понедельник, 12 сентября 2011 г.

Scientists observe how a close bond activates the immune system

The immune system is highly complex. The cast of characters alone required to marshal an immune response to a foreign invader can number in the millions as the body's soldiers, T cells, are called into action. What triggers this complex response begins when T cells and dendritic cells, another type of immune cell, form a kind of molecular embrace, or immunological synapse, to relay information about intruders.


The communication between these immune cells hasn't been well understood because scientists had no suitable techniques to manipulate it. Now that problem has been solved. In a new study scientists at New York University School of Medicine and the University of California, Berkeley, report that they have observed the exchange of information between immune cells that is required to spark a body wide response to infection.


"This is the first time that anyone has been able to physically manipulate the immunological synapse and measure the effect on T cell signaling," says Michael L. Dustin, Ph.D., the Irene Diamond Associate Professor of Immunology and Associate Professor of Pathology at NYU School of Medicine, and one of the lead authors of the study.


The research by Dr. Dustin and Jay T. Groves of University of California, Berkeley, and their colleagues is a fusion of biology and nanotechnology--devices at the molecular scale. The study sheds new light on the workings of T cells, the body's most specific and potent line of defense against viruses, bacteria, and other pathogens, says Dr. Dustin who is also an investigator in the molecular pathogenesis program at NYU's Skirball Institute of Biomolecular Medicine.


The study, published in the November 18, 2005, issue of Science, reveals how T cells analyze and react to the signals of infection at the immunological synapse.


Every T cell wears a unique molecule, called a T cell antigen receptor, on its surface that it uses to detect pieces of foreign proteins called antigens. These receptors exist in astonishing, and for all practical purposes, unlimited variety--allowing the body to recognize any pathogen it might encounter.


Just as police need evidence of a crime to begin an investigation, T cells must recognize a specific antigen before they start to fight an infection. Dendritic cells constantly scour the body for antigens and present these to T cells for review in the lymph nodes. It is a demanding job. "Just 10 dendritic cells can show viral antigens to over a million T cells in a day," says Dr. Dustin.


Once a T cell's antigen receptor finds an antigen match, the T cell forms an immunological synapse with a dendritic cell through which it queries the dendritic cell for additional information about the antigen and its source in the body. Is the antigen a danger or simply a harmless food protein? The interrogation may last hours, and if the antigen is deemed a threat the T cell starts multiplying, eventually producing thousands of copies of itself. These T cell clones are capable of killing invaders outright and marshaling other cells to destroy them.


In the new study, Gabriele Campi, a graduate student in Dr. Dustin's laboratory, and Kaspar Mossman, a graduate student of Dr. Groves's, created a synthetic dendritic cell using purified antigen and adhesion molecules (molecules that the cell can grip) in a thin fluid coating on a glass surface. In prior studies the antigen was free to move over the entire glass surface, but in this study they set up miniscule chrome barriers, allowing them to modify the pattern of T-cell antigen receptor clusters in the immunological synapse.


Previous research has shown that T cell receptors cluster in a bull's eye-pattern at the interface between the T cell and the synthetic dendritic cell but the significance of this arrangement has been unknown. Thanks to the chrome barriers, Dr. Dustin and his colleagues discovered that the T cell receptor signal is strongest when they are physically held in the outer ring of the bull's eye rather than the center.


"We locked the receptors in the periphery and saw enhanced signaling over a prolonged period of time. It was quite a surprise," says Dr. Dustin. Researchers had speculated that the concentrated bull's eye structure somehow allowed T cells to maintain their state of activation. But the new work shows that it is actually the outer edge of immunological synapse that boosts activation, not the center.


Dr. Dustin's group is now conducting additional experiments to see if dendritic cells actively present proteins to T cells in patterns that stimulate the periphery of the bull's eye in the immunological synapse, using molecular organization to provide information about the precise nature of the threat associated with the antigen.


Pam McDonnell

Pamela.McDonnellnyumc

New York University Medical Center and School of Medicine

med.nyu.edu

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Small World Explored By Big Book: Stuart Lindsay's Guide To Nanoscience

Stuart Lindsay, Arizona State University Regents' professor and director of the Biodesign Institute's Center for Single Molecule Biophysics, has just released the first comprehensive guide to a tiny world a million times smaller than a single grain of sand. Introduction to Nanoscience (published by Oxford University Press) provides readers with an overview of an emerging discipline which has in recent years, produced remarkable achievements in areas as varied as DNA sequencing, molecular machinery, nanocrystals and microscopy.



In discussing the impetus for the book, Lindsay notes that his far-flung research has always been coupled with a passion for teaching biophysical concepts to talented students. Introduction to Nanoscience also offers researchers worldwide a first-of-its kind, all-inclusive treatment of nanoscience. The book integrates several disciplines and spans basic quantum phenomena, tools of the trade, and nanoscale applications. In the course of this overview, Lindsay returns again and again to the theme of emergent behavior - how minute fluctuations at the nanoscale level can result in the appearance of striking, often unanticipated new phenomena.



The book is an outgrowth of professor Lindsay's lectures in nanoscience, refined over many years, with invaluable input from his students. Oxford University Press learned of the course and, believing it would make a fine resource, requested that Lindsay assemble the material into a book.



"What is so striking," Lindsay insists, "is that events occurring at the nanoscale have implications for chemistry, biology, physics, materials science, engineering, you name it." Nonetheless, the nanorealm lacked a textbook that could draw together the field's disparate elements. "It's sort of remarkable that the knowledge was not there in a collected way. I put together a course that was very comprehensive, starting with physics and ending with biology," he says.



Given the breakneck pace of scientific advance, particularly in nanoscience, Lindsay faced a daunting challenge. "I knew that some current issues in the field would become obsolete by the time my fingers left the keyboard." Hoping to produce a work that could remain relevant, Lindsay chose to include a wealth of fundamental principles that would be broadly applicable, regardless of the novel conditions students were likely to encounter in the future.



The book is divided into three parts. Part I (The Basics) is a self-contained introduction to quantum mechanics, statistical mechanics and chemical kinetics, requiring only basic college calculus. Part II (The Tools) covers microscopy, single molecule manipulation and measurement, nanofabrication and self-assembly. Part III (Applications) covers electrons in nanostructures, molecular electronics, nano-materials and nanobiology. "If you wander around the lab," Lindsay says, "you'll see dog-eared copies of the Xeroxed version of the book at students' desks - it's really a compendium of everything I think they need to know in nanoscience."



Life in the nanoworld can be disconcerting to the uninitiated, so distinct are its workings compared with conditions of everyday experience. A nanometer is roughly 10,000 times smaller than the diameter of a human hair. Chance fluctuations dominate the scene and, as Lindsay stresses, provide vital raw material on which Darwinian selective processes operate. "The more I study the components of biology, the more I would say that fluctuations aren't just a nuisance to be lived with - they actually are the story of biology."



This leitmotif runs throughout the book, uniting many distinct areas of nanoscience. One such startling illustration of this central theme occurs near the end of the text, where Lindsay reviews important research into neural development in the fruit fly. Random fluctuations in gene expression and splicing serve to shuffle the genetic deck to produce an enormous number of variants of sticky-ended proteins, which are essential for proper neural assembly. When the number of these splicing variants in a particular gene was reduced from roughly 30,000 to 20,000, the creatures were unable to form proper brains. "The evolution of a neural network in a brain involves the interaction between an incredibly diverse and randomly put together Darwinian dice throw of neural connections and an environment acting selectively on the results," Lindsay says.



Introduction to Nanoscience is a vital contribution to one of the most dynamic fields, geared toward inspiring a new type of young investigator - one steeped in a multidisciplinary scientific culture. "This differently trained and diverse group of talented young people are not only going to produce scientific breakthroughs in their own rights," Lindsay says, "they're also the people who are going to start the next generation of companies that generate wealth and drive the national economy and they're going to create new things with their brains because they've learned new ways to think."



Richard Harth

Biodesign Institute science writer



Introduction to Nanoscience, by Stuart Lindsay


Paperback: 448 pages


Publisher: Oxford University Press, USA; Pap/Cdr edition (December 20, 2009)


Language: English


ISBN-10: 0199544212


ISBN-13: 978-0199544219



Source:

Joe Caspermeyer

Arizona State University

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Information Relevant To HIV-1 Vaccine Strategies Generated By Non-Human Primate Study

Monkeys repeatedly immunized with a particular form the HIV-1 envelope glycoprotein generated antibodies capable of neutralizing diverse strains of HIV-1, according to a paper published online in the Journal of Experimental Medicine on August 2.



Antibodies in the blood of monkeys immunized with a HIV-1 envelope trimer neutralized a broader variety of HIV-1 strains than antibodies in the blood of humans immunized with an HIV-1 envelope monomer during the VAX04 phase III clinical trial.



However, the immunized monkeys showed only weak protection against subsequent rectal infection with a simian HIV virus. This weak protection may be due to the fact that neutralizing antibody titers were at least 1,000-fold lower in rectal and vaginal tissues than in the blood.



These findings suggest that methods to boost neutralizing antibody abundance in rectal and vaginal tissues might be needed to better prevent HIV-1 transmission.



Source:

Rita Sullivan

Rockefeller University Press

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House Will Take 'Major Step' Toward Comprehensive Health Care Reform In 2009, Speaker Pelosi Spokesperson Says

House Democrats will "take a major step" toward comprehensive health care reform in 2009, and lawmakers already have taken "incremental steps" to expand coverage, a spokesperson for House Speaker Nancy Pelosi (D-Calif.) wrote in an e-mail on Monday, The Hill reports. According to The Hill, Pelosi spokesperson Brendan Daly issued the statement to clarify recent comments by House Majority Whip James Clyburn (D-S.C.) that appeared to lower expectations for health care reform this year.

In an interview on Sunday with C-SPAN, Clyburn said that while he does not expect health care reform legislation to pass Congress this year, he would like to see lawmakers take on the task in an incremental manner, The Hill reports. Clyburn said, "I would much rather see it done that way, incrementally, than to go out and just bite something you can't chew," adding, "We've been down that road. I still remember 1994," when the Clinton administration attempted to overhaul the health care system.

In the e-mail, Daly wrote, "There are some incremental steps that we are taking -- first we did SCHIP, then in our economic recovery package, we have money to help stem the tide of people losing health insurance -- coverage for Medicaid and COBRA. There is also money for quality, health IT, comparative effectiveness and wellness, and money for prevention," adding, "And we will take a major step forward this year to increase the number of people who have health care coverage."

Kristie Greco, a spokesperson for Clyburn, said, "What [Clyburn's] saying is that these steps ... shouldn't be overlooked as important strides" toward health care reform. Clyburn's comments also do not represent the strategy that the House Democratic leadership plans to take to address the issue of health care reform, she noted, adding, "There hasn't been a determination of when that bill will come to the floor in the House or the Senate" (Young, The Hill, 1/26).

Clinton
Former President Bill Clinton on Monday said that the current economic recession positions President Obama to draw support for the development of a universal health care system, the AP/Raleigh News & Observer reports. In a speech at North Carolina State University, Clinton said that his administration encountered several roadblocks when it tried to overhaul the health care system, including a lack of cooperation from Congress. He said that because of the recession, Obama is free to spend money and political capital, the AP/News & Observer reports. "Frankly, we're spending like crazy so there's no concern about the deficit for the next two or three years," adding, "That's one of the good news is that we can do health care now because we have to grow the economy. We must do it. That's a good thing" (Baker, AP/Raleigh News & Observer, 1/26).

Broadcast Coverage

American Public Media's "Marketplace" on Monday interviewed Health Net CEO Jay Gellert about the health care industry and its support of overhauling the U.S. health care system (Ryssdal, "Marketplace," American Public Media, 1/26).


Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.



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Killing Leukemia Stem Cells While They Sleep

In people with chronic myeloid leukemia (CML), the drug Imatinib has been shown to drive cancer into remission, but the disease often returns when treatment is stopped. New research by UC Irvine scientists indicates that Imatinib could cure CML under certain circumstances if it is taken over a long enough period of time.



Mathematician Natalia Komarova and biologist Dominik Wodarz also developed a tool that eventually could help doctors determine which combination of drugs would be most beneficial to a CML patient, and they determined why, in some cases, Imatinib does not block cancer growth. The results of their study appear Oct. 3 in the journal Public Library of Science ONE.



CML is a quick-progressing cancer that starts in the bone marrow and moves into the blood. The disease proceeds in three stages, the last one characterized by patient survival of only a few months. In 2007, an estimated 4,570 people in the United States will develop CML, and 490 people will die from it, according to the National Cancer Institute, a division of the U.S. National Institutes of Health.



The drug Imatinib is a promising cancer treatment because it has few side effects, and it specifically targets cancer cells. In their study, the UCI scientists focused on Imatinib and the behavior of cancerous stem cells. Just as normal stem cells maintain organs and a functioning body, cancer stem cells are thought to maintain cancer growth and are tough to kill with treatment.



Many scientists believe that Imatinib can kill regular cancer cells but not stem cells. When treatment ends, the remaining stem cells can produce more cancer cells, thus exacerbating the disease. According to this view, there is no hope to cure CML.



The UCI scientists, however, believe Imatinib can kill cancerous stem cells but not when the stem cells temporarily stop dividing, a state known as quiescence. All cancerous stem cells have the ability to enter the quiescent state. Evidence indicates that when such sleeping stem cells wake up, Imatinib can kill them.



In their paper, the scientists present a mathematical formula that can calculate how long it would take to kill all of the stem cells and cure the cancer. This length of time -- which could be different for each patient -- is based on how often the cancerous stem cells fall asleep and how quickly they wake up. Once the scientists can test their theory with patients, they will be able to determine how long the cure might take.



"There is evidence that a complete cure is possible. Several patients have been reported to have no symptoms after two months without therapy, which is thought to suggest a complete cure," Komarova said. "This evidence supports our theory. Basically, one has to be on therapy long enough for all of the stem cells to wake up and be killed by the drug."



In addition to sleeping stem cells, another barrier to eradication by Imatinib is that cancer cells can mutate to become unresponsive to certain drugs. Conventional thought is that if sleeping stem cells prolong a cure, other cancer cells will have ample time to mutate and become drug resistant.



The UCI scientists, however, have proved this theory wrong. Their calculations show that mutant cells develop early on, in many cases before the patients know they are sick, and do not develop during the treatment process. Using mathematics, they developed a way to calculate the probability that certain mutations exist in a patient. Based on this, one can determine what course of treatment should be used to overcome the resistance.



"The model requires the number of cancer cells that exist, how fast the cells divide and die, and how fast they go to sleep and wake up," Wodarz said. "Once you have those numbers, you can determine how many drugs to use in combination to make sure drug resistant mutants do not become problems."







This research was supported in part by a National Institutes of Health grant and a Sloan Fellowship.



About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 25,000 undergraduate and graduate students and about 1,800 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.7 billion.



Source: Jennifer Fitzenberger


University of California - Irvine



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UC Irvine School Of Medicine's Revolutionary IPad Program To Utilize E-Textbooks From Elsevier

Elsevier, publisher of scientific, technical and medical information products and services, announced it will provide four key electronic textbook titles for UC Irvine School of Medicine's new program that gives Apple iPads to its first-year medical students.


Elsevier will provide UCI's incoming medical students with access to Netter: Atlas of Human Anatomy, Gartner: Color Textbook of Histology, Costanzo Physiology and Nussbaum: Thompson & Thompson Genetics in Medicine all through their new iPads.


"We believe a digitally based curriculum is the future of medical education," said Dr. Ralph V. Clayman, dean of the UCI School of Medicine. "Our commitment to provide these students with the best technology platform and content available is shared by Elsevier, which has responded quickly and positively to our request for high-quality e-textbooks accessible through the iPad."


UCI School of Medicine students and faculty will use their iPads to access Student Consult, Elsevier's online portal where students can access full textbooks plus additional interactive content. Student Consult is where UCI med students will find the four e-textbooks selected for the first term courses. Elsevier will work closely with UCI to monitor the use of the content and the iPads.


"UCI is setting the bar high for how medical schools students and professors should be interacting with medical textbooks," said Randy Charles, Managing Director for Elsevier's Global Clinical Reference Group. "We fully support UCI's progressive move and are working hard to make more of our respected medical content available through mobile devices like the iPad and iPhone."


UCI anticipates it will add further Elsevier texts as the school year progresses.



Sources: Elsevier, AlphaGalileo Foundation.

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FDA Announces Collaboration With Drugs.com

The U.S. Food and Drug Administration announced that it will collaborate with the Web site Drugs to expand access to the FDA's consumer health information.


Drugs seeks to provide patients with information to better manage their own health care and to assist in the reduction of medication errors. It attracts more than 12 million unique visitors each month.


"The FDA's partnership with Drugs means that reliable, useful, and timely health information will be available to an even wider audience," said Beth Martino, the FDA's associate commissioner for external affairs. "Partnerships like this are an important part of the FDA's effort to ensure the public has easy access to reliable, useful information that can help people protect and improve their health."


The FDA's partnership with Drugs will provide consumers with a joint resource on the Drugs site featuring FDA Consumer Update articles, videos, and slideshows. The partnership will also provide access to FDA health information on Drugs's mobile phone platform.


"We are very excited about partnering with the FDA to provide consumers with public health and safety information on our site as well as our mobile phone platform," said Philip Thornton, CEO of Drugs.


The complete terms and components of the partnership with Drugs are described in a Memorandum of Understanding published in the May 26, 2010, Federal Register and available online here.



For more information:


- How to Partner With FDA

- Drugs/FDA partnership Home Page

Source
U.S. Food and Drug Administration

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