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Archive - Nov 23, 2019

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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.