Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values &lt;5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.</p

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Coral Reef Community Changes in Karimunjawa National Park, Indonesia: Assessing the Efficacy of Management in the Face of Local and Global Stressors

Karimunjawa National Park is one of Indonesia's oldest established marine parks. Coral reefs across the park are being impacted by fishing, tourism and declining water quality (local stressors), as well as climate change (global pressures). In this study, we apply a multivariate statistical model to detailed benthic ecological datasets collected across Karimunjawa's coral reefs, to explore drivers of community change at the park level. Eighteen sites were surveyed in 2014 and 2018, before and after the 2016 global mass coral bleaching event. Analyses revealed that average coral cover declined slightly from 29.2 +/- 0.12% (Standard Deviation, SD) to 26.3 +/- 0.10% SD, with bleaching driving declines in most corals. Management zone was unrelated to coral decline, but shifts from massive morphologies toward more complex foliose and branching corals were apparent across all zones, reflecting a park-wide reduction in damaging fishing practises. A doubling of sponges and associated declines in massive corals could not be related to bleaching, suggesting another driver, likely declining water quality associated with tourism and mariculture. Further investigation of this potentially emerging threat is needed. Monitoring and management of water quality across Karimunjawa may be critical to improving resilience of reef communities to future coral bleaching

Monitoring of coral reefs using artificial intelligence: A feasible and cost-effective approach

Ecosystemmonitoring is central to effectivemanagement, where rapid reporting is essential to provide timely advice. While digital imagery has greatly improved the speed of underwater data collection formonitoring benthic communities, image analysis remains a bottleneck in reporting observations. In recent years, a rapid evolution of artificial intelligence in image recognition has been evident in its broad applications in modern society, offering new opportunities for increasing the capabilities of coral reef monitoring. Here, we evaluated the performance of Deep Learning Convolutional Neural Networks for automated image analysis, using a global coral reefmonitoring dataset. The study demonstrates the advantages of automated image analysis for coral reef monitoring in terms of error and repeatability of benthic abundance estimations, as well as cost and benefit. We found unbiased and high agreement between expert and automated observations (97%). Repeated surveys and comparisons against existing monitoring programs also show that automated estimation of benthic composition is equally robust in detecting change and ensuring the continuity of existing monitoring data. Using this automated approach, data analysis and reporting can be accelerated by at least 200x and at a fraction of the cost (1%). Combining commonly used underwater imagery inmonitoring with automated image annotation can dramatically improve how wemeasure andmonitor coral reefs worldwide, particularly in terms of allocating limited resources, rapid reporting and data integration within and acrossmanagement areas.</p

Measurement of charged-particle multiplicities in gluon and quark jets in p(p)over-bar collisions at root s=1.8 TeV

We report the first largely model independent measurement of charged particle multiplicities in quark and gluon jets, N-q and N-g, produced at the Fermilab Tevatron in p (p) over bar collisions with a center-of-mass energy of 1.8 TeV and recorded by the Collider Detector at Fermilab. The measurements are made for jets with average energies of 41 and 53 GeV by counting charged particle tracks in cones with opening angles of θ(c)=0.28, 0.36, and 0.47 rad around the jet axis. The corresponding jet hardness Q=E-jetθ(c) varies in the range from 12 to 25 GeV. At Q=19.2 GeV, the ratio of multiplicities r=N-g/N-q is found to be 1.64&PLUSMN; 0.17, where statistical and systematic uncertainties are added in quadrature. The results are in agreement with resummed perturbative QCD calculations