The rockefeller university

BACKGROUND: Highly palatable food triggers behavioral responses including strong motivation. These effects involve the reward system and dopamine neurons, which modulate neurons in the nucleus accumbens (NAc). The molecular mechanisms underlying the long-lasting effects of highly palatable food on feeding behavior are poorly understood. METHODS: We studied the effects of 2-week operant conditioning of mice with standard or isocaloric highly palatable food. We investigated the behavioral responses and dendritic spine modifications in the NAc. We compared the translating messenger RNA in NAc neurons identified by the type of dopamine receptors they express, depending on the kind of food and training. We tested the consequences of invalidation of an abundant RESULTS: Operant conditioning for highly palatable food increased motivation for food even in well-fed mice. In wildtype mice, free choice between regular and highly palatable food increased weight compared with access to regular food only. Highly palatable food increased spine density in the NAc. In animals trained for highly palatable food, translating messenger RNAs were modified in NAc neurons expressing dopamine D2 receptors, mostly corresponding to striatal projection neurons, but not in neurons expressing D1 receptors. Knockout of Ncdn, an abundant downregulated gene, opposed the conditioning-induced changes in satiety-sensitive feeding behavior and apparent motivation for highly palatable food, suggesting that downregulation may be a compensatory mechanism. CONCLUSIONS: Our results emphasize the importance of messenger RNA alterations in D2 striatal projection neurons in the NAc in the behavioral consequences of highly palatable food conditioning and suggest a modulatory contribution of Ncdn downregulation.

An inclusive search for long-lived exotic particles (LLPs) decaying to final states with a pair of muons is presented. The search uses data corresponding to an integrated luminosity of 36.6 fb(-1) collected by the CMS experiment from the proton-proton collisions at root s - 13.6TeV in 2022, the first year of Run 3 of the CERN LHC. The experimental signature is a pair of oppositely charged muons originating from a secondary vertex spatially separated from the proton-proton interaction point by distances ranging from several hundred mu m to several meters. The sensitivity of the search benefits from new triggers for displaced dimuons developed for Run 3. The results are interpreted in the framework of the hidden Abelian Higgs model, in which the Higgs boson decays to a pair of long-lived dark photons, and of an R-parity violating supersymmetry model, in which long-lived neutralinos decay to a pair of muons and a neutrino. The limits set on these models are the most stringent to date in wide regions of lifetimes for LLPs with masses larger than 10 GeV.

A measurement is presented of the primary Lund jet plane (LJP) density in inclusive jet production in proton-proton collisions. The analysis uses 138 fb(-1) of data collected by the CMS experiment at root s = 13TeV. The LJP, a representation of the phase space of emissions inside jets, is constructed using iterative jet declustering. The transverse momentum kT and the splitting angle Delta R of an emission relative to its emitter are measured at each step of the jet declustering process. The average density of emissions as function of ln( k(T)/GeV) and ln( R/Delta R) is measured for jets with distance parameters R = 0.4 or 0.8, transverse momentum p(T) > 700 GeV, and rapidity |y| < 1.7. The jet substructure is measured using the charged-particle tracks of the jet. The measured distributions, unfolded to the level of stable charged particles, are compared with theoretical predictions from simulations and with perturbative quantum chromodynamics calculations. Due to the ability of the LJP to factorize physical effects, these measurements can be used to improve different aspects of the physics modeling in event generators.

Hepatitis B virus (HBV) is a small double -stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two overlapping reading frames, and during evolution, multiple selective pressures can act on shared nucleotides. This study combines an RNA -based HBV cell culture system with deep mutational scanning (DMS) to uncouple cis - and trans -acting sequence requirements in the HBV genome. The results support a leaky ribosome scanning model for polymerase translation, provide a fitness map of the HBV polymerase at single -nucleotide resolution, and identify conserved prolines adjacent to the HBV polymerase termination codon that stall ribosomes. Further experiments indicated that stalled ribosomes tether the nascent polymerase to its template RNA, ensuring cis -preferential RNA packaging and reverse transcription of the HBV genome.

Infectious diseases continue to claim many lives. Prevention of morbidity and mortality from these diseases would benefit not just from new medicines and vaccines but also from a better understanding of what constitutes protective immunity. Among the major immune signals that mobilize host defense against infection is interferon-gamma (IFN-gamma), a protein secreted by lymphocytes. Forty years ago, IFN-gamma was identified as a macrophage-activating factor, and, in recent years, there has been a resurgent interest in IFN-gamma biology and its role in human defense. Here we assess the current understanding of IFN-gamma, revisit its designation as an "interferon," and weigh its prospects as a therapeutic against globally pervasive microbial pathogens.

Sex-limited polymorphism has evolved in many species including our own. Yet, we lack a detailed understanding of the underlying genetic variation and evolutionary processes at work. The brood parasitic common cuckoo (Cuculus canorus) is a prime example of female-limited color polymorphism, where adult males are monochromatic gray and females exhibit either gray or rufous plumage. This polymorphism has been hypothesized to be governed by negative frequency-dependent selection whereby the rarer female morph is protected against harassment by males or from mobbing by parasitized host species. Here, we show that female plumage dichromatism maps to the female-restricted genome. We further demonstrate that, consistent with balancing selection, ancestry of the rufous phenotype is shared with the likewise female dichromatic sister species, the oriental cuckoo (Cuculus optatus). This study shows that sex-specific polymorphism in trait variation can be resolved by genetic variation residing on a sex-limited chromosome and be maintained across species boundaries.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells. IL-27RA-IL-27 has a critical role in the immunity to EBV, and this defence is hijacked by Epstein-Barr virus to promote the expansion of infected transformed B cells

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.

A search for the production of a top quark in association with a photon and additional jets via flavor changing neutral current interactions is presented. The analysis uses proton-proton collision data recorded by the CMS detector at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb(-1). The search is performed by looking for processes where a single top quark is produced in association with a photon, or a pair of top quarks where one of the top quarks decays into a photon and an up or charm quark. Events with an electron or a muon, a photon, one or more jets, and missing transverse momentum are selected. Multivariate analysis techniques are used to discriminate signal and standard model background processes. No significant deviation is observed over the predicted background. Observed (expected) upper limits are set on the branching fractions of top quark decays: B(t -> u gamma) < 0.95 x 10(-5) (1.20 x 10(-5)) and B(t -> c gamma) < 1.51 x 10(-5) (1.54 x 10(-5)) at 95% confidence level, assuming a single nonzero coupling at a time. The obtained limit for B(t -> u gamma) is similar to the current best limit, while the limit for B(t -> u gamma) is significantly tighter than previous results.