55 research outputs found

    Numerical and experimental investigation of propeller noise with trailing-edge serrations

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    The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

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    The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved. Here we discuss what is known about their structure and function and highlight some of the knowledge gaps that affect development of drugs targeting these enzymes

    Anthropology on Economic Development in Hanoi, Capital of Vietnam Analysis of Commercial Activities of Hanghom Paint Shops Street

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    The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis

    Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease.

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    The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response, but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)- 6. These late immunometabolic and immune defects may have clinical implication

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    Taxometric Investigation of Multi-Impulsive Bulimia

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    Previous researchers have proposed that Multi-impulsive Bulimia (MIB), a constellation of self-destructive impulsive behaviours including theft, self-harm, suicide attempts, sexual disinhibition, and substance use, may be a distinct sub-type of Bulimia Nervosa (BN). Prior to this study, the validity of MIB as a subtype of BN had not been empirically examined. In the current study, taxometric procedures were used to address the question of whether MIB represents a distinct subtype or occurs on one or more continua. Participants were women (N = 419) diagnosed with BN seeking treatment at a residential eating disorders facility. Taxometric procedures used were mean above below minus a cut, maximum covariance, and latent mode analyses. Indicators were bulimic behaviours (bingeing and purging), theft, suicide attempts, self-harm and alcohol use. Analyses included comparisons with simulated taxonic and dimensional data. Results were inconsistent across analyses, perhaps due to problems with indicator validity. However there was some evidence of taxonicity

    Genetics and the Causes of Ankylosing Spondylitis

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    Ankylosing spondylitis (AS) is a common inflammatory arthritis in which genetic factors are the primary determinants of disease risk and severity. Substantial progress has been made in identifying genetic pathways involved in the disease, and in translating those discoveries to drug discovery programs. Recently discovered novel disease pathways include those involved in control of DNA methylation, bacterial sensing, and mucosal immunity. Additional pathways are likely to be identified as a higher proportion of the genetic risk of AS is determined
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