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2014 Chemistry Nobel Awarded to Two Americans, One German for Development of Fluorescence-Based Nano-Microscopy

On October 8, 2014, The Royal Swedish Academy of Sciences announced that it had decided to award the Nobel Prize in Chemistry for 2014 to Eric Betzig (photo), Ph.D., Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA, Stefan W. Hell, Ph.D., Max Planck Institute for Biophysical Chemistry, Göttingen, and German Cancer Research Center, Heidelberg, Germany, and William E. Moerner, Ph.D., Stanford University, Stanford, CA, USA “for the development of super-resolved fluorescence microscopy.” For a long time optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength of light. Helped by fluorescent molecules, the Nobel Laureates in Chemistry 2014 ingeniously circumvented this limitation. Their ground-breaking work has brought optical microscopy into the nanodimension. In what has become known as nanoscopy, scientists visualize the pathways of individual molecules inside living cells. They can see how molecules create synapses between nerve cells in the brain; they can track proteins involved in Parkinson’s, Alzheimer’s, and Huntington’s diseases as they aggregate; they follow individual proteins in fertilized eggs as these divide into embryos. It was all but obvious that scientists should ever be able to study living cells in the tiniest molecular detail. In 1873, the microscopist Ernst Abbe stipulated a physical limit for the maximum resolution of traditional optical microscopy: it could never become better than 0.2 micrometers. Eric Betzig, Stefan W. Hell, and William E. Moerner are awarded the Nobel Prize in Chemistry 2014 for having bypassed this limit. Due to their achievements the optical microscope can now peer into the nanoworld. Two separate principles are rewarded.

High-Sugar Diet No Problem for Worms with Mutant SKN-1 Gene

Imagine being able to take a pill that lets you eat all of the ice cream, cookies, and cakes that you wanted – without gaining any weight. New research from the University of Southern California (USC) suggests that dream may not be impossible. A team of scientists led by Dr. Sean Curran of the USC Davis School of Gerontology and the Keck School of Medicine of USC has found a new way to suppress the obesity that typically accompanies a high-sugar diet, pinning it down to a key gene that pharmaceutical companies have already developed drugs to target. So far, Dr. Curran's work has been carried out solely on the worm Caenorhabditis elegans (C. elegans) (image) and human cells in a petri dish – but the genetic pathway he studied is found in almost all animals from yeast to humans. Next, he plans to test his findings in mice. Dr. Curran's research is outlined in a study that was published online on October 6, 2014 in an open-access article in Nature Communications. Building on previous work with C. elegans, Dr. Curran and his colleagues found that certain genetic mutants – specifically, those with a hyperactive SKN-1 gene – could be fed incredibly high-sugar diets without gaining any weight, while regular C. elegans worms ballooned on the same diet. "The high-sugar diet that the bacteria (sic—worms) ate was the equivalent of a human eating the Western diet," Dr. Curran said, referring to the diet favored by the Western world, characterized by high-fat and high-sugar foods, such as burgers, fries, and soda. The SKN-1 gene also exists in humans, where it is called Nrf2, suggesting that the findings might translate, he said.

Natural Gene Selection Can Produce Orange Corn Rich in Provitamin A

Purdue researchers and collaborators have identified a set of genes that can be used to naturally boost the provitamin A content of corn kernels, a finding that could help combat vitamin A deficiency in developing countries and macular degeneration in the elderly. Professor of Agronomy Torbert Rocheford and fellow researchers found gene variations that can be selected to change nutritionally poor white corn into biofortified orange corn with high levels of provitamin A carotenoids - substances that the human body can convert into vitamin A. Vitamin A plays key roles in eye health and the immune system, as well as in the synthesis of certain hormones. "This study gives us the genetic blueprint to quickly and cost-effectively convert white or yellow corn to orange corn that is rich in carotenoids - and we can do so using natural plant breeding methods, not transgenics," said Dr. Rocheford, the Patterson Endowed Chair of Translational Genomics for Crop Improvement at Purdue. The research was published online on September 25, 2014 in Genetics. Vitamin A deficiency causes blindness in 250,000 to 500,000 children every year, half of whom die within a year of losing their eyesight, according to the World Health Organization. The problem most severely affects children in Sub-Saharan Africa, an area in which white corn, which has minimal amounts of provitamin A carotenoids, is a dietary mainstay. Insufficient carotenoids may also contribute to macular degeneration in the elderly, a leading cause of blindness in older populations in Europe and the U.S. Identifying the genes that determine carotenoid levels in corn kernels will help plant breeders develop novel biofortifed corn varieties for Africa and the U.S.

EpiCypher Announces Five Epigenetics Grant Winners

On October 7, 2014, EpiCypher™, Inc., announced the award of five grants for Histone Peptide Array Screening Services to researchers at Indiana University, Memorial Sloan-Kettering Cancer Center, The University of Florida, The University of Montreal, and The Structural Genomics Consortium, as part of their first annual grant program in support of chromatin biology and epigenetics research. The scientific founders of EpiCypher reviewed each grant application and selected the winners, each of whom will receive histone modification screening services employing EpiCypher’s world-class EpiTitan™ Histone Peptide Arrays, along with a statistical analysis of their protein’s or antibody’s histone modification binding profile. The grantees are: Levi Blazer, Ph.D., Structural Genomics Consortium; El Bachir Affar, Ph.D., University of Montreal; Omar Abdel-Wahab, M.D., Memorial Sloan-Kettering Cancer Center; Feng-Chun Yang, Ph.D., Indiana University School of Medicine; and Daiqing Liao, Ph.D, University of Florida. The grant recipients and their respective organizations will work individually but collaboratively with EpiCypher’s scientific team to help answer each project’s fundamental biological question. EpiCypher is dedicated to giving researchers access to the highest-quality, most productive approaches for more meaningful investigations into chromatin biology and epigenetics research. “We look forward to introducing these winners to the many benefits of our transformative products and incorporating them into their research so they can experience their advantages to chromatin research first hand,” says EpiCypher CEO Sam Tetlow.

Nobel Prize Awarded for Discovery of GPS in Brain

The Nobel Assembly at Karolinska Institutet has today (October 6, 2014) decided to award The 2014 Nobel Prize in Physiology or Medicine with one half to John O´Keefe, Ph.D. (photo), in the UK, and the other half jointly to the wife-husband team of May-Britt Moser, Ph.D., and Edvard I. Moser, Ph.D., in Norway, for their discoveries of cells that constitute a positioning system in the brain. How do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? This year´s Nobel Laureates have discovered a positioning system, an “inner GPS” in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function. In 1971, Dr. O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. Dr. O´Keefe concluded that these “place cells” formed a map of the room. More than three decades later, in 2005, Drs. May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells,” that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate. The discoveries of Drs.

Glia-Secreted Exosomes Play Key Role in Functioning of Nerve Cells

Tiny vesicles containing protective substances which they transmit to nerve cells apparently play an important role in the functioning of neurons. As cell biologists at Johannes Gutenberg University Mainz (JGU) have discovered, nerve cells can enlist the aid of mini-vesicles of neighboring glial cells to defend themselves against stress and other potentially detrimental factors. These vesicles, called exosomes, appear to stimulate the neurons on various levels: they influence electrical stimulus conduction, biochemical signal transfer, and gene regulation. Exosomes are thus multifunctional signal emitters that can have a significant effect in the brain. The scientists reported these results in the September 2014 issue of The Philosophical Transactions of the Royal Society B (Biological Sciences). The researchers in Mainz already observed in a previous study that oligodendrocytes release exosomes on exposure to neuronal stimuli. These exosomes are absorbed by the neurons and improve neuronal stress tolerance. Oligodendrocytes are a type of glial cell and they form an insulating myelin sheath around the axons of neurons. The exosomes transport protective proteins such as heat shock proteins, glycolytic enzymes, and enzymes that reduce oxidative stress from one cell type to another, but also transmit genetic information in the form of ribonucleic acids. "As we have now discovered in cell cultures, exosomes seem to have a whole range of functions," explained Dr. Eva-Maria Krämer-Albers. By means of their transmission activity, the small bubbles that are the vesicles not only promote electrical activity in the nerve cells, but also influence them on the biochemical and gene regulatory level. "The extent of activities of the exosomes is impressive," added Dr. Krämer-Albers.

Pain Receptor Found on T-Cells; Regulates Calcium Influx and Cell Activation

Researchers at the University of California, San Diego, School of Medicine have discovered that T-cells – a type of white blood cell that learns to recognize and attack microbial pathogens – are activated by a pain receptor. The study, reported online on October 5, 2014 in Nature Immunology, shows that the receptor helps regulate intestinal inflammation in mice and that its activity can be manipulated, offering a potential new target for treating certain autoimmune disorders, such as Crohn's disease and possibly multiple sclerosis. "We have a new way to regulate T-cell activation and potentially better control immune-mediated diseases," said senior author Eyal Raz, M.D., Professor of Medicine. The receptor, called a TRPV1 channel (image), has a well-recognized role on nerve cells that help regulate body temperature and alert the brain to heat and pain. It is also sometimes called the capsaicin receptor because of its role in producing the sensation of heat from chili peppers. The study is the first to show that these channels are also present on T-cells, where they are involved in gating the influx of calcium ions into cells – a process that is required for T-cell activation. "Our study breaks current dogma in which certain ion channels called CRAC are the only players involved in calcium entry required for T-cell function," said lead author Dr. Samuel Bertin, a postdoctoral researcher in the Raz laboratory. "Understanding the physical structures that enable calcium influx is critical to understanding the body's immune response." T-cells are targeted by the HIV virus and their destruction is why people with AIDS have compromised immune function. Certain vaccines also exploit T-cells by harnessing their ability to recognize antigens and trigger the production of antibodies, conferring disease resistance.

Crystallography Breakthrough Will Democratize Ability to See Molecules Move; Huge Boon to Research

A new crystallographic technique developed at the University of Leeds is set to transform scientists' ability to observe how molecules work. A research paper, published online in the journal Nature Methods on October 5, 2014, describes a new way of doing time-resolved crystallography, a method that researchers use to observe changes within the structure of molecules. The article is entitled, “Time-Resolved Crystallography Using the Hadamard Transform.” Although fast time-resolved crystallography (Laue crystallography) has previously been possible, it has required advanced instrumentation that is only available at three sites worldwide. Only a handful of proteins have been studied using the traditional technique. The new method will allow researchers across the world to carry out dynamic crystallography and is likely to provide a major boost in areas of research that rely on understanding how molecules work, such as the development of novel smart materials or new drugs. Observing how structure and dynamics are linked to function is key to designing better medicines that are targeted at specific states of molecules, helping to avoid unwanted side effects. "A time-resolved structure is a bit like having a movie for crystallographers," said Professor Arwen Pearson, who led the team at Leeds. "Life wiggles. It moves about and, to understand it, you need to be able to see how biological structures move at the atomic scale. This breakthrough allows us to do that." Traditional X-ray crystallography fires X-rays into crystallized molecules and creates an image that allows researchers to work out the atomic structure of the molecules. A major limitation is that the picture created is the average of all the molecules in a crystal and their motions over the time of an experiment. Dr.

Preosteoclasts and Their Secreted PDGF-BB Crucial to Bone Rebuilding; Finding Explains Success of Experimental New Osteoporosis Drug Odanacatib from Merck

Experiments in mice with a bone disorder similar to that in women after menopause show that a scientifically overlooked group of cells are likely crucial to the process of bone loss caused by the disorder, according to Johns Hopkins researchers. Their discovery, they say, not only raises the research profile of the cells, called preosteoclasts, but also explains the success and activity of an experimental osteoporosis drug with promising results in phase III clinical trials. A summary of the researchers’ work was published online on October 5, 2014 in Nature Medicine. "We didn't know that the drug affects preosteoclasts, nor did we understand how important preosteoclasts are in maintaining healthy bones," says Xu Cao, Ph.D., the Lee H. Riley Jr., M.D., Professor of Orthopaedic Surgery. "Now drug companies hoping to reverse osteoporosis can look for even more drugs that make use of and target these interesting cells." The bones of mice, people, and all land animals are not only necessary for strength and structure, but also as warehouses for calcium, which cells throughout the body use continuously for everyday tasks like cell-to-cell communication, muscle strength, and even embryo fertilization and hormone balance. Calcium is taken from digested food and stored in the semi-hollow space inside bones. To access the stored calcium, the inner bone goes through a process called resorption, in which cells called osteoclasts attach to the bone and dissolve the calcium and other stored minerals. Nearby, specialized blood vessels pick up the calcium and send it throughout the body. They also bring in nutrients needed for new bone formation. Under normal conditions, bone resorption is carefully balanced with bone rebuilding to maintain bone strength.

Rare Heart and Gut Disease Identified, Linked to Mutation of Single Gene, Traced to Founder Effect in 12th Century Vikings

Physicians and researchers at CHU Sainte-Justine, Université de Montréal, CHU de Québec, Université Laval, and Hubrecht Institute have discovered a rare disease affecting both heart rate and intestinal movements. The disease, which has been named "Chronic Atrial Intestinal Dysrhythmia syndrome" (CAID), is a serious condition caused by a rare genetic mutation. This finding demonstrates that rhythmic contractions of heart and guts are closely linked by a single gene in the human body, as shown in the study published online on October 5, 2014 in Nature Genetics. The research teams in Canada have also developed a diagnostic test for the CAID syndrome. "This test will identify with certainty the syndrome, which is characterized by the combined presence of various cardiac and intestinal symptoms," said Dr. Gregor Andelfinger, a pediatric cardiologist and researcher at CHU Sainte-Justine "The symptoms are severe, and treatments are very aggressive and invasive,” added Dr. Philippe Chetaille, a pediatric cardiologist and researcher at the University Hospital CHU de Québec." At cardiac level, patients suffer primarily from a slow heart rate, a condition which will require the implantation of a pacemaker for half of them, often as early as in their childhood. At digestive level, a chronic intestinal pseudo-obstruction will often force patients to feed exclusively intravenously. Furthermore, many of them will also have to undergo bowel surgery. By analyzing the DNA of patients of French-Canadian origin and a patient of Scandinavian origin showing both the cardiac and the gastrointestinal condition, the researchers were able to identify a mutation in the gene SGOL1 that is common to all of patients showing both profiles.

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