© MPG/ Massih Media Synaptic Glutamate Receptors. When The Neurotransmitter Glutamate (Red) Binds To The Receptors Of The So-Called NMDA-Type (Blue), These Receptors Open And Sodium And Calcium Ions (Yellow, Green) Flow Into The Cell. The Result Is An Improved Information Transfer At The Synapse. Newswise — If the immune system attacks its own body, it can often have devastating consequences: autoantibodies bind to the body’s structures, triggering functional disorders. The receptors for glutamate, a neurotransmitter, can also become the target of autoantibodies. Researchers at the Max Planck Institute of Experimental Medicine in Göttingen have been investigating the circumstances under which autoantibodies for a particular glutamate receptor - known as the NMDA receptor - are formed, and their effects in the brain. The researchers have discovered that the level of these autoantibodies in the blood can fluctuate considerably over a person’s lifetime - independent of health conditions - and increases with age. Chronic stress can, however, drive up the concentration of these autoantibodies in the blood even in early life. According to the researchers, when the antibodies are able to enter the brain to act on NMDA receptors, people suffer less depression and anxiety. These autoantibodies are clearly acting as the body’s own antidepressants. Glutamate receptors sit in the nerve cell membrane and bind to glutamate, a neurotransmitter. The NMDA receptor is a receptor type essential for learning and memory. Up to 20 percent of the population have antibodies against this receptor in their blood. Usually, the blood-brain barrier prevents these antibodies crossing from the blood into the brain. Only if this barrier is damaged can the antibodies have any greater effect. If the antibodies bind to NMDA receptors in the brain, these are then removed from the nerve cell membrane (‘internalized’). This disrupts the signalling to neighbouring cells. If an inflammation is present in the brain, for example, due to a viral infection, the presence of these autoantibodies can lead to a so-called ‘anti-NMDAR-encephalitis’: an illness brought to the public’s attention by the 2016 film ‘Brain on Fire’. The effect of these NMDA receptor autoantibodies can typically influence the symptoms of the underlying encephalitis, contributing to epileptic seizures, impaired movement, psychosis and loss of cognitive function. Autoantibody levels increase with age In a new study, Hannelore Ehrenreich and her colleagues from the Max Planck Institute of Experimental Medicine in Göttingen have discovered that the concentration of these autoantibodies in the blood of mice and humans can fluctuate considerably over time. However, the level rises with age, as the body is continually exposed to factors which stimulate the immune system, and with it, autoantibody production. One of these factors is stress. According to the researchers, chronically stressed mice show a higher level of NMDA receptor autoantibodies in their blood compared to their non-stressed conspecifics. Ehrenreich and her team also analysed the concentration of antibodies in the blood of young migrants. “People who are subjected to high stress in their lives have a greater probability of carrying NMDA receptor autoantibodies in their blood, even at a young age,” says Ehrenreich. These are like a ticking time bomb in the body. “If an infection or some other factor appears which weakens the blood-brain barrier, the autoantibodies enter the brain and can cause epileptic seizures or other neurological disorders,” says Ehrenreich. A good example would be Knut, the famous Berlin polar bear. Positive effect of antibodies However, the researchers’ recent study has for the first time indicated that the autoantibodies can also play a positive role in the brain. Mice with a more permeable blood-brain barrier and NMDA receptor autoantibodies in the brain were significantly more mobile and less depressed during times of chronic stress than their conspecifics with an intact blood-brain barrier. An analysis of a large patient database revealed that people with NMDA autoantibodies and a permeable blood-brain barrier also suffered significantly less depression and anxiety. The NMDA autoantibody obviously plays a role in the brain similar to ketamine, an antidepressant that also acts on NMDA receptors. “The effect of these autoantibodies - whether they contribute to the symptoms of an encephalitis or inhibit depression - is evidently determined not only by their level in the brain, but also by any underlying condition, in particular the presence or absence of inflammation,” explains Ehrenreich.
Newswise — Northfield, IL — Recognizing a need for evidence-based recommendations to guide molecular testing in the management of patients with cancer, the College of American Pathologists (CAP) and three collaborating societies are developing a clinical guideline for testing DNA mismatch repair (MMR) and microsatellite instability (MSI) status in patients with a range of cancer types. Today, the groups open the public comment period for the guideline “MMR and MSI Testing in Patients Being Considered for Checkpoint Inhibitor Therapy.” All stakeholders—including pathologists who refer and perform molecular testing, oncologists, laboratory personnel, and allied health professionals—should provide feedback on the draft recommendations before March 13 to ensure final recommendations are clinically practical. “This guideline is the first to address testing based more on the methodology status of a biomarker and less on the cancer type or tumor origin,” explains guideline developer, pathologist Russell Broaddus, MD, PhD, FCAP. “As we’ve learned more about patient response to checkpoint inhibitor therapy, we’ve seen that patients whose cancers had high levels of MSI or defective MMR would respond well, specifically to a checkpoint inhibitor drug such as pembrolizumab.” Dr. Broaddus chairs the panel of experts representing the societies collaborating on the guideline: the American Society of Clinical Oncology (ASCO), the Association for Molecular Pathology (AMP), and Fight Colorectal Cancer (Fight CRC). The panel will consider all comments garnered during the comment period prior to finalizing the recommendations and submitting the guideline for publication. “For patients, knowing your MSI status is extremely important prior to selecting a treatment,” according to experts at Fight CRC. “Many patients with MSI-high tumors have had a positive response to immunotherapy treatments, also known as immune-checkpoint therapies.” And while the FDA approved a drug for patients with MSI-high or MMR-deficient tumor status, regardless of cancer type, it did not detail how to test for that status. This new CAP guideline aims to fill that gap and provide oncologists, pathologists, and laboratories of all sizes with evidence-based recommendations to efficiently deploy specific assays and accurately identify patients eligible for treatment. In particular, the panel developing the guideline sought evidence to answer these questions: Which test modality best predicts DNA MMR? Does cancer type matter when choosing a testing modality? Does MMR by immunohistochemistry, MSI by polymerase chain reaction, or MSI by next generation sequencing results predict improved clinical outcomes in patients treated with checkpoint inhibitors? Does tumor mutation burden predict improved clinical outcomes in patients treated with checkpoint inhibitors? As drafted, the guideline includes six recommendations and three “good practice statements” that impact testing for patients with colorectal, endometrial, gastroesophageal and small bowel, and other types of cancer. In addition, the recommendations provide guidance on the role of tumor mutational burden in MMR testing and the evaluation of Lynch Syndrome. To read and comment on the draft guideline, visit cap.org until March 13, 2020. About the College of American Pathologists As the world's largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. For more information, read the CAP Annual Report at cap.org.
New research shows how rapid SUMOylation of cell surface cardiac sodium channels causes late sodium current in response to hypoxia, a challenge that confronts many people with heart disease. This discovery offers new targets for therapeutics to prevent late current and arrhythmia associated with heart attacks, chronic heart failure and other life-threatening low oxygen cardiac conditions. Newswise — Irvine, Calif. February 18, 2020 – Low oxygen levels in the heart have long been known to produce life-threatening arrhythmias, even sudden death. Until now, it was not clear how. New findings, in a study led by Steve A. N. Goldstein, MD, PhD, vice chancellor for Health Affairs at the University of California, Irvine, and distinguished professor in the UCI School of Medicine Departments of Pediatrics and Physiology & Biophysics, reveal the underlying mechanism for this dangerous heart disorder. “Our research shows that within seconds, at low levels of oxygen (hypoxia), a protein called small ubiquitin-like modifier (SUMO) is linked to the inside of the sodium channels which are responsible for starting each heartbeat,” said Goldstein. “And, while SUMOylated channels open as they should to start the heartbeat, they re-open when they should be closed. The result is abnormal sodium currents that predispose to dangerous cardiac rhythms.” Titled, “Hypoxia produces pro-arrhythmic late sodium current in cardiac myocytes by SUMOylation of NaV1.5 channels,” the study was published today in Cell Reports. Lead author, Leigh D. Plant, PhD, assistant professor at the Bouvé College of Health Sciences, Department of Pharmaceutical Sciences at Northeastern University, was a former post-doctoral fellow with Dr. Goldstein. Every heartbeat begins when sodium channels open and ions to rush into heart cells—this starts the action potential that causes the heart muscle to contract. When functioning normally, the sodium channels close quickly after opening and stay closed. Thereafter, potassium channels open, ions leave the heart cells, and the action potential ends in a timely fashion, so the muscle can relax in preparation for the next beat. If sodium channels re-open and produce late sodium currents, as observed in this study with low oxygen levels, the action potential is prolonged and new electrical activity can begin before the heart has recovered risking dangerous, disorganized rhythms. Fifteen years ago, the Goldstein group reported SUMO regulation of ion channels at the surface of cells, an unexpected finding since the SUMO pathway had been thought to operate solely to control gene expression in the nucleus. “This new research shows how rapid SUMOylation of cell surface cardiac sodium channels causes late sodium current in response to hypoxia, a challenge that confronts many people with heart disease,” said Goldstein. “Previously, the danger of late sodium current was recognized in patients with rare, inherited mutations of sodium channels that cause cardiac Long QT syndrome, and to result from a common polymorphism in the channel we identified in a subset of babies with sudden infant death syndrome (SIDS).” The information, gained through the current study, offers new targets for therapeutics to prevent late current and arrhythmia associated with heart attacks, chronic heart failure and other life-threatening low oxygen cardiac conditions. This study was funded by National Institutes of Health. About UCI Health Affairs UCI Health Affairs comprises the schools, institutes, and centers in the Susan and Henry Samueli College of Health Sciences and an academic health system, UCI Health. The college unites the disciplines of medicine, nursing, pharmacy and pharmaceutical sciences, and population and public health to advance a transformative educational and healthcare delivery model that is patient-centered, science-based, transdisciplinary, and team-delivered. About the UCI School of Medicine Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and master’s students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu. Photo Credit: UCI School of Medicine
Newswise — WASHINGTON—Eating a big breakfast rather than a large dinner may prevent obesity and high blood sugar, according to new research published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.Our body expends energy when we digest food for the absorption, digestion, transport and storage of nutrients. This process, known as diet-induced thermogenesis (DIT), is a measure of how well our metabolism is working, and can differ depending on mealtime.“Our results show that a meal eaten for breakfast, regardless of the amount of calories it contains, creates twice as high diet-induced thermogenesis as the same meal consumed for dinner,” said the study’s corresponding author, Juliane Richter, M.Sc., Ph.D., of University of Lübeck in Germany. “This finding is significant for all people as it underlines the value of eating enough at breakfast.”The researchers conducted a three-day laboratory study of 16 men who consumed a low-calorie breakfast and high-calorie dinner, and vice versa in a second round. They found identical calorie consumption led to 2.5 times higher DIT in the morning than in the evening after high-calorie and low-calorie meals. The food-induced increase of blood sugar and insulin concentrations was diminished after breakfast compared with dinner. The results also show eating a low-calorie breakfast increased appetite, specifically for sweets.“We recommend that patients with obesity as well as healthy people eat a large breakfast rather than a large dinner to reduce body weight and prevent metabolic diseases,” Richter said.Other authors include: Nina Herzog, Simon Janka, Thalke Baumann, Alina Kistenmacher and Kerstin M. Oltmanns of the University of Lübeck.The study was supported by the German Research Foundation.The manuscript, “Twice as High Diet-Induced Thermogenesis After Breakfast Versus Dinner on High Calorie as Well as Low-Calorie Meals,” was published online, ahead of print.
According to the U.S. Centers for Disease Control and Prevention, more than 859,000 Americans die of heart attacks or stroke every year, which account for more than 1 in 3 of all U.S. deaths. Newswise — The most recent guidelines for primary prevention recommend aspirin use for individuals ages 40 to 70 years who are at higher risk of a first cardiovascular event, but not for those over 70. Yet, people over 70 are at increasingly higher risks of cardiovascular events than those under 70. There has been considerable confusion from recently reported results of three large-scale randomized trials of aspirin in high risk primary prevention subjects, one of which showed a significant result, but the other two, based possibly on poor adherence and follow up, did not. As a result, health care providers are understandably confused about whether or not to prescribe aspirin for primary prevention of heart attacks or strokes, and if so, to whom. In a commentary published online ahead of print in the American Journal of Medicine, researchers from Florida Atlantic University’s Schmidt College of Medicine and collaborators from the University of Wisconsin School of Medicine and Public Health, and the Harvard Medical School and Brigham and Women’s Hospital, provide guidance to health care providers and their patients. They urge that to do the most good for the most patients in primary care, health care providers should make individual clinical judgements about prescribing aspirin on a case-by-case basis. “All patients suffering from an acute heart attack should receive 325 mg of regular aspirin promptly, and daily thereafter, to reduce their death rate as well as subsequent risks of heart attacks and strokes,” said Charles H. Hennekens, M.D., Dr.P.H., senior author, the first Sir Richard Doll Professor, and senior academic advisor in FAU’s Schmidt College of Medicine. “In addition, among long-term survivors of prior heart attacks or occlusive strokes, aspirin should be prescribed long-term unless there is a specific contraindication. In primary prevention, however, the balance of absolute benefits, which are lower than in secondary prevention patients, and risks of aspirin, which are the same as in secondary prevention, is far less clear.” The researchers emphasize that, based on the current totality of evidence, any judgments about prescribing long-term aspirin therapy for apparently healthy individuals should be based on individual clinical judgments between the health care provider and each of his or her patients that weighs the absolute benefit on clotting against the absolute risk of bleeding. The increasing burden of cardiovascular disease in developed and developing countries underscores the need for more widespread therapeutic lifestyle changes as well as the adjunctive use of drug therapies of proven net benefit in the primary prevention of heart attacks and strokes. The therapeutic lifestyle changes should include avoidance or cessation of smoking, weight loss and increased daily physical activity, and the drugs should include statins for lipid modification, and multiple classes of drugs likely to be necessary to achieve control of high blood pressure. “When the magnitudes of the absolute benefits and risks are similar, patient preference assumes increasing importance,” said Hennekens. “This may include consideration of whether the prevention of a first heart attack or stroke is a more important consideration to a patient than their risk of a gastrointestinal bleed.” Individual clinical judgements by health care providers about prescribing aspirin in primary prevention may affect a relatively large proportion of their patients. For example, primary prevention patients with metabolic syndrome, a constellation of overweight and obesity, hypertension, high cholesterol, and insulin resistance, a precursor to diabetes mellitus, affects about 40 percent of Americans over age 40. Their high risks of a first heart attack and stroke may approach those in survivors of a prior event. “General guidelines for aspirin in primary prevention do not seem to be justified,” said Hennekens. “As is generally the case, the primary care provider has the most complete information about the benefits and risks for each of his or her patients.” According to the United States Centers for Disease Control and Prevention, more than 859,000 Americans die of heart attacks or stroke every year, which account for more than 1 in 3 of all U.S. deaths. These common and serious diseases take a very large economic toll, costing $213.8 billion a year to the health care system and $137.4 billion in lost productivity from premature death alone. Collaborators in this commentary are Alexander Gitin, B.S., first author, an honors graduate of FAU and a first-year medical student at the University of Florida College of Medicine; David L. DeMets, Ph.D., the first Max Halperin Professor and chair emeritus of biostatistics and informatics at the University of Wisconsin School of Medicine and Public Health; and Marc A. Pfeffer, M.D., Ph.D., the first Dzau Professor of Medicine at Harvard Medical School. Hennekens was the first to discover that aspirin prevents a first heart attack in men and stroke in women and has lifesaving benefits when given during a heart attack as well as among long-term survivors’ prior events. Science Watch ranked him as the third most widely cited medical researcher in the world from 1995 to 2005, and five of the top 20 were his former trainees and/or fellows. Science Heroes also ranked Hennekens No. 81 in the history of the world for having saved more than 1.1 million lives, and the Via Academy lists him as the No. 14 top living medical researcher in the world. He has accepted an invitation to present these findings at the International Academy of Cardiology meeting in July in Boston. – FAU – About the Charles E. Schmidt College of Medicine: FAU’s Charles E. Schmidt College of Medicine is one of approximately 152 accredited medical schools in the U.S. The college was launched in 2010, when the Florida Board of Governors made a landmark decision authorizing FAU to award the M.D. degree. After receiving approval from the Florida legislature and the governor, it became the 134th allopathic medical school in North America. With more than 70 full and part-time faculty and more than 1,300 affiliate faculty, the college matriculates 64 medical students each year and has been nationally recognized for its innovative curriculum. To further FAU’s commitment to increase much needed medical residency positions in Palm Beach County and to ensure that the region will continue to have an adequate and well-trained physician workforce, the FAU Charles E. Schmidt College of Medicine Consortium for Graduate Medical Education (GME) was formed in fall 2011 with five leading hospitals in Palm Beach County. The Consortium currently has five Accreditation Council for Graduate Medical Education (ACGME) accredited residencies including internal medicine, surgery, emergency medicine, psychiatry, and neurology. About Florida Atlantic University: Florida Atlantic University, established in 1961, officially opened its doors in 1964 as the fifth public university in Florida. Today, the University, with an annual economic impact of $6.3 billion, serves more than 30,000 undergraduate and graduate students at sites throughout its six-county service region in southeast Florida. FAU’s world-class teaching and research faculty serves students through 10 colleges: the Dorothy F. Schmidt College of Arts and Letters, the College of Business, the College for Design and Social Inquiry, the College of Education, the College of Engineering and Computer Science, the Graduate College, the Harriet L. Wilkes Honors College, the Charles E. Schmidt College of Medicine, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science. FAU is ranked as a High Research Activity institution by the Carnegie Foundation for the Advancement of Teaching. The University is placing special focus on the rapid development of three signature themes – marine and coastal issues, biotechnology and contemporary societal challenges – which provide opportunities for faculty and students to build upon FAU’s existing strengths in research and scholarship. For more information, visit www.fau.edu. Photo Credit: Florida Atlantic University
Newswise — As Valentine’s Day approaches, a Cleveland Clinic survey finds that two-thirds of Americans (66%) in a committed relationship are concerned with their partner’s heart health. Moreover, 60% of Americans say they are more motivated to live a heart healthy lifestyle for their partners than for themselves. This is especially true for men – 67% compared to 52% for women. The survey was conducted as part of Cleveland Clinic Heart, Vascular and Thoracic Institute’s “Love your Heart” consumer education campaign in celebration of American Heart Month. It looked at how relationships affect heart health. The survey found most Americans in committed relationships are looking to their partners for motivation. An overwhelming majority (83%) agreed that if their partner adopted a heart-healthy diet, they would join in, and 57% said they are more likely to exercise with their partner than by themselves. “We know that strong emotions can affect the heart, if only temporarily. But, partners can make a long-term impact on each other’s heart health,” said Samir Kapadia, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. “I recommend partners undertake heart healthy habits together. Make it fun but hold each other accountable – find new healthy recipes and cook them together, join an exercise class, or go on daily walks with your partner. Simple lifestyle changes can go a long way in keeping your heart strong and healthy.” Alternatively, partners can be a negative influence. About two-thirds (64%) of Americans in committed relationships acknowledge that they enable or are enabled by their partner in unhealthy heart habits. For example, far more couples said they were likely to binge watch a TV show with their partner (66%) than exercise together (46%). Additional survey findings include: The majority of Americans (86%) believe that emotional heartbreak can result in physical pain, and seven-in-ten (71%) also believe it’s possible to die of a broken heart. Physicians say there is a “broken heart syndrome”, called Takotsubo cardiomyopathy, which is a response to sudden emotional stress, but it is rare. Seven-in-ten (70%) Americans consider sex exercise, especially younger Americans under 55. Men in a committed relationship especially said that their partners were a positive influence on their heart health- 78% compared to 67% of women. Heart disease is the leading cause of death in the United States, accounting for 1 in every 4 deaths. Cleveland Clinic has been ranked the No. 1 hospital in the country for cardiology and cardiac surgery for 25 years in a row by US News & World Report. Methodology Cleveland Clinic’s survey of the general population gathered insights into Americans’ perceptions of heart health and prevention. This was an online survey conducted among a national probability sample consisting of 1,000 adults 18 years of age and older, living in the continental United States. The total sample data is nationally representative based on age, gender, ethnicity and educational attainment census data. The online survey was conducted by Dynata and completed between September 23 and September 26, 2018. The margin of error for the total sample at the 95% confidence level is +/- 3.1 percentage points. About Cleveland Clinic Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 66,000 employees are more than 4,200 salaried physicians and researchers and 16,600 nurses, representing 140 medical specialties and subspecialties. Cleveland Clinic’s health system includes a 165-acre main campus near downtown Cleveland, 11 regional hospitals in northeast Ohio, more than 180 northern Ohio outpatient locations – including 18 full-service family health centers and three health and wellness centers – and locations in southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2018, there were 7.9 million total outpatient visits, 238,000 hospital admissions and observations, and 220,000 surgical cases throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/CCforMedia and twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
Newswise — (SACRAMENTO, Calif.) -- A Western diet rich in fat and sugar may lead to inflammatory skin diseases such as psoriasis, a study by UC Davis Health researchers has found. The study, published today in Journal of Investigative Dermatology, suggests that dietary components, rather than obesity itself, may lead to skin inflammation and the development of psoriasis. A common and chronic skin disease, psoriasis causes skin cells to form scales and red patches that are itchy and sometimes painful. Diet and Skin Inflammation Previous studies have shown that obesity is a risk factor for the development or worsening of psoriasis. The Western diet, characterized by a high dietary intake of saturated fats and sucrose and low intake of fiber, has been linked to the increased prevalence of obesity in the world. “In our study, we found that short-term exposure to Western diet is able to induce psoriasis before significant body weight gain,” said Sam T. Hwang, professor and chair of dermatology at UC Davis and senior author on the study. For the UC Davis Health study, which used a mouse model, Hwang and his colleagues found that a diet containing both high fat and high sugar (mimicking the Western diet in human) was required to induce observable skin inflammation. In four weeks only, mice on Western diet had significantly increased ear swelling and visible dermatitis compared to mice fed a controlled diet and those on high fat diet alone. “Eating an unhealthy diet does not affect your waistline alone, but your skin immunity too,” said Zhenrui Shi, visiting assistant researcher in UC Davis Department of Dermatology and lead author on the study. Bile Acids and Skin Inflammation The study detailed the mechanisms by which inflammation happens following a Western diet. It identified bile acids as key signaling molecules in the regulation of skin immunity. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. They play an important role in dietary lipid absorption and cholesterol balance in the blood. The study found that cholestyramine, a drug used to lower cholesterol levels by binding to bile acids in the intestine, helped reduce the risk of skin inflammation. The finding suggests that bile acids mediate the development of psoriasis. The binding of cholestyramine to bile acids in the gut and its subsequent release through the stool allows for lowering of skin inflammation. Further studies are needed to understand the mechanism behind diet-induced skin inflammation and the interaction between metabolism, microbes and immunity. This study was supported by a National Psoriasis Foundation Discovery Grant, an NIH/NIAMS R01 grant (1R01AR063091-01A1) and an NCI/NIH grant (U01-CA179582-03A1). Other collaborators include Xuesong Wu, Mindy Huynh and Mimi Nguyen from Department of Dermatology at UC Davis, Prasant Jena and Yui-Jui Yvonne Wan from Medical Pathology and Laboratory Medicine at UC Davis and Sebastian Yu from Department of Dermatology at Kaohsiung Medical University.
This painting depicts a coronavirus just entering the lungs, surrounded by mucus secreted by respiratory cells, secreted antibodies, and several small immune systems proteins. The virus is enclosed by a membrane that includes the S (spike) protein, which will mediate attachment and entry into cells, M (membrane) protein, which is involved in organization of the nucleoprotein inside, and E (envelope) protein, which is a membrane channel involved in budding of the virus and may be incorporated into the virion during that process. The nucleoprotein inside includes many copies of the N (nucleocapsid) protein bound to the genomic RNA. Newswise — The Protein Data Bank archive, which contains more than 160,000 3D structures for proteins, DNA, and RNA, this month released a new Coronavirus protease structure following the recent coronavirus outbreak, an ongoing viral epidemic primarily affecting mainland China that now threatens to spread to populations in other parts of the world. The structure, the topic of the PDB’s current ‘Molecule of the Month’ feature, is a high-resolution crystal structure of 2019-nCoV coronavirus 3CL hydrolase (Mpro) as determined by Zihe Rao and Haitao Yang's research team at ShanghaiTech University. Rapid public release of this structure of the main protease of the virus, known within the archive as PDB 6lu7, will enable research on this newly-recognized human pathogen. More details from the PDB can be found here. The PDB archive is jointly managed by the Worldwide Protein Data Bank partnership, involving data centers in the United States, Europe and Asia. U.S. operations are led by the RCSB Protein Data Bank at Rutgers, the San Diego Supercomputer Center (SDSC) at UC San Diego, and UC San Francisco. PDB data provide a starting point for structure-guided drug discovery. Such viruses have increasingly become a danger to world health, given the increase in global travel, according to the PDB release. Particularly virulent forms have emerged from their natural animal hosts and pose a threat to human communities. In 2003, the Severe Acute Respiratory Syndrome (SARS) virus emerged in China from bat populations, moving to civets and finally to humans. Ten years later, the MERS virus also emerged from bats, transferring in the Middle East to dromedary camels and then to humans. While the latest entry is currently the only public-domain 3D structure from this specific coronavirus, the PDB archive also contains structures of the corresponding enzyme from other coronaviruses. The 2003 outbreak of the closely-related SARS virus led to the first 3D structures, and today there are more than 200 PDB structures of SARS proteins. “Function follows form in biology,” said Stephen K. Burley, physician-scientist and director of the RCSB Protein Data Bank and faculty member at Rutgers University and UC San Diego-SDSC. “Open access to PDB data ensures that rapid access to rigorously validated and expertly curated 3D structure information contributes broadly to research and education in fundamental biology, biomedicine, bioenergy, and biotechnology.” The coronavirus 3CL hydrolase (Mpro) enzyme, also known as the main protease, is essential for proteolytic maturation of the virus. It is thought to be a promising target for discovery of small-molecule drugs that would inhibit cleavage of the viral polyprotein and prevent spread of the infection. Comparison of the protein sequence of the 2019-nCoV coronavirus 3CL hydrolase (Mpro) against the PDB archive identified 95 PDB proteins with at least 90% sequence identity. Furthermore, these related protein structures contain approximately 30 distinct small molecule inhibitors, which could guide discovery of new drugs. Of particular significance for drug discovery is the very high amino acid sequence identity (96%) between the 2019-nCoV coronavirus 3CL hydrolase (Mpro) and the SARS virus main protease (PDB 1q2w). Summary data about these closely-related PDB structures are available (CSV) to help researchers more easily find this information. In addition, the PDB houses 3D structure data for more than 20 unique SARS proteins represented in more than 200 PDB structures, including a second viral protease, the RNA polymerase, the viral spike protein, a viral RNA, and other proteins (CSV). “Coronavirus main proteases represent attractive targets for drug discovery and development. 3D structure information freely available from the PDB includes small chemicals bound tightly to the enzyme active site (the business end of the main protease), confirming that they are druggable targets,” explained Burley. “Some of these structures provide starting points for structure-guided drug discovery of protease inhibitors with drug-like properties suitable for preclinical testing. We hope that this new structure, and those from SARS and MERS, will help researchers and clinicians address the 2019-nCoV coronavirus global public health emergency.” Reproducible and Scalable Structural Bioinformatics Scientists face time-consuming barriers when applying structural bioinformatics analysis, including complex software setups, non-interoperable data formats, and lack of documentation, all which make it difficult to reproduce results and reuse software pipelines. A further challenge is the ever-growing size of datasets that need to be analyzed. To address these challenges, SDSC’s Structural Bioinformatics Laboratory, directed by Peter Rose, is developing a suite of reusable, scalable software components called MMTF-PySpark, using three key technologies: its parallel distributed processing framework provides scalable computing; the MacroMolecular Transmission Format (MMTF), a new binary and compressed representation of Macromolecular structures, which enables high-performance processing of PDB structures. “The use of MMTF-PySpark could easily shave off a year of a graduate student’s or postdoc’s work in Structural Bioinformatics,” said Rose. “We bank on contributions from the community to develop and share an eco-system of interoperable tools.” About SDSC As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s petascale Comet supercomputer is a key resource within the National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) program. Image Credit: David S. Goodsell, RCSB Protein Data Bank
Credit: U.S. Centers for Disease Control and Prevention An influenza virus binds to receptors on a respiratory tract cell, allowing the virus to enter and infect the cell. Newswise — A Rutgers-led team has developed a tool to monitor influenza A virus mutations in real time, which could help virologists learn how to stop viruses from replicating.The gold nanoparticle-based probe measures viral RNA in live influenza A cells, according to a study in The Journal of Physical Chemistry C. It is the first time in virology that experts have used imaging tools with gold nanoparticles to monitor mutations in influenza, with unparalleled sensitivity.“Our probe will provide important insight on the cellular features that lead a cell to produce abnormally high numbers of viral offspring and on possible conditions that favor stopping viral replication,” said senior author Laura Fabris, an associate professor in the Department of Materials Science and Engineering in the School of Engineering at Rutgers University–New Brunswick.Viral infections are a leading cause of illness and deaths. The new coronavirus, for example, has led to more than 24,000 confirmed cases globally, including more than 3,200 severe ones and nearly 500 deaths as of Feb. 5, according to a World Health Organization report.Influenza A, a highly contagious virus that arises every year, is concerning due to the unpredictable effectiveness of its vaccine. Influenza A mutates rapidly, growing resistant to drugs and vaccines as it replicates.The new study highlights a promising new tool for virologists to study the behavior of influenza A, as well as any other RNA viruses, in host cells and to identify the external conditions or cell properties affecting them. Until now, studying mutations in cells has required destroying them to extract their contents. The new tool enables analysis without killing cells, allowing researchers to get snapshots of viral replication as it occurs. Next steps include studying multiple segments of viral RNA and monitoring the influenza A virus in animals.The lead author is Kholud Dardir, who earned a doctorate at Rutgers. Rutgers co-authors include senior postdoctoral associate Hao Wang and Maria Atzampou, a doctoral student. Researchers at the University of Illinois at Urbana Champaign contributed to the study.
Credit: Zhen Gu Lab/UCLA Schematic picture of cold plasma patch for cancer immunotherapy. Newswise — Los Angeles - An interdisciplinary team of researchers at the UCLA Jonsson Comprehensive Cancer Center has developed a medicated patch that can deliver immune checkpoint inhibitors and cold plasma directly to tumors to help boost the immune response and kill cancer cells. The thumb-sized patch has more than 200 hollow microneedles that can penetrate the skin and enter the tumor tissue. The cold plasma is delivered through the hollow structure, destroying cancer cells, which facilitates the release of tumor-specific antigens and boosts an immune response. The immune checkpoint inhibitors — antibodies that block checkpoint proteins, which interferes with immune system function and prevents the immune system from destroying cancer cells — are also released from the sheath of microneedles to boost the T cell-mediated anti-cancer effects. In the study, which is published in the Proceedings of the National Academy of Sciences, the UCLA researchers found that delivering the two therapies to mice with melanoma using the patch enabled the immune system to better attack the cancer, significantly inhibiting the growth of the tumor and prolonging the survival of the mice. The team also found that the therapy not only inhibit the growth of the targeted tumor, but it also could inhibit the growth of tumors that had spread to other parts of the body. “Immunotherapy is one of the most groundbreaking advances in cancer treatment,” said study senior author Zhen Gu, professor of bioengineering at the UCLA Samueli School of Engineering and member of the Jonsson Cancer Center. “Our lab has been working on engineering new ways to apply or deliver drugs to the diseased site that could help improve the effectiveness of cancer immunotherapy, and we found the patch to be a quite promising delivery system.” The study is also the first to demonstrate that cold plasma can be effective in synergizing cancer immunotherapy. Plasma, which is usually hot, is an ionized gas that comprises more than 99% of the universe. Here, cold plasma is generated by a small device operating at atmospheric pressure and room temperature. Therefore, cold plasma can be applied directly to the body — internally or externally. “This study represents an important milestone for the field of plasma medicine,” said co-senior author Richard Wirz, professor of mechanical and aerospace engineering at UCLA Samueli. “It demonstrates that the microneedle patch can realize the plasma delivery while also working with the drug to improve the effectiveness of cancer therapy.” “Plasma can generate reactive oxygen species and reactive nitrogen species, which are a group of chemical species that can destroy cancer cells,” said Guojun Chen, who is the co-first author of the study and a postdoctoral fellow in Gu’s laboratory. “Those cancers can then release tumor-associated antigens, which can enhance immune response to kill cancers,” said Zhitong Chen, who is the other co-first author and a postdoctoral fellow in Wirz’s lab. The team tested the cold plasma patch on mice with melanoma tumors. The mice that received the treatment showed an increased level of dendritic cells, which are a specific type of white blood cells that alert the immune system of a foreign invader and initiate a T cell-mediated immune response. The group of mice also showed delayed tumor growth compared to the untreated group and 57% were still alive at 60 days, while mice in other control groups had all died. “This treatment strategy can potentially go beyond cancer immunotherapy,” said Gu, who is also a member of the California NanoSystems Institute at UCLA. “Integrated with other treatments, this minimally invasive method can be extended to treat different cancer types and a variety of diseases.” The patch will have to go through further testing and approvals before it could be used in humans. But the team members believe the approach holds great promise. The work was funded by the National Institutes of Health and the Air Force Office of Scientific Research.