ReportWire

Tag: Cell (journal)

  • Cockatoos know to bring along multiple tools when they fish for cashews

    Cockatoos know to bring along multiple tools when they fish for cashews

    [ad_1]

    Newswise — Goffin’s cockatoos have been added to the short list of non-human animals that use and transport toolsets. In a study publishing in the journal Current Biology on February 10, researchers show that the cockatoos carry multiple tools to their worksite when the job calls for it. This behavior has only been previously reported in chimpanzees, our closest relatives.

    Goffin’s cockatoos are small white parrots that hail from the Tanimbar Islands archipelago in Indonesia. Captive Goffin’s cockatoos use and manufacture tools, and a recent study of wild-caught cockatoos reported that they can use up to three different tools to extract seeds from a particular fruit. Up until now, though, it wasn’t clear whether the cockatoos considered these tools as a “set”; it’s possible that what may look like a toolset is instead nothing more than a chain of single tool uses, with the need for each new tool appearing to the animal as the task evolves.

    Now, a team of researchers have used controlled experiments to clarify that the cockatoos do indeed recognize when a job requires more than one tool. “With this experiment we can say that, like chimpanzees, Goffin’s cockatoos not only appear to be to using toolsets, but they know that they are using toolsets,” says first author Antonio Osuna-Mascaró, an evolutionary biologist at the University of Veterinary Medicine Vienna. “Their flexibility of behavior is stunning.”

    Osuna-Mascaró was inspired by the termite-fishing Goualougo Triangle chimpanzees of northern Congo, the only other known non-human animal to use toolsets. These chimpanzees fish for termites via a two-step process: first, they use a blunt stick to break holes in the termite mound, and then they insert a long, flexible probe to “fish” the termites out of the holes. In this study, Osuna-Mascaró’s team tasked the cockatoos with fishing for cashews instead of termites.

    To mimic the termite-fishing set-up, the researchers presented the cockatoos with a box containing a cashew behind a transparent paper membrane. To reach the cashew, the cockatoos had to punch through the membrane and then “fish” the cashew out. They were provided with a short, pointy stick for punching holes and a vertically halved plastic straw for fishing.

    Seven of the ten cockatoos tested taught themselves to extract cashews successfully by punching through the membrane, and two of the cockatoos (Figaro and Fini) completed the task within 35 seconds on their first attempt. The cockatoos don’t have an equivalent foraging behavior in the wild, so there was no chance that their tool use was based on innate behaviors, and each cockatoo used a slightly different technique.

    Next, the team tested the cockatoos’ ability to change their tool use in a flexible manner depending on the situation. To do this, they presented each cockatoo with two different types of box: one with a membrane and one without. The cockatoos were given the same two tools, but they only needed the pointy stick when a membrane was in the way. “The cockatoos had to act according to the problem; sometimes the toolset was needed, and sometimes only one tool was enough,” says Osuna-Mascaró.

    All of the cockatoos mastered the test in a very short period of time and were able to recognize when a single tool was sufficient. However, the birds engaged in an interesting behavior during this choosing phase. “When making the choice between which tool to use first, they were picking one up, releasing it, then picking up the other one, releasing it, returning to the first one, and so on,” says Osuna-Mascaró. The researchers found that when cockatoos did this switching, they performed better on the tests.

    Next, the team tested the cockatoos’ ability to transport the tools as a set on an as-needed basis. They put the cockatoos through a series of increasingly challenging trials to reach the boxes: first they had to climb a short ladder while carrying their tools; then they had to fly horizontally with them; and in the final test, they had to carry the tools while flying vertically. As before, the birds were only sometimes presented with a box with a membrane barrier, so they had to decide whether the problem required one or both tools.

    Some cockatoos learned to carry the two tools together—by inserting the short punching stick into the groove of the halved straw—when they were presented with a box that required both. This meant they only had to make one trip, albeit while carrying a heavier toolset. Most of the cockatoos transported the toolset on an as-needed basis, further indicating that they knew ahead of time when two tools were required, though some made two trips when necessary. One cockatoo, Figaro, decided not to waste time thinking and instead carried both tools in almost every trial.

    “We really did not know whether the cockatoos would transport two objects together,” says Alice Auersperg, senior author on the study and a cognitive biologist at the University of Veterinary Medicine Vienna. “It was a little bit of a gamble because I have seen birds combining objects playfully, but they very rarely transport more than one object together in their normal behavior.”

    There’s a lot more to be learned about cockatoo tool use, the researchers say. “We feel that, in terms of technical cognition and tool use, parrots have been underestimated and understudied,” says Auersperg.

    “We’ve learned how dexterous the cockatoos are when using a toolset, and we have a lot of things to follow-up on,” says Osuna-Mascaró. “The switching behavior is very interesting to us, and we are definitely going to use it to explore their decision making and their metacognition—their ability to recognize their own knowledge.”

    ###

    This research was supported by the Vienna Science and Technology Fund and the Austrian Science Fund.

    Current Biology, Osuna-Mascaró et al. “Flexible tool set transport in Goffin’s cockatoos,” https://www.cell.com/current-biology/fulltext/S0960-9822(23)00057-X

    Current Biology (@CurrentBiology), published by Cell Press, is a bimonthly journal that features papers across all areas of biology. Current Biology strives to foster communication across fields of biology, both by publishing important findings of general interest and through highly accessible front matter for non-specialists. Visit: http://www.cell.com/current-biology. To receive Cell Press media alerts, contact [email protected].

    [ad_2]

    Cell Press

    Source link

  • Microbiome disturbances reported as signature of chronic fatigue syndrome/myalgic encephalomyelitis

    Microbiome disturbances reported as signature of chronic fatigue syndrome/myalgic encephalomyelitis

    [ad_1]

    Newswise — New research reveals differences in the gut microbiomes of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) compared to those of healthy controls.

    ME/CFS is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, among other symptoms.

    The study was led by scientists at the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health, as part of the Center for Solutions for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, an inter-disciplinary, inter-institutional research group dedicated to understanding the biology of the disease in order to develop effective means to diagnose, treat and prevent it. Findings appear in the journal Cell Host & Microbe.

    The researchers conducted metagenomic and metabolomic analyses of fecal samples collected from geographically diverse cohort of 106 cases and 91 healthy controls. Results revealed differences in gut microbiome diversity, abundances, functional biological pathways, and interactions between bacteria. Cases and controls were matched for age, sex, geography, and socioeconomic status.

    Gut bacteria Faecalibacterium prausnitzii and Eubacterium rectale, which are both normally abundant and health-promoting, were reduced in ME/CFS participants. For both bacteria, researchers also found a deficient microbial capacity for synthesizing butyrate, the main fuel for the body’s colon cell, with ME/CFS. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity.

    The only other species identified with reduced relative abundance in ME/CFS was C. secundus, an acetate-producer, that could contribute to the net acetate deficiency the researchers found in ME/CFS subjects. Acetate is used by butyrate-producing bacteria to produce butyrate.

    An additional nine species had increased relative abundance in ME/CFS compared to healthy controls, including C. bolteae which in other research has correlated with fatigue in multiple sclerosis. Another, R. gnavus, has been associated with inflammatory bowel disease.

    “The gut microbiome is a complex ecological community teeming with diverse inter-species interactions that can be beneficial or harmful. Our research finds that in people with ME/CFS, there can be extensive rewiring of the networks of bacteria in this system,” says study senior author Brent Williams, PhD, assistant professor of epidemiology in CII at Columbia Mailman School of Public Health.

    “Understanding the connection between ME/CFS and disturbances in the gut microbiome may lead to ways to classify the disease and targets for therapeutic trials,” adds co-author W. Ian Lipkin, MD, CII director and John Snow Professor of Epidemiology at Columbia Mailman School.

    The study’s first author is Cheng Guo, PhD, senior programmer analyst at CII. Additional co-authors are listed in the publication.

    The research was funded by the National Institutes of Health grant to the Center for Solutions for ME/CFS at Columbia University (grant number 1U54AI138370), NIH grant R56AI120724, and anonymous donors through the Crowdfunding Microbe Discovery Project.

    The authors declare no competing interests.

    About ME/CFS

    Experts estimate there are between 800,000 and 2 million Americans with ME/CFS, a complex, debilitating disorder characterized by extreme fatigue after exertion and other symptoms including muscle and joint pain, cognitive dysfunction, sleep disturbance, and orthostatic intolerance. Currently, there is no diagnostic test for the disease; instead, patients are diagnosed based on a clinical examination and history and an exclusion of other disorders.

    Prior Research on ME/CFS

    In a 2017 study, CII scientists reported discovered abnormal levels of specific gut bacteria related to ME/CFS in patients with and without concurrent irritable bowel syndrome, IBS. A year later, another study identified a constellation of metabolites related to ME/CFS, providing the ability to predict whether or not someone has the disorder with a confidence of 84 percent.

    In a 2015 study, CII researchers identified distinct immune changes in patients diagnosed with ME/CFS. These immune signatures represented the first robust physical evidence that ME/CFS is a biological illness as opposed to a psychological disorder, and the first evidence that the disease has distinct stages. In a 2012 study, researchers ruled out a purported link between a mouse retrovirus called XMRV and ME/CFS.

    [ad_2]

    Columbia University, Mailman School of Public Health

    Source link

  • A new understanding of reptile coloration

    A new understanding of reptile coloration

    [ad_1]

    Newswise — Snakes and mice don’t look alike. But much of what we know about skin coloration and patterning in vertebrates generally, including in snakes, is based on lab mice. However, there are limits to what mice can tell us about other vertebrates because they don’t share all of the same types of color-producing cells, known as chromatophores. For example, snakes have a type of chromatophore called iridophores that can generate iridescent colours by reflecting light.

    To gain a better understanding of the genetic basis of coloration in vertebrates, a McGill University-led research team combined a range of techniques (whole gene sequencing, gene-editing, and electron microscopy) to look more closely at color variations and patterning in the skin shed by ball pythons bred in captivity. They were able to identify a particular gene (tfec) that plays a crucial role in reptile pigmentation generally and more specifically in a classic color variant found across vertebrates and distinguished by blotches of white, the piebald.

    Crowdsourcing biological data with the help of snake breeders

    The sale of captive-bred reptiles is a $1.4 billion industry within the U.S. alone. Over 4.5 million American households keep reptiles, and close to one in five of these are snakes bred in captivity. Due to the spectacular color variations produced through captive breeding, an individual ball python (Python regius – originally found in West and Central Africa) can sell for tens of thousands of dollars.

    “Ball pythons show incredible variation in skin coloring and patterning, which is part of their appeal for hobbyists, but also makes them really useful for researchers who want to understand the genetic basis of coloration,” says Rowan Barrett, Interim Director of McGill University’s Redpath Museum, the Canada Research Chair in Biodiversity Science, and the senior author on the recent paper in Current Biology. “The pet trade has created a huge pool of colour variation that would not have existed otherwise. This provides a catalogue for us to figure out the many ways that genes produce the amazing diversity of colors, spots, and stripes we see across different animals.”

    Gene-editing confirms role of mutation in reptile colouration

    To identify the genes that control a particular trait, scientists look for genetic variants that are present in animals that have the trait and absent in animals that don’t. Using shed skin collected from snake breeders, Barrett’s team found that piebald snakes carried the same mutation in the tfec gene.

    But a common problem for scientists is that finding a correlation between a gene and a particular trait, such as the piebaldism, does not imply causation. To make that functional link, the McGill researchers collaborated with Doug Menke’s lab at the University of Georgia to modify tfec in a different reptile species, the brown anole lizard, using the gene-editing technology CRISPR. They found that genetically modified lizards do indeed show altered colouration, proving that mutations to tfec cause changes to color-producing cells. 

    “Our research advances knowledge of the genetics of vertebrate colouration generally and particularly of the development of iridescent cells, which haven’t been studied as much as other color pathways” adds Alan Garcia-Elfring, a PhD student in McGill’s Biology Department and the first author on the paper. “It also highlights the potential benefits of working with non-academic communities like ball python breeders to accelerate discoveries in fundamental science. Our job, at this point, is to figure out what other mutations underlie all this variation seen in captivity, and how these mutations interact. It’s an exciting time for both researchers and reptile hobbyists.”

     

    “Piebaldism and chromatophore development in reptiles are linked to the tfec gene” in Current Biology by Alan Garcia-Elfring et al

    https://doi.org/10.1016/j.cub.2023.01.004

    [ad_2]

    McGill University

    Source link

  • Evolution of wheat spikes since the Neolithic revolution

    Evolution of wheat spikes since the Neolithic revolution

    [ad_1]

    Newswise — Around 12,000 years ago, the Neolithic revolution radically changed the economy, diet and structure of the first human societies in the Fertile Crescent of the Near East. With the beginning of the cultivation of cereals —such as wheat and barley— and the domestication of animals, the first cities emerged in a new social context marked by a productive economy. Now, a study published in the journal Trends in Plant Science and co-led by the University of Barcelona, the Agrotecnio centre and the University of Lleida, analyses the evolution of wheat spikes since its cultivation began by the inhabitants of ancient Mesopotamia —the cradle of agriculture in the world— between the Tigris and the Euphrates.

    The authors of the study are Rut Sánchez-Bragado and Josep Lluís Araus-Ortega, from the UB Faculty of Biology and Agrotecnio-UdL; Gustavo A. Slafer, ICREA researcher at the UdL School of Agrifood and Forestry Science and Engineering, and Gemma Molero, from the International Maize and Wheat Improvement Center in Mexico, currently a researcher at KWS Seeds Inc.

    A cereal that changed human history

    The cultivation of wheat —a grass that became basic food— represented a turning point in the progress of human civilisation. Today it is the world’s most important crop in terms of food security, but EU data warn that the impact of climate change could significantly increase its price and modify its production process in certain areas of the world.

    Throughout the domestication process of wheat, the plant phenotype has undergone both rapid (within a few hundred years) and slow (thousands of years) changes, such as the weakening of the rachis, the increase in seed size, and the reduction or disappearance of the awns. In particular, awned and awnless wheat varieties are found all over the world, although the latter tend to be abundant in regions with arid climates, especially during the final stages of cultivation in late spring, a condition typical of Mediterranean environments.

    “It is important to conduct studies that show which wheat varieties are best adapted to different environmental growing conditions, especially in a context of climate change. Studying the past retrospectively can give us an idea of the evolution of wheat cultivation over the millennia since agriculture appeared in ancient Mesopotamia”, says Rut Sánchez-Bragado, first author of the study, who got a PhD at the UB.

    “Awns are organs of the spike that have traditionally been associated with the plant’s adaptations to drought conditions”, says Josep Lluís Araus, professor at the Department of Evolutionary Biology, Ecology and Environmental Sciences of the Faculty of Biology.

    “However, archaeological and historical records show that the wheat spike has existed predominantly with awns for more than ten millennia after the domestication of wheat. It is not until the last millennium that evidence shows in many cases the absence of awns, indicating a selection by farmers —probably in an undirected way— against this organ”, stresses Araus, one of the most cited authors in the world according to Clarivate Analytics’ Highly Cited Researchers (2022).

    “The role of wheat awns in their performance remains controversial despite decades of studies”, says researcher Gustavo A. Slafer, corresponding author of the study.

    Spike awns: beneficial for the plant?

    Is the presence of awns on the spike beneficial for the plant and the crops? Although there is no scientific consensus, “everything suggests that in conditions where the plant does not suffer from water stress, the extra photosynthetic capacity of the awns does not compensate for other potential negative effects (reduced susceptibility to fungal diseases, limitation in the total number of large ones that an ear supports, etc.)”, says Araus.

    “However, in wetter climates the awns accumulate moisture and can promote the spread of diseases”, says Rut Sánchez-Bragado. “So, as the world’s population is continuously growing, it is necessary to investigate the role of the awned spikes in the changing conditions of our climate in order to meet the world’s demand for a primary food commodity such as wheat”.

    In arid conditions, the spikes —including the awns— “have better physiological characteristics than the leaves. In addition, the awns allow the light captured by the crop to be more diffused, which facilitates a better distribution of light energy and allows the crop to photosynthesise more. Therefore, in arid conditions, the awns can still be beneficial for the crop, or at most, neutral”, concludes Professor Josep Lluís Araus.

    [ad_2]

    Universidad De Barcelona

    Source link

  • Establishing cell lines to improve iPSC research

    Establishing cell lines to improve iPSC research

    [ad_1]

    Newswise — Farmington, CT– iPSC lines have become essential for determining the underlying genetic drivers of human disease. Genomes of iPSCs can be easily edited using the bacteria-based CRISPR/Cas9 technology to introduce or correct disease-associated variants. 

    By focusing on one gene variation at a time, results of experiments have a clear genetic cause and effect to be easily compared to previous data. What poses a challenge for accurate disease modeling is the inherent variation between iPSC lines, as well as the wide variety of cell lines used in research between institutions, creating unwanted obstacles in data interpretation.

    Jackson Laboratory (JAX) Professor of Cellular Engineering Bill Skarnes, Ph.D., and colleagues have developed a cell line to address the challenges facing cellular modeling of disease. The study, published in Cell Stem Cell, details genetic properties characterization of eight iPSC lines, with one rising above the rest. 

    The cell line KOLF2.1J proved to be an all-around well-performing iPSC line with high genomic stability in post-edited clones. Meeting all the criteria for cellular engineering research, KOLF2.1J can act as a stable foundation for modeling hundreds of genetic alterations relevant to Alzheimer’s disease, rare disease, cancer, and more.

    Through the partnership between the iPSC Neurodegenerative Disease Initiative and the Chan Zuckerberg Initiative, KOLF2.1J is available as both a reference parental line and with selected single nucleotide variants (SNVs) as part of the catalog of human iPSCs at JAX. 

    By selecting KOLF2.1J as a cell line of choice, researchers will be able to generate consistent, integratable data and help accelerate human disease research. In collaboration with UConn Health, Skarnes and fellow JAX researchers are now planning to derive additional similarly well-characterized iPSC lines from healthy individuals of diverse genetic backgrounds.

    About The Jackson Laboratory

    The Jackson Laboratory is an independent, nonprofit biomedical research institution with a National Cancer Institute-designated Cancer Center and nearly 3,000 employees in locations across the United States (Maine, Connecticut, California) and Japan, as well as a joint venture in China. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. For more information, please visit www.jax.org​​​​​​​.

    [ad_2]

    Jackson Laboratory

    Source link

  • When bugs swipe left

    When bugs swipe left

    [ad_1]

    Newswise — It’s almost Valentine’s Day, and love is in the air. Or in the waxy coating on your skin, if you are a vinegar fly. That’s where flies encounter pheromones that play an important role in regulating sexual attraction.

    Flies use pheromones to ensure that they court and mate with members of the same species. As new fly species split off from a common ancestor, but continue to share the same environment, they need a way to rapidly diversify their pheromones to suppress inter-species mating. When members of two related species stop finding each other attractive, this helps prevent interbreeding.

    But it’s more complicated than “she loves me, she loves me not.“

    Because the perception and production of pheromones are mediated by different tissues and cellular pathways, evolving new mating pheromones requires a coordinated evolution of both the genes responsible for sensing the pheromones as well as the genes that produce them.

    A new study in iScience led by Yehuda Ben-Shahar at Washington University in St. Louis identifies a link between the genetic instructions for the production and perception of sex pheromones. The research was conducted in collaboration with Jocelyn Millar from the University of California, Riverside.

    Researchers reported that a single protein called Gr8a is expressed in different organs in male and female flies and appears to play an inhibitory role in mating decision-making. The findings point to one of the ways that flies could put up behavioral barriers to protect against mating with the wrong kind of partner.

    “Mating pheromones often show rapid evolution,” said Ben-Shahar, a professor of biology in Arts & Sciences. “Because pheromonal communication requires a very robust and specific structural recognition of chemicals used as pheromones by the proteins that bind them in sensory neurons (chemoreceptors), it means that major molecular changes in either the receptor or the pheromone would reduce sexual attraction between males and females.”

    Ben-Shahar and his team found that Gr8a was expressed in tissues in fly mouthparts, including the proboscis, as well as in taste neurons in the forelegs of both males and females. They also found Gr8a in cells in the abdomens of males. This was important because it provided Ben-Shahar and his team the first hint that a gene that had been previously identified as a sensory chemoreceptor must also have non-neuronal functions.

    “Our findings provide a relatively simple molecular explanation for how signal production and perception are tied together in vinegar flies,” Ben-Shahar said. “A single pleiotropic protein can function as both a receptor for pheromones in sensory neurons, as well as contribute to their production in the pheromone-producing cells (oenocytes) of males, by way of a less-understood process.”

    In one of the experiments that Ben-Shahar and his team conducted, the scientists took flies that were mutant for the Gr8a receptor and reconstituted them using input from a different vinegar fly species. This experiment showed that introducing Gr8a from another species was enough to change the overall pheromone profile of the animal.

    The scientists still have not pinpointed exactly how the chemoreceptor affects the way the signal is produced, but they do know that it causes quantitative and qualitative differences in pheromones. And even small changes in pheromones could be enough to keep closely related flies from finding each other attractive — and change their mate choice behaviors.

    The question of how closely related species evolve and maintain behavioral mating barriers is one that has implications for several different basic and applied biological research fields.

    “Based on what we have observed, mutations in a single gene could provide a molecular path for a pheromonal communication system to evolve while still maintaining the functional coupling between a pheromone and its receptor,” Ben-Shahar said. “Our research uncovers a potential avenue for pheromonal systems to rapidly evolve when new species arise.”

    —

    This work was supported by National Science Foundation grants 1322783, 1754264 and 1707221, and National Institutes of Health (NIH) grant NS089834.

    [ad_2]

    Washington University in St. Louis

    Source link

  • Forests face fierce threats from multiple industries, not just agricultural expansion

    Forests face fierce threats from multiple industries, not just agricultural expansion

    [ad_1]

    Newswise — Intact forests are important climate regulators and harbors of biodiversity, but they are rapidly disappearing. Agriculture is commonly considered to be the major culprit behind forest loss, but the authors of a new paper publishing on January 20 in the journal One Earth show that agriculture isn’t solely to blame. For forest loss associated with the 2014 world economy, over 60% was related to final consumption of non-agricultural products, such as minerals, metals and wood-related goods, and the authors argue that we must consider international trade markets when designing conservation strategies.

    “Regional land use change is no longer simply driven by local demand; it is also indirectly influenced by international markets and the surging consumption of land-based products,” say the authors, led by Bin Chen, a postdoctoral fellow at Fudan University. “Countries with forest conservation goals can import finished land-based products via global supply chains, displacing land-use pressure and related eco-environmental impacts outside their own territory borders.”

    The researchers used multi-source geographic information data and economic modeling to evaluate the direct and indirect causes of intact forest landscape loss. Intact forests support more diverse species, are more resilient to natural disturbances such as wildfires, and in Africa and South America, can store more than three times the amount of carbon per hectare compared to disturbed or managed forests.

    Previous studies have focused on deforestation—the complete removal of tree cover—but focusing on intact forests instead allowed the authors to shine a spotlight on the insidious roles played by degradation and fragmentation.

     “Even the removal of narrow tracts of forests can affect overall forest structure and composition,” say the authors. “Considering the exceptional conservation value of intact forest landscapes in terms of stabilizing terrestrial carbon stocks and harboring biodiversity, intact forest landscapes loss displacement can also reflect potential indirect driving forces behind carbon emissions and biodiversity loss.”

    “It is widely thought that beef production drives deforestation in the Amazon, but it is hard for consumers to realize that the production of highly processed equipment may involve timber and metals produced at the expense of intact forest and that services provided by tertiary sectors may be supported by electricity generated from oil and gas associated with this loss” the authors say. “The more dispersed nature of intact forest loss drivers and their indirect links to individual final consumers call for stronger government engagement and supply-chain interventions.”

    [ad_2]

    Cell Press

    Source link

  • Collision risk and habitat loss: Wind turbines in forests impair threatened bat species

    Collision risk and habitat loss: Wind turbines in forests impair threatened bat species

    [ad_1]

    Newswise — In order to meet climate protection goals, renewable energies are booming – often wind power. More than 30,000 turbines have already been installed on the German mainland so far, and the industry is currently scrambling to locate increasingly rare suitable sites. Thus, forests are coming into focus as potential sites. A scientific team from the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) now demonstrated in a new paper published in the scientific journal “Current Biology” that wind turbines in forests impair endangered bat species: Common noctules (Nyctalus noctula), a species with a high risk of colliding with rotor blades, are attracted to forest wind turbines if these are located near their roosts. Far from roosts, common noctules avoid the turbines, essentially resulting in a loss of foraging space and thus habitat for this species.

    The research results show that common noctules suffer in two ways from wind turbines in forests: If the wind turbines are built near roosts, noctules face an increasing risk of colliding with the turbines, and they lose foraging habitat because they avoid wind turbines far from roosts. In their paper the team concludes that wind power development in forests must be avoided or, if there is no alternative, should be undertaken with great care and caution. The wind turbine should be placed at least at a distance of 500 meters away from bat roosting sites, and loss of foraging habitat should be compensated for by taking forests out of use for wind power (or other anthropogenic activities) elsewhere.

    Wind energy production is an important pillar for the energy transition to renewable energies in Germany and makes a significant contribution to reducing greenhouse gas emissions. Approximately eight percent of wind turbines in Germany have already been built in forests. This number is expected to significantly increase in the coming years as suitable sites in open landscapes become increasingly scarce. “A large number of bat species occur in forests because there are many tree roosts and suitable foraging habitats with a high abundance of insects, their prey”, says Christian Voigt, head of the Department of Evolutionary Ecology at the Leibniz-IZW. “These include species such as the common noctule, which is the most common victim among the bat species of wind turbines in Germany. According to the German Federal Agency for Nature Conservation (BfN), common noctule populations are declining throughout Germany. It is therefore a matter of urgency to take a closer look at the interaction of bats with wind turbines in forests.”

    Voigt and his colleagues investigated the space-use behaviour of common noctules using miniaturised GPS loggers. These loggers recorded the flight paths of 60 bats with a high temporal and spatial resolution over 1-2 nights before the loggers automatically came off each animal. “We found that the common noctules were particularly likely to approach wind turbines if the latter were located close to bat roosts”, explains Voigt. As highly social mammals, the bats use exposed structures as meeting spots. This could be the reason why they often approach wind turbines, which rise well above the canopy, if turbines are located near roosts. This poses a high risk to the animals of colliding with the rotor blades. “Wind turbines would therefore have to be erected at a sufficient distance from existing tree roosts”, concludes Christine Reusch, first author of the paper. “As roosts can also be newly created, there is a risk that supposedly safe wind turbines, which were initially erected at a sufficiently large distance from the then existing bat roosts during the approval phase, later become death traps”, Reusch adds.

    The authors also found that further away from tree roosts, common noctules avoided wind turbines. They discovered this after they had carried out a data analysis in which all bat GPS locations in the vicinity of roosts were excluded from the analysis. This showed that bats avoid wind turbines if placed well beyond roosts. “This sounds like good news but it has a problematic side to it”, says Voigt. “Owing to their avoidance behaviour, common noctule bats essentially lose important hunting habitats.” The scientists therefore recommend, firstly, that wind turbines should not be sited in forests, and secondly, that special care should be taken if there are no alternatives. A minimum distance of 500 meters of wind turbines to known bat roosts should be taken into account during the approval procedures and the loss of foraging habitat in the vicinity of wind turbines should be compensated for elsewhere. The expansion of wind energy production into forests is therefore a major challenge to conservation in view of the complex interaction of bats with wind turbines in forests, according to Voigt and Reusch.  

    [ad_2]

    Leibniz Institute for Zoo and Wildlife Research (IZW)

    Source link

  • Scientists Publish New Findings in Quest to Build a Better Opioid

    Scientists Publish New Findings in Quest to Build a Better Opioid

    [ad_1]

    Newswise — CHAPEL HILL, NC – In the continuing effort to improve upon opioid pain relievers, American and Chinese scientists used cryoEM technology to solve the detailed structures of the entire family of opioid receptors bound to their naturally occurring peptides. Subsequent structure-guided biochemical studies were then performed to better understand the mechanisms of peptide-receptor selectivity and signaling drugs.

    This work, published in Cell, provides a comprehensive structural framework that should help drug developers rationally design safer drugs to relieve severe pain.

    This work was spearheaded by the lab of Eric Xu, PhD, at the CAS Key Lab of Receptor Research in China, in collaboration with the lab of Bryan L. Roth, MD, PhD, at the UNC School of Medicine, where graduate student Jeff DiBerto led the pharmacological experiments to understand the receptors’ signaling mechanisms.

    Opioid drugs relieve pain by mimicking a naturally occurring pain-relief function within our nervous symptoms. They are the best, strongest pain relievers we have. Unfortunately, they come with side effects, some severe such as numbness, addiction, and respiratory depression, leading to overdose deaths.

    Scientists have been trying for many years to overcome the side-effect problem in various ways, all involving one or more of four opioid receptors to no avail. One way scientists continue to explore is the creation of peptide or peptide-inspired small molecule drugs.

    Peptides are short chains of amino acids; think of them as short proteins. Certain naturally occurring, or endogenous, peptides bind to opioid receptors on the surface of cells to create an analgesic effect, also known as pain relief. Think of an analgesic like an anesthetic, except that analgesics do not “turn off” the nerves to numb the body or alter consciousness. So, the idea is to create a peptide drug that has a strong analgesic effect, without numbing nerves or altering consciousness or causing digestive, respiratory, or addiction issues.

    “The problem in the field is we’ve lacked the molecular understanding of the interplay between opioid peptides and their receptors,” said Roth, co-senior author and the Michael Hooker Distinguished Professor of Pharmacology. “We’ve needed this understanding in order to try to rationally design potent and safe peptide or peptide-inspired drugs.”

    Using cryogenic electron microscopy, or cryoEM, and a battery of biomechanistic experiments in cells, the Xu and Roth labs systematically solved the detailed structures of endogenous peptides bound to all four opioid receptors. These structures revealed details and insights into how specific naturally occurring opioid peptides selectively recognize and activate opioid receptors. The researchers also used exogenous peptides, or drug-like compounds, in some of their experiments to learn how they activate the receptors.

    The cryoEM structures of agonist-bound receptors in complex with their G protein effectors (called their “active state”) represents what these receptors look like when they are signaling in cells, giving a detailed view of peptide-receptor interactions. The Roth lab used the structures solved by the Xu lab to guide the design of mutant receptors, and then tested these receptors in biochemical assays in cells to determine how they alter receptor signaling. Understanding these interactions can then be used to design drugs that are selective for opioid receptor subtypes, as well as to produce certain signaling outcomes that may be more beneficial than those of conventional opioids.

    “This collaboration revealed conserved, or shared, mechanisms of activation and recognition of all four opioid receptors, as well as differences in peptide recognition that can be exploited for creating subtype-selective drugs,” said DiBerto, first author and PhD candidate in the Roth lab. “We provide more needed information to keep pushing the field forward, to answer basic science questions we hadn’t been able to answer before now.”

    Previous research showed the structure of opioid receptors in their inactive or active-like states, with active state structures only existing for the mu-opioid receptor subtype, the primary target of drugs like fentanyl and morphine. In the Cell paper, the authors show agonist-bound receptors in in complex with their G protein effectors, made possible through cryoEM technology that did not exist when currently used medications were being developed.

    Drugs such as oxycontin, oxycodone, and morphine cause various effects inside cells and throughout the nervous symptom, including pain relief. But they have effects in the digestive and respiratory systems, too, and interact with cells to lead to addiction. Fentanyl, meanwhile, is another powerful pain reliever, but it binds to opioid receptors in such a way as to cause severe side effects, including the shutdown of the respiratory system.

    The thrust behind such research led by Xu and Roth is to home in on the mechanistic reasons for pain relief potency without triggering the cellular mechanisms that lead to severe side effects and overdosing.

    “We are attempting to build a better kind of opioid,” Roth says, “We’re never going to get there without these kind of basic molecular insights, wherein we can see why pain is relieved and why side effects occur.”

    Co-first authors of the Cell paper are Yue Wang and Youwen Zhuang of the CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research at the Shanghai Institute of Materia Medica in the Chinese Academy of Sciences. Other authors are Edward Zhou and Karsten Melcher of the Van Andel Research Institute in Grand Rapids, MI, Gavin Schmitz and Manish Jain at the UNC School of Medicine, and Qingning Yuan, Weiyi Liu, and Yi Jiant at the CAS Key Laboratory.

    [ad_2]

    University of North Carolina School of Medicine

    Source link

  • Salmonella exposure a risk for colon cancer

    Salmonella exposure a risk for colon cancer

    [ad_1]

    Newswise — A new study published in the journal Cell Reports Medicine links exposure to salmonella bacteria to colon cancer risk. 

    The researchers, including a team led by Jun Sun from the University of Illinois Chicago, studied human colon cancer tissue samples and animal models and found that exposure to salmonella was linked with colon cancers that developed earlier and grew larger.  

    The study authors first looked at data from a Netherlands-based retrospective study of colon cancer patients that found tissue samples taken during routine colon cancer surgery with salmonella antibodies tended to be from people who had worse colon cancer outcomes. 

    Using salmonella strains isolated from these tissue samples, Sun and her U.S.-based team studied mice with colon cancer that had been exposed to the bacteria. They observed accelerated tumor growth and larger tumors in mice with salmonella exposure. They also saw that there was increased salmonella translocated to the tumors. 

    “During infection, salmonella hijacks essential host signaling pathways, and these molecular manipulations may cause oncogenic transformation. The current study tells us that more research is needed into the connection between salmonella exposure and colon cancer risk in the USA, and that simply by practicing safe food preparation, we can potentially help to protect ourselves,” said Sun, UIC professor of medicine. 

    Sun’s collaborators in the Netherlands also studied the bacteria in vitro. They combined human cancer cells and pre-cancer cells with the salmonella strain in the lab and measured any growth or changes in the tumor. They saw that even one infection caused transformation and that each salmonella infection exponentially increased the rate of cell transformation. 

    “The mouse and tissue culture experiments show that salmonella infection had a chronic effect to accelerate tumor growth,” said Sun, who also is a member of the University of Illinois Cancer Center at UIC. “This evidence tells us that we need to look closer at salmonella exposure as an environmental risk factor for chronic diseases, such as colon cancer.” 

    Leiden University Medical Center, the National Institute for Public Health and the Environment, and Utrecht University, all in the Netherlands, collaborated on this study.  

    In addition to Sun, co-authors of “Repetitive non-typhoidal Salmonella exposure is an environmental risk factor for colon cancer and tumor growth” include Daphne van Elsland, Janneke Duijster, Jilei Zhang, Virginie Stevenin, Yongguo Zhang, Lang Zha, Yinglin Xia, Eelco Franz, Lapo Mughini-Gras and Jacques Neefjes. 

    [ad_2]

    University of Illinois Chicago

    Source link

  • Using paleogenomics to elucidate 10,000 years of immune system evolution

    Using paleogenomics to elucidate 10,000 years of immune system evolution

    [ad_1]

    Newswise — Scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France have used paleogenomics to trace 10,000 years of human immune system evolution. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia. They were able to date the increase in frequency of most of the mutations that are advantageous in defending against pathogens to after the Bronze Age, 4,500 years ago. The scientists also observed that mutations conferring a higher risk of developing inflammatory disorders have become more frequent over the past 10,000 years. These enlightening results on the effects of natural selection on immunity genes were published in the journal Cell Genomics on January 13, 2023.

    In the 1950s, the geneticist J.B.S. Haldane attributed the maintenance or persistence of the mutation responsible for anomalies in red blood cells commonly observed in Africa to the protection these anomalies provided against malaria, an endemic infection that claims millions of lives. This theory suggested that pathogens are among the strongest selective pressures faced by humans. Several population genetics studies subsequently confirmed the theory. But major questions remained, especially regarding the specific epochs during which the selective pressures exerted by pathogens on human populations were strongest and their impact on the present-day risk of developing inflammatory or autoimmune disorders.

    To address these questions, scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France, in collaboration with the Imagine Institute and The Rockefeller University (United States), adopted an approach based on paleogenomics. This discipline, which studies the DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as illustrated by the decision to award the 2022 Nobel Prize in Physiology or Medicine to the paleogeneticist Svante Pääbo. In the study led by the Institut Pasteur, published on January 13 in the journal Cell Genomics, the scientists analyzed the variability of the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia – a period covering the Neolithic, the Bronze Age, the Iron Age, the Middle Ages and the present.

    By reconstituting the evolution over time of hundreds of thousands of genetic mutations, the scientists initially identified mutations that rapidly increased in frequency in Europe, indicating that they were advantageous. These mutations that evolved under “positive” natural selection are mainly located in 89 genes enriched in functions relating to the innate immune response, including especially the OAS genes – which are responsible for antiviral activity – and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which demonstrate a genetic adaptation to the pathogenic environment, began recently, from the start of the Bronze Age, around 4,500 years ago. The scientists explain this “acceleration” in adaptation by the growth in the human population during this period and/or by strong selective pressures exerted by pathogens in the Bronze Age, probably linked to the spread of severe infectious diseases such as plague.

    At the same time, the scientists also looked at the opposite situation, in other words, mutations whose frequency fell significantly over the past ten millennia. These mutations are probably subject to “negative” selection because they increase the risk of disease. They noted that once again, these selection events mainly began in the Bronze Age. Many of these disadvantageous mutations were also located in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and have been confirmed in experimental research to have a deleterious effect in terms of infectious disease risk. The results emphasize the value of adopting an evolutionary approach in research on genetic susceptibility to infectious diseases.

    Finally, the scientists explored the theory that the selection exerted by pathogens in the past gave an advantage to alleles conferring resistance to infectious diseases, but that in turn these alleles have increased the present-day risk of autoimmune or inflammatory disorders. They investigated the few thousand mutations known to increase susceptibility firstly to tuberculosis, hepatitis, HIV or COVID-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they observed that those associated with an increased risk of inflammatory disorders – including Crohn’s disease – became more frequent over the past 10,000 years, while the frequency of those associated with a risk of developing infectious diseases decreased. “These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period because of a positive selection of mutations improving resistance to infectious diseases,” explains Lluis Quintana-Murci, director of the study and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS Evolutionary Genomics, Modeling and Health Unit/Université Paris Cité).

    The results of the study, which harnessed the huge potential of paleogenomics, show that natural selection has targeted human immunity genes over the past ten millennia in Europe, especially since the start of the Bronze Age, and contributed to present-day disparities in terms of the risk of infectious and inflammatory diseases.

    As well as the institutions mentioned above, this research was supported by the French Foundation for Medical Research (FRM), the Allianz-Institut de France Foundation and the Fondation de France.

    [ad_2]

    Institut Pasteur

    Source link

  • Evolution of uniquely human DNA was a balancing act, study concludes

    Evolution of uniquely human DNA was a balancing act, study concludes

    [ad_1]

    Newswise — SAN FRANCISCO, CA—January 13, 2023—Humans and chimpanzees differ in only one percent of their DNA. Human accelerated regions (HARs) are parts of the genome with an unexpected amount of these differences. HARs were stable in mammals for millennia but quickly changed in early humans. Scientists have long wondered why these bits of DNA changed so much, and how the variations set humans apart from other primates.

    Now, researchers at Gladstone Institutes have analyzed thousands of human and chimpanzee HARs and discovered that many of the changes that accumulated during human evolution had opposing effects from each other.

    “This helps answer a longstanding question about why HARs evolved so quickly after being frozen for millions of years,” says Katie Pollard, PhD, director of the Gladstone Institute of Data Science and Biotechnology and lead author of the new study published today in Neuron. “An initial variation in a HAR might have turned up its activity too much, and then it needed to be turned down.”

    The findings, she says, have implications for understanding human evolution. In addition—because she and her team discovered that many HARs play roles in brain development—the study suggests that variations in human HARs could predispose people to psychiatric disease.

    “These results required cutting-edge machine learning tools to integrate dozens of novel datasets generated by our team, providing a new lens to examine the evolution of HAR variants,” says Sean Whalen, PhD, first author of the study and senior staff research scientist in Pollard’s lab.

    Enabled by Machine Learning

    Pollard discovered HARs in 2006 when comparing the human and chimpanzee genomes. While these stretches of DNA are nearly identical among all humans, they differ between humans and other mammals. Pollard’s lab went on to show that the vast majority of HARs are not genes, but enhancers— regulatory regions of the genome that control the activity of genes.

    More recently, Pollard’s group wanted to study how human HARs differ from chimpanzee HARs in their enhancer function. In the past, this would have required testing HARs one at a time in mice, using a system that stains tissues when a HAR is active.

    Instead, Whalen input hundreds of known human brain enhancers, and hundreds of other non-enhancer sequences, into a computer program so that it could identify patterns that predicted whether any given stretch of DNA was an enhancer. Then he used the model to predict that a third of HARs control brain development.

    “Basically, the computer was able to learn the signatures of brain enhancers,” says Whalen.

    Knowing that each HAR has multiple differences between humans and chimpanzees, Pollard and her team questioned how individual variants in a HAR impacted its enhancer strength. For instance, if eight nucleotides of DNA differed between a chimpanzee and human HAR, did all eight have the same effect, either making the enhancer stronger or weaker?

    “We’ve wondered for a long time if all the variants in HARs were required for it to function differently in humans, or if some changes were just hitchhiking along for the ride with more important ones,” says Pollard, who is also chief of the division of bioinformatics in the Department of Epidemiology and Biostatistics at UC San Francisco (UCSF), as well as a Chan Zuckerberg Biohub investigator.

    To test this, Whalen applied a second machine learning model, which was originally designed to determine if DNA differences from person to person affect enhancer activity. The computer predicted that 43 percent of HARs contain two or more variants with large opposing effects: some variants in a given HAR made it a stronger enhancer, while other changes made the HAR a weaker enhancer.

    This result surprised the team, who had expected that all changes would push the enhancer in the same direction, or that some “hitchhiker” changes would have no impact on the enhancer at all.

    Measuring HAR Strength

    To validate this compelling prediction, Pollard collaborated with the laboratories of Nadav Ahituv, PhD, and Alex Pollen, PhD, at UCSF. The researchers fused each HAR to a small DNA barcode. Each time a HAR was active, enhancing the expression of a gene, the barcode was transcribed into a piece of RNA. Then, the researchers used RNA sequencing technology to analyze how much of that barcode was present in any cell—indicating how active the HAR had been in that cell.

    “This method is much more quantitative because we have exact barcode counts instead of microscopy images,” says Ahituv. “It’s also much higher throughput; we can look at hundreds of HARs in a single experiment.”

    When the group carried out their lab experiments on over 700 HARs in precursors to human and chimpanzee brain cells, the data mimicked what the machine learning algorithms had predicted.

    “We might not have discovered human HAR variants with opposing effects at all if the machine learning model hadn’t produced these startling predictions,” said Pollard.

    Implications for Understanding Psychiatric Disease

    The idea that HAR variants played tug-of-war over enhancer levels fits in well with a theory that has already been proposed about human evolution: that the advanced cognition in our species is also what has given us psychiatric diseases.

    “What this kind of pattern indicates is something called compensatory evolution,” says Pollard. “A large change was made in an enhancer, but maybe it was too much and led to harmful side effects, so the change was tuned back down over time—that’s why we see opposing effects.”

    If initial changes to HARs led to increased cognition, perhaps subsequent compensatory changes helped tune back down the risk of psychiatric diseases, Pollard speculates. Her data, she adds, can’t directly prove or disprove that idea. But in the future, a better understanding of how HARs contribute to psychiatric disease could not only shed light on evolution, but on new treatments for these diseases.

    “We can never wind the clock back and know exactly what happened in evolution,” says Pollard. “But we can use all these scientific techniques to simulate what might have happened and identify which DNA changes are most likely to explain unique aspects of the human brain, including its propensity for psychiatric disease.”

    ###

    About the Study

    The paper “Machine learning dissection of human accelerated regions in primate neurodevelopment,” was published in the journal Neuron on January 13, 2023.

    Other authors are Kathleen Keough, Alex Williams, Md. Abu Hassan Samee, and Sean Thomas of Gladstone; Fumitaka Inoue, Hane Ryu, Tyler Fair, Eirene Markenscoff-Papadimitrious, Beatriz Alvarado, Orry Elor, Dianne Laboy Cintron, Erik Ullian, Arnold Kriegstein, and John Rubenstein of UC San Francisco; Martin Kircher, Beth Martin, and Jay Shendure of University of Washington; and Robert Krencik of Houston Methodist Research Institute.

    The work was supported by the Schmidt Futures Foundation and the National Institutes of Health (DP2MH122400-01, R35NS097305, FHG011569A, R01MH109907, U01MH116438, UM1HG009408, UM1HG011966, 2R01NS099099).

    About Gladstone Institutes

    To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.

    [ad_2]

    Gladstone Institutes

    Source link

  • High levels of ammonia in colon tumors inhibits T cell growth and response to immunotherapy

    High levels of ammonia in colon tumors inhibits T cell growth and response to immunotherapy

    [ad_1]

    Newswise — High levels of ammonia in tumors leads to fewer T cells and immunotherapy resistance in mouse models of colorectal cancer, new findings from the University of Michigan Rogel Cancer Center revealed. Researchers found that ammonia inhibits the growth and function of T cells, which are vital for anti-tumor immunity. The findings appear in Cell Metabolism.

    “We identified the mechanism of how ammonia dysregulates T cell function and showed that reducing ammonia levels using FDA-approved drugs for hyperammonemia can reduce tumor size in several different models including metastatic colorectal cancer,” says Hannah Bell, Ph.D., a postdoctoral fellow in cancer biology and author on this paper. “Use of this drug also synergizes with immunotherapy. If you treat the mice with immunotherapy when you also treat them with this ammonia reducing agent, you’re able to sensitize the tumors to treatment.”

    “Most colorectal cancers are insensitive to immune therapies,” adds Yatrik Shah, Ph.D., Horace W. Davenport Collegiate Professor of Physiology and first author of the study. “We’ve found that one of the mechanisms that leads to this resistance is likely the high level of ammonia that accumulates in the microenvironment.”

    Bell explains that while there are many factors that contribute to immunotherapy resistance, there are few therapeutic interventions that can reactivate therapy sensitivity. “Our study shows that this is a relatively safe and FDA-approved method that could work alongside immunotherapy to make treatment more effective for patients. This new method provides a potentially direct avenue to treat tumors and reactivate the immune system.”

    How does ammonia accumulate in colorectal tumors in the first place? Ammonia levels are regulated by a balance of production and cellular detoxification. Most ammonia is generated by the microbiota, but Bell and Shah’s work suggests that increased production of ammonia is not what results in accumulation. “Our work demonstrates that tumors have lost the ability to detoxify ammonia leading to build up,” said Shah.

    Further, the accumulation of ammonia is likely not isolated to just colorectal tumors. Shah says this discovery may open doors in explaining resistance to other cancer types as well. “Only about 20-30% of all cancer patients are sensitive to immunotherapy. 70% of patients don’t derive any benefit from it,” Shah said. “Now, we have a mechanism that could explain this resistance in tumors beyond colon cancer.”

    More work needs to be done before researchers can bring these findings into the clinic.

     

    Additional Authors: Amanda K. Huber; Rashi Singhal; Navyateja Korimerla; Ryan J. Rebernick; Roshan Kumar; Marwa O. El-derany; Peter Sajjakulnukit; Nupur K. Das; Samuel A. Kerk; Sumeet Solanki; Jadyn G. James; Donghwan Kim; Li Zhang; Brandon Chen; Rohit Mehra; Timothy L. Frankel; Balázs Győrffy; Eric R. Fearon; Marina Pasca di Magliano; Frank J. Gonzalez; Ruma Banerjee; Daniel R. Wahl; Costas A. Lyssiotis; Michael Green

     

    COI: N/A

     

    Funding: NIH grants: R01CA148828, R01CA245546, R01DK095201, R37CA237421, R01CA248160, R01CA244931 (C.A.L); UMCCC Core Grant P30CA046592 and R35GM130183; T32 training grant GM008322 and F30CA257292. American Heart Association (826245) and NIH grant F30CA257292. NIH F31 fellowship (F31CA247457) and NIH fellowship (F99CA264414).CMB Graduate Program T32GM007315. American Physiological Society postdoctoral fellowship (032650). Crohn’s and Colitis Foundation Research fellowship award (623914) and the American Heart Association postdoctoral fellowship (19POST34380588). National Research, Development and Innovation Office (PharmaLab, RRF-2.3.1-21-2022-00015 and 2020-1.1.6-JÖVŐ-2021-00013).

     

    DOI: “Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer,” Cell Metabolism. DOI: 10.1172/JCI143691

    [ad_2]

    Michigan Medicine – University of Michigan

    Source link

  • How nerve and vascular cells coordinate their growth

    How nerve and vascular cells coordinate their growth

    [ad_1]

    Newswise — Nerve cells need a lot of energy and oxygen. They receive both through the blood. This is why nerve tissue is usually crisscrossed by a large number of blood vessels. But what prevents neurons and vascular cells from getting in each other’s way as they grow? Researchers at the Universities of Heidelberg and Bonn, together with international partners, have identified a mechanism that takes care of this. The results have now appeared in the journal Neuron. 

    Nerve cells are extremely hungry. About one in five calories that we consume through food goes to our brain. This is because generating voltage pulses (the action potentials) and transmitting them between neurons is very energy-intensive. For this reason, nerve tissue is usually crisscrossed by numerous blood vessels. They ensure a supply of nutrients and oxygen.

    During embryonic development, a large number of vessels sprout in the brain and spinal cord, but also in the retina of the eye. Additionally, masses of neurons are formed there, which network with each other and with structures such as muscles and organs. Both processes have to be considerate of each other so as not to get in each other’s way. “We have identified a new mechanism that ensures this,” explains Prof. Dr. Carmen Ruiz de Almodóvar, member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Area Life & Health at the University of Bonn.

    The researcher moved to the Institute of Neurovascular Cell Biology at the University Hospital Bonn in early 2022. Since this spring, she has held one of the special established Schlegel Professorships, with which the university aims to attract outstanding researchers to Bonn. However, most of the research was still done at her old place of work, the European Center for Angioscience at the Medical Faculty Mannheim, which is part of the University of Heidelberg. The work was then completed at the University of Bonn. In her study, she and international partners took a close look at the formation of blood vessels in the spinal cord of mice.

    Growth pause in the spine

    “The appearance of blood vessels in the spinal cord begins in the animals about 8.5 days after fertilization,” she says. “Between days 10.5 and 12.5, however, blood vessels do not grow in all directions. This is despite the fact that large amounts of growth-promoting molecules are present in their environment during this time. Instead, during this time, numerous nerve cells – the motor neurons – migrate from their place of origin in the spinal cord to their final position. There, they then form extensions called axons that lead from the spine to the various targeting muscles.”

    This means that the motor neurons self-organize and grow at the time that blood vessels do not grow towards them. Only then after, do the vessels begin to sprout again. “The whole thing resembles a carefully choreographed dance,” explains José Ricardo Vieira. The doctoral student in Ruiz de Almodóvar’s research group did much of the work in the study. “In the course of this, each partner takes care not to get in the other’s way.”

    But how is this dance coordinated? Apparently, by the motor neurons shouting a “stop, now it’s my turn” message to the vascular cells. To do this, they use a protein that they release into their environment – semaphorin 3C (Sema3C). It diffuses to the vascular cells and docks there at a receptor called PlexinD1 – in a sense, this is the ear for which the molecular message is intended.

    Deafened vascular cells grow uncontrollably

    “When we stop the production of Sema3C in neurons in mice, blood vessels form prematurely in the region where these neurons are located,” explains Prof. Ruiz de Almodóvar. “This prevents the axons of the neurons from developing properly – they are prevented from doing so by the vessels.” The researchers achieved a similar effect when they experimentally stopped the formation of PlexinD1 in the vascular cells: Since these were now deaf to the Sema3C signal from the neurons, they did not stop growing but continued to sprout.

    The results document the importance of coordinated operation of the two processes during embryonic development. These findings could also contribute to a better understanding of certain diseases, such as retinal defects caused by strong and uncontrolled vessel growth. The use of the newly discovered mechanism may also potentially help in regenerating destroyed brain areas, for example after a spinal cord injury, in the long term.

    Participating institutions and funding:

    In addition to the University of Heidelberg and its Medical Faculty Mannheim, the University Hospital Bonn and the University of Bonn, the San Raffaele Scientific Institute in Milan, University College London, and the German Center for Neurodegenerative Diseases in Bonn were involved in the study. The work was financially supported by the German Research Foundation (DFG) and the European Research Council (ERC).

    Publication: José Ricardo Vieira et. al.: Endothelial PlexinD1 signaling instructs spinal cord vascularization and motor neuron development; Neuron; DOI: 10.1016/j.neuron.2022.12.005

    [ad_2]

    University of Bonn

    Source link

  • Humans continue to evolve with the emergence of new genes

    Humans continue to evolve with the emergence of new genes

    [ad_1]

    Newswise — Modern humans evolutionarily split from our chimpanzee ancestors nearly 7 million years ago, yet we are continuing to evolve. 155 new genes have been identified within the human lineage that spontaneously arose from tiny sections of our DNA. Some of these new genes date back to the ancient origin of mammals, with a few of these “microgenes” predicted to be associated with human-specific diseases. This work is publishing on December 20th in the journal Cell Reports.

    “This project started back in 2017 because I was interested in novel gene evolution and figuring out how these genes originate,” says first author Nikolaos Vakirlis (@vakirlis), a scientist at the Biomedical Sciences Research Center “Alexander Fleming” in Vari, Greece. “It was put on ice for a few years, until another study got published that had some very interesting data, allowing us to get started on this work.”

    Taking the previously published dataset of functionally relevant new genes, the researchers created an ancestral tree comparing humans to other vertebrate species. They tracked the relationship of these genes across evolution and found 155 that popped up from regions of unique DNA. New genes can arise from duplication events that already exist in the genome; however, these genes arose from scratch.

    “It was quite exciting to be working in something so new,” says senior author Aoife McLysaght (@aoifemcl), a scientist at Trinity College Dublin. “When you start getting into these small sizes of DNA, they’re really on the edge of what is interpretable from a genome sequence, and they’re in that zone where it’s hard to know if it is biologically meaningful.”

    Of these 155 new genes, 44 of them are associated with growth defects in cell cultures, demonstrating the importance of these genes in maintaining a healthy, living system. Since these genes are human specific, it makes direct testing difficult. Researchers must seek another way to explore what effects these new genes may have on the body. Vakirlis and his team examined patterns found within the DNA that can hint at if these genes play a role in specific diseases.

    Three of these 155 new genes have disease-associated DNA markers that point to connections with ailments such as muscular dystrophy, retinitis pigmentosa, and Alazami syndrome. Apart from disease, the researchers also found a new gene that is associated with human heart tissue. This gene emerged in human and chimp right after the split from gorilla and shows just how fast a gene can evolve to become essential for the body.

    “It will be very interesting in future studies to understand what these microgenes might do and whether they might be directly involved in any kind of disease,” says Vakirlis.

    “These genes are convenient to ignore because they’re so difficult to study, but I think it’ll be increasingly recognized that they need to be looked at and considered,” says McLysaght. “If we’re right in what we think we have here, there’s a lot more functionally relevant stuff hidden in the human genome.”

    ###

    Financial support provided by the European Research Council and by Greece and the European Union. Aoife McLysaght was a member of the journal’s Advisory Board at the time of this article’s initial submission.

    Cell Reports, Vakirlis et al., “De novo birth of functional microproteins in the human lineage.” https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01696-5 

    Cell Reports (@CellReports), published by Cell Press, is a weekly open access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. Visit: http://www.cell.com/cell-reports. To receive Cell Press media alerts, contact [email protected].

    [ad_2]

    Cell Press

    Source link

  • Why aren’t all black bears black?

    Why aren’t all black bears black?

    [ad_1]

    Newswise — Sometimes a name is just a name. Take bears, for example. In Yellowstone National Park, black bears outnumber their brownish-colored grizzly bear cousins, and in coastal areas of the Pacific Northwest, if someone says “brown bear,” they mean grizzly bear. But not all brown bears are grizzly bears.

    American black bears (Ursus americanus), which one would logically assume are, well, black, actually come in a range of colors, including brown (also known as cinnamon), blond, or bluish-grey. Others have coats that are a mixture of several colors. So, how do you tell a cinnamon-colored Ursus americanus from its brown (grizzly) Ursus arctos cousin? Differences in body shape and size can be subtle. One hypothesis for the cinnamon color of Ursus americanus is that it mimics the appearance of a grizzly bear, helping with camouflage or defense.

    Now, researchers at HudsonAlpha, the University of Memphis, and the University of Pennsylvania, have discovered what causes the cinnamon color, which sheds some light on this color confusion.

    Gene variant responsible for cinnamon morph black bear

    Emily Puckett, PhD, an Assistant Professor of Biological Sciences at the University of Memphis, has devoted her career to learning more about the evolution and genetics of bears. With help from partners in state, provincial, and federal wildlife agencies, she collected hundreds of DNA and hair samples from North American bears. She teamed up with Greg Barsh, MD, PhD, Faculty Investigator at HudsonAlpha, and animal pigmentation expert to figure out why black bears aren’t always black.

    In mammals, pigment is produced by skin cells called melanocytes. There are two types of melanin: eumelanin is black or brown, and pheomelanin is red or yellow. It is widely accepted that genetic variation in melanin biosynthesis gives rise to differences in hair, eye, and skin color. By studying photos of bears and chemically analyzing their corresponding hair samples, the team determined that cinnamon-colored black bears have reduced amounts of eumelanin, just like grizzly bears. 

    Genome sequence analysis of nearly 200 bears uncovered different missense mutations in the gene Tyrosinase-related protein 1 (TYRP1): cinnamon-colored black bears have a mutation called TYRP1R153C, while most (but not all) grizzly bears have a mutation called TYRP1R114C. The TYRP1 gene produces an enzyme within melanocytes that helps produce eumelanin, so it makes sense that the cinnamon and grizzly bears have less eumelanin. Furthermore, functional studies carried out by Mickey Marks, PhD, Professor of Pathology at the University of Pennsylvania, and his lab, determined that the TYRP1R153C and TYRP1R114C mutations interfere with melanin synthesis and distribution.

    “When we looked at other species, we were surprised to find the TYRP1R153C variant responsible for cinnamon U. americanus is identical to one previously described as a cause of oculocutaneous albinism (OCA3) in humans,” says Barsh. OCA3 is characterized by reddish skin and hair and frequent visual abnormalities and is most common in people of African or Puerto Rican ancestry. But according to Puckett, bears with TYRP1 mutations have normal skin and can see just fine.

    When and where did the cinnamon morph arise?

    The TYRP1R153C variant was primarily found in the southwest United States, at lower frequencies moving northward to Southeast Alaska and the Yukon Territory. TYRP1R153C was associated with the cinnamon color in black bears and the chocolate and light brown colors, meaning it accounts for almost all of the color diversity among U. americanus.

    The researchers used their data to learn more about the TYRP1R153C mutation. One hypothesis is that it may have started in grizzly bears and then was transferred to black bears, but demographic analysis indicated that was not the case. Instead, the TYRP1R153C mutation arose spontaneously about 9,360 years ago in black bears living in the western United States, then spread as the bears moved across their current geographic range.

    “Based on its wide range today, the TYRP1R153C mutation that arose in black bears over 9,000 years ago probably gave an advantage to the cinnamon bears,” says Puckett. “We used genetic modeling and simulations to predict the selective forces acting on the cinnamon morph. But our predictions ruled out the grizzly mimicry hypothesis as well as another hypothesis having to do with thermoregulation.”

    As to why the coat color variant arose in the first place, the team presents a new hypothesis: crypsis. Crypsis refers to the ability of an animal to conceal itself and blend into the environment. Generally, crypsis is found in prey species and ambush predators who color match within their environments. Here, the researchers suggest crypsis as a broader adaptive mechanism for large-bodied species.

    “These results illustrate how genetic variation in melanin biosynthesis can underlie iconic phenotypes and inform our understanding of color variation and recent evolution in large carnivores,” says Barsh.

    [ad_2]

    HudsonAlpha Institute for Biotechnology

    Source link

  • Climate change played key role in dinosaur success story

    Climate change played key role in dinosaur success story

    [ad_1]

    Newswise — Climate change, rather than competition, played a key role in the ascendancy of dinosaurs through the Late Triassic and Early Jurassic periods.

    According to new research, changes in global climate associated with the Triassic-Jurassic mass extinction – which wiped out many large terrestrial vertebrates such as the giant armadillo-like aetosaurs – actually benefitted the earliest dinosaurs.

    In particular, sauropod-like dinosaurs, which became the giant herbivore species of the later Jurassic like Diplodocus and Brachiosaurus, were able to thrive and expand across new territories as the planet warmed up after the extinction event, 201 million years ago.

    The new evidence is published in Current Biology, by an international team of palaeontologists led by the Universities of Birmingham and Bristol, in the UK, Friedrich-Alexander University Erlangen-Nürnberg (FAU), in Germany, and the University of São Paulo in Brazil.

    The team compared computer models of prehistoric global climate conditions such as temperature and rainfall with data on the different locations of dinosaurs taken from sources such as the Paleobiology Database. They showed how the sauropods, and sauropod-like animals, with their long tails and necks and small heads, were the runaway success story of a turbulent period of evolution.

    Dr Emma Dunne, now a lecturer in palaeontology at FAU, carried out the research while at the University of Birmingham. She said: “What we see in the data suggests that instead of dinosaurs being outcompeted by other large vertebrates, it was variations in climate conditions that were restricting their diversity. But once these conditions changed across the Triassic-Jurassic boundary, they were able to flourish.

    “The results were somewhat surprising, because it turns out that sauropods were really fussy from the get-go: later in their evolution they continue to stay in warmer areas and avoid polar regions.”

    Co-author on the paper, Professor Richard Butler, at the University of Birmingham, said: “Climate change appears to have been really important in driving the evolution of early dinosaurs. What we want to do next is use the same techniques to understand the role of climate in the next 120 million years of the dinosaur story”.

    The research was funded by the Leverhulme Trust and the European Research Council.

    [ad_2]

    University of Birmingham

    Source link

  • New Computer Model Tracks Origin of Cell Changes That Drive Development

    New Computer Model Tracks Origin of Cell Changes That Drive Development

    [ad_1]

    Newswise — Scientists at Johns Hopkins Medicine say they have developed a computer model — dubbed quantitative fate mapping — that looks back in the developmental timeline to trace the origin of cells in a fully grown organism. The new model, they say, can help researchers more precisely spot which cells acquire alterations during development that change an organism’s fate from healthy to disease states, including cancer and dementia.

    The achievement, described in the Nov. 23 issue of Cell, uses mathematical algorithms that take into account the general speed with which cells divide and differentiate, the rate at which mutations naturally accumulate and other known factors of organism development.

    “We can use this method to examine the development of organisms from cell samples, including those from non-model organisms such as humpback whales that we don’t ordinarily study,” says Reza Kalhor, Ph.D., assistant professor of biomedical engineering, genetic medicine, molecular biology and genetics and neuroscience at The Johns Hopkins University and School of Medicine. “For example, with a cell sample from the carcass of a humpback whale, we can understand how it developed as an embryo.”

    The new computer model is based on the fact that every complex living organism comes from a single, fertilized cell, or zygote. That cell divides, and the daughter cells continue dividing, eventually differentiating into specialized cells in tissues. Humans, for example, have about 70 trillion individual cells and several thousand types of cells.

    Each time a cell divides, a mutation can occur, and that alteration gets passed on to the daughter cells, which divide again, perhaps acquiring a second mutation, both of which are passed to their daughter cells, and so on. The mutations act as a kind of barcode that is detectable with genomic sequencing equipment. Scientists can track these mutations in reverse order to construct a cell’s lineage, they say.

    The quantitative fate mapping program has two parts. One is a computer program called Phylotime, which reads cell mutations as barcodes to infer the timescale associated with cell divisions. The name Phylotime stands for Phylogeny Reconstruction Using Likelihood of Time. In biology, phylogeny describes and depicts lines of evolutionary development. The second part developed by the Johns Hopkins team is a computer algorithm called ICE-FASE, which creates a model of the hierarchy and lineages of cells within an organism based on the timescales of cell divisions.

    To test the computer model, the Johns Hopkins team induced mutations in human induced pluripotent cells (iPSCs) at certain locations in the genome and at random times. Such iPSCs give rise to nearly any cell in the human body. They cultured the cells and let them divide, following the original mutation and ones that occurred spontaneously in subsequent daughter cells.

    At the end of the experiment, the researchers performed genomic sequencing on the final group of daughter cells and entered any mutations they found into the computer model.

    The result was a kind of family tree extending from the original human iPSC.

    The researchers can construct an ancestry of mature cells by comparing the combinations of mutations and drawing a far more precise picture of how the organism developed. They tested the model with computer simulations of mouse cells and human iPSCs.

    Kalhor says the new tool can help scientists compare normal versus disease states in organisms, including humans. “This tool may be helpful in showing how and when cells deviate from the normal path, which can aid the development of disease prevention tools or curative therapies,” adds Kalhor.

    The so-called cell “fate maps” developed by the quantitative fate mapping tool provide a history of cell fate determination events that happened during an organism’s development, but unlike genomic sequencing studies alone, the new tool shows when the fate commitment occurred and the relationship of a large number of different cell types in the population, says Weixiang Fang, Ph.D., postdoctoral fellow in the department of biomedical engineering at Johns Hopkins and first author of the study.

    While the computer model can construct how and when cells develop in an organism, it cannot determine whether the spontaneous mutations occur because of external, internal or random factors.

    Fang and Kalhor have made Phylotime free to use by other scientists, and it is available online.

    The research was supported by the Simons Foundation, the National Institutes of Health and the David and Lucile Packard Foundation.

    Other scientists who contributed to the research include Hongkai Ji, Ph.D., professor of biostatistics at the Johns Hopkins Bloomberg School of Public Health, who co-supervised the study, as well as Claire Bell, Abel Sapirstein, Soichiro Asami, Kathleen Leeper and Donald Zack from Johns Hopkins.

    DOI: 10.1016/j.cell.2022.10.028

    [ad_2]

    Johns Hopkins Medicine

    Source link

  • Expanding the arsenal of drugs against COVID-19

    Expanding the arsenal of drugs against COVID-19

    [ad_1]

    Newswise — Tokyo, Japan – The ongoing COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been devastating the entire world. While the vaccination program is advancing, drug treatments for COVID-19 are still highly important for those who become infected. Now, a team at Tokyo Medical and Dental University (TMDU), National Center for Global Health and Medicine (NCGM), Tohoku University, NCI/NIH, and Kumamoto University has designed and synthesized compounds that have the potential to be novel drugs targeting SARS-CoV-2.

    The SARS-CoV-2 virus contains an enzyme called the “main protease”, or Mpro, that cleaves other proteins encoded in the SARS-CoV-2 genome as part of viral activity and replication. Mpro is an important and appealing target for drugs treating COVID-19 because it is both essential for viral replication and very different from any human molecules, so drugs targeting Mpro are likely to have few side effects and be very effective.

    When testing a panel of compounds known to have inhibitory activity against SARS-CoV, the virus responsible for the 2002 SARS outbreak, the team identified a compound named 5h/YH-53 that showed some activity inhibiting SARS-CoV-2 Mpro, but was inefficient and unstable. Therefore, they used 5h as a starting point to develop other compounds with increased efficiency and stability. “Our strategy involved introducing fluorine atoms into the part of the molecule responsible for inhibiting Mpro to increase its binding affinity, as well as replacing a bond within 5h that is easily broken down by the liver with a different structure to increase biostability,” explains lead author Kohei Tsuji.

    “Of the compounds we developed, compound 3 showed high potency and was able to block SARS-CoV-2 infection in vitro without any viral breakthrough,” explains senior author Hirokazu Tamamura. “Compound 4, a derivative of compound 3 in which an easily broken-down amide bond had been replaced with a stable thioamide bond, also showed remarkable anti-SARS-CoV-2 activity.” Although compound 4 had lower Mpro inhibitory activity than compound 3, the increased stability meant that the overall activity of compound 4 was comparable to that of compound 3.

    When they tested these novel compounds on a variety of strains of SARS-CoV-2, compound 3 was as effective on mutant strains of the virus as on the ancestral Wuhan strain. Additionally, neither compound 3 or 4 showed any toxicity to cultured cells. These data suggest that these compounds show high potential as drug treatments for COVID-19.

    A repertory of drug choice is important for treating disease, and so the development of efficient drugs to target the novel SARS-CoV-2 virus is highly important. This work identifies two compounds as potential drugs, and further development of these compounds continues. It also proves the principle that easily broken-down amide bonds can be replaced with thioamide bonds in drug development to increase the stability of the resulting compounds. Taken together, this is an important advance in both the wider drug development field as well as for drugs to treat COVID-19.

    ###

    The article, “Potent and Biostable Inhibitors of the Main Protease of SARS-CoV-2”, was published in iScience at DOI: 10.1016/j.isci.2022.105365

    [ad_2]

    Tokyo Medical and Dental University

    Source link

  • LJI scientists confirm smallpox vaccine also teaches T cells to fight mpox

    LJI scientists confirm smallpox vaccine also teaches T cells to fight mpox

    [ad_1]

    Newswise — LA JOLLA, CA—There’s even more reason to think a vaccine developed against smallpox can help the body fight against mpox (monkeypox virus disease) as well, according to researchers at La Jolla Institute for Immunology (LJI). Their new study, published in Cell Host & Microbe, is the first to provide evidence that the vaccinia vaccine MVA-BN (brand name JYNNEOS) should also train virus-fighting T cells to recognize mpox sequences.

    “This study gives us confidence that T cell response induced by the JYNNEOS vaccine should be able to also recognize mpox virus,” says LJI Professor Alessandro Sette, Dr.Biol.Sci., who co-led the new study with LJI Instructor Alba Grifoni, Ph.D.

    The study comes as more than 100 countries reported unprecedented mpox outbreaks. In the United States, there have been more than 28,000 reported cases and 11 deaths attributed to mpox since May 2022.

    Why we need mpox vaccine data

    Although the JYNNEOS vaccine, based on a non-live attenuated orthopox virus called modified vaccine ankara (MVA), is approved to prevent mpox infection and severe disease, researchers don’t yet have clinical efficacy data from human trials. Still, researchers know that mpox virus is similar enough to other orthopoxviruses that immunization against an orthopoxvirus called vaccinia (VACV) can also train the immune system to fight mpox.

    Mpox (termed “monkeypox” until recently) is a member of the orthopox family of viruses. The deadliest, of course, was variola virus,causing the disease known as smallpox. Smallpox was eradicated worldwide in 1980 thanks to a massive and successful vaccination campaign to administer the Dryvax vaccine, based on VACV.

    VACV and variola virus have a lot of immune system targets (called antigens), in common. This means training the body to recognize VACV also taught immune cells to recognize variola virus. But there was a downside—Dryvax (and a newer version called Acambis 2000) had harmful side effects, especially in immunocompromised people.

    JYNNEOS was designed to have a better safety profile. While the vaccine performed well in pre-clinical tests, the eradication of smallpox meant scientists couldn’t see how JYNNEOS performed in human patients in real-world infection scenarios, such as a smallpox outbreak or possible case of smallpox-based biological warfare (a concern in the early days of the Iraq War).

    How a smallpox vaccine protects against mpox

    For the new study, the LJI team set out to study if the viral proteins known to be targeted by T cells induced by VACV vaccination, would also be conserved in JYNNEOS and in mpox. As Grifoni explains, while antibodies are key for vaccine efficacy and preventing reinfections, T cells are essential for both preventing severe infections and “remembering” past infections.

    “By recognizing infected cells, T cells are able to limit how much viruses can spread inside the body modulate disease severity, and ultimately terminate the infection” says Grifoni. “T cell responses also tend to be long lasting, and resilient to viral mutations to escape immune recognition. What we have seen in the context of SARS-CoV-2 is that even if the virus mutates somewhat, T cells reactivity is still largely preserved.”

    The researchers demonstrated that the known targets of T cell responses seen in the VACV proven -efficacy vaccine, are also found in JYNNEOS and mpox, suggesting that the JYNNEOS vaccine can indeed trigger an effective T cell response against mpox infection.  The initial test of their hypothesis was based on developing viral peptide “megapools,” or reagents designed to detect T cell reactivity to mpox antigens. The experiments further showed that these megapools can be used to accurately detect specific T cells.

    “Vaccines such as JYNNEOS should be able to induce T cells that also recognize mpox and can provide protection from severe disease,” says Grifoni.

    Could the vaccine work in immunocompromised patients?

    “The majority of mpox cases have been in men who have sex with men,” Sette explains. “In that community, a significant fraction of the people that have been infected with mpox also happened to be HIV-positive. So it is important to learn how people who are HIV-positive respond to infection and vaccination compared to HIV-negative individuals. The present study enables future study to establish this key point”

    Sette emphasizes that most HIV-positive individuals are not necessarily at greater risk of mpox infection or severe disease. “We do not expect that HIV-positive individuals will respond differently to infection and vaccination, because in most cases, people who live with HIV live with a controlled HIV because of the available therapies,” he says. “Nevertheless, it’s important to provide these data to the community affected by this outbreak and to the general scientific community.”

    Whether the JYNNEOS vaccine sparks a similar immune response in people with and without HIV—and the role of T cells—will have to be determined in future studies. “We also expect to see no difference in the duration of protection between HIV positive and HIV negative individuals, but that still all needs to be proven and evaluated experimentally. We are actively engaging the community most affected by the outbreak and the scientific community at large ” says Sette.

    Next steps for the LJI team

    The researchers are now working to characterize the T cell response to mpox in more detail. They are especially interested in how T cell responses differ after vaccination versus natural infection. Sette and Grifoni would also like to compare T cell responses following JYNNEOS vaccination with the older Dryvax vaccination.

    Just as they’ve done throughout the COVID-19 pandemic, Sette and his colleagues hope to share their reagents freely to and spur more life-saving studies around the globe. “We want to make these reagents widely available to whoever asks,” says Sette.

    Additional authors of the study, “Defining antigen targets to dissect vaccinia virus (VACV) and Monkeypox virus (MPXV)-specific T cell responses in humans,” include Yun Zhang, Alison Tarke, John Sidney, Paul Rubiro, Maria Reina-Campos, Gilberto Filaci, Jennifer Dan, and Richard H. Scheuermann.

    This research was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (Contract No. 75N93019C00001, 75N9301900065, and HHS75N93019C00076) and through a Ph.D. student fellowship from the Clinical and Experimental Immunology Course at the University of Genoa, Italy, and with support from other private foundations.

    DOI: 10.1016/j.chom.2022.11.003

    [ad_2]

    La Jolla Institute for Immunology

    Source link