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November 26th, 2019

Multiple Sclerosis (MS) Linked to HHV-6A Variant of Common Herpes Virus Through New Method

Researchers at Karolinska Institutet in Sweden have developed a new method to distinguish between two different types of a common herpes virus (HHV-6) that has been linked to multiple sclerosis (MS). By analyzing antibodies in the blood against the two most divergent proteins of herpesvirus 6A and 6B, the researchers were able to show that MS patients carry the herpesvirus 6A to a greater extent than healthy individuals. The findings, published online on November 26, 2019 in Frontiers in Immunology, point to a role for HHV-6A in the development of MS, which is an autoimmune disease that affects the central nervous system. The open-access article is titled “Increased Serological Response Against Human Herpesvirus 6A Is Associated with Risk for Multiple Sclerosis.” The cause of MS is unclear, but one plausible explanation is that a virus stimulates the immune system to attack the body's own tissue. Human herpesvirus 6 (HHV-6) has previously been associated with MS, but, in those studies, it wasn't possible to distinguish between 6A and 6B. Through virus isolation from ill individuals, researchers have been able to show that HHV-6B can cause mild conditions such as roseola in children, but it has been unclear if HHV-6A is the cause of any disease. According to estimates, as many as 80 percent of all children are infected with the HHV-6 virus before 2 years of age, and many also carry protection in the form of antibodies against this particular virus for the rest of their lives. But because it hasn't been possible to tell the two variants apart post-infection, it has been difficult to say whether HHV-6A or B is a risk factor for MS.

November 24th

Study in Green Monkeys Suggests That Wound Healing Mechanism in Mucous Tissues Might Help Ward Off Development of AIDS

Wound healing events in mucous tissues during early infection by simian immunodeficiency virus (SIV), guard some primate species against developing AIDS, a recent study has learned. The research looked at why certain species can carry the virus throughout their lives, and still avoid disease progression. SIV is closely related to the human immunodeficiency virus (HIV). It is used as a laboratory model for many studies seeking AIDS and HIV cures and preventions. Despite effective treatments to manage HIV, the virus remains a major global health threat. Approximately 37.9 million people in the world are living with an HIV infection. Each year approximately 770,000 people die of AIDS. As yet, there are no clinically available vaccines against HIV, or cures for the infection. In this latest study, reported online on November 8, 2019 in Nature Communications, scientists sought to uncover, in natural hosts, successful virus-fighting tactics that could inform the design of better antiviral drugs to treat HIV in people. The researchers found that the biological events involved in wound healing of mucosal tissues create an environment inside the body that protects against the destructive consequences of SIV infection. (Mucosal tissues are part of the body's defense against germs.) Aspects of this wound-healing immune response could become targets for developing new therapies to prevent AIDS in people with HIV infections.

November 23rd

Scientists Crack Rabies Virus Weaponry; Elucidate Binding of Virus P-Protein to Host STAT1

Researchers from Monash University and the University of Melbourne, both in Australia, have found a way to stop the rabies virus shutting down the body’s immune defense against it. In doing so, they have solved a key scientific puzzle and have laid the foundation for the development of new anti-rabies vaccines. Rabies kills an estimated 60,000 people a year, most of them in developing countries, overwhelmingly through dog bites. Dr Greg Moseley, from the Monash Biomedicine Discovery Institute (BDI), and Associate Professor Paul Gooley, from the Bio21 Institute were senior authors in the study, published in the November 12, 2019 issue of Cell Reports. The open-access article is titled “Structural Elucidation of Viral Antagonism of Innate Immunity at the STAT1 Interface.” “It’s been known for a long time that many viruses target the human protein STAT1 and related proteins to shut down the host’s immune defences, and it’s also assumed that this is very important for diseases,” Long-term rabies researcher Dr Moseley said. However, it was not known exactly how P-protein ¬– the main ”immune antagonist” of lyssaviruses including the rabies virus – takes hold of STAT1, due to a lack of direct structural data on STAT1 complexes with viral proteins. “The challenge was to produce the key proteins on the viral and host sides in a test tube and keep them stable so we could interrogate the interaction directly; this hadn’t been done before, at least not for the full-size human protein,” Dr Moseley said. The researchers then brought the two proteins together and, using nuclear magnetic resonance spectroscopy, showed the precise regions where the viral protein sticks onto STAT1 and holds onto it to keep it away from locations in the cell where it needs to be to activate the immune response.

Scientists Clarify How RNA Molecules Are Folded in Ribosomes; Findings Reveal Unprecedented Detail

A team of scientists from Scripps Research and Stanford University has recorded in real time a key step in the assembly of ribosomes--the complex and evolutionarily ancient "molecular machines" that make proteins in cells and are essential for all life forms. The achievement, reported on November 21, 2019 in Cell, reveals, in unprecedented, detail how strands of ribonucleic acid (RNA), cellular molecules that are inherently sticky and prone to misfold, are "chaperoned" by ribosomal proteins into folding properly and forming one of the main components of ribosomes. The Cell article is titled “Transient Protein-RNA Interactions Guide Nascent Ribosomal RNA Folding.” The findings overturn the longstanding belief that ribosomes are assembled in a tightly controlled, step-wise process. "In contrast to what had been the dominant theory in the field, we revealed a far more chaotic process," says James R. Williamson, PhD, a professor in the Department of Integrative Structural & Computational Biology at Scripps Research. "It's not a sleek Detroit assembly line--it's more like a trading pit on Wall Street." For the study, Williamson's lab collaborated with the lab of Joseph Puglisi, PhD, a Professor at Stanford University. Although the work is a significant feat of basic cell biology, it should enable important advances in medicine. For example, some current antibiotics work by inhibiting bacterial ribosomes; the new research opens up the possibility of designing future antibiotics that target bacterial ribosomes with greater specificity--and thus, fewer side effects. More generally, the research offers biologists a powerful new approach to the study of RNA molecules, hundreds of thousands of which are active at any given time in a typical cell.

Researchers Show Immunotherapy Highly Effective in Extending Life in Those with Heat & Neck Cancer and Also Expressing High Levels of PD-L1 Marker

Immunotherapy is better than standard ‘extreme’ chemotherapy as first-line treatment for advanced head and neck cancer and can keep some patients alive for more than three years, a major new trial reports. The immunotherapy drug pembrolizumab (Keytruda) alone or in combination with chemotherapy extended patients’ lives compared with standard treatment – with some groups of patients treated with single-agent pembrolizumab responding for five times longer than with standard extreme chemotherapy. Crucially, the researchers showed it was possible to predict in advance who was more likely to benefit from pembrolizumab by testing for the PD-L1 immune marker in tumors and on surrounding cells – a key step in establishing the drug’s use as a new standard of care. Pembrolizumab has recently been approved in Europe as first-line treatment for patients diagnosed with advanced head and neck cancer, marking a key milestone in the use of immunotherapy as a standard part of cancer treatment. The phase III trial was led in the UK by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and involved 882 patients from all over the world who were diagnosed with advanced head and neck cancer. The research, published online on October 31, 2019 in The Lancet, was funded by the treatment’s manufacturer, Merck & Co., Inc., known as MSD outside the US and Canada. The article is titled “Pembrolizumab Alone or with Chemotherapy Versus Cetuximab with Chemotherapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (KEYNOTE-048): A Randomised, Open-Label, Phase 3 Study.” Currently, many patients diagnosed in the UK with advanced head and neck cancer first receive an “extreme” triple combination of two chemotherapies and targeted drug cetuximab.

November 22nd

Mount Sinai Researchers Uncover New Molecular Drivers of Parkinson's Disease; New Approach May Lead to a Better Understanding of Most Cases

Scientists at the Icahn School of Medicine at Mount Sinai have uncovered new molecular drivers of Parkinson's disease using a sophisticated statistical technique called multiscale gene network analysis (MGNA). The team was also able to determine how these molecular drivers impact the functions of genes involved in the disease. The results, which may point to potential new treatments, were published online on November 20, 2019 in Nature Communications. The open-access article is titled “The Landscape of Multiscale Transcriptomic Networks and Key Regulators in Parkinson’s Disease.” Some cases of Parkinson's are directly caused by genetic mutations, but these cases are rare. Approximately 80 percent of cases have no known cause, and though there are some genes that may slightly increase an individual's risk of developing the disease, the biological impacts of these genes remain unclear. "This study offers a novel approach to understanding the majority of cases of Parkinson's," said Bin Zhang, PhD, Professor of Genetics and Genomic Sciences at the Icahn Institute for Data Science and Genomic Technology and Director of the Mount Sinai Center for Transformative Disease Modeling at the Icahn School of Medicine at Mount Sinai. "The strategy not only reveals new drivers, but it also elucidates the functional context of the known Parkinson's disease risk factor genes."

November 20th

Study Suggests Deep Involvement of Transposable Elements in Emergence of the Mammary Gland and Its Evolution Within Mammals

The human genome contains 4.5 million copies of transposable elements (TEs), so-called selfish DNA sequences capable of moving around the genome through cut-and-paste or copy-and-paste mechanisms. Accounting for 30-50% of all of the DNA in the average mammalian genome, these TEs have conventionally been viewed as genetic freeloaders, hitchhiking along in the genome without providing any benefit to the host organism. More recently, however, scientists have begun to uncover cases in which TE sequences have been co-opted by the host to provide a useful function, such as encoding part of a host protein. In a new study published online on October 23, 2019 in Nucleic Acids Research, Professor Hidenori Nishihara has undertaken one of the most comprehensive analyses of TE sequence co-option to date, uncovering tens of thousands of potentially co-opted TE sequences and suggesting that they have played a key role in mammalian evolution. The open-access NAR article is titled “Retrotransposons Spread Potential Cis-Regulatory Elements During Mammary Gland Evolution.” "I was specifically interested in the potential influence of TE sequences on the evolution of the mammary gland," notes Dr. Nishihara, "an organ that is responsible for producing milk and is, as the name suggests, a key distinguishing feature of mammals." To identify potentially co-opted TE sequences, Dr. Nishihara used four proteins--ERα, FoxA1, GATA3, and AP2γ--that bind to DNA to regulate the production of proteins involved in mammary gland development. Dr. Nishihara then located all of the DNA sequences in the genome to which these proteins bind. Surprisingly, 20-30% of all of the binding sites across the genome were located in TEs, with as many as 38,500 TEs containing at least one binding site.

November 15th

Genome-Wide Screen of Malaria Parasite Genome with Corresponding Metabolic Models Represents Major Breakthrough in Malaria Research; Allows Researchers to Focus on Essential Genes

Despite great efforts in medicine and science, more than 400,000 people worldwide are still dying of malaria. The infectious disease is transmitted by the bite of mosquitoes infected with the malaria parasite Plasmodium (image). The genome of the parasite is relatively small, with about 5,000 genes. In contrast to human cells, Plasmodium parasites only have a single copy of each individual gene. If one removes a gene from the entire genome of the parasite, this leads therefore directly to a change in the phenotype of the parasite. An international consortium led by Professors Volker Heussler from the Institute of Cell Biology (ICB) at the University of Bern and Oliver Billker from the Umeå University in Sweden and formerly at the Sanger Institute in Great Britain has taken advantage of this fact. The researchers have carried out a genome-wide gene deletion study on malaria parasites: They specifically removed over 1300 individual genes, observed the effects during the entire life cycle of the parasite and were thus able to identify many new targets in the pathogen. The present study was published in the November 14, 2019 issue of Cell. The open-access article is titled “Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage.” The researchers used a malaria mouse model established at the Institute of Cell Biology at the University of Bern. Each of the 1,300 parasite genes was replaced by an individual genetic code to analyze how the removal of the individual genes affects the parasite. The use of individual codes allows the scientists to study many parasites simultaneously and thus drastically shortens the time of their analysis.

November 13th

Phage Therapy Shows Promise for Alcoholic Liver Disease; Gut Bacteria Toxin Linked to Worse Clinical Outcomes; Treatment With Bacteriophages Clears the Harmful Bacteria and Eliminates Disease In Mice

Bacteriophages (phages) are viruses that specifically attack and destroy bacteria. In the early 20th century, researchers experimented with phages as a potential method for treating bacterial infections. But then antibiotics emerged and phages fell out of favor. With the rise of antibiotic-resistant infections, however, researchers have renewed their interest in phage therapy. In limited cases, patients with life-threatening multidrug-resistant bacterial infections have been successfully treated with experimental phage therapy after all other alternatives were exhausted. Researchers at the University of California San Diego School of Medicine and their collaborators have now, for the first time, successfully applied phage therapy in mice for a condition that's not considered a classic bacterial infection: alcoholic liver disease. The study was published in the November 13, 2019 issue of Nature. The article is titled “Bacteriophage Targeting of Gut Bacterium Attenuates Alcoholic Liver Disease.” "We not only linked a specific bacterial toxin to worse clinical outcomes in patients with alcoholic liver disease, we found a way to break that link by precisely editing gut microbiota with phages," said senior author Bernd Schnabl, MD, Professor of Medicine and Gastroenterology at UC San Diego School of Medicine and Director of the NIH-funded San Diego Digestive Diseases Research Center. Up to 75 percent of patients with severe alcoholic hepatitis, the most serious form of alcohol-related liver disease, die within 90 days of diagnosis. The condition is most commonly treated with corticosteroids, but these drugs are not highly effective. Early liver transplantation is the only cure, but is only offered at select medical centers to a limited number of patients.

After Decades of Little Progress, Researchers May Be Catching Up to Sepsis; PERSEVERE Platform Assays Five Risk-Associated Biomarkers

After decades of little or no progress, biomedical researchers are finally making some headway at detecting and treating sepsis, a deadly medical complication that sends a surge of pathogenic infection through the body and remains a major public health problem. Researchers at Cincinnati Children's Hospital Medical Center report in the November 13, 2019 issue of Science Translational Medicine that they have developed and successfully tested a new rapid blood assay that measures five biomarkers and accurately predicts which patients are at low, medium, or high risk for death from sepsis (colloquially referred to as blood poisoning). Called PERSEVERE, the new test allows physicians to detect and stratify sepsis at its earliest moments, just as the body is about to unleash a storm of bacterial infection, according to study's senior investigator, Hector Wong (photo), MD, Director of Critical Care Medicine at Cincinnati Children's. By knowing which five proteins/genes make up the assay's five-biomarker blood panel, physicians should be able to start medical interventions much earlier and with greater precision. Dr. Wong said, not only can patients be stratified into low, medium and high-risk groups, the biomarker test allows physicians to pick the right interventions for specific patients, including which drugs and dosages. The article is titled “Prospective Clinical Testing and Experimental Validation of the Pediatric Sepsis Biomarker Risk Model.” "The PERSEVERE platform focuses on stratification and prognostication, not diagnostics," says Dr. Wong. "Prognostic enrichment is a fundamental tool of precision medicine.