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MGH-Harvard Study Demonstrates the Neuronal Basis of Cooperative Social Interactions; Results May Lead to Targeted Treatment of Autism Spectrum Disorders (ASDs) and Other Social Behavioral Maladies

Social interactions rely on the ability to anticipate others' intentions and actions, and the identificantion of neurons that reflect another individual's so-called "state of mind" has been a long-sought goal in neuroscience. A study published online on February 26, 2015 in Cell reveals that a newly discovered set of neurons in a frontal brain region called the anterior cingulate is used in primates to predict whether or not an opponent will cooperate in a strategic decision-making task, providing information about the inherently unobservable and unknown decisions of others. By shedding light on the neuronal basis of cooperative interactions, the study paves the way for the targeted treatment of social behavioral disorders such as autism spectrum disorders. The Cell article is titled “Neuronal Prediction of Opponent's Behavior During Cooperative Social Interchange in Primates." "Many conflicts or adversarial interactions arise from an inability to accurately read another's intentions or hidden state of mind," says lead author Keren Haroush, M.D., a postdoctoral fellow at the Massachusetts General Hospital (MGH)-Harvard Medical School (HMS) Center for Nervous System Repair. "Therefore, understanding where and how these computations are performed within the brain may help us better understand how such complex social interactions occur." Previous studies had shown that brain cells called mirror neurons reflect the known and observable actions of one’s self and others. But these neurons do not represent another's imminent decisions or intentions. While neurons that predict another's intended actions have been widely hypothesized and are a cornerstone of many theories on social behavior, their existence had never before been demonstrated.

New Drug Effective Against MDR Tuberculosis, Also Shows Signs of Anti-HIV Activity

Researchers at the University of Georgia (UGA) have developed a new small molecule drug that may serve as a treatment for multi-drug resistant (MDR) tuberculosis, a form of the disease that cannot be cured with conventional therapies. The scientists describe their findings in an article available online and scheduled to be published in the March 15, 2015 issue of Bioorganic and Medicinal Chemistry Letters. The article is titled “A Novel Molecule with Notable Activity Against Multi-Drug Resistant Tuberculosis.” Nine million people contracted tuberculosis in 2013, and 1.5 million died from the disease, according to the World Health Organization (WHO). While standard anti-TB drugs can cure most people of Mycobacterium tuberculosis infection, improper use of antibiotics has led to new strains of the bacterium that are resistant to the two most powerful medications, isoniazid and rifampicin. "Multi-drug resistant TB is spreading rapidly in many parts of the world," said Dr. Vasu Nair (photo), Georgia Research Alliance Eminent Scholar in Drug Discovery in the University of Georgia (UGA) College of Pharmacy and lead author of the paper. "There is a tremendous need for new therapies, and we think our laboratory has developed a strong candidate that disrupts fundamental steps in the bacterium's reproduction process." Just as in other living organisms, the genetic information contained in M. tuberculosis undergoes a complex process known as transcription in which the bacterial enzyme, DNA-dependent RNA polymerase, or RNAP, produces TB RNA. This molecule is involved in processes that produce critical bacterial proteins that the organism needs to survive. The compound that Dr. Nair and his colleagues developed works by binding to magnesium and specific amino acids found within the bacterium, interrupting the production of RNA.

Wyoming’s Big Horn Basin Reveals Fossil Evidence of New Species of Tropical Turtle; Finding Offers Clues to Modern Perils Facing Turtle Migration in Response to Climate Change

Tropical turtle fossils discovered in Wyoming by University of Florida (UF) scientists reveal that when the earth got warmer, prehistoric turtles headed north. But if today's turtles try the same technique to cope with warming habitats, they might run into trouble. While the fossil turtle and its kin could move northward with higher temperatures, human pressures and habitat loss could prevent a similar modern-day migration, and lead to the extinction of some modern species. The newly discovered genus and species, Gomphochelys nanus, provides a clue to how animals might respond to future climate change, said Dr. Jason Bourque, a paleontologist at the Florida Museum of Natural History at UF and the lead author of the study, which was published online on February 20, 2015 in the Journal of Vertebrate Paleontology. The wayfaring turtle was among the species that researchers believe migrated 500-600 miles north 56 million years ago, during a temperature peak known as the Paleocene-Eocene Thermal Maximum. Lasting approximately 200,000 years, this temperature peak resulted in significant movement and diversification of plants and animals. "We knew that some plants and lizards migrated north when the climate warmed, but this is the first evidence that turtles did the same," Dr. Bourque said. "If global warming continues on its current track, some turtles could once again migrate northward, while others would need to adapt to warmer temperatures or go extinct." The newly identified turtle is an ancestor of the endangered Central American river turtle and other warm-adapted turtles in Belize, Guatemala, and southern Mexico. These modern turtles, however, could face significant roadblocks on a journey north, because much of the natural habitat of these species is in jeopardy, said co-author Dr.

Genetic Underpinnings of Motion Sickness

23andMe, Inc., a leading personal genetics company, has announced the publication of the first-ever genome-wide association study of motion sickness. Published online on February 17, 2015 in the prestigious Human Molecular Genetics journal, this study is the first to identify genetic variants associated with motion sickness, a condition that affects roughly one in three people around the world. The title of this report is “Genetic Variants Associated with Motion Sickness Point to Roles for Inner Ear Development, Neurological Processes, and Glucose Homeostasis.” Motion sickness has been shown to have high heritability, meaning genetics accounts for a large part of why some people are more prone to motion sickness than others. Estimates indicate that up to 70 percent of the variation in risk for motion sickness is due to genetics. "Until now there's been a poor understanding of the genetics of motion sickness, despite it being a fairly common condition," said 23andMe scientist Dr. Bethann Hromatka, lead author of the study. "With the help of 23andMe customers, we've been able to uncover some of the underlying genetics of this condition. These findings could help provide clues about the causes of motion sickness and other related conditions, and how to treat them, which is very exciting." The new study, which involved the consented participation of more than 80,000 23andMe customers, found 35 genetic factors associated with motion sickness at a genome-wide significant level. Many of these factors, referred to as single-nucleotide polymorphisms (SNPs), are in or near genes involved in balance, and in eye, ear, and cranial development (e.g., PVRL3, TSHZ1, MUTED, HOXB3, HOXD3 genes). Other SNPs may affect motion sickness through nearby genes with roles in the nervous system, glucose homeostasis, or hypoxia.

In the Genetic Comfort Zone--“Canalization” Buffers Developing Organisms Against Effects of Mutations and Envirnmental Stress; “Decanalization” (Departure from Genetic Comfort Zone) May Contribute to Variety of Complex Diseases in Humans

The information encoded in the DNA of an organism is not sufficient to determine the expression pattern of genes. This fact was known even before the discovery of epigenetics, which refers to external modifications to the DNA that turn genes "on" or "off." These modifications do not change the DNA sequence, but instead, they affect how genes are expressed. Another, less known mechanism called “canalization” ( keeps organisms robust despite genetic mutations and environmental stressors. If an organism experiences environmental or genetic perturbations during its development, such as extreme living conditions or genetic mutations, canalization acts as a way of buffering these disturbances. The organism remains stable and can continue to develop without recognizable changes. The article, entitled “Temperature Stress Mediates Decanalization and Dominance of Gene Expression in Drosophila melanogaster,” was published on February 26, 2015 in the open-access journal PLOS Genetics. Dr. Christian Schlötterer, at the Institute of Population Genetics, The University of Veterinary Medicine, Vienna, in Austria, together with colleagues, studied the mechanism of canalization in fruit flies. The researchers subjected two genetically distinct strains of fruit flies, Oregon and Samarkand, to different temperatures (13°C, 18°C, 23°C, and 29°C). Subsequently, the scientists analyzed the variation in gene expression in response to the different temperatures. The results revealed a homogeneous pattern of gene expression among the two strains at 18°C. No matter whether the flies were from the Oregon or to the Samarkand strain, their gene expression was almost indistinguishable.

Two-Pore Channels (TPCs) in Host Endosomes Are Critical to Ebola Virus Infectivity; Inhibiting These TPCs with Existing Drug May Prevent Ebola Infection

Dr. Robert Davey, Scientist and Ewing Halsell Scholar in the Department of Immunology and Virology at Texas Biomedical Research Institute, announced on February 26, 2015, that a small molecule called Tetrandrine, derived from an Asian herb, has shown to be a potent small molecule inhibiting infection of human white blood cells in in vitro experiments and prevented Ebola virus disease in mice. Tetrandine is currently approved for use in humans as a blood pressure medication. In their new work, the scientists found that Ebola virus entry into host cells requires the endosomal calcium channels called “two-pore channels” (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule the scientists tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficiency in mice. The scientists concluded that TPC proteins play a key role in Ebola virus infection and may be effective targets for anti-viral therapy. The work will be reported on February 27, 2015 in Science in an article entitled “Two-Pore Channels Control Ebola Virus Host Cell Entry and Are Drug Targets for Disease Treatment.” The latest outbreak of Ebola virus disease has caused the death of more than 9,400 people worldwide and created an international crisis that has shown few signs of stopping, continuing to infect thousands in West Africa. Ebola virus causes hemorrhagic fever in humans and currently has no approved therapy or vaccine. Scientists at Texas Biomed have been working in the Institute's Biosafety Level 4 containment laboratory for more than ten years to find a vaccine, therapies, and detection methods for the virus. Dr.

Full Crop Protection from Colorado Potato Beetle Achieved by Generating High Concentrations of Beetle-Gene-Specific dsRNA in Host Plant Chloroplasts for Powerful RNA Interference Effect

Colorado potato beetles are a dreaded pest of potatoes all over the world. Because they do not have natural enemies in most potato-producing regions, farmers try to control them with pesticides. However, this strategy is often ineffective because the pest has developed resistances against nearly all insecticides. Now, scientists from the Max Planck Institutes of Molecular Plant Physiology in Potsdam-Golm and Chemical Ecology in Jena have shown that potato plants can be protected from herbivory using RNA interference (RNAi). The scientists genetically modified plants to enable their chloroplasts to accumulate double-stranded RNAs (dsRNAs) targeted against essential beetle genes. The results will be published in the February 27, 2015 iissue of Science. The article title is “Full Crop Protection from an Insect Pest by Expression of Long Double-Stranded RNAs in Plastids.” RNA interference (RNAi) is a type of gene regulation that occurs naturally in eukaryotes. In plants, fungi, and insects it also is used for protection against certain viruses. During infection, many viral pathogens transfer their genetic information into the host cells as double-stranded RNA (dsRNA). Replication of viral RNA leads to high amounts of dsRNA which is recognized by the host's RNAi system and chopped up into smaller RNA fragments, called siRNAs (small interfering RNAs). The cell then uses siRNAs to detect and destroy the foreign RNA. But the RNAi mechanism can also be exploited to knock down any desired gene, by tailoring dsRNA to target the gene's messenger RNA (mRNA). When the targeted mRNA is destroyed, synthesis of the encoded protein will be diminished or blocked completely. Targeting an essential gene of a crop pest can turn dsRNA into a precise and potent insecticide.

Subset of Pancreatic Cancer Patients May Benefit from Anti-Angiogenesis Approaches and Targeting of Jak1, Jak2, and Stat3 Pathways to Alter Tumor-Stimulating Effect of Molecules Released from Blood Vessel Endothelial Cells

Cancer researchers at Indiana University report that approximately 15 percent of people with pancreatic cancer may benefit from therapy targeting a newly identified gene signature associated with up-regulated angiogenesis. Using data from The Cancer Genome Atlas (TCGA), Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, and colleagues found that a sub-group of pancreatic cancer patients who possess a strong angiogenic gene signature could benefit from personalized therapies that cut off the angiogenic pathways that feed the cancer's growth. This particular gene signature is associated with enabling abnormal blood vessels to form in tumors, which feeds the tumor's growth. The finding, published online on February 25, 2015 in Oncotarget, is new because the prevalence of this signature was not previously known. The authors also demonstrated, for the first time, that endothelial cells, the main type of cell found in the inside lining of blood vessels, can produce molecules that directly stimulate the growth of pancreatic cancer cells. "We showed that endothelial cells can stimulate the growth of pancreatic cancer cells and that by silencing or inhibiting certain pathways--JAK1-2 and STAT3--we can alter that effect," Dr. Korc explained. "We demonstrated that it is possible to target these pathways and prolong the survival of genetically modified mice whose pancreatic cancers also have a strong pro-angiogenic gene signature." Thus, for pancreatic patients with a strong pro-angiogenic gene signature, the finding suggests that they may benefit from targeted therapy that is directed against one of these pathways.

Mayo Scientists ID a Gene for Pancreatic Cancer; Discovery May Lead to Treatment, and Even Prevention

A research team led by investigators from Mayo Clinic’s campus in Jacksonville, Florida, and the University of Oslo, Norway, has identified a molecule that pushes normal pancreatic cells to transform their shape, laying the groundwork for the development of pancreatic cancer, one of the most difficult tumors to treat. The team’s findings, reported online on February 20, 2015 in Nature Communications, suggest that inhibiting the gene, protein kinase D1 (PKD1), and its protein could halt progression and spread of this form of pancreatic cancer, and possibly even reverse the transformation. “As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes. Given this finding, we are busy developing a PKD1 inhibitor that we can test further,” says the study’s co-lead investigator, Peter Storz, Ph.D., a cancer researcher at the Mayo Clinic. “We need a new strategy to treat, and possibly prevent, pancreatic cancer. While these are early days, understanding one of the key drivers in this aggressive cancer is a major step in the right direction,” he says. In the U.S., pancreatic cancer is the fourth most common cause of deaths due to cancer, according to the American Cancer Society. A quarter of patients do not live longer than a year after diagnosis. The title of the Nature Communications article is “Protein Kinase D1 Drives Pancreatic Acinar Cell Reprogramming and Progression to Intraepithelial Neoplasia.” Pancreatic cancer can occur when acinar cells--pancreatic cells that secrete digestive enzymes--morph into duct-like structures. This usually occurs after injury or inflammation of the pancreas, and is a reversible process. However, the presence of oncogenic signaling (Kras mutations, EGF-R) can push these duct cells to develop lesions that are at risk for tumor development.

Four Distinct Types of Pancreatic Cancer Identified Based on Extent of DNA Rearrangements; May Lead to More Personalized Treatment

Researchers have found that pancreatic cancer can be split into four unique types, a discovery that could be used to improve treatments for the disease, according to a study published in the February 26, 2015 issue of Nature. The article was titled “Whole Genomes Redefine the Mutational Landscape of Pancreatic Cancer’. Nature.” An international team of scientists, including Cancer Research UK researchers, found that these four types were created when large chunks of DNA are shuffled around. The team also identified the genes that could be damaged in this way. These four disease types are based on the extent of the cancer’s genetic shuffling, with the tumors classified depending on the frequency, location, and types of DNA rearrangements. This shuffling of chunks of DNA causes genetic chaos with genes deleted, wrongly switched on and off, or entirely new versions being created. The four subgroups were classified as having DNA that was stable, locally rearranged, scattered, or unstable. Among the genetic faults found are some that could potentially be targeted with existing drugs. Study co-lead, Professor Andrew Biankin, a Cancer Research UK scientist at the University of Glasgow, said: “Despite many decades of research into pancreatic cancer we have faced numerous obstacles in finding new and effective treatments. But our crucial study sheds light on how the chaotic chromosomal rearrangements cause a huge range of genetic faults that are behind the disease and provide opportunities for more personalized pancreatic cancer treatment.” The study also suggests which pancreatic cancer patients may benefit from platinum-based drugs – these are commonly used chemotherapy treatments, typically used for testicular or ovarian cancer.

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