Simulating Microdosimetry in a Virtual Hepatic Lobule

The liver plays a key role in removing harmful chemicals from the body and is therefore often the first tissue to suffer potentially adverse consequences. To protect public health it is necessary to quantitatively estimate the risk of long-term low dose exposure to environmental pollutants. Animal testing is the primary tool for extrapolating human risk but it is fraught with uncertainty, necessitating novel alternative approaches. Our goal is to integrate in vitro liver experiments with agent-based cellular models to simulate a spatially extended hepatic lobule. Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule. We analyzed the effects of vascular topology and metabolism on the cell-level distribution following oral exposure to chemicals. The spatial distribution of metabolically inactive chemicals was similar across different vascular networks and a baseline well-mixed compartment. When chemicals were rapidly metabolized, concentration heterogeneity of the parent compound increased across the vascular network. As a result, our spatially extended lobule generated greater variability in dose-dependent cellular responses, in this case apoptosis, than were observed in the classical well-mixed liver or in a parallel tubes model. The mass-balanced graphical approach to modeling the hepatic lobule is computationally efficient for simulating long-term exposure, modular for incorporating complex cellular interactions, and flexible for dealing with evolving tissues

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations

Evidence for the Higgs-boson Yukawa coupling to tau leptons with the ATLAS detector

Results of a search for H → τ τ decays are presented, based on the full set of proton-proton collision data recorded by the ATLAS experiment at the LHC during 2011 and 2012. The data correspond to integrated luminosities of 4.5 fb−1 and 20.3 fb−1 at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV respectively. All combinations of leptonic (τ → `νν¯ with ` = e, µ) and hadronic (τ → hadrons ν) tau decays are considered. An excess of events over the expected background from other Standard Model processes is found with an observed (expected) significance of 4.5 (3.4) standard deviations. This excess provides evidence for the direct coupling of the recently discovered Higgs boson to fermions. The measured signal strength, normalised to the Standard Model expectation, of µ = 1.43 +0.43 −0.37 is consistent with the predicted Yukawa coupling strength in the Standard Model

Search for neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at √s=8 TeV with the ATLAS detector

A search for the neutral Higgs bosons predicted by the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is performed on data from proton-proton collisions at a centre-of-mass energy of 8 TeV collected with the ATLAS detector at the Large Hadron Collider. The samples used for this search were collected in 2012 and correspond to integrated luminosities in the range 19.5-20.3 fb−1. The MSSM Higgs bosons are searched for in the ττ final state. No significant excess over the expected background is observed, and exclusion limits are derived for the production cross section times branching fraction of a scalar particle as a function of its mass. The results are also interpreted in the MSSM parameter space for various benchmark scenarios

Search for additional heavy neutral Higgs and gauge bosons in the ditau final state produced in 36 fb−1 of pp collisions at √s=13 TeV with the ATLAS detector

A search for heavy neutral Higgs bosons and Z′ bosons is performed using a data sample corresponding to an integrated luminosity of 36.1 fb−1 from proton-proton collisions at √s=13 TeV recorded by the ATLAS detector at the LHC during 2015 and 2016. The heavy resonance is assumed to decay to τ+τ− with at least one tau lepton decaying to final states with hadrons and a neutrino. The search is performed in the mass range of 0.2-2.25 TeV for Higgs bosons and 0.2-4.0 TeV for Z′ bosons. The data are in good agreement with the background predicted by the Standard Model. The results are interpreted in benchmark scenarios. In the context of the hMSSM scenario, the data exclude tan β > 1.0 for mA= 0.25 TeV and tan β > 42 for mA=1.5 TeV at the 95% confidence level. For the Sequential Standard Model, ZSSM′ with mZ′< 2.42 TeV is excluded at 95% confidence level, while Z NU′ with mZ ′ < 2.25 TeV is excluded for the non-universal G(221) model that exhibits enhanced couplings to third-generation fermions

Search for heavy resonances decaying into WW in the eνμν eνμν final state in pp collisions at √s=13 TeV with the ATLAS detector

A search for neutral heavy resonances is performed in the WW→eνμν decay channel using pp collision data corresponding to an integrated luminosity of 36.1fb−1, collected at a centre-of-mass energy of 13TeV by the ATLAS detector at the Large Hadron Collider. No evidence of such heavy resonances is found. In the search for production via the quark–antiquark annihilation or gluon–gluon fusion process, upper limits on σX×B(X→WW) as a function of the resonance mass are obtained in the mass range between 200GeV GeV and up to 5TeV for various benchmark models: a Higgs-like scalar in different width scenarios, a two-Higgs-doublet model, a heavy vector triplet model, and a warped extra dimensions model. In the vector-boson fusion process, constraints are also obtained on these resonances, as well as on a Higgs boson in the Georgi–Machacek model and a heavy tensor particle coupling only to gauge bosons

Search for a high-mass Higgs boson decaying to a W boson pair in pp collisions at √s = 8 TeV with the ATLAS detector

A search for a high-mass Higgs boson H is performed in the H → WW → ℓνℓν and H → WW → ℓνqq decay channels using pp collision data corresponding to an integrated luminosity of 20.3 fb−¹ collected at √s = 8 TeV by the ATLAS detector at the Large Hadron Collider. No evidence of a high-mass Higgs boson is found. Limits on σH × BR(H → WW) as a function of the Higgs boson mass mH are determined in three different scenarios: one in which the heavy Higgs boson has a narrow width compared to the experimental resolution, one for a width increasing with the boson mass and modeled by the complex-pole scheme following the same behavior as in the Standard Model, and one for intermediate widths. The upper range of the search is mH = 1500 GeV for the narrow-width scenario and mH = 1000 GeV for the other two scenarios. The lower edge of the search range is 200–300 GeV and depends on the analysis channel and search scenario. For each signal interpretation, individual and combined limits from the two WW decay channels are presented. At mH = 1500 GeV, the highest-mass point tested, σH × BR(H → WW) for a narrow-width Higgs boson is constrained to be less than 22 fb and 6.6 fb at 95% CL for the gluon fusion and vector-boson fusion production modes, respectively

Test of CP Invariance in vector-boson fusion production of the Higgs boson using the Optimal Observable method in the ditau decay channel with the ATLAS detector

A test of CP invariance in Higgs boson production via vector-boson fusion using the method of the Optimal Observable is presented. The analysis exploits the decay mode of the Higgs boson into a pair of τ leptons and is based on 20.3 fb −1 of proton-proton collision data at s √ = 8 TeV collected by the ATLAS experiment at the LHC. Contributions from CP-violating interactions between the Higgs boson and electroweak gauge bosons are described in an effective field theory framework, in which the strength of CP violation is governed by a single parameter d ~ . The mean values and distributions of CP-odd observables agree with the expectation in the Standard Model and show no sign of CP violation. The CP-mixing parameter d ~ is constrained to the interval [-0.11,0.05] at 68% confidence level, consistent with the Standard Model expectation of d ~ =0

Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy

Search for an additional, heavy Higgs boson in the H -> ZZ decay channel at root s=8 TeV in pp collision data with the ATLAS detector

A search is presented for a high-mass Higgs boson in the $H\rightarrow\ell\ell\ell\ell$, $H\rightarrow\ell\ell\nu\nu$, $H\rightarrow\ell\ell qq$, and $H\rightarrow\nu\nu qq$ decay modes using the ATLAS detector at the CERN Large Hadron Collider. The search uses proton-proton collision data at a centre-of-mass energy of 8 TeV corresponding to an integrated luminosity of 20.3 fb$^{-1}$. The results of the search are interpreted in the scenario of a heavy Higgs boson with a width that is small compared with the experimental mass resolution. The Higgs boson mass range considered extends up to 1 TeV for all four decay modes and down to as low as 140 GeV, depending on the decay mode. No significant excess of events over the Standard Model prediction is found. A simultaneous fit to the four decay modes yields upper limits on the production cross-section of a heavy Higgs boson times the branching ratio to Z boson pairs. 95% confidence level upper limits range from 0.53 pb at $m_H=195$ GeV to 0.008 pb at $m_H=950$ GeV for the gluon-fusion production mode and from 0.31 pb at $m_H=195$ GeV to 0.009 pb at $m_H=950$ GeV for the vector-boson-fusion production mode. The results are also interpreted in the context of Type-I and Type-II two-Higgs-doublet models.Comment: 46 pages plus author list + cover pages (62 pages total), 17 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HIGG-2013-20