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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.

Across species, a major axis of variation in social behaviour relates to how offspring are reared. Parental care behaviours have independently evolved in hundreds of animal lineages. Care is usually limited to one or both parents, but in some lineages parenting is a highly cooperative endeavour. In social insects, for example, entire societies have evolved around parenting, complete with distinct adult morphs that specialize in reproduction, nursing, foraging and defence. Recent advances in omic technologies have enabled data collection across diverse taxa, revealing broad patterns in the molecular regulation of parental behaviour. These studies indicate that evolution has systematically co-opted molecular machinery that pleiotropically regulates three deeply interlinked biological processes: feeding, growth and reproduction. Where more sophisticated social systems have evolved, the same factors have been further co-opted to additionally regulate the developmental differentiation of distinct morphs, division of labour between adults and behavioural changes associated with ageing. These findings suggest that complex behaviours evolve through repeated and predictable co-option of ancient molecular systems.

Transcription elongation by RNA polymerase II (Pol II) is an integral step in eukaryotic gene expression. The speed of Pol II is controlled by a multitude of elongation factors, but the exact regulatory mechanisms remain incompletely understood, especially for higher eukaryotes. Here we develop a single-molecule platform to visualize the dynamics of individual mammalian transcription elongation complexes (ECs) reconstituted from purified proteins. This platform allows us to follow the elongation and pausing behavior of EC in real time and unambiguously determine the role of each elongation factor in the kinetic control of Pol II. We find that the mammalian EC harbors multiple speed gears dictated by its associated factors and phosphorylation status. Moreover, the elongation factors are not functionally redundant but act hierarchically and synergistically to achieve optimal elongation activity. We propose that such elaborate kinetic regulation underlies the major speed-changing events during the transcription cycle and enables cells to adapt to a changing environment.