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Differential cross sections for top quark pair (t (t) over bar) production are measured in proton-proton collisions at a center-of-mass energy of 13 TeV using a sample of events containing two oppositely charged leptons. The data were recorded with the CMS detector at the CERN Large Hadron Collider and correspond to an integrated luminosity of 138 fb(-1). The differential cross sections are measured as functions of kinematic observables of the t (t) over bar system, the top quark and antiquark and their decay products, as well as of the number of additional jets in the event. The results are presented as functions of up to three variables and are corrected to the parton and particle levels. When compared to standard model predictions based on quantum chromodynamics at different levels of accuracy, it is found that the calculations do not always describe the observed data. The deviations are found to be largest for the multi-differential cross sections.

The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact tuning properties remain unclear. For example, what happens when an object by chance resembles a face? Everyday objects can sometimes, through the accidental positioning of their internal components, appear as faces. This phenomenon is known as face pareidolia. Behavioral experiments have suggested that macaques, like humans, perceive illusory faces in such objects. However, it is an open question whether such stimuli would naturally stimulate neurons residing in cortical face patches. To address this question, we recorded single unit activity from four fMRI-defined face-selective regions: the anterior medial (AM), anterior fundus (AF), prefrontal orbital (PO), and perirhinal cortex (PRh) face patches. We compared neural responses elicited by images of real macaque faces, pareidolia-evoking objects, and matched control objects. Contrary to expectations, we found no evidence of a general preference for pareidolia-evoking objects over control objects. Although a subset of neurons exhibited stronger responses to pareidolia-evoking objects, the population responses to both categories of objects were similar, and collectively much less than to real macaque faces. These results suggest that neural responses in the four regions we tested are principally concerned with the analysis of realistic facial characteristics, whereas the special attention afforded to face-like pareidolia stimuli is supported by activity elsewhere in the brain.

Evidence suggests that bats are important hosts of filoviruses, yet the specific species involved remain largely unidentified. Niemann-Pick C1 (NPC1) is an essential entry receptor, with amino acid variations influencing viral susceptibility and species-specific tropism. Herein, we conducted combinatorial binding studies with seven filovirus glycoproteins (GPs) and NPC1 orthologs from 81 bat species. We found that GP-NPC1 binding correlated poorly with phylogeny. By integrating binding assays with machine learning, we identified genetic factors influencing virus-receptor-binding and predicted GP-NPC1-binding avidity for additional filoviruses and bats. Moreover, combining receptor-binding avidities with bat geographic distribution and the locations of previous Ebola outbreaks allowed us to rank bats by their potential as Ebola virus hosts. This study represents a comprehensive investigation of filovirus-receptor binding in bats (1,484 GP-NPC1 pairs, 11 filoviruses, and 135 bats) and describes a multidisciplinary approach to predict susceptible species and guide filovirus host surveillance.

Background: Lichenification, common in moderate to severe atopic dermatitis (AD) at any age, is often difficult to treat. This analysis assessed dupilumab vs placebo in AD lichenification by age and race-defined groups. Methods: This post hoc analysis included pooled data from 5 clinical trials of dupilumab (NCT03054428, NCT03345914, NCT02277743, NCT02277769, NCT02395133), including 1,997 patients aged 6 to 88 years of all races with moderate to severe AD. Results: Placebo/dupilumab randomized groups analyzed by age (n=1,535) included 123/244 children, 85/166 adolescents, and 460/457 adults; groups analyzed by self-reported racial background (n=1,902) included 132/234 Asian, 74/112 Black/African American, and 427/923 White patients. Dupilumab treatment resulted in nominally significant reductions vs placebo in Global Individual Signs Score lichenification from week 1 (adults/adolescents) or week 2 (children) through week 16. Lichenification measured by SCORing Atopic Dermatitis and Eczema Area and Severity Index improved similarly. By week 16, dupilumab significantly improved lichenification, with nominal significance vs placebo across all racial groups. Conclusion: Dupilumab treatment resulted in rapid and sustained improvement in lichenification across anatomic regions in all ages. Lichenification improved to a similar extent across racial groups.

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms5,6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11. This study highlights the importance of considering both the genotype and the 'transcriptotype' in analyses of the penetrance and expressivity of monogenic disorders.

Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis.

Background The combination of 2 broadly neutralizing antibodies (bNAbs), teropavimab and zinlirvimab, plus the capsid inhibitor lenacapavir, is a potential twice-yearly regimen for HIV-1 treatment. The level of bNAb susceptibility to maintain virologic suppression is unknown; therefore, we evaluated this combination in participants meeting stringent viral sensitivity criteria to only 1 of the 2 bNAbs.Methods This was a pilot study within a proof-of-concept phase 1b study.Results No serious treatment-emergent adverse events occurred and 8 of 10 participants remained virologically suppressed at week 26.Conclusions More inclusive bNAb susceptibility criteria may be appropriate for future studies of this combination treatment. Clinical Trials Registration. NCT04811040.Conclusions More inclusive bNAb susceptibility criteria may be appropriate for future studies of this combination treatment. Clinical Trials Registration. NCT04811040. A single dose of lenacapavir, teropavimab, and zinlirvimab maintained virological suppression for 6 months in 8 of 10 people with HIV-1 highly susceptible to either teropavimab or zinlirvimab. Future studies should investigate broader susceptibility criteria for using this long-acting regimen.

Complete datasets of genetic variants are key to biodiversity genomic studies. Long-read sequencing technologies allow the routine assembly of highly contiguous, haplotype-resolved reference genomes. However, even when complete, reference genomes from a single individual may bias downstream analyses and fail to adequately represent genetic diversity within a population or species. Pangenome graphs assembled from aligned collections of high-quality genomes can overcome representation bias by integrating sequence information from multiple genomes from the same population, species or genus into a single reference. Here, we review the available tools and data structures to build, visualize and manipulate pangenome graphs while providing practical examples and discussing their applications in biodiversity and conservation genomics across the tree of life.