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A measurement is presented of the associated production of a single top quark and a W boson in proton -proton collisions at root s = 13 TeV by the CMS Collaboration at the CERN LHC. The data collected corresponds to an integrated luminosity of 35.9 fb(-1). The measurement is performed using events with one electron and one muon in the final state along with at least one jet originated from a bottom quark. A multivariate discriminant, exploiting the kinematic properties of the events, is used to separate the signal from the dominant tt background. The measured cross section of 63.1 +/- 1.8(stat) +/- 6.4(syst) +/- 2.1 (lumi) pb is in agreement with the standard model expectation.

The epithelial barrier of the gastrointestinal tract is home to numerous intraepithelial T cells (IETs). IETs are functionally adapted to the mucosal environment and are among the first adaptive immune cells to encounter microbial and dietary antigens. They possess hallmark features of tissue-resident T cells: they are long-lived nonmigratory cells capable of rapidly responding to antigen challenges independent of T cell recruitment from the periphery. Gut-resident T cells have been implicated in the relapsing and remitting course and persisting low-grade inflammation of chronic gastrointestinal diseases, including IBD and coeliac disease. So far, most data IETs have been derived from experimental animal models; however, IETs and the environmental makeup differ between mice and humans. With advances in techniques, the number of human studies has grown exponentially in the past 5 years. Here, we review the literature on the involvement of human IETs in gut homeostasis and inflammation, and how these cells are influenced by the microbiota and dietary antigens. Finally, targeting of IETs in therapeutic interventions is discussed. Broad insight into the function and role of human IETs in gut homeostasis and inflammation is essential to identify future diagnostic, prognostic and therapeutic strategies.

The polymerase-associated factor 1 (Paf1) complex is a general transcription elongation factor of RNA polymerase II, which is composed of five core subunits, Paf1, Ctr9, Cdc73, Leo1, and Rtf1, and functions as a diverse platform that broadly affects gene expression genome-wide. In this study, we solved the 2.9-A crystal structure of the core region composed of the Ctr9-Paf1-Cdc73 ternary complex from a thermophilic fungi, which provides a structural perspective of the molecular details of the organization and interactions involving the Paf1 subunits in the core complex. We find that Ctr9 is composed of 21 tetratricopeptide repeat (TPR) motifs that wrap three circular turns in a right-handed superhelical manner around the N-terminal region of an elongated singlepolypeptide-chain scaffold of Paf1. The Cdc73 fragment is positioned within the surface groove of Ctr9, where it contacts mainly with Ctr9 and minimally with Paf1. We also identified that the Paf1 complex preferentially binds single-strand-containing DNAs. Our work provides structural insights into the overall architecture of the Paf1 complex and paves the road forward for understanding the molecular mechanisms of the Paf1 complex in transcriptional regulation.

Prior studies demonstrate that astrotactin (ASTN1) provides a neuronal receptor for glial-guided CNS migration. Here we report that ASTN1 binds N-cadherin (CDH2) and that the ASTN1: CDH2 interaction supports cell-cell adhesion. To test the function of ASTN1: CDH2 binding in glial-guided neuronal migration, we generated a conditional loss of Cdh2 in cerebellar granule cells and in glia. Granule cell migration was slowed in cerebellar slice cultures after a conditional loss of neuronal Cdh2, and more severe migration defects occurred after a conditional loss of glial Cdh2. Expression in granule cells of a mutant form of ASTN1 that does not bind CDH2 also slowed migration. Moreover, in vitro chimeras of granule cells and glia showed impaired neuron-glia attachment in the absence of glial, but not neuronal, Cdh2. Thus, cis and trans bindings of ASTN1 to neuronal and glial CDH2 form an asymmetric neuron-glial bridge complex that promotes glial-guided neuronal migration.

The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4(+)/CD8(+) and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-gamma, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4(+)/CD8(+) T cells, with inducible co-stimulator molecule and HLA-DR defining mid-and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, trans-epidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P<0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17-(P<0.05) and IL-22-producing (P<0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P<0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P<0.05) and similar IFN-gamma frequencies (P>0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-gamma clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.

Hypoglycemia can alter arousal and negatively impact mood. This study tests the hypothesis that acute drops in glucose metabolism cause an aversive state mediated by monoamine activity. In experiment 1, male Sprague-Dawley rats were either food deprived (FD) or pre-fed (PF) and tested on conditioned place avoidance (CPA; biased place conditioning design; 3 pairings drug/vehicle, each 30 min-long) induced by the glucose antimetabolite 2-deoxy-d-glucose (2-DG; 0, 300 or 500 mg/kg, SC). Locomotion and blood glucose were also assessed. Experiment 2 examined whether clonidine (noradrenergic alpha 2 agonist, 0, 10 or 40 mu g/kg, SC) or bupropion (monoamine reuptake blocker, 0, 10 or 30 mg/kg, SC) could alter CPA induced by 500 mg/kg 2-DG. In experiment 3, blood corticosterone (CORT) was measured in response to 500 mg/kg 2-DG, alone or in combination with 40 mu g/kg clonidine or 30 mg/kg bupropion. Finally, experiment 4 controlled for possible place conditioning induced by 10 or 40 mu g/kg clonidine, or 10 or 30 mg/kg bupropion injected without 2-DG. It was found that 2-DG increased blood glucose and produced a robust CPA. The feeding status of the animals modulated these effects, including CORT levels. Both clonidine and bupropion attenuated the effects of 2-DG on CPA and CORT, but only bupropion reversed suppression of locomotion. Taken together, these results in rats suggest that impaired glucose metabolism can negatively impact arousal and mood via effects on HPA and monoamine systems.

Determination of the molecular properties of genetically targeted cell types has led to fundamental insights into mouse brain function and dysfunction. Here, we report an efficient strategy for precise exploration of gene expression and epigenetic events in specific cell types in a range of species, including postmortem human brain. We demonstrate that classically defined, homologous neuronal and glial cell types differ between rodent and human by the expression of hundreds of orthologous, cell specific genes. Confirmation that these genes are differentially active was obtained using epigenetic mapping and immunofluorescence localization. Studies of sixteen human postmortem brains revealed gender specific transcriptional differences, cell-specific molecular responses to aging, and the induction of a shared, robust response to an unknown external event evident in three donor samples. Our data establish a comprehensive approach for analysis of molecular events associated with specific circuits and cell types in a wide variety of human conditions.

Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise in amyotrophic lateral sclerosis (ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1 transgenic mice (SOD1-G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1 alpha are depleted. Unexpectedly, Parkin genetic ablation delays disease progression and prolongs survival in SOD1-G93A mice, as it slows down motor neuron loss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1 alpha. Our results indicate that Parkin is a disease modifier in ALS, because chronic Parkin-mediated MQC activation depletes mitochondrial dynamics-related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.