The rockefeller university

Differential and double-differential cross sections for the production of top quark pairs in proton-proton collisions at root s = 13 TeV are measured as a function of kinematic variables of the top quarks and the top quark-antiquark (t (t) over bar) system. In addition, kinematic variables and multiplicities of jets associated with the t (t) over bar production are measured. This analysis is based on data collected by the CMS experiment at the LHC in 2016 corresponding to an integrated luminosity of 35.8 fb(-1). The measurements are performed in the lepton + jets decay channels with a single muon or electron and jets in the final state. The differential cross sections are presented at the particle level, within a phase space close to the experimental acceptance, and at the parton level in the full phase space. The results are compared to several standard model predictions that use different methods and approximations. The kinematic variables of the top quarks and the t (t) over bar system are reasonably described in general, though none predict all the measured distributions. In particular, the transverse momentum distribution of the top quarks is more steeply falling than predicted. The kinematic distributions and multiplicities of jets are adequately modeled by certain combinations of next-to-leading-order calculations and parton shower models.

Contrave (R) is an adjunct pharmacotherapy for obesity that contains bupropion (BUP) and naltrexone (NTX). To further explore the psychopharmacology of this drug combination, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing: 40 mg/kg/day BUP, 4 mg/kg/day NTX, or 40 + 4 mg/kg/day BUP and NTX (BN). During 12 days of exposure, the animals were tested on operant intraoral self-administration (IOSA) of high fructose corn syrup (HFCS) on continuous (FR1) and progressive ratio (PR) schedules, on home cage drinking of HFCS, and on HFCS taste reactivity. Locomotion activity was also assessed. At the conclusion of the study, mRNA expression of genes involved in reward processing, appetite and mood were quantified. It was found that BN produced effects that could largely be ascribed to either BUP or NTX independently. More specifically, BN-induced reductions of HFCS IOSA on a FR1 schedule and home cage drinking, as well as alterations of MOR and POMC mRNA in the nucleus accumbens core and hypothalamus respectively, were attributable to NTX; while alterations of hippocampal BDNF mRNA was attributable to BUP. But, there was also some evidence of drug synergy: only BN caused persistent reductions of HFCS IOSA and drinking; BN produced the least gain of body weight; and only BN-treated rats displayed altered D2R mRNA in the caudate-putamen. Taken together, these observations support the use of BUP + NTX as a mean to alter consumption of sugars and reducing their impact on brain systems involved in reward, appetite and mood. (C) 2018 Elsevier Ltd. All rights reserved.

Chlorins have unique photophysical properties that are exploited in diverse biological and materials applications. De novo chlorin synthesis with specific exocyclic motifs can be challenging and many are not stable to photobleaching and/or oxidation. A facile approach to a stable synthetic chlorin with a fused N-methyl pyrrolidine uses cyclo addition of a sarcosine-based azomethine ylide on 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)-porphyrin (TPPF20) is reported, but this approach has limitations. We report the synthesis of stable chlorin scaffolds starting with TPPF20 using a new glycine-based N-(hydroxymethyl)-N-methelenemethanideaminium ylide. Careful control of the 1,3-dipolar cycloaddition reaction allows a divergent use of the glycine derived ylide to yield four new chlorins, including the fused NH-pyrrolidine, two dimers, and the same N-methyl chlorin product from the sarcosine ylide reaction. The mechanism begins with the formation of a bis(hydroxymethyl)glycine, which then dehydrates and decarboxylates to form the active N-(hydroxymethyl)-N-methelenemethanideaminium ylide, which then reacts with TPPF20 to form a key N-(hydroxymethyl)-17,18-pyrrolidinyl-chlorin intermediate. Deformylation of this intermediate affords the (17,18- pyrrolidinyl)-chlorin, whereas a Cannizzaro-type reaction promotes a hydride attack to an imine chlorin cation to yield the N-methyl chlorin. The exocyclic NH-pyrrolidine provides a unique mode of attaching chiral moieties that avoids formation of diasteromers at the bridgehead carbons.

Measurements of open charm and beauty production cross sections in deep inelastic ep scattering at HERA from the H1 and ZEUS Collaborations are combined. Reduced cross sections are obtained in the kinematic range of negative four-momentum transfer squared of the photon 2.5 GeV2 <= Q(2) <= 2000 GeV2 and Bjorken scaling variable 3 . 10(-5) <= x(Bj) <= 5 . 10(-2). The combination method accounts for the correlations of the statistical and systematic uncertainties among the different datasets. Perturbative QCD calculations are compared to the combined data. A next-to-leading order QCD analysis is performed using these data together with the combined inclusive deep inelastic scattering cross sections from HERA. The running charmand beauty-quark masses are determined as m(c)(m(c)) = 1.290(-0.041)(+0.046)(exp/fit)(-0.014)(+0.062)(model)(0.031)(+0.003)(par ameterisation) GeV and m(b)(m(b)) = 4.049(-0.109)(+0.104)(exp/fit)(-0.032)(+0.090)(model)(-0.031)(+0.001)(pa rameterisation) GeV.

Leptin expression decreases after fat loss and is increased when obesity develops, and its proper quantitative regulation is essential for the homeostatic control of fat mass. We previously reported that a distant leptin enhancer 1 (LE1), 16 kb upstream from the transcription start site (TSS), confers fat-specific expression in a bacterial artificial chromosome transgenic (BACTG) reporter mouse. However, this and the other elements that we identified do not account for the quantitative changes in leptin expression that accompany alterations of adipose mass. In this report, we used an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to identify a 17-bp noncanonical peroxisome proliferator-activated receptor gamma (PPAR gamma)/retinoid X receptor alpha (RXR alpha)-binding site, leptin regulatory element 1 (LepRE1), within LE1, and show that it is necessary for the fat-regulated quantitative control of reporter (luciferase) expression. While BACTG reporter mice with mutations in this sequence still show fat-specific expression, luciferase is no longer decreased after food restriction and weight loss. Similarly, the increased expression of leptin reporter associated with obesity in oWob mice is impaired. A functionally analogous LepRE1 site is also found in a second, redundant DNA regulatory element 13 kb downstream of the TSS. These data uncouple the mechanisms conferring qualitative and quantitative expression of the leptin gene and further suggest that factor(s) that bind to LepRE1 quantitatively control leptin expression and might be components of a lipid-sensing system in adipocytes.

Biochemical pathways are often genetically encoded as simple transcription regulation networks, where one transcription factor regulates the expression of multiple genes in a pathway. The relative timing of each promoter's activation and shut-off within the network can impact physiology. In the DNA damage repair pathway (known as the SOS response) of Escherichia coli, approximately 40 genes are regulated by the LexA repressor. After a DNA damaging event, LexA degradation triggers SOS gene transcription, which is temporally separated into subsets of 'early', 'middle', and 'late' genes. Although this feature plays an important role in regulating the SOS response, both the range of this separation and its underlying mechanism are not experimentally defined. Here we show that, at low doses of DNA damage, the timing of promoter activities is not separated. Instead, timing differences only emerge at higher levels of DNA damage and increase as a function of DNA damage dose. To understand mechanism, we derived a series of synthetic SOS gene promoters which vary in LexA-operator binding kinetics, but are otherwise identical, and then studied their activity over a large dose-range of DNA damage. In distinction to established models based on rapid equilibrium assumptions, the data best fit a kinetic model of repressor occupancy at promoters, where the drop in cellular LexA levels associated with higher doses of DNA damage leads to non-equilibrium binding kinetics of LexA at operators. Operators with slow LexA binding kinetics achieve their minimal occupancy state at later times than operators with fast binding kinetics, resulting in a time separation of peak promoter activity between genes. These data provide insight into this remarkable feature of the SOS pathway by demonstrating how a single transcription factor can be employed to control the relative timing of each gene's transcription as a function of stimulus dose.

Measurements of differential t (t) over bar production cross sections are presented in the single-lepton decay channel, as a function of a number of kinematic event variables. The measurements are performed with proton-proton collision data at root s = 13 TeV, collected by the CMS experiment at the LHC during 2016, with an integrated luminosity of 35.9 fb(-1). The data are compared to a variety of state-of-the-art leading-order and next-to-leading order t (t) over bar simulations.

Severe combined immunodeficiency is the first immune deficiency disorder which was included in the newborn screening program in the United States in 2010. In Hungary, newborn screening for severe combined immunodeficiencies is crucial because of the routine BCG vaccination, as in the case of an affected newborn with negative family history, the vaccine may lead to fatal BCG-itis. This paper analyzes the possibilities of introducing newborn screening for severe combined immunodeficiencies and summarizes current experiences and results.

The staphylococcal bi-component leukocidins Panton-Valentine leukocidin (PVL) and gamma-haemolysin CB (HlgCB) target human phagocytes. Binding of the toxins' S-components to human complement C5a receptor 1 (C5aR1) contributes to cellular tropism and human specificity of PVL and HlgCB. To investigate the role of both leukocidins during infection, we developed a human C5aR1 knock-in (hC5aR1(KI)) mouse model. HlgCB, but unexpectedly not PVL, contributed to increased bacterial loads in tissues of hC5aR1(KI) mice. Compared to humans, murine hC5aR1(KI) neutrophils showed a reduced sensitivity to PVL, which was mediated by the toxin's F-component LukF-PV. By performing a genome-wide CRISPR-Cas9 screen, we identified CD45 as a receptor for LukF-PV. The human-specific interaction between LukF-PV and CD45 provides a molecular explanation for resistance of hC5aR1(KI) mouse neutrophils to PVL and probably contributes to the lack of a PVL-mediated phenotype during infection in these mice. This study demonstrates an unsuspected role of the F-component in driving the sensitivity of human phagocytes to PVL.

Thus far, optical recording of neuronal activity in freely behaving animals has been limited to a thin axial range. We present a head-mounted miniaturized light-field microscope (MiniLFM) capable of capturing neuronal network activity within a volume of 700 x 600 x 360 mu m(3) at 16 Hz in the hippocampus of freely moving mice. We demonstrate that neurons separated by as little as similar to 15 mu m and at depths up to 360 mu m can be discriminated.