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Scientists ID Cellular Connetion Between Diabetes and Blood Vessel Narrowing; Further Study Could Confirm Molecular Target for Possible Reduction of Blood Vessel Complications of Diabetes

A team of University of Calfornia (UC)-Davis Health scientists and physicians has identified a cellular connection between diabetes and one of its major complications -- blood vessel narrowing that increases risks of several serious health conditions, including heart disease and stroke. The authors hope their work leads to diabetes treatments -- beyond blood sugar monitoring and insulin therapy -- that target the molecular source of the disease’s damaging effects on the vascular system. The same team previously found that high blood glucose, the hallmark symptom of diabetes, activates an enzyme known as protein kinase A (PKA), which increases calcium channel activity and constricts blood vessels. "This was a surprise, because PKA is typically associated with blood vessel widening and wasn't really on our radar," said senior author Manuel Navedo, PhD, Professor of Pharmacology at UC Davis Health. "We wanted to understand the molecular processes that created this opposite reaction." For the new study, published online on June 4, 2019, in The Journal of Clinical Investigation, the Navedo lab team conducted a series of experiments on the effects of high glucose on cerebral blood vessels and arterial cells that control blood flow. The tests were conducted on a unique genetically modified mouse and two mouse models of diabetes that were developed at UC Davis for studies of cardiovascular health. The open-access article is titled “Adenylyl Cyclase 5-Generated cAMP Controls Cerebral Vascular ReactivityDuring Diabetic Hyperglycemia.”

Pioneering Study Shows Decrease in One Type of Dopapime Receptor in Wild Songbirds Under Captivity Stress

Dopamine is a chemical in the brain that is important for learning and memory. Louisiana State University (LSU) Department of Biological Sciences Assistant Professor Christine Lattin, PhD, and colleagues conducted this study of wild songbirds showing that dopamine is important in responding to chronic stressors, which can help wildlife conservation efforts in response to environmental stressors such as habitat destruction, natural disasters, extreme weather events and increases in predation. Dr. Lattin, who is the lead author on the study published online on July 18, 2019 in Nature Scientific Reports, applied a biomedical imaging technology called Positron Emission Tomography (PET) scans, that are used commonly on humans but rarely on wild animals, to quantify dopamine receptors in house sparrows. The open-access article is titled “In Vivo Imaging of D2 Receptors and Corticosteroids Predict Behavioural Responses to Captivity Stress in a Wild Bird.”"This Study Is Exciting Because It Is The first time PET scans have been used in wildlife to quantify dopamine receptors in the brain. Developing this technique has opened the door to being able to scan animals and release them back into the wild," she said. "We need to know how these wild birds are coping with stressors and responding to changes to the environment so we can understand how to best protect them." In addition to the biomedical imaging, Dr. Lattin and colleagues tracked changes in the birds' body mass and hormone levels, and observed their behavior using a remotely operated video camera to study wild house sparrows' response to captivity over four weeks. The birds were scanned after being brought in to the lab and then again four weeks later. By using PET scans, the scientists were able to study how the stress of captivity affected the birds over time.

NIH Publishes Largest Genomic Study on Type 2 Diabetes In Sub-Saharan African Populations; Researchers Show Critical Association Between Diabetes and Previously Unlinked ZRANB3 Gene

National Institutes of Health researchers have reported the largest genomic study of type 2 diabetes (T2D) in sub-Saharan Africans, with data from more than 5,000 individuals from Nigeria, Ghana, and Kenya. Researchers confirmed known genomic variants and identified a novel gene ZRANB3, which may influence susceptibility to the disease in sub-Saharan African populations. The gene could also influence the development of T2D in other populations and inform further research. In a study published online on July 19, 2019 in Nature Communications, researchers analyzed genomic data available on participants through the Africa America Diabetes Mellitus study, the single largest diabetes genomic association study conducted on the continent of Africa. Using the information available from 5,231 people, the rsearchrs found many genomic variants to be significantly associated with T2D. The open-access article is titled “ZRANB3 Is an African-Specific Type 2 Diabetes Locus Associated with Beta-Cell Mass and Insulin Response.” The findings replicate results for many of the variants which other research studies have already been implicated in T2D in mostly European ancestry populations. The work was funded by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases, and the Office of the Director at the National Institutes of Health. "Africa is the original cradle of all humanity, to which all humans can trace their genetic origin," said Francis S. Collins, MD PhD, co-author of the paper and senior investigator with the NHGRI Medical Genomics and Metabolic Genetics Branch.

Link Between Increased Expression of AEBP1 Gene and Severe Liver Disease Suggested by Study Results

Researchers have found that a gene known as AEBP1 may play a central role in the development, severity, and potential treatment of liver disease, according to a study by Temple University, the Geisinger Obesity Institute, and the Translational Genomics Research Institute (TGen), an affiliate of City of Hope. The findings are detailed in a study published online on July 12, 2019 in PLoS One. The open-access article is titled “AEBP1 Expression Increases with Severity of Fibrosis in NASH and Is Regulated by Glucose, Palmitate, and miR-372-3p.” The study results suggest that increased expression of AEBP1 correlates with the severity of liver fibrosis in patients with NASH (nonalcoholic steatohepatitis), which is a type of NAFLD (nonalcoholic fatty liver disease), the most common cause of liver damage. NASH indicates there is both inflammation and liver cell damage, along with fat in the liver. "Given the strong link between fibrosis and risk of liver-related mortality, efforts to identify and characterize the specific mechanisms contributing to NAFLD progression are critical for the development of effective therapeutic and preventative strategies," said Dr. Johanna DiStefano, Head of the Diabetes and Fibrotic Disease Unit at TGen and senior author of the PLoS article. One of the study's major findings is that AEBP1 regulates the expression of a network of at least nine genes related to fibrosis: AKR1B10, CCDC80, DPT, EFEMP1, ITGBL1, LAMC3, MOXD1, SPP1, and STMN2. "These findings indicate that AEBP1 may be a central regulator of a complex fibrosis gene expression network in the human liver," said Dr. DiStefano.

SIRT6 Over-Expression May Prevent Progression of Diabetes, Study Suggests

Targeting obesity through exercise and calorie restriction is often the first line of approach to treat diabetes and related cardiovascular disorders, such as cardiomyopathy. A recent animal study published in online on July 12, 2019 in The FASEB Journal explored an alternative sirtuin-based therapy to block the development of obesity and cardiomyopathy under conditions of excess nutrition, when diet restriction and regular exercise are not feasible. The article is titled “The Nuclear and Mitochondrial Sirtuins, Sirt6 and Sirt3, Regulate Each Other’s Activity and Protect the Heart from Developing Obesity-Mediated Diabetic Cardiomyopathy.” For this study, researchers assessed the potential of SIRT6 (image)- often considered a longevity factor - to protect the heart from developing diabetic cardiomyopathy. Prior research has shown that a deficiency of nuclear sirtuin SIRT6 can lead to the development of cardiomyopathy in mice. To conduct the experiment, researchers generated a group of whole-body SIRT6-overexpressing transgenic mice (Tg.SIRT6). The research team then observed the following groups of mice for 24 weeks: 1) control non-transgenic (N.Tg) mice fed a normal diet; 2) Tg.SIRT6 mice fed a normal diet; 3) control non-transgenic (N.Tg) mice fed a high-fat, high-sucrose (HF-HS) diet; and 4) Tg.SIRT6 mice fed a HF-HS diet. As expected, the control N.Tg mice fed a HF-HS diet developed obesity, compared to the N.Tg and Tg.SIRT6 mice fed a normal diet. Surprisingly, however, the Tg.SIRT6 mice fed a HF-HS diet did not develop obesity. This unexpected finding demonstrated that over-expression of SIRT6 can prevent the development of obesity under the conditions of excessive nutrition.

Newly Identified Protein (KHNYN) Works with ZAP Protein to Promote Destruction of HIV Virus Containing Clustered CpG Dinucleotides

A newly identified protein called KHNYN teams up with ZAP (image), a known virus-killing protein, to destroy viruses related to HIV. KHNYN has been identified as a missing piece in a natural antiviral system that kills viruses by targeting a specific pattern in viral genomes, according to new findings published online on July 9, 2019 in eLife. The open-access article is titled “KHNYN Is Essential for the Zinc Finger Antiviral Protein (ZAP) to Restrict HIV-1 Containing Clustered CpG Dinucleotides.” Studying the body's natural defenses to viruses and how viruses evolve to evade them is crucial to developing new vaccines, drugs, and anticancer treatments. The genetic information that makes up the genomes for many viruses is comprised of building blocks called RNA nucleotides. Recently, it was discovered that a protein called ZAP binds to a specific sequence of RNA nucleotides: a cytosine followed by a guanosine, or CpG for short. The human immunodeficiency virus (HIV) normally escapes being inhibited by ZAP because it has evolved to have few CpGs in its genome. However, when CpGs are added back to the virus, ZAP promotes its destruction. This helps us understand why HIV with more CpGs multiplies less successfully, and likely explains why many strains of HIV have evolved to have few CpGs. But a mystery remained because ZAP is unable to break down the viral RNA by itself. "As ZAP can't degrade RNA on its own, we believed that it must recruit other proteins to the viral RNA to destroy it," says lead author Mattia Ficarelli, a PhD student in Dr. Chad Swanson's Lab, Department of Infectious Diseases, King's College London.

Two Potentiator Drugs Act on CFTR Protein in Cystic Fibrosis by Holding Hinge Open to Allow Ion Flow; Focus on This Mechanism May Enable Further Progress on Drug Development & Disease Treatment

In recent decades, treatment options for people with cystic fibrosis have improved dramatically. The newest drugs, known as potentiators, target a protein called cystic fibrosis transmembrane conductance regulator (image), which is mutated in people with the disease. Yet, while these medications can help some people with CF, they are far from perfect. Moreover, researchers haven't been able to figure out how the drugs actually work--until now. A new study by Rockefeller University scientists in New York characterizes, for the first time, the interaction between potentiators and the protein they target at atomic resolution. The research, described in a report in the June 21, 2019 issue of Science, shows that two distinct compounds act on the same protein region--a finding that points to strategies for developing more effective drugs. The article is titled “Structural Identification of a Hotspot on CFTR for Potentiation.” The cystic fibrosis transmembrane conductance regulator (CFTR) is a channel that, when open, allows chloride ions to move in and out of cells. When CFTR is mutated, ions cannot flow freely, leading to changes in the make-up of mucus lining internal organs. These changes can be particularly dangerous in the lungs where they cause thick mucus to accumulate, often leading to impaired breathing and persistent infections. Potentiators are used to increase the flow of ions through CFTR, ameliorating some symptoms of cystic fibrosis (CF). Currently, only one such drug, known as ivacaftor, is on the market; another, called GLPG1837, is now in development. "Ivacaftor can improve lung function by about ten percent. It can help a lot, but it's not a cure and not everybody responds to it," says Jue Chen, PhD, the William E. Ford Professor at Rockfeller.

Scientists Identify an RNA-Binding Protein (SRSF3) As Essential for Correct Heart Contraction & Survival—Capping of Contraction-Related mRNAs Revealed As Key Process Influenced by SRSF3; This Capping Protects Against Development of Systolic Heart Failure

A team of scientists led by Dr. Enrique Lara Pezzi (photo) at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain, has identified the RNA-binding protein SRSF3 as an essential factor for proper heart contraction and survival. In a study published online on July 5, 2019 in Circulation Research, the researchers found that loss of cardiac expression of SRSF3 leads to a critical reduction in the expression of genes involved in contraction. The new article is titled “Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction.” Knowledge of the mechanism of action of SRSF3 in the heart could open the way to the design of new therapeutic approaches for the treatment of heart disease. Cardiovascular disease is the leading cause of death in the world. In 2015 alone, cardiovascular disease killed 17.7 million people, with 6.7 million of these deaths caused by heart attack. Unfortunately, knowledge is limited about the molecular mechanisms that regulate progression of a myocardial infarction, sytmying the development of new therapeutic approaches. The recent development of massive-scale mRNA sequencing technology has permitted the identification of gene expression patterns associated with the development of heart disease. Nevertheless, understanding of post-transcriptional regulation (a type of gene regulation) remains limited, in particular about the roles played by RNA-binding proteins (RBPs) in myocardial infarction and the development of heart disease. RNA-binding proteins perform important tasks in the cell. "In this study, we have investigated the role of the RBP SRSF3 in the heart, which was unknown until now," explained Dr. Lara Pezzi. Study first author Dr.

Infection-Fighting Protein (HRI) Also Senses Protein Misfolding In Non-Infected Cells; Finding May Offer Insights into Approaches to Prevent/Treat Neurodegenerative Diseases Like Parkinson’s

Researchers at the University of Toronto in Canada have uncovered an immune mechanism by which host cells combat bacterial infection, and, at the same time, found that a protein crucial to that process can sense and respond to misfolded proteins in all mammalian cells. The protein is called heme-regulated inhibitor (HRI), and the researchers showed that during bacterial infection it triggers and coordinates a chain reaction among other proteins that form a larger complex. That larger group or “signalosome” amplifies inflammation and leads to an anti-bacterial response. But HRI can also regulate protein folding in other cell types, the researchers showed. Protein folding, which helps determine the 3-D shape of a protein and is essential for its function, is implicated in non-infectious diseases including the neurodegenerative disorders Parkinson's, Alzheimer's, and ALS. "The innate immune function that we discovered is essentially a mechanism of protein scaffolding, which is important because you want a quick and orderly response to bacterial infection," says Stephen Girardin (photo), PhD, a Professor of Laboratory Medicine and Pathobiology and of Immunology at th U of Toronto. "But we also found that same pathway is important for protein scaffolding and aggregation in other cells, which opens promising research angles for neurodegenerative and other diseases." The findings were published online in Science nline on July 5, 2019. The article is titled “The Heme-Regulated Inhibitor Is a Cytosolic Sensor Of Protein Misfolding That Controls Innate Immune Signaling.” Researchers have studied HRI for over three decades, but mostly in the context of red blood cell disorders.

First Complete Wiring Diagram of an Animal (C. elegans) Nervous System Established

In a study published online on July 3, 2019 in Nature, researchers at Albert Einstein College of Medicine in New York describe the first complete wiring diagram of the nervous system of an animal, the roundworm Caenorhabditis elegans, used by scientists worldwide as a model organism. The study includes adults of both sexes and reveals substantial differences between them. The Nature article is titled “Whole-Animal Connectomes of Both C. elegans Sexes.” The article findings mark a major milestone in the field of "connectomics," the effort to map the myriad neural connections in a brain, brain region, or nervous system to find the specific nerve connections responsible for particular behaviors. "Structure is always central in biology," said study leader Scott Emmons, PhD, Professor of Genetics and in the Dominick P. Purpura Department of Neuroscience and the Siegfried Ullmann Chair in Molecular Genetics at Einstein. "The structure of DNA revealed how genes work, and the structure of proteins revealed how enzymes function. Now, the structure of the nervous system is revealing how animals behave and how neural connections go wrong to cause disease." Researchers have hypothesized that some neurological and psychiatric disorders, such as schizophrenia and autism, are "connectopathies," that is, problems caused by "faulty wiring." "This hypothesis is strengthened by the finding that several mental disorders are associated with mutations in genes that are thought to determine connectivity," said Dr. Emmons. "Connectomics has the potential to help us understand the basis of some mental illnesses, possibly suggesting avenues for therapy." Because C.

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