Revealing cytotoxic substructures in molecules using deep learning

In drug development, late stage toxicity issues of a compound are the main cause of failure in clinical trials. In silico methods are therefore of high importance to guide the early design process to reduce time, costs and animal testing. Technical advances and the ever growing amount of available toxicity data enabled machine learning, especially neural networks, to impact the field of predictive toxicology. In this study, cytotoxicity prediction, one of the earliest handles in drug discovery, is investigated using a deep learning approach trained on a highly consistent in-house data set of over 34,000 compounds with a share of less than 5% of cytotoxic molecules. The model reached a balanced accuracy of over 70%, similar to previously reported studies using Random Forest. Albeit yielding good results, neural networks are often described as a black box lacking deeper mechanistic understanding of the underlying model. To overcome this absence of interpretability, a Deep Taylor Decomposition method is investigated to identify substructures that may be responsible for the cytotoxic effects, the so-called toxicophores. Furthermore, this study introduces cytotoxicity maps which provide a visual structural interpretation of the relevance of these substructures. Using this approach could be helpful in drug development to predict the potential toxicity of a compound as well as to generate new insights into the toxic mechanism. Moreover, it could also help to de-risk and optimize compounds

Factors related to functional exercise capacity amongst people with HIV in Durban, South Africa

Background: People with HIV (PWH), who engage in regular physical activity, have improved fitness, muscular strength, body composition, health-related quality of life and mental health symptoms, but PWH have amongst the lowest physical activity levels of those with any chronic health condition. Furthermore, there is scant evidence examining these relationships in PWH in Africa. Aim: To address these critical gaps, this cross-sectional descriptive research study examined the relationships between demographic, HIV-related, anthropometric factors, neighbourhood walkability and physical activity, amongst PWH in Durban, South Africa. Setting: Respondents (N = 100) were receiving primary healthcare in six eThekwini nurse-run municipal clinics. Methods: Self-reported socio-demographic data were collected, and HIV-related medical data were extracted from respondent’s medical charts. Height and weight were measured to calculate the body mass index (BMI, kg/m2); neighbourhood walkability was measured on the Neighbourhood Environment scale; and physical activity, specifically functional exercise capacity, was measured by the 6-min walk test (6MWT). Results: On average, respondents were black African, female, approximately 38 years old and unemployed; men were of normal weight whilst women were overweight. Only 65% of the respondents reached the age- and sex-predicted distance during the 6MWT. Correlational analyses did not reveal any significant relationships between the functional exercise capacity and socio-demographic, HIV-related factors or anthropometric measures. Conclusion: South African PWH do not reach their predicated walking distance on the 6MWT. Engaging community agencies to promote walking as both a means of transportation and leisure physical activity may decrease the risks of a sedentary lifestyle and improve progression towards recommended physical activity targets

Senate Banking: Financial Regulatory Improvement Act

This report briefly highlights some of the major policy proposals included in a May 12, 2015 discussion draft released by Senator Richard Shelby that is scheduled for markup by the Senate Banking Committee. The draft encompasses a broad package of reforms to the financial regulatory system, including some changes to the Dodd-Frank Act (P.L. 111-203)

AC-coupled GaAs microstrip detectors with a new type of integrated bias resistors

Full size single-sided GaAs microstrip detectors with integrated coupling capacitors and bias resistors have been fabricated on 3'' substrate wafers. PECVD deposited SiO_2 and SiO_2/Si_3N_4 layers were used to provide coupling capacitaces of 32.5 pF/cm and 61.6 pF/cm, respectively. The resistors are made of sputtered CERMET using simple lift of technique. The sheet resistivity of 78 kOhm/sq. and the thermal coefficient of resistance of less than 4x10^-3 / degree C satisfy the demands of small area biasing resistors, working on a wide temperature range.Comment: 20 pages, 9 figures, to be published in NIM

The Relationship Between Physical Activity and Cardiorespiratory Fitness Among People Living With Human Immunodeficiency Virus Throughout The Life Span

BACKGROUND: People living with human immunodeficiency virus (PLHIV) are at an increased risk for developing cardiovascular disease (CVD). Physical activity and cardiorespiratory fitness in PLHIV are poorly understood. OBJECTIVE: The aims of this study were to describe physical activity and cardiorespiratory fitness by sex and age and to examine the association between physical activity and cardiorespiratory fitness in PLHIV, controlling for covariates. METHODS: Seven hundred two PLHIV participated in a cross-sectional study and completed validated measures of self-reported physical activity (7-day Physical Activity Recall) and cardiorespiratory fitness (6-minute walk test). Participants were recruited from 7 diverse sites in the United States and Thailand, and data were analyzed using descriptive statistics and multiple regression to examine the relationship between physical activity and cardiorespiratory fitness. RESULTS: On average, participants self-reported engaging in 115 minutes of, mostly light (75%), physical activity. Men reported twice the amount of physical activity as women (155 vs 73 minutes, P = .01). Participants\u27 ability to achieve their predicted 6-minute walk test distances was similar between men (68%) and women (69%) (P \u3e .01). For women, vigorous physical activity was associated with a 6.6% increase in cardiorespiratory fitness and being temporarily unemployed was associated with an 18% decline in cardiorespiratory fitness. Cardiorespiratory fitness increased with age (P \u3c .01). CONCLUSIONS: Weekly physical activity of people living with human immunodeficiency virus averaged 85 minutes of mostly light activity, well below the recommended 150 minutes of moderate activity. Vigorous physical activity was associated with improved cardiorespiratory fitness in women, but not men. Although PLHIV would benefit from interventions to increase physical activity, our data suggest a need to develop sex-specific physical activity strategies

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN