Carbon Chemist

Tag: Cell

  • High blood levels of TMAO predicts chronic kidney disease risk in future

    High blood levels of TMAO predicts chronic kidney disease risk in future

    [ad_1]

    New findings from Cleveland Clinic and Tufts University researchers show high blood levels of TMAO (trimethylamine N-oxide) predicts future risk of developing chronic kidney disease over time.

    The findings build on more than a decade of research spearheaded by Stanley Hazen, M.D., Ph.D., and a team related to the gut microbiome’s role in cardiovascular health and disease, including the adverse effects of TMAO, a byproduct formed by the gut bacteria from nutrients abundant in red meat, eggs and other animal source foods.

    The study, published in the Journal of the American Society of Nephrology, was a collaboration between a Cleveland Clinic research team led by Dr. Hazen and investigators from the Food is Medicine Institute at the Friedman School of Nutrition Science and Policy at Tufts University, including first author Meng Wang, Ph.D., and co-senior author Dariush Mozaffarian, M.D., Dr.PH.

    The large-scale study measured blood levels of TMAO over time in two large National Institutes of Health populations and followed the kidney function of more than 10,000 U.S. adults with normal kidney function at baseline over an average follow-up period of 10 years. The investigators found that participants with elevated TMAO blood levels were at increased risk for future development of chronic kidney disease.

    Higher TMAO levels were also associated with a faster rate of declining kidney function in people with normal or impaired kidney function at baseline. These associations were independent of sociodemographic characteristics, lifestyle habits, diet and other known risk factors for kidney disease. The findings also are consistent with earlier reported preclinical model studies showing TMAO directly fosters both kidney functional decline and tissue fibrosis.

    The findings indicate a remarkably strong clinical link between elevated TMAO and increased risk for developing chronic kidney disease. The results are from individuals of diverse ethnic and sociodemographic backgrounds who had normal kidney function at the start. The diversity of the participants helps ensure the results are generalizable.”


    Dr. Stanley Hazen, chair of the Department of Cardiovascular and Metabolic Sciences and at Cleveland Clinic’s Lerner Research Institute and co-section head of Preventive Cardiology in the Heart, Vascular & Thoracic Institute

    Chronic kidney disease is a major and growing public health challenge in both the U.S. and globally, affecting about 10-15% of the population worldwide. It also is a strong risk factor for cardiovascular disease. The study showed that TMAO levels were as strong or even stronger an indicator of chronic kidney disease risk than the well-known risk factors such as diabetes, hypertension, advancing age and race.

    The study results reinforce the growing body of evidence indicating that lowering TMAO with prescribed drugs could be an effective treatment in patients at risk for, or with early signs of, kidney disease.

    “Our study is a crucial complement to studies in preclinical models supporting TMAO as a novel biological risk factor for chronic kidney disease,” said Dr. Wang, research assistant professor at the Friedman School. “TMAO levels are highly modifiable by both lifestyle-like diet and pharmacologic interventions. Besides using novel drugs to lower TMAO in patients, using dietary interventions to lower TMAO in the general population could be a cost-efficient and low-risk preventive strategy for chronic kidney disease development.”

    Plans for future studies include examining genetic data to help assess the potential cause-and-effect relationship between TMAO and chronic kidney disease, as well as studying more definitively whether lifestyle changes may prevent chronic kidney disease development and progression.

    Dr. Hazen also directs Cleveland Clinic’s Center for Microbiome and Human Health and holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis.

    This research was supported by grants from the National Institutes of Health, as well as the American Heart Association Postdoctoral Fellowship.

    Source:

    Journal reference:

    Wang, M., et al. (2024). The Gut Microbial Metabolite Trimethylamine N-oxide, Incident CKD, and Kidney Function Decline. Journal of the American Society of Nephrology. doi.org/10.1681/ASN.0000000000000344.

    [ad_2]

    Source link

  • Researchers find new clues to understanding the progression of primary membranous nephropathy

    Researchers find new clues to understanding the progression of primary membranous nephropathy

    [ad_1]

    No therapies currently exist that can halt the progression of chronic kidney disease in children or restore the ability of kidney cells to filter blood. Recently, researchers at the GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology in The Saban Research Institute of Children’s Hospital Los Angeles found new clues to understanding how chronic kidney disease progresses. By mapping the underlying genetic drivers of a type of chronic kidney disease called primary membranous nephropathy, they seek disease markers that could point the way to developing new treatments for children. In a paper published in the journal JCI Insight, the research team found that an unexpected mechanism was responsible for the loss of the kidney cells’ ability to filter toxins from blood.

    We have a good idea of what happens in the process of various types of chronic kidney failure, but we still don’t know precisely why and where it happens. Our goal was to scrutinize the molecular processes of any underlying mechanisms that could cause kidney podocytes to fail and lose their blood filtering capacity. Membranous nephropathy, which affects adults, can serve as a disease model for other chronic kidney disease processes that affect children and adults alike. The glomerulus-on-a-chip platform that we developed at the GOFARR lab allowed us to agnostically query different pathways involved in disease progression and measure their impact.”


    Stefano Da Sacco, PhD, Investigator, Urology Research at CHLA and study senior author

    A different culprit entirely

    In membranous nephropathy, infection-fighting autoantibodies destroy the kidney’s glomerular structures that contain the specialized podocytes that maintain the kidney’s filtration barrier. The researchers modeled membranous nephropathy caused by anti-phospholipase A2 receptor (PLA2R) antibodies. PLA2R is a target antigen recognized by the body’s immune system in about 70% of adults with membranous nephropathy. (Another antigen, SEMA3B, is prevalent in the rare pediatric cases that make up between 1% to 3% of total membranous nephropathy patients.) As the anti-phospholipase A2 receptor autoantibodies bind to the target PLA2R antigen-;which resides on the surface of kidney podocytes-;they trigger a cascade of events that leads to podocyte injury, destroying the kidney glomerular cells’ capacity to filter toxins from blood.

    Previously, researchers believed that the membrane-attack-complex (MAC) was the sole driver of podocyte injury, and that inhibiting it was key to halting disease progression. The GOFARR research team discovered instead that signaling in the C3a/C3aR pathway plays a critical role in the progression of membranous nephropathy. The team tested this insight both in vitro and using the glomerulus-on-a chip-tissue model, showing that administering a C3aR antagonist could preserve the podocyte’s ability to filter blood. When Dr. Da Sacco’s team specifically blocked signaling in the C3aR gene pathway by silencing the C3aR gene in podocytes, they observed that the system retained filtration capabilities. But when the researchers prevented MAC formation, podocyte function kept deteriorating.

    “By probing what is actually happening at the molecular level, we found that an entirely different pathway than we initially thought was the main driver for primary membranous neuropathy,” says Dr. Da Sacco, Assistant Professor of Research Urology at the Keck School of Medicine of USC. “We had previous knowledge that this pathway could cause damage to podocytes, but no confirmation that it was important in membranous nephropathy. We were a bit surprised and greatly encouraged. Finding what causes podocytes to fail is a step toward preventing-;and eventually reversing-;kidney deterioration. Our patients need better treatment options.”

    This work was supported by grants from NIH/NIDDK (RO1, R01DK123234) and by the GOFARR Foundation from the Schenkman Family.

    Source:

    Children’s Hospital Los Angeles

    Journal reference:

    Zhang, Q., et al. (2024). C3aR-initiated signaling is a critical mechanism of podocyte injury in membranous nephropathy. JCI Insight. doi.org/10.1172/jci.insight.172976.

    [ad_2]

    Source link

  • Research identifies how leukemia develops resistance to first line treatments

    Research identifies how leukemia develops resistance to first line treatments

    [ad_1]

    Relapses in a common form of leukemia may be preventable following new research which has identified how the cancer develops resistance to first line treatments.

    New research published in iScience by researchers from the University of Birmingham, the Institute of Cancer Research (ICR), Newcastle University, the Princess Maxima Centre of Pediatric oncology and the University of Virginia identified changes in a mutated form of acute myeloid leukemia (AML) samples from patients who relapsed after receiving FLT3 inhibitor treatment.

    The team found that the resistant cancer had up-regulated multiple other signalling pathways to overcome the drug’s action, and that the genetic change was able to be replicated in lab tests.

    These experiments revealed that by targeting RAS family proteins, using a small molecule inhibitor developed from a chemical library screen using the paratope of an inhibitory intracellular antibody by Terry Rabbitts’ team at the Weatherall Institute of Molecular Medicine University of Oxford and the ICR, increased signalling no longer rescued the cells from cell death.

    The team identified that the transcription factors AP-1 and RUNX1 were at the heart of mediating drug resistance. The two factors cooperate and bind to their target genes together, but only in the presence of growth factor signalling. The drugs targeting FLT3 rewire the cell, resulting in the upregulation of other signalling pathway associated genes, which then restored AP-1 and RUNX1 binding. Drugging RAS, which is a key component in multiple signalling pathways, prevented this restoration of RUNX1 binding, and therefore signalling from growth factors no longer rescued the cancer cells from death.

    Professor Constanze Bonifer from the Institute of Cancer and Genomic Sciences at the University of Birmingham, who has just taken up a position at the University of Melbourne, and is one of the senior authors of the paper said:

    “The pharmaceutical industry had high hopes that drugs targeting aberrant growth factor receptors such as the FLT3-ITD would prevent people from relapse. However, cancer cells are smart, and rewire their growth control machinery to use other growth factors present in the body. Targeting RAS family members prevents the cancer from rewiring and using different signalling pathways to escape cell death.”

    Targeting RAS blocks rewiring

    The small molecule inhibitors used to target RAS in this study were developed using intracellular antibody technology. This technology involves screening a large number of antibody fragments to identify those which bind to the target protein in cells and prevent their protein-protein interactions. Small molecule inhibitors are can be screened from chemical libraries that interact with the parts of the target protein where these antibody fragments bind (the paratope). Due to the unparalleled natural specificity of these antibody fragments, this technology (called Antibody derived or Abd technology) can be used to target difficult to drug proteins and identify new parts of the protein which can be targeted to prevent protein-protein interactions.

    Professor Terry Rabbitts from the Institute of Cancer Research who developed these drugs said:

    “The strength of the Antibody-derived technology approach is that intracellular antibodies can selected to essentially any protein. In turn, their specific binding sites can be employed to select chemical compounds for drug discovery against hard to drug proteins. Mutant RAS was considered undruggable, but the Abd technology facilitated the development of the RAS-binding compounds used in the current study of cancer cell re-wiring. Abd technology will allow development of a new generation of drugs to hard-to-drug and intrinsically disordered proteins.“

    AML with a FLT3-ITD mutation occurs in nearly 30% of all patients and is a highly aggressive disease with a poor prognosis. This genetic change causes the expression of a mutant growth factor receptor which is always active and therefore cancer cells expressing it grow uncontrollably. While inhibitors which specifically target the FLT3 protein are now in use in the clinic, patients treated with these inhibitors frequently relapse.

    This work was funded by Leukaemia Research UK, the Medical Research Council, Blood Cancer Research UK, the Royal Society, the Wellcome and Cancer Research UK. The first author, Daniel Coleman is a John Goldman Fellow of Leukaemia UK.

    Source:

    Journal reference:

    Daniel J.L., et al. (2024). Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1. iScience. doi.org/10.1016/j.isci.2024.109576.

    [ad_2]

    Source link

  • Researchers elucidate how gene mutation mechanism causes autism

    Researchers elucidate how gene mutation mechanism causes autism

    [ad_1]

    Researchers show how mutations of gene transcription and chromatin regulation-related genes cause autism.

    The loss-of-function mutation of KMT2C, a gene involved in histone modification, leads to the development of autism and other neurodevelopmental deficits. However, the precise mechanism of the disease progression is still unknown. Now, researchers from Japan have developed an animal model and elucidated the mechanism by which mutation in genes involved in chromatin modification causes autism. They have also discovered a drug that can be used in the treatment of autism.

    Autism spectrum disorder (ASD) encompasses neurodevelopmental conditions where patients display repetitive behavior and impaired sociality. Genetic factors have been shown to influence the development of ASD. Additionally, recent studies have shown that the genes involved in chromatin modification and gene transcription are involved in the pathogenesis of ASD. Among the many genes implicated in this process, the gene KMT2C (lysine methyltransferase 2c), which codes for a catalytic unit of H3K4 (histone H3 lysine 4) methyltransferase complex, has been identified to be associated with the development of autism and other neurodevelopmental disorders. Previous studies have shown that haploinsufficiency (a condition where, of the two copies of the gene, only one remains functional) of KMT2C is a risk factor for ASD and other neurodevelopmental disorders. However, the molecular mechanism through which the loss-of-function mutation in KMT2C leads to these conditions remains unclear.

    To address this knowledge gap, researchers from Juntendo University, RIKEN, and the University of Tokyo in Japan aimed to provide answers to these questions in a benchmark study published in the journal Molecular Psychiatry on 26 March 2024. The research team included Professor Tadafumi Kato from the Department of Psychiatry and Behavioral Science at Juntendo University Graduate School of Medicine, Dr. Takumi Nakamura and Dr. Atsushi Takata from the RIKEN Center for Brain Science, and Professor Takashi Tsuboi from Graduate School of Arts and Sciences, The University of Tokyo.

    To get to the bottom of KMT2C‘s role in ASD pathogenesis, the team developed and analyzed genetically engineered strain mice (Kmt2c+/fs) having a frameshift mutation that models the KMT2C haploinsufficiency. They then performed various behavioral analyses, in which they observed that the mutant mice exhibited lower sociality, inflexibility, auditory hypersensitivity, and cognitive impairments, which are all ASD-related symptoms.

    Next, they performed transcriptomic and epigenetic profiling to understand the basis of the molecular changes observed in the mutant mice. What they discovered was remarkable: the genes associated with increased ASD risk showed higher expression in these mutant mice.

    This was somewhat unexpected. KMT2C mediates H3K4 methylation, which is thought to activate gene expression, and thereby KMT2C haploinsufficiency was expected to cause reduced expression of target genes.”


    Dr. Atsushi Takata, RIKEN Center for Brain Science

    To gain mechanistic insights into their finding, the researchers carried out chromatin immunoprecipitation, a technique to determine the location on the DNA where the protein interacts with it. They found an overlap between KMT2C and the differentially expressed genes exhibiting reduced expression, suggesting that KMT2C haploinsufficiency leads to ASD-related transcriptomic changes through an indirect effect on gene expression.

    Further, to identify the cell types that contribute more to the pathological changes seen in the mutant mice, the researchers performed single-cell RNA sequencing of newborn mice brains. They observed that the altered genes associated with ASD risk were predominant in undifferentiated radial glial cells. However, a gross change in the cell composition was not observed, implying that the transcriptomic dysregulation does not severely impact cell fate.

    Finally, the researchers tested the effects of vafidemstat, a brain penetrant inhibitor of LSD1 (lysine-specific histone demethylase 1A), that could ameliorate histone methylation abnormalities. They found that vafidemstat improved the social deficits in the mutant mice and had an exceptional rescuing effect by changing the expression levels of the differentially expressed genes to their normal expression level. This finding showed that vafidemstat is a valid drug for mutant mice and can potentially help restore the normal transcriptomic state.

    What sets this discovery apart is that it challenges the commonly held belief that ASD disability may not be cured and demonstrates the efficacy of vafidemstat in improving ASD-like phenotypes. The results open doors to future research to strengthen the foundation for the pharmacologic treatment of ASD and other neurodevelopmental disorders. Prof. Kato concludes, “Our research shows that drugs similar to vafidemstat may be generalizable to multiple categories of psychiatric disorders.”

    Source:

    Journal reference:

    Nakamura, T., et al. (2024). Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor. Molecular Psychiatry. doi.org/10.1038/s41380-024-02479-8.

    [ad_2]

    Source link

  • The complex relationship between obesity and male reproductive function

    The complex relationship between obesity and male reproductive function

    [ad_1]

    In a review article published in the journal Molecular Aspects of Medicine, authors have analyzed current evidence on the impact of obesity on the male reproduction system.

    They have thoroughly discussed molecular mechanisms responsible for male infertility in obese or overweight individuals.

    Study: Obesity and male fertility disorders. Image Credit: Shidlovski/Shutterstock.comStudy: Obesity and male fertility disorders. Image Credit: Shidlovski/Shutterstock.com

    Background

    Obesity is considered to be one of the major causes of male infertility globally. An increased body weight is known to impair testicular development and function starting from prenatal age. Moreover, recent evidence shows that obesity can significantly reduce sperm parameters in adults.

    According to the World Health Organization, more than one billion people are living with obesity worldwide.

    With an ever-increasing prevalence of obesity in the global population, it has become necessary to precisely understand the relationship between obesity and male reproductive dysfunctions.

    Impact of obesity on male infertility

    A body mass index (BMI) of 30kg/m2 or more is defined as obesity. The body fat percentages of more than 25% in men and 30% in women are also described as obesity, which are often poorly correlated with BMI in the context of obesity diagnosis.

    Studies conducted on couples with an obese male partner have shown that male obesity can significantly increase the risk of infertility. However, studies investigating the direct effect of obesity on conventional sperm parameters have produced mixed or conflicting results.

    Studies involving couples undergoing fertility-related treatments have shown that obesity does not have any significant impact of obesity on sperm count, morphology, and motility.

    In contrast, findings of meta-analyses have indicated that obesity can reduce total sperm count, sperm concentration, semen volume, sperm vitality, and total sperm motility.

    One most recent meta-analysis, including studies following the 2010 WHO manual for sperm parameter analysis, has shown that obesity can significantly reduce total sperm count, sperm concentration, and sperm progressive, and total motility.

    This study has also shown that obesity affects overall sperm quality through the induction of hypogonadism (reduced production of male sex hormones).

    Regarding sperm bio-functional parameters, evidence indicates that obesity can lead to sperm DNA fragmentation and reduced mitochondrial membrane potential. These parameters might be associated with reduced sperm quality and motility.

    Regarding serum hormone levels, evidence indicates that obesity can reduce testosterone and sex hormone-binding globulin levels and increase estrogen levels.

    Mechanisms involved in obesity-related male infertility

    One of the potential factors responsible for hypogonadism is excess visceral fat deposition. Hypogonadism is associated with excessive conversion of testosterone into 17ß-estradiol by adipocytes, which further promotes the secretion of sex hormone-binding globulin by the liver.

    This protein can bind to testosterone and inhibit its biological functions. Furthermore, low blood levels of testosterone due to hypogonadism can trigger fat accumulation in the body.

    A reduced testosterone can lead to impaired proliferation and differentiation of Sertoli cell (somatic cells of the testis) and spermatogonial stem cells, negatively affecting spermatogenesis or sperm cell production.

    A high blood estrogen level due to hypogonadism can also negatively affect male reproductive system by inhibiting the release of lactate (an essential substrate) to germ cells, as well as by impairing the integrity of blood-testis barrier.

    Increased visceral fat can induce insulin resistance, reducing sex hormone-binding globulin secretion and subsequent induction in free estrogen levels. Free estrogen and inflammatory mediators produced due to insulin resistance can negatively affect the hypothalamic-pituitary-gonadal axis.

    Insulin resistance can also interfere with follicle-stimulating hormone signaling pathways at the testicular level, leading to impaired spermatogenesis.

    An increased insulin level in the blood can impair the growth, proliferation, metabolism, and survival of testicular cells, which in turn can impair male reproductive functions.

    Obesity-related low-grade chronic inflammation can influence male reductive functions in many ways. Increased production of pro-inflammatory cytokines can regulate Leydig cell function and subsequently reduce testosterone production.

    Obesity-related chronic inflammation can also increase the production of free radicals, leading to sperm DNA damage and reduced sperm quality.

    Obesity can affect the levels of adipokines produced by fat cells. These adipokines, including adiponectin, chemerin, leptin, resistin, and visfatin, play vital roles in modulating the immune, metabolism, and reproductive systems.

    Leptin is the most studied adipokine that regulates food intake, reproductive functions, and proinflammatory immune responses. A high-fat diet is known to induce leptin resistance in obese people. Highly increased blood levels of leptin characterize this condition.

    An increased leptin level can reduce lactate dehydrogenase activity and activate the PI3K/AKT/mTOR signaling pathway, leading to reduced lactate production by Sertoli cells and impaired nutritional support to germ cells.

    Sirtuins are NAD+-dependent deacetylases that play a role in modulating spermatogenesis. Sirtuin 1-knock-out mice have been found to have reduced sperm count and increased sperm DNA fragmentation.

    Gut hormones, such as ghrelin, Glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptide, secreted by gastrointestinal tract cells, play important roles in regulating lipid and glucose metabolism. An increased secretion of these hormones can lead to impaired functioning of Sertoli cells and Leydig cells.

    The gut microbiota provides essential nutrients and factors required for testicular function. Any alteration in gut microbiota composition and function can lead to local inflammation, which in turn can cause Leydig cell death, disrupted blood-testicular-barrier, and abnormal spermatogenesis.

    Sperm RNAs, including messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), micro RNAs (miRNAs), Piwi-interacting RNAs (piRNAs), and transfer of RNA-derived small RNAs (tsRNAs), play vital roles in spermatogenesis, fertilization, and embryo development.

    Certain sperm miRNAs have been found to induce inflammatory responses and impair iron homeostasis, glucose metabolism, meiotic recombination, fertilization, and sperm maturation and motility.

    [ad_2]

    Source link

  • Rogue immune cell found to cause poor antibody responses in chronic viral infections

    Rogue immune cell found to cause poor antibody responses in chronic viral infections

    [ad_1]

    Australian researchers have discovered a previously unknown rogue immune cell that can cause poor antibody responses in chronic viral infections. The finding, published today (9 April) in the journal, Immunity, may lead to earlier intervention and possibly prevention of some types of viral infections such as HIV or hepatitis.

    One of the remaining mysteries of the human immune system is why a certain cell, called a B cell, which retains a memory for past infections – ensuring we fight off diseases we have experienced before – often only has a weak capacity to protect us from persistent infections.

    Researchers from the Monash University Biomedicine Discovery Institute have essentially solved this mystery by discovering how chronic viral infection induces a previously unknown immune B memory cell that does not produce high levels of antibody.

    Importantly the research team, led by Professor Kim Good-Jacobson and Dr Lucy Cooper, also determined the most effective time during the immune response for therapeutics such as anti-viral and anti-cancer drugs to better boost immune memory cell development.

    What we discovered was a previously unknown cell that is produced by chronic viral infection. We also determined that early intervention with therapeutics was the most effective to stop this type of memory cell being formed, whereas late intervention could not.”  

    Professor Kim Good-Jacobson 

    According to Dr Cooper, chronic viral infections have been known to alter our ability to form effective long-term protective antibody responses, but how that happens is unknown.

    “In the future, this research may result in new therapeutic targets, with the aim to reduce the devastating effect of chronic infectious diseases on global health, specifically those that are not currently preventable by vaccines,” she said.

    “Revealing this new immune memory cell type, and what genes it expresses, allows us to determine how we can target it therapeutically and whether that will lead to better antibody responses.”

    The research team are also looking to see whether this population is a feature of long COVID, which results in some people having a reduced capacity to fight off the symptoms of COVID infection long after the virus has dissipated.

    Source:

    Journal reference:

    Cooper, L., et al. (2024) Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection. Immunity. doi.org/10.1016/j.immuni.2024.03.016.

    [ad_2]

    Source link

  • Fluent BioSciences awarded NIH SBIR grant to commercialize low-cost million-cell transcriptome profiling kits

    Fluent BioSciences awarded NIH SBIR grant to commercialize low-cost million-cell transcriptome profiling kits

    [ad_1]

    Fluent BioSciences, a cutting-edge life sciences company leading the charge in revolutionizing single-cell analysis through simple, cost-effective, and highly scalable single-cell RNA sequencing solutions is thrilled to announce the award of an NIH Small Business Innovation Research (SBIR) Phase II grant, funded by the National Institute of General Medical Sciences (NIGMS, 2 R44 GM137648). This funding will support the commercialization of million-cell analysis kits enabled by low-cost, high-capacity sequencing by Ultima Genomics.

    Prototype million-cell PIPseq kits developed by Fluent BioSciences that enable the profiling of an unprecedented number of cells within a single reaction were recently tested in the laboratory of Samantha Morris at Washington University, St. Louis (WUSTL). The WUSTL team employs single-cell lineage tracing to interrogate how to recreate physiologically accurate cell types with cellular reprogramming. Ultima Genomics sequencing of the prototype million-cell PIPseq data revealed clonal lineage trees with restriction of specific cell reprogramming fates. Leveraging the unmatched scalability of PIPseq with the affordable high-capacity sequencing of Ultima Genomics, WUSTL demonstrated that cellular reprogramming studies can be easily and affordably conducted at scale.

    Sample preparation was simple and the scale of the million-cell kit provided impressive power to our single-cell lineage tracing observations.” 

    Samantha Morris, Associate Professor, WUSTL

    “The collaboration between Fluent BioSciences and Ultima represents a remarkable synergy in pushing the boundaries of single-cell analysis,” said Brian McKernan, CEO of Fluent BioSciences. “This collaboration harnesses the strengths and expertise of both companies to address a critical challenge faced by researchers – the ability to perform single-cell sequencing on larger cell inputs for improved scalability and reduced cost. By eliminating the need for microfluidics devices or chips, the PIPseq technology offers unparalleled flexibility in the scale of beads per sample.”

    “We are excited to work with Fluent BioSciences to demonstrate compatibility of PIPseq on Ultima sequencers, optimize library construction for Ultima-specific sequencing, and demonstrate high-capacity single cell analysis across several applications developed by Fluent, including high cell input neuroscience, multi-sample hashing, and complex CRISPR editing applications. “The single-cell market is undergoing another major wave of growth with larger-scale experiments enabled by low-cost sequencing and advancement of single-cell technology”, said Doron Lipson, CSO of Ultima Genomics.

    Through this partnership, Fluent BioSciences and Ultima aim to revolutionize the field of single-cell analysis by enabling researchers to unlock deeper insights into cellular mechanisms and disease pathways with unparalleled throughput and accuracy.

    [ad_2]

    Source link

  • How microbes influence healing and infection risks

    How microbes influence healing and infection risks

    [ad_1]

    In a recent Nature Reviews Microbiology study, researchers review how the wound microbiota interferes with skin repair processes and facilitates infection onset by modulating host immune responses.

    Study: The wound microbiota: microbial mechanisms of impaired wound healing and infection. Image Credit: A3pfamily / Shutterstock.com

    Background

    The skin protects the human body from the potentially harmful effects of invading pathogens and chemicals. Any injury or damage to the skin can lead to wound development; therefore, dressing and infection control are standard practices of wound care.

    The wound-healing process involves coagulation, hemostasis, inflammation, cell proliferation and migration, and tissue remodeling. Any alteration to these processes can lead to delayed wound healing and the development of a chronic wound.

    Non-healing and chronic wounds are associated with certain risk factors, including advanced age and the presence of specific comorbidities, such as diabetes, obesity, systemic diseases, immunosuppressive diseases, and autoimmune diseases.

    Microorganisms colonizing in wounds, collectively referred to as the wound microbiota, can significantly impact the healing process. While some microorganisms facilitate faster skin repair, some can acquire virulence factors and antibiotic resistance, thereby increasing the risk of infection.

    Both exogenous and endogenous microorganisms can contaminate an open wound. The wound can facilitate microbial growth by exposing subcutaneous tissues and nutrients, which can subsequently lead to the colonization of microorganisms in the wound. This type of colonization can cause local infection and biofilm formation, which has the potential to spread to other tissues and organs.

    Wound microbiota composition

    The most common microbial populations found in both acute and chronic wounds include Staphylococcus spp., Pseudomonas spp., Corynebacterium spp., Enterococcus spp., Streptococcus spp. and Cutibacterium spp, all of which are microorganisms that are also commonly found in healthy skin microbiota.

    Staphylococcus aureus

    A skin wound can significantly alter its surrounding environment through the secretion of molecules from damaged tissues to support the growth, invasion, adhesion, and migration of pathogens such as Staphylococcus aureus. High abundance of fibronectin- and collagen-binding proteins facilitates Staphylococcus aureus to easily invade broken skin and induce intracellular infection.

    Staphylococcus aureus also produces pore-forming toxins that disrupt the host cell membrane to prevent immune clearance. Furthermore, serine proteases produced by this bacterium act as enterotoxins that induce chronic inflammation and create severe, non-healing diabetic wounds.

    Staphylococcus aureus has multiple master regulators, including the accessory gene regulator quorum-sensing system and sarA, which help activate its virulence factors. Glucose transporters acquired by Staphylococcus aureus further induce the production of virulence factors under hyperglycemic conditions.

    Pseudomonas aeruginosa

    Pseudomonas aeruginosa is a pathogen that can be found in burn wounds, chronic surgical wounds, and diabetic wounds. High-level antibiotic resistance and robust ability to form biofilm allow Pseudomonas aeruginosa to create chronic and non-healing wounds. Pseudomonas aeruginosa also comprises a type III secretion system that controls the production of effector toxins, further facilitating the production of virulence factors.

    Streptococcus

    Streptococcus spp., including β-Hemolytic group A streptococci (GAS), group B streptococci (GBS), and group C streptococci, can be found in invasive and non-invasive wounds.

    GAS bacteria contain multiple adhesins that promote their access to diverse tissue surfaces. Virulence factors present in GAS bacteria work in synergy to bind to and activate host plasminogens and create a proteolytic environment that alters wound-site architecture.    

    Anaerobic bacteria

    Anaerobic bacteria commonly found in wound infections include Finegoldia magna, B. fragilis, and Clostridium perfringens. These bacteria can be introduced to the wound during injury, such as bite or abdominal penetrating wounds. In diabetic or other chronic wounds, these bacteria thrive in conditions of low tissue oxygenation and can exist in mixed facultative and obligate anaerobes communities.

    Fungi

    Candida albicans is a fungal species most commonly found in chronic, surgical, and burn wounds. These fungi can enter host cells by binding to E-cadherin and triggering endocytosis. The pathogenicity of C. albicans is dependent on its ability to switch between yeast and a highly invasive hyphal phenotype.

    Viruses

    Viruses can also impact wound healing and skin repair processes. Whereas specific bacteriophages can worsen wound infections by increasing the virulence of bacteria they have infected, other bacteriophages can improve wound healing by changing bacterial virulence.

    Risk factors for wound infection

    The outcomes of wound microbial infections primarily depend on microbial virulence, polymicrobial interactions, and complex crosstalk between microbes and the wound microenvironment.

    Multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) or multidrug-resistant Pseudomonas aeruginosa, can complicate the treatment of wound infections. Likewise, a compromised immune system or certain genetic factors can further delay the wound-healing process and increase the risk of infection.

    Microbial virulence is also an important determinant of wound outcomes and treatment modalities. Wound bioburden, characterized by microbial load, microbial diversity, and the presence of pathogenic microbes, is a key contributor to delayed wound healing and infection onset.

    Journal reference:

    • Uberoi, A., McCready-Vangi, A., & Grice, E. A. (2024). The wound microbiota: microbial mechanisms of impaired wound healing and infection. Nature Reviews Microbiology. doi:10.1038/s41579-024-01035-z.

    [ad_2]

    Source link

  • Childhood obesity not linked to adult skin cancer risk, study says

    Childhood obesity not linked to adult skin cancer risk, study says

    [ad_1]

    A recent Scientific Reports study investigates whether genetically predicted childhood adiposity influences the risk of developing skin cancer in adulthood.

    Study: Genetic predisposition to childhood obesity does not influence the risk of developing skin cancer in adulthood. Image Credit: Gorodenkoff / Shutterstock.com

    Background

    Several studies have reported that childhood obesity increases the risk of several types of cancers in adulthood. Although a causal link between body mass index (BMI) and melanoma has been established, no studies have evaluated whether childhood obesity influences the risk of developing basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) in adulthood.

    Several mechanisms have been proposed to contribute to the potential causal link between BMI and melanoma. For example, some studies have suggested that obesity increases the risk of melanoma due to greater body surface area (BSA) that subsequently increases the number of target cells at risk. This hypothesis has been supported by some observational studies indicating that BSA positively correlates with increased melanoma risk.

    Nevertheless, other studies have hypothesized that obese people receive less sunlight exposure than their non-obese counterparts due to limited outdoor recreational activity. This reduced sunlight exposure could indirectly reduce the risk of melanoma. 

    About the study

    The current study utilized a Mendelian randomization (MR) approach to determine the effect of genetically predicted childhood adiposity on the development of skin cancer in adulthood. MR uses genetic variation to investigate potential relationships that may exist between exposures and outcomes documented in observational studies.

    Generic variants and other relevant data associated with childhood obesity were obtained from a recently published genome-wide association study (GWAS) meta-analysis. The analysis included 61,111 children of European descent between two and ten years of age.

    Importantly, these data were pooled from 40 individual studies from the original meta-analysis. The final analyses comprised 10,557 SCC cases, 36,479 BCC cases, and controls.

    Study findings

    Of the twenty-five genome-wide significant variants for childhood obesity, five were not associated with cSCC, BCC, or melanoma GWAS datasets. Therefore, twenty variants were eligible for the analysis, which explained 2.3% of the variance of BMI in childhood.

    The calculated risk estimates did not identify any significant association between genetically predicted childhood BMI and the risk of skin cancer development. Sensitivity analyses were performed to determine any breaches of MR assumptions that resulted in null findings. However, this result was also consistent with the risk estimates obtained in the MR inverse-variance-weighted (IVW) method.

    No pleiotropic variants for melanoma or cSCC were detected through the MR pleiotropy residual sum and outlier (MR-PRESSO) method. Here, three outlier variants for BCC were detected. Taken together, genetically predicted childhood obesity exhibited no significant effect on the development of skin cancer, including melanoma, cSCC, or BCC later in life.

    The lack of an observed association between genetically predicted childhood obesity and the risk of skin cancer development in adulthood indicates that body size is not likely to increase the risk of different types of skin cancer. Thus, the current study failed to validate whether obesity reduced the risk of melanoma due to limited outdoor activities. However, future studies could further analyze this potential association using pigmentation genes as a proxy for sun exposure.

    Strengths and limitations

    Key strengths of the current study include the consideration of vital confounding factors and the utilization of a large dataset to determine potential causal effects. Since the childhood GWAS meta-analysis encompassed thousands of children of European descent, population stratification could be effectively performed.

    Nevertheless, the current study is associated with certain limitations, such as the inclusion of participants exclusively of European descent, which limits the generalizability of the findings to a broader ethnic population. The genetic predictors of childhood obesity could also differ based on geography and ethnicity.

    Conclusions

    Despite the limitations, the current study strongly indicated that genetically predicted childhood adiposity does not influence skin cancer risks.

    Even if genetically predicted adiposity has an effect on risk of skin cancer, the magnitude of the effect would be very low so would likely have limited public health implications or clinical relevance.”

    Future studies are needed to understand whether genetic differences may impact the risk of developing skin cancer. Although genetically predicted adiposity provides essential information, it is not a faultless proxy, as genetic predisposition interacts with lifestyle and environmental factors that might influence childhood BMI.

    Journal reference:

    • Keatley, J., Law, M. H., Seviiri, M., et al. (2024) Genetic predisposition to childhood obesity does not influence the risk of developing skin cancer in adulthood. Scientific Reports 14(1); 1-5. doi:10.1038/s41598-024-58418-8

    [ad_2]

    Source link

  • Researchers develop first genetic maps for disease-linked DNA repeats

    Researchers develop first genetic maps for disease-linked DNA repeats

    [ad_1]

    A research team led by the University of California, Irvine has built the first genetic reference maps for short lengths of DNA repeated multiple times which are known to cause more than 50 lethal human diseases, including amyotrophic lateral sclerosis, Huntington’s disease and multiple cancers.

    The UC Irvine Tandem Genome Aggregation Database enables researchers to study how these mutations – called tandem repeat expansions – are connected to diseases, to better understand health disparities and to improve clinical diagnostics.

    The study, published online today in the journal Cell, introduces the UC Irvine TR-gnomAD, which addresses a critical gap in current biobank genome sequencing efforts. Although TR expansions constitute about 6 percent of our genome and substantially contribute to complex congenial conditions, scientific understanding of them remains limited.

    This groundbreaking project positions UC Irvine as a leader in human and medical genetics by addressing the critical gap in the ability to interpret TR expansions in individuals with genetic disorders. The TR-gnomAD advances our ability to determine how certain diseases might affect diverse groups of people based on variations in these mutations among ancestries. Genetic consulting companies can then develop products to interpret this information and accurately report how certain traits might be linked to different groups of people and diseases.”


    Wei Li, the Grace B. Bell Chair and professor of bioinformatics and co-corresponding author

    To build the database, the team utilized two software tools to analyze the genomic data of 338,963 participants across 11 sub-populations. Of the .91 million TRs identified, .86 million were of high enough quality to be retained for further study. It was also discovered that 30.5 percent of them had at least two common alternative forms of a gene caused by a mutation located in the same place on a chromosome.

    “Although we’ve successfully genotyped a substantial number of TRs, that is still just a fraction of the total number in the human genome,” Li said. “Our next steps will be to prioritize the integration of a greater number of high-quality TR and include more underrepresented ancestries, such as Australian, Pacific Islander and Mongolian, as we move closer to realizing personalized precision medicine.”

    UC Irvine team members involved in the research included co-corresponding author and research assistant professor Ya Cui; Wenbin Ye, postdoctoral scholar; Jason Sheng Li, biological chemistry graduate student; and Eric Vilain, professor of pediatrics and the director of the Institute for Clinical and Translational Science. Also participating were Jingi Jessica Le, UCLA biostatistics professor, and Dr. Tamer Sallam, vice chair and associate professor at the UCLA David Geffen School of Medicine.

    Source:

    University of California, Irvine

    Journal reference:

    Cui, Y., et al. (2024) A genome-wide spectrum of tandem repeat expansions in 338,963 humans. Cell. doi.org/10.1016/j.cell.2024.03.004.

    [ad_2]

    Source link