Androgen receptor signalling in Vascular Endothelial cells is dispensable for spermatogenesis and male fertility

<p>Abstract</p> <p>Background</p> <p>Androgen signalling is essential both for male development and function of the male reproductive system in adulthood. Within the adult testis, Germ cells (GC) do not express androgen receptor (AR) suggesting androgen-mediated promotion of spermatogenesis must act via AR-expressing somatic cell-types. Several recent studies have exploited the Cre/lox system of conditional gene-targeting to ablate AR function from key somatic cell-types in order to establish the cell-specific role of AR in promotion of male fertility. In this study, we have used a similar approach to specifically ablate AR-signalling from Vascular Endothelial (VE) cells, with a view to defining the significance of androgen signalling within this cell-type on spermatogenesis.</p> <p>Findings</p> <p>AR expression in VE cells of the testicular vasculature was confirmed using an antibody against AR. A Cre-inducible fluorescent reporter line was used to empirically establish the utility of a mouse line expressing Cre Recombinase driven by the Tie2-Promoter, for targeting VE cells. Immunofluorescent detection revealed expression of YFP (and therefore Cre Recombinase function) limited to VE cells and an interstitial population of cells, believed to be macrophages, that did not express AR. Mating of Tie2-Cre males to females carrying a floxed AR gene produced Vascular Endothelial Androgen Receptor Knockout (VEARKO) mice and littermate controls. Ablation of AR from all VE cells was confirmed; however, no significant differences in bodyweight or reproductive tissue weights could be detected in VEARKO animals and spermatogenesis and fertility was unaffected.</p> <p>Conclusions</p> <p>We demonstrate the successful generation and empirical validation of a cell-specific knockout of AR from VE cells, and conclude that AR expression in VE cells is not essential for spermatogenesis or male fertility.</p

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Measurements of the charge asymmetry in top-quark pair production in the dilepton final state at s √ =8 TeV with the ATLAS detector

Measurements of the top-antitop quark pair production charge asymmetry in the dilepton channel, characterized by two high-pT leptons (electrons or muons), are presented using data corresponding to an integrated luminosity of 20.3  fb−1 from pp collisions at a center-of-mass energy s√=8  TeV collected with the ATLAS detector at the Large Hadron Collider at CERN. Inclusive and differential measurements as a function of the invariant mass, transverse momentum, and longitudinal boost of the tt¯ system are performed both in the full phase space and in a fiducial phase space closely matching the detector acceptance. Two observables are studied: AℓℓC based on the selected leptons and Att¯C based on the reconstructed tt¯ final state. The inclusive asymmetries are measured in the full phase space to be AℓℓC=0.008±0.006 and Att¯C=0.021±0.016, which are in agreement with the Standard Model predictions of AℓℓC=0.0064±0.0003 and Att¯C=0.0111±0.0004

Measurement of the dependence of transverse energy production at large pseudorapidity on the hard-scattering kinematics of proton-proton collisions at √s=2.76 TeV with ATLAS

The relationship between jet production in the central region and the underlying-event activity in a pseudorapidity-separated region is studied in 4.0 pb-1 of s=2.76 TeV pp collision data recorded with the ATLAS detector at the LHC. The underlying event is characterised through measurements of the average value of the sum of the transverse energy at large pseudorapidity downstream of one of the protons, which are reported here as a function of hard-scattering kinematic variables. The hard scattering is characterised by the average transverse momentum and pseudorapidity of the two highest transverse momentum jets in the event. The dijet kinematics are used to estimate, on an event-by-event basis, the scaled longitudinal momenta of the hard-scattered partons in the target and projectile beam-protons moving toward and away from the region measuring transverse energy, respectively. Transverse energy production at large pseudorapidity is observed to decrease with a linear dependence on the longitudinal momentum fraction in the target proton and to depend only weakly on that in the projectile proton. The results are compared to the predictions of various Monte Carlo event generators, which qualitatively reproduce the trends observed in data but generally underpredict the overall level of transverse energy at forward pseudorapidity

Measurement of W boson angular distributions in events with high transverse momentum jets at s√= 8 TeV using the ATLAS detector

The W boson angular distribution in events with high transverse momentum jets is measured using data collected by the ATLAS experiment from proton–proton collisions at a centre-of-mass energy at the Large Hadron Collider, corresponding to an integrated luminosity of . The focus is on the contributions to processes from real W emission, which is achieved by studying events where a muon is observed close to a high transverse momentum jet. At small angular separations, these contributions are expected to be large. Various theoretical models of this process are compared to the data in terms of the absolute cross-section and the angular distributions of the muon from the leptonic W decay.Fil: Aaboud, M.. Université Mohamed Premier and LPTPM; MarruecosFil: Aad, G.. Aix-Marseille Université ; FranciaFil: Abbott, B.. Oklahoma State University; Estados UnidosFil: Abdallah, J.. Academia Sinica; ChinaFil: Abdinov, O.. Azerbaijan Academy of Sciences; AzerbaiyánFil: Alconada Verzini, María Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Alonso, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Arduh, Francisco Anuar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Dova, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Hoya, Joaquín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Monticelli, Fernando Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Wahlberg, Hernan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Bossio Sola, Jonathan David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Marceca, Gino. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Otero y Garzon, Gustavo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Piegaia, Ricardo Nestor. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Sacerdoti, Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Zibell. A.. Julius-Maximilians-Universität ; AlemaniaFil: Zieminska, D.. Indiana University; Estados UnidosFil: Zimine, N. I.. Joint Institute for Nuclear Research; RusiaFil: Zimmermann, C.. Universität Mainz ; AlemaniaFil: Zimmermann, S.. Albert-Ludwigs-Universität ; AlemaniaFil: Zinonos, Z.. Georg-August-Universität ; AlemaniaFil: Zinser, M.. Universität Mainz ; AlemaniaFil: Ziolkowski, M.. Universität Siegen ; AlemaniaFil: Živković, L.. University of Belgrade ; SerbiaFil: Zobernig, G.. University of Wisconsin; Estados UnidosFil: Zoccoli, A.. Università di Bologna ; ItaliaFil: Nedden, M. zur. Humboldt University; AlemaniaFil: Zurzolo, G.. Università di Napoli; ItaliaFil: Zwalinski, L.. Cern - European Organization For Nuclear Research; SuizaFil: The ATLAS Collaboration. No especifica

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Study of the B-c(+) -> J/psi D-s(+) and Bc(+) -> J/psi D-s*(+) decays with the ATLAS detector

The decays B-c(+) -> J/psi D-s(+) and B-c(+) -> J/psi D-s*(+) are studied with the ATLAS detector at the LHC using a dataset corresponding to integrated luminosities of 4.9 and 20.6 fb(-1) of pp collisions collected at centre-of-mass energies root s = 7 TeV and 8 TeV, respectively. Signal candidates are identified through J/psi -> mu(+)mu(-) and D-s(()*()+) -> phi pi(+)(gamma/pi(0)) decays. With a two-dimensional likelihood fit involving the B-c(+) reconstructed invariant mass and an angle between the mu(+) and D-s(+) candidate momenta in the muon pair rest frame, the yields of B-c(+) -> J/psi D-s(+) and B-c(+) -> J/psi D-s*(+), and the transverse polarisation fraction in B-c(+) -> J/psi D-s*(+) decay are measured. The transverse polarisation fraction is determined to be Gamma +/-+/-(B-c(+) -> J/psi D-s*(+))/Gamma(B-c(+) -> J/psi D-s*(+)) = 0.38 +/- 0.23 +/- 0.07, and the derived ratio of the branching fractions of the two modes is B-Bc+ -> J/psi D-s*+/B-Bc+ -> J/psi D-s(+) = 2.8(-0.8)(+1.2) +/- 0.3, where the first error is statistical and the second is systematic. Finally, a sample of B-c(+) -> J/psi pi(+) decays is used to derive the ratios of branching fractions B-Bc+ -> J/psi D-s*+/B-Bc+ -> J/psi pi(+) = 3.8 +/- 1.1 +/- 0.4 +/- 0.2 and B-Bc+ -> J/psi D-s*+/B-Bc+ -> J/psi pi(+) = 10.4 +/- 3.1 +/- 1.5 +/- 0.6, where the third error corresponds to the uncertainty of the branching fraction of D-s(+) -> phi(K+ K-)pi(+) decay. The available theoretical predictions are generally consistent with the measurement

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases