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Nischarin Protein Plays Key Role in Energy Metabolism; Inhibition May Prove Useful in Treatment or Prevention of Obesity & Diabetes, According to JBC Article

Research led by Suresh Alahari, PhD, Fred Brazda Professor of Biochemistry and Molecular Biology at LSU Health New Orleans School of Medicine, has demonstrated the potential of a particular protein to treat or prevent metabolic diseases including obesity and diabetes. The findings were published online on August 24, 2017 in the Journal of Biological Chemistry. The open-access article is titled “Nischarin Inhibition Alters Energy Metabolism by Activating AMP-Activated Protein Kinase.” Nischarin is a novel protein discovered by the Alahari lab. The research team demonstrated that it functions as a molecular scaffold that holds and interacts with several protein partners in a number of biological processes. The lab's earlier research found that Nischarin acts as a tumor suppressor that may inhibit the metastasis of breast and other cancers. The current research project, conducted in a knockout mouse model, found that Nischarin interacts with and controls the activity of a gene called AMPK. AMPK regulates metabolic stability. The research team discovered that Nischarin binds to AMPK and inhibits its activity. In Nischarin-deleted mice, the researchers found decreased activation of genes that make glucose. The study showed that Nischarin also interacts with a gene regulating glucose uptake. Blood glucose levels were lower in the knockout mice, with improved glucose and insulin tolerance. As well, the researchers showed that Nischarin mutation inhibits several genes involved in fat metabolism and the accumulation of fat in the liver. The knockout mice displayed increased energy expenditure despite their smaller growth and appetite suppression leading to decreased food intake and weight reduction.

Pathogenic Tick-Borne Virus Uses Host Neurons’ Transportation System to Move Its RNA

Flaviviruses are a significant threat to public health worldwide, and some infected patients develop severe, potentially fatal, neurological diseases. Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, causes encephalic diseases resulting in photophobia, irritability, and sleep disorders. However, little is known about the pathogenic mechanisms and no effective treatment is available at present. A research team at Hokkaido University in Japan has previously showed that, in mouse neurons, genomic RNAs of TBEV are transported from the cell body to dendrites, the neuron's wire-like protrusions. Viral RNAs then reproduce viruses locally in dendrites disturbing normal neuronal activities. In the new study published online on August 28, 2017 in PNAS, the team looked into the transportation mechanism of viral RNAs in neurons, and discovered these RNAs make use of the cell's transportation system, which is normally used to move neuronal RNAs in dendrites. A specific non-coding sequence near the terminus of viral RNAs was found pivotal in interacting with the transportation system. When the sequence was mutated, the infected mouse showed reduced neurological symptoms. In the researchers’ biochemical experiments, viral RNAs could bind to a protein that forms a neuronal granule, which is part of the neuron's transportation system. Furthermore, their data shows that normal transportation of neuronal RNAs becomes affected by viral RNAs as a result of competition to use the transportation network. Associate Professor Kentaro Yoshii, who led the research team, commented "It is unprecedented for a neuropathogenic virus to hijack the neuronal granule system to transport their genomic RNA, which results in severe neurological diseases.

Gut Bacteria That “Talk” to Human Cells May Lead to New Treatments

We have a symbiotic relationship with the trillions of bacteria that live in our bodies—they help us and we help them. It turns out that they may even speak the same language as we do. And new research from The Rockefeller University and the Icahn School of Medicine at Mount Sinai suggests these newly discovered commonalities may open the door to “engineered” gut flora that can have therapeutically beneficial effects on disease. “We call it mimicry,” says Dr. Sean Brady, Director of Rockefeller University’s Laboratory of Genetically Encoded Small Molecules, where the research was conducted. The breakthrough is described in a paper published online on August 30, 2017 in Nature. The article is titled “Commensal bacteria Make GPCR Ligands That Mimic Human Signalling Molecules.” In a double-barreled discovery, Dr. Brady and co-investigator Dr. Louis Cohen found that gut bacteria and human cells, though different in many ways, speak what is basically the same chemical language, based on molecules called ligands. Building on that, they developed a method to genetically engineer the bacteria to produce molecules that have the potential to treat certain disorders by altering human metabolism. In a test of their system on mice, the introduction of modified gut bacteria led to reduced blood glucose levels and other metabolic changes in the animals. The method involves the lock-and-key relationship of ligands, which bind to receptors on the membranes of human cells to produce specific biological effects. In this case, the bacteria-derived molecules are mimicking human ligands that bind to a class of receptors known as GPCRs, for G-protein-coupled receptors. Many of the GPCRs are implicated in metabolic diseases, Dr. Brady says, and are the most common targets of drug therapy.

Variants in Fetal Genome Associated with Risk of Preeclampsia in Mother

For the first time, a relationship has been found between fetal genes and the risk of preeclampsia in the mother. Norwegian researchers, including a team from the Norwegian University of Science and Technology (NTNU), figure prominently in the international group that presented the discovery in Nature Genetics, first published online earlier this summer, on June 19, 2017. The article is titled “Variants in the Fetal Genome Near FLT1 Are Associated with Risk Of Preeclampsia.” Preeclampsia affects approximately 3 per cent of births in Norway; worldwide, that number is estimated to be about 5 per cent. In the vast majority of cases, the mother has mild symptoms, typically high blood pressure. Nevertheless, preeclampsia is one of the leading causes of death in both mothers and babies around the time of birth, and sometimes the only way to treat it is to deliver the baby, even prematurely. "For the first time ever, we have discovered a fetal gene that increases the risk of preeclampsia," says Dr. Ann-Charlotte Iversen at the Department of Clinical and Molecular Medicine at NTNU. She says there has not been much research on the role of fetal genes in triggering the illness. Preeclampsia usually begins with a problem in the placenta, which is mainly composed of fetal cells. For that reason, it makes sense that fetal cells might have a hand in causing the illness, Dr. Iversen said, even though it is the mother's symptoms during the last part of the pregnancy that lead to the diagnosis. Dr. Iversen is head of a research group at NTNU's Centre of Molecular Inflammation Research (CEMIR).

FDA Approval of Novartis’ Kymriah Brings First Gene Therapy to United States; CAR T-Cell Therapy Approved to Treat Certain Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia (ALL)

On August 30, 2017, the U.S. Food and Drug Administration issued a historic action making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases. The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, MD. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.” Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

Rare Genetic Variant in CX3CR1 Gene for Microglia Receptor May Contribute to Risk of Schizophrenia and Autism

Huntington's disease, cystic fibrosis, and muscular dystrophy are each diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy – if you have the mutation, then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism. "Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism," says Osaka University Professor Toshihide Yamashita, one of the authors of the study. "Microglia contribute to the structure and function of synapse connectivities." Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. Such mutations have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders. Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7,000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction. "Rare variants alter gene function, but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause," said Dr. Yamashita, who added the alanine-to-threonine substitution was a rare variant. The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

University of Buffalo Pharmacy Professor Awarded $1.5 Million to Silence Exosome-Mediated Chatter Among Cancer Cells

With the support of a new $1.58 million grant from the National Institutes of Health (NIH), University at Buffalo researchers aim to develop a targeted treatment to prevent communication between cancer cells. By developing biomaterials that target exosomes – lipid vesicles secreted by many cells that act as a courier between them – the researchers will deliver anti-cancer drugs to alter the pathogenic messages being delivered. Exosomes, once thought of as the cell’s garbage disposal, have the ability to transport genetic information, allowing them to reprogram cells and alter their function. When secreted by a cancer cell into the circulatory system, exosomes may carry genetic material that enhances the spread of cancer to surrounding tissue and other parts of the body. “Reprograming these exosomes may disarm the dangerous package that they carry, potentially preventing tumor growth and spread to distant sites or organs,” says Juliane Nguyen (photo), PharmD, PhD, Principal Investigator and Assistant Professor in the Department of Pharmaceutical Sciences in the School of Pharmacy and Pharmaceutical Sciences. The announcement was made in a UB press release dated August 28, 2017 and authored by Marcene Robinson. “This will lay the foundation for the development of novel drug carriers for treating diseases in which exosomes are pathological. More specifically, these new carriers have the potential to prevent metastasis in cancer patients.” Currently, there are no therapeutic strategies capable of disrupting the pathogenic communication facilitated by exosomes. The four-year grant is provided through the NIH’s National Institute of Biomedical Imaging and Bioengineering.

Some Women with History of Pre-Eclampsia Have Significantly Lower Risk for Breast Cancer

Researchers have demonstrated that women with a history of pre-eclampsia, a pregnancy complication characterized by high blood pressure, have as much as a 90% decrease in breast cancer risk if they carry a specific common gene variant. Further studies are now underway to determine the mechanism of this protection in an effort to develop new breast cancer prevention strategies for all women. The study was published online on August 18, 2017 in Cancer Causes & Control. The open-access article is titled "Functional IGF1R Variant Predicts Breast Cancer Risk in Women with Preeclampsia in California Teachers Study.” The research, directed by lead author Mark Powell, MD, MPH, and Buck Institute Professor Christopher Benz, MD, was carried out in the large California Teachers Study. Women with pre-eclampsia were found to have a 74% lower risk of the most common type of breast cancer (hormone receptor positive) if they carried two T alleles of a variant of the insulin-like growth factor receptor gene when compared to women carrying no T alleles. This decrease in risk increased to 90% if the pregnancy with preeclampsia occurred before the age of 30. "We are thrilled to work with researchers from our Scientific Advisory Board on this exciting project with the potential for developing a new approach to prevention. This very much fits with our goal of reducing the risk of breast cancer," said Rose Barlow, Executive Director of Zero Breast Cancer, which administered the study with funding from the Avon Foundation for Women. "This research could contribute to understanding the key impact of pregnancy on breast cancer risk, and may help explain why some women are protected while others are not," said Dr. Powell, who is a visiting scientist at the Buck Institute and is Director of the Breast Cancer Prevention Project. Dr.

DroNc-Seq, A Technology That Merges Single-Nucleus RNA Sequencing with Microfluidics, Brings Massively Parallel Measurement to Gene Expression Studies in Complex Tissues

Last year, Broad Institute researchers described a single-nucleus RNA sequencing method called sNuc-Seq. This system enabled researchers to study the gene expression profiles of difficult-to-isolate cell types, as well as cells from archived tissues. Now, a Broad-led team has overcome a key stumbling block to sNuc-Seq's widespread use: i.e., scale. In a paper published online on August 28, 2017 in Nature Methods, postdoctoral fellows Dr. Naomi Habib, Dr. Inbal Avraham-Davidi, and Dr. Anindita Basu; core institute members Dr. Feng Zhang and Dr. Aviv Regev; and their colleagues reveal DroNc-Seq, a single-cell expression profiling technique that merges sNuc-Seq with microfluidics, allowing massively parallel measurement of gene expression in structurally-complicated tissues. The article is titled “Massively Parallel Single-Nucleus RNA-Seq with DroNc-Seq.” Researchers struggled in the past to study expression in neurons and other cells from complex tissues, like the brain, at the single-cell level. This was because the procedures for isolating the cells affected their RNA content and did not always accurately capture the true proportions of the cell types present in a sample. Moreover, the procedures did not work for frozen archived tissues. sNuc-Seq bypassed those problems by using individual nuclei extracted from cells as a starting point instead. sNuc-Seq, however, is a low-throughput technology, using 96- or 384-well plates to collect and run samples. To scale the method up to the level needed in order to efficiently study thousands of nuclei at a time, the team turned to microfluidics. Their inspiration was: Drop-Seq, a single-cell RNA-seq (scRNAseq) technique that encapsulates single cells together with DNA barcoded-beads in microdroplets to greatly accelerate expression-profiling experiments and reduce cost.

New NAS Member from Hawaii Reveals How Animals Select Good Microbes, Reject Harmful Ones

Margaret McFall-Ngai, Professor and Director of the Pacific Biosciences Research Center (PBRC), School of Ocean and Earth Science and Technology, at the University of Hawai'i (UH) at Mānoa, is the only woman at UH who is a member of the National Academy of Sciences (NAS). In her inaugural article published this week (August 28 – Seoptember 1) in PNAS commemorating her induction into one of the country's most distinguished scientific groups, she and a team of researchers reveal a newly discovered mechanism by which organisms select beneficial microbes and reject harmful ones. The internal microbial communities, or consortia, of mammals, such as humans, are complex in that they require many bacterial types for healthy function. Tissues in the respiratory system, the Fallopian tubes, and the Eustachian tubes are lined with cilia--microscopic hair-like structures that extend out from the surface of many animal cells. A central role attributed to these ciliated tissues is to effectively clear out toxic molecules and undesirable microbes; in work performed largely by Dr. Janna Nawroth (now at Emulate, Inc., Boston) and co-led by Dr. McFall-Ngai and Dr. Eva Kanso, a mathematical modeler at the University of Southern California (USC), these ciliated tissues are shown to also selectively recruit beneficial microbes, called symbionts. "A few years ago, when the biomedical community discovered that all of these surfaces of mammals have a rich co-evolved microbial consortium, a microbiome, that promotes the health of those systems, the question became: how do they do it--that is, by what mechanisms do they select the good microbes and reject the harmful ones?" explained Dr. McFall-Ngai. The ciliated tissues of most animals are inaccessible to observation and study.

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