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Exosomes May Have “Huge Relevance” to Treating & Diagnosing Developmental Brain Disorders; New Work at Scripps Suggests Cellular Cargo Transporters Play Profound Role in Creating Brain Cells & Circuits

Like overpacked suitcases unloaded from the underbelly of a jet, molecular satchels called exosomes are continuously deployed from all cells in the body—many brimming with an assortment of contents that another cell may unpack and use. By sending off these biological parcels, cells communicate with each other via shared proteins and genetic material. Once simply thought to be microscopic sacks of cellular “garbage,” exosomes are now understood to hold immense importance for our health. An outflowing of research in recent years has even shown they can transport molecules that are linked to the spread of cancer and neurodegenerative disorders such as Alzheimer’s. Yet, until recently, their role in brain development has remained a mystery. In new research published online on July 22, 2019 in PNAS, Hollis Cline (photo), PhD, and her colleagues at Scripps Research begin to close that knowledge gap by showing that exosomes are not only integral to the development of neurons and neural circuits, but they can restore health to brain cells affected by developmental disease. The open-access PNAS article is titled “Exosomes Regulate Neurogenesis and Circuit Assembly.” “During different stages of brain development, signaling between cells is absolutely essential,” says Dr. Cline, Co-Chair of the Department of Neuroscience at Scripps Research and Director of the Dorris Neuroscience Center at Scripps. “We found that exosomes are one of the ways cells communicate these signals.” Our bodies use spherical containers called “vesicles” to traffic different materials within and among cells. Exosomes are a type of vesicle tasked specifically with transporting various biological cargo—lipids, proteins, RNA,—from one cell to another. Dr.

Nunavik Inuit in Canada’s Arctic Are Genetically Unique & Share Variants That May Correlate with Brain Aneurysms, Among Distinct Genetic Signatures In Pathways Involving Lipid Metabolism & Cell Adhesion, Possibly Adaptive to High-Fat Diets & Extreme Cold

A new study has found that an Inuit population in Canada's Arctic are genetically distinct from any known group, and certain genetic variants in the population are correlated with brain aneurysm. Geographically isolated populations often develop unique genetic traits that result from their successful adaptation to specific environments. Unfortunately, these adaptations sometimes predispose them to certain health issues if the environment is changed. The genetic background of these populations are often poorly understood because they live far from scientific research centres. Canada's Inuit have a higher prevalence of cardiovascular disorders, as well as increased incidence of brain aneurysms, relative to the the general population. To learn about the possible genetic origin of these disorders, researchers at The Neuro (Montreal Neurological Institute and Hospital) of McGill University analyzed the genetic characteristics of 170 Inuit volunteers from Nunavik, a region of northern Quebec. This was done with approval from the Nunavik Nutrition and Health Committee in Kuujjuaq, Nunavik. Using exome sequencing and genome-wide genotyping, the researchers found several interesting traits among the Nunavik Inuit. They are a distinct genetic population, whose closest relatives are the Paleo-Eskimos, a people that inhabited the Arctic before the Inuit. The Nunavik Inuit have distinct genetic signatures in pathways involving lipid metabolism and cell adhesion. These may be adaptations to adjust to the high-fat diet and extreme cold of the Canadian north. One of these unique genetic variants correlates with a higher risk of brain aneurysm, also known as intracranial aneurysm, a weakening in the wall of a cerebral artery that causes ballooning of the artery.

New Study Explains Molecular Mechanism for Therapeutic Anti-Convulsive Effects of Cilantro

Herbs, including cilantro, have a long history of use as folk medicine anticonvulsants. Until now, many of the underlying mechanisms of how the herbs worked remained unknown. In a new study, researchers have uncovered the molecular action that enables cilantro to effectively delay certain seizures common in epilepsy and other diseases. The study, published online on July 16, 2019 in The FASEB Journal, explains the molecular action of cilantro (Coriandrum sativum) as a highly potent KCNQ channel activator This new understanding may lead to improvements in therapeutics and the development of more efficacious drugs. The article is titled “Cilantro Leaf Harbors A Potent Potassium Channel–Activating Anticonvulsant.” "We discovered that cilantro, which has been used as a traditional anticonvulsant medicine, activates a class of potassium channels in the brain to reduce seizure activity," said Geoff Abbott, PhD, Professor of Physiology and Biophysics at the UC-Irvine School of Medicine and principal investigator on the study. "Specifically, we found one component of cilantro, called dodecenal, binds to a specific part of the potassium channels to open them, reducing cellular excitability. This specific discovery is important as it may lead to more effective use of cilantro as an anticonvulsant, or to modifications of dodecenal to develop safer and more effective anticonvulsant drugs." Researchers screened cilantro leaf metabolites, revealing that one - the long-chain fatty aldehyde (E)-2-dodecenal - activates multiple potassium channels including the predominant neuronal isoform and the predominant cardiac isoform, which are responsible for regulating electrical activity in the brain and heart.

Diabetes-Associated Heart Failure Risk, High in General, Is Much Higher in Women Than in Men, New Global Study Shows

A global study of 12 million people has found that diabetes increases the risk of heart failure and this increase is greater for women than men. Researchers from The George Institute for Global Health headquartered in Australia determined that this differential was greater in type 1 than type 2 diabetes. Type 1 diabetes is associated with a 47% excess risk of heart failure in women compared to men, while type 2 diabetes has a 9% higher excess risk of heart failure for women than men. The findings published on online on July 18, 2019 (see article link below) and in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) highlights the need for further sex-specific research into diabetes and how the condition can potentially contribute to heart complications. The article is titled “Diabetes As a Risk Factor for Heart Failure in Women and Men: A Systematic Review and Meta-Analysis of 47 Cohorts Including 12 Million Individuals.” According to the International Diabetes Federation (IDF), currently 415 million adults world-wide live with diabetes - with approximately 199 million of them being women. The IDF expects by the year 2040 approximately 313 million women will be suffering from the disease. Diabetes is the ninth leading cause of death in women and claims 2.1 million female lives every year, more so than men. The number one leading cause of death for women is heart disease. "It is already known that diabetes puts you at greater risk of developing heart failure, but what our study shows, for the first time, is that women are at far greater risk - for both type 1 and type 2 diabetes," said lead author and research fellow Dr Toshiaki Ohkuma from The George Institute.

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.

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