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Archive - Jul 2012

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July 18th

Stanford Study Identifies Potential Target for Treating Major Symptom of Depression

Stanford University School of Medicine scientists have laid bare a novel molecular mechanism responsible for the most important symptom of major depression: anhedonia, the loss of the ability to experience pleasure. While the study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, increasing the odds that the findings point toward new therapies for depression and other disorders. Additionally, opinion leaders hailed the study's inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers. While as many as one in six Americans are likely to suffer a major depression in their lifetimes, current medications either are inadequate or eventually stop working in as many as 50 percent of those for whom they're prescribed. "This may be because all current medications for depression work via the same mechanisms," said Robert Malenka, M.D., Ph.D., the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences at Stanford. "They increase levels of one or another of two small molecules that some nerve cells in the brain use to signal one another. To get better treatments, there's a great need to understand in greater detail the brain biology that underlies depression's symptoms." The study's first author is Byung Kook Lim, Ph.D., a postdoctoral scholar in Dr. Malenka's laboratory. Dr. Malenka is the senior author of the new study, published online on July 11, 2012 in Nature, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain's ability to experience pleasure when an animal is stressed.

July 16th

New Gene Mutations Linked to Lou Gehrig’s Disease

Researchers have linked newly discovered gene mutations in a particular gene to some cases of the progressive fatal neurological disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. Shedding light on how ALS destroys the cells and leads to paralysis, the researchers found that mutations in this gene affect the structure and growth of nerve cells. The results were published online on July 15, 2012 in Nature. ALS attacks motor neurons, the nerve cells responsible for controlling muscles. People with ALS experience such early symptoms as limb weakness or swallowing difficulties. In most people, the disease leads to death three to five years after symptoms develop, usually as a result of respiratory failure. Scientists at the University of Massachusetts Medical School, Worcester, collaborated with international ALS researchers to search for gene mutations in two large families with an inherited form of ALS. The researchers used a technique known as exome sequencing to decode only the protein-encoding portions of DNA, known as the exome, allowing an efficient yet thorough search of the DNA regions most likely to contain disease-causing mutations. This deep sequencing of the exome led to the identification of several different mutations in the gene for profilin (PFN1) which were present only in the family members that developed ALS. Further investigations of 272 other familial ALS cases across the world showed that profilin mutations were also found in a small subset (about 1 to 2 percent) of the familial ALS cases studied. The protein profilin plays a key role in the creation and remodeling of a nerve cell's scaffolding or cytoskeleton. In fly models, disrupting profilin stunts the growth of axons – the long cell projections used to relay signals from one neuron to the next or from motor neurons to muscle cells.

July 12th

Salt Cress Genome Yields New Clues to Salt Tolerance

An international team, led by the Institute of Genetics and Developmental Biology, the Chinese Academy of Science, and BGI, the world's largest genomics organization, has completed the genomic sequence and analysis of salt cress (Thellungiella salsuginea), a wild salt-tolerant plant. The salt cress genome serves as a useful tool for exploring mechanisms of adaptive evolution and sheds new light on understanding the genetic characteristics underlying plant abiotic stress tolerance. The study was published online on July 9, 2012 in PNAS. Salt cress is a typical halophyte with high resistance to cold, drought, oxidative stresses, and salinity. Due to its small plant size, short life cycle, copious seed production, small genome size, and an efficient transformation, salt cress could serve as an important genetic model system for botanists, geneticists, and breeders to better explore the genetic mechanisms of abiotic stress tolerance. In the study, researchers sequenced the genome of salt cress (Shandong ecotype) using the paired-end Solexa sequencing technology. The genomic data yielded a draft sequence of salt cress with about 134-fold coverage. The final length of the assembled sequences amounted to about 233.7 Mb, covering about 90% of the estimated size (~260 Mb). A total of 28,457 protein-coding regions were predicted in the sequenced salt cress genome. Researchers found that the average exon length of salt cress and A. thaliana genes was similar, whereas the average intron length of salt cress was about 30% larger than that of A. thaliana. The evolutionary analysis indicated that salt cress and its close relative- Arabidopsis thaliana- diverged from approximately 7-12 million years ago. When tracing the differences between salt cress and A.

July 11th

Researchers Discover Molecule That Could Aid Fight Against Atherosclerosis

Cleveland Clinic researchers have discovered that a naturally occurring molecule may play a role in preventing plaque buildup inside arteries, possibly leading to new plaque-fighting drugs and improved screening of patients at risk of developing atherosclerosis. The study was published in the June 6, 2012 issue of Cell Metabolism. Sometimes called hardening or clogging of the arteries, atherosclerosis is the buildup of cholesterol, fatty cells, and inflammatory deposits on the inner walls of the arteries, restricting blood flow to the heart. The disease can affect the arteries in the heart, legs, brain, kidneys, and other organs, and is the most common cause of heart attacks, strokes, and peripheral vascular disease. At the cellular level, plaque buildup is the result of macrophages in the vessel wall absorbing, processing, and storing cholesterol (lipids) and then accumulating it in large amounts, eventually leading to the development of arterial lesions. The researchers, led by Eugene Podrez, M.D., Ph.D., of the Department of Molecular Cardiology at Cleveland Clinic's Lerner Research Institute, have discovered that the naturally occurring molecule Akt3 regulates lipid entry into macrophages and prevents the cells from storing excessive amounts of cholesterol and collecting in the artery. Dr. Podrez says the discovery could lead to new drugs designed to prevent atherosclerosis. It could also help doctors develop screening tests to determine patient risk level for developing the disease. Dr. Podrez and his colleagues are now looking into the particular mechanisms behind Akt3's role in regulating lipid processing and will attempt to replicate their results in humans.

July 10th

Suppression of Sox10 Gene Inhibits Melanoma in Mice

Melanoma is particularly aggressive and becoming increasingly common in Switzerland. Despite intensive research, however, there is still no treatment. Researchers from the University of Zurich, and collaborators, have now identified a gene that plays a central role in melanoma. Suppressing this gene in mice inhibits the development of melanoma and its proliferation – a discovery that could pave the way for new forms of therapy. This work was published online on July 8, 2012 in Nature Cell Biology. Until recently, it was assumed that a tumor was composed of many equivalent cells that all multiply malignantly and can thus contribute to tumor growth. According to a more recent hypothesis, however, a tumor might also consist of malignant cancer stem cells and other less aggressive tumor cells. Normally, stem cells are responsible for the formation of organs. Cancer stem cells can divide in a very similar way and develop into other tumor cells to form the tumor. Efficient tumor therapy thus primarily needs to fight cancer stem cells. Consequently, a team of stem-cell researchers from the University of Zurich headed by Professor Lukas Sommer decided to find out whether mechanisms that are important for normal stem cells also play a role in cancer stem cells. Melanoma cells are rogue skin-pigment cells formed by so-called neural crest stem cells during embryonic development. Professor Sommer’s group teamed up with dermatologists and pathologists to investigate whether cells with characteristics of these specific stem cells are present in human tumor tissue. “This was indeed the case, as we were able to prove based on numerous biopsies performed on melanoma patients,” says Professor Sommer. In particular, one gene that effectively controls the stem-cell program was highly active in all the tumor tissue studied.

July 8th

Exome Sequencing of Health Condition Extremes Can Reveal Susceptibility Genes

Comparing the DNA from patients at the best and worst extremes of a health condition can reveal genes for resistance and susceptibly. This approach has led to the discovery of rare variations in the DCTN4 gene among cystic fibrosis patients most prone to early, chronic airway infections. The DCTN4 gene codes for dynactin 4. This protein is a component of a molecular motor that moves trouble-making microbes along a cellular conveyer belt into miniscule chemical vats, called lysosomes, for annihilation. This study, led by the University of Washington (UW), is part of the National Heart Lung and Blood Institute GO Exome Sequencing Project and its Lung GO, both major National Institutes of Health chronic disease research efforts. Similar "testing the extremes" strategies may have important applications in uncovering genetic factors behind other more common, traits, such as healthy and unhealthy hearts. The results of the cystic fibrosis infection susceptibility study were published online on July 8, 2012 in Nature Genetics. The infection in question was Pseudomonas aeruginosa, an opportunistic soil bacterium that commonly infects the lungs of people with cystic fibrosis and other airway-clogging disorders. The bacteria can unite into a slithery, hard-to-treat biofilm that hampers breathing and harms lung tissue. Chronic infections are linked to poor lung function and shorter lives among cystic fibrosis patients. These bacteria rarely attack people with normal lungs and well-functioning immune systems. In the study, these rare variations in DCTN4 did not appear in any of the cystic fibrosis patients who were the most resistant to Pseudomonas infection. The study subjects most susceptible to early, chronic infection had at least one DCTN4 missense variant. A missense variant produces a protein that likely can't function properly.

Inhibitor of Melanoma Growth Identified

Researchers from Brigham and Women's Hospital (BWH) in Boston have made a potentially groundbreaking discovery that may shape the future of melanoma therapy. The team, led by Thomas S. Kupper, M.D., chair of the BWH Department of Dermatology, and Rahul Purwar, Ph.D., found that high expression of a cell-signaling molecule, known as interleukin-9, in immune cells inhibits melanoma growth. Their findings were published online on July 8, 2012 in Nature Medicine. After observing mice without genes responsible for development of an immune cell called T helper cell 17 (TH17), researchers found that these mice had significant resistance to melanoma tumor growth, suggesting that blockade of the TH17 cell pathway favored tumor inhibition. The researchers also noticed that the mice expressed high amounts of interleukin-9. "These were unexpected results, which led us to examine a possible contribution of interleukin-9 to cancer growth suppression." said Dr. Purwar. The researchers next treated melanoma-bearing mice with T helper cell 9 (TH9), an immune cell that produces interleukin-9. They saw that these mice also had a profound resistance to melanoma growth. This is the first reported finding showing an anti-tumor effect of TH9 cells. Moreover, the researchers were able to detect TH9 cells in both normal human blood and skin, specifically in skin-resident memory T cells and memory T cells in peripheral blood mononuclear cells. In contrast, TH9 cells were either absent or present at very low levels in human melanoma. This new finding paves the way for future studies that will assess the role of interleukin-9 and TH9 cells in human cancer therapy. "Immunotherapy of cancer is coming of age, and there have been exciting recent results in patients with melanoma treated with drugs that stimulate the immune system," said Dr.

July 5th

Non-Invasive Sequencing of Fetal Genome from Mother’s Blood

Researchers at the Stanford University School of Medicine have for the first time sequenced the genome of an unborn baby using only a blood sample from the mother. The findings from the new approach, published online on July 4, 2012 in Nature, are related to research that was reported a month ago from the University of Washington. That research used a technique previously developed at Stanford to sequence a fetal genome using a blood sample from the mother, plus DNA samples from both the mother and father. The whole genome sequencing in the new Stanford study, however, did not require DNA from the father — a significant advantage when a child’s true paternity may not be known (a situation estimated to affect as many as one in 10 births in this country) or the father may be unavailable or unwilling to provide a sample. The technique brings fetal genetic testing one step closer to routine clinical use. “We’re interested in identifying conditions that can be treated before birth, or immediately after,” said Stephen Quake, Ph.D., the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics. “Without such diagnoses, newborns with treatable metabolic or immune system disorders suffer until their symptoms become noticeable and the causes determined.” Dr. Quake is the senior author of the research. Former graduate student H. Christina Fan, Ph.D., now a senior scientist at ImmuMetrix, and current graduate student Wei Gu are co-first authors of the article. As the cost of such technology continues to drop, it will become increasingly common to diagnose genetic diseases within the first trimester of pregnancy, the researchers believe. In fact, they showed that sequencing just the exome, the coding portion of the genome, can provide clinically relevant information.

Yak Genome Sequence Provides Insights into High-Altitude Adaptation

An international team, led by Lanzhou University, and including BGI, the world's largest genomics organization, the Institute of Kunming Zoology, the Chinese Academy of Sciences, as well as twelve other institutes, has completed the genomic sequence and analyses of a female domestic yak, which provides important insights into understanding mammalian divergence and adaptation at high altitude. This study was published online on July 1, 2012 in Nature Genetics. As an iconic symbol of Tibet and of high altitude, the yak (Bos grunniens) is the most important domesticated species for Tibetans living at high altitude in China's Qinghai Province, which could provide meat and other basic resources, such as milk, transportation, dried dung for fuel, and hides for tented accommodation. Yaks have many anatomical and physiological traits that enable them to live at high altitude, including high metabolism, acute senses, impressive foraging ability, enlarged hearts and lungs, and a lack of blood vessel constriction in the lungs when faced with relatively low oxygen conditions. In the study, researchers sequenced the genome of a female domestic yak using high-throughput sequencing technology. The genomic data yielded a 2,657-Mb draft yak genome assembly that had 65-fold coverage. The researchers also conducted transcriptome sequencing on RNA samples derived from fresh heart, liver, brain, stomach, and lung tissues collected from the same yak. Based on the transcriptome data, researchers estimated that the yak genome contains 22,282 protein-coding genes and 2.2 million heterozygous SNPs. In order to understand evolutionary adaptation of yak to the high altitude, the team conducted comparative genomic analyses between yak and cattle, a closely related animal that typically lives at much lower altitudes.

July 3rd

Pathway Understanding Key to Cancer Drug Discovery

As the Genetics Society of America's Model Organism to Human Biology (MOHB): Cancer Genetics Meeting in Washington, D.C. drew to a close, it was clear that the mantra for drug discovery to treat cancers in the post-genomic era is pathways. Pathways are ordered series of actions that occur as cells move from one state, through a series of intermediate states, to a final action. Because model organisms – fruit flies, roundworms, yeast, zebrafish, and others – are related to humans, they share many of the same pathways, but in systems that are much easier to study. Focusing on pathways in model organisms can therefore reveal new drug targets that may be useful in treating human disease. "By reading evolution's notes, we can discover what really matters in the genome," keynote speaker Eric Lander, Ph.D., founding director of the Broad Institute of Harvard and MIT and professor of biology at MIT, told a packed crowd at the MOHB: Cancer Genetics Meeting on June 19, 2012. What matters the most in the genome of a cancer cell may be the seeds of drug resistance, the genetic changes that enable cells to evade our best drugs, Bert Vogelstein, M.D., director of the Ludwig Center at Johns Hopkins University and an investigator with the Howard Hughes Medical Institute and a keynote speaker on June 17, told participants. He called drug resistance to single agents a "fait accompli," as a side effect of the evolution of cancer. "About 3,000 resistant cells are present in every visible metastasis," said Dr. Vogelstein. "That's why we see resistance with all therapeutics, even when they work. And we can't get around it with single agents.