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The inclusive jet cross section is measured as a function of jet transverse momentum p(T) and rapidity y. The measurement is performed using proton-proton collision data at root s = 5.02 TeV, recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 27.4 pb(-1). The jets are reconstructed with the anti-k(T) algorithm using a distance parameter of R = 0.4, within the rapidity interval |y| < 2, and across the kinematic range 0.06 < p(T)< 1 TeV. The jet cross section is unfolded from detector to particle level using the determined jet response and resolution. The results are compared to predictions of perturbative quantum chromodynamics, calculated at both next-to-leading order and next-to-next-to-leading order. The predictions are corrected for nonperturbative effects, and presented for a variety of parton distribution functions and choices of the renormalization/factorization scales and the strong coupling alpha(S).

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.

Purpose CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4. Methods We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4. We investigated the clinical and immunological phenotypes and genotypes of these patients. Results We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single- nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes. We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype. Conclusion Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

The alpha V beta 3 receptor is a member of the integrin family of receptors, which includes 24 members involved in a variety of key biological processes. It is widely expressed in multiple cell types and is involved in cell adhesion and migration, angiogenesis and immune cell regulation. These processes play important roles in both normal placentation and placental progression through pregnancy. This review describes the potential roles of alpha V beta 3 integrin receptor throughout gestation in normal and abnormal conditions, and the need for additional studies to better define its precise contributions.

Dystocia, a common murine reproductive condition, is classified as either obstructive, a result of fetal factors such as an oversized fetus, or functional, a result of dam factors such as advanced age. Treatment is based on the dam's clinical condition and the underlying etiology, but usually requires euthanasia. A prospective study was conducted to characterize the etiology of murine dystocia to determine if treatment is warranted. The signalment and experimental, clinical, and breeding histories were obtained, and a targeted serum chemistry panel, radiographs, and a gross necropsy were conducted on mice presenting with clinical signs consistent with dystocia. Obstructive dystocia was diagnosed if the pelvic canal width was less than the diameter of the fetal head closest to the cervix or a fetus was lodged in the pelvic canal. Functional dystocia was diagnosed based on clinicopathologic abnormalities. A total of 54 mice were evaluated over 7 mo with 45/54 (83%) confirmed to have dystocia with the remaining 9 (17%) having other reproductive abnormalities. Of the confirmed cases, 27/45 (60%) were C57BL/6 or on a C57BL/6 background, and the average age at presentation was 181 +/- 85 d. The number of mice categorized as having an obstructive (n = 16) compared with a functional (n = 11) dystocia was not significantly different than those in which the definitive category could not be ascertained (n = 18). Neither clinical signs nor clinical pathology were significantly different between mice categorized as having an obstructive compared with a functional dystocia. Hunched posture, lethargy, and vaginal discharge were the most common presentation. Azotemia (BUN: 66.6 +/- 10.2 mg/dL, mean +/- SE), hypoglycemia (96.11 +/- 8.5 mg/dL), and hyperglobulinemia (3.13 +/- 0.14 mg/dL) were common. Differentiating obstructive from functional dystocia could not be determined cageside with strong confidence.

ObjectiveSystemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. Although previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II receptor type 1 (AT1) and endothelin-1 type A receptor (ETAR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of IgG derived from patients with SSc (SSc IgG) on AT1 and ETAR signaling, the downstream EC response, and the presence of AT1-binding autoantibodies in circulation.MethodsQuantitative polymerase chain reaction and cytokine enzyme-linked immunosorbent assay, alongside a real-time cell analyzer, were used to assess receptor-specific functional characteristics of purified SSc IgG (n = 18). Additionally, a novel protein capture assay using solubilized epitope-tagged AT1 was developed to detect AT1-binding autoantibodies in plasma samples from patients with SSc (n = 28) and healthy donors (n = 14).ResultsNo evidence for EC activation in an AT1- or ETAR-dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation or alter G protein-coupled receptor signaling on agonist stimulation in a model with receptor overexpression. Lastly, no AT1-binding autoantibodies were detected in plasma samples from patients with SSc when using epitope-tagged solubilized AT1.ConclusionOverall, our study did not provide evidence to support the presence of AT1- or ETAR-activating autoantibodies in purified SSc IgG or AT1-binding autoantibodies in the circulation of patients with SSc.

In the arboviral vector Aedes aegypti, adaptation to anthropogenic environments has led to a major evolutionary shift separating the domestic Aedes aegypti aegypti (Aaa) ecotype from the wild Aedes aegypti formosus (Aaf) ecotype. Aaa mosquitoes are distributed globally and have higher vectorial capacity than Aaf, which remained in Africa. Despite the evolutionary and epidemiological relevance of this separation, inconsistent morphological data and a complex population structure have hindered the identification of genomic signals distinguishing the two ecotypes. Here we assessed the correspondence between the geographic distribution, population structure and genome-wide selection of 511 Aaf and 123 Aaa specimens and report adaptive signals in 186 genes that we call Aaa molecular signatures. Our results indicate that Aaa molecular signatures arose from standing variation associated with extensive ancestral polymorphisms in Aaf populations and have been co-opted for self-domestication through genomic and functional redundancy and local adaptation. Overall, we show that the behavioural shift of Ae. aegypti mosquitoes to live in association with humans relied on the fine regulation of chemosensory, neuronal and metabolic functions, as seen in the domestication processes of rabbits and silkworms. Our results also provide a foundation for the investigation of new genic targets for the control of Ae. aegypti populations.