pinecone/core-2020-05-10-deduplication huggingface dataset:
Measurement of the inclusive energy spectrum in the very forward
  direction in proton-proton collisions at sqrt(s) = 13 TeV

The differential cross section for inclusive particle production as a
function of energy in proton-proton collisions at a center-of-mass energy of 13
TeV is measured in the very forward region of the CMS detector. The measurement
is based on data collected with the CMS apparatus at the LHC, and corresponds
to an integrated luminosity of 0.35 inverse microbarns. The energy is measured
in the CASTOR calorimeter, which covers the pseudorapidity region -6.6 < eta <
-5.2. The results are given as a function of the total energy deposited in
CASTOR, as well as of its electromagnetic and hadronic components. The spectra
are sensitive to the modeling of multiparton interactions in pp collisions, and
provide new constraints for hadronic interaction models used in collider and in
high energy cosmic ray physics.Comment: Replaced with the published version. Added the journal reference and
  DOI. All figures and tables, including additional supplemental figures, can
  be found at
  http://cms-results.web.cern.ch/cms-results/public-results/publications/FSQ-16-00
Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.

PDB ID codes\ud
5EI3, 5EIR, 5EKV, 5EHC.Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5'-terminal mRNA cap structure (m(7)GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N(7)-substituent of m(7)GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N'-(2-methyl-propyl)-N-(phenyl-methyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m(7)GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5'-deoxy-5'-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N(7)-methyl-guanosine (4a), N(7)-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N(7)-benzyl-5'-deoxy-5'-(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.The work presented here was funded by the Association for International Cancer Research (AICR; grant reference 06-063), the Medical Research Council (MRC), and Cancer Research UK (CRUK; grant reference C18648/A10174) and was supported by the Wellcome Trust Multi-User Equipment Grants 081287/Z/06/Z and 101527/Z/13/Z. FS was supported by a Scholarship from the University of Damascus, Syria.Peer-reviewedPublisher Versio
International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling
Genome-wide association study with 1000 genomes imputation identifies signals for nine sex-hormone-related phenotypes

Genetic factors contribute strongly to sex-hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2,913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardized for age, sex, BMI, stage of menstrual cycle, and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex-hormone binding globulin and t 47 estosterone. Eight independent genetic variants reached genome-wide significance (p<5×10^-8), with minor allele frequencies of 1.3%–23.9%. Novel signals included variants for progesterone (p=7.68×10^-12), oestradiol (p=1.63×10^-8) and FAI (p=1.50×10^-8). A genetic variant near the FSHB gene was identified which influenced both FSH (p=1.74×10^-8) and LH (p=3.94×10^-9) levels. A separate locus on chromosome 7 was associated with both DHEAS (p=1.82×10^-14) and progesterone (p=6.09×10^-14). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.We thank Roche Diagnostics Australia Pty Limited, Castle Hill, Australia, who provided support for the analysis of the hormones. We thank the volunteer twins for their participation in the study. Twins UK received funding support from NIHR Biomedical Research Centre (grant to Guys’ and St. Thomas’ Hospitals and King’s College London); the Chronic Disease Research Foundation; Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Fonds de la Recherche en Santé Québec, The Lady Davis Institute, the Jewish General Hospital and Ministère du Développement économique, de l'Innovation et de l'Exportation du Quebec. The Australian National Health and Medical Research Council (NHMRC project grants 1010494, 1048216), and Sir Charles Gairdner Hospital Research (grant PP2009/028). This work was supported by funding from the Wellcome Trust (092447/Z/10/Z) and Medical Research Council (MC_U106179472).This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ejhg.2015.10
2MASS J20261584–2943124: AN UNRESOLVED L0.5 + T6 SPECTRAL BINARY

We identify the L dwarf 2MASS J20261584–2943124 as an unresolved spectral binary, based on low-resolution, near-infrared spectroscopy from IRTF/SpeX. The data reveal a peculiar absorption feature at 1.6 μm, previously noted in the spectra of other very low-mass spectral binaries, which likely arises from overlapping FeH and CH[subscript 4] absorption bands in the blended light of an L dwarf/T dwarf pair. Spectral template matching analysis indicates component types of L0.5 and T6, with relative brightness ΔH = 4.2 ± 0.6. Laser guide star adaptive optics imaging observations with Keck/NIRC2 fail to resolve the source, indicating a maximum separation at the observing epoch of 0['' over .]25, or a projected separation of 9 AU assuming a distance of 36 ± 5 pc. With an age that is likely to be relatively older ([> over ~]5 Gyr) based on the system's large V [subscript tan] and mass ratio arguments, the relative motion of the potentially "massive" (0.06-0.08 M [subscript ☉]) components of 2MASS J2026–2943 may be detectable through radial velocity variations, like its earlier-type counterpart 2MASS J03202839–0446358 (M8+T5), providing dynamical mass measurements that span the hydrogen burning limit
Search for R-parity violating decays of a top squark in proton-proton collisions at $\sqrt{s}$ = 8 TeV

The results of a search for a supersymmetric partner of the top quark (top squark), pair-produced in proton–proton collisions at $\sqrt{s}$=8 TeV , are presented. The search, which focuses on R-parity violating, chargino-mediated decays of the top squark, is performed in final states with low missing transverse momentum, two oppositely charged electrons or muons, and at least five jets. The analysis uses a data sample corresponding to an integrated luminosity of 19.7 fb$^{−1}$ collected with the CMS detector at the LHC in 2012. The data are found to be in agreement with the standard model expectation, and upper limits are placed on the top squark pair production cross section at 95% confidence level. Assuming a 100% branching fraction for the top squark decay chain, $\tilde{t}→t\tilde{x}^{±}_{1},\tilde{x}^{±}_{1}→ℓ^{±} + jj$ , top squark masses less than 890 (1000) GeV for the electron (muon) channel are excluded for the first time in models with a single nonzero R-parity violating coupling $λ^{′}_{ijk}$ (i,j,k≤2) , where i,j,k correspond to the three generations
Search for heavy lepton resonances decaying to a Z boson and a lepton in pp collisions at root s = 8 TeV with the ATLAS detector

A search for heavy leptons decaying to a Z boson and an electron or a muon is presented. The search is based on pp collision data taken at √s = 8 TeV by the ATLAS experiment at the CERN Large Hadron Collider, corresponding to an integrated luminosity of 20.3 fb⁻¹. Three high-transverse-momentum electrons or muons are selected, with two of them required to be consistent with originating from a Z boson decay. No significant excess above Standard Model background predictions is observed, and 95% confidence level limits on the production cross section of high-mass trilepton resonances are derived. The results are interpreted in the context of vector-like lepton and type-III seesaw models. For the vector-like lepton model, most heavy lepton mass values in the range 114–176 GeV are excluded. For the type-III seesaw model, most mass values in the range 100–468 GeV are excluded.G. Aad ... P. Jackson ... L. Lee ... A. Petridis ... N. Soni ... M.J. White ... et al. (ATLAS Collaboration
Tracking Advanced Planetary Systems (TAPAS) with HARPS-N: IV. TYC 3667-1280-1: The most massive red giant star hosting a warm Jupiter

Astronomy and Astrophysics 589. (2016): L1 reproduced with permission from Astronomy & AstrophysicsContext. We present the latest result of the TAPAS project that is devoted to intense monitoring of planetary candidates that are identified within the PennState-Toruń planet search. Aims. We aim to detect planetary systems around evolved stars to be able to build sound statistics on the frequency and intrinsic nature of these systems, and to deliver in-depth studies of selected planetary systems with evidence of star-planet interaction processes. Methods. The paper is based on precise radial velocity measurements: 13 epochs collected over 1920 days with the Hobby-Eberly Telescope and its High-Resolution Spectrograph, and 22 epochs of ultra-precise HARPS-N data collected over 961 days. Results. We present a warm-Jupiter (Teq = 1350 K, m2 sin i = 5.4 ± 0.4 MJ) companion with an orbital period of 26.468 days in a circular (e = 0.036) orbit around a giant evolved (log g = 3.11 ± 0.09, R = 6.26 ± 0.86 R⊙) star with M∗ = 1.87 ± 0.17 M⊙. This is the most massive and oldest star found to be hosting a close-in giant planet. Its proximity to its host (a = 0.21 au) means that the planet has a 13.9 ± 2.0% probability of transits; this calls for photometric follow-up study. Conclusions. This massive warm Jupiter with a near circular orbit around an evolved massive star can help set constraints on general migration mechanisms for warm Jupiters and, given its high equilibrium temperature, can help test energy deposition models in hot JupitersE.V. acknowledges support from the Spanish Ministerio de Economía y Competitividad under grant AYA2014-55840
Contribution of mode-coupling and phase-mixing of Alfvén waves to coronal heating

This research has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 647214) and from the UK Science and Technology Facilities Council. This work used the DiRAC Data Centric system at Durham University, operated by the Institute for Computational Cosmology on behalf of the STFC DiRAC HPC Facility (www.dirac.ac.uk. This equipment was funded by a BIS National E-infrastructure capital grant ST/K00042X/1, STFC capital grant ST/K00087X/1, DiRAC Operations grant ST/K003267/1 and Durham University.Context. Phase-mixing of Alfvén waves in the solar corona has been identified as one possible candidate to explain coronal heating. While this scenario is supported by observations of ubiquitous oscillations in the corona carrying sufficient wave energy and by theoretical models that have described the concentration of energy in small-scale structures, it is still unclear whether this wave energy can be converted into thermal energy in order to maintain the million-degree hot solar corona. Aims. The aim of this work is to assess how much energy can be converted into thermal energy by a phase-mixing process triggered by the propagation of Alfvénic waves in a cylindric coronal structure, such as a coronal loop, and to estimate the impact of this conversion on the coronal heating and thermal structure of the solar corona. Methods. To this end, we ran 3D MHD simulations of a magnetised cylinder where the Alfvén speed varies through a boundary shell, and a footpoint driver is set to trigger kink modes that mode couple to torsional Alfvén modes in the boundary shell. These Alfvén waves are expected to phase-mix, and the system allows us to study the subsequent thermal energy deposition. We ran a reference simulation to explain the main process and then we varied the simulation parameters, such as the size of the boundary shell, its structure, and the persistence of the driver. Results. When we take high values of magnetic resistivity and strong footpoint drivers into consideration, we find that i) phase-mixing leads to a temperature increase of the order of 105 K or less, depending on the structure of the boundary shell, ii) this energy is able to balance the radiative losses only in the localised region involved in the heating, and iii) we can determine the influence of the boundary layer and the persistence of the driver on the thermal structure of the system. Conclusions. Our conclusion is that as a result of the extreme physical parameters we adopted and the moderate impact on the heating of the system, it is unlikely that phase-mixing can contribute on a global scale to the heating of the solar corona.PostprintPeer reviewe
The TREAT-NMD DMD global database: Analysis of more than 7,000 duchenne muscular dystrophy mutations

© 2015 The Authors.Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).published_or_final_versio
The rate of hypo-osmotic challenge influences regulatory volume decrease (RVD) and mechanical properties of articular chondrocytes

SummaryObjectivesOsteoarthritis (OA) is associated with a gradual reduction in the interstitial osmotic pressure within articular cartilage. The aim of this study was to compare the effects of sudden and gradual hypo-osmotic challenge on chondrocyte morphology and biomechanics.MethodsBovine articular chondrocytes were exposed to a reduction in extracellular osmolality from 327 to 153 mOsmol/kg applied either suddenly (<5 s) or gradually (over 180 min). Temporal changes in cell diameter and the existence of regulatory volume decrease (RVD) were quantified along with changes in cortical actin and chromatin condensation. The cellular viscoelastic mechanical properties were determined by micropipette aspiration.ResultsIn response to a sudden hypo-osmotic stress, 66% of chondrocytes exhibited an increase in diameter followed by RVD, whilst 25% showed no RVD. By contrast, cells exposed to gradual hypo-osmotic stress exhibited reduced cell swelling without subsequent RVD. There was an increase in the equilibrium modulus for cells exposed to sudden hypo-osmotic stress. However, gradual hypo-osmotic challenge had no effect on cell mechanical properties. This cell stiffening response to sudden hypo-osmotic challenge was abolished when actin organization was disrupted with cytochalasin D or RVD inhibited with REV5901. Both sudden and gradual hypo-osmotic challenge reduced cortical F-actin distribution and caused chromatin decondensation.ConclusionsSudden hypo-osmotic challenge increases chondrocyte mechanics by activation of RVD and interaction with the actin cytoskeleton. Moreover, the rate of hypo-osmotic challenge is shown to have a profound effect on chondrocyte morphology and biomechanics. This important phenomenon needs to be considered when studying the response of chondrocytes to pathological hypo-osmotic stress
Identification of a SIRT1 Mutation in a Family with Type 1 Diabetes

SummaryType 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes
The frequency and magnitude of post-glacial explosive eruptions at Volcán Mocho-Choshuenco, southern Chile

AbstractVolcán Mocho-Choshuenco (39°55′S 72°2′W) is one of the most hazardous volcanoes in Chile′s Southern Volcanic Zone (SVZ). To better evaluate these hazards, we have reconstructed a high resolution eruption history, the most detailed to date for a volcano in Chile, from detailed field observations and geochemical analyses. Mocho-Choshuenco has experienced ca. 75 post-glacial (<18ka) explosive eruptions, including three large (volume ≥1km3) Plinian eruptions (Neltume, Pirehueico and Huilo) and a large pyroclastic density current and associated sub-Plinian event (Enco). Poor preservation and lack of exposure made it difficult to distinguish between medial to distal deposits solely on field observations. Instead, deposits have been correlated using a combination of glass chemistry and Fe–Ti oxide compositions. New radiocarbon dates were obtained and integrated with existing dates in a Bayesian age model (OxCal) to constrain the tempo of the volcanism. Based on preserved deposits, we derive a post-glacial eruptive frequency of one explosive eruption every ~220years with the youngest, confirmed eruption from Mocho-Choshuenco in 1864. The total post-glacial volume of tephra erupted is estimated at ≥20km3 (ca. 50% with a dacitic or rhyolitic glass composition) with ≥4km3 erupted from the monogenetic cones on the flanks, making Mocho-Choshuenco one of the most productive (ca. 1km3/kyr) and active volcanoes in the SVZ during post-glacial times. Many tephra deposits from Mocho-Choshuenco could be preserved in one or more lakes in the region, and have the potential to form regional tephra markers. In particular the Neltume deposits, which are dispersed to the NNE, are found interbedded with tephra deposits from the Villarrica–Quetrupillán–Lanín chain and should be preserved around Sollipulli and Llaima (~140km NNE of Mocho-Choshuenco). This study highlights how a multi-technique approach enables a complicated tephrostratigraphy to be unravelled so more robust estimates of the past eruptive frequency and size can be determined