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Archive - 2019

December 13th

DNA Stress Sensed by Mitochondria Can Cause Them to Activate Innate Immune System, Including Interferon-Stimulated Genes (ISGs) That Act to Protect Nuclear DNA and This May Support Development of Resistance to DNA-Damaging Chemotherapy

Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy. The article is titled “Mitochondrial DNA Stress Signalling Protects the Nuclear Genome.” "Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, 'Hey, I'm under attack, you better protect yourself,'" says Gerald Shadel, PhD, a Professor in Salk's Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science. Most of the DNA that a cell needs to function is found inside the cell's nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds--or even thousands--of mitochondria. Dr. Shadel's lab group previously showed (in “Mitochondrial DNA Stress Primes the Antiviral Innate Immune Response” at https://www.nature.com/articles/nature14156) that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus--by releasing it from mitochondria and launching an immune response that beefs up the cell's defenses.

Why Giant Pandas Are Born So Tiny; Short Gestation Period May Be Cause

Born pink, blind, and helpless, giant pandas typically weigh about 100 grams at birth -- the equivalent of a stick of butter. Their mothers are 900 times more massive than that. This unusual size difference has left researchers puzzled for years. With a few exceptions among animals such as echidnas and kangaroos, no other mammal newborns are so tiny relative to their mothers. No one knows why, but a Duke University study of bones across 10 species of bears and other animals finds that some of the current theories don't hold up. Duke biology professor Kathleen Smith, PhD, and her former student Peishu Li published their findings this month in the Journal of Anatomy. The article was published online on December 2, 2019 and is titled "Comparative Skeletal Anatomy of Neonatal Ursids and the Extreme Altriciality of the Giant Panda.” Baby panda skeletons are hard to come by, but the researchers were able to study the preserved remains of baby pandas born at the Smithsonian's National Zoo in Washington, D.C. The National Zoo's first panda couple, Ling-Ling and Hsing-Hsing, had five full-term cubs in the 1980s, but none of them survived long after birth. The researchers took micro-CT scans of two of those cubs, along with newborn grizzlies, sloth bears, polar bears, dogs, a fox, and other closely related animals from the Smithsonian National Museum of Natural History and the North Carolina State College of Veterinary Medicine. They used the scans to create 3-D digital models of each baby's bony interior at birth. As a baby animal grows and develops inside the womb, its bones and teeth do also. The researchers examined the degree of ossification, or how much the skeleton has formed by the time of birth.

Multiple Distinct Psychiatric Diseases Share Common Genetic Structure, According to Large MGH Study Published in Cell; Results May Provide New Clues for Treatment and Prevention of Psychiatric Disorders

Many distinct psychiatric diseases share a common genetic structure, according to new research by scientists at Massachusetts General Hospital (MGH) and the Psychiatric Genomics Consortium, an international team of investigators. Psychiatric disorders affect more than 25 percent of the population in a given year. In the largest-ever study of its kind, published in the December 12, 2019 issue of Cell, researchers identified more than 100 genetic variants that affect the risk for more than one mental health condition. The article is titled “Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms Across Eight Psychiatric Disorders.” A gene is made up of segments of DNA; an alteration in the DNA sequence produces a gene variant, which can increase or decrease the risk for disease. Many individual gene variants that affect the risk for specific psychiatric disorders have been identified. However, genes are often pleiotropic, meaning they produce multiple effects in the body. Identifying gene variants that influence the risk for more than one psychiatric disorder is an important step toward improving the diagnosis and treatment of these conditions, says the study’s senior author, Jordan W. Smoller, MD, ScD, Director of MGH’s Psychiatric and Neurodevelopmental Genetics Unit and a Professor of Psychiatry at Harvard Medical School (HMS). “Understanding how specific genetic variations may contribute to a broad spectrum of illnesses can tell us something about the degree to which these disorders may have a shared biology,” says Dr. Smoller. To identify these multi-purpose gene variants, the researchers used a technique called genome-wide association to analyze genetic data from 494,162 healthy control subjects and 232,964 people diagnosed with at least one of eight common psychiatric disorders.

November 26th

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.