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Differential cross sections are measured for the standard model Higgs boson produced in association with vector bosons (W, Z) and decaying to a pair of b quarks. Measurements are performed within the framework of the simplified template cross sections. The analysis relies on the leptonic decays of theW and Z bosons, resulting in final states with 0, 1, or 2 electrons or muons. The Higgs boson candidates are either reconstructed from pairs of resolved b-tagged jets, or from single large-radius jets containing the particles arising from two b quarks. Proton-proton collision data at root s = 13 TeV, collected by the CMS experiment in 2016-2018 and corresponding to a total integrated luminosity of 138 fb(-1), are analyzed. The inclusive signal strength, defined as the product of the observed production cross section and branching fraction relative to the standard model expectation, combining all analysis categories, is found to be mu = 1.15(-0.20)(+0.22). This corresponds to an observed (expected) significance of 6.3 (5.6) standard deviations.

The brain's remarkable properties arise from the collective activity of millions of neurons. Widespread application of dimensionality reduction to multi-neuron recordings implies that neural dynamics can be approximated by low-dimensional "latent"signals reflecting neural computations. However, can such low-dimensional representations truly explain the vast range of brain activity, and if not, what is the appropriate resolution and scale of recording to capture them? Imaging neural activity at cellular resolution and nearsimultaneously across the mouse cortex, we demonstrate an unbounded scaling of dimensionality with neuron number in populations up to 1 million neurons. Although half of the neural variance is contained within sixteen dimensions correlated with behavior, our discovered scaling of dimensionality corresponds to an ever-increasing number of neuronal ensembles without immediate behavioral or sensory correlates. The activity patterns underlying these higher dimensions are fine grained and cortex wide, highlighting that largescale, cellular-resolution recording is required to uncover the full substrates of neuronal computations.

CD4 T helper cells use the SNARE protein SYNTAXIN-11 to promote B cell differentiation, germinal center formation, and class switching by facilitating CD40L mobilization and IL-2 and IL-10 secretion. Variable hypogammaglobulinemia is a novel phenotype of human STX11 deficiency. SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.

Since the initial data taking of the CERN LHC, the CMS experiment has undergone substantial upgrades and improvements. This paper discusses the CMS detector as it is configured for the third data-taking period of the CERN LHC, Run 3, which started in 2022. The entire silicon pixel tracking detector was replaced. A new powering system for the superconducting solenoid was installed. The electronics of the hadron calorimeter was upgraded. All the muon electronic systems were upgraded, and new muon detector stations were added, including a gas electron multiplier detector. The precision proton spectrometer was upgraded. The dedicated luminosity detectors and the beam loss monitor were refurbished. Substantial improvements to the trigger, data acquisition, software, and computing systems were also implemented, including a new hybrid CPU/GPU farm for the high-level trigger.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

A search is presented for charged, long-lived supersymmetric particles in final states with one or more disappearing tracks. The search is based on data from proton-proton collisions at a center-of-mass energy of 13 TeV collected with the CMS detector at the CERN LHC between 2016 and 2018, corresponding to an integrated luminosity of 137 fb(-1). The search is performed over final states characterized by varying numbers of jets, b-tagged jets, electrons, and muons. The length of signal-candidate tracks in the plane perpendicular to the beam axis is used to characterize the lifetimes of wino- and Higgsino-like charginos produced in the context of the minimal supersymmetric standard model. The dE/dx energy loss of signal-candidate tracks is used to increase the sensitivity to charginos with a large mass and thus a small Lorentz boost. The observed results are found to be statistically consistent with the background-only hypothesis. Limits on the pair-production cross section of gluinos and squarks are presented in the framework of simplified models of supersymmetric particle production and decay, and for electroweakino production based on models of wino and Higgsino dark matter. The limits presented are the most stringent to date for scenarios with light third-generation squarks and a wino- or Higgsino-like dark matter candidate capable of explaining the observed dark matter relic density.

This study describes clinical features and cellular and molecular mechanisms underlying immune deficiency in seven patients with biallelic germline variants in CD4. The data reveal important roles for CD4 in host defense against a range of pathogens, particularly human papilloma virus. CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCR alpha beta+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- alpha beta T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

In this review, we provide an overview of the intricate host-virus interactions that have emerged from the study of SARS-CoV-2 infection. We focus on the antiviral mechanisms of interferonstimulated genes (ISGs) and their modulation of viral entry, replication, and release. We explore the role of a selection ISGs, restricting SARS-CoV-2 infection and discuss the virus's countermeasures. By synthesizing the latest research on SARSCoV-2 and host antiviral responses, this review aims to provide a deeper understanding of the antiviral state of the cell under SARS-CoV-2 and other viral infections, offering insights for the development of novel antiviral strategies and therapeutics.

Drugs of abuse are thought to promote addiction in part by "hijacking" brain reward systems, but the underlying mechanisms remain undefined. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we found that drugs of abuse augment dopaminoceptive ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell type-specific manner. Combining FOS-Seq, CRISPR-perturbation, and single-nucleus RNA sequencing, we identified Rheb as a molecular substrate that regulates cell type-specific signal transduction in NAc while enabling drugs to suppress natural reward consumption. Mapping NAc-projecting regions activated by drugs of abuse revealed input-specific effects on natural reward consumption. These findings characterize the dynamic, molecular and circuit basis of a common reward pathway, wherein drugs of abuse interfere with the fulfillment of innate needs.

Background: Nursing professionals are vitally involved in the cascade of care for opioid use disorders (OUDs). The global spread of COVID-19 has had complex effects on public health aspects of major diseases, including OUDs. There are limited data on the major ways in which the COVID-19 pandemic has affected the functions of nursing professionals in the care of OUDs. Method: This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines and examined published data for trends in OUD care during the first 2 years of the COVID-19 pandemic, focusing on nursing functions. The National Library of Medicine PubMed database and the EMBASE database were examined for peer-reviewed studies with primary data published between January 1, 2020, and December 31, 2021. Review Findings and Conclusions: Rapid changes were observed in numerous aspects of OUDs during the early pandemic stage, as well as its care by nursing and other health professionals. These changes include increased overdoses (primarily from synthetic opioids such as fentanyl) and emergency department visits. These trends varied considerably across U.S. jurisdictions, underscoring the importance of region-specific examinations for public health policy and intervention. Out of necessity, healthcare systems and nursing professionals adapted to the challenges of OUD care in the pandemic. These adaptations included increases in telehealth services, increases in take-home doses of methadone or buprenorphine/naloxone, and expansion of layperson training in the use of naloxone for overdose reversal. It is likely that some of these adaptations will result in long-term changes in standards of care practices for OUDs by nursing professionals.