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Archive - Dec 13, 2014

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New Approach May Reduce Dialysis Inflammation and Associated Pathologies

Frequent kidney dialysis is essential for the approximately 350,000 end-stage renal disease (ESRD) patients in the United States. But it can also cause systemic inflammation, leading to complications such as cardiovascular disease and anemia, and patients who rely on the therapy have a five-year survival rate of only 35 percent. Such inflammation can be triggered when the complement cascade, part of the body's innate immune system, is inadvertently activated by modern polymer-based dialysis blood filters. New work by University of Pennsylvania (Penn) researchers has found an effective way to avoid these problems by temporarily suppressing complement during dialysis. Their work appeared online on November 3, 2014 in Immunobiology. Over the past several years, lead author John Lambris, Ph.D., the Dr. Ralph and Sallie Weaver Professor of Research Medicine, Perelman School of Medicine at the University of Pennsylvania, and his colleagues have developed small molecule versions of the drug compstatin, which inhibits a component of the complement immune response called C3. Dr. Lambris explains that this next-generation compound, called Cp40, "is a small peptide similar to cyclosporine in many aspects, however it uses a different mechanism of action." Previous studies by Dr. Lambris and his team, in which modern polymer-based hemodialysis filters were perfused with human blood, showed significant complement activation and an increase in inflammatory biomarkers. This response could be suppressed using compstatin, suggesting that it might be used in dialysis to decrease the inflammatory response side effect.

Microglia in Mouse Brain Respond to Fat in Diet, Causing Mice to Eat More

Immune cells perform a previously unsuspected role in the brain that may contribute to obesity, according to a new study by UC San Francisco researchers. When the scientists fed mice a diet high in saturated milk fats, microglia, a type of immune cell, underwent a population explosion in the brain region called the hypothalamus, which is responsible for feeding behavior. The researchers used an experimental drug and, alternatively, a genetic approach to knock out these microglia, and both strategies resulted in a complete loss of microglia-driven inflammation in the hypothalamus. Remarkably, doing so also resulted in the mice eating less food each day than did their untreated counterparts, without any apparent ill effects. Furthermore, removing microglia from mice only reduced food intake when the content of saturated fat from milk in their diets was high. It had no effect on mice fed a low-fat diet, or a diet high in other types of fat, including olive oil or coconut oil. UCSF postdoctoral fellow Martin Valdearcos Contreras, Ph.D., first author on the paper, published online on December 11, 2014 in an open-access article in Cell Reports, discovered that when mice consumed large amounts of saturated fats, the fat entered their brains and accumulated in the hypothalamus. According to the senior scientist for the study, Suneil Koliwad, M.D., Ph.D., an assistant professor of medicine at the UCSF Diabetes Center, the microglia senses the saturated fat and sends instructions to brain circuits in the hypothalamus. These instructions are important drivers of food intake, he said. Microglia are primarily known for causing inflammation in the brain in response to infection or injury, but the new study indicates that they also play a key role in shaping the brain's response to diet, according to Dr. Koliwad.

How White Fat Cells Are Reprogrammed to Become Browner

White adipose tissue stores excess calories as fat that can be released for use in other organs during fasting. Mammals also have small amounts of brown adipose tissue, which primarily acts as an effective fat burner for the production of heat. Now, researchers from the University of Southern Denmark and colleagues have uncovered the mechanism by which white fat cells from humans are reprogrammed to become browner. Browning of white adipose tissue increases the energy consumption of the body and therefore constitutes a potential strategy for future treatment of obesity. The challenge is to reprogram the energy-storing white fat cells into so-called "brite" (brown-in-white) fat cells in the body's white adipose tissue and thus make adipose tissue burn off excess energy as heat instead of storing it. The research team from the Department of Biochemistry and Molecular Biology headed by Professor Susanne Mandrup published a paper entitled "Browning of Human Adipocytes Requires KLF11 and Reprogramming of PPAR Super-Enhancers" online on December 12, 2014 in Genes & Development that describes their results from working with "brite" fat cells. "We have investigated how the genome of white adipocytes is reprogrammed during browning using advanced genome sequencing technologies. We stimulated browning in human white adipocytes by a drug used to treat type II diabetes and compared white and "brite" fat cells. This showed that "brite" fat cells have distinct gene programs which, when active, make these cells particularly energy-consuming," says Dr. Mandrup .

TGen Test Uses Unique Genetics of Women to Uncover Neurologic Disorder

Using a basic genetic difference between men and women, the Translational Genomics Research Institute (TGen) has uncovered a way to track down the source of a neurological disorder in a young girl. TGen's discovery relies on a simple genetic fact: men have one X and one Y chromosome, while women have two X chromosomes. This women-only factor was leveraged by TGen investigators to develop a highly accurate method of tracking down a previously unrecognized disorder of the X-chromosome. The study of a pre-teen girl, who went years with an undiagnosed neurobehavioral condition, was published online on December 13, 2014 in an open-access article in PLOS ONE. TGen's findings were made within its Dorrance Center for Rare Childhood Disorders, where investigators and clinicians apply the latest tools of genomic medicine to provide answers for parents seeking to identify the disease or disorder affecting their child. The scientists sequenced, or spelled out in order, the complete genetic codes of DNA and RNA of the girl. Because girls inherit an X chromosome from each of their parents (boys inherit a Y chromosome from their father), the scientists also sequenced the girl’s mother and father. On average, about half of all X chromosomes active in a female come from the mother and the other half from the father. "We now have the tools to significantly accelerate the diagnostic process, reducing the need for children to undergo multiple tests that can be emotionally and physically taxing for the entire family," said Dr. David Craig, TGen's Deputy Director of Bioinformatics, Co-Director of the Dorrance Center and the paper's senior author. Sequencing would reveal the proportion of X chromosomes, and if disproportionate, whether the more abundant of the two were damaged in some way, which often leads to X-linked genetic conditions.

Glial Cells Communicate Back to Neurons

Scientists at Johannes Gutenberg University Mainz (JGU) in Germany have discovered a new signaling pathway in the brain that plays an important role in learning and the processing of sensory input. It was already known that distinct glial cells receive information from neurons. However, it was not known that these same glial cells also transmit information to neurons. The glia release a specific protein fragment that influences neuronal cross-talk, most likely by binding to the synaptic contacts that neurons use for communication. Disruption of this information flow from the glia results in changes in the neural network, for example during learning processes. The research team composed of Dr. Dominik Sakry, Dr. Angela Neitz, Professor Jacqueline Trotter, and Professor Thomas Mittmann unravelled the underlying mechanism, from the molecular and cellular level to the network and finally the resulting behavioral consequences. Their findings constitute major progress in understanding complex pathways of signal transmission in the brain. In mammalian brains, glial cells outnumber nerve cells, but their functions are still largely unelucidated. A group of glial cells, so-called oligodendrocyte precursor cells (OPC), develop into the oligodendrocytes which ensheathe neuronal axons with a protective myelin layer, thus promoting the rapid transmission of signals along the axon. Interestingly, these OPCs are present as a stable proportion – some five to eight percent of all cells in all brain regions, including adult brains. The Mainz-based researchers decided to take a closer look at these OPCs. Their research results were published online on November 11, 2014 in an open-access article in PLOS Biology.