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Sloan Kettering Scientists May Have Solved 100-Year-Old Mystery About Cancer; Warburg Effect (Switch from Aerobic to Anaerobic Glycolysis) Linked with Activity of Powerhouse Enzyme PI3 Kinase

The year 2021 marks the 100th anniversary of a fundamental discovery that's taught in every biochemistry textbook. In 1921, German physician Otto Warburg observed that cancer cells harvest energy from glucose sugar in a strangely inefficient manner: rather than "burning" it using oxygen (aerobic glycolysis; cancer cells do what yeast do--they ferment it, in an oxygen-independent process (anaerobic glycolysis) that occurs quickly, but leaves much of the energy in glucose untapped. Various hypotheses to explain the “Warburg effect” have been proposed over the years, including the idea that cancer cells have defective mitochondria--their "energy factories"--and therefore cannot perform the controlled burning of glucose. But none of these explanations has withstood the test of time. (Cancer cells' mitochondria work just fine, for example.) Now, a research team at the Sloan Kettering Institute led by immunologist Ming Li, PhD, offers a new answer, based on a large set of genetic and biochemical experiments and published in the January 22, 2021 issue of Science. It comes down to a previously unappreciated link between Warburg metabolism and the activity of a powerhouse enzyme in the cell called PI3 kinase. The article is titled “Glycolysis Fuels Phosphoinositide 3-Kinase Signaling to Bolster T Cell Immunity.” "PI3 kinase is a key signaling molecule that functions almost like a commander-in-chief of cell metabolism," Dr. Li says. "Most of the energy-costly cellular events in cells, including cell division, occur only when PI3 kinase gives the cue." As cells shift to Warburg metabolism, the activity of PI3 kinase is increased, and, in turn, the cells' commitment to divide is strengthened. It's a bit like giving the commander-in-chief a megaphone.

Researchers Develop Mathematical Model to Explain Complex Architecture of Termite Mounds; "Termite Mounds Are Amongst the Greatest Examples of Animal Architecture on Our Planet"

Following a series of studies on termite mound physiology and morphogenesis over the past decade, researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences have now developed a mathematical model to help explain how termites construct their intricate mounds. The research is published in the February 2, 2021 issue of PNAS. The article is titled “Self-Organized Biotectonics of Termite Nests.” "Termite mounds are amongst the greatest examples of animal architecture on our planet," said Lakshminarayanan Mahadevan, PhD, the Lola England de Valpine Professor of Applied Mathematics, of Organismic and Evolutionary Biology, and of Physics at Harvard University, and lead author of the study. "What are they for? How do they work? How are they built? These are the questions that have puzzled many scientists for a long time." In previous research, Dr. Mahadevan and his team showed that day-to-night temperature variations drive convective flow in the mound that, not only ventilates the colony, but also move pheromone-like cues around, which trigger building behavior in termites. Here, the team zoomed in further to understand how termites build the intricately connected floors in individual mounds without a plan or a planner. With experimentalists from the University of Toulouse, France led by Guy Theraulaz, PhD, the researchers mapped the interior structures of two nests using CT scans, and quantified the spacing and arrangement of floors and ramps. Adding to the complexity of the nests is the fact that not only do termites build simple ramps to connect floors but they also build spiral ramps, like the ramps in parking garages, to connect multiple floors.

Developmental Origins of Eczema & Psoriasis Discovered; Results Provide Completely New Understanding of Inflammatory Diseases, Open Up New Avenues for Research on Other Inflammatory Diseases Such As Rheumatoid Arthritis & Inflammatory Bowel Disease

Scientists have created a highly detailed map of skin, which reveals that cellular processes from development are re-activated in cells from patients with inflammatory skin disease. The researchers from the Wellcome Sanger Institute, Newcastle University, and Kings College London, all in the UK, discovered that skin from eczema and psoriasis patients share many of the same molecular pathways as developing skin cells. This offers potential new drug targets for treating these painful skin diseases. Published in the January 22, 2021 issue of Science, the study also provides a completely new understanding of inflammatory disease, opening up new avenues for research on other inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. The Science article is titled “Developmental Cell Programs Are Co-Opted In Inflammatory Skin Disease.” Part of the global Human Cell Atlas effort (https://www.humancellatlas.org/) to map every cell type in the human body, the new comprehensive atlas of developing and adult skin is a valuable resource* for scientists worldwide. It could also provide a template for regenerative medicine, helping researchers grow skin in the laboratory more effectively. Our skin acts as a barrier, protecting us against invading bacteria or viruses, and is vital for health. Inflammatory skin diseases such as atopic eczema and psoriasis are chronic conditions, where the immune system becomes overactive, causing itchy or flaky skin that can be very painful and prone to infection. These conditions can have significant impact on people's lives, but the trigger is unknown and there is no cure, with treatments only helping to relieve the symptoms, not the cause. Skin is a complex tissue made up of many different types of cells.

COVID-19 Risk Reduced Up to 80% by Lilly's Neutralizing Monoclonal Antibody Bamlanivimab (LY-Cov555) at Nursing Homes in BLAZE-2 Phase 3 Trial

Bamlanivimab (LY-CoV555), monoclonal antibody, significantly reduced the risk of contracting symptomatic COVID-19 among residents and staff of long-term care facilities, Eli Lilly and Company (NYSE: LLY) announced in Januart 21, 2021. The Phase 3 BLAZE-2 COVID-19 prevention trial--conducted in partnership with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the COVID-19 Prevention Network (CoVPN)--enrolled residents and staff at skilled nursing and assisted living facilities, commonly referred to as nursing homes, across the U.S. The 965 participants who tested negative for the SARS-CoV-2 virus at baseline (299 residents and 666 staff) were included in the analysis of primary and key secondary endpoints for assessing prevention, while the 132 participants (41 residents and 91 staff) who tested positive for the virus at baseline were included in exploratory analyses for assessing treatment, adding to the growing body of evidence for treatment with bamlanivimab. All participants were randomized to receive either 4,200 mg of bamlanivimab or placebo. After all participants reached 8 weeks of follow-up, there was a significantly lower frequency of symptomatic COVID-19 (the primary endpoint) in the bamlanivimab treatment arm versus placebo (odds ratio 0.43, p=0.00021). Results for all key secondary endpoints also reached statistical significance in both the overall and resident populations. For the pre-specified subgroup of nursing home residents, there was also a significantly lower frequency of symptomatic COVID-19 in those treated with bamlanivimab versus placebo in this important population (odds ratio 0.20; p=0.00026).

Intoxicating Chemicals in Catnip and Silver Vine Protect Felines from Mosquito Bites; Results May Provide Clues to Mosquito Repellant for Humans

Rubbing against catnip and silver vine transfers plant chemicals that researchers have now shown protect cats from mosquitoes. The results also demonstrate that engaging with nepetalactol, which the study identified as the most potent of the many intoxicating iridoid compounds found in silver vine, activates the opioid reward system in both domesticated felines and big jungle cats. While nepetalactol had been previously identified, these studies directly illuminate its extremely potent effect on cats. And, by revealing the biological significance of well-known feline behaviors, this study opens the door to further inquiry into how nepetalactol's twin effects--pest repellence and intoxication--may have driven the evolution of these behaviors. Catnip and silver vine are known to hold a special place in felines' hearts. When cats encounter these plants, they rub their heads and faces against them and roll around on the ground, displaying undeniable enjoyment. Afterward, the cats lounge around in a state of intoxicated repose. But while pet owners around the world gift their cats toys laced with catnip or silver vine leaves, the biological significance of these plants and the neurophysiological mechanism triggered when cats sniff and rub against them has not been known. To investigate, Reiko Uenoyama (Department of Biological Chemistry and Food Sciences, Faculty of Agriculture, Iwate University, Japan) and colleagues in Japan and the UK, tested how 25 laboratory cats, 30 feral cats, and several captive big cats, including an Amur leopard, two jaguars, and two Eurasian lynx, responded to filter paper impregnated with nepetalactol, finding that the cats showed a more prolonged response than they did with untreated control filter papers. In contrast, dogs and laboratory mice showed no interest in the nepetalactol-containing papers.

New Treatment for Central Nervous System Tumors, Such As Glioblastoma, Enters Phase I Clinical Trials; Peptide Immune Checkpoint Ligand from OX2 Therapeutics Is First-of-Its Kind Cancer Treatment

On January 12, 2021, OX2 Therapeutics, Inc. (https://ox2therapeutics.com/), a privately held Minneapolis company, announced that it had treated its first patient in a phase one human trial of a new treatment developed to combat recurrent high-grade brain tumors. “This is a first-of-its kind immunotherapy that works to treat one of the most aggressive and deadly cancers today,” said Christopher Moertel, MD, OX2 Therapeutics, Inc. “Central nervous system cancers are the number one cause of cancer-related mortality in children, and a major cause of morbidity and mortality in adults.” OX2 Therapeutics developed the first immune checkpoint peptide platform targeting the immune system to attack solid tumors. Focusing on high-grade gliomas, OX2 Therapeutics has been treating dogs diagnosed with spontaneous high-grade glioma in a canine clinical trial at the University of Minnesota, Veterinary Hospital. “This is the first therapy Dr. Olin and I have used to significantly extend the life of dogs with high-grade gliomas with no adverse events,” said G. Elisabeth Pluhar, DVM, PhD, Director of the University of Minnesota College of Veterinary Medicine’s Canine Brain Tumor Program (https://vetmed.umn.edu/centers-programs/clinical-investigation-center/cu...). The OX2 peptide, known as CD200AR-L, is a single peptide that has the potential to replace the toxic antibody therapies that are currently used to block immune checkpoints,” stated Michael Olin (photo), PhD, OX2 Therapeutics, Inc.

First High-Resolution, Quantitative Tracking of Bacterial Membrane Vesicles (MVs) in Response to Antibiotic Treatment; Results “Will Undoubtedly Open a New Avenue of Research on This Fascinating and Currently Hot Topic"

Once regarded as merely cast-off waste products of cellular life, bacterial membrane vesicles (MVs) have since become an exciting new avenue of research, due to the wealth of biological information they carry to other bacteria, as well as other cell types. These tiny particles, produced by most bacteria, can bud off from outer cellular membranes, traveling along cell surfaces and occasionally migrating into intercellular spaces. Luis Cisneros (https://biodesign.asu.edu/luis-cisneros), PhD, is a researcher in the Biodesign Center for Biocomputing, Security and Society (https://newsroom.asu.edu/college-unit/biodesign-center-biocomputing-secu...), and the BEYOND Center for Fundamental Concepts in Science (https://science.asu.edu/beyond-center-fundamental-concepts-science), both at Arizona State University (ASU). In a new study, Dr. Cisneros and his colleagues describe the effects of antibiotics on MVs, demonstrating that such drugs actively modify the properties of vesicle transport. Under the influence of antibiotics, MVs were produced and released by bacteria in greater abundance and traveled faster and farther from their origin. The researchers suggest that the altered behaviors of MVs may represent a stress response to the presence of antibiotics and, further, that MVs liberated from the cell membrane may transmit urgent warning signals to neighboring cells and perhaps foster antibiotic resistance. "It's long been believed that membrane vesicles are involved in the cell-cell signaling process leading to changes in the collective behavior of living cells, like the coordination of survival responses due to antibiotic stress," Dr. Cisneros says. "But many details in the dynamics of this process are not yet well understood.

Butterfly Wing Clap Explains Mystery of Their Fluttery, Apparently Inefficient Flight; Expelled Air from Pocket Between Cupped Wings Acts Like Expelled Air from Jet Engine, Enabling Highly Efficient Flight

The fluttery flight of butterflies has so far been something of a mystery to researchers, given their unusually large and broad wings relative to their body size. Now researchers at Lund University in Sweden have studied the aerodynamics of butterflies in a wind tunnel. The results suggest that butterflies use a highly effective clap technique, therefore making use of their unique wings. This helps them rapidly take off when escaping predators. The study explains the benefits of both the wing shape and the flexibility of their wings. The Lund researchers studied the wingbeats of freely flying butterflies during take-off in a wind tunnel. During the upward stroke, the wings cup, creating an air-filled pocket between them. When the wings then collide, the air is forced out, resulting in a backward jet that propels the butterflies forward. The downward wingbeat has another function: the butterflies stay in the air and do not fall to the ground. The wings colliding was described by researchers almost 50 years ago, but it is only in this new study that the theory has been tested on real butterflies in free flight. Until now, the common perception has been that butterfly wings are aerodynamically inefficient, however, the researchers suggest that the opposite is actually true. The new study was published online on January 20, 2021 in the Journal of the Royal Society. The open access article is titled “Butterflies Fly Using Efficient Propulsive Clap Mechanism Owing to Flexible Wings.” (Links to videos are provided below.) “That the wings are cupped when butterflies clap them together, makes the wing stroke much more effective. It is an elegant mechanism that is far more advanced than we imagined, and it is fascinating.

Intense Immunosuppression Followed by Hematopoietic Stem Cell Transplant May Provide Long-Term Benefit for People with Multiple Sclerosis

A new study shows that intense immunosuppression followed by a hematopoietic stem cell transplant may prevent disability associated with multiple sclerosis (MS) from getting worse in 71% of people with relapsing-remitting MS for up to 10 years after the treatment. The research was published online on January 20, 2021 in Neurology, the medical journal of the American Academy of Neurology. The article is titled “Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis.” The study also found that in some people their disability improved over 10 years after treatment. Additionally, more than half of the people with the secondary progressive form of MS experienced no worsening of their symptoms 10 years after a transplant. While most people with MS are first diagnosed with relapsing-remitting MS, marked by symptom flare-ups followed by periods of remission, many people with relapsing-remitting MS eventually transition to secondary progressive MS, which does not have wide swings in symptoms, but instead, a slow, steady worsening of the disease. The study involved autologous hematopoietic stem cell transplants, which use healthy blood stem cells from the participant's own body to replace diseased cells. "So far, conventional treatments have prevented people with MS from experiencing more attacks and worsening symptoms, but not in the long term," said study author Matilde Inglese (photo), MD, PhD, of the University of Genoa in Italy and a member of the American Academy of Neurology. "Previous research shows more than half of the people with MS who take medication for their disease still get worse over a 10-year period.

Exosomes & EVs in Infectious Diseases--Virtual Conference Jan 25-28; Registration Ends Jan 25

The International Society for Extracellular Vesicles (ISEV) "Infectious Diseases and Extracellular Vesicles" Virtual Meeting will take place from Monday, January 25 to Thursday, January 28, 2021 starting at 11:00 am Eastern Standard Time each day. The meeting will feature invited talks, selected abstract talks, live Q&A, and panel discussions. In lieu of a second showing, a recorded version of the broadcast will be sent via a private YouTube link each day to the attendees to watch, if you are unable to watch for the 11:00 am broadcast. You may view the complete program at this link (https://cdn.ymaws.com/www.isev.org/resource/resmgr/id_meeting_sponsor_lo...). Registration closes January 25, so please register quickly if you wish to attend. If you are an ISEV member and would like to take advantage of the member rate, be sure that you are logged in as an ISEV member. You can register by clicking here (https://www.isev.org/event/isevidmeeting?utm_source=ISEV&utm_medium=Emai...). Additional registration and program information can be found here (https://www.isev.org/event/isevidmeeting).

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