Epigenetic changes can drive cancer, study shows

Cancer has long been thought to be primarily a genetic disease, but in recent decades scientists have come to believe that epigenetic changes — which don’t change the DNA sequence but how it is ‘read’ — also play a role in cancer. In particular DNA methylation, the addition of a methyl group (or molecule), is an epigenetic switch that can stably turn off genes, suggesting the potential to cause cancer just as a genetic mutation can. Until now, however, direct evidence that DNA methylation drives cancer formation was lacking.Researchers at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital have now created a mouse model providing the first in vivo evidence that epigenetic alterations alone can cause cancer. Their report appears in the Journal of Clinical Investigation.”We knew that epigenetic changes are associated with cancer, but didn’t know whether these were a cause or consequence of cancer. Developing this new approach for ‘epigenetic engineering’ allowed us to test whether DNA methylation changes alone can drive cancer,” said Dr. Lanlan Shen, associate professor of pediatrics at Baylor and senior author of the study.Shen and colleagues focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a broad spectrum of human cancers. They devised an approach to engineer DNA methylation specifically to the mouse p16 regulatory region (promoter). As intended, the engineered p16 promoter acted as a ‘methylation magnet’. As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers, and reduced survival.”This is not only the first in vivo evidence that epigenetic alteration alone can cause cancer,” said Shen. “This also has profound implications for future studies, because epigenetic changes are potentially reversible. …

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New class of antibiotics discovered by chemists

A team of University of Notre Dame researchers led by Mayland Chang and Shahriar Mobashery have discovered a new class of antibiotics to fight bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant bacteria that threaten public health. Their research is published in the Journal of the American Chemical Society in an article titled “Discovery of a New Class of Non-beta-lactam Inhibitors of Penicillin-Binding Proteins with Gram-Positive Antibacterial Activity.”The new class, called oxadiazoles, was discovered in silico (by computer) screening and has shown promise in the treatment of MRSA in mouse models of infection. Researchers who screened 1.2 million compounds found that the oxadiazole inhibits a penicillin-binding protein, PBP2a, and the biosynthesis of the cell wall that enables MRSA to resist other drugs. The oxadiazoles are also effective when taken orally. This is an important feature as there is only one marketed antibiotic for MRSA that can be taken orally.MRSA has become a global public-health problem since the 1960s because of its resistance to antibiotics. In the United States alone, 278,000 people are hospitalized and 19,000 die each year from infections caused by MRSA. Only three drugs currently are effective treatments, and resistance to each of those drugs already exists.The researchers have been seeking a solution to MRSA for years. “Professor Mobashery has been working on the mechanisms of resistance in MRSA for a very long time,” Chang said. “As we understand what the mechanisms are, we can devise strategies to develop compounds against MRSA.””Mayland Chang and Shahriar Mobashery’s discovery of a class of compounds that combat drug resistant bacteria such as MRSA could save thousands of lives around the world. We are grateful for their leadership and persistence in fighting drug resistance,” said Greg Crawford, dean of the College of Science at the University of Notre Dame.Story Source:The above story is based on materials provided by University of Notre Dame. …

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How neurons control fine motor behavior of the arm

Motor commands issued by the brain to activate arm muscles take two different routes. As the research group led by Professor Silvia Arber at the University of Basel’s Biozentrum and the Friedrich Miescher Institute for Biomedical Research has now discovered, many neurons in the spinal cord send their instructions not only towards the musculature, but at the same time also back to the brain via an exquisitely organized network. This dual information stream provides the neural basis for accurate control of arm and hand movements. These findings have now been published in Cell.Movement is a fundamental capability of humans and animals, involving the highly complex interplay of brain, nerves and muscles. Movements of our arms and hands, in particular, call for extremely precise coordination. The brain sends a constant stream of commands via the spinal cord to our muscles to execute a wide variety of movements. This stream of information from the brain reaches interneurons in the spinal cord, which then transmit the commands via further circuits to motor neurons innervating muscles. The research group led by Silvia Arber at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research has now elucidated the organization of a second information pathway taken by these commands.Cc to the brain: one command — two directionsThe scientists showed that many interneurons in the mouse spinal cord not only transmit their signals via motor neurons to the target muscle, but also simultaneously send a copy of this information back to the brain. Chiara Pivetta, first author of the publication, explains: “The motor command to the muscle is sent in two different directions — in one direction, to trigger the desired muscular contraction and in the other, to inform the brain that the command has actually been passed on to the musculature.” In analogy to e mail transmission, the information is thus not only sent to the recipient but also to the original requester.Information to brainstem nucleus segregated by functionWhat happens to the information sent by spinal interneurons to the brain? As Arber’s group discovered, this input is segregated by function and spatially organized within a brainstem nucleus. …

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A home for the microbiome: Biologists identify how beneficial bacteria reside and thrive in gastrointestinal tract

Aug. 19, 2013 — The human body is full of tiny microorganisms — hundreds to thousands of species of bacteria collectively called the microbiome, which are believed to contribute to a healthy existence. The gastrointestinal (GI) tract — and the colon in particular — is home to the largest concentration and highest diversity of bacterial species. But how do these organisms persist and thrive in a system that is constantly in flux due to foods and fluids moving through it? A team led by California Institute of Technology (Caltech) biologist Sarkis Mazmanian believes it has found the answer, at least in one common group of bacteria: a set of genes that promotes stable microbial colonization of the gut.A study describing the researchers’ findings was published as an advance online publication of the journal Nature on August 18.”By understanding how these microbes colonize, we may someday be able to devise ways to correct for abnormal changes in bacterial communities — changes that are thought to be connected to disorders like obesity, inflammatory bowel disease and autism,” says Mazmanian, a professor of biology at Caltech whose work explores the link between human gut bacteria and health.The researchers began their study by running a series of experiments to introduce a genus of microbes called Bacteriodes to sterile, or germ-free, mice. Bacteriodes, a group of bacteria that has several dozen species, was chosen because it is one of the most abundant genuses in the human microbiome, can be cultured in the lab (unlike most gut bacteria), and can be genetically modified to introduce specific mutations.”Bacteriodes are the only genus in the microbiome that fit these three criteria,” Mazmanian says.Lead author S. Melanie Lee (PhD ’13), who was an MD/PhD student in Mazmanian’s lab at the time of the research, first added a few different species of the bacteria to one mouse to see if they would compete with each other to colonize the gut. They appeared to peacefully coexist. Then, Lee colonized a mouse with one particular species, Bacteroides fragilis, and inoculated the mouse with the same exact species, to see if they would co-colonize the same host. To the researchers’ surprise, the newly introduced bacteria could not maintain residence in the mouse’s gut, despite the fact that the animal was already populated by the identical species.”We know that this environment can house hundreds of species, so why the competition within the same species?” Lee says. …

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A more nuanced genetic code: Rules governing expression of developmental genes in embryonic stem cells

Aug. 11, 2013 — A decade ago, gene expression seemed so straightforward: genes were either switched on or off. Not both. Then in 2006, a blockbuster finding reported that developmentally regulated genes in mouse embryonic stem cells can have marks associated with both active and repressed genes, and that such genes, which were referred to as “bivalently marked genes,” can be committed to one way or another during development and differentiation.This paradoxical state — akin to figuring out how to navigate a red and green traffic signal — has since undergone scrutiny by labs worldwide. What has been postulated is that the control regions (or promoters) of some genes, particularly those critical for development during the undifferentiated state, stay “poised” for plasticity by communicating with both activating and repressive histones, a state biologists term “bivalency.”A study by researchers at the Stowers Institute for Medical Research now revisits that notion. In this week’s advance online edition of the journal Nature Structural and Molecular Biology, a team led by Investigator Ali Shilatifard, Ph.D., identifies the protein complex that implements the activating histone mark specifically at “poised” genes in mouse embryonic stem (ES) cells, but reports that its loss has little effect on developmental gene activation during differentiation. This suggests that there is more to learn about interpreting histone modification patterns in embryonic and even cancer cells.”There has been a lot of excitement over the idea that promoters of developmentally regulated genes exhibit both the stop and go signals,” explains Shilatifard. “That work supports the idea that histone modifications could constitute a code that regulates gene expression. However, we have argued that the code is not absolute and is context dependent.”Shilatifard has a historic interest in gene regulation governing development and cancer. In 2001, his laboratory was the first to characterize a complex of yeast proteins called COMPASS, which enzymatically methylates histones in a way that favors gene expression. …

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Rethinking the genetic code

Aug. 11, 2013 — A decade ago, gene expression seemed so straightforward: genes were either switched on or off. Not both. Then in 2006, a blockbuster finding reported that developmentally regulated genes in mouse embryonic stem cells can have marks associated with both active and repressed genes, and that such genes, which were referred to as “bivalently marked genes,” can be committed to one way or another during development and differentiation.This paradoxical state — akin to figuring out how to navigate a red and green traffic signal — has since undergone scrutiny by labs worldwide. What has been postulated is that the control regions (or promoters) of some genes, particularly those critical for development during the undifferentiated state, stay “poised” for plasticity by communicating with both activating and repressive histones, a state biologists term “bivalency.”A study by researchers at the Stowers Institute for Medical Research now revisits that notion. In this week’s advance online edition of the journal Nature Structural and Molecular Biology, a team led by Investigator Ali Shilatifard, Ph.D., identifies the protein complex that implements the activating histone mark specifically at “poised” genes in mouse embryonic stem (ES) cells, but reports that its loss has little effect on developmental gene activation during differentiation. This suggests that there is more to learn about interpreting histone modification patterns in embryonic and even cancer cells.”There has been a lot of excitement over the idea that promoters of developmentally regulated genes exhibit both the stop and go signals,” explains Shilatifard. “That work supports the idea that histone modifications could constitute a code that regulates gene expression. However, we have argued that the code is not absolute and is context dependent.”Shilatifard has a historic interest in gene regulation governing development and cancer. In 2001, his laboratory was the first to characterize a complex of yeast proteins called COMPASS, which enzymatically methylates histones in a way that favors gene expression. …

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Discovery of a new class of white blood cells uncovers target for better vaccine design

July 17, 2013 — Scientists at A*STAR’s Singapore Immunology Network (SIgN) have discovered a new class of white blood cells in human lung and gut tissues that play a critical role as the first line of defence against harmful fungal and bacterial infections. This research will have significant impact on the design of vaccines and targeted immunotherapies for diseases caused by infectious microbes such as the hospital-acquired pneumonia.The scientists also showed for the first time that key immune functions of this new class of white blood cells are similar to those found in mice. This means that findings in the mouse studies can be applied to develop advanced clinical therapies for the human immune system. The study done in collaboration with Newcastle University was published in the journal Immunity.New Class of White Blood CellsAll immune responses against infectious agents are activated and regulated by dendritic cells (DCs), a specialised group of white blood cells which present tiny fragments from micro-organisms, vaccines or tumours to the T cells. T cells are immune cells that circulate around our bodies to scan for cellular abnormalities and infections. Of the different T cells, T helper 17 (Th17) cells specialise in activating a protective response crucial for our body to eliminate harmful bacteria or fungi.In this study, the scientists identified a new subset of DCs (named CD11b+ DCs), which are capable of activating such protective Th17 response. They also showed that mice lacking the CD11b+ DCs were unable to induce the protective Th17 response against the Aspergillus fumigatus, one of the most common fungal species in hospital-acquired infections.The team leader, Dr Florent Ginhoux from SIgN said, “As dendritic cells have the unique ability to ‘sense’ the type of pathogen present in order to activate the appropriate immune response, they are attractive targets to explore for vaccine development. This discovery revealed fresh inroads to better exploit dendritic cells for improved vaccine design against life-threatening fungal infections.”Acting Executive Director of SIgN, Associate Professor Laurent Rénia said, “Life-threatening fungal infections have increased over the years yet treatment options remain limited. This study demonstrates how fundamental research that deepens our understanding of the body’s immune system can translate into potential clinical applications that could save lives and impact healthcare.”

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Nerves play key role in triggering prostate cancer and influencing its spread

July 11, 2013 — Researchers at Albert Einstein College of Medicine of Yeshiva University have found that nerves play a critical role in both the development and spread of prostate tumors. Their findings, using both a mouse model and human prostate tissue, may lead to new ways to predict the aggressiveness of prostate cancer and to novel therapies for preventing and treating the disease. The study published online today in the July 12 edition of Science.Prostate cancer is second to skin cancer as the most common cancer in men. The National Cancer Institute estimates that 238,590 new cases of prostate cancer will be diagnosed in 2013, and 29,720 men will die from the disease.The study was led by stem-cell expert Paul Frenette, M.D., professor of medicine and of cell biology and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein. In earlier research, Dr. Frenette and colleagues had discovered that the sympathetic nervous system regulates hematopoeitic stem cell niches — the sites in the bone marrow where red blood cells are formed.Nerves are commonly found around tumors, but their role in the growth and progression of cancer has not been clear. “Since there might be similarities between the hematopoeitic stem cell niche and the stem cell niches found in cancer, we thought that sympathetic nerves might also have a role in tumor development,” said Dr. Frenette. …

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Research points to biomarker that could track Huntington’s disease progression

July 8, 2013 — A hallmark of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s is that by the time symptoms appear, significant brain damage has already occurred — and currently there are no treatments that can reverse it. A team of SRI International researchers has demonstrated that measurements of electrical activity in the brains of mouse models of Huntington’s disease could indicate the presence of disease before the onset of major symptoms.The findings, “Longitudinal Analysis of the Electroencephalogram and Sleep Phenotype in the R6/2 Mouse Model of Huntington’s Disease,” are published in the July 2013 issue of the neurology journal Brain, published by Oxford University Press.SRI researchers led by Stephen Morairty, Ph.D., a director in the Center for Neuroscience in SRI Biosciences, and Simon Fisher, Ph.D., a postdoctoral fellow at SRI, used electroencephalography (EEG), a noninvasive method commonly used in humans, to measure changes in neuronal electrical activity in a mouse model of Huntington’s disease. Identification of significant changes in the EEG prior to the onset of symptoms would add to evidence that the EEG can be used to identify biomarkers to screen for the presence of a neurodegenerative disease. Further research on such potential biomarkers might one day enable the tracking of disease progression in clinical trials and could facilitate drug development.”EEG signals are composed of different frequency bands such as delta, theta and gamma, much as light is composed of different frequencies that result in the colors we call red, green and blue,” explained Thomas Kilduff, Ph.D., senior director, Center for Neuroscience, SRI Biosciences. “Our research identified abnormalities in all three of these bands in Huntington’s disease mice. Importantly, the activity in the theta and gamma bands slowed as the disease progressed, indicating that we may be tracking the underlying disease process.”EEG has shown promise as an indicator of underlying brain dysfunction in neurodegenerative diseases, which otherwise occurs surreptitiously until symptoms appear. Until now, most investigations of EEG in patients with neurodegenerative diseases and in animal models of neurodegenerative diseases have shown significant changes in EEG patterns only after disease symptoms occurred.”Our breakthrough is that we have found an EEG signature that appears to be a biomarker for the presence of disease in this mouse model of Huntington’s disease that can identify early changes in the brain prior to the onset of behavioral symptoms,” said Morairty, the paper’s senior author. “While the current study focused on Huntington’s disease, many neurodegenerative diseases produce changes in the EEG that are associated with the degenerative process. This is the first step in being able to use the EEG to predict both the presence and progression of neurodegenerative diseases.”Although previous studies have shown there are distinct and extensive changes in EEG patterns in Alzheimer’s and Huntington’s disease patients, researchers are looking for changes that may occur decades before disease onset.Huntington’s disease is an inherited disorder that causes certain nerve cells in the brain to die, resulting in motor dysfunction, cognitive decline and psychiatric symptoms. It is the only major neurodegenerative disease where the cause is known with certainty: a genetic mutation that produces a change in a protein that is toxic to neurons.

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New mouse model reveals a mystery of Duchenne muscular dystrophy

July 7, 2013 — Children with Duchenne muscular dystrophy often die as young adults from heart and breathing complications. However, scientists have been puzzled for decades by the fact that laboratory mice bearing the same genetic mutation responsible for the disease in humans display only mild symptoms and no cardiac involvement.Now, researchers at the Stanford University School of Medicine have developed a mouse model that accurately mimics the course of the disease in humans. The study is the first to demonstrate a molecular basis for the cardiac defect that is the primary killer of people with Duchenne muscular dystrophy. Furthermore, the study provides evidence for a potential treatment to help prolong heart function. The mouse model also will allow researchers and clinicians to test a variety of therapies for the inherited condition.”Until now, scientists had no animal model of Duchenne muscular dystrophy that manifests the symptoms of the cardiac disease that kills children and young adults with the condition,” said Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor at Stanford and director of the Baxter Laboratory for Stem Cell Biology. “This has been a conundrum for three decades. We found that mice with moderately shortened telomeres and the Duchenne mutation exhibit profound cardiac defects and die at a young age, just like human patients.”Blau, who is also a member of the Stanford University Institute for Stem Cell Biology and Regenerative Medicine and a professor of microbiology and immunology, is the senior author of the study, which will be published July 7 in Nature Cell Biology. Foteini Mourkioti, PhD, an instructor at the Baxter Laboratory, is the lead author of the study.The investigators found that the reason humans suffer more serious symptoms than mice has to do with the length of the protective caps, called telomeres, on the ends of chromosomes: Mice have telomeres about 40 kilobases in length, while human telomeres range from around 5 to 15 kilobases (a kilobase is 1,000 nucleotides). …

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Drug improves cognitive function in mouse model of Down syndrome

July 2, 2013 — An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.”This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy,” said Ahmed Salehi, MD, PhD, the study’s senior author and a clinical associate professor of psychiatry and behavioral sciences. The study will be published online July 2 in Biological Psychiatry.Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers’ cognitive development. In addition, adults with Down syndrome develop Alzheimer’s-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi’s team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.The new study refined this work by targeting only one group of receptors that respond to norepinephrine: the beta-2 adrenergic receptors in the brain. The researchers began by giving mice a compound that blocks the action of beta-2 adrenergic receptors outside the brain. …

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Inactivation of taste genes causes male sterility

July 1, 2013 — Scientists from the Monell Center report the surprising finding that two proteins involved in oral taste detection also play a crucial role in sperm development.”This paper highlights a connection between the taste system and male reproduction,” said lead author Bedrich Mosinger, MD, PhD, a molecular biologist at Monell. “It is one more demonstration that components of the taste system also play important roles in other organ systems.”While breeding mice for taste-related studies, the researchers discovered that they were unable to produce offspring that were simultaneously missing two taste-signaling proteins.As reported online in advance of print in the Proceedings of the National Academy of Sciences, the critical proteins were TAS1R3, a component of both the sweet and umami (amino acid) taste receptors, and GNAT3, a molecule needed to convert the oral taste receptor signal into a nerve cell response.Breeding experiments determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.In order to explore the reproductive function of the two proteins, the research team engineered mice that were missing genes for the mouse versions of TAS1R3 and GNAT3 but expressed the human form of the TAS1R3 receptor. These mice were fertile.However, when the human TAS1R3 receptor was blocked in the engineered mice by adding the drug clofibrate to the rodents’ diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm. The sterility was quickly reversed after clofibrate was removed from the diet.Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies from the Monell team had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor, Mosinger speculates that these compounds could be negatively affecting human fertility, an increasing problem worldwide.He in turn notes positive implications related to the research. “If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive.”Previous work from Monell and other groups has shown that some taste genes can be found in other parts of the body, including stomach, intestines, pancreas, lungs, and brain, where they are increasingly thought to have important physiological functions.”Like much good science, our current findings pose more questions than answers,” comments Monell molecular neurobiologist Robert Margolskee, MD, PhD, also an author on the paper. “We now need to identify the pathways and mechanisms in testes that utilize these taste genes so we can understand how their loss leads to infertility.”

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Molecule that reduces fats in blood identified

June 24, 2013 — Hyperlipidemia, a condition with high levels of fats circulating in the bloodstream, is a known risk factor for various cardiovascular and metabolic disorders. While the Western diet often contributes to high levels of lipids such as cholesterol and triglycerides, over-production of the body’s own lipoproteins can lead to hyperlipidemia, independent of food intake.In a discovery that may pave the way towards new treatments for high cholesterol, researchers led by M. Mahmood Hussain, PhD, Professor of Cell Biology at SUNY Downstate Medical Center, found that a regulatory RNA molecule interferes with the production of lipoproteins and, in a mouse model, reduces hyperlipidemia and atherosclerosis. Their study was published recently in the online edition of Nature Medicine.Dr. Hussain, whose laboratory focuses on molecular mechanisms of intestinal lipoprotein assembly, says, “High plasma lipid and lipoprotein levels are a risk factor for atherosclerosis, and lowering plasma lipid levels is a national goal. While current medications and changes in diet can be effective, cardiovascular disease remains the number one cause of death in the United States, and additional approaches to decrease lipid levels are needed.”In their Nature Medicine article, Dr. Hussain and colleagues note that “overproduction of lipoproteins, a process that is dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia.” They demonstrate that microRNA-30c (miR-30c), a genetic regulator, interacts with MTP and induces its degradation, leading to reductions in MTP activity, the production of lipoproteins, plasma lipids, and atherosclerosis. This molecule also reduces lipid synthesis independently of MTP thereby avoiding complications associated with drug therapies aimed at lowering lipoprotein production.The authors conclude that a medication mimicking miR-30c could potentially be effective in reducing hyperlipidemia in humans.This work was supported in part by U.S. National Institutes of Health grants R01DK046900, from the National Institute of Diabetes and Digestive and Kidney Diseases, and R01HL095924, from the National Heart, Lung and Blood Institute.

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Personality test finds some mouse lemurs shy, others bold

June 18, 2013 — Anyone who has ever owned a pet will tell you that it has a unique personality.Yet only in the last 10 years has the study of animal personality started to gain ground with behavioral ecologists, said Jennifer Verdolin of the National Evolutionary Synthesis Center, in Durham, NC.She and a colleague have now found distinct personalities in the grey mouse lemur (Microcebus murinus), the tiny, saucer-eyed primate native to the African island of Madagascar.In a study published in the journal Primates, Verdolin gave fourteen gray mouse lemurs living at the Duke Lemur Center a personality test.Verdolin filmed the lemurs’ reactions to a variety of familiar and unfamiliar objects — such as a tissue box, an egg carton, an orange ball, and a stuffed toy frog — which she placed one at a time into the animals’ enclosures. She then measured how long it took each animal to work up the nerve to approach and investigate each object. Mouse lemurs that were quick to approach objects were considered “bold,” whereas those that behaved more cautiously were considered “shy.”She also noted how agitated the lemurs got when handled by their human caretakers during routine weigh-ins and cleanings.Verdolin found that those that hung back were also harder for their human caretakers to handle, meaning the lemurs’ distinct personality traits held up across a range of situations.The report that mouse lemurs have distinct personalities doesn’t come as a shock to staff at the Duke Lemur Center. “[The mouse lemur named] Pesto is very chatty. Asparagus gets beat up by the girls. Wasabi is mean as sin, and her favorite flavor is human fingers,” said Duke Lemur Center researcher Sarah Zehr, who was not an author of the study. Other scientists have also found evidence of personality differences among grey mouse lemurs living in the wild.But for animals living in captivity, Verdolin hopes that personality studies like hers will help researchers determine which individuals are best candidates for breeding programs or for reintroduction back into the wild, as has been done with the North American swift fox, the giant panda, and the golden lion tamarin.The next step, Verdolin says, is to determine the extent to which lemur personalities are influenced by the presence of other individuals, or whether behavioral training for some personality types could improve their chances of surviving in the wild.

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Brain circuits link obsessive-compulsive behavior and obesity

June 10, 2013 — What started as an experiment to probe brain circuits involved in compulsive behavior has revealed a surprising connection with obesity.The University of Iowa-led researchers bred mice missing a gene known to cause obesity, and suspected to also be involved in compulsive behavior, with a genetic mouse model of compulsive grooming. The unexpected result was offspring that were neither compulsive groomers nor obese.The study, published the week of June 10 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), suggests that the brain circuits that control obsessive-compulsive behavior are intertwined with circuits that control food intake and body weight. The findings have implications for treating compulsive behavior, which is associated with many forms of psychiatric disease, including obsessive-compulsive disorder (OCD), Tourette syndrome, and eating disorders.UI neuro-psychiatrists Michael Lutter, M.D., Ph.D. and Andrew Pieper, M.D., Ph.D., led the study. The team also included researchers from Stanford University School of Medicine, University of Texas Southwestern Medical Center, Beth Israel Deaconess Medical Center, and Harvard Medical School.Lutter, an assistant professor of psychiatry, and Pieper, an associate professor of psychiatry and neurology at the UI Carver College of Medicine, both recently arrived at the UI and use mouse models in their laboratories to study human disorders and conditions.Pieper is interested in compulsive behavior. His mouse model of compulsivity lacks a brain protein called SAPAP3. These mice groom themselves excessively to the point of lesioning their skin, and their compulsive behavior can be effectively treated by fluoxetine, a drug that is commonly used to treat OCD in people.Lutter works with a mouse that genetically mimics an inherited form of human obesity. This mouse lacks a brain protein known a MC4R. Mutations in the MC4R gene are the most common single-gene cause of morbid obesity and over-eating in people.“I study MC4R signaling pathways and their involvement in the development of obesity,” Lutter explains. “I’m also interested in how these same molecules affect mood and anxiety and reward, because it’s known that there is a connection between depression and anxiety and development of obesity.”An old study hinted that in addition to its role in food intake and obesity, MC4R might also play a role in compulsive behavior, which got Lutter and Pieper thinking of ways to test the possible interaction.”We knew in one mouse you could stimulate excessive grooming through this MC4R pathway and in another mouse a different pathway (SAPAP3) caused compulsive grooming,” Lutter says. …

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Interferon-beta aids balance and movement in mice with spinocerebellar ataxia 7; first in vivo study of the treatment for this condition shows…

June 9, 2013 — The first in vivo trial of the use of interferon-beta in a mouse model of the group of fatal diseases known as spinocerebellar ataxia has shown that its use can significantly improve their physical condition and control symptoms. Researchers in France and the US believe that their results show that a clinical trial in humans is merited.The group of genetic conditions known as spinocerebellar ataxias currently have no treatment or cure and are always fatal, in the case of affected children at an early age. Symptoms include a progressive lack of co-ordination of gait, and poor co-ordination of hands, speech and eye movements, due to a failure of co-ordination of muscle movements. Now researchers from France and the US have found a new way of controlling the symptoms and significantly improving the physical condition of animal models of the disease, the annual conference of the European Society of Human Genetics will hear today (Monday June 10).Dr. Annie Sittler, from the Centre National de la Recherche Scientifique (CNRS), working in the team of Professor Alexis Brice at the research centre Brain and Spinal Cord Institute (CR-ICM), Paris, France described the team’s work in the field of polyglutamine disease, a group of neurodegenerative conditions involving abnormal protein conformation. “Accumulation of a polyglutamine-containing protein known as mutant ataxin -7 is responsible for neurotoxicity, neuronal dysfunction, and eventually neuronal death,” she explains. “We had previously shown in cells that mutant ataxin-7 was degraded in nuclear bodies, structures found in the nucleus of cells, by a protein known as promyeloctyic leukemia protein or PML, and that interferon-beta could help with this process and protect against disease.”The researchers used a mouse model of a particular form of spinocerebellar ataxia known as SCA7. The genetically-modified ‘knock-in’ mice develop the severe type of the disease, similar to the infantile human version, and have a very short lifespan of around 14 weeks. They were injected with mouse interferon-beta three times a week, starting at five weeks of age, just before their first symptoms of disease were due to appear. Investigation of their brains post-mortem showed that the mice who had received the interferon-beta, as opposed to those in the control group, had a reduced load of mutant ataxin-7.On the physical level, substantial improvements in the interferon-beta treated mice were noticed. …

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3-D map of blood vessels in cerebral cortex holds suprises

June 9, 2013 — Blood vessels within a sensory area of the mammalian brain loop and connect in unexpected ways, a new map has revealed.The study, published June 9 in the early online edition of Nature Neuroscience, describes vascular architecture within a well-known region of the cerebral cortex and explores what that structure means for functional imaging of the brain and the onset of a kind of dementia.David Kleinfeld, professor of physics and neurobiology at the University of California, San Diego, and colleagues mapped blood vessels in an area of the mouse brain that receives sensory signals from the whiskers.The organization of neural cells in this brain region is well-understood, as was a pattern of blood vessels that plunge from the surface of the brain and return from the depths, but the network in between was uncharted. Yet these tiny arterioles and venules deliver oxygen and nutrients to energy-hungry brain cells and carry away wastes.The team traced this fine network by filling the vessels with a fluorescent gel. Then, using an automated system, developed by co-author Philbert Tsai, that removes thin layers of tissue with a laser while capturing a series of images to reconstructed the three-dimensional network of tiny vessels.The project focused on a region of the cerebral cortex in which the nerve cells are so well known that they can be traced to individual whiskers. These neurons cluster in “barrels,” one per whisker, a pattern of organization seen in other sensory areas as well.The scientists expected each whisker barrel to match up with its own blood supply, but that was not the case. The blood vessels don’t line up with the functional structure of the neurons they feed.”This was a surprise, because the blood vessels develop in tandem with neural tissue,” Kleinfeld said. Instead, microvessels beneath the surface loop and connect in patterns that don’t obviously correspond to the barrels.To search for patterns, they turned to a branch of mathematics called graph theory, which describes systems as interconnected nodes. Using this approach, no hidden subunits emerged, demonstrating that the mesh indeed forms a continous network they call the “angiome.”The vascular maps traced in this study raise a question of what we’re actually seeing in a widely used kind of brain imaging called functional MRI, which in one form measures brain activity by recording changes in oxygen levels in the blood. The idea is that activity will locally deplete oxygen. So they wiggled whiskers on individual mice and found that optical signals associated with depleted oxygen centered on the barrels, where electrical recordings confirmed neural activity. Thus brain mapping does not depend on a modular arrangement of blood vessels.The researchers also went a step further to calculate patterns of blood flow based on the diameters and connections of the vessels and asked how this would change if a feeder arteriole were blocked. …

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Alzheimer’s, schizophrenia, autism now have new research tool: Mature brain cells derived from skin cells

June 6, 2013 — Difficult-to-study diseases such as Alzheimer’s, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed skin cells.According to Gong Chen, the Verne M. Willaman Chair in Life Sciences and professor of biology at Penn State University and the leader of the research team, “the most exciting part of this research is that it offers the promise of direct disease modeling, allowing for the creation, in a Petri dish, of mature human neurons that behave a lot like neurons that grow naturally in the human brain.” Chen added that the method could lead to customized treatments for individual patients based on their own genetic and cellular information. The research will be published in the journal Stem Cell Research.”Obviously, we don’t want to remove someone’s brain cells to experiment on, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening,” Chen said. Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized or undifferentiated pluripotent stem cells (iPSCs). “A pluripotent stem cell is a kind of blank slate,” Chen explained. “During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell. So, after generating iPSCs from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish.”Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. Chen explained that, in their natural environment, neurons are always found in close proximity to star-shaped cells called astrocytes, which are abundant in the brain and help neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained.To test this hypothesis, Chen and his colleagues began by culturing iPSC-derived neural stem cells, which are stem cells that have the potential to become neurons. These cells were cultured on top of a one-cell-thick layer of astrocytes so that the two cell types were physically touching each other.”We found that these neural stem cells cultured on astrocytes differentiated into mature neurons much more effectively,” Chen said, contrasting them with other neural stem cells that were cultured alone in a Petri dish. …

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Candidate drug provides benefit in spinal muscular atrophy animal models

June 4, 2013 — In a new publication that appears in Human Molecular Genetics, the laboratory of Christine DiDonato, PhD reports on their pharmacological characterization of the drug RG3039, demonstrating that it can extend survival and improve function in two spinal muscular atrophy (SMA) mouse models. They have determined the minimum effective dose and drug action, thus contributing to dose selection and exposure estimates for the first studies with RG3039 in humans. As in cellular assays, the animal studies have shown that drug treatment leads to improvement in nuclear gem/Cajal body numbers in motor neurons.Share This:Gem loss is a cellular hallmark of fibroblasts derived from SMA patients; gem numbers inversely correlate with SMA disease severity. In addition, the laboratory has shown improved functional outcomes, including treadmill walking and gait dynamics, in animals receiving the drug. The laboratory has been testing RG3039 in SMA mouse models with disease phenotypes ranging from mild to severe.The collective results suggest that RG3039 positively modifies motor unit pathologies and dysfunction, and that it may have therapeutic benefit for SMA.Spinal muscular atrophy (SMA) is a devastating hereditary disease that is a leading cause of infant and early childhood mortality. Motor neurons in the spinal cord are affected, resulting in muscle weakness and in many cases breathing problems. SMA is caused by insufficient levels of the survival motor neuron (SMN) protein; depending on the level of SMN protein, patients may have mild to severe forms of SMA. There is currently no cure for the disease.The goal of early SMA drug discovery programs has been to identify small molecules that induce the SMN gene to produce sufficient levels of protein to improve motor neuron functioning in affected patients. A promising drug candidate is RG3039, which has been shown to increase nuclear gem/Cajal body numbers in cellular assays.Says DiDonato: “We are very happy that our research was able to assist in the pharmacological characterization of RG3039 and contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects. We are indebted to my colleague, Nancy Kuntz, MD, and co-author laboratories of Drs. …

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New evidence on easing inflammation of brain cells for Alzheimer’s disease

Oct. 3, 2012 — New research proves the validity of one of the most promising approaches for combating Alzheimer’s disease (AD) with medicines that treat not just some of the symptoms, but actually stop or prevent the disease itself, scientists are reporting.Share This:The study, in the journal ACS Medicinal Chemistry Letters, also identifies a potential new oral drug that the scientists say could lead the way.Wenhui Hu and colleagues point out that existing drugs for AD provide only “minimal” relief of memory loss and other symptoms, creating an urgent need for new medicines that actually combat the underlying destruction of brain cells. Research suggests that inflammation of nerve cells in the brain is a key part of that process. One medicine, Minozac, is in clinical trials. But Hu says Minozac still has more space to improve its efficacy. So the scientists sifted through compounds with a molecular architecture similar to Minozac in an effort to find more active substances.The report describes success in doing so. They discovered one compound that appeared especially effective in relieving nerve inflammation and in improving learning and memory in lab mice widely used in AD research. “In general, this study not only proves that countering neuroinflammation is indeed a potential therapeutic strategy for Alzheimer’s disease, but also provides a good lead compound with efficacy comparable to donepezil [an existing AD medicine] for further oral anti-AD drug discovery and development,” the report states.Share this story on Facebook, Twitter, and Google:Other social bookmarking and sharing tools:|Story Source: The above story is reprinted from materials provided by American Chemical Society. Note: Materials may be edited for content and length. For further information, please contact the source cited above. …

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