Mrs. Shillingford
S.T.E.M./S.T.E.A.M. Coordinator
Environmental Specialist
Mrs. Angel Haye
School Counselor
[email protected]
Thank You, | https://us18.campaign-archive.com/?u=0639a853a6128915a75e03ee0&id=8196810bd0 |
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The Emergency Utility and Rental Assistance program serves Chester County residents and can only be accessed by dialing 2-1-1 and selecting the prompt for "Housing Crisis."
To access the program, residents must call 2-1-1 to conduct an initial intake and referral to one of Chester County’s five contracted providersFunding will serve individuals and families that are obligated to pay rent and meet the following three criteria:
Priority of service shall be prioritized to eligible applicants, including: | https://phoenixville.org/CivicAlerts.aspx?AID=210 |
Background Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of underserved groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of underserved groups in clinical trials.
Methods The project comprised three main strands: 1) a targeted scoping review of literature to identify previous work characterising underserved groups and barriers to inclusion; 2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice; 3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans, and a strategic roadmap for future development work in this area.
Results ‘Underserved groups’ was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of underserved groups did not currently exist; definition was challenging and context-specific but exemplar groups (e.g. those with language barriers or mental illness) were identified as underserved. Barriers to successful inclusion of underserved groups could be clustered into: communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with underserved groups; developing training resources to improve design and delivery of trials for underserved groups; developing infrastructure and systems to support this work, and working with funders, regulators and other stakeholders to remove barriers to inclusion.
Conclusions The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different underserved groups to improve the representativeness of trial populations. | https://www.researchsquare.com/article/rs-11920/v2 |
My client is a highly regarded, interior design practice known for their design work both nationally as well as internationally within the high-end residential, hospitality and commercial sectors.
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The Role:
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Key Responsibilities:
- Producing documentation packages
- Preparing renders
- Working as part of a high performing, award-winning team as well as individually
To be considered for this position, you should posses:
- A minimum of 1 years' local, post-graduate experience in a similar position
- Tertiary qualifications in Interior Design or a related discipline
- Proven technical abilities with AutoCAD & Adobe Creative Suite (particularly InDesign and Illustrator)
- Strong documentation skills - as evidenced in your portfolio
- Prior experience working on residential and commercial/hospitality projects ideally
- Full Australian Working Rights
If the above position appeals to you, please click 'Apply Now' and submit your application. | https://www.cgcrecruitment.com/job/draftsperon/ |
WASHINGTON—President Barack Obama and the congressional leadership sit down for lunch at the White House on Friday to search for ways to co-operate and try to break Washington’s gridlock when Republicans take control of both chambers in the next Congress.
The midterm election earlier this week produced a stunning rebuke to Obama and his Democrats, with Republicans snatching control of the Senate and widening their dominance in the House of Representatives.
The new configuration leaves Obama and the Republicans with the choice of finding points of compromise — on issues such as overhauling the tax code and immigration reform — or to continue acting on the ideological gulf that has seized the nation’s politics.
Obama’s only defence, if compromise cannot be found, would be his presidential veto power over legislation when it hits his desk. The Republicans, while in power in both houses, do not have a sufficiently large majority to override a presidential veto.
Both Republicans and Democrats in Congress could temper their partisanship as they look forward to the next election that will include choosing a new president. One of the big messages voters delivered this year was disgust with the government’s inability to act.
Republicans have said that they must show the American public they can use their new powers to govern, not just oppose the president.
Republicans took over at least seven seats in the 100-member Senate on Tuesday, more than enough to grab the majority next year. With three Senate races still uncalled, the Republicans could win more seats for a majority. In the House, the Republican dominance increased to levels not seen since shortly after the end of World War II.
Sitting down for lunch with the president are 16 top-ranking lawmakers. They will be looking at a way forward on unfinished business that must be wrapped up before the end of this year’s session. But even more important will be the atmospherics that could set the tone for the next Congress is sworn in after the New Year.
Democratic Senate Majority Leader Harry Reid, Obama’s failsafe for his first six years in office, is about to lose his grip on the upper chamber. Senate Republican leader Mitch McConnell is riding a wave of electoral success into the top job. Republican House Speaker John Boehner is carrying himself with renewed confidence after padding his majority. House Democratic leader Nancy Pelosi of California presides over a diminished minority.
In the hours after voters delivered their verdict, both Obama and McConnell voiced optimism about the potential to find common ground, despite the rancour and wide ideological gulf that has undermined such co-operation in the past.
“I’m sure there will be plenty of things for us to disagree about,” White House spokesman Josh Earnest said Thursday. “But if there’s an opportunity for us to find some common ground, let’s make sure that our differences don’t get in the way of us being able to make some progress for the American people.”
But bipartisan aspirations for compromise were quickly tempered. Many of the thorny issues that divided Democrats and Republicans before the election began to rise to the surface yet again now that Republicans are able to push legislation through both chambers and to Obama’s desk unimpeded by Senate Democrats.
McConnell vowed renewed efforts next year to chip away at Obama’s health care law — his signature legislative achievement from the brief era just after his election when Democrats controlled both the House and Senate. Republicans in both chambers put Obama on notice they plan to twist his arm on the long-delayed Keystone XL oil pipeline that the Republican Party wants approved.
Boehner, in his first news conference after the elections, warned Obama on Thursday that following through with his plans to take sweeping executive action on immigration would be like playing with matches.
“He’s going to burn himself if he continues to go down this path,” Boehner said.
While Obama will be hobbled in the final two years of his presidency, McConnell and Boehner will find compromise very difficult because of the ultra-conservative tea party Republicans who remain determined to do little other than stymie the president’s agenda. | https://www.thestar.com/news/world/2014/11/07/obama_republicans_search_for_common_ground_at_first_postelection_meeting.html |
BACKGROUND OF THE INVENTION
(a) Field of the Invention
(b) Description of the Related Art
SUMMARY OF THE INVENTION
BRIEF DESCRIPTION OF THE DRAWINGS
DETAILED DESCRIPTION AND THE PREFERRED EMBODIMENTS
[Example 1]
Preparation of an anode
Preparation of a cathode
[Examples 2 to 5]
[Comparative Example]
[Experiment 1]
[Experiment 2]
The present invention relates to a non-aqueous electrolyte additive for improving safety and a lithium ion secondary battery comprising the same, and more particularly to a non-aqueous electrolyte additive that can improve cycle life and safety properties of a lithium ion secondary battery.
In concert with the development of the information electronics industry, studies regarding batteries, which are referred to as the heart of all electronic equipment, are actively in progress. Specifically, a lithium ion secondary battery with a light weight and a high capacity has attracted attention as one of the essential parts of electronic equipment with the miniaturization of high-technology electronics equipment.
4
6
The lithium ion secondary battery uses a transition metal complex oxide such as lithium, cobalt, etc. as a cathode active material; a crystallized carbon such as graphite as an anode active material; and an aprotic organic solvent in which lithium salts such as LiClO, LiPF, etc. are dissolved as an electrolyte. Such a battery has high performance and a light weight, rendering it suitable as a battery for miniature electronic equipment such as cellular phones, camcorders, notebook computers, etc. However, this battery has many safety problems since it does not use an aqueous electrolyte but instead uses a highly flammable organic solvent as an electrolyte. Safety is the most important aspect of a lithium ion secondary battery using a non-aqueous electrolyte, and specifically, preventing short circuits and overcharging problems are very important factors thereof.
In the lithium secondary battery, the method of stopping a fire of the battery due to a short circuit of the battery have not been well known except a design aspect of the battery. As the capacity of the battery increases, the discharge current increases, and therefore the dangerousness due to a short circuit becomes more serious.
Recently, in order to prevent overcharge, a various additive is developed. This is method that an organic materials added as an additive is decomposed on electrode surface to intercept a current by forming a polymer insulating film on the electrode when reaching fixed overvoltage. However, although the method has superior effect on overcharge, it has a problem reduced cycle life of the battery due to a necessity a many additive in order to reveal its effect.
In addition to, a method involves using electronic circuit shch as the method a mechanically intercepting a current by aggravating the occurrence of gas when overcharging, or the method shutting down a circuit by melting a separator.
As a further method, it is the use of a chemical reaction using a suitable redox shuttle additive in the electrolyte of the lithium battery. However, the method may be effective since overcharge current between a negative electrode and a positive electrode can be consumed, only on condition that reversibility of oxidation-reduction reaction is excellent.
1-206571 (1989
In relation to this method, Japanese Patent Publication No. ) discloses that ferrocene compound is applied in the 3 Voltage class batteries, which can be a useful method in terms of cost efficiency. However, because the practical lithium secondary battery has the voltage of about 4V region, the battery needs oxidation-reduction agent un-decomposed in the voltage region.
7-302614 (1995
n
2n+1
3
Japanese Patent Publication No. ) proposes a new redox shuttle additive applicable in 4V grade, which combines the alkyl group (R: CH) or the methoxy group (OCH) as the electron-donating group of benzene ring. However, because the amperage capable of reversible redox shuttle is low, the effect has been defective in case of high amperage.
U.S. Pat. No. 5,709,968
1998
() discloses that the capability of a redox shuttle in the battery of 4V grade is improved largely by combining benzene with halogen. However, as amperage inflicted in case of overcharge increases with a high capacity of battery, a concentration of additive capable of consuming a current also increases as an adverse effect in a cycle life etc.
US patent n°6,168,885
discloses methods and compositions for manufacture of an electrode using a fire-retardant solvent. The fire-retardant solvent can be either a solvent that generate a fire-retardant gas upon decomposition or an electro-chemically inactive compound, chosen in particular from phosphates, phosphazones, borates, siloxanes, fluorinated carbonates and fluorinated ether.
WO 97/44842
International patent application discloses a lithium battery comprising a fire-retardant electrolyte composition, which comprises a lithium salt dissolved in a solvent selected from the group consisting of a phosphate, a phospholane, a cyclophosphazone, a silane, a fluorinated carbonate, a fluorinated polyether, and mixtures thereof.
Analysis of Redox Additive-Based Overcharge Protection for Rechargeable Lithium Batteries", J. Electrochem. Soc., vol. 138, N° 8, August 1991, pages 2224-2229
The publication entitled ", discloses the results of a theoretical study of the overcharge situation in lithium batteries in the presence of a redox additive (1,1'-dimethylferrocene).
11 162508
Japanese patent application n° discloses an electrolyte for use in a battery which is produced by reacting an organic silane compound with a fluorine compound in a non-aqueous solvent.
WO 01/29920
International patent application discloses a battery for electrochemical storage cell in which the electrolyte comprises a shutdown additive selected from halogenated benzenes, substituted methoxybenzenes, substituted benzodioxoles, alkyl polyethers, and substituted nitrogen containing heterocycles.
Polymer electrolytes based on a dimethylsiloxane-polyethylene oxide copolymer", Eur. Polym. J. 26, 987 (1990
The publication entitled ") discloses the results of ionic conductivity for a lithium perchlorate-doped polymer. The polymer has an enhanced ionic conductivity at room temperature.
WO 00/19552
International patent application discloses a composite electrode for a rechargeable lithium battery. The composite electrode consists of an organic polymer laminate rendered electrically conductive by embedded electrically conductive particles.
The present invention is made in consideration of the problems of the prior art, and it is an object of the present invention to provide a non-aqueous electrolyte additive that can achieve superior safety even under dangerous circumstances caused by misoperation or misuse of the battery, including a large current discharge due to an overcharge or a short circuit in a 4V grade lithium and lithium secondary battery charged with a large current and a high energy density.
It is another object of the present invention to provide a lithium ion secondary battery comprising the non-aqueous electrolyte additive.
1
2
3
3
wherein R and R, which are independently or simultaneously an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an acetyl group, a sulfonic acid group, or fluorocarbon, acetoxy, -OSOH, -CF, or a phenyl group or phenoxy group substituted by an alkyl group with 1 to 4 carbon atoms or a halogen;
M is an atom selected from the group consisting of Al, B, Si, Ti, Nb, V, Cr, Mn, Fe, Co, Ni, Ga, Zr and Ta;
x is a valence of a central metal atom;
y is a value satisfying 0≤ y < x-2.
In order to achieve these objects, the present invention provides a non-aqueous electrolyte additive comprising an organometallic compound represented by the following Chemical Formula 1:
a) an anode capable of adsorbing and releasing lithium;
b) a cathode capable of adsorbing and releasing lithium; and
c) a non-aqueous electrolyte comprising an organometallic compound represented by the above Chemical Formula 1.
The present invention also provides a lithium ion secondary battery comprising:
Fig. 1
shows a structure of the lithium ion secondary battery of the present invention.
Fig. 2
shows change in temperature and voltage of the battery of the Comparative Example, according to overcharge time.
Fig. 3
shows change in temperature and voltage of the battery of Example 1 of the present invention, according to overcharge time.
The present invention will now be explained in detail.
The present invention provides an organometallic compound represented by the above Chemical Formula 1 wherein around the central atom are substituted by a substituent, preferably a phenyl group and oxygen, as a non-aqueous additive for a non-aqueous electrolyte in which a lithium salt is dissolved, for improving safety of a lithium ion secondary battery. In addition, the present invention provides a lithium ion secondary battery that uses lithium or carbon capable of adsorbing and releasing lithium as an anode, a specific complex oxide of lithium and a transition metal as a cathode, and an organometallic compound represented by the Chemical Formula 1 as a non-aqueous electrolyte. According to the present invention, a large current discharge due to a short circuit or overcharge caused by battery misoperation or misuse can be prevented by a chemical reaction of additives included in a non-aqueous electrolyte, and thus safety of a battery can be improved.
The organometallic compound represented by the Chemical Formula 1 used as additive for non-aqueous electrolyte in the present invention does not function in a battery operated within the normal voltage range, and thus it does not affect the cycle life properties of the battery.
On the other hand, if the voltage abnormally increases by being overcharged, etc., additives of the non-aqueous electrolyte of the lithium ion secondary battery that decompose at the surface of the cathode under a completely charged state produce decomposition by-products (preferably benzene-based compounds) that form radicals that polymerize and thereby form an insulating film on a cathode surface. In addition, a metallic inorganic substance of the residue is activated to improve thermal stability of an insulating film formed on the cathode surface. Moreover, at a large current discharge, coordinators hydrated by hydrolysis with moisture are converted into hydroxy functional groups and react with lithium rushed from the anode to form an insulating film on the cathode surface, thereby giving safety to the battery.
1
2
Specifically, the organometallic compound represented by the Chemical Formula 1 is preferable benzene-based compound having a stable R, and it is a metal compound that consists of the oxygen having a strong reactivity with a metal, and R having a good affinity with a non-aqueous electrolyte. Therefore, the compound does not function in a battery operated within the normal voltage range. And, since oxygen, a phenyl group and an alkyl group coordinated a metal has superior affinity with a non-aqueous electrolyte, the compound is a good dissolved in the non-aqueous electrolyte, and thus it does not affect the cycle life properties of the battery. Furthermore, the compound has oxygen bonded with a metal, and thus if a sudden current such as a large current discharge flows, the compound decreases the diffusion rate of lithium and it reacts with lithium to form an insulating inorganic compound on the cathode surface, thereby improving safety of the battery due to interception of an electron flow. The organometallic compound represented by the Chemical Formula 1, if a battery is abnormally overcharged in a non-aqueous electrolyte are decomposed into a benzene-based compound and a metal compound having oxygen. The decomposed benzene-based compound forms an insulating polymer film on the cathode surface to intercept a current due to overcharge, and thus the safety of the battery can be obtained. In addition, in order to intercept an electron flow, a reside metal compound reacts with the polymer insulating film, thereby restraining an ignition of the battery caused by exothermic reaction due to overcharge.
1
2
1
2
1
2
1
2
1
2
In the compound of Chemical Formula 1, R and R is not a necessity that will be always coexistence, and there are changed by a valance of metal of a central atom due to a bond of a metal of a central atom and oxygen. That is, if the valance of metal is triply-charged, R and R is not coexistence, and thus the compound existing only one of R and R becomes. If the valance of metal is fifth-charged, one of R and R is combined a substituent of 2 or more with the metal of central atom. Furthermore, in case of an additive having many a phenyl group such as R and R, a formation of a polymer insulating film is superior. However, since the oxygen bonded with the metal atom has a high reactivity, at a large current discharge due to a short circuit, the compound reacts with lithium rushed from the anode to form an insulating film on the cathode surface, thereby giving safety to the battery.
1
2
As explained, a preferable the compound as a non-aqueous electrolyte additive is a compound that a metal atom is in center and a phenyl group, a sulfonic acid group, a fluorocarbon or an alkyl group with 1 to 4 carbon atoms the around is combined thereto. Wherein, the alkyl group is changed reaction degree according to a value of n, but it is a stable form in an organic solvent. Therefore, a reactivity of the oxygen bonded with the metal existing in the compound changes according to an atom located in center. The metal atom bonded with the oxygen easily reacts with activated lithium to form an insulator of a glass configuration. The phenyl group of the compound provides a benzene-based compound and activated metal oxide by decomposing when overcharging, and thus a safety of the battery further improves by forming a polymer insulating film and a ceramic insulating film forms due to a benzene-based compound. In addition to, the phenyl group of the compound reacts with lithium deposited in the anode to remove activity of lithium and form a ceramic insulating film, thereby providing effective methods for achieving battery safety. If R and R of the compound is a sulfonic acid group, or a fluorocarbon, when the compound is decomposed due to overcharge and a large current discharge, the thermal stability of the battery can be improved by forming a fireproofing gas.
2
x
The ceramic insulating film capable of form in the present invention is an amorphous form, and it can be formed a shape of LiO · MO (wherein x is changed according to a valance of M) or lithium metal inorganic compound.
According to the present invention, a non-aqueous electrolyte lithium ion secondary battery comprising the compound represented by the Chemical Formula 1 as a non-aqueous electrolyte additive is prepared.
The non-aqueous electrolyte lithium secondary battery of the present invention comprises an anode capable of adsorbing and releasing lithium, a cathode capable of adsorbing and releasing lithium, and a non-aqueous electrolyte comprising the compound represented by the Chemical Formula 1. The anode and cathode capable of adsorbing and releasing lithium are prepared by a common method, and a non-aqueous electrolyte comprising the compound is injected therein to prepare a secondary battery.
The active material for the anode capable of adsorbing and releasing lithium is preferably a carbon-based material selected from the group consisting of graphite, carbon fiber, and active carbon. The anode further comprises a binder, preferably polyvinylidene fluoride (PVDF).
x
2
As the active material for the cathode, a lithium transition metal complex oxide represented by the following Chemical Formula 2 can be used.
[Chemical Formula 2] LiMO
wherein M is Ni, Co, or Mn; and x is a value satisfying 0.05 ≤x ≤ 1.10.
4
6
4
The compound represented by the Chemical Formula 1 used as a non-aqueous electrolyte additive in the, present invention is present at 0.01 to 20 wt% of the electrolyte. As the non-aqueous electrolyte additive, an aprotic organic solvent wherein lithium salts such as LiClO, LiPF, LiBF, etc. are dissolved is used.
Fig. 1
The preferable Example of fabrication of the non-aqueous electrolyte lithium ion secondary battery of the present invention is as shown in .
Fig. 1
As shown in , the lithium secondary battery of the present invention comprises an anode 1 formed of an anode current collector on which anode active material is coated, and a cathode 2 formed of a cathode current collector on which cathode active material is coated. The anode and the cathode are rolled together in a jelly roll configuration with a separator 3 therebetween, an insulator is located at upper and lower sides of the anode and cathode roll, and a can 4 receives it. A battery cover 5, enclosed with a laser, seals the battery can 4. The battery cover 5 is electrically connected to the cathode 2 through a cathode lead, and the can 4 is electrically connected to the anode 1 through an anode lead. For the battery of the present invention, the cathode lead is welded to a pressure-release valve 6 in which a protuberance selectively seals a pressure-release vent, and thus the cathode lead electrically connects with the battery cover 5 through the pressure-release valve 6. In a battery with this construction, when pressure inside the battery increases, the protuberance of the pressure-release valve 6 is forced from the vent, and inner pressure is released through the vent.
The present invention will be explained in more detail with reference to the following Examples and the Comparative Example. However, these are to illustrate the present invention and the present invention is not limited to them.
A non-aqueous electrolyte lithium ion secondary battery was prepared as follows:
µ
After mixing carbon powder and polyvinylidene fluoride (PVDF) as a binder in a weight ratio of 90 : 10, the mixture was dispersed in N-methyl-pyrrolidone (NMP) as a solvent to prepare an anode mixture slurry. The anode mixture slurry was uniformly coated on both sides of an anode current collector Cu foil at a thickness of 10 m and dried, and then was compression molded with a roll press to prepare an anode of a band shape.
2
µ
Lithium carbonate and cobalt carbonate were mixed in a mole ratio of 1 : 1 and calcined at 900 °C for 7 hours to obtain LiCoO. 92 wt% of the lithium cobalt complex oxide, 4 wt% of carbon as a conductor, and 4 wt% of PVDF as a binder were added to a solvent NMP to prepare a cathode mixture slurry. The cathode mixture slurry was coated on a cathode current collector Al thin film at a thickness of 20 m and dried, and then was compression molded with a roll press to prepare a cathode of a band shape.
Porous polyethylene film was used as a separator, and the band-shaped anode and the band-shaped cathode were laminated and rolled together in a jelly roll configuration. The length and width of the anode and cathode roll were controlled so as to be appropriately received into a battery can of a rectangle with a height of 48 mm, a width of 30 mm, and a thickness of 6.0 mm. The anode and cathode roll was deposited in the battery can with insulating plates disposed above and below it. Then, an anode lead formed of nickel was attached to the anode current collector and welded to the battery can, and a cathode lead formed of aluminum that was connected to the cathode current collector was welded to an aluminum pressure-relief valve mounted at the battery cover.
6
The non-aqueous electrolyte of the present invention was then injected into the fabricated battery. A solvent for the non-aqueous electrolyte was a mixed solvent of EC and EMC at a ratio of 1 : 2. LiPF was used as an electrolyte, and diphenyl disilanediol was added at 2 wt% of the electrolyte to prepare a non-aqueous electrolyte.
2
The fabricated battery was charged to 4.2 V with a constant current of 0.4 mA/cm. Standard capacity of a non-aqueous electrolyte secondary battery is 700 mAh and charge/discharge cycles were performed at a rate of 1 C (700 mA/h) with a constant current of from 4.2 V to 3 V.
A non-aqueous electrolyte secondary battery was fabricated by the same method as in Example 1, except that compounds shown in Table 1 were used as additives instead of titanium oxide acetyl acetonate.
A secondary battery was fabricated by the same method as in Example 1, except that no additive was added to the non-aqueous electrolyte.
[Table 1]
Additive
Whether or not exploded as a result of pin test
Example 1
Titanium oxide acetyl acetonate
No explosion
Example 2
Phenyl boric anhydride
No explosion
Example 3
[1,2-benzene diolato(2)-o,o]oxotitanium
No explosion
Example 4
Phenyl methyl silicon oxide
No explosion
Example 5
p-tolyl boronic anhydride
No explosion
Comparative Example
None
Explosion
The batteries fabricated in Examples 1 to 5 and the Comparative Example were charged and pins were passed through them to perform pin tests, and the results are as shown in Table 1.
As shown in Table 1, the batteries of Examples 1 to 5 comprising non-aqueous electrolytes to which additives were added did not ignite or explode after having pins passed through them and being short circuited, even after charging. This is because in the additive-added non-aqueous electrolyte, at a large current discharge due to a short circuit, a speed of lithium rushed from an anode is controlled or lithium rushed from an anode reacts with lithium rushed from a cathode surface to form an insulating film on the surface.
[Table 2]
Cycle life property (%)
Overcharge Test
Whether or not exploded
Capacity fraction (capacity after 100 cycles/initial capacity)
Maximum temperature of battery after blocking current (°C)
No explosion
Example 1
97
117
No explosion
Example 2
90
113
No explosion
Example 3
95
118
No explosion
Example 4
96
119
No explosion
Example 5
94
111
Explosion
Comparative Example
95
122
The cycle life properties and maximum temperature after blocking current by overcharge of the batteries fabricated in Examples 1 to 5 and the Comparative Example are shown in Table 2.
As can be seen from Table 2, adding a compound represented by the Chemical Formula 1 as an additive, although slight variations occur according to the kinds of compounds, generally improves cycle life properties. Regarding maximum temperature after blocking current by overcharge, the battery of the Comparative Example comprising an electrolyte without an additive exploded by thermal influx, but those of Examples 1 to 5 with additives were prevented from ignition by thermal influx. It is considered that, at overcharge, the additive forms a polymer insulating film on the cathode surface to block the overcharge current or reduce the activity of lithium that causes battery ignition.
Figs. 2 and 3
Fig. 2
was shown change in temperature and voltage of batteries of Example 1 and Comparative Example according to overcharge time respectively. As shown in , the battery of the Comparative Example without an additive have a short circuit before was arrived in a fixed voltage value by occurring explosion due to a rise of a temperature according to overcharge.
On the other hand, in case of the battery of Example 1 a rise of a temperature was a low, and the temperature was decreased after was arrived in a fixed voltage without a short circuit compared with Comparative Example.
As explained, according to the present invention, an organometallic compound represented by the Chemical Formula 1 is added to a non-aqueous electrolyte of a battery as an additive, and thus, if a battery voltage is out of normal operation voltage range due to a short circuit and overcharge of the battery, an additive decomposes and a part of the decomposed additive forms an insulating film on a cathode surface, and metal reacts with the insulating film formed on the cathode surface to improve thermal stability of the battery, thereby improving safety of the battery. Furthermore, in case of a short circuit a part of the metal oxide of the additive is removed an activity of lithium or is reduced movement speed of lithium by reacting with lithium rushed from an anode to a cathode, and thus safety of the battery can be obtained on a short circuit by delaying a flow of current. | |
Q:
What is non-duality in Buddhism?
I noticed some questioners on this site using the term "non-duality".
What is non-duality in Buddhism?
This is a well-known idea in Hinduism i.e. advaita. But does it exist in Buddhism?
Is it an official term in Buddhism, or just a convenient Western philosophy terminology to describe a concept just like the terms "ontology" or "epistemology"?
How is it used in Theravada and Mahayana? What are the Pali and Sanskrit terms for it?
AN 10.29 seems to have the word "advayam" which Bhikkhu Sujato translates as "non-dual" but Bhikkhu Bodhi translates as "undivided". Not sure if this is related.
A:
There's a post here on that subject, which isn't long but difficult to summarise: The Dharma of Non-Duality
In the first (main) part the author says:
The word for "non-duality" is advaita
The Buddha didn't use that term (because it was already used then to mean "union of soul with God")
The Buddha did teach "non-duality" is many ways -- e.g. "neither self nor no-self", "middle way", "form and emptiness" (in the Heart Sutra), and "dependent origination implies neither self nor other"
Nagarjuna "used non-duality" in his Mulakarika
Etc.
In a second part (posted as a long comment on the first part), Hans Gruber argues that neither Nargajuna nor the Buddha teach non-duality:
Non-clinging isn't non-duality
Emptiness isn't non-duality, and different things are different even if they are dependently originated
Moving towards liberation (by reducing ignorance etc.) isn't non-duality
The Buddha didn't teach non-dualism as a metaphysical principle, instead he taught dependent origination (also didn't teach anatta as a metaphysical principle or abstract terms, but only as a "predicate" or "practice instruction" applicable to concrete terms i.e. any and all dhammas).
AN 10.29 seems to have the word "advayam" which Bhikkhu Sujato translates as "non-dual" but Bhikkhu Bodhi translates as "undivided". Not sure if this is related.
Yes I expect it's the same root: a+dvaya ("not a pair").
Looking at advaita compared with advaya reminds me of, I wonder if it's similar to, tatha versus tathata -- where one is the adjective (e.g. "true" or "non-dual, single") and the other is an abstract noun ("truth, suchness" or "non-duality") -- or Suñña versus Suññata i.e. "empty" versus "emptiness".
That might fit with Hans Gruber's saying that the Buddha didn't non-duality as a principle (e.g. as an abstract noun).
| |
This Z-paper 824 by Herb Zinser uses Nature's SYMBOL MACHINE words, languages, proper nouns, equations, and concepts to understand the CRYPTIC writings of newspaper reporters, editors and publishers, and book authors.
The SYMBOL MACHINE is comprised of English language words and concepts, math and physics equations, biochemistry diagrams, electromagnetic sin wave schematics, etc. The SYMBOL MACHINE equivalent are basic college textbooks in math and science that may be found in any bookstore or a bookstore near a university.
We are reminded of ......
Language in thought and action - S. I. Hayakawa - Google ...
books.google.com › Language Arts & Disciplines › Linguistics › General
A revised, updated edition of S. I. Hayakawa's classic work on semantics. He discusses the role of language, its many functions, and how language shapes our ... .... Semantics is primarily concerned with meaning and reference, i.e. what Hayakawa calls the relationship between the «map» and the «territory» ...
Maps and Territories - Rijnlandmodel
Language in Thought and Action, S.I. Hayakawa.
Chapter 2 Symbols Maps and Territories
There is a sense in which we all live in two worlds.
Thus we have the source domain of SYMBOL LIFE and thought that may get mapped to the destination range of physical biology with human activities of the geography surface of
EARTH.
Let's look at some proper nouns and other words that provide CLUES to Nature's message processing system ... with possible messages for people that are interested in CRYPTIC situations.
clerk - definition of clerk by the Free Online Dictionary ...
www.thefreedictionary.com/clerk
TheFreeDictionary.com
(Law) clerk to the justices (in England) a legally qualified person who sits in court with lay justices to advise them on points of law. 3. (Government, Politics ...
Clerking - Bank clerk - Salesclerk - Shop clerk
County Clerk | County of Union, New Jersey - ucnj.org
ucnj.org/government/county-clerk/
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James Clerk Maxwell - Wikipedia, the free encyclopedia
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James Clerk Maxwell FRS FRSE (13 June 1831 – 5 November 1879) was a Scottish mathematical physicist. His most prominent achievement was to formulate a ...
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Thus we have some clues about parts of TOE Theory.
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A theory of everything (ToE) or final theory, ultimate theory or master theory refers to the hypothetical presence of a single, all-encompassing, coherent ... | https://zinser.jimdo.com/2014/04/29/z-paper-824-electromagnetic-dna-war/ |
Anchovy (Engraulis encrasicolus) is the key fish species in the Black Sea food web and has high ecological and economic importance for the Black Sea fisheries. Moreover, anchovy is an important predator of zooplankton (especially copepods) and is a main food resource for top predators (dolphins, spiny dogfish, mackerel, whiting, turbot, skates etc.).
Its migration pattern covers the whole Black Sea. In October-November migration starts to the wintering grounds along the Anatolian and Caucasian coasts in the southern Black Sea. In November-March it forms dense wintering schools that are subject to intensive commercial fishing. During the rest of the year, the species occupies spawning and feeding habitats across the Black Sea with some preference for shelf areas mainly in the northwestern part of the Black Sea where the largest and most productive shelf areas are located. However, according to the studies carried out in the southern Black Sea anchovy also spawns there. This may be a result from climatic changes and other ecological impacts occurring in the last three decades.
Anchovy mature at age 1, spawns during summer, which is also the main feeding and growth season. Anchovy spawn mainly in the surface layer and eggs and larvae are retained in the coastal layer stabilized in depth by the thermocline and protected from the offshore by thermo-haline fronts.
Anchovy is mostly exploited by the commercial purse-seine fishery, and Turkey is responsible for > 97% of the total Black sea catch. Anchovy is also captured in artisanal fisheries with coastal trap nets and beach seines mainly in Bulgaria, Romania and Ukraine. The catch of the Black Sea countries increased until 1984 up to 566,000 tonnes, remained at a high level until 1988 (526,000 tonnes) and then abruptly dropped to 86,000 tonnes in 1988. Overfishing and accidental introduction of the ctenophore (Mnemiopsis leidyi, which preys on anchovy larvae and competes with anchovy adults) are believed primarily responsible for the collapse. From 1995 to 2010 the catch ranged with wide oscillations from year to year in the range 135,000-400,000 tonnes. In 2012, total Black Sea catch was 193181 tonnes.
Such rapid fluctuations in catch could be attributed to several factors, including changes in the species targetted by the Turkish purse seiners, an increase of predators, invasive species, and climate effects. The collapse of small and medium-sized pelagic fish stocks happened at the same time and in all regions of the Black Sea, and suggests that factors such as eutrophication, climatic effects, Mnemiopsis population explosion as well as overfishing drive population dynamics. As zooplanktivores, anchovy have similar prey preferences as other organisms at the same trophic level such as sprat, shad, pilchard and comb jellyfish and therefore compete for the same food resource.
In this workpackage recruitment and migration of anchovy will be analysed in relation to variations in zooplankton abundance. Some new samples of anchovy and zooplankton will be obtained to maintain long time series and to provide data for skill assessment of lower trophic level oceanographic models. | http://www.goforit-cofasp.net/about/wp3 |
Technological advances are vital, but some of the effects on society are less than desirable. This man’s call to “look up” is certainly not misplaced. While it’s not featured in the Diagnostic and Statistical Manual of Mental Disorders (DSOM) just yet, technology addiction is quickly being recognized as a serious problem.
Studies done on the subject have shown a link between excessive use of a smartphone and insomnia, depression and social withdrawal. While there isn’t a standard treatment for excessive use of technology, experts in addiction suggest identifying triggers for the overuse, such as boredom or stress. Then, the learned automatic response of using the smartphone to relieve these triggers must be challenged and reversed.
While I love my smartphone as much as anyone else, I have to say I do sometimes feel guilty of relying on it too often. Sometimes, it’s crucial to put down the technology, and simply look up.
If you know someone who might like this, please click “Share! | https://www.forgottothink.com/ad-about-phone/ |
Mediterranea is a series of digital and analog photographs which describes the timeless beauty of Sicily. It is a reflection of Giulia De Marchi’s soul, a young photographer from Treviso, bewitched by this so subtle and intense language that she feels as an essential aspect of her life. The collection is an ‘ongoing project’, born from a fast and natural, spontaneous and instinctual photography, linked to the artist’s travels and not so premeditated. My eye, she explains, “tells a story, without restrictions, but capturing gestures, geometries and movements close to me”. In particular, in the case of Sicily, for many summers she lived this land with curiosity, leaving it with great melancholy. Come il mare instead, is a fragment of ‘Italian summer’, if so can be called the marine scenery of Salento. In both cases, the final form of the story, with which the albums are presented, results from a subsequent meticulous work of selection and small-format printing on which Giulia scrupulously works alone.
From the shots of the two collections emerges a supertemporal vision, a naturalness and a balance of shapes, colors and tints, that seems to share unknowingly her works, as if her eye followed an aesthetic that exceeds time. The subjects portrayed passing through, caught by surprise, the way in which the light crosses the frame, all these elements imprint at each shot the ineffable beauty of what Giulia has seen. During our talk, the artist remembers some words she associates to the perception of her images; it is something about “deferred spaces, romantic aspects of harmonious musicality and the continuous pursuit of perfection”. Walk and observe everything to catch the surprise effect around the corner. Pay attention to meetings and stories that photography can freeze in a moment and, at the same time, get breathe. These are the directions she follows.
Travel reports from Sicily and Salento do not miss, in the fast and authentic street photography, the historical and traditional details of the places visited, or the people who live there with their daily habits. In Mediterranea old men walk to the ruins of a temple, an iron statue with angel’s wings lying on the ground as a resting place, a lady sits soaking in the natural pools looking at the sea and some children climb the Scala dei Turchi; flicking through the pages of Come il mare, the arc of Santa Maria al Bagno frames the bathers, an elderly woman waits for the low tide to enter the water jumping on the pebbles. Giulia seeks beauty in small gestures. Let the observer wander with his imagination, triggering his fantasy on anecdotes and stories, features and expressions of the protagonists thinking about how they continued their way after their fleeting and unsuspecting encounter with the camera.
Since childhood, more easily behind the lens than in front of, Giulia tells of having bought with the first salary an entry model Level Canon, fully exploited after some basic notion exchanged with a friend and a short course of photography. He studied economics in his city without but it never hindered her path and self-taught interest in photography. “Over time I collected books and manuals, attended exhibitions and browsed catalogues, understanding how– specifies the artist – immortalizing what surrounds me has become almost a kind of natural dependence”. She does not define herself addicted to photography but fullfilled by this passion that maximizes her emotions, “a kind of outlet valve that helps me get out of everyday life and what normally surrounds me”. Among the influences and inspirations that prompt her from the outside, in addition to photography ça va sans dire, music and cinema, “looking in the author’s message for something that can enrich me without distorting my natural vision of the world”. | https://www.pellicolamag.com/blog/giulia-de-marchi-sicily-salento/ |
Because of increasing concentrations of human occupancy and extensive history of poor energy usage, it is of increasing imperative that new, contemporary, and legacy buildings improve their loss and use energy.
There thankfully are a great deal of commercial products, services, methods and technologies being increasingly directed at these problems, responsibilities, and opportunities.
NRI’s work in this area involves:
- (at the highest level) integrating environmental sensors, energy-usage sensors, controllable energy entities, and control systems, and
- (at the lowest levels) medium-granularity “Internet of Things” (IoT) approaches to measuring micro-scale affairs in distributed electrical consumption at the room/office level. The IoT networking can include wireless networking and multi-tap electrical bus arrangements. Examples of such multi-tap electrical bus arrangements can include, for example, carrier-wave signal transmission on AC power wiring not unlike that used in InsteonTM and X10TM products. | https://newrenaissanceinstitute.com/?page_id=272 |
Quick Tips How To Do Biochemistry Homework Efficiently
Doing exercises is the most reliable long-term technique to master calculation skills in most science matters. Regarding biochemistry homework, it works the same way. However, you may need to review the theory content of the topics in order to have the necessary basis for the calculations. In most textbooks, you will find a list of problems which are meant for the student to work with the contents explained in class. Read more to understand how to become more efficient in these tasks.
- Prepare for the study
- Create a study plan
- Improve your weak points
First of all, you will need a support teacher if you are completely lost in this subject. If that is not your case, i.e. you manage with some exercises but struggle with a few others, you may opt for self-study. However, considering occasional assistance is something to keep in mind. Having someone who helps you out with your biochemistry homework will save you not only a lot of time but frustration. The latter is important so as to stay motivated with the study.
Now that you have gathered the necessary tools and resources, i.e. you count on a support teacher and have got problem with solutions to study, you are able to focus on your strong and weak points. The strategy is a bit different for each case. For instance, you want to make sure that you correctly solve the exercises that you master in an exam or assignment.
The key point is being quick in this kind of problems. By doing so, you will be able to have more time to focus on the remaining questions. In other words, complete the better understood exercises first and then proceed to work on those which are more troublesome for you. Create a cheat sheet which summarizes the most common formulae in your problems and use it to study until you learn the equations by heart.
Most students have some difficulties with certain topics when solving biochemistry homework exercises. By practising, you will locate these issues so that you will be able to dedicate more time to understanding how to perform better. In case of doubt, practising is the only way to become more effective with science subjects. You could ask your teacher for more problems or look for additional exercises online. Fortunately, nowadays it is very easy to find plenty of information regarding the most common subjects. | http://www.piercecollegefootball.com/great-instructions-on-how-to-do-biochemistry-homework/ |
Lilac Gallery New York is pleased to present “Symbolic Energy” an exhibition from a private collection of works by Albert Nemethy, from October 14 - November 24, 2015. The exhibition will open with a reception on October 14 from 7-9 p.m.
It is a privilege to present these beautifully composed paintings, developing a greater awareness and appreciation for their remarkable symbolism. We are all part of an ongoing human conversation, beautifully illustrate to our modern world. This understanding and interrelatedness should serve to ignite our philosophical insight.
These especially collected pieces were selected for this exhibition with a variety of individual viewpoints of what Albert Nemethy (Albert Szatmar Nemethy) would like the public to explore, with a better vision and with a better understanding of the trends and problems of our lives today. He has simplified this task by isolating the elements of his biograohical life style.
Albert Szatmar Nemethy is one of the many historical and classical artists whose paintings have become recognized through out the northeast with compelling compositions that left an impression to the art world. In this collection he uses passionate symbolic ideas that transformed his spiritual themes into a whole new modern style of his own. Sometimes he would present this new style with a look of impressionism, although much of his work would be to a higher extremity of a new style, especially toward the end of his time.
As a student, he acquired skills from varying masters. A battle of his style was fought with in his imagination from dissecting plants and studying nature and opening seeds. For this reason his paintings resemble nature; aesthetically portraying a botanical art form. Considering many elements that he would use simultaneously, he consumed theory as being made from the Cosmos and spiritual elements equally significant to the narratives and certainly many compositions to the intersecting of love, sex, death, and destruction; all remaining prominent to their significance.
During the course of the years of his teaching in 1966 Nemethy had developed a passion for carving. At that time he was not sure what purpose this would have, but little did he know then of how this would all connect to his later years of painting. This is where the underlining and meaning started to form about his philosophy and impact that began to a development of his modern paintings. Albert Szatrnar Nemethy was very encouraged to arrange new ideas about the United Nations, where this symbol lead him to paint themes of the Ten Commandments. For him this was the most important reason to be an artist and to show how beautiful this symbolism can really be. | https://www.lilacgallerynyc.com/symbolic-energy |
Clear Backpacks No Longer Required
At the beginning of this school year, in an effort to provide additional safety and security for our students, staff, and visitors, Ennis ISD implemented several new safety and security measures. These included additional officers, new security gates, ID badges for EJHS/EHS students, and the requirement for all students to use clear backpacks.
Although the use of clear backpacks by our students has worked as intended, the lack of durability and local availability of even the highest quality PVC backpack products has created an undue burden on an increasing number of our students and parents. With this in mind, upon the return from our Fall Break (Monday, November 26th), EISD students will no longer be required to use clear backpacks. Those using clear backpacks that are in good condition may continue to use them, if desired. All other safety and security measures adopted by the district will remain in place.
We appreciate the cooperation regarding this issue. Ennis ISD will continue to be steadfastly committed to providing a safe and secure environment for all of our campuses and for all those using our facilities.
| |
By Silvanus Lamin It has been more than one and half month since I return to my home village due to corona crisis. I discovered that the corona situation has mostly changed their way of living, practice of rituals, social interaction, religious practices and even economic life. The word corona ...Continue Reading...
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Newspaper news:Local heroes raise climate hopes
:: Abu Bakar Siddique, Rajib Bhowmick Farida Parvin (left) distributes seeds of salinity-tolerant paddy, which she developed, to fellow farmers in her village of Shyamnagar in Satkhira. Like her, a local farmer in Chapainawabganj has revived Magurshail (right), a nearly extinct local variety of ...Continue Reading...
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Climate change and the Khasis in Bangladesh
:: Silvanus Lamin The Khasis in Bangladesh The Khasi is one of the ethnic communities in Bangladesh living in Bangladesh from the time immemorial. The existence, culture, tradition, customs, language of this community is almost in the last line of marginalization. There are several reasons ...Continue Reading...
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The Enlightened Riku Rani Paul
:: By Parboti Rani Singh (Translated by Silvanus Lamin):: Riku Rani Paul, a young girl of potter community from Netrakona set up a Learning Centre for students of her community who are deprived from the light of education with her own initiative. She herself also has to struggle for education ...Continue Reading...
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How a day labor becomes sustainable agriculture’s trainer!
Md. Abdul Motaleb of Kalmankanda under Netrakona district is a successful farmer who produces crops adopting sustainable agriculture. He makes the maximum use of his fallow lands to farm crops and vegetable as well as initiate nursery in an organic way. Farming chemical free vegetable and ...Continue Reading...
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Biodiversity and productivity
A.B.M Touhidul Alam from Dhaka:: The earth is only planet that has unique natural assets made up of plants, animals, land, water, the atmosphere and human. Together we all form part of the planet’s ecosystems, which means if there is a biodiversity crisis, our health and livelihoods are at risk ...Continue Reading...
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Let us know the history of and love our language
Parbati Singh from Netrakona:: Education is the backbone Education is the backbone of nation. No nation can prosper without education. Bangladesh has taken different initiatives such as distributing free books, scholarships, stipends, food for education and many other projects keeping this fact ...Continue Reading...
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Exclusive talks with environment medalist farmer Md. Yousuf Mulla
BARCIKnews.com recently had an intensive interaction with Yousuf Mulla, a farmer of Duboil village under Nachol of Chapainawabgonj district who is well-known as ideal farmer to others. He has been adopting sustainable agriculture since his father was alive. He has been conserving many seed of ...Continue Reading...
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Protector of extinct rice varieties
Anowar Hossein, Chapainawabgonj:: This article was publised in daily Prothom Alo, a Bengali newspaper on 16 March, 2013. Silvanus Lamin translates it for our online readers with a slight change of the main article It was because of his deep love that has led him conserving the diverse rice ...Continue Reading...
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Consumable Salt from salty soil!
Silvanus Lamin:: There are processes of preparing salt from the coastal saline water and its detergents but we hardly know about the making of salt from salty soil. But people of the Sunderbans area have their unique knowledge to make salt from the salty soil. However, it could be claimed that ...Continue Reading... | https://en.barciknews.com/tag/barciknews/ |
How To Think Like a Computer Scientist
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Page
Table of Contents
General Introduction
Simple Python Data
Debugging Interlude 1
Python Turtle Graphics
Python Modules
Functions
Selection
More About Iteration
Strings
Lists
Files
Dictionaries
Recursion
Defining Classes
Labs
Appendices
Acknowledgements
Indices and tables
Table of Contents
¶
General Introduction
¶
The Way of the Program
Algorithms
The Python Programming Language
Special Ways to Execute Python in this Book
More About Programs
What is Debugging?
Syntax errors
Runtime Errors
Semantic Errors
Experimental Debugging
Formal and Natural Languages
A Typical First Program
Comments
Glossary
Simple Python Data
¶
Variables, Expressions and Statements
Values and Data Types
Type conversion functions
Variables
Variable Names and Keywords
Statements and Expressions
Operators and Operands
Input
Order of Operations
Reassignment
Updating Variables
Glossary
Exercises
Debugging Interlude 1
¶
How to be a Successful Programmer
How to Avoid Debugging
Beginning tips for Debugging
Python Turtle Graphics
¶
Hello, Little Turtles!
Our First Turtle Program
Instances — A Herd of Turtles
The
for
Loop
Flow of Execution of the for Loop
Iteration Simplifies our Turtle Program
The range Function
A Few More turtle Methods and Observations
Summary of Turtle Methods
Glossary
Exercises
Python Modules
¶
Modules and Getting Help
Modules
More About Using Modules
The
math
module
The
random
module
Glossary
Exercises
Functions
¶
Functions
Functions
Functions that return values
Variables and parameters are local
The Accumulator Pattern
Functions can call other functions
Flow of Execution Summary
A Turtle Bar Chart
Glossary
Exercises
Selection
¶
Decisions and Selection
Boolean Values and Boolean Expressions
Logical operators
Precedence of Operators
Conditional Execution: Binary Selection
Omitting the
else
Clause: Unary Selection
Nested conditionals
Chained conditionals
Boolean Functions
Glossary
Exercises
More About Iteration
¶
Iteration Revisited
The
for
loop revisited
The
while
Statement
Randomly Walking Turtles
The 3n + 1 Sequence
Newton’s Method
Algorithms Revisited
Simple Tables
2-Dimensional Iteration: Image Processing
Image Processing on Your Own
Glossary
Exercises
Strings
¶
Strings
Strings Revisited
A Collection Data Type
Operations on Strings
Index Operator: Working with the Characters of a String
String Methods
Length
The Slice Operator
String Comparison
Strings are Immutable
Traversal and the
for
Loop: By Item
Traversal and the
for
Loop: By Index
Traversal and the
while
Loop
The
in
and
not
in
operators
The Accumulator Pattern with Strings
Turtles and Strings and L-Systems
Looping and counting
A
find
function
Optional parameters
Character classification
Summary
Glossary
Exercises
Lists
¶
Lists
List Values
List Length
Accessing Elements
List Membership
Concatenation and Repetition
List Slices
Lists are Mutable
List Deletion
Objects and References
Aliasing
Cloning Lists
Repetition and References
List Methods
The Return of L-Systems
Append versus Concatenate
Lists and
for
loops
Using Lists as Parameters
Pure Functions
Which is Better?
Functions that Produce Lists
List Comprehensions
Nested Lists
Strings and Lists
list
Type Conversion Function
Tuples and Mutability
Tuple Assignment
Tuples as Return Values
Glossary
Exercises
Files
¶
Working with Data Files
Finding a File on your Disk
Reading a File
Dictionaries
¶
Dictionaries
Dictionary operations
Dictionary methods
Aliasing and copying
Sparse matrices
Glossary
Exercises
Recursion
¶
Recursion
Objectives
What Is Recursion?
Calculating the Sum of a List of Numbers
The Three Laws of Recursion
Converting an Integer to a String in Any Base
Stack Frames: Implementing Recursion
Visualizing Recursion
Sierpinski Triangle
Glossary
Programming Exercises
Defining Classes
¶
Classes and Objects - the Basics
Object-oriented programming
A change of perspective
Objects Revisited
User Defined Classes
Improving our Constructor
Adding Other Methods to our Class
Objects as Arguments and Parameters
Converting an Object to a String
Instances as Return Values
Glossary
Exercises
Classes and Objects - Digging a little deeper
Fractions
Objects are Mutable
Sameness
Arithmetic Methods
Glossary
Exercises
Labs
¶
Astronomy Animation
Turtle Racing Lab
Drawing a Circle
Lessons from a Triangle
Finally a Circle
Counting Letters
Letter Count Histogram
Approximating the Value of Pi
Python Beyond the Browser
Experimenting With the 3n+1 Sequence
Plotting a sine Wave
Appendices
¶
Debugging
Python Beyond the Browser
Acknowledgements
¶
Copyright Notice
Preface to the Interactive Edition
Whats the deal with Logging in? | http://interactivepython.org/runestone/static/CSC226/toc.html |
Michael Applebaum and Gérald Tremblay unveiled the components of the Hippodrome Project, an ambitious five-year plan to create a new inclusive model community on the former racetrack site.
The project’s main goal is to transform the former Blue Bonnets site into a world-class neighbourhood environment never before seen in North America, while incorporating the best practices of sustainable development, urban design and community participation.
“This is a city within a city,” said CDN-NDG Mayor Michael Applebaum during a press conference. “At the end of all of the construction, there will be 20,000 new residents in the sector.”
The Hippodrome Project on the currently vacant site, roughly the size of 60 football fields, has a development potential of 5,000 to 8,000 housing units. City of Montreal Mayor Gerald Tremblay gave assurances that at least 15 per cent of the units would be dedicated to social housing and made a point of insisting on the importance of family-oriented units. Applebaum talked about plans to incorporate schools, community centres and a police station, as well as a strong green presence.
Drawing from projects already underway in Europe such as Stockholm’s Hammarby and Amsterdam’s GWL-Terrein, the city is envisioning a new neighbourhood featuring the latest innovations in urban design, green architecture and ecological management. “It is important that this neighbourhood reflect our talent and Montreal’s UNESCO City of Design title,” added Tremblay.
The site is closed in by railroads, the Décarie expressway and heavily congested Jean-Talon, which is why the mayor said they are counting on public transit. “We’ll do exactly what we did when U2 held the massive concert that 80,000 people attended. We already have two metro stations near the site (Namur and De La Savane) and we also have a tramway project in mind.”
Projet Montréal opposition councillor Peter McQueen approves of the project’s green strategy. “That’s exactly the way we want to go - to completely base the development there on transit usage and active transport. If they continue down that vein, then it’s okay.” He proposes augmenting social housing to at least 20 per cent and beginning transit development right away.
In an unprecedented situation, the Quebec government has ceded the land to the city free of charge, in exchange for a 50-50 share on revenue generated from land sales. “This is a win-win situation for the City of Montreal and the provincial government,” said Applebaum.
“We will start to sell off pieces of land by 2017, ensuring that we have green spaces, community centres, social and affordable housing,” added the borough mayor. “Property values will increase over time and for that reason the provincial government will receive more money than expected and we’ll be able to use that money to invest in infrastructure and public transit.”
The process, which is set to begin this fall, will be formulated over a five-year period with five phases: mobilization of citizens and experts; an international urban design competition; development of the master plan; consultation meetings by the Office de consultation publique de Montréal (OCPM); and adoption of the master plan in the winter of 2016.
Because community participation is actively encouraged, the OCPM will conduct public hearings at each step of the planning process. The city invites residents and owners of neighbouring properties, as well as civic/social organizations, to help delineate this concept via its web site - ville.montreal.qc.ca/hippodrome. | http://www.lesactualites.ca/01_anciensite/?site=CDN§ion=page&1=C121031&2=C121031_hyppodrome |
Ontario has introduced new legislation that would, if passed, help keep rental housing costs predictable and affordable while strengthening protections for tenants across Ontario.
The Rental Fairness Act, 2017, would address rising rental costs faced by people in Ontario by expanding rent control to all private rental units, including those occupied on or after November 1, 1991. Expanding rent control is a key component of Ontario’s Fair Housing Plan to help more people find an affordable place to call home.
The legislation also includes additional changes to the Residential Tenancies Act, including:
Ontario is also strengthening its transitional housing system to support the goal of ending chronic homelessness by 2025. The proposed amendments would exempt transitional housing providers from the Residential Tenancies Act for up to four years, as long as participants are protected by written tenancy agreements. This would allow transitional housing providers to deliver their programs and services over a longer period of time, and help more people successfully transition to longer-term, stable housing.
Expanding rent control and strengthening protections for tenants is part of our plan to create jobs, grow our economy and help people in their everyday lives. | https://cornwallfreenews.com/2017/04/24/queens-park-introduces-rent-control-reform-eviction-protection-april-24-2017/ |
TO BE A CHRISTIAN AND IN BUSINESS!
Abstract
The article investigates the implications of Christian commitment for the practice and ethics of business. Attention is paid to the traditional schism between the spheres of faith and business, and an argument is developed to challenge this schism. Christianity's rightful concern about ethical business is defended in terms of its prophetic (vis-a-vis mystic) identity. The implications of Christian identity for business practice are finally spelt out with reference to the acquisition of a realistic anthropology, the possibility of reinterpreting key concepts in the business world, the responsibility of care for the needy and the potential for facilitating dialogue.
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DOI: https://doi.org/10.7833/62-0-629
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SpaceX sent Indonesia’s Merah Putih telecommunications satellite into orbit tonight, marking the first reuse of its new-generation Falcon 9 Block 5 rocket booster.
Liftoff came on time at 1:19 a.m. ET Tuesday (10:19 p.m. PT Monday) after a trouble-free countdown at Cape Canaveral Air Force Station in Florida.
Minutes after launch, the booster flew itself back down for an at-sea touchdown on SpaceX’s autonomous drone ship in the Atlantic Ocean.
The launch and landing kicked off a new chapter in SpaceX’s quest to increase rocket reusability and reduce the cost of access to space. The company says its Block 5 booster can be reused 10 times, a significant step up from the now-retired Block 4 version.
Tonight’s focus on the refurbished, soot-stained booster stole the spotlight from Merah Putih, an SSL-built satellite that’s designed to provide a range of telecommunication services from geostationary orbit, including mobile broadband access across Indonesia and Southeast Asia.
The booster was the first Block 5 first stage to fly, and helped put Bangladesh’s Banghabandu-1 telecom satellite into geosynchronous transfer orbit back in May. It was successfully recovered and spruced up for tonight’s rerun of the GTO launch profile.
As in May, the reflown first-stage booster relit its engines after stage separation, and went through a series of burns to set down on the drone ship, christened “Of Course I Still Love You.” Meanwhile, the second stage continued onward and went through its own follow-up firing to send Merah Putih into its intended orbit.
Launch commentator Lauren Lyons said the booster would be prepared for its third launch later this year. “This is possible due to those Block 5 upgrades, which brings SpaceX closer to its goal of full and rapid rocket reusability,” she said on tonight’s webcast, which was watched by more than 25,000 YouTube users at its peak.
SpaceX has tried to advance that reusability campaign by making as-yet unsuccessful attempts to recover the Falcon 9’s nose cone, or fairing, after West Coast launches. But such attempts haven’t yet been tried for East Coast missions like tonight’s. The company’s billionaire founder, Elon Musk, said engineers are also working on ways to recover the Falcon 9’s second stage.
Musk has said Block 5 will be the last major iteration for the Falcon 9. Attention will soon shift to the Falcon Heavy and the development of an even bigger launch vehicle known as the BFR, or Big Falcon Rocket.
The Falcon 9 Block 5 and SpaceX’s Crew Dragon are destined to be used for launching astronauts to the space station, starting as early as next April. Uncrewed tests of the full human-rated launch system still have to be completed, but each successful Block 5 launch gives NASA (and SpaceX) greater confidence. | http://androidtechnews.com/spacex-launches-indonesian-satellite-and-kicks-off-new-round-for-rocket-reusability/ |
There is a growing consensus in the literature on the applicability of the jus ad bellum to cyber-attacks that the effects caused by an attack should determine whether the attack constitutes a use of force (Article 2(4) of the UN Charter) or an armed attack giving rise to self-defence (Article 51 of the UN Charter). This article argues that this approach is inconsistent and dangerous. The push to include cyber-attacks in the existing framework on the use of force disregards the consensus on other non-conventional uses of force like economic sanctions and damage caused by espionage, and it is premised on dangerous hyperbole in sensational media stories. Such an approach ignores serious practical problems regarding the attribution of cyber-attacks and would open the door wide for abuse. There is no reason to weaken the effectiveness of a deliberately narrow system on the use of force based on dystopian scenarios. | https://repository.canterbury.ac.uk/item/88392/you-can-t-cyber-in-here-this-is-the-war-room-a-rejection-of-the-effects-doctrine-on-cyberwar-and-the-use-of-force-in-international-law |
Tag: International Medical Corps (IMC)
International Medical Corps (IMC) is a global humanitarian nonprofit organization established by volunteer doctors and nurses. The organization is a global first responder during disaster and humanitarian crisis providing emergency medical relief, delivering health care to underserved regions, building clinics, and training local health care workers with the goal of creating self-reliant, self-sustaining medical services and infrastructure in places where that had previously been lacking.
International Medical Corps focuses on health services support including primary and secondary health care, prevention and treatment of infectious diseases, supplemental food for malnourished children, clean water and hygiene education, mental health and psychosocial care, women’s & children’s health including gender-based violence, and emergency response and preparedness.
International Medical Corps is a founding member of the ONE Campaign and a member of the Clinton Global Initiative. | https://www.jobinformant.com/tag/international-medical-corps-imc |
Polytrauma Patients Face Cancer Risk from Imaging Radiation
Orthopaedic surgeons work with radiation in some capacity almost every day. We would struggle to provide quality patient care if it were not for the many benefits that radiographic images provide us. But the more we are exposed to something, the less we tend to think about it. For example, how often do we discuss the risks of radiation exposure with our patients—especially those who are exposed to a large amount of it after an acute traumatic injury?
The article by Howard et al. in the August 7, 2019 issue of JBJS strongly suggests that polytrauma patients need to better understand the risks associated with radiation exposure as they progress through treatment of their injuries. The authors evaluated the cumulative 12-month postinjury radiation exposure received by almost 2,400 trauma patients who had an Injury Severity Score of 16+ upon admission. Those patients received a median radiation dose (not counting fluoroscopy) of 18.46 mSv, and their mean radiation exposure was 30.45 mSv. These median-versus-mean data indicate that a small subset of patients received substantially more radiation than others, and in fact, 4.8% of the cohort was exposed to ≥100 mSv of radiation. To put these amounts in context, the average human in the UK (where this study was performed) is exposed to about 2 mSv of background radiation per year, and there is good evidence suggesting that carcinogenesis risk increases with acute radiation doses exceeding 50 mSv.
Based on mathematical models (actual occurrences of cancer were not tracked), the authors conclude that for these patients, the median risk of fatal carcinogenesis as a result of medical radiation following injury was 3.4%. In other terms, 85 of these patients would be expected to develop cancer as a result of medical imaging—which struck me as a startling estimate.
So what are we to do? In a Commentary accompanying this study, David A. Rubin, MD, FACR offers some practical suggestions for reducing unnecessary radiation exposure. I personally feel that because the radiation associated with CT scans and radiographs can be, quite literally, life-saving for patients who have sustained traumatic injuries, increasing the chance that patients develop cancer later in life in order to save their life now is a good risk-benefit proposition. But the findings from this study should make us think twice about which imaging tests we order, and they should encourage us to help patients better understand the risks involved.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
JBJS Editor’s Choice: Research into Female Surgeon Safety
The evolution of more rational educational programs and other societal changes point to a future where an increasing number of orthopaedic surgeons will be female. Thankfully, we have made gains in adjusting the medical community’s perspective on careers in orthopaedic surgery. No longer are we perceived to be “stronger than a mule and twice as smart” or merely “buckles and braces men.” Evolving interventional techniques that rarely require brute force have also helped change this view.
At the same time, with the rapidly increasing need for musculoskeletal care as the population ages, we need every orthopaedic practitioner—male and female—to remain as healthy and active as possible. Epidemiologic studies of surgeon health have revealed real concerns for neck and back degenerative changes and cancer risk.
In the November 2, 2016 edition of The Journal, Valone et al. tackle the issue of exposure of the female breast to intraoperative radiation. In a nifty study incorporating C-arm fluoroscopy and an anthropomorphic torso phantom equipped with breast attachments and dosimeters, the authors found that:
- The median dose-equivalent rate of scatter radiation to the breast’s upper outer quadrant (UOQ) was higher than that to the lower inner quadrant.
- C-arm cross-table lateral projection was associated with higher breast radiation exposure than anteroposterior projection.
- Size, fit, and breast coverage of lead protection matter.
The findings should prompt redesign of protective aprons and vests to more effectively cover the breast and axilla. We could also use more well-designed longitudinal studies to identify the risk factors for neck, back, and shoulder injury as well as gain a better understanding of the real risk of surgeon exposure to intraoperative radiation.
Annual occupational radiation dose limits to the breast have not yet been established. But in the meantime, Valone et al. recommend distancing the axilla from the C-arm and placing the X-ray source beneath the operating table or on the contralateral side to reduce radiation exposure to the UOQ of the breast.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Protecting Surgeons’ Hands from Radiation during Fluoroscopy
The International Commission on Radiological Protection (ICRP) currently recommends a maximum of 50 rem (500 millisieverts, or mSv) of occupational hand-radiation exposure annually. A fascinating study using a surgeon manikin, mini and standard fluoroscopic c-arms, and a Sawbones model of distal radial fracture fixation showed that hand-radiation exposure averaged 31 µSv per minute. That finding suggests that hand surgeons would not approach the ICRP-recommended hand-exposure limit unless they performed close to 2,000 hand procedures involving fluoroscopy each year. However, authors Hoffler et al. are quick to add that “the effect of consistent exposure that does not exceed the annual limit, but continues for a multiple-decade career, is unknown.”
It comes as little surprise that treating a distal radial fracture can be a high-exposure event. To quantify the situation more precisely, Hoffler et al. fit a surgeon manikin with radiation-attenuating glasses, thyroid shield/apron, and gloves, and measured radiation exposure with dosimeters placed on the manikin in both exposed and shielded positions. They exposed the Sawbones model and the manikin, which was in a standard seated position for hand surgery, to radiation from three mini and three standard fluoroscopes for fifteen minutes continuously. The authors explained their rationale for fifteen minutes of continuous exposure as follows: “The mean fluoroscopy time for volar radial plating at our institution is sixty seconds…It is common for hand surgeons to use a fluoroscope fifteen times a month…If exposures average sixty seconds each, the hand surgeon could be routinely exposed to fifteen minutes of fluoroscopy monthly.”
The authors found that hand exposure was 13 times higher than exposures at the thyroid, groin, or chest. The eyes, the second-most exposed site, received an average of 4 µSv per minute. Radiation-attenuating gloves reduced hand exposure by a mean of 69%, and radiation-attenuating glasses decreased eye exposure by a mean of 65%. There were no significant differences in hand exposure between the mini and standard fluoroscopes.
OrthoBuzz encourages orthopaedic surgeons to consider these findings in light of the current proliferation of fluoroscopes outside the OR, especially in office settings. For their part, the authors encourage surgeons to minimize their own and their patients’ radiation exposure “by understanding the basic physics of x-ray radiation and maximizing all of the safety technologies that their specific fluoroscopy units offer,” including the use of personal protective equipment. | https://orthobuzz.jbjs.org/tag/radiation-exposure/ |
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