Predicting Human Nucleosome Occupancy from Primary Sequence

Nucleosomes are the fundamental repeating unit of chromatin and comprise the structural building blocks of the living eukaryotic genome. Micrococcal nuclease (MNase) has long been used to delineate nucleosomal organization. Microarray-based nucleosome mapping experiments in yeast chromatin have revealed regularly-spaced translational phasing of nucleosomes. These data have been used to train computational models of sequence-directed nuclesosome positioning, which have identified ubiquitous strong intrinsic nucleosome positioning signals. Here, we successfully apply this approach to nucleosome positioning experiments from human chromatin. The predictions made by the human-trained and yeast-trained models are strongly correlated, suggesting a shared mechanism for sequence-based determination of nucleosome occupancy. In addition, we observed striking complementarity between classifiers trained on experimental data from weakly versus heavily digested MNase samples. In the former case, the resulting model accurately identifies nucleosome-forming sequences; in the latter, the classifier excels at identifying nucleosome-free regions. Using this model we are able to identify several characteristics of nucleosome-forming and nucleosome-disfavoring sequences. First, by combining results from each classifier applied de novo across the human ENCODE regions, the classifier reveals distinct sequence composition and periodicity features of nucleosome-forming and nucleosome-disfavoring sequences. Short runs of dinucleotide repeat appear as a hallmark of nucleosome-disfavoring sequences, while nucleosome-forming sequences contain short periodic runs of GC base pairs. Second, we show that nucleosome phasing is most frequently predicted flanking nucleosome-free regions. The results suggest that the major mechanism of nucleosome positioning in vivo is boundary-event-driven and affirm the classical statistical positioning theory of nucleosome organization

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Randomised controlled trial of tailored interventions to improve the management of anxiety and depressive disorders in primary care

Contains fulltext : 96261.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Anxiety and depressive disorders are highly prevalent disorders and are mostly treated in primary care. The management of these disorders by general practitioners is not always consistent with prevailing guidelines because of a variety of factors. Designing implementation strategies tailored to prospectively identified barriers could lead to more guideline-recommended care. Although tailoring of implementation strategies is promoted in practice, little is known about the effect on improving the quality of care for the early recognition, diagnosis, and stepped care treatment allocation in patients with anxiety or depressive disorders in general practice. This study examines whether the tailored strategy supplemented with training and feedback is more effective than providing training and feedback alone. METHODS: In this cluster randomised controlled trial, a total of 22 general practices will be assigned to one of two conditions: (1) training, feedback, and tailored interventions and (2) training and feedback. The primary outcome measure is the proportion of patients who have been recognised to have anxiety and/or depressive disorder. The secondary outcome measures in patients are severity of anxiety and depressive symptoms, level of functioning, expectation towards and experience with care, quality of life, and economic costs. Measures are taken after the start of the intervention at baseline and at three- and six-month follow-ups. Secondary outcome measures in general practitioners are adherence to guideline-recommended care in care that has been delivered, the proportion of antidepressant prescriptions, and number of referrals to specialised mental healthcare facilities. Data will be gathered from the electronic medical patient records from the patients included in the study. In a process evaluation, the identification of barriers to change and the relations between prospectively identified barriers and improvement interventions selected for use will be described, as well as the factors that influence the provision of guideline-recommended care. DISCUSSION: It is hypothesised that the adherence to guideline recommendations will be improved by designing implementation interventions that are tailored to prospectively identified barriers in the local context of general practitioners. Currently, there is insufficient evidence on the most effective and efficient approaches to tailoring, including how barriers should be identified and how interventions should be selected to address the barriers. TRIAL REGISTRATION: NTR1912

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models

High incidence of antimicrobial resistant organisms including extended spectrum beta-lactamase producing Enterobacteriaceae and methicillin-resistant Staphylococcus aureus in nasopharyngeal and blood isolates of HIV-infected children from Cape Town, South Africa

<p>Abstract</p> <p>Background</p> <p>There is little information on nasopharyngeal (NP) flora or bacteremia in HIV-infected children. Our aim was to describe the organisms and antimicrobial resistance patterns in children enrolled in a prospective study comparing daily and three times weekly trimethoprim-sulfamethoxazole (TMP-SMX) and isoniazid (INH) or placebo prophylaxis.</p> <p>Methods</p> <p>NP swabs were taken at baseline from HIV-infected children enrolled in the study. Standard microbiological techniques were used. Children were grouped according to previous or current exposure to TMP-SMX and whether enrolled to the study during a period of hospitalization. Blood culture results were also recorded within 12 months of baseline.</p> <p>Results</p> <p>Two hundred and three children, median age 1.8 (Interquartile [IQ]: 0.7–4) years had NP swabs submitted for culture. One hundred and eighty-four (90.7%) had either stage B or C HIV disease. One hundred and forty-one (69.8%) were receiving TMP-SMX and 19 (9.4%) were on antiretroviral therapy. The majority, 168 (82%) had a history of hospitalization and 91 (44.8%) were enrolled during a period of hospitalization. Thirty-two subjects (16.2%) died within 12 months of study entry.</p> <p>One hundred and eighty-one potential pathogens were found in 167 children. The most commonly isolated organisms were <it>Streptococcus pneumoniae </it>(48: 22.2%), Gram-negative respiratory organisms (<it>Haemophilus influenzae </it>and <it>Moraxella catarrhalis</it>) (47: 21.8%), <it>Staphylococcus aureus </it>(44: 20.4%), Enterobacteriaceae 32 (14.8%) and Pseudomonas 5 (2.3%).</p> <p>Resistance to TMP-SMX occurred in > 80% of pathogens except for <it>M. catarrhalis </it>(2: 18.2% of tested organisms). TMP-SMX resistance tended to be higher in those receiving it at baseline (p = 0.065). Carriage of Methicillin resistant <it>S. aureus </it>(MRSA) was significantly associated with being on TMP-SMX at baseline (p = 0.002). Minimal inhibitory concentrations (MIC) to penicillin were determined for 18 <it>S. pneumoniae </it>isolates: 7 (38.9%) were fully sensitive (MIC ≤ 0.06 μg/ml), 9 (50%) had intermediate resistance (MIC 0.12 – 1 μg/ml) and 2 (11.1%) had high level resistance (MIC ≥2 μg/ml). Fifty percent of Enterobacteriaceae produced extended spectrum beta-lactamases (ESBL) (resistant to third generation cephalosporins) and 56% were resistant to gentamicin. Seventy-seven percent of <it>S. aureus </it>were MRSA. Carriage of resistant organisms was not associated with hospitalization.</p> <p>On multivariate logistic regression, risk factors for colonization with Enterobacteriaceae were age ≤ one year (Odds ratio 4.4; 95% Confidence Interval 1.9–10.9; p = 0.0008) and CDC stage C disease (Odds ratio 3.6; 95% Confidence Interval 1.5–8.6; p = 0.005)</p> <p>Nineteen (9.4%) subjects had 23 episodes of bacteremia. Enterobacteriaceae were most commonly isolated (13 of 25 isolates), of which 6 (46%) produced ESBL and were resistant to gentamicin.</p> <p>Conclusion</p> <p>HIV-infected children are colonized with potential pathogens, most of which are resistant to commonly used antibiotics. TMP-SMX resistance is extremely common. Antibiotic resistance is widespread in colonizing organisms and those causing invasive disease. Antibiotic recommendations should take cognizance of resistance patterns. Antibiotics appropriate for ESBL-producing Enterobacteriaceae and MRSA should be used for severely ill HIV-infected children in our region. Further study of antibiotic resistance patterns in HIV-infected children from other areas is needed.</p

Patient safety in elderly hip fracture patients: design of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The clinical environment in which health care providers have to work everyday is highly complex; this increases the risk for the occurrence of unintended events. The aim of this randomised controlled trial is to improve patient safety for a vulnerable group of patients that have to go through a complex care chain, namely elderly hip fracture patients.</p> <p>Methods/design</p> <p>A randomised controlled trial that consists of three interventions; these will be implemented in three surgical wards in Dutch hospitals. One surgical ward in another hospital will be the control group. The first intervention is aimed at improving communication between care providers using the SBAR communication tool. The second intervention is directed at stimulating the role of the patient within the care process with a patient safety card. The third intervention consists of a leaflet for patients with information on the most common complications for the period after discharge. The primary outcome measures in this study are the incidence of complications and adverse events, mortality rate within six months after discharge and functional mobility six months after discharge. Secondary outcome measures are length of hospital stay, quality and completeness of information transfer and patient satisfaction with the instruments.</p> <p>Discussion</p> <p>The results will give insight into the nature and scale of complications and adverse events that occur in elderly hip fracture patients. Also, the implementation of three interventions aimed at improving the communication and information transfer provides valuable possibilities for improving patient safety in this increasing patient group. This study combines the use of three interventions, which is an innovative aspect of the study.</p> <p>Trial registration</p> <p>The Netherlands National Trial Register <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1562">NTR1562</a></p

Mitochondrial Pseudogenes in the Nuclear Genomes of Drosophila

Mitochondrial pseudogenes in nuclear chromosomes (numts) have been detected in the genomes of a diverse range of eukaryotic species. However, the numt content of different genomes and their properties is not uniform, and study of these differences provides insight into the mechanisms and dynamics of genome evolution in different organisms. In the genus Drosophila, numts have previously only been identified on a genome-wide scale in the melanogaster subgroup. The present study extends the identification to 11 species of the Drosophila genus. We identify a total of 302 numts and show that the numt complement is highly variable in Drosophilids, ranging from just 4 in D. melanogaster to 67 in D. willistoni, broadly correlating with genome size. Many numts have undergone large-scale rearrangements in the nucleus, including interruptions, inversions, deletions and duplications of sequence of variable size. Estimating the age of the numts in the nucleus by phylogenetic tree reconstruction reveals the vast majority of numts to be recent gains, 90% having arisen on terminal branches of the species tree. By identifying paralogs and counting duplications among the extant numts we estimate that 23% of extant numts arose through post-insertion duplications. We estimate genus average rates of insertion of 0.75 per million years, and a duplication rate of 0.010 duplications per numt per million years