ReportWire

Tag: Cell (journal)

  • The mechanism of tuberculosis infection via cord-like bacterial aggregates.

    The mechanism of tuberculosis infection via cord-like bacterial aggregates.

    Newswise — The ability of Mycobacterium tuberculosis (MTB), a serious respiratory infection, to form snake-like cords was first noted nearly 80 years ago. In a study published October 20 in the journal Cell, investigators report the biophysical mechanisms by which these cords form and demonstrate how several generations of dividing bacteria hang together to create these structures that enable resistance to antibiotics.

    “Our work clearly showed that cord formation is important for infection and why this highly ordered architecture might be important for pathogenesis,” says senior author Vivek Thacker (@DrVivekThacker), who led the work at the Global Health Institute at École Polytechnique Fédérale de Lausannen (EPFL) in Switzerland and is now based at the Department of Infectious Diseases at Heidelberg University in Germany.

    The study used a unique combination of technologies to address the role of MTB cord formation. One was a lung-on-chip model, which allowed the researchers to get a direct look at “first contact” between MTB and host cells at the air-liquid interface in the lungs. This revealed that cord formation is prominent in early infection. The researchers also used a mouse model that develops pathologies mimicking human tuberculosis, allowing them to obtain tissue that could be studied using confocal imaging and confirming that cording also occurs early in infection in vivo.

    The work yielded several new findings about how these cords interact with and compress the cell nucleus, how this compression affects the immune system and connections between host cells and epithelial cells, and how cord formation affects the alveoli in the lungs. The study also revealed how these cords retain their structural integrity and how they increase tolerance to antibiotic therapy.

    “There is an increasing understanding that these mechanical forces influence cellular behavior and responses, but this aspect has been overlooked since traditional cell culture models do not recapitulate the mechanical environment of a tissue,” says Melanie Hannebelle (@MelanieHanneb), formerly at EPFL’s Global Health Institute and now at Stanford University. “Understanding how forces at the cellular and tissue level or crowding at the molecular level affects cell and tissue function is therefore important to develop a complete picture of how biosystems work.”

    “By thinking of MTB in infection as aggregates and not single bacteria, we can imagine new interactions with host proteins for known effectors of MTB pathogenesis and a new paradigm in pathogenesis where forces from bacterial architectures affect host function,” says Thacker.

    Future research will focus on understanding whether cord formation enables new functionality to known effectors of MTB pathogenesis, many of which are located on the MTB cell wall. In addition, it will look at the consequence of tight-packing on the bacteria within the clump and how this may lead to a protective effect against antibiotics.

    “Antibiotic therapy is the mainstay of treatment for tuberculosis infections, but therapeutic regimens are long and complicated, with an increasing threat of drug resistance,” says Richa Mishra, the other first author who is currently at EPFL’s Global Health Institute. “There is a recognized need for host-directed therapies or therapies that inhibit specific virulence mechanisms that can shorten and improve antibiotic therapy.”

    Cell Press

    Source link

  • Newsmakers: Basic Research Findings by Johns Hopkins Scientists Focus on Gene Sequencing, Hearing Loss and a Brain Disorder

    Newsmakers: Basic Research Findings by Johns Hopkins Scientists Focus on Gene Sequencing, Hearing Loss and a Brain Disorder

    Newswise — Yes, Scientists Have Sequenced the Entire Human Genome, But They’re Not Done Yet

    The human genome, from end to end, has been sequenced, meaning scientists worldwide have identified most of the nearly 20,000 protein-coding genes. However, an international group of scientists notes there’s more work to be done. The scientists point out that even though we have nearly converged on the identities of the 20,000 genes, the genes can be cut and spliced to create approximately 100,000 proteins, and gene experts are far from agreement on what those 100,000 proteins are.

    The group, which convened last fall at Cold Spring Harbor Laboratory in New York, has now published a guide for prioritizing the next steps in the effort to complete the human gene “catalog.”

    “Many scientists have been working on efforts to fully understand the human genome, and it’s much more difficult and complex than we thought,” says Steven Salzberg, Ph.D., Bloomberg Distinguished Professor of Biomedical Engineering, Computer Science, and Biostatistics at The Johns Hopkins University. “We have provided a state of the human gene catalog and a guide on what’s needed to complete it.”

    Salzberg, along with Johns Hopkins biomedical engineer and associate professor Mihaela Pertea, Ph.D., M.S., M.S.E., postdoctoral researcher Ales Varabyou and 19 other scientists, offered perspectives on the human gene catalog Oct. 4 in the journal Nature.

    The scientists say that while the final list of protein coding genes is nearly complete, scientists have not yet fully cataloged the variety of ways that a gene can be cut, or spliced, resulting in “isoforms” of proteins that are slightly different. Some protein isoforms will not affect the protein’s function but some may be different enough to result in increased risk for a particular trait, condition or illness.

    To complete the catalog, the scientists propose a comprehensive look at how each gene is expressed into functional and nonfunctional proteins and the three-dimensional shape of those proteins.

    The scientists also propose a focus on cataloging non-coding RNA genes. RNA is the genetic material that is transcribed by DNA and follows a molecular path to making proteins. Instead of proteins, non-coding RNA genes encode other types of molecular material that performs a cellular function.

    Finally, the international group emphasizes the importance of enhancing commonly used databases of gene variations that cause illness and disease, improving clinical laboratory standards for annotating DNA sequencing results and developing new technology to enable more effective and precise methods to match the wide array of proteins with their gene products.

    When It Comes to Hearing, the Left and Right Sides of the Brain Work Together, Mouse Research Shows

    Johns Hopkins-led research has revealed an extensive network of connections between the right and left sides of the brain when mice are exposed to different sounds. The researchers also found that some areas of the brain are specialized to recognize certain sounds, such as “calls” from the animals. Further, the researchers also found that deaf mice had far fewer right and left brain connections, suggesting that the brain needs to “hear” and process sound during early ages to spur development of left-right brain connections.

    The findings, say the researchers, may eventually help scientists pinpoint the time period when such brain connections and specialization form, and offer potential insights into how to restore hearing loss.

    “The auditory system is a collection of parts, which need to be connected properly,” says Johns Hopkins neuroengineer Patrick Kanold, Ph.D., a professor of biomedical engineering. “Using a novel microscope that enabled us to see both brain hemispheres at the same time, we found that some of those connections are between the right and left brain hemispheres, allowing functional specialization. When the brain does not get the right inputs, for example in hearing loss, these brain connections are missing. This obviously is an issue if we hope to restore hearing at a later age.”

    In efforts to find new ways to restore hearing, Kanold’s team will continue its work to identify the specific time period when brain connections form in response to sound and how to restore abnormal connections. The team is also continuing research to understand how the brain adapts to and modulates sound processing to filter out distracting signals, such as its recent work indicating that the brain’s frontal cortex provides specific signals to the auditory system during behaviors that might help in this filtering process.

    New Mouse Models May Help Scientists Find Therapies for Brain Development Disorder

    For more than 25 years, Richard Huganir, Ph.D., Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences and director of the Solomon H. Snyder Department of Neuroscience, at the Johns Hopkins University School of Medicine, has studied the protein SYNGAP1 that is now known to be linked to a group of neurodevelopmental disorders that are usually diagnosed during early childhood. Working with biotechnology companies to find new therapies for the conditions, his team at Johns Hopkins Medicine reports it has developed new mouse models that more accurately represent genetic mutations in people who have SYNGAP1-related disorders.

    The new collection of mouse models, now available to scientists developing treatments, have several variations in the SYNGAP1 gene, which were discovered to cause conditions marked by seizures, cognitive impairment, social deficits and sleep disturbances.

    The SYNGAP1 gene, found also in humans, makes proteins that regulate synapses, the space between two neurons where they trade chemical and molecular messages. When SYNGAP1 is mutated, as in the case of SYNGAP1-related disorders in people, neurons make less of the protein in the synapse, and learning and memory are impaired.

    In other mouse models, called “knock-out” models, the SYNGAP1 gene is removed entirely. Huganir says both the knock-out models and the new versions — “knock-in” models, which carry a variety of SYNGAP1 mutations linked to the disorders — will be helpful in finding therapies that boost SYNGAP1 protein production.

    ###

    Johns Hopkins Medicine

    Source link

  • Scientists Take Next Big Step in Understanding Genetics of Schizophrenia

    Scientists Take Next Big Step in Understanding Genetics of Schizophrenia

    Newswise — CHAPEL HILL, NC – Genetically speaking, we are individuals different from each other because of slight variations in our DNA sequences – so-called genetic variants – some of which have dramatic effects we can see and comprehend, from the color of our eyes to our risk for developing schizophrenia – a debilitating psychiatric condition affecting many millions worldwide. For several years, scientists have studied the entire genomes of thousands of people – called genome-wide association studies, or GWAS – to find approximately 5,000 genetic variants associated with schizophrenia.

    Now, UNC School of Medicine scientists and colleagues are figuring out which of these variants have a causal effect in the development of the schizophrenia. They are finding that some of genetic variants regulate or alter the expression of genes involved in the condition.

    Published in the journal Cell Genomics, this research marks a big step forward in our understanding of the genetic basis of schizophrenia.

     “Our findings not only provide insights into the intricate regulatory landscape of genes, but also propose a groundbreaking approach to decoding the cumulative effect of genetic variants on gene regulation in individuals with schizophrenia,” said senior author Hyejung Won, PhD, associate professor of genetics at the UNC School of Medicine. “This comprehension could potentially pave a path for more precise interventions and therapies in the future. Right now, therapeutic options are limited, and some people do not respond to drugs available.”

    For this study, Won and first authors Jessica McAfee and Sool Lee, both UNC-Chapel Hill graduate students, led a team of researchers from UCLA, Harvard, the University of Michigan, and Human Technopole in Italy to explore the genetic variants already linked to the risk of schizophrenia through GWAS research. Their goal was to figure out a way to tease apart meaningless variants from those with potential for biological activity important for developing schizophrenia. This isn’t easy for a few reasons, one of which is that genetic variants are often inherited together from parents. So, right next to each other could be two genetic variants associated with the condition – one might be important for gene expression that plays a major role in the condition, but the other variant might not have any role in the condition.

    To tackle this problem, the researchers used a special technique called a massively parallel reporter assay (MPRA) – essentially a genetic sequencing technique that can parse which variants trigger gene expression and which ones don’t. To use this method, the researchers introduced the 5,000 variants into human brain cells in a dish, cells that are essential for early brain development. These variants may or may not cause the expression of their downstream gene and genetic barcode.  The barcode, a 20bp DNA sequence, is unique to each variant. This is what the group uses to distinguish the variant sequences. The MPRA revealed 439 genetic variations with actual biological effects, meaning they can alter expression of gene.

    “Traditionally, scientists have used other epigenetic data, such as transcription factor binding and biochemically defined enhancers, to identify variants with biological effects,” Won said. “However, these conventional methods failed to predict a large portion of variants we identified to have biological effects. Our work points to a wealth of unexplored variants with biological effects.”

    To understand how these variants work together to influence gene activity, Won and colleagues developed a new model that combines data from MPRA with chromatin architecture of brain cells – that is, the genetic information important for how brain cell DNA is organized. By doing this, the researchers could connect these 439 variants to how genes are turned on or off.

    “Schizophrenia is a complex condition that is highly heritable,” Won said. “To find these 439 potentially causal variants is a big step, but we still have a lot of work ahead to figure out the complicated genetic architecture that leads an individual to develop this condition. With that information in hand, we could begin to understand the biological mechanism underlying this complex disorder, which may eventually lead to targeted therapies.”

    University of North Carolina School of Medicine

    Source link

  • New antibiotic from ‘dark matter’ targets superbugs

    New antibiotic from ‘dark matter’ targets superbugs

    Newswise — A new powerful antibiotic, isolated from bacteria that could not be studied before, seems capable to combat harmful bacteria and even multi-resistant ‘superbugs’. Named Clovibactin, the antibiotic appears to kill bacteria in an unusual way, making it more difficult for bacteria to develop any resistance against it. Researchers from Utrecht University, Bonn University (Germany), the German Center for Infection Research (DZIF), Northeastern University of Boston (USA), and the company NovoBiotic Pharmaceuticals (Cambridge, USA) now share the discovery of Clovibactin and its killing mechanism in the scientific journal Cell.

    Urgent need for new antibiotics

    Antimicrobial resistance is a major problem for human health and researchers worldwide are looking for new solutions. “We urgently need new antibiotics to combat bacteria that become increasingly resistant to most clinically used antibiotics,” says Dr. Markus Weingarth, a researcher from the Chemistry Department of Utrecht University.

    However, the discovery of new antibiotics is a challenge: few new antibiotics have been introduced into the clinics over the last decades, and then they often resemble older, already known antibiotics.

    “Clovibactin is different,” says Weingarth. “Since Clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance.”

    Antibiotic from bacterial dark matter

    Clovibactin was discovered by NovoBiotic Pharmaceuticals, a small US-based early-stage company, and microbiologist Prof. Kim Lewis from Northeastern University, Boston. Earlier, they developed a device that allows to grow ‘bacterial dark matter’, which are so-called unculturable bacteria. Intriguingly, 99% of all bacteria are ‘unculturable’ and could not be grown in laboratories previously, hence they could not be mined for novel antibiotics. Using the device, called iCHip, the US researchers discovered Clovibactin in a bacterium isolated from a sandy soil from North Carolina: E. terrae ssp. Carolina.

    In the joint Cell publication, NovoBiotic Pharmaceuticals shows that Clovibactin successfully attacks a broad spectrum of bacterial pathogens. It was also successfully used to treated mice infected with the superbug Staphylococcus aureus. 

    A broad target spectrum

    Clovibactin appears to have an unusual killing mechanism. It targets not just one, but three different precursor molecules that are all essential for the construction of the cell wall, an envelope-like structure that surrounds bacteria. This was discovered by the group of Prof. Tanja Schneider from the University of Bonn in Germany, one of the Cell paper’s co-authors.

    Schneider: “The multi-target attack mechanism of Clovibactin blocks bacterial cell wall synthesis simultaneously at different positions. This improves the drug’s activity and substantially increases its robustness to resistance development.”

    A cage-like structure

    How exactly Clovibactin blocks the synthesis of the bacterial cell wall was unraveled by the team of Dr. Markus Weingarth from Utrecht University. They used a special technique called solid-state nuclear magnetic resonance (NMR) that allows to study Clovibactin’s mechanism under similar conditions as in bacteria.

    “Clovibactin wraps around the pyrophosphate like a tightly sitting glove. Like a cage that encloses its target” says Weingarth. This is was gives Clovibactin its name, which is derived from Greek word “Klouvi”, which means cage. The remarkable aspect of Clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it ignores that variable sugar-peptide part of the targets. “As Clovibactin only binds to the immutable, conserved part of its targets, bacteria will have a much harder time developing any resistance against it. In fact, we did not observe any resistance to Clovibactin in our studies.”

    Fibrils capture the targets

    Clovibactin can do even more. Upon binding the target molecules, it self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.

    “Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why Clovibactin selectively damages bacterial cells but is not toxic to human cells,” says Weingarth. “Clovibactin hence has potential for the design of improved therapeutics that kill bacterial pathogens without resistance development.”.

     

    Utrecht University

    Source link

  • Un estudio indica que las anomalías cromosómicas podrían dificultar el crecimiento de algunos tumores agresivos

    Un estudio indica que las anomalías cromosómicas podrían dificultar el crecimiento de algunos tumores agresivos

    Newswise — ROCHESTER, Minnesota — Las anomalías cromosómicas son un rasgo característico de las células cancerosas. Los defectos en el genoma derivados de la separación incorrecta de cromosomas (y el ADN que contienen) en cada división celular conllevan crecimiento tumoral y resistencia al tratamiento.

    Sin embargo, lo opuesto también sucede, ya que los niveles altos de este cifrado genómico persistente y caótico, conocido como inestabilidad cromosómica, son perjudiciales para los tumores. Como resultado, las células cancerosas necesitan controlar estas anomalías para sobrevivir.

    En un estudio de investigación publicado recientemente en la revista Cell Reports Medicine, la Dra. en Ciencias Veronica Rodriguez-Bravo, bióloga molecular y de células cancerosas de Mayo Clinic, y su equipo identificaron un “freno” que usan las células tumorales que les permite sobrevivir a una alta inestabilidad cromosómica y volverse más agresivas. Los investigadores también descubrieron que los tumores cancerosos de próstata resistentes al tratamiento exhiben una inestabilidad cromosómica mayor que otros tipos de tumores. Si los tratamientos futuros se desarrollaran para continuar la inestabilidad, es decir, para impedir el efecto “freno”, esto podría detener el crecimiento y la supervivencia de las células cancerosas.  

    “Este estudio desafía el dogma de que las anomalías cromosómicas son principalmente promotoras de tumores y propone que, en realidad, estas pueden ser el talón de Aquiles de los tumores agresivos, como en el caso del cáncer prostático metastásico”, explica la Dra. Rodriguez-Bravo. “En general, estos tumores se consideran ‘invencibles’; por eso, descubrir que son selectivamente sensibles a medicamentos que derivan de aberraciones cromosómicas aún mayores en las células tumorales fue muy importante. Durante muchos años, las anomalías cromosómicas se consideraron principalmente promotoras de los tumores porque se asocian con la evolución de los tumores agresivos”.

    Los investigadores estudiaron modelos experimentales, como los modelos preclínicos en células cancerosas de la próstata y derivados de pacientes, combinados con el análisis de los datos de pacientes. El equipo descubrió que las células cancerosas de la próstata con un alto nivel de inestabilidad cromosómica activan genes específicos que impiden que las células desarrollen más anomalías cromosómicas con lo que garantizan la supervivencia de las células cancerosas y continúan propiciando el crecimiento tumoral. De esta forma, los tumores resistentes al tratamiento pueden evitar alcanzar niveles de anomalías genómicas catastróficas que los destruirían.

    “El estudio demuestra que alterar terapéuticamente el ‘freno’ como estrategia para forzar a las células cancerosas a acumular niveles letales de anomalías cromosómicas ocasiona la muerte de las células tumorales resistentes al tratamiento y mejora la supervivencia en modelos preclínicos derivados de pacientes”, afirma la Dra. Rodriguez-Bravo. “El estudio proporciona pruebas del concepto para desarrollar una nueva estrategia terapéutica contra los tumores agresivos con alta inestabilidad cromosómica”.

    Este estudio es producto de un trabajo científico en equipo en Mayo Clinic en el que participaron investigadores del Departamento de Urología y del Departamento de Bioquímica y Biología Molecular.

    “El propósito principal de nuestra investigación es descubrir las vulnerabilidades cromosómicas de los tumores agresivos, como el cáncer de próstata, para ayudar a desarrollar nuevas terapias combinadas para los pacientes”, concluye la Dra. Rodriguez-Bravo. “Estudiar los procesos fundamentales mediante la investigación oncológica básica a traslacional es clave para alcanzar ese objetivo y descubrir oportunidades ocultas”.

    La investigación contó con el respaldo de la Fundación Mayo Clinic, el Centro Oncológico Integral de Mayo Clinic y el Instituto Nacional del Cáncer de los Estados Unidos.

    Para obtener más información, visite Discovery’s Edge.

    PERIODISTAS: la Dra. Bravo ofrece entrevistas en español e inglés.

    ###

    Información sobre Mayo Clinic
    Mayo Clinic es una organización sin fines de lucro, dedicada a innovar la práctica clínica, la educación y la investigación, así como a ofrecer pericia, compasión y respuestas a todos los que necesitan recobrar la salud. Visite la Red Informativa de Mayo Clinic para leer más noticias sobre Mayo Clinic.

    Mayo Clinic

    Source link

  • New algorithm may fuel vaccine development

    New algorithm may fuel vaccine development

    Newswise — LA JOLLA, CA—Immune system researchers have designed a computational tool to boost pandemic preparedness. Scientists can use this new algorithm to compare data from vastly different experiments and better predict how individuals may respond to disease.

    “We’re trying to understand how individuals fight off different viruses, but the beauty of our method is you can apply it generally in other biological settings, such as comparisons of different drugs or different cancer cell lines,” says Tal Einav, Ph.D., Assistant Professor at La Jolla Institute for Immunology (LJI) and co-leader of the new study in Cell Reports Methods.

    This work addresses a major challenge in medical research. Laboratories that study infectious disease—even laboratories focused on the same viruses—collect wildly different kinds of data. “Each dataset becomes its own independent island,” says Einav.

    Some researchers might study animal models, others might study human patients. Some labs focus on children, others collect samples from immunocompromised senior citizens. Location matters too. Cells collected from patients in Australia might react differently to a virus compared with cells collected from a patient group in Germany, just based on past viral exposures in those regions.

    “There’s an added level of complexity in biology. Viruses are always evolving, and that changes the data too,” says Einav. “And even if two labs looked at the same patients in the same year, they might have run slightly different tests.”

    Working closely with Rong Ma, Ph.D., a postdoctoral scholar at Stanford University, Einav set out to develop an algorithm to help compare large datasets. His inspiration came from his background in physics, a discipline where—no matter how innovative an experiment is—scientists can be confident that the data will fit within the known laws of physics. E will always equal mc2.

    “What I like to do as a physicist is collect everything together and figure out the unifying principles,” says Einav.

    The new computational method doesn’t need to know precisely where or how each dataset was acquired. Instead, Einav and Ma harnessed machine learning to determine which datasets follow the same underlying patterns. 

    “You don’t have to tell me that some data came from children or adults or teenagers. We just ask the machine ‘how similar are the data to each other,’ and then we combine the similar datasets into a superset that trains even better algorithms,” says Einav. Over time, these comparisons could reveal consistent principles in immune responses—patterns that are hard to detect across the many scattered datasets that abound in immunology. 

    For example, researchers could design better vaccines by figuring out exactly how human antibodies target viral proteins. This is where biology gets really complicated again. The problem is that humans can make around one quintillion unique antibodies. Meanwhile a single viral protein can have more variations than there are atoms in the universe. 

    “That’s why people are collecting bigger and bigger data sets to try and explore biology’s nearly infinite playground,” says Einav. 

    But scientists don’t have infinite time, so they need ways to predict the vast reaches of data they can’t realistically collect. Already, Einav and Ma have shown that their new computational method can help scientists fill in these gaps. They demonstrate that their method to compare large datasets can reveal myriad new rules of immunology, and these rules can then be applied to other datasets to predict what missing data should look like.

    The new method is also thorough enough to provide scientists with confidence behind their predictions. In statistics, a “confidence interval” is a way to quantify how certain a scientist is of a prediction.

    “These predictions work a bit like the Netflix algorithm that predicts which movies you might like to watch,” says Einav. The Netflix algorithm looks for patterns in movies you’ve selected in the past. The more movies (or data) you add to these prediction tools, the more accurate those predictions will get.

    “We can never gather all the data, but we can do a lot with just a few measurements,” says Einav. “And not only do we estimate the confidence in predictions, but we can also tell you what further experiments would maximally increase this confidence. For me, true victory has always been to gain a deep understanding of a biological system, and this framework aims to do precisely that.”

    Einav recently joined the LJI faculty after completing his postdoctoral training in the laboratory of Jesse Bloom, Ph.D., at the Fred Hutch Cancer Center. As he continues his work at LJI, he plans to focus on the use of computational tools to learn more about human immune responses to many viruses, beginning with influenza. He’s looking forward to collaborating with leading immunologists and data scientists at LJI, including Professor Bjoern Peters, Ph.D., also a trained physicist.

    “You get beautiful synergy when you have people coming from these different backgrounds,” says Einav. “With the right team, solving these big, open problems finally becomes possible.”

    The study, “Using Interpretable Machine Learning to Extend Heterogeneous Antibody-Virus Datasets,” was supported by the Damon Runyon Cancer Research Foundation (grant DRQ 01-20) and by Professor David Donoho at Stanford University.

    DOI: https://doi.org/10.1016/j.crmeth.2023.100540

    View article as pdf

    La Jolla Institute for Immunology

    Source link

  • Fly Toolkit Created for Investigating COVID-19 Infection Mechanisms

    Fly Toolkit Created for Investigating COVID-19 Infection Mechanisms

    Newswise — Millions of deaths and ongoing illnesses caused by the COVID-19 pandemic have prompted scientists to seek new ways of understanding how viruses so skillfully enter and reprogram human cells. Urgent innovations leading to the development of new therapies are needed since virologists predict that future deadly viruses and pandemics may again emerge from the coronavirus family.

    One approach to developing new treatments for such coronaviruses, including the SARS-CoV-2 virus that causes COVID-19, is to block the mechanisms by which the virus reprograms our cells and forces them to produce more viral particles. But studies have identified nearly 1,000 human proteins that have the potential to bind with viral proteins, creating overwhelming challenges in identifying which of the many possible interactions are most relevant to infection.

    A multi-institutional collaboration has now developed a toolkit in fruit flies (Drosophila) to sort through the pile of possibilities. The new Drosophila COVID Resource (DCR) provides a shortcut for assessing key SARS-CoV-2 genes and understanding how they interact with candidate human proteins.

    The study, published in Cell Reports, was led by Annabel Guichard and Ethan Bier of the University of California San Diego and Shenzhao Lu, Oguz Kanca, Shinya Yamamoto and Hugo Bellen of the Baylor College of Medicine and Texas Children’s Hospital.

    “A defining feature of viruses is their ability to rapidly evolve—a characteristic that has proven particularly challenging in controlling the SARS-CoV-2 virus,” said Bier a professor in the UC San Diego School of Biological Sciences. “We envision that this new resource will offer researchers the ability to quickly assess the functional effects of factors produced by this once-in-a century pathogen as well as future naturally occurring variants.”

    The researchers designed the DCR as a versatile discovery system. It features an array of fruit fly lines that produce each of the 29 known SARS-CoV-2 proteins and more than 230 of their key human targets. The resource also offers more than 300 fly strains for analyzing the function of counterparts to human viral targets.

    “By harnessing the powerful genetic tools available in the fruit fly model system, we have created a large collection of reagents that will be freely available to all researchers,” Bellen said. “We hope these tools will aid in the systematic global analysis of in vivo interactions between the SARS-CoV-2 virus and human cells at the molecular, tissue and organ level and help in the development of new therapeutic strategies to meet current and future health challenges that may arise from the SARS-CoV-2 virus and related family members.”

    As they tested and analyzed the potential of the DCR, the researchers found that nine out of 10 SARS-CoV-2 proteins known as non-structural proteins (NSPs) they expressed in flies resulted in wing defects in adult flies. These defects can serve as a basis to understand how the viral proteins affect host proteins to disrupt or reorient essential cellular processes to benefit the virus.

    They also made an intriguing observation: one of these viral proteins, known as NSP8, functions as a type of hub, coordinating with other NSPs in a mutually reinforcing manner. NSP8 also strongly interacted with five of the 24 human binding candidate proteins, the researchers noted. They discovered that the human protein that exhibited the strongest interactions with NSP8 was an enzyme known as arginyltransferase 1, or “ATE1.”

    “ATE1 adds the amino acid arginine to other proteins to alter their functions,” said Guichard. “One such target of ATE1 is actin, a key cytoskeletal protein that is present in all of our cells.” Guichard noted that the researchers found much higher levels of arginine-modified actin than normal in fly cells when NSP8 and ATE1 were produced together. “Intriguingly, abnormal ring-like structures coated with actin formed in these fly cells,” she said, “and these were reminiscent of similar structures observed in human cells infected with the SARS-CoV-2 virus.”

    However, when flies were given drugs that inhibit the activity of the human ATE1 enzyme, the effects of NSP8 were considerably reduced, offering a path to promising new therapeutics.

    Calling their method a “fly-to-bedside” resource, the researchers say these initial results are just the tip of the iceberg for drug screening. Eight of the other NSPs they tested also produced distinctive phenotypes, laying the groundwork for pinpointing other new drug candidates.

    “In several cases, identification of new candidate drugs targeting functionally important viral-human interactions might prove valuable in combination with existing anti-viral formulations such as Paxlovid,” said Bier. “These new discoveries may also provide clues to the causes of various long-COVID symptoms and strategies for future treatments.”

    The complete coauthor list includes: Annabel Guichard, Shenzhao Lu, Oguz Kanca, Daniel Bressan, Yan Huang, Mengqi Ma, Sara Sanz Juste, Jonathan Andrews, Kristy Jay, Marketta Sneider, Ruth Schwartz, Mei-Chu Huang, Danqing Bei, Hongling Pan, Liwen Ma, Wen-Wen Lin, Ankush Auradkar, Pranjali Bhagwat, Soo Park, Kenneth Wan, Takashi Ohsako, Toshiyuki Takano-Shimizu, Susan Celniker, Michael Wangler, Shinya Yamamoto, Hugo Bellen and Ethan Bier.

    Funding for the study was provided by the National Institutes of Health (grants R24OD022005-07S1, R24OD022005, R24OD031447, R24OD031447-02S1, R01GM117321, R01GM144608 and R01AI162911); the Kyoto Institute of Technology; the Tata Trusts in India to the Tata Institute for Genetics and Society at UC San Diego; Jan and Dan Duncan Neurological Research Institute at Texas Christian Hospital; and a CAPES fellowship (88887.659907/2021-00).

    Note: Bier has equity interests in Synbal Inc., a company that may potentially benefit from the research results, and also serves on the board of directors and scientific advisory board of Synbal.

    University of California San Diego

    Source link

  • Brain cell sensor captures dynamic connections

    Brain cell sensor captures dynamic connections

    Newswise — Osaka, Japan – When brain cells, or neurons, are putting out processes to connect with other neurons, how do they tell the difference between their own processes and those of other neurons? One important part of this puzzle involves a molecule called clustered protocadherin (Pcdh).

    In a recent publication in iScience, researchers from SANKEN (The Institute of Scientific and Industrial Research) and the Graduate School of Frontier Biosciences at Osaka University reported the development of a sensor to look at Pcdh interactions in live neurons, which brings us closer to understanding this mystery.

    In the brain, millions of neurons make trillions of connections with each other. To do so, each neuron puts out tiny processes that grow and travel until they find another cell’s processes to connect with. However, because each cell has so many processes all over the place, cells can accidentally make connections with themselves rather than with others. One way to avoid this involves Pcdh, which is expressed in different combinations on each neuron’s surface.

    One role of Pcdh is in cell adhesion; if two neuronal processes have exactly the same combination of Pcdh molecules, the molecules bind to one another. Conversely, if the combinations are even slightly different, they are viewed as “other” rather than “self,” and do not bind. Although there are conventional techniques for detecting molecular interactions between cell surfaces, which can show us when the molecules bind, but not when they split apart again. Researchers from Osaka University wanted to tackle this issue.

    “We developed a fluorescent-based sensor that we named IPAD, or Indicators for Protocadherin Alpha 4 interactions upon Dimerization,” says lead author of the study Takashi Kanadome. “This sensor allows us to see not only interactions between processes, but also the dissociation of these interactions for the first time.”

    This new technique does have a few disadvantages. For example, its fluorescence is much duller than that observed using older techniques, and it is unable to differentiate connections between processes from the same cell and those from two different cells with the same combinations of Pcdh on the surface. 

    “Despite its current drawbacks, we think that our new sensor will be useful for a number of different research applications,” explains Tomoki Matsuda, senior author of the study. “The development of IPAD is an important step toward a better understanding of the neuronal recognition of self/other.”

    The sensors developed in this study have many potential applications. In particular, the technique may be used to develop a range of fluorescent sensors to visualize neuronal self-connectivity, which is implicated in brain disorders such as autism and epilepsy. A better understanding of neuronal self-connectivity may lead to improved treatments for these disorders.

    ###

    The article, “Visualization of trans-interactions of a protocadherin-α between processes originating from single neurons,” was published in iScience at DOI: https://doi.org/10.1016/j.isci.2023.107238

    Osaka University

    Source link

  • Enhanced stem cell culture boosts genome editing safety

    Enhanced stem cell culture boosts genome editing safety

    Newswise — Tsukuba, Japan—Hematopoietic stem cells (HSCs) are rare cells found in the bone marrow that produce red blood cells, white blood cells, and platelets. Their correct functioning is indispensable for the growth and health of an organism. Accordingly, defects in the DNA of hematopoietic stem cells (mutations) can cause impaired blood production and severe diseases.

    Gene therapy seeks to treat such types of genetic diseases. A breakthrough technology that has driven the entire field in recent years is gene editing via clustered regularly interspaced palindromic repeats/Cas9 (CRISPR/Cas9). Using this technology, one can modify disease-causing mutations and transplant HSCs with recovered function, potentially curing the disease.

    However, the CRISPR/Cas9 system is not perfect. It only corrects mutations in a small fraction of cells and can introduce new, potentially dangerous mutations into other cells. Therefore, selecting corrected cells before transplantation is crucial.

    In 2019, the research group reported a method of expanding HSCs over a long time period using a polymer-based culture system and cytokines. In response to this problem, the authors have developed a novel culture system using a novel high-molecular-weight polymer. This system facilitates the growth of single HSCs in transplantable cell colonies that achieve high blood-producing capacity after long-time ex vivo culture. After editing a mutation in a murine immune deficiency model, the authors individually grow several hundred HSCs and screen them for clones that contain only the desired edit and are expected to engraft successfully. Using this method, the fraction of successfully corrected HSCs used for transplantation can be increased from 20%-30% to 100% while eliminating potentially dangerous mutations from the graft. We believe that this culture system might contribute to improving the efficiency and safety of genome editing in HSCs.

    ###
    This work was supported by the German Research Foundation (BE 6847/1-1 to H.J.B.), the Japan Society for the Promotion of Science (JSPS; #20K16234 to M.S.J.L., #23K15315 to H.J.B., #21F21108 and #20K21612 to S.Y.), the Kay Kendall Leukaemia Fund (A.C.W.), the Japan Science and Technology Agency (JST; #18071245 to C.C.), and the Japanese Agency for Medical Research and Development (AMED; #21bm0404077h0001 and #21bm0704055h0002 to S.Y.). The D.G.K. laboratory is supported by a Blood Cancer UK Bennett Fellowship (15008), an ERC Starting Grant (ERC-2016-STG-715371), a CR-UK Programme Foundation award (DCRPGF100008), the MRC Mouse Genetics Network Haematopoiesis Cluster (MC_PC_21043), and an MRC-AMED joint award (MR/V005502/1).

    University of Tsukuba

    Source link

  • Migrating for Climate Change Success?

    Migrating for Climate Change Success?

    Newswise — A new study by an international team from Africa, Asia and Europe has put forward three criteria for evaluating the success of migration as adaptation in the face of climate change: well-being, equity and sustainability.

    The study shows that while migration is increasingly recognised as an effective way to deal with climate risks, or a form of adaptation, it is far from a silver-bullet solution.

    For example, remittances – which include flows of money, ideas, skills and goods between migrants and their places of origin – are thought to be key to facilitating adaptation to climate change.

    But, drawing on evidence from every continent for the past decades, this research shows that while remittances help improve material well-being for families and households in places where migrants move from, this often comes at a cost to the well-being of migrants themselves.

    For example, migrants in Bangladesh are not sufficiently considered in planning and policy and remain excluded from urban structures and services.

    This has repercussions for all aspects of their everyday lives in urban destinations such as living conditions, income security, and eventually their ability to keep supporting their families back home. 

    Dr Lucy Szaboova from the University of Exeter, the study’s lead author, said: “The idea of migration as adaptation places the responsibility of predicting and responding to future risks on individuals, and could justify policy inaction.

    “This is problematic, because where migration is not met with appropriate policy support, it can reinforce vulnerability and marginality and ultimately jeopardise the success of adaptation.”

    Tensions in well-being, equity and sustainability

    The study found that migration often leads to tensions within and between well-being, equity, and sustainability. These tensions can create winners and losers.

    Experiences of migration as adaptation are not equal for everyone involved.

    Depending on the context and on people’s social characteristics such as age, gender, ethnicity, for instance, migration can have different outcomes for different people.

    Some might benefit while others lose out.

    For example, the household overall may be financially better off thanks to remittances from the migrant, but female household members whose work burden increases with men’s migration, may be struggling to maintain the farm and must make tricky choices that can eventually undermine the success of migration as adaptation.

    Dr Mumuni Abu, from the Regional Institute for Population Studies at the University of Ghana, said: “In the absence of equity, migration can exacerbate rather than reduce vulnerability to climate change.

    “For example, in rural places of origin, constraints on gender equity between men and women at the household and community level, often result in the unsustainable use and management of natural resources.”

    Dr Amina Maharjan, of the International Centre for Integrated Mountain Development (ICIMOD), added: “Remittances are often lauded for their potential to support development and adaptation, but experiences point to the need to consider their role along longer time horizons.”

    Indeed, the implications of migration for the success of adaptation often unfold over extended timescales, including across different generations.

    Creating an enabling policy environment

    The authors suggest that evaluations of the success of migration as adaptation should, therefore, take into account outcomes for migrants, their households and family members in places of origin, and for the host society.

    They should also recognise that some implications might not be immediately obvious but might unfold over longer timeframes.

    To address tensions that can stand in the way of success, migration as a plausible adaptation option should be made visible in policy and planning.

    Drawing on extensive research with migrants and policy and planning stakeholders in urban migration destinations, Professor Neil Adger from the University of Exeter highlighted potential solutions for creating an enabling policy environment.

    “Migrants in cities are disproportionately exposed to social and environmental hazards which negatively affect their health and wellbeing,” he said.

    “Despite this, they remain largely invisible and voiceless in policy circles.

    “Participatory urban planning and deliberative approaches can support the inclusion of diverse perspectives on building safe, sustainable and resilient cities and can support migration as successful adaptation.”

    The paper, published in the journal One Earth, is entitled: “Evaluating migration as successful adaptation to climate change: trade-offs in well-being, equity and sustainability.”

    It is the outcome of collaboration between researchers from the University of Exeter, University of Vienna, University of Ghana, the London School of Economics and Political Science, and the International Centre for Integrated Mountain Development (ICIMOD).

    This research was funded by Canada’s International Development Research Centre (IDRC).

    University of Exeter

    Source link

  • Flexible Nanoelectrodes Stimulate Brain with Precision

    Flexible Nanoelectrodes Stimulate Brain with Precision

    Newswise — Traditional implantable medical devices intended for brain stimulation frequently possess a rigidity and bulkiness that is incongruous with one of the human body’s most supple and fragile tissues.

    In response to this issue, engineers at Rice University have created nanoelectrodes that are minimally invasive and exceptionally flexible. These nanoelectrodes have the potential to function as an implanted platform, enabling long-term, high-resolution stimulation therapy.

    As reported in Cell Reports, a study revealed that these minute implantable devices established stable and enduring tissue-electrode interfaces in rodents with minimal scarring or deterioration. The devices were capable of delivering electrical pulses that closely resembled neuronal signaling patterns and amplitudes, surpassing the capabilities of traditional intracortical electrodes.

    Due to their exceptional biocompatibility and precise spatiotemporal stimulus control, these devices have the potential to facilitate the advancement of novel brain stimulation therapies. These therapies, such as neuronal prostheses, could greatly benefit individuals with impaired sensory or motor functions.

    Lan Luan, a corresponding author on the study and an assistant professor of electrical and computer engineering, explained that the research paper utilizes imaging, behavioral, and histological methods to demonstrate the enhanced effectiveness of stimulation achieved by these tissue-integrated electrodes. The electrodes have the capability to administer precise and minute electrical pulses, thereby facilitating controlled neural activity excitation.

    The team of researchers successfully achieved a significant reduction in the required current for neuronal activation, surpassing an order of magnitude. This means that the electrical pulses delivered by the electrodes can be as subtle as a duration of a couple hundred microseconds and an amplitude of one or two microamps. Such precise and low-intensity stimulation holds great potential for advancing the field of brain stimulation therapies.

    The recently developed electrode design by the researchers at the Rice Neuroengineering Initiative marks a substantial advancement compared to traditional implantable electrodes utilized for treating conditions like Parkinson’s disease, epilepsy, and obsessive-compulsive disorder. Conventional electrodes often lead to adverse tissue reactions and unintended alterations in neural activity. The new electrode design aims to address these challenges and offers a promising solution for enhancing the effectiveness and safety of treatments for such neurological conditions.

    Chong Xie, a corresponding author of the study and an associate professor of electrical and computer engineering, stated that traditional electrodes are highly invasive in nature. These electrodes typically activate thousands or even millions of neurons simultaneously.

    “When all these neurons are stimulated simultaneously, their individual functions and coordination, which are supposed to follow specific patterns, get disrupted,” explained Chong Xie. “While this simultaneous stimulation may have the desired therapeutic effect in certain cases, it lacks the necessary precision and control, especially when it comes to encoding sensory information. To achieve more precise and effective outcomes, greater control over the stimuli is essential.”

    Xie drew a comparison between the stimulation provided by traditional electrodes and the disruptive impact of “blowing an airhorn in everyone’s ear or having a loudspeaker blaring” in a room filled with people. This analogy emphasizes the lack of specificity and precision in conventional electrode stimulation, which can lead to a generalized and disruptive effect on neural activity.

    “We used to have this very big loudspeaker, and now everyone has an earpiece,” he said.

    Xie drew a comparison between the stimulation provided by traditional electrodes and the disruptive impact of “blowing an airhorn in everyone’s ear or having a loudspeaker blaring” in a room filled with people. This analogy emphasizes the lack of specificity and precision in conventional electrode stimulation, which can lead to a generalized and disruptive effect on neural activity.

    The capacity to modify the frequency, duration, and intensity of the signals holds the potential for the advancement of innovative sensory prosthetic devices.

    Luan stated, “When a larger current is employed, neuron activation becomes more widespread and diffuse. However, we successfully reduced the current and demonstrated a significantly more focused activation. This achievement can pave the way for the development of higher-resolution stimulation devices.”

    Both Luan and Xie are integral members of the Rice Neuroengineering Initiative, and their respective laboratories are engaged in a collaborative effort to develop an implantable visual prosthetic device aimed at assisting visually impaired patients.

    Luan envisions a future where electrode arrays can be implanted to restore impaired sensory function. He highlights that the precision and specificity of neuron activation play a crucial role in generating accurate and precise sensations. Luan emphasizes that the more focused and deliberate the activation of neurons, the higher the level of precision in the generated sensation.

    Luan, who will be assuming the position of associate professor starting from July 1, expressed the significance of their electrode’s ultraflexible design in achieving enhanced tissue integration. They have published a series of research papers demonstrating the electrode’s capability to facilitate improved recording of brain activity over extended periods, yielding superior signal-to-noise ratios.

    The study has been led by Roy Lycke, a postdoctoral associate in electrical and computer engineering, and Robin Kim, a graduate student. Both Lycke and Kim have played crucial roles as lead authors in conducting the research.

    The National Institute of Neurological Disorders and Stroke (R01NS109361, U01 NS115588) and Rice internal funds supported the research.

    -30-

    Rice University

    Source link

  • A New Strategy to Break Through Bacterial Barriers in Chronic Treatment-Resistant Wounds

    A New Strategy to Break Through Bacterial Barriers in Chronic Treatment-Resistant Wounds

    Newswise — CHAPEL HILL, N.C. – Chronic wounds are open sores or injured tissue that fail to heal properly. These types of wounds are notoriously challenging to treat because of bacterial infections like Staphylococcus aureus, or S. aureus. Additionally, bacterial infections that are highly resistant to antibiotics, such as methicillin-resistant S. aureus (MRSA), are one of the main causes of life-threatening infections in hospital patients.

    To defend itself from our immune system and other threats, S. aureus can band together, creating a slick, slimy forcefield – or biofilm – around itself. The biofilm barrier is so thick that neither immune cells nor antibiotics can penetrate through and neutralize the harmful bacteria.

    Researchers at the UNC School of Medicine and the UNC-NC State Joint Department of Biomedical Engineering have developed a new method that combines palmitoleic acid, gentamicin, and non-invasive ultrasound to help improve drug delivery in chronic wounds that have been infected with S. aureus.

    Using their new strategy, researchers were able to reduce the challenging MRSA infection in the wounds of diabetic mice by 94%. They were able to completely sterilize the wounds in several of the mice, and the rest had significantly reduced bacterial burden. Their results were published in Cell Chemical Biology.

    “When bacteria are not completely cleared from chronic wounds, it puts the patient at high risk for the infection recurring or of developing a secondary infection,” said senior author Sarah Rowe-Conlon, PhD, a research associate professor in the Department of Microbiology and Immunology. “This therapeutic strategy has the potential to improve outcomes and reduce relapse of chronic wound infections in patients. We are excited about the potential of translating this to the clinic, and that’s what we’re exploring right now.”

    Biofilms act as a physical barrier to many classes of antibiotics. Virginie Papadopoulou, PhD, a research assistant professor in the UNC-NCSU Joint Department of Biomedical Engineering, was curious to know if non-invasive cavitation-enhanced ultrasound could create enough agitation to form open spaces in the biofilm to facilitate drug-delivery.

    Liquid droplets which can be activated by ultrasound, called phase change contrast agent (PCCA), are applied topically to the wound. An ultrasound transducer is focused on the wound and turned on, causing the liquid inside the droplets to expand and turn into microscopic gas-filled microbubbles, when then move rapidly.

    The oscillation of these microbubbles agitates the biofilm, both mechanically disrupting it as well as increasing fluid flow. Ultimately, the combination of the biofilm disruption and the increased permeation of the drugs through the biofilm allowed the drugs to come in and kill the bacterial biofilm with very high efficiency.

    “Microbubbles and phase change contrast agents act as local amplifiers of ultrasound energy, allowing us to precisely target wounds and areas of the body to achieve therapeutic outcomes not possible with standard ultrasound,” said Dayton, the William R. Kenan Jr. Distinguished Professor and Department Chair of the UNC-NCSU Joint Department of Biomedical Engineering. “We hope to be able to use similar technologies to locally delivery chemotherapeutics to stubborn tumors or drive new genetic material into damaged cells as well.”

    When the bacterial cells are trapped inside the biofilm, they are left with little access to nutrients and oxygen. To conserve their resources and energy, they transition into a dormant or sleepy state. The bacteria, which are known as persister cells in this state, are extremely resistant to antibiotics.

    Researchers chose gentamicin, a topical antibiotic typically ineffective against S. aureus due to widespread antibiotic resistance and poor activity against persister cells. The researchers also introduced a novel antibiotic adjuvant, palmitoleic acid, to their models.

    Palmitoleic acid, an unsaturated fatty acid, is a natural product of the human body that has strong antibacterial properties. The fatty acid embeds itself into the membrane of bacterial cells, and the authors discovered that it facilitates the antibiotic’s successful entry into S. aureus cells and is able to kill persister cells and reverse antibiotic resistance.

    Overall, the team is enthusiastic about the new topical, non-invasive approach because it may give scientists and doctors more tools to combat antibiotic resistance and to lessen the serious adverse effects of taking oral antibiotics.

    “Systemic antibiotics, such as oral or IV, work very well, but there’s often a large risk associated with them such as toxicity, wiping out gut microflora and C. difficile infection,” said Rowe-Conlon. “Using this system, we are able to make topical drugs work and they can be applied to the site of infection at very high concentrations, without the risks associated with systemic delivery.”

     

    About UNC School of Medicine

    The UNC School of Medicine (SOM) is the state’s largest medical school, graduating more than 180 new physicians each year. It is consistently ranked among the top medical schools in the US, including 5th overall for primary care by US News & World Report, and 6th for research among public universities. More than half of the school’s 1,700 faculty members served as principal investigators on active research awards in 2021. Two UNC SOM faculty members have earned Nobel Prize awards.

    About the Joint Department of Biomedical Engineering

    The Joint Department is ranked in the top 10 biomedical engineering programs in the US by the Blue Ridge Institute for Medical Research, top 20 biomedical engineering programs worldwide by the Shanghai Academic Ranking of World Universities, and is a top 5 institution for total bachelor’s degrees awarded in biomedical engineering (ASEE).

    # # # #

    University of North Carolina School of Medicine

    Source link

  • Reviving exhausted T cells to tackle immunotherapy-resistant cancers

    Reviving exhausted T cells to tackle immunotherapy-resistant cancers

    Newswise — LA JOLLA, CALIF. – May 03, 2023 – When the cells of our immune system are under constant stress due to cancer or other chronic diseases, the T cells of the immune system shut down in a process called T cell exhaustion. Without active T cells, which kill tumor cells, it’s impossible for our bodies to fight back against cancer. One of the biggest goals of immunotherapy is to reverse T cell exhaustion to boost the immune system’s ability to destroy cancerous cells.

    Researchers at Sanford Burnham Prebys studying melanoma have found a new way to make this happen. Their approach, described in Cell Reports, can reduce T cell exhaustion even in tumors that are resistant to clinically approved immunotherapies. It can also help T cells from becoming exhausted.

    “Slowing or reversing T cell exhaustion is a huge focus in cancer research, and many researchers are working on different ways to accomplish this,” says first author Jennifer Hope, Ph.D., who completed this research as a postdoctoral researcher at Sanford Burnham Prebys and is now an assistant professor at Drexel University. “This new approach could be a viable treatment on its own, but it also has tremendous potential to work synergistically with existing therapies.”

    Although there are established immunotherapies that target T cell exhaustion, the new approach is unique in that it targets several different aspects of the process at once. This means that it could help people overcome resistance to various anti-cancer immunotherapies that are currently available.

    “One of the foundational ideas of modern cancer treatment is not relying on a single therapy, since this can cause the cancer to become resistant to that treatment,” says senior author Linda Bradley, Ph.D., a professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. “The more tools at our disposal to slow down or reverse T cell exhaustion in different ways, the better chance we have of improving precision medicine and helping more people with cancer benefit from immunotherapy.”

    Their approach hinges on a protein called PSGL-1, which is found in most blood cells. By studying mice with a genetic deficiency in PSGL-1, the researchers determined that this protein helps facilitate T cell exhaustion, a major roadblock to effective anti-cancer immunity.

    The researchers then used an antibody to block the activity of PGSL-1 in mice with immunotherapy-resistant melanoma. They found that targeting PSGL-1 slowed the process of T cell exhaustion and helped exhausted T cells switch back into functioning T cells. These two effects significantly reduced tumor growth in the mice.

    “One of the things that makes this approach unique compared to existing immunotherapies is that it directly alters the way T cells become exhausted and helps them regain their function,” says Hope. “I think this is going to be crucial in terms of its translational potential.”

    The researchers were also able to replicate this effect in mice with mesothelioma, suggesting that the approach could be applicable to a wide range of cancers. Although the treatment they used in this study is not yet suited for clinical use in humans, the overall approach of using antibodies or recombinant proteins for immunotherapy is well established. This means that translating these results for people with cancer may just be a matter of time and testing.

    “Once we’ve done all the necessary science, this could be really valuable, or even lifesaving, for a lot of people with cancers that are resistant to current treatments,” says Bradley. “We still have a long way to go, but I’m optimistic that we’re onto something game-changing here.”

    ###

    Additional authors on the study include Dennis C. Otero, Eun-Ah Bae, Christopher J. Stairiker, Ashley B. Palete, Hannah A. Faso, Michelle Lin, Monique L., Henriquez, Sreeja Roy, Xue Lei, Eric S. Wang, Savio Chow, Roberto Tinoco, Kevin Yip, Alexandre Rosa Campos, Jun Yin, Peter D. Adams and Linda M. Bradley, Sanford Burnham Prebys; Anjana Rao and Hyungseok Seo, La Jolla Institute for Immunology; and Gregory A. Daniels, Moores Cancer Center at UC San Diego Health.

    The study was supported by grants from the American Cancer Society (PF-20-113-01-LIB), the National Institutes of Health (T32 AI125209, R01 AI106895, R21 CA249353, R21 CA216678, R03 CA252144, R01 AI040127, R01 AI109842, P30 CA030199), the Melanoma Research Alliance (MRA 696326), the Department of Defense (W81XWH-20-1-0324), the American Association of Immunologists, the San Diego Cancer Centers Council (C3 2018), the Association of Immunologists Careers in Immunology Fellowship Program, and was supported in part by the following Sanford Burnham Prebys Core facilities: Flow Cytometry, Vivarium, Histology, Bioinformatics, Proteomics, and Cancer Metabolism.

    The study’s DOI is 10.1016/j.celrep.2023.112436

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

    Sanford Burnham Prebys

    Source link

  • Too Much Insulin Can Be as Dangerous as Too Little

    Too Much Insulin Can Be as Dangerous as Too Little

    Newswise — Just over a century has passed since the discovery of insulin, a time period during which the therapeutic powers of the hormone have broadened and refined. Insulin is an essential treatment for type 1 diabetes and often for type 2 diabetes, as well. Roughly 8.4 million Americans use insulin, according to the American Diabetes Association.

    One hundred years of research have greatly advanced medical and biochemical understanding of how insulin works and what happens when it is lacking, but the reverse, how potentially fatal insulin hyper-responsiveness is prevented, has remained a persistent mystery.

    In a new study, published in the April 20, 2023 online edition of Cell Metabolism, a team of scientists at the University of California San Diego School of Medicine, with colleagues elsewhere, describe a key player in the defense mechanism that safeguards us against excessive insulin in the body.

    “Although insulin is one of the most essential hormones, whose insufficiency can result in death, too much insulin can also be deadly,” said senior study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine.

    “While our body finely tunes insulin production, patients who are treated with insulin or drugs that stimulate insulin secretion often experience hypoglycemia, a condition that if gone unrecognized and untreated can result in seizures, coma and even death, which collectively define a condition called insulin shock.”

    Hypoglycemia (low blood sugar) is a significant cause of death among persons with diabetes.

    In the new study, Karin, first author Li Gu, PhD, a postdoctoral scholar in Karin’s lab, and colleagues describe “the body’s natural defense or safety valve” that reduces the risk of insulin shock.

    That valve is a metabolic enzyme called fructose-1,6-bisphosphate phosphatase or FBP1, which acts to control gluconeogenesis, a process in which the liver synthesizes glucose (the primary source of energy used by cells and tissues) during sleep and secretes it to maintain steady supply of glucose in the bloodstream.

    Some antidiabetic drugs, such as metformin, inhibit gluconeogenesis but without apparent ill effect. Children born with a rare, genetic disorder in which they do not produce sufficient FBP1 can also remain healthy and live long lives.

    But in other cases, when the body is starved for glucose or carbohydrates, an FBP1 deficiency can result in severe hypoglycemia. Without a glucose infusion, convulsions, coma and possibly death can ensue.

    Compounding and confounding the problem, FPB1 deficiency combined with glucose starvation produces adverse effects unrelated to gluconeogenesis, such as an enlarged, fatty liver, mild liver damage and elevated blood lipids or fats.

    To better understand the roles of FBP1, researchers created a mouse model with liver specific FBP1 deficiency, accurately mimicking the human condition. Like FBP1-deficient children, the mice appeared normal and healthy until fasted, which quickly resulted in the severe hypoglycemia and the liver abnormalities and hyperlipidemia described above.

    Gu and her colleagues discovered that FBP1 had multiple roles. Beyond playing a part in the conversion of fructose to glucose, FBP1 had a second non-enzymatic but critical function: It inhibited the protein kinase AKT, which is the primary conduit of insulin activity.

    “Basically, FBP1 keeps AKT in check and guards against insulin hyper-responsiveness, hypoglycemic shock and acute fatty liver disease,” said first author Gu.

    Working with Yahui Zhu, a vising scientist from Chongqing University in China and second author of the study, Gu developed a peptide (a string of amino acids) derived from FBP1 that disrupted the association of FBP1 with AKT and another protein that inactivates AKT.

    “This peptide works like an insulin mimetic, activating AKT,” said Karin. “When injected into mice that have been rendered insulin resistant, a highly common pre-diabetic condition, due to prolonged consumption of high-fat diet, the peptide (nicknamed E7) can reverse insulin resistance and restore normal glycemic control.”

    Karin said the researchers would like to further develop E7 as a clinically useful alternative to insulin “because we have every reason to believe that it is unlikely to cause insulin shock.”

    Co-authors include: Kosuke Watari, Maiya Lee, Junlai Liu, Sofia Perez, Melinda Thai, Joshua E. Mayfield, Bichen Zhang, Karina Cunha e Rocha, Alexander C. Jones, Igor H. Wierzbicki, Xiao Liu, Alexandra C. Newton, Tatiana Kisseleva, Wei Ying, David J. Gonzalez and Alan R. Saltiel, all at UC San Diego; Fuming Li, University of Pennsylvania and Fudan University, China; Laura C. Kim and M. Celeste Simon, University of Pennsylvania; Jun Hee Lee, University of Michigan.

    Funding for this research came, in part, from the National Institutes of Health (grants R01DK120714, R01CA234128, R01DK133448, P01CA104838, R35CA197602, R01DK117551, R01DK125820, R01DK76906, P30DK063491, R21HD107516, R00DK115998, R01DK125560 AND R35GM122523), the UC San Diego Graduate Training Program in Cellular and Molecular Pharmacology (GM007752) and the National Science Foundation Graduate Research Fellowship (#DGE-1650112).

    # # #

    Disclosure: Michael Karin and Alan Saltiel are founders and stockholders in Elgia Pharmaceuticals. Karin has received research support from Merck and Janssen Pharmaceuticals.

    University of California San Diego

    Source link

  • Researchers Id Biomarkers of Response to Immunotherapy for Kidney Cancer

    Researchers Id Biomarkers of Response to Immunotherapy for Kidney Cancer

    Newswise — The number of immune cells in and around kidney tumors, the amount of dead cancer tissue, and mutations to a tumor suppressor gene called PBRM1 form a biomarker signature that can predict — before treatment begins — how well patients with kidney cancer will respond to immunotherapy, according to new research directed by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

    In reviews of 136 kidney tumor biopsies taken for previous studies, investigators found that patients who had three positive factors — presence of immune cells in and around tumors, known as tumor-infiltrating immune cells, absence of dead cancer tissue, called necrosis, and a mutation in the PBRM1 gene — had the best overall survival at five years compared with patients who did not have this combination of factors. A report about the work was published online Feb. 21 in the journal Cell Reports Medicine.

    Therapies for patients with metastatic clear cell renal carcinoma, a type of kidney cancer, are rapidly evolving and include immunotherapy-based regimens, says lead study author Julie Stein Deutsch, M.D., a clinical fellow in dermatopathology at the Johns Hopkins University School of Medicine. However, there is an unmet need for biomarkers that can help match patients to the regimens most likely to help, she says. Such markers have been investigated in lung and other cancers, but have not shown the same predictive ability in patients with kidney cancers.

    The classic hematoxylin and eosin-stained (H&E) pathology slide — the gold standard for diagnosing and staging cancer in medical practices worldwide — has largely been overlooked as a possible source of biomarker information, Deutsch says. “There are many studies investigating biomarkers for response to immunotherapy using advanced technologies that require expensive machines and experienced technicians. The ability to use information from an H&E slide, pretreatment, to predict overall survival of patients receiving this therapy is extremely powerful, and is something that can be used in resource-poor settings as well,” she says.

    Immunotherapies that target PD-1 (programmed cell death 1), a protein found on immune cells, can unleash an immune response against cancer cells and has become a vanguard of cancer therapy, says senior author Janis Taube, M.D., M.Sc., co-director of the Tumor Microenvironment Laboratory at the Bloomberg~Kimmel Institute for Cancer Immunotherapy and director of the Division of Dermatopathology. However, she points out that anti-PD-1 immunotherapies do not work in all patients. The new findings could be used to help preselect patients for the most appropriate therapy, says Taube.

    Investigators examined H&E slides from 136 metastatic tumor samples, before treatment, from patients with renal cell cancers to determine the biomarker potential of this commonly available material. They reviewed 63 biopsies obtained before treatment from patients who received the immunotherapy nivolumab as a first cancer treatment or later treatment; 58 biopsies from patients receiving later-line nivolumab or the chemotherapy drug everolimus; and 15 biopsies from patients who hadn’t received therapy before, who received nivolumab plus the immunotherapy ipilimumab. Researchers scored the specimens for the amount of tumor-infiltrating immune cells (here called TILplus) and presence of necrosis (dead tissue).

    In the first group of 63 biopsies, and in samples from all three groups of patients who received immunotherapy, patients with specimens that had immune infiltrates (e.g., tumor-infiltrating lymphocytes, macrophages, plasma cells) interfacing with tumor (TILplus score of 1) showed improved overall survival compared with those without (i.e., specimens with TILplus score of 0). Median overall survival was 47.9 months in those with a TILplus score of 1 versus 16 months in those with a score of 0. Median progression-free survival was 7.5 months in those with a TILplus score of 1 versus 2.7 months in those with a score of 0. However, TILplus score was not associated with overall survival among patients receiving everolimus, indicating the findings were specific to immunotherapy.

    The presence of necrosis was found to modify the benefits of having immune system infiltration in the tumor. In two groups of biopsies studied, patients whose tumors had substantial necrosis (greater than 10% surface area) had lower overall survival compared with patients who had the same TILplus score but whose tumors lacked necrosis. This finding was observed in patients from two cohorts. Again, combining TILplus and necrosis scores was not predictive of outcomes for patients receiving everolimus.

    “This is important, because traditionally, areas of necrosis are often excluded from biomarker studies because it can’t be used for genomic or transcriptomic studies since the tissue is dead,” Deutsch says. “We show there is important information in that necrotic area that’s conferring some sort of negative disadvantage to patients. It’s important not to overlook these areas when you’re investigating biomarkers that predict how patients are going to do.”

    Finally, investigators looked at mutations in the PBRM1 gene and how that impacts the other factors. Such mutations were correlated with overall survival but were not associated with TILplus. However, a statistical analysis of all three factors found that the combination of H&E scoring with PBRM1 mutation status stratified patients into three groups. Patients who had all three positive factors — a TILplus score of 1, necrosis score of 0 and a PBRM1 mutation — had the best overall survival at five years. Patients with two of the three features demonstrated intermediate survival, while those with only one feature had the worst survival.

    When investigators performed a literature search, they were unable to find other studies that used H&E features as part of tumor characterization using multimodality approaches. “This demonstrates the underutilization of these insights in biomarker discovery for immunotherapies,” Deutsch says.

    Taube says next steps will include validating the findings in larger groups of patients and potentially prospectively in a clinical trial.

    In addition to Taube and Deutsch, study co-authors were Evan J. Lipson, Ludmila Danilova, Suzanne L. Topalian, Jaroslaw Jerdych, Ezra Baraban, Yasser Ged, Nirmish Singla, Toni K. Choueiri, Saurabh Gupta, Robert J. Motzer, David McDermott, Sabina Signoretti and Michael Atkins. Other institutions participating in the research were Dana-Farber Cancer Institute in Boston, Bristol-Myers Squibb, Memorial Sloan Kettering Cancer Center in New York, Beth Israel Deaconess Medical Center in Boston and the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

    The work was supported by The Mark Foundation for Cancer Research, Bristol-Myers Squibb, a Sidney Kimmel Cancer Center Core Grant (P30 CA006973), the National Cancer Institute (R01 CA142779), the National Institutes of Health (grants T32 CA193145 and R50 CA243627), Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16 and Program 5P30CA006516-56), the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund, Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

    Taube reported grants and consulting fees from Bristol-Myers Squibb and Akoya Biosciences, consulting for Merck, AstraZeneca, Genentech, GlaxoSmithKline, Regeneron, Lunaphone and Compugen outside this work. Deutsch and Taube filed an institutional patent on machine learning for scoring pathologic response to immunotherapy. These relationships are managed by The Johns Hopkins University in accordance with its conflict of interest policies.

    Johns Hopkins Medicine

    Source link

  • How do we know if our brain is capable of repairing itself?

    How do we know if our brain is capable of repairing itself?

    Newswise — Is our brain able to regenerate? And can we harness this regenerative potential during aging or in neurodegenerative conditions? These questions sparked intense controversy within the field of neuroscience for many years. A new study from the Netherlands Institute for Neuroscience shows why there are conflicting results and proposes a roadmap on how to solve these issues.

    The notion of exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing or restoring brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders like Alzheimer’s disease. The question of whether the human brain does possess the ability to regenerate or not has been at the center of a fierce scientific debate for many years and recent studies yielded conflicting results. A new study from Giorgia Tosoni and Dilara Ayyildiz, under the supervision of Evgenia Salta in the laboratory of Neurogenesis and Neurodegeneration, critically discusses and re-analyzes previously published datasets. How is it possible that we haven’t yet found a clear answer to this mystery?

    Previous studies in which dividing cells were labeled in postmortem human brain, showed that new cells can indeed arise throughout adulthood in the hippocampus of our brain, a structure that plays an important role in learning and memory, and is also severely affected in Alzheimer’s disease. However, other studies contradict these results and cannot detect the generation of new brain cells in this area. Both conceptual and methodological confounders have likely contributed to these seemingly opposing observations. Hence, elucidating the extent of regeneration in the human brain remains a challenge.

    New state-of-the-art technologies

    Recent advances in single-cell transcriptomics technologies have provided valuable insights into the different cell types found in human brains from deceased donors with different brain diseases. To date, single-cell transcriptomic technologies have been used to characterize rare cell populations in the human brain. In addition to identifying specific cell types, single-nucleus RNA sequencing can also explore specific gene expression profiles to unravel full the complexity of the cells in the hippocampus.

    The advent of single-cell transcriptomics technologies was initially viewed as a panacea to resolving the controversy in the field. However, recent single-cell RNA sequencing studies in human hippocampus yielded conflicting results. Two studies indeed identified neural stem cells, while a third study failed to detect any neurogenic populations. Are these novel approaches – once again – failing to finally settle the controversy regarding the existence of hippocampal regeneration in humans? Will we eventually be able to overcome the conceptual and technical challenges and reconcile these -seemingly- opposing views and findings?

    Technical issues

    In this study, the researchers critically discussed and re-analyzed previously published single-cell transcriptomics datasets. They caution that the design, analysis and interpretation of these studies in the adult human hippocampus can be confounded by specific issues, which ask for conceptual, methodological and computational adjustments. By re-analyzing previously published datasets, a series of specific challenges were probed that require particular attention and would greatly profit from an open discussion in the field.

    Giorgia Tosoni: ‘We analyzed previously published single-cell transcriptomic studies and performed a meta-analysis to assess whether adult neurogenic populations can reliably be identified across different species, especially when comparing mice and humans. The neurogenic process in adult mice is very well characterized and the profiles of the different cellular populations involved are known. These are actually the same molecular and cellular signatures that have been widely used in the field to also identify neurogenic cells in the human brain. However, due to several evolutionary adaptations, we would expect the neurogenesis between mice and humans to be different. We checked the markers for every neurogenic cell type and looked at the amount of marker overlap between the two species.’

    ‘We found very little, if no, overlap between the two, which suggests that the mouse-inferred markers we have been long using may not be suitable for the human brain. We also discovered that such studies require enough statistical power: if regeneration of neuronal cells does happen in the adult human brain, we expect it to be quite rare. Therefore, enough cells would need to be sequenced in order to identify those scarce, presumably neurogenic populations. Other parameters are also important, for example the quality of the samples. The interval between the death of the donor and the downstream processing is critical, since the quality of the tissue and of the resulting data drops over time.’

    Reproducibility is key

    Dilara Ayyildiz: ‘These novel technologies, when appropriately applied, offer a unique opportunity to map hippocampal regeneration in the human brain and explore which cell types and states may be possibly most amenable to therapeutic interventions in aging, neurodegenerative and neuropsychiatric diseases. However, reproducibility and consistency are key. While doing the analysis we realized that some seemingly small, but otherwise very critical details and parameters in the experimental and computational pipeline, can have a big impact on the results, and hence affect the interpretation of the data.’

    ‘Accurate reporting is essential for making these single-cell transcriptomics experiments and their analysis reproducible. Once we re-analyzed these previous studies applying common computational pipelines and criteria, we realized that the apparent controversy in the field may in reality be misleading: with our work we propose that there may actually be more that we agree on than previously believed.’

    Netherlands Institute for Neuroscience

    Source link

  • Team uncovers new details of SARS-COV-2 structure

    Team uncovers new details of SARS-COV-2 structure

    Newswise — Worcester, Mass. – March 30, 2023 – A new study led by Worcester Polytechnic Institute (WPI) brings into sharper focus the structural details of the COVID-19 virus, revealing an elliptical shape that “breathes,” or changes shape, as it moves in the body. The discovery, which could lead to new antiviral therapies for the disease and quicker development of vaccines, is featured in the April edition of the peer-reviewed Cell Press structural biology journal Structure.

    “This is critical knowledge we need to fight future pandemics,” said Dmitry Korkin, Harold L. Jurist ’61 and Heather E. Jurist Dean’s Professor of Computer Science and lead researcher on the project. “Understanding the SARS-COV-2 virus envelope should allow us to model the actual process of the virus attaching to the cell and apply this knowledge to our understanding of the therapies at the molecular level. For instance, how can the viral activity be inhibited by antiviral drugs? How much antiviral blocking is needed to prevent virus-to-host interaction? We don’t know. But this is the best thing we can do right now—to be able to simulate actual processes.”

    Feeding genetic sequencing information and massive amounts of real-world data about the pandemic virus into a supercomputer in Texas, Korkin and his team, working in partnership with a group led by Siewert-Jan Marrink at the University of Groningen, Netherlands, produced a computational model of the virus’s envelope, or outer shell, in “near atomistic detail” that had until now been beyond the reach of even the most powerful microscopes and imaging techniques. 

    Essentially, the computer used structural bioinformatics and computational biophysics to create its own picture of what the SARS-COV-2 particle looks like. And that picture showed that the virus is more elliptical than spherical and can change its shape. Korkin said the work also led to a better understanding of the M proteins in particular: underappreciated and overlooked components of the virus’s envelope. 

    The M proteins form entities called dimers with a copy of each other, and play a role in the particle’s shape-shifting by keeping the structure flexible overall while providing a triangular mesh-like structure on the interior that makes it remarkably resilient, Korkin said. In contrast, on the exterior, the proteins assemble into mysterious filament-like structures that have puzzled scientists who have seen Korkin’s results, and will require further study. 

    Korkin said the structural model developed by the researchers expands what was already known about the envelope architecture of the SARS-COV-2 virus and previous SARS- and MERS-related outbreaks. The computational protocol used to create the model could also be applied to more rapidly model future coronaviruses, he said. A clearer picture of the virus’ structure could reveal crucial vulnerabilities.

    “The envelope properties of SARS-COV-2 are likely to be similar to other coronaviruses,” he said. “Eventually, knowledge about the properties of coronavirus membrane proteins could lead to new therapies and vaccines for future viruses.”

    The new findings published in Structure were three years in the making and built upon Korkin’s work in the early days of the pandemic to provide the first 3D roadmap of the virus, based on genetic sequence information from the first isolated strain in China.

     

    About Worcester Polytechnic Institute

    WPI, a global leader in project-based learning, is a distinctive, top-tier technological university founded in 1865 on the principle that students learn most effectively by applying the theory learned in the classroom to the practice of solving real-world problems. Recognized by the National Academy of Engineering with the 2016 Bernard M. Gordon Prize for Innovation in Engineering and Technology Education, WPI’s pioneering project-based curriculum engages undergraduates in solving important scientific, technological, and societal problems throughout their education and at more than 50 project centers around the world.  WPI offers more than 70 bachelor’s, master’s, and doctoral degree programs across 18 academic departments in science, engineering, technology, business, the social sciences, and the humanities and arts. Its faculty and students pursue groundbreaking research to meet ongoing challenges in health and biotechnology; robotics and the internet of things; advanced materials and manufacturing; cyber, data, and security systems; learning science; and more.  www.wpi.edu

    Worcester Polytechnic Institute (WPI)

    Source link

  • River deltas: Valuable and under threat

    River deltas: Valuable and under threat

    Newswise — The livelihoods of millions of people who live in river deltas, among the world’s most productive lands, are at risk. Created where large rivers meet the ocean and deposit their natural sediment load, river deltas are often just a few meters above sea level. And while they make up less than 0.5 % of the world’s land area, river deltas contribute more than 4 % of the global GDP, 3% of global crop production, and are home to 5.5 % of the world’s population. All of these values are highly vulnerable to imminent global environmental change, according to a new Stanford University-led study.

    “It is often not rising seas, but sinking land due to human activities that puts coastal populations most at risk,” said study lead author Rafael Schmitt, a lead scientist with the Stanford Natural Capital Project. “Our research highlights that this relevant global risk is grossly understudied for all but very few coastal regions”

    Under natural conditions, deltas are subject to a number of factors that together create dynamic but stable systems. For instance, sediment supplied from upstream river basins builds new land even when sea levels are rising. Sediment supply is also critical to offset the effect that the recent, unconsolidated delta land compacts continuously under its own weight.

    Today, all of these processes are out of balance. River deltas are cut off from their natural sediment supply by dams and reservoirs, and the little sediment still reaching deltas cannot spread because of artificial levees and dikes. Additionally, groundwater pumping and extraction of hydrocarbons creates subsidence, and coastal vegetation, which can provide some protection, is lost to make space for farmland and tourism.

    Those local drivers, together with global sea level rise, lead to relative sea level rise, meaning that sinking lands amplifies the effect of rising seas, a combination that could cause significant parts of the world’s largest deltas to fall below the rising sea by the end of the century.

    Little is known about local and regional drivers of relative sea level rise. So, Schmitt’s study set out to identify key drivers of land loss and vulnerability across the world’s major deltas, and the knowledge gaps impeding more sustainable delta management, for specific deltas and on a global scale.

    In their synthesis effort, the authors find overwhelming evidence that it is not sea level rise, but sinking land, that puts global deltas most at risk. This is of great importance for managing river deltas, according to Schmitt. While climate change is increasingly recognized as a risk to coastal livelihoods and global wealth and security, this is only one part of the story.

    Of course, climate mitigation is important to curb global sea level rise. However, fighting overuse of local natural resources in river deltas and their contributing basins would have much greater and more immediate effects, posing both an opportunity and a responsibility for coastal nations.

    Stanford Woods Institute for the Environment

    Source link

  • Evolution: Miniproteins appeared “from nowhere”

    Evolution: Miniproteins appeared “from nowhere”

    Newswise — Every biologist knows that small structures can sometimes have a big impact: Millions of signaling molecules, hormones, and other biomolecules are bustling around in our cells and tissues, playing a leading role in many of the key processes occurring in our bodies. Yet despite this knowledge, biologists and physicians long ignored a particular class of proteins – their assumption being that because the proteins were so small and only found in primates, they were insignificant and functionless. The discoveries made by Professor Norbert Hübner at the Max Delbrück Center and Dr. Sebastiaan van Heesch at the Princess Máxima Center for Pediatric Oncology in the Netherlands changed this view a few years ago: “We were the first to prove the existence of thousands of new microproteins in human organs,” says Hübner.

    In a new paper published in Molecular Cell, the team led by Hübner and van Heesch now describe how they systematically studied these miniproteins, and what they learned from them: “We were able to show which genome sequences the proteins are encoded in, and when DNA mutations occurred in their evolution,” explains Dr. Jorge Ruiz-Orera, an evolutionary biologist in Hübner’s lab and one of the paper’s three lead authors, who work at the Max Delbrück Center and the German Center for Cardiovascular Research (DZHK). Ruiz-Orera’s bioinformatic gene analyses revealed that most human microproteins developed millions of years later in the evolutionary process than the larger proteins currently known to scientists.

    Yet the huge age gap doesn’t appear to prevent the proteins from “talking” to each other. “Our lab experiments showed that the young and old proteins can bind to each other – and in doing so possibly influence each other,” says lead author Dr. Jana Schulz, a researcher in Hübner’s team and at the DZHK. She therefore suspects that, contrary to long-held assumptions, the microproteins play a key role in a variety of cellular functions. The young proteins might also be heavily involved in evolutionary development thanks to comparatively rapid “innovations and adaptations.” “It’s possible that evolution is more dynamic than previously thought,” says van Heesch.

    Proteins only found in humans

    The researchers were surprised to find that the vastly younger microproteins could interact with the much older generation. This observation came from experiments performed using a biotechnical screening method developed at the Max Delbrück Center in 2017. In collaboration with Dr. Philipp Mertins and the Proteomics Platform, which the Max Delbrück Center operates jointly with the Berlin Institute of Health at Charité (BIH), the miniproteins were synthesized on a membrane and then incubated with a solution containing most of the proteins known to exist in a human cell. Sophisticated experimental and computer-aided analyses then allowed the researchers to identify individual binding pairs. “If a microprotein binds to another protein, it doesn’t necessarily mean that it will influence the workings of the other protein or the processes that the protein is involved in,” says Schulz. However, the ability to bind does suggest the proteins might influence each other’s functioning. Initial cellular experiments conducted at the Max Delbrück Center in collaboration with Professors Michael Gotthardt and Thomas Willnow confirm this assumption. This leads Ruiz-Orera to suspect that the microproteins “could influence cellular processes that are millions of years older than they are, because some old proteins were present in the very earliest life forms.”

    Unlike the known, old proteins that are encoded in our genome, most microproteins emerged more or less “out of nowhere – in other words, out of DNA regions that weren’t previously tasked with producing proteins,” says Ruiz-Orera. Microproteins therefore didn’t take the “conventional” and much easier route of being copied and derived from existing versions. And because these small proteins only emerged during human evolution, they are missing from the cells of most other animals, such as mice, fish and birds. These animals, however, have been found to possess their own collection of young, small proteins.

    The smallest proteins so far

    During their work, the researchers also discovered the smallest human proteins identified to date: “We found over 200 super-small proteins, all of which are smaller than 16 amino acids,” says Dr. Clara Sandmann, the study’s third lead author. Amino acids are the sole building blocks of proteins. Sandmann says this raises the question of how small a protein can be – or rather, how big it must be to be able to function. Usually, proteins consist of several hundred amino acids.

    The small proteins that were already known to scientists are known as peptides and function as hormones or signal molecules. They are formed when they split off from larger precursor proteins. “Our work now shows that peptides of a similar size can develop in a different way,” says Sandmann. These smallest-of-the-small proteins can also bind very specifically to larger proteins – but it remains unclear whether they can become hormones or similar: “We don’t yet know what most of these microproteins do in our body,” says Sandmann.

    Yet the study does provide an inkling of what the molecules are capable of: “These initial findings open up numerous new research opportunities,” says van Heesch. Clearly, the microproteins are much too important for researchers to keep ignoring them. Van Heesch says the biomolecular and medical research communities are very enthusiastic about these new findings. One conceivable scenario would be “that these microproteins are involved in cardiovascular disease and cancer, and could therefore be used as new targets for diagnostics and therapies,” says Hübner. Several U.S. biotech companies are already doing research in this direction. And the team behind the current paper also has big plans: Their study investigated 281 microproteins, but the aim now is to expand the experiments to include many more of the 7,000 recently cataloged microproteins – in the hope that this will reveal many as-yet-undiscovered functions.

     

    Further information

    Unchartered territory in the human genome

    Unknown miniproteins in the heart

    Hübner Lab

    Van Heesch Lab

     

    Literature

    Clara-L. Sandmann, Jana F. Schulz, Jorge Ruiz-Orera, et al. (2023): “Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames,” Molecular Cell, DOI: 10.1016/j.molcel.2023.01.023
     

    Downloads

    An evolutionarily young protein that arose de novo in Old World monkeys: The microprotein in the mitochondria (green) and in the nucleus (blue) was overexpressed in human cells. The yellow and pink areas show that the signal of the microprotein overlaps with the mitochondrial and nuclear signals. Photo: Clara Sandmann, MDC

     

    Max Delbrück Center

    The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) is one of the world’s leading biomedical research institutions. Max Delbrück, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the Center’s locations in Berlin-Buch and Mitte, researchers from some 70 countries analyze the human system – investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The Max Delbrück Center therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC), as well as with the Berlin Institute of Health (BIH) at Charité and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the Max Delbrück Center today employs 1,800 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin. www.mdc-berlin.de

    Max Delbruck Center for Molecular Medicine in the Helmholtz Association

    Source link

  • ‘Natural killer’ immune cells can modify tissue inflammation: study

    ‘Natural killer’ immune cells can modify tissue inflammation: study

    Newswise — Melbourne researchers have improved our understanding of how the immune system is regulated to prevent disease, identifying a previously unknown role of ‘natural killer’ (NK) immune cells. 

    The Monash University-led study identified a new group of immune cells, known as tissue-resident memory natural killer (NKRM) cells. NKRM cells limited immune responses in tissues and prevented autoimmunity, which is when the immune system makes a mistake and attacks the body’s own tissues or organs.

    While additional research is required, the discovery may ultimately be used to treat autoimmune diseases like Sjogren’s Syndrome and possibly chronic inflammatory conditions.

    Published in Immunity, the preclinical research is led by senior author Professor Mariapia Degli-Esposti  and first author Dr Iona Schuster from the Monash Biomedicine Discovery Institute (BDI), in close ongoing collaboration with the Lions Eye Institute.

    Originally, NK cells were thought to be short lived cells that circulate in the blood with the sole function of identifying and quickly killing virally infected or damaged cells.

    The team’s previous research established that NK cells’ role is far more complex, and the latest study demonstrates for the first time that a subset of NK cells, NKRM, are critical in regulating immune responses in tissues.

    “This is key to preserving tissue function and preventing autoimmunity from developing,” Dr Schuster said. “While long-lived tissue resident memory T cells (TRM) have been described, the primary known function of these cells is to protect the host against reinfection.

    “Our discovery of tissue-resident memory natural killer (NKRM) cells establishes that the function of some memory cells that live in tissues is to protect from excessive inflammation rather than protect against recurring infection.”

    Professor Degli-Esposti, BDI Head of Experimental and Viral Immunology, said the findings significantly improved our fundamental understanding of how the immune system is regulated to prevent disease. 

    “One of the main obstacles in cancer immunotherapy … is the development of immune related adverse events, which include the development or flare-up of autoimmune complications,” she said.
    “These events are due to ‘super’ or ‘uncontrolled’ activation of the immune system as a result of the brakes being removed by the therapeutic strategy.

    “Furthermore, many therapies cause collateral damage to tissues where tumours are localised. Thus, NKRM may be an adjunct or follow-up therapy to restore immune balance and bring back tissue health.”

    Read the full paper in Immunity: Infection induces tissue resident memory NK cells that safeguard tissue health. https://www.cell.com/immunity/fulltext/S1074-7613(23)00026-2

    Key findings

    1. Following infection with a common virus, cytomegalovirus, ‘natural killer’ (NK) cells were recruited from the circulation into inflamed tissues where they were retained and developed into a long-lived population of cells that researchers called tissue-resident memory natural killer (NKRM) cells.
    2.  Unlike NK cells, NKRM did not participate in virus control.
    3. In the absence of NKRM, infection led to tissue damage and the development of autoimmunity which presented as Sjogren’s Syndrome, one of the most common autoimmune diseases.
    Therefore, researchers identified a new population of cells that specifically localise to tissues to modulate immune responses to prevent immune pathology and autoimmunity.

    About the immune system

    Dysregulated immune or inflammatory processes contribute to many diseases. While the immune system protects against infection, a dysregulated immune response can lead to chronic inflammation, and in some instances cause tissue damage. Viral infections can trigger these processes, as the Covid pandemic has highlighted.

    About autoimmune diseases

    Autoimmune diseases arise when immune responses are misdirected and the immune system attacks host tissues and organs. Appropriate regulation of immune responses is therefore critical. As an example, Sjogren’s Syndrome is one of the most common autoimmune diseases and severely affects vision as patients are not able to produce tears. In most cases this leads to severe discomfort, but complications can lead to corneal damage and compromise vision. There is no cure for Sjogren’s Syndrome or its ocular complications.

    About the Monash Biomedicine Discovery Institute
    Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

    About the Lions Eye Institute
    At the Lions Eye Institute, we make a difference to people’s lives through excellent patient care and by pushing the frontiers of science to discover new treatments and cures for eye disease. As a not for profit organisation, the Lions Eye Institute spans the dual complementary pathways of research and clinical care. We bring together a globally recognised team of researchers and clinicians who continually build on each other’s discoveries, knowledge and expertise to deliver sight-saving treatment and care around the world. The quest for knowledge and its life-changing applications for patients is what drives our work.
    For more Lions Eye Institute media stories, visit our news site.

    For more Monash media stories, visit our news and events site. 

    Monash University

    Source link