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Tarantula Toxin Locks Voltage-Gated Sodium Channels in Nerve Cells; Cryo-EM Study of Mechanism May Offer Clues to Treating Chronic Pain

Tararantulas may be unsightly and venomous, but surprisingly their hunter toxin may hold answers to better control of chronic pain. A bird-catching Chinese tarantula bite contains a stinger-like poison that plunges into a molecular target in the electrical signaling system of their prey's nerve cells. A new, high-resolution cryo-electron microscopy study shows how the stinger quickly locks the voltage sensors on sodium channels, the tiny pores on cell membranes that create electrical currents and generate signals to operate nerves and muscles. Trapped in their resting position, the voltage sensors are unable to activate. The findings were published online on November 23, 2020 in Molecular Cell, a journal of Cell Press. The article is titled “Structural Basis for High-Affinity Trapping of the NaV1.7 Channel in Its Resting State by Tarantula Toxin.” "The action of the toxin has to be immediate because the tarantula has to immobilize its prey before it takes off," said William Catterall, PhD, Professor and Chair of Pharmacology at the University of Washington School of Medicine. He was the senior researcher, along with Pharmacology Professor and Howard Hughes Medical Institute Investigator, Ning Zheng, PhD, on the study of the molecular damage inflicted by tarantula venom. While some might dismiss tarantulas as ugly, tough, and mean, medical scientists are actually interested in their venom's ability to trap the resting state of the voltage sensor on voltage-gated sodium channels and shut them down. Such studies of toxins from these "big, nasty dudes," as Dr. Catterall describes them, could point to new approaches to structurally designing drugs that might treat chronic pain by blocking sensory nerve signals. Dr. Catterall explained that chronic pain is a difficult-to-treat disorder.

Fat-Released Exosomes May Offer Clues to COVID-19; Adipose Tissue May Be Source of Inflammatory Factors That Aggravate COVID-19; Adipose Tissue of COVID-19 Patients Develop Syndrome Similar to Cachexia, Wasting Disease Seen in Cancer, Other Diseases

There is growing evidence that adipose tissue plays a key role in the aggravation of COVID-19. One of the theories under investigation is that fat cells (adipocytes) act as a reservoir for SARS-CoV-2 and increase viral load in obese or overweight individuals. Scientists also suspect that during infection fat cells release into the bloodstream substances that boost the inflammatory reaction triggered by the virus in the organism. These hypotheses are being investigated by researchers at the University of São Paulo's Medical School (FM-USP) in Brazil under the coordination of Marilia Cerqueira Leite Seelaender (https://bv.fapesp.br/en/pesquisador/5631/marilia-cerqueira-leite-seelaen...), PhD, a Professor in the Department of Clinical Surgery. Peter Ratcliffe, MD, PhD, a Professor at the University of Oxford in the UK and one of the winners of the 2019 Nobel Prize for Physiology or Medicine (“for discoveries of how cells sense and adapt to oxygen availability”), is collaborating. "A cytokine storm resulting in systemic inflammation similar to sepsis occurs in some severe COVID-19 patients. We believe these inflammatory factors come from adipose tissue. It's been shown that when adipocytes expand too much, they can cause inflammation throughout the body, even in the brain," Dr. Seelaender told Agência FAPESP (news agency). The FM-USP group analyzed samples of adipose tissue obtained from autopsies of people who died from COVID-19, and also from patients infected with SARS-CoV-2 who had to be submitted to emergency surgery at the university's hospital for appendicitis or other reasons not related to the viral infection. Preliminary results confirmed that the virus can be found in fat cells, whose membranes are rich in ACE-2, the main receptor used by the virus to invade human cells.

Regeneron's REGEN-COV2 Antibody Cocktail for COVID-19 Receives FDA Emergency Use Authorization (EUA) for Recently Diagnosed, Mild to Moderate COVID-19 In High-Risk Patients

On November 21, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced that the antibody cocktail casirivimab and imdevimab administered together (also known as REGN-COV2 or REGEN-COV2), a therapy currently being investigated for use in COVID-19, has received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA). Casirivimab and imdevimab administered together are authorized for the treatment of mild to moderate COVID-19 in adults, as well as in pediatric patients at least 12 years of age and weighing at least 40 kg, who have received positive results of direct SARS-CoV-2 viral testing and are at high risk for progressing to severe COVID-19 and/or hospitalization. The clinical evidence from Regeneron's outpatient trial suggests that monoclonal antibodies such as REGEN-COV2 have the greatest benefit when given early after diagnosis and in patients who have not yet mounted their own immune response or who have high viral load. The criteria for “high-risk” patients are described in the Fact Sheet for Health Care Providers (https://www.regeneron.com/sites/default/files/treatment-covid19-eua-fda-...). Casirivimab and imdevimab are not authorized for use in patients who are hospitalized or require oxygen therapy due to COVID-19, or for people currently using chronic oxygen therapy because of an underlying comorbidity who require an increase in baseline oxygen flow rate due to COVID-19. "This FDA Emergency Use Authorization is an important step in the fight against COVID-19, as high-risk patients in the United States will have access to a promising therapy early in the course of their infection," said Leonard S. Schleifer, MD, PhD, President and Chief Executive Officer of Regeneron.

Home Monitoring of Glaucoma May Be Enabled by New Technology Approach (“Eyecatcher”)

Glaucoma is a chronic condition that affects cells at the back of the eye. It is the leading cause of irreversible blindness worldwide, and is responsible for 1 in 10 cases of serious sight impairment in the UK. People with glaucoma, or at risk of developing glaucoma, require lifelong monitoring, including regular eye tests to track the progression of the disease. Currently, these examinations require regular hospital visits (e.g., twice yearly, for life) and require the use of expensive, specialist equipment. Aging populations make this hospital-only model of patient-management unsustainable, and many clinics are already overstretched, with appointments routinely delayed or cancelled. In the UK today, around 20 people a month are going blind as a result of this appointment backlog. This situation has been compounded by the COVID-19 pandemic, because the inability to sanitize equipment between use has led to all routine sight assessments being suspended in the UK. The long-term effects of this are unknown, but experts suggest that further increases in appointment delays and avoidable blindness appear inevitable. Even if routine assessments are ever fully resumed, it is also thought that the current system of annual hospital visits is insufficient to track the most aggressive forms of glaucoma. Multiple studies have already suggested that more frequent (e.g., monthly) glaucoma eye tests could substantially improve clinical outcomes: allowing high-risk patients to be treated sooner and more appropriately. A new study from City, University of London adds to a body of evidence suggesting that the solution to all these problems may lie in home-monitoring. The study was published online on August 31, 2020 in the American Journal of Ophthalmology.

Zebra Finches Can Rapidly Memorize Signature Sounds of at Least 50 Different Members of Their Flock

If songbirds could appear on "The Masked Singer" reality TV competition, zebra finches would likely steal the show. That's because they can rapidly memorize the signature sounds of at least 50 different members of their flock, according to new research from the University of California, Berkeley. In findings published in the November 13, 2020 issue of Science Advances, these boisterous, red-beaked songbirds, known as zebra finches, have been shown to pick one another out of a crowd (or flock) based on a particular peer's distinct song or contact call. The article is titled “High-Capacity Auditory Memory for Vocal Communication in a Social Songbird.” Like humans who can instantly tell which friend or relative is calling by the timbre of the person's voice, zebra finches have a near-human capacity for language mapping. Moreover, they can remember each other's unique vocalizations for months and perhaps longer, the findings suggest. "The amazing auditory memory of zebra finches shows that birds' brains are highly adapted for sophisticated social communication," said study lead author Frederic Theunissen, PhD, a UC Berkeley Professor of Psychology, Integrative Biology and Neuroscience.
Dr. Theunissen and fellow researchers sought to gauge the scope and magnitude of zebra finches' ability to identify their feathered peers based purely on their unique sounds. As a result, they found that the birds, which mate for life, performed even better than anticipated. "For animals, the ability to recognize the source and meaning of a cohort member's call requires complex mapping skills, and this is something zebra finches have clearly mastered," Dr. Theunissen said.

PROGERIA: First-Ever Treatment (Zokinvy) for Ultra-Rare, Rapid-Aging Disease Receives U.S. FDA Approval; “Monumental Event,” Foundation Leader States; Connections with Heart Disease & Aging May Result in Much Broader Insights Applicable to Millions

On November 20, 2020, the Progeria Research Foundation (PRF) announced a historic medical milestone with the U.S. Food and Drug Administration (FDA)’s approval (see link below) of Zokinvy™ (lonafarnib), for the treatment of Progeria and for processing-deficient Progeroid Laminopathies (PL). Progeria (https://en.wikipedia.org/wiki/Progeria) is an ultra-rare, fatal, pediatric, rapid-aging, autosomal dominant disease. The PRF, a pioneer in the rare disease research foundation space, has led Zokinvy clinical trial research since 2007. Zokinvy is a farnesyltransferase inhibitor (FTI) that has shown survival benefit in children with Progeria. Data based on information from the PRF International Patient Registry and clinical trials co-coordinated by the PRF and Boston Children’s Hospital demonstrated that in patients with Progeria, Zokinvy reduced the incidence of mortality by 60% (p=0.0064) and increased average survival time by 2.5 years. Without Zokinvy treatment, children with Progeria die of heart disease at an average age of 14.5 years. Eiger BioPharmaceuticals (Eiger) began supplying Zokinvy for the Progeria clinical trials in 2015, and entered into a pioneering partnership with the PRF in 2018 with the objective of leading Zokinvy through the FDA approval process. “Today, we have achieved one important piece of PRF’s mission—the first-ever approved treatment for these beautiful children,” said Audrey Gordon, President and Executive Director of The Progeria Research Foundation. “Progeria is now one of the few rare diseases with an FDA-approved treatment.

Researchers Create First Global Map of Bee Species Diversity (20,000+); New Work May Help in the Conservation of Bees As Global Pollinators

There are over 20,000 species of bee, but accurate data about how these species are spread across the globe are sparse. However, researchers reporting in the journal Current Biology on November 19, 2020 have created a map of bee diversity by combining the most complete global checklist of known bee species with the almost 6 million additional public records of where individual species have appeared around the world. The open-access article is titled “Global Patterns and Drivers of Bee Distribution.” The team's findings support that there are more species of bees in the Northern Hemisphere than the Southern and more in arid and temperate environments than in the tropics. "People think of bees as just honey bees, bumble bees, and maybe a few others, but there are more species of bees than of birds and mammals combined," says senior author John Ascher, PhD, an Assistant Professor of Biological Sciences at the National University of Singapore. "The United States has by far the most species of bees, but there are also vast areas of the African continent and the Middle East which have high levels of undiscovered diversity, more than in tropical areas." Many plants and animals follow a pattern, known as a latitudinal gradient, where diversity increases toward the tropics and decreases toward the poles. Bees are an exception to this rule, having more species concentrated away from the poles and fewer near the equator, a pattern known as a bimodal latitudinal gradient. There are far fewer bee species in forests and jungles than in arid desert environments because trees tend to provide fewer sources of food for bees than low-lying plants and flowers.

Researchers ID Potential Cellular Target for Eliminating Bone Breakdown in Osteoporosis

New research has discovered a cell type that governs the way bones form and maintain themselves, opening up a potential target for future therapies for bone disorders like osteoporosis. Led by faculty from the Perelman School of Medicine at the University of Pennsylvania, a rodent study showed that bone marrow adipogenic lineage precursors (MALPs) play a distinct role in the way bones remodel themselves. Defects in this process are the key issue at play in osteoporosis, so a therapy using these MALP cells to better regulate bone remodeling could result in better treatments. This research was published online on November 18, 2020 in the Journal of Clinical Investigation. The open-access article is titled “Bone Marrow Adipogenic Lineage Precursors (MALPs) Promote Osteoclastogenesis in Bone Remodeling and Pathologic Bone Loss.” "Discovering new cellular and molecular mechanisms to control bone turnover will enable fine-tuning of existing therapies or design of novel therapeutics," said the study's senior author, Ling Qin, PhD, an Associate Professor of Orthopaedic Surgery. "For example, with the advance of gene-editing technology and novel cell-specific delivery approaches, in the future it would be possible to regulate MALP behavior as a therapy for bone disorders like osteoporosis." Healthy bone maintenance is a balance between osteoblasts, which secrete the materials necessary to form new bone, and osteoclasts, which absorb old bone material to make way for the new. A disruption in this balance one way or the other can result in unhealthy bone. In the case of osteoporosis, overactive osteoclasts eat away at bone faster than it can be reformed, resulting in bones that are less dense and more susceptible to fracture.

Preliminary Evidence That Inhibitors of Thiol-Mediated Uptake May Block Entry of SARS-C0V-2 into Target Cells

The cell membrane is impermeable to viruses: to get inside and infect a cell, viruses use a range of strategies to exploit the cellular and biochemical properties of the membranes. The thiol-mediated uptake of organic molecules similar to alcohols, where oxygen is replaced by a sulphur atom, is one of the entry mechanisms, with its use by human immunodeficiency virus (HIV) demonstrated a few years ago. No effective inhibitor is currently available because of the robustness of the chemical reactions and bonds at work. A research group from the University of Geneva (UNIGE) has identified inhibitors that are up to 5,000 times more effective than the one most often used today. Preliminary tests--published online on November 18, 2020 in Chemical Science, the flagship journal of the Royal Society of Chemistry--demonstrate the blocking of the cellular entry of viruses expressing the SARS-CoV-2 proteins. The article is titled “Inhibitors of Thiol-Mediated Uptake.” The open-access study paves the way for research into new antivirals. Since 2011, the laboratory led by Professor Stefan Matile in UNIGE's Department of Organic Chemistry, member of the two National Centres of Competence in Research (NCCR) “Chemical Biology” and “Molecular Systems Engineering,” has been investigating the way thiols react with other structures containing sulfur: sulfides, molecules where sulfur is combined with another chemical element. “These are very special chemical reactions because they can change state dynamically,” begins Professor Matile. In fact, covalent bonds, based on sharing electrons between two atoms, freely oscillate between sulfur atoms, depending on conditions. Sulfur compounds are present in nature, particularly on the membrane of eukaryotic cells and on the envelope of viruses, on bacteria, and on toxins.

Study Finds Evidence That Hyperbaric Oxygen Treatments Can Halt/Reverse Aging Process—Telomeres Lengthened and Number of Senescent Cells Reduced

A new study from Tel Aviv University (TAU) and the Shamir Medical Center in Israel indicates that hyperbaric oxygen treatments (HBOT) in healthy aging adults can stop the aging of blood cells and reverse the aging process. In the biological sense, the adults' blood cells actually grow younger as the treatments progress. The researchers found that a unique protocol of treatments with high-pressure oxygen in a pressure chamber can reverse two major processes associated with aging and its illnesses: the shortening of telomeres (protective regions located at both ends of every chromosome) and the accumulation of old and malfunctioning cells in the body. Focusing on immune cells containing DNA obtained from the participants' blood, the study discovered a lengthening of up to 38% of the telomeres, as well as a decrease of up to 37% in the presence of senescent cells. The study was led by Professor Shai Efrati of the Sackler School of Medicine and the Sagol School of Neuroscience at TAU and Founder and Director of the Sagol Center of Hyperbaric Medicine at the Shamir Medical Center; and Dr. Amir Hadanny, Chief Medical Research Officer of the Sagol Center for Hyperbaric Medicine and Research at the Shamir Medical Center. The clinical trial was conducted as part of a comprehensive Israeli research program that targets aging as a reversible condition. The paper was published online in Aging on November 18, 2020. The open-access article is titled “Hyperbaric Oxygen Therapy Increases Telomere Length and Decreases Immunosenescence in Isolated Blood Cells : A Prospective Trial.” "For many years, our team has been engaged in hyperbaric research and therapy--treatments based on protocols of exposure to high-pressure oxygen at various concentrations inside a pressure chamber," Professor Efrati explains.

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