Syndicate content

Archive

December 9th, 2020

Subcompartments Discovered in Peroxisomes; Finding “Requires Us to Rethink Everything We Thought We Knew About Peroxisomes,” Lab Leader Says

In his first year of graduate school, Rice University biochemist Zachary Wright discovered something hidden inside a common piece of cellular machinery that's essential for all higher order life from yeast to humans. What Wright saw in 2015 --subcompartments inside organelles called peroxisomes is described in a study published online on December 4, 2020 in Nature Communications. The open-access article is titled “Peroxisomes Form Intralumenal Vesicles with Roles in Fatty Acid Catabolism and Protein Compartmentalization in Arabidopsis” (https://www.nature.com/articles/s41467-020-20099-y). "This is, without a doubt, the most unexpected thing our lab has ever discovered," said study co-author Bonnie Bartel, PhD, Wright's PhD advisor and a member of the National Academy of Sciences. "This requires us to rethink everything we thought we knew about peroxisomes." Dr.Bartel is the Ralph and Dorothy Looney Professor of BioSciences at Rice. Peroxisomes (https://en.wikipedia.org/wiki/Peroxisome)--are compartments where cells turn fatty molecules into energy and useful materials, like the myelin sheaths that protect nerve cells. In humans, peroxisome dysfunction has been linked to severe metabolic disorders, and peroxisomes may have wider significance for neurodegeneration, obesity, cancer, and age-related disorders. Much is still unknown about peroxisomes, but their basic structure--a granular matrix surrounded by a sack-like membrane--wasn't in question in 2015. Dr. Bartel said that's one reason Wright's discovery was surprising. "We're geneticists, so we're used to unexpected things. But usually they don't come in Technicolor," she said, referring to another surprising aspect of Wright's find: beautiful color images that show both the walls of the peroxisome subcompartments and their interiors.

December 9th

Neuropeptide Discoveries in Cockroach Could Be Targets for Someday Defeating Dreaded Pest

Cockroaches are notorious for their abilities to survive and reproduce, much to humanity's chagrin. In addition to scurrying around at night, feeding on human and pet food, and generating an offensive odor, the pests can transmit pathogens and cause allergic reactions. Now, in an article published online on November 9, 2020 in the American Chemical Society’s Journal of Proteome Research, scientists have reported identifying 36 neuropeptides produced by the American cockroach (Periplaneta americana) that could someday be targeted by new, more selective and effective pesticides. The article is titled “Genomics- and Peptidomics-Based Discovery of Conserved and Novel Neuropeptides in the American Cockroach.” Neuropeptides are small proteins produced by neurons or endocrine cells that send messages to other cells. In insects, neuropeptides often act as neurotransmitters, hormones, or growth factors, influencing an organism's development, growth, metabolism, behavior, and reproduction. Therefore, disrupting these processes by targeting neuropeptides or their receptors is a potential new approach to pest control. Recently, Na Li, PhD, of the Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Institute of Insect Science and Technology, School of Life Sciences, South China Normal University, Guangzhou, China, and colleagues determined the genome sequence of P. americana. In the current work, they wanted to use this sequence, combined with peptide analysis, to characterize the neuropeptides of the American cockroach and study how their expression varies by tissue, developmental stage, and sex.

Non-Hallucinogenic Analog of Psychedelic Ibogaine May Have Potential to Treat Addiction, Depression, Other Psychiatric Disorders

A non-hallucinogenic version of the psychedelic drug ibogaine, with potential for treating addiction, depression, and other psychiatric disorders, has been developed by researchers at the University of California (UC), Davis, and colleagues. A paper describing the work was published online on December 9, 2020 in Nature. The article is titled “A Non-Hallucinogenic Psychedelic Analogue with Therapeutic Potential.” "Psychedelics are some of the most powerful drugs we know of that affect the brain," said David Olson, PhD, Assistant Professor of Chemistry at UC Davis and senior author on the paper. "It's unbelievable how little we know about them." Ibogaine is extracted from the plant Tabernanthe iboga (image). There are anecdotal reports that it can have powerful anti-addiction effects such as reducing drug cravings and preventing relapse. But there are also serious side-effects, including hallucinations and cardiac toxicity, and the drug is a Schedule 1 controlled substance under U.S. law. Dr. Olson's laboratory at UC Davis is one of a few in the U.S. licensed to work with Schedule 1 substances. His group set out to create a synthetic analog of ibogaine which retained therapeutic properties without the undesired effects of the psychedelic compound. Dr. Olson's team worked through a series of similar compounds by swapping out parts of the ibogaine molecule. They engineered a new, synthetic molecule which they named tabernanthalog or TBG. Unlike ibogaine, the new molecule is water-soluble and can be synthesized in a single step. Experiments with cell cultures and zebrafish show that it is less toxic than ibogaine, which can cause heart attacks and has been responsible for several deaths.

Targeting T Cell Protein (OCA-B) Might Prevent Type 1 Diabetes, Study Suggests

Researchers at the University of Utah School of Medicine have identified a potential new therapeutic target for the treatment of patients with type 1 diabetes. The study, which was published December 9, 2020 in the Journal of Experimental Medicine (JEM), reveals that inhibiting a protein called OCA-B protects mice from type 1 diabetes by limiting the activity of immune cells that would otherwise destroy the pancreas' insulin-producing β cells (https://rupress.org/jem/article/218/3/e20200533/211581/Targeting-transcr...). The open-access article is titled “Targeting Transcriptional Coregulator OCA-B/Pou2af1 Blocks Activated Autoreactive T Cells in the Pancreas and Type 1 Diabetes.” Type 1 diabetes is an autoimmune disease in which the body's immune system mistakenly attacks pancreatic β cells, cutting off the production of insulin. Patients require life-long insulin therapy to maintain appropriate blood glucose levels. At present, there are no treatments that can prevent the immune system from targeting β cells while preserving its ability to fight infection. White blood cells called T cells can recognize specific molecules produced by invading bacteria and viruses. When T cells encounter these molecules, known as antigens, they turn on hundreds of genes that allow them to fight the infection. A protein called OCA-B binds to many of these genes and helps ensure that they can easily be reactivated if the T cells reencounter the same antigens at a later date. In many autoimmune diseases, T cells mistakenly recognize and respond to antigens produced by normal, healthy cells.

December 8th

Hopkins Scientists Develop Potential Antibiotic for Deadly Drug-Resistant Pathogen (M. abscessus) Related to Tuberculosis Pathogen; M. abscessus Often Lethal in Cystic Fibrosis & Other Lung Ailments

Scientists from Johns Hopkins University and Medicine have developed a possible new antibiotic for a pathogen that is notoriously resistant to medications and frequently lethal for people with cystic fibrosis and other lung ailments. The pathogen, called Mycobacterium abscessus, is related to a better-known bacterium that causes tuberculosis and leprosy, but has recently emerged as a distinct species presenting most often as a virulent lung infection. The team of scientists from the Hopkins Krieger School of Arts & Sciences' Department of Chemistry and the School of Medicine's infectious diseases department published its findings online on December 7, 2020 in Communications Biology. The open-access article is titled “Development of a Penem Antibiotic Against Mycobacteroides abscessus.” The team has developed one of the first potential treatments of a bacterium that has no FDA-approved treatments and a cure rate less than 50%. Before the new antibiotic, called T405, can move closer to becoming a clinical treatment, researchers need to improve its pharmacological potency using a preclinical animal model of the infection. "People die of this in our hospitals every week," said Craig Townsend, PhD, a Professor of Chemistry, who served as a principal investigator on the study, along with Gyanu Lamichhane, PhD, an Associate Professor of Medicine. "The data we have is very promising." Despite years of urgent calls for more studies to understand M. abscessus bacteria and to explore possible treatments, researchers have been wary of experimenting with the most dangerous member of its Non-Tuberculosis Mycobacteria (NTM) family. "It's still considered an emerging disease," Dr. Lamichhane said. "There are now more NTM than tuberculosis cases in the United States.

December 4th

Europe’s EVerZom Raises $1.4 Million to Industrialize Its Exosome Biomanufacturing Platform; Paris Company’s Ambition Is to Transform Regenerative Medicine and Biotherapeutics Using These “Super” Biological Nanoparticles

On December 1, 2020, EVerZom (http://www.everzom.com), a biopharmaceutical company specialized in the bioproduction of exosomes and headquartered in Paris, France, announced that it has raised €1.1 million (~$1.48 million) in funding from institutional and private investors to develop its exosome bioproduction platform. This funding will speed up the platform development and scale-up, with the objective to allow routine clinical grade production by 2022. Exosomes are biological nanoparticles released by cells as an intercellular communication system to transport biomolecules. Exosomes have the ability to deliver therapeutics or regenerate tissue in several pathologies, including osteoarthritis, heart failure, and liver and kidney diseases, conditions which impact more than 150 million patients worldwide. Exosomes are now considered one of the safest and most promising future regenerative therapy solutions. They are also easy to store and have a low immunogenic profile, thus reinforcing their potential. Increasingly, academic and industrial players are working on the therapeutic potential of exosomes. The main obstacle to the translation of exosomes into clinical development is industrial manufacturing, while maintaining robust quality and reproducibility. EVerZom's proprietary innovation consists in applying turbulence stimulation on cells to trigger massive exosome release. This approach enables the production of ten times more exosomes ten times more rapidly than classical methods. The technology is being developed and already implemented in GMP-certified systems, simplifying the clinical transfer. This technology and the know-how developed around exosomes allows EVerZom to offer a scalable and reproducible exosome production process with robust quality controls.

November 28th

Early Detection of Over 50 Cancers Via One-Draw Blood Test--GRAIL and UK Government Partner to Make Revolutionary GRAIL “Galleri” Test Available to Patients; Potential to Reduce UK Cancer Deaths by 20%; Planned Commercially Availability in USA in 2021

On November 26, 2020, GRAIL, Inc. (https://grail.com/), a California-based healthcare company whose mission is to detect cancer early, when it has a much greater likelihood of being be cured, announced a partnership with the United Kingdom’s (UK) National Health Service (NHS) to help transform cancer outcomes by making GRAIL’s multi-cancer early detection blood test, Galleri™ (https://grail.com/galleri/), available to UK patients starting in 2021. The commercial partnership program aims to confirm Galleri’s clinical and economic performance in the NHS system as a precursor to its routine use by the NHS. The partnership program will involve approximately 165,000 people in the UK and includes two groups. The first will include 140,000 people over the age of 50 without any suspicion of cancer, and the second will include 25,000 people aged 40 and above with suspicious signs or symptoms of cancer. Based on data from this program, access to the test could be expanded to approximately one million people across 2024 and 2025 and may be rolled out to a larger population thereafter. In a clinical validation study in the U.S., an earlier version of Galleri detected over 50 types of cancer with a low false-positive rate of less than 1% through a single blood draw. Modeling data show that adding Galleri to existing standard of care has the potential to decrease the number of cancers diagnosed at late stage by nearly half, which could reduce the total number of cancer deaths in the UK by approximately one-fifth. “Every year, nearly 200,000 people in the UK die from cancer. Many of these people are diagnosed too late for treatment to be effective,” said Lord David Prior, Chair of NHS England.

November 24th

Hormone (Lipocalin-1) Found to Switch Off Hunger; Potential to Help Treat Body Weight Problems

A hormone that can suppress food intake and increase the feeling of fullness in mice has shown similar results in humans and non-human primates, says a new study published online on November 24, 2020 in eLife. The article Is titled “'Lipocalin-2 Is an Anorexigenic Signal in Primates.” The hormone, called lipocalin-2 (LCN2)(image), could be used as a potential treatment in people with obesity whose natural signals for feeling full no longer work. LCN2 is mainly produced by bone cells and is found naturally in mice and humans. Studies in mice have shown that giving LCN2 to the animals long term reduces their food intake and prevents weight gain, without leading to a slow-down in their metabolism. "LCN2 acts as a signal for satiety after a meal, leading mice to limit their food intake, and it does this by acting on the hypothalamus within the brain," explains lead author Peristera-Ioanna Petropoulou, PhD, who was a Postdoctoral Research Scientist at Columbia University Irving Medical Center, New York, USA, at the time the study was carried out, and is now at the Helmholtz Diabetes Center, Helmholtz Zentrum München, Munich, Germany. "We wanted to see whether LCN2 has similar effects in humans, and whether a dose of it would be able to cross the blood-brain barrier." The team first analyzed data from four different studies of people in the USA and Europe who were either normal weight, overweight, or living with obesity. The people in each study were given a meal after an overnight fast, and the amount of LCN2 in their blood before and after the meal was studied. The researchers found that in those who were of normal weight, there was an increase in LCN2 levels after the meal, which coincided with how satisfied they felt after eating.

AstraZeneca/Oxford Vaccine for COVID-19 Achieves Interim Efficacies of 90% and 62% in Trials of Two Different Dose Regimens; Up to 3 Billion Doses Planned for 2021

Positive high-level results from an interim analysis of clinical trials of the COVID-19 vaccine AZD1222, manufactured by AstraZeneca and co-invented by the University of Oxford and its spin-out company Vaccitech, tested in the UK and Brazil, showed the vaccine was highly effective in preventing COVID-19, the primary endpoint, and no hospitalizations or severe cases of the disease were reported in participants receiving the vaccine. The announcement was made on November 23, 2020. There were a total of 131 COVID-19 cases in the interim analysis. AZD1222 uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein. After vaccination, the surface spike protein is produced, priming the immune system to attack the SARS-CoV-2 virus if it later infects the body. In the interim results, one dosing regimen (n=2,741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8,895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001). More data will continue to accumulate and additional analysis will be conducted, refining the efficacy reading and establishing the duration of protection. An independent Data Safety Monitoring Board (DSMB) determined that the analysis met its primary endpoint showing protection from COVID-19 occurring 14 days or more after receiving two doses of the vaccine. No serious safety events related to the vaccine have been confirmed. AZD1222 was well tolerated across both dosing regimens.

November 23rd

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.