Syndicate content

Modulating Rapamycin Target Protein FKBP51 with Small Molecule SAFit2 Promotes Autophagy, Lowering Toxic Huntingtin Protein

Researchers world-wide are focused on clearing the toxic mutant Huntingtin protein that leads to neuronal cell death and systemic dysfunction in Huntington's disease (HD), a devastating, incurable, progressive neurodegenerative genetic disorder. Scientists in the lab of Buck Institute Professor Linda Ellerby (https://www.buckinstitute.org/lab/ellerby-lab/), PhD, lab have found that the targeting the protein called FK506-binding protein 51 (FKBP51) promotes the clearing of those toxic proteins via autophagy, a natural process whereby cells recycle damaged proteins and mitochondria and use them for nutrition. In an article published online on May 24, 2021 in Autophagy (https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1904489), researchers showed that FKBP51 promotes autophagy through a new mechanism that could avoid worrisome side effects associated with rapamycin, an immune-suppressing drug which also extends lifespan in mice. They show that both rapamycin and the small pharmacological inhibitor of FKBP51, SAFit2, protect HD neurons but that the mechanisms of the two drugs are distinct. The open-access Autophagy article is titled “Modulating FKBP5/FKBP51 and Autophagy Lowers HTT (Huntingtin) Levels.” Researchers focused on a family of binding proteins called FKBP's and specifically on FKBP51, which was most changed in mouse and human stem cell models of HD. During the course of the study, scientists found that FKBP51 acts on a pathway independent of mTOR (mammalian target of rapamycin), which is associated with rapamycin. Scientists also identified a small molecule, SAFit2, which crossed the blood-brain barrier and promoted autophagy and reduced the toxic disease-causing protein HTT through that mTOR-independent pathway.

Global Study of Microbes in 60 Cities Finds Each City Has Signature Microbial Fingerprint; “If You Gave Me Your Shoe, I Could Tell You with About 90% Accuracy the City in the World from Which You Came," Senior Author Says

An international consortium has reported the largest-ever global metagenomic study of urban microbiomes, spanning both the air and the surfaces of multiple cities. The international project, which sequenced and analyzed samples collected from public transit systems and hospitals in 60 cities around the world, features comprehensive analysis and annotation for all the microbial species identified--including thousands of viruses and bacteria and two archaea not found in reference databases. The study was published online on May 26, 2021 in Cell. The open-access article is titled “A Global Metagenomic Map of Urban Microbiomes and Antimicrobial Resistance.” "Every city has its own 'molecular echo' of the microbes that define it," says senior author Christopher Mason (@mason_lab), Associate Professor at Weill Cornell Medicine (WCM) and Director of the WorldQuant Initiative for Quantitative Prediction. "If you gave me your shoe, I could tell you with about 90% accuracy the city in the world from which you came." The findings are based on 4,728 samples from cities on six continents taken over the course of three years, characterize regional antimicrobial resistance markers, and represent the first systematic worldwide catalogue of the urban microbial ecosystem. In addition to distinct microbial signatures in various cities, the analysis revealed a core set of 31 species that were found in 97% of samples across the sampled urban areas. The researchers identified 4,246 known species of urban microorganisms, but they also found that any subsequent sampling will still likely continue to find species that have never been seen before, which highlights the raw potential for discoveries related to microbial diversity and biological functions awaiting in urban environments.

Neuroscientists Have Identified Mechanism Behind Antidepressant Effect of Lactate, a Molecule Produced During Exercise; Key Features Are NADH and Neurogenesis, Which May Be Clues to Treatment Improvements

Depression is the leading cause of disability worldwide. Neuroscientists from Synapsy--the Swiss National Centre of Competence in Research into Mental Illness--based at Lausanne University Hospital (CHUV) and Lausanne University (UNIL) in Swizerland have recently demonstrated that lactate, a molecule produced by the body during exercise, has an antidepressant effect in mice. Lactate is best known for the pivotal role it plays in the nutrition of neurons inside the brain. Yet it can also counter the inhibition of the survival and proliferation of new neurons, a loss seen in patients suffering from depression and in stressed animal. Furthermore, the research team pinpointed NADH as a vital component in the mechanism: this is a molecule with antioxidant properties that is derived from the metabolism of lactate. The findings, published online on May 14, 2021 in Molecular Psychiatry, provide a better understanding of the physiological mechanisms that underpin physical activity, which should lead to an improvement in the way depression is treated in the future. The open-access article is titled “Role of Adult Hippocampal Neurogenesis in the Antidepressant Actions of Lactate.” The WHO recognizes depression--which affects nearly 264 million people--as the leading cause of disability worldwide. Treatments based on antidepressants and psychotherapy are available to help people suffering from the disorder.

Chemical Secret to Stunning Success of Pfizer & Moderna mRNA Vaccines; Decades of Painstaking, Slowly Progressing Research Underlie “Warp-Speed” Development of Miracle Vaccines for COVID-19

Dr. Gerald Zon’s latest “Zone in with Zon” blog post, dated May 25, 2021, and published by TriLink BioTechnologies of San Diego (https://www.trilinkbiotech.com), discusses the key component for the Pfizer-BioNTech and Moderna mRNA vaccines, namely the chemically modified mRNA (modRNA) synthesized by in vitro transcription (IVT) reactions, wherein one of the natural (aka wild-type) A, G, C, and U nucleotide 5’-triphosphates is replaced by a base-modified analog. Dr. Zon notes that interest in chemically modified mRNA (modRNA) (https://onlinelibrary.wiley.com/doi/10.1002/jmv.26924) can be traced back to a 2005 report by Karikó et al. (https://pubmed.ncbi.nlm.nih.gov/16111635/) demonstrating that modRNAs comprised of 5-methycytidine (5mC), N6-methyladenosine (m6A), pseudouridine (Ψ), 5-methyluridine (m5U), and 2-thiouridine (s2U), either separately or in combination, can reduce immunogenicity mediated by toll-like receptors (TLRs). Dr. Zon notes that “subsequently, it was shown that Ψ modification, in particular, could increase the translational capacity and biological stability of mRNA (Karikó et al. 2008) (https://pubmed.ncbi.nlm.nih.gov/18797453/). Along the lines of the familiar saying ‘good, better, best…,’ later studies by others (Andries et al. 2015) (https://pubmed.ncbi.nlm.nih.gov/26342664/) found that simply adding a methyl group to the N1 position in Ψ (N1-methylpseudouridine, N1mΨ) in modRNA via IVT with the corresponding 5’-triphosphate produced N1mΨ-mRNA that outperformed Ψ-mRNA.

Stunning Success Reported in Partially Restoring Sight in Blind Patient Using Optogenetics Gene Therapy; Recovery “Breathtaking to Witness,” Says Senior Author

On May 25, 2021, GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible) (https://www.gensight-biologics.com/), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced that the highly-regarded journal Nature Medicine has published the first case report of partial recovery of visual function in a blind patient with late-stage retinitis pigmentosa (RP). The subject is a participant in the ongoing PIONEER Phase I/II clinical trial of GenSight Biologics’ GS030 optogenetic therapy. Published online on May 24, 2021, under the title “Partial Recovery of Visual Function in a Blind Patient After Optogenetic Therapy,” the open-access paper is the first peer-reviewed documentation of visual recovery after a blind patient was treated with optogenetic therapy. “These are truly groundbreaking findings that move the promise of optogenetics (https://en.wikipedia.org/wiki/Optogenetics) another step from therapeutic concept to clinical use,” commented Bernard Gilly, PhD, Co-Founder and Chief Executive Officer of GenSight. “These could not have occurred without the close collaboration we enjoyed with our partners at the Institut de la Vision, the Institute of Ophthalmology Basel, and Streetlab. We are especially grateful to the patients who are participating in our trial, whose experiences and input will help us design the next stage of GS030’s clinical development. We will now accelerate the GS030 program to make it our second product to reach the market after LUMEVOQ.” Optogenetic therapies combine cellular expression of light-sensitive opsins with light stimulation using a medical device.

Experimental Broadcast of Whitewater River Noise Drives Most Bats and Birds Away; Intense Noise Reduces Bird Foraging Activity and Causes Bats to Switch Hunting Strategies

While many might consider a walk in the woods to be a quiet, peaceful escape from their noisy urban life, we often don't consider just how incredibly noisy some natural environments can be. Although we use soothing natural sounds in our daily lives--to relax or for meditation--the thunder of a mountain river or the crash of pounding surf have likely been changing how animals communicate and where they live for eons. A new experimental study published in the journal Nature Communications finds that birds and bats often avoid habitat swamped with loud whitewater river noise. The open-access article is titled “Phantom Rivers Filter Birds and Bats By Acoustic Niche.” Dr. Dylan Gomes, a recent PhD graduate of Boise State University and first author on the paper, summarizes the aims of the work this way, "naturally-loud environments have been largely neglected in ecological research. We aimed to test the hypothesis that intense natural noise can shape animal distributions and behavior by experimentally broadcasting whitewater river noise at a massive scale." In fact, the scientists had to transport literal tons of gear across roadless terrain to place solar-powered speaker arrays in half of their 60 locations in the Pioneer Mountains of Idaho where they monitored bird and bat populations for two summers. The speaker arrays were arranged along riparian areas (i.e., near rivers or streams), filling each bubbling brook with the auditory experience of a rushing whitewater river. The team took advantage of their experimental approach to broadcast both realistic reproductions of river noise, as well as river noise that had been shifted upwards in frequency to understand how the noise caused changes in animal numbers.

New Data Offers Potential Biomarkers for Characterizing Dengue Virus Infection & Novel Pathways That Could Be Leveraged to Combat Viral Replication; Over 400 Million Dengue Cases Worldwide in 2019; Work Also Provides Clues to Boosting Immune Response

There have been more than 130 million cases of SARS-CoV-2 infections to date worldwide, yet another global pathogen--the Aedes mosquito-borne dengue virus--saw a record number of over 400 million cases in 2019. But vaccine development has been challenging due to the need to protect equally against all four dengue strains. The discovery of new possible biomarkers to predict clinical and immune responses to dengue virus infection, published on May 24, 2021 in Nature Communications, could be critical to informing future vaccines. The open-access article is titled “Immunotranscriptomic Profiling the Acute and Clearance Phases of a Human Challenge Dengue Virus Serotype 2 Infection Model.” As with SARS-CoV-2 infection, the effects of dengue virus infection can range from asymptomatic to severe disease that can be fatal. Climate change has expanded the viruses' geographic distribution far beyond tropical areas like Southeast Asia and Latin America to the southern U.S. and Europe. Only one vaccine, Dengvaxia, has been approved for a subset of at-risk individuals in endemic areas. The current study, led by University of Vermont (UVM) Associate Professor of Microbiology and Molecular Genetics (MMG) Sean Diehl, PhD, set out to determine biomarker candidates and predictors for clinical and immunological responses resulting from serotype 2 dengue infection. Previous research published by Dr. Diehl and MMG Chair Beth Kirkpatrick, MD, Director of the UVM Vaccine Testing Center, has shown how a dengue vaccine being developed together with Johns Hopkins and the National Institutes of Health activates an immune response that protects against challenge with this dengue virus. Live, weakened viruses are the basis for the most-effective and longest-lasting vaccines against many viral diseases.

Trinity’s Pharmacology Chair Lorraine O’Driscoll Awarded Ireland’s Highest Academic Honor—Prominent Medical Scientist Inducted into Royal Irish Academy

Professor Lorraine O’Driscoll (nee McElroy) (photo), Chair of Pharmacology and Biomedicine at Trinity College Dublin, from Annamartin, Smithborough, Ireland was inducted into the Royal Irish Academy, Ireland’s leading body of experts in the sciences and humanities, on Friday, May 21, 2021. Membership is by election and is considered to be the highest academic honor in Ireland. The Royal Irish Academy has been honoring Ireland’s leading contributors to the world of learning since its establishment in 1785. Admittance to the Academy is a prestigious honor, and those elected are entitled to use the designation “MRIA” after their name, for Member of the Royal Irish Academy. For 235 years, new members of the Royal Irish Academy were admitted with a handshake, but this year Dr. Mary Canning, President of the Academy, greeted this group of exceptional individuals who are internationally renowned in their respective fields with no handshakes but much joy, Dr. O’Driscoll was the only female of the ten scientists recently elected to membership of the RIA. Among the others elected in 2021 are Professor John Crown, Consultant Medical Oncologist, St. Vincent’s University Hospital; Professor Noel McElvaney, Professor of Medicine at the Royal College of Surgeons; and Professor Philip Nolan, President of Maynooth University and Chair of Ireland’s National Public Health Emergency Team (NPHET). Lorraine, daughter of Bridget and Francie McElroy, Annaghmartin, Smithboro, grew up on a small farm near Smithborough and has gone on to be a scientist and academic of international standing. The family lived at Drummons, Scotstown till Lorraine was aged six and then the family moved to Annamartin and Lorraine completed her primary education at Magherarney NS, followed by St. Louis Secondary School, Monaghan.

GSDMB Protein Kills Bacteria by Creating Holes in Bacterial Membrane; Shigella Survives by Tagging GSDMB Protein for Destruction; Results May Shed Light on Other Conditions, Including Asthma, Type 1 Diabetes, and Crohn’s Disease

One member of a large protein family that is known to stop the spread of bacterial infections by prompting infected human cells to self-destruct appears to kill the infectious bacteria instead, a new study led by University of Texas Southwestern (UTSW) scientists shows. However, some bacteria have their own mechanism to thwart this attack, nullifying the deadly protein by tagging it for destruction. The findings, published online on May 21, 2021 in Cell, could lead to new antibiotics to fight bacterial infections. And insight into this cellular conflict could shed light on a number of other conditions in which this protein is involved, including asthma, Type 1 diabetes, primary biliary cirrhosis, and Crohn’s disease. The Cell article is titled “Pathogenic Ubiquitination of GSDMB Inhibits NK Cell Bactericidal Functions.” “This is a wonderful example of an arms race between infectious bacteria and human cells,” says study leader Neal M. Alto (https://profiles.utsouthwestern.edu/profile/96781/neal-alto.html), PhD, Professor of Microbiology at UTSW and a member of the Harold C. Simmons Comprehensive Cancer Center. Previous research has shown that the protein, called gasdermin B (GSDMB), was different from other members of the mammalian gasdermin family. Related gasdermin proteins form pores in the membranes of infected cells, killing them while allowing inflammatory molecules to leak out and incite an immune response. However, GSDMB--found in humans, but not in some other mammalian species, including rodents--doesn’t form pores in the membranes of cultured mammalian cells, leaving its target a mystery. Using a novel screening technology, Dr. Alto and colleagues discovered that a protein toxin called IpaH7.8 from Shigella flexneri, a bacterium that causes diarrheal disease, directly inhibits GSDMB.

Entire Genome from 35,00-Year-Old Human Female Skull (Peştera Muierii 1) Sequenced; Suggests Greatest Loss of Human Genetic Diversity Occurred During Last Ice Age (Ending ~10,000 Years Ago) Not During Out-of-Africa Migration (~80,000 Years Ago)

For the first time, researchers have successfully sequenced the entire genome from the skull of Peştera Muierii 1, a woman who lived in today's Romania ~35,000 years ago. Her high genetic diversity shows that the out-of-Africa migration was not the great bottleneck in human development, but rather this occurred during and after the most recent Ice Age. This is the finding of a new study led by Mattias Jakobsson, PhD, at Sweden’s Uppsala University and published online on May 18, 2021 in Current Biology. The open-access article is titled “Genome of Peştera Muierii Skull Shows High Diversity and Low Mutational Load in Pre-Glacial Europe.” "She is a bit more like modern-day Europeans than the individuals in Europe 5,000 years earlier, but the difference is much less than we had thought. We can see that she is not a direct ancestor of modern Europeans, but she is a predecessor of the hunter-gathers that lived in Europe until the end of the last Ice Age," says Mattias Jakobsson, Professor at the Department of Organismal Biology at Uppsala University and head of the study. Very few complete genomes older than 30,000 years have been sequenced. Now that the research team can read the entire genome from Peştera Muierii 1, they can see similarities with modern humans in Europe while also seeing that she is not a direct ancestor. In previous studies, other researchers observed that the shape of her cranium has similarities with both modern humans and Neanderthals. For this reason, they assumed that she had a greater fraction of Neanderthal ancestry than other contemporaries, making her stand out from the norm. But the genetic analysis in the current study shows that she has the same low level of Neanderthal DNA as most other individuals living in her time.

Syndicate content