pinecone/core-2020-05-10-deduplication huggingface dataset:
Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

© 2015 Nature America, Inc. All rights reserved.Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases
Psychosocial morbidity in women with abnormal cervical cytology managed by cytological surveillance or initial colposcopy: longitudinal analysis from the TOMBOLA randomised trial

Objective To compare psychosocial outcomes (follow-up related worries and satisfaction with follow-up related information and support) over 30 months of two alternative management policies for women with low-grade abnormal cervical cytology. Methods Women aged 20–59 years with low-grade cytological abnormalities detected in the National Health Service Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. A total of 3399 women who completed psychosocial questionnaires at recruitment were invited to complete questionnaires at 12, 18, 24 and 30 months. Linear mixed models were used to investigate differences between arms in the two psychosocial outcomes. Each outcome had a maximum score of 100, and higher scores represented higher psychosocial morbidity. Results On average, over 30 months, women randomised to colposcopy scored 2.5 points (95%CI −3.6 to −1.3) lower for follow-up related worries than women randomised to cytological surveillance. Women in the colposcopy arm also scored significantly lower for follow-up related satisfaction with information and support (−2.4; −3.3 to −1.4) over 30 months. For both outcomes, the average difference between arms was greatest at 12th- and 18th-month time points. These differences remained when the analysis was stratified by post-school education. Conclusions Women with low-grade cytology, irrespective of their management, have substantial initial psychosocial morbidity that reduces over time. Implementation of newer screening strategies, which include surveillance, such as primary HPV screening, need to consider the information and support provided to women
Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use
Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress
Structure, mechanism and cooperation of bacterial multi drug transporters

Cells from all domains of life encode energy-dependent trans-membrane transporters that can expel harmful substances including clinically applied therapeutic agents. As a collective body, these transporters perform as a super-system that confers tolerance to an enormous range of harmful compounds and consequently aid survival in hazardous environments. In the Gram-negative bacteria, some of these transporters serve as energy-transducing components of tripartite assemblies that actively efflux drugs and other harmful compounds, as well as deliver virulence agents across the entire cell envelope. We draw together recent structural and functional data to present the current models for the transport mechanisms for the main classes of multi-drug transporters and their higher-order assemblies.BL and DD are supported by the Medical Research Council (MRC), Human Frontiers Science Program (HFSP), and the Wellcome Trust. Work in the Van Veen lab is supported by the Biotechnology and Biological Sciences Research Council (BBSRC), MRC, HFSP, Royal Society, Society for Antimicrobial Chemotherapy (BSAC), Herchel Smith Foundation, and Commonwealth Trust. Work in the Pos lab is supported by the German Research Foundation (SFB 807, Transport and Communication across Biological Membranes and FOR2251, Adaptation and persistence of the emerging pathogen Acinetobacter baumannii), the DFG-EXC115 (Cluster of Excellence Macromolecular Complexes at the Goethe-University Frankfurt), Innovative Medicines Initiative Joint Undertaking Project Translocation (IMI-Translocation), EU Marie Curie Actions ITN, HFSP and the German-Israeli Foundation (GIF). The SM laboratory is supported by ERATO Murata Lipid Active Structure Project, Japan Science and Technology Agency, the Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO) and HFSP.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.sbi.2015.07.01
Search for new phenomena in photon+jet events collected in proton–proton collisions at √s = 8 TeV with the ATLAS detector

This Letter describes a model-independent search for the production of new resonances in photon + jet (γ+jet) events using 20 fb[superscript −1] of proton–proton LHC data recorded with the ATLAS detector at a centre-of-mass energy of √s = 8 TeV. The γ+jet mass distribution is compared to a background model fit from data; no significant deviation from the background-only hypothesis is found. Limits are set at 95% credibility level on generic Gaussian-shaped signals and two benchmark phenomena beyond the Standard Model: non-thermal quantum black holes and excited quarks. Non-thermal quantum black holes are excluded below masses of 4.6 TeV and excited quarks are excluded below masses of 3.5 TeV.United States. Dept. of EnergyNational Science Foundation (U.S.)Brookhaven National Laborator
Observation of the strange sea in the proton via inclusive phi-meson production in neutral current deep inelastic scattering at HERA

Inclusive phi (1020)-meson production in neutral current deep inelastic e(+) p scattering has been Measured with the ZEUS detector at HERA using an integrated luminosity of 45 pb(-1) The phi mesons were studied in the range 10 < Q(2) < 100 GeV2, where Q(2) is the virtuality of the exchanged photon and in restricted kinematic regions in the transverse momentum, p(T) pseudorapidity, eta and the scaled momentum in the Breit frame, x(p). Monte Carlo models with the strangeness-suppression factor as determined by analyses of e(+)e(+) annihilation events overestimate the cross sections. A smaller value of the strangeness-suppression factor reduces the predicted cross sections but fails to reproduce the shapes of the Measured differential cross sections. High-momentum phi mesons in the current region of the Breit frame give the first direct evidence for the strange sea in the proton at low x. (C) 2002 Published by Elsevier Science B.V
Age-related patterns of vigorous-intensity physical activity in youth: the International Children's Accelerometry Database

This is an open access article published by Elsevier and distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0).Physical activity declines during youth but most evidence reports on combined moderate and vigorous-intensity physical activity. We investigated how vigorous-intensity activity varies with age.Cross-sectional data from 24,025 participants (5.0-18.0 y; from 20 studies in 10 countries obtained 2008-2010) providing ≥. 1 day accelerometer data (International Children's Accelerometry Database (ICAD)). Linear regression was used to investigate age-related patterns in vigorous-intensity activity; models included age (exposure), adjustments for monitor wear-time and study. Moderate-intensity activity was examined for comparison. Interactions were used to investigate whether the age/vigorous-activity association differed by sex, weight status, ethnicity, maternal education and region.A 6.9% (95% CI 6.2, 7.5) relative reduction in mean vigorous-intensity activity with every year of age was observed; for moderate activity the relative reduction was 6.0% (5.6%, 6.4%). The age-related decrease in vigorous-intensity activity remained after adjustment for moderate activity. A larger age-related decrease in vigorous activity was observed for girls (-. 10.7%) versus boys (-. 2.9%), non-white (-. 12.9% to -. 9.4%) versus white individuals (-. 6.1%), lowest maternal education (high school (-. 2.0%)) versus college/university (ns) and for overweight/obese (-. 6.1%) versus healthy-weight participants (-. 8.1%). In addition to larger annual decreases in vigorous-intensity activity, overweight/obese individuals, girls and North Americans had comparatively lower average vigorous-intensity activity at 5.0-5.9 y.Age-related declines in vigorous-intensity activity during youth appear relatively greater than those of moderate activity. However, due to a higher baseline, absolute moderate-intensity activity decreases more than vigorous. Overweight/obese individuals, girls, and North Americans appear especially in need of vigorous-intensity activity promotion due to low levels at 5.0-5.9 y and larger negative annual differences
Incorporation of Drosophila CID/CENP-A and CENP-C into Centromeres during Early Embryonic Anaphase

SummaryThe centromere/kinetochore complex is indispensable for accurate segregation of chromosomes during cell divisions when it serves as the attachment site for spindle microtubules. Centromere identity in metazoans is believed to be governed by epigenetic mechanisms, because the highly repetitive centromeric DNA is neither sufficient nor required for specifying the assembly site of the kinetochore [1–4]. A candidate for an epigenetic mark is the centromere-specific histone H3 variant CENP-A that replaces H3 in alternating blocks of chromatin exclusively in active centromeres [1, 2, 5, 6]. CENP-A acts as an initiator of kinetochore assembly, but the detailed dynamics of the deposition of metazoan CENP-A and of other constitutive kinetochore components are largely unknown [1, 2, 7–10]. Here we show by quantitative fluorescence measurements in living early embryos that functional fluorescent fusion proteins of the Drosophila CENP-A and CENP-C homologs are rapidly incorporated into centromeres during anaphase. This incorporation is independent of ongoing DNA synthesis and pulling forces generated by the mitotic spindle, but strictly coupled to mitotic progression. Thus, our findings uncover a strikingly dynamic behavior of centromere components in anaphase
Towards a solution of pure Yang–Mills theory in 3+1 dimensions

AbstractWe discuss an analytic approach towards the solution of pure Yang–Mills theory in (3+1)-dimensional spacetime. The approach is based on the use of local gauge invariant variables in the Schrödinger representation and the large N, planar limit. In particular, within this approach we point out unexpected parallels between pure Yang–Mills theory in 2+1 and 3+1 dimensions. The most important parallel shows up in the analysis of the ground state wave-functional especially in view of the numerical similarity of the existing large N lattice simulations of the spectra of 2+1 and 3+1 Yang–Mills theories
Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints

SummarySteroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6–7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors
SU(2)L×SU(2)R minimal dark matter with 2 TeV W′

AbstractWe construct the minimal dark matter models in the left–right symmetric extensions of the standard model (SM), where the gauge symmetry SU(3)C×SU(2)L×SU(2)R×U(1)B−L is broken into its subgroup SU(3)C×U(1)em by nonzero VEVs of a SU(2)R doublet HR and a SU(2)L×SU(2)R bidoublet H. A possible candidate of dark matter is explored in the framework of minimal dark matter considering SU(2)L,R multiplet scalar bosons and fermions. Then we focus on SU(2)R quintuplet fermions with B−L charges 0, 2 and 4 as the minimal dark matter candidates and investigate their phenomenology. We show that the dark matter in the model can provide observed relic density with 2 TeV W′ boson which is motivated by the ATLAS diboson excess and CMS eejj excess. The possible mass of dark matter is predicted for each B−L charge. We then estimate the scattering cross section of dark matter with nucleon and production cross section of charged components in the quintuplets at the LHC
B¯→Xsγ with a warped bulk Higgs

AbstractWe study the decay B¯→Xsγ in Randall–Sundrum models with an IR-localised bulk Higgs. The two models under consideration are a minimal model and a model with a custodial protection mechanism. We include the effects of tree- and one-loop diagrams involving 5D gluon and Higgs exchanges as well as QCD corrections arising from the evolution from the Kaluza–Klein scale to the typical scale of the decay. We find the RS corrections to the branching fraction can be sizeable for large Yukawas and moderate KK scales T; for small Yukawas the RS contribution is small enough to be invisible in current experimental data
Equality of hemisphere soft functions for e+e−, DIS and pp collisions at O(αs2)

AbstractWe present a simple observation about soft amplitudes and soft functions appearing in factorizable cross sections in ee, ep, and pp collisions that has not clearly been made in previous literature, namely, that the hemisphere soft functions that appear in event shape distributions in e+e−→dijets, deep inelastic scattering (DIS), and in Drell–Yan (DY) processes are equal in perturbation theory up to O(αs2), even though individual amplitudes may have opposite sign imaginary parts due to changing complex pole prescriptions in eikonal propagators for incoming vs. outgoing lines. We also explore potential generalizations of this observation to soft functions for other observables or with more jets in the final state
DNAI2 Mutations Cause Primary Ciliary Dyskinesia with Defects in the Outer Dynein Arm

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G > A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes
Ca isotope stratigraphy across the Cenomanian–Turonian OAE 2: Links between volcanism, seawater geochemistry, and the carbonate fractionation factor

AbstractThe Ca isotope composition of marine carbonate rocks offers potential to reconstruct drivers of environmental change in the geologic past. This study reports new, high-precision Ca isotope records (δCa44/40; 2σSD=±0.04‰) for three sections spanning a major perturbation to the Cretaceous ocean-climate system known as Ocean Anoxic Event 2 (OAE 2): central Colorado, USA (Portland #1 core), southeastern France (Pont d'Issole), and Hokkaido, Japan (Oyubari, Yezo Group). In addition, we generated new data for selected samples from Eastbourne, England (English Chalk), where a previous Ca isotope study was completed using different methodology (Blättler et al., 2011). Strata of the Yezo Group contain little carbonate (∼1 wt.% on average) and accordingly did not yield a clear δCa44/40 signal. The Portland core and the Pont d'Issole section display comparable δCa44/40 values, which increase by ∼0.10–0.15‰ at the onset of OAE 2 and then decrease to near-initial values across the event. The Eastbourne δCa44/40 values are higher than previously reported. They are also higher than the δCa44/40 values for the Portland core and the Pont d'Issole section but define a similar pattern. According to a numerical model of the marine Ca cycle, elevated hydrothermal inputs have little impact on seawater δCa44/40 values. Elevated riverine (chemical weathering) inputs produce a transient negative isotope excursion, which significantly differs from the positive isotope excursions observed in the Portland, Pont d'Issole, and Eastbourne records. A decrease in the magnitude of the carbonate fractionation factor provides the best explanation for a positive shift in δCa44/40 values, especially given the rapid nature of the excursion. Because a decrease in the fractionation factor corresponds to an increase in the Ca/CO3 ratio of seawater, we tentatively attribute the positive Ca isotope excursion to transient ocean acidification, i.e., a reduction in the concentration of CO32− during CO2 uptake. Recent studies utilizing a variety of isotope proxies, e.g., Nd, Os, and Pb, implicate eruption of the Caribbean Large Igneous Province as a likely source of increased CO2. Moreover, integration of C, Ca, and Os isotope data reveals new information about the timing of events during the onset of OAE 2
Characterizations of vertex pancyclic and pancyclic ordinary complete multipartite digraphs

AbstractA digraph obtained by replacing each edge of a complete multipartite graph by an arc or a pair of mutually opposite arcs with the same end vertices is called a complete multipartite graph. Such a digraph D is called ordinary if for any pair X, Y of its partite sets the set of arcs with both end vertices in X ∪ Y coincides with X × Y = {(x, y): xϵX, yϵY} or Y × X or X × Y ∪ Y × X. We characterize all the pancyclic and vertex pancyclic ordinary complete multipartite graphs. Our charcterizations admit polynomial time algorithms