400 research outputs found

    A draft human pangenome reference

    No full text
    Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals 1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.</p

    Effects of Ibuprofen On Muscle Hypertrophy and Inflammation: A Review of Literature

    No full text
    Purpose of Review: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for post-exercise recovery and reduction of muscle soreness and pain. While many studies have contradictory results on whether NSAIDs hinder the post-exercise recovery process, this study sought to identify more clearly the effects of NSAIDs on the exercise-induced inflammatory response, muscle protein synthesis, and overall post-exercise muscle recovery. Recent Findings: NSAID ingestion is common for the reduction of delayed onset muscle soreness after exercise or to decrease pain and inflammation during the rehabilitation of a muscle injury. However, there is evidence that while NSAIDs reduce the activity of cyclooxygenase (Cox-2) which generates prostaglandins that mediate inflammation and pain, they may also play a role in the reduction of protein synthesis and slow the restoration of functional recovery by disrupting the natural anti-inflammatory response during muscle recovery. Summary: While most of the ten articles selected for this review had low-participant numbers, they provided evidence that large doses of NSAIDs used after high-intensity interval training can reduce muscle protein synthesis and hypertrophy while lower doses have little to no effect on these factors. Thus, taking large doses of NSAIDs can be detrimental to muscle recovery and hypertrophy after exercise training. Further research is required to determine the varying effects of different NSAIDs and dosages

    Mu2e Run I Sensitivity Projections for the Neutrinoless mu(-) -> e(-) Conversion Search in Aluminum

    No full text
    The Mu2e experiment at Fermilab will search for the neutrinoless μ−→e− conversion in the field of an aluminum nucleus. The Mu2e data-taking plan assumes two running periods, Run I and Run II, separated by an approximately two-year-long shutdown. This paper presents an estimate of the expected Mu2e Run I search sensitivity and includes a detailed discussion of the background sources, uncertainties of their prediction, analysis procedures, and the optimization of the experimental sensitivity. The expected Run I 5σ discovery sensitivity is Rμe=1.2×10−15, with a total expected background of 0.11±0.03 events. In the absence of a signal, the expected upper limit is Rμe&lt;6.2×10−16 at 90% CL. This represents a three order of magnitude improvement over the current experimental limit of Rμe&lt;7×10−13 at 90% CL set by the SINDRUM II experiment.</jats:p

    Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

    Get PDF
    To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

    A draft human pangenome reference.

    No full text
    Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected&nbsp;per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample

    ENDPOINT DEFENSE AS CODE (EDAC): CONFIGURABLE CONTEXTUAL ANALYSIS OF PROCESS BEHAVIORS FROM KERNEL/USER EVENT TRACING

    Get PDF
    The current industry standard to detect cyber threat activity on endpoints (workstations, servers, etc.) centers around the use of endpoint defense software. The software products marketed are Endpoint Protection Platforms (EPP), Endpoint Detection and Response (EDR), and eXtended Detection and Response (XDR) solutions. These solutions are typically deployed onto endpoints across enterprises and monitor various aspects of each operating system for malicious activity. Current generations of these three solutions have similar underlying software architectures, user workflows, and detection capabilities. These solutions also have a number of issues that inadvertently allow advanced cyber threat actors to succeed in their operations, such as, lack of resilience to intentional evasions against critical software components, lack of resilience against user configuration errors, low detection rates of atomic techniques, low configurability for process-level behaviors, and semantically inappropriate alert messages. As proven in prior research and research that the author is conducting concurrently alongside this research, these issues can be capitalized on by knowledgeable and observant attackers to enable their technique chains to succeed undetected. Through years of professional experience deploying, testing, and evaluating various commercial endpoint solutions in various system architectures (commercial enterprise systems, government systems, disconnected/air-gapped systems, etc.), the author has learned that many commercial endpoint defense technologies are designed to make decisions for the operators on what activity is benign and what activity is malicious, without giving operators the ability to change this decision making. Vendors of these solutions add to this by illustrating a measure of trust in the solution’s ecacy by releasing their detection statistics of known Indicators of Compromise (IOCs). These IOCs may or may not be used by attackers in the future as new attack techniques are developed. This creates a iv detection gap between known techniques that can be detected, and actual techniques that are being executed. In addition to this, the author has observed in organizations across many industries a level of indiscriminate trust in commercial endpoint solutions. Many organizations fully trust endpoint solutions to be the sole defense mechanism on an endpoint without fully testing the solution for resiliency or detection gaps. All of these facts and circumstances create gaps, inconsistencies, and avenues for highly observant cyber attackers to maneuver in and out of systems undetected. This document illustrates all of the research that has been completed as part of this dissertation to solve the identified issues with current-generation endpoint defense solutions. The overarching approach to solving the identified problems was to use the Design Science Research (DSR) methodology to develop a software artifact that is su- ciently di↵erent and more impactful than existing solutions, and test the designed artifact against real-world attack technique stimulus to prove its validity and usefulness within real-world system architectures. The developed artifact gives operators the flexibility to define attack technique behaviors of interest through a custom developed configuration syntax and utilizes Event Tracing for Windows (ETW) telemetry emanating from the Windows operating system in a unique way to detect the defined attack behaviors. Validation experiments on the developed artifact proved that the artifact, along with the user-defined configuration file, successfully detected 36/48 of the chosen atomic attack technique stimuli. The results represent a significantly broad coverage of detection that current-generation endpoint solutions fail to accomplish, thereby illustrating the need to incorporate the developed artifact into real-world environments to combat cyber-attack activity

    Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques

    No full text
    Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2M-/-CIITA-/-CD47+). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected

    Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19

    Get PDF
    Background While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

    The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection

    Get PDF
    Background The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. Results Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. Conclusions These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions

    Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

    Get PDF
    Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes
    • …
    corecore