Interplay of Mre11 Nuclease with Dna2 plus Sgs1 in Rad51-Dependent Recombinational Repair

The Mre11/Rad50/Xrs2 complex initiates IR repair by binding to the end of a double-strand break, resulting in 5′ to 3′ exonuclease degradation creating a single-stranded 3′ overhang competent for strand invasion into the unbroken chromosome. The nuclease(s) involved are not well understood. Mre11 encodes a nuclease, but it has 3′ to 5′, rather than 5′ to 3′ activity. Furthermore, mutations that inactivate only the nuclease activity of Mre11 but not its other repair functions, mre11-D56N and mre11-H125N, are resistant to IR. This suggests that another nuclease can catalyze 5′ to 3′ degradation. One candidate nuclease that has not been tested to date because it is encoded by an essential gene is the Dna2 helicase/nuclease. We recently reported the ability to suppress the lethality of a dna2Δ with a pif1Δ. The dna2Δ pif1Δ mutant is IR-resistant. We have determined that dna2Δ pif1Δ mre11-D56N and dna2Δ pif1Δ mre11-H125N strains are equally as sensitive to IR as mre11Δ strains, suggesting that in the absence of Dna2, Mre11 nuclease carries out repair. The dna2Δ pif1Δ mre11-D56N triple mutant is complemented by plasmids expressing Mre11, Dna2 or dna2K1080E, a mutant with defective helicase and functional nuclease, demonstrating that the nuclease of Dna2 compensates for the absence of Mre11 nuclease in IR repair, presumably in 5′ to 3′ degradation at DSB ends. We further show that sgs1Δ mre11-H125N, but not sgs1Δ, is very sensitive to IR, implicating the Sgs1 helicase in the Dna2-mediated pathway

Structures and waves in a nonlinear heat-conducting medium

The paper is an overview of the main contributions of a Bulgarian team of researchers to the problem of finding the possible structures and waves in the open nonlinear heat conducting medium, described by a reaction-diffusion equation. Being posed and actively worked out by the Russian school of A. A. Samarskii and S.P. Kurdyumov since the seventies of the last century, this problem still contains open and challenging questions.Comment: 23 pages, 13 figures, the final publication will appear in Springer Proceedings in Mathematics and Statistics, Numerical Methods for PDEs: Theory, Algorithms and their Application

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

THE α1 and α2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-cell repertoire. Although the α3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CDS. CDS is important in the selection of T cells as anti-CDS antibody injected into perinatal mice interfers with this process. We previously used a hybrid class I molecule with the α1/α2 domains from L^d and the α3 domain from Q7^b and showed that this molecule binds an L^d-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes. Expression of this molecule in transgenic mice fails to negatively select a subpopulation of anti-L^d cytotoxic T lymphocytes. In addition, positive selection of virus-specific L^d-restricted cytotoxic T lymphocytes does not occur. We conclude that besides the α1/α2 domains of class I, the α3 domain plays an important part in both positive and negative selection of antigen-specific cells

Pediatricians' perspectives on the impact of MRSA in primary care: a qualitative study

<p>Abstract</p> <p>Background</p> <p>The incidence of skin and soft-tissue infections (SSTIs) has rapidly increased among children in primary care settings since the emergence of community-associated methicillin-resistant <it>Staphylococcus aureus </it>(CA-MRSA). Recent treatment recommendations emphasize CA-MRSA as the primary cause, performing incision and drainage (I&D) as the primary therapy, and not prescribing antibiotics for uncomplicated cases. It is unknown how this epidemic has impacted primary care pediatricians in terms of their practice patterns and barriers they face to providing recommended therapies.</p> <p>Methods</p> <p>3 Focus groups among 29 primary care pediatricians in the San Francisco Bay Area were conducted. Transcripts were reviewed and coded into major themes by two investigators using modified grounded theory.</p> <p>Results</p> <p>Substantial changes in clinical practice have occurred since the emergence of CA-MRSA. These include increased office visits for SSTIs, patients with multiple recurrences and transmission within households. Additionally, our participants reported increased visits for mild skin problems due to media reports contributing to fears about CA-MRSA. Participants routinely prescribed antibiotics for SSTIs, however, few performed I&D. Few were aware of recent SSTI treatment recommendations. Barriers to prescribing antibiotics with CA-MRSA activity included concerns about side-effects and lack of local epidemiologic data showing that it is the primary etiology. Barriers to performing I&D included lack of training, resources and skepticism about its necessity. Important clinical challenges included increased time demands for follow-up visits and patient education along with the lack of evidence-based strategies for preventing recurrent inections and household transmission.</p> <p>Conclusion</p> <p>CA-MRSA has influenced the presentation and treatment of SSTIs especially in terms of case numbers and recurrences. Barriers to providing recommended therapies can be addressed through improved dissemination of treatment guidelines and epidemiologic data. Studies are urgently needed toimprove theevidence-base for treatment and prevention strategies.</p

Repetition Enhancement for Frequency-Modulated but Not Unmodulated Sounds: A Human MEG Study

BACKGROUND: Decoding of frequency-modulated (FM) sounds is essential for phoneme identification. This study investigates selectivity to FM direction in the human auditory system. METHODOLOGY/PRINCIPAL FINDINGS: Magnetoencephalography was recorded in 10 adults during a two-tone adaptation paradigm with a 200-ms interstimulus-interval. Stimuli were pairs of either same or different frequency modulation direction. To control that FM repetition effects cannot be accounted for by their on- and offset properties, we additionally assessed responses to pairs of unmodulated tones with either same or different frequency composition. For the FM sweeps, N1m event-related magnetic field components were found at 103 and 130 ms after onset of the first (S1) and second stimulus (S2), respectively. This was followed by a sustained component starting at about 200 ms after S2. The sustained response was significantly stronger for stimulation with the same compared to different FM direction. This effect was not observed for the non-modulated control stimuli. CONCLUSIONS/SIGNIFICANCE: Low-level processing of FM sounds was characterized by repetition enhancement to stimulus pairs with same versus different FM directions. This effect was FM-specific; it did not occur for unmodulated tones. The present findings may reflect specific interactions between frequency separation and temporal distance in the processing of consecutive FM sweeps

A Lagrangian scheme for the solution of nonlinear diffusion equations using moving simplex meshes

A Lagrangian numerical scheme for solving nonlinear degenerate Fokker{Planck equations in space dimensions d>2 is presented. It applies to a large class of nonlinear diffusion equations, whose dynamics are driven by internal energies and given external potentials, e.g. the porous medium equation and the fast diffusion equation. The key ingredient in our approach is the gradient ow structure of the dynamics. For discretization of the Lagrangian map, we use a finite subspace of linear maps in space and a variational form of the implicit Euler method in time. Thanks to that time discretisation, the fully discrete solution inherits energy estimates from the original gradient ow, and these lead to weak compactness of the trajectories in the continuous limit. Consistency is analyzed in the planar situation, d = 2. A variety of numerical experiments for the porous medium equation indicates that the scheme is well-adapted to track the growth of the solution's support

Chronic illness and multimorbidity among problem drug users: a comparative cross sectional pilot study in primary care

<p>Abstract</p> <p>Background</p> <p>Although multimorbidity has important implications for patient care in general practice, limited research has examined chronic illness and health service utilisation among problem drug users. This study aimed to determine chronic illness prevalence and health service utilisation among problem drug users attending primary care for methadone treatment, to compare these rates with matched 'controls' and to develop and pilot test a valid study instrument.</p> <p>Methods</p> <p>A cross-sectional study of patients attending three large urban general practices in Dublin, Ireland for methadone treatment was conducted, and this sample was compared with a control group matched by practice, age, gender and General Medical Services (GMS) status.</p> <p>Results</p> <p>Data were collected on 114 patients. Fifty-seven patients were on methadone treatment, of whom 52(91%) had at least one chronic illness (other then substance use) and 39(68%) were prescribed at least one regular medication. Frequent utilisation of primary care services and secondary care services in the previous six months was observed among patients on methadone treatment and controls, although the former had significantly higher chronic illness prevalence and primary care contact rates. The study instrument facilitated data collection that was feasible and with minimal inter-observer variation.</p> <p>Conclusion</p> <p>Multimorbidity is common among problem drug users attending general practice for methadone treatment. Primary care may therefore have an important role in primary and secondary prevention of chronic illnesses among this population. This study offers a feasible study instrument for further work on this issue. (238 words)</p

The Space Weather Atmosphere Models and Indices (SWAMI) project: Overview and first results

This is the final version. Available on open access from EDP Open via the DOI in this recordSpace weather driven atmospheric density variations affect low Earth orbit (LEO) satellites during all phases of their operational lifetime. Rocket launches, re-entry events and space debris are also similarly affected. A better understanding of space weather processes and their impact on atmospheric density is thus critical for satellite operations as well as for safety issues. The Horizon 2020 project Space Weather Atmosphere Model and Indices (SWAMI) project, which started in January 2018, aims to enhance this understanding by: Developing improved neutral atmosphere and thermosphere models, and combining these models to produce a new whole atmosphere model. Developing new geomagnetic activity indices with higher time cadence to enable better representation of thermospheric variability in the models, and improving the forecast of these indices. The project stands out by providing an integrated approach to the satellite neutral environment, in which the main space weather drivers are addressed together with model improvement. The outcomes of SWAMI will provide a pathway to improved space weather services as the project will not only address the science issues, but also the transition of models into operational services. The project aims to develop a unique new whole atmosphere model, by extending and blending the Unified Model (UM), which is the Met Office weather and climate model, and the Drag Temperature Model (DTM), which is a semi-empirical model which covers the 120–1500 km altitude range. A user-focused operational tool for satellite applications shall be developed based on this. In addition, improved geomagnetic indices shall be developed and shall be used in the UM and DTM for enhanced nowcast and forecast capability. In this paper, we report on progress with SWAMI to date. The UM has been extended from its original upper boundary of 85 km to run stably and accurately with a 135 km lid. Developments to the UM radiation scheme to enable accurate performance in the mesosphere and lower thermosphere are described. These include addition of non-local thermodynamic equilibrium effects and extension to include the far ultraviolet and extreme ultraviolet. DTM has been re-developed using a more accurate neutral density observation database than has been used in the past. In addition, we describe an algorithm to develop a new version of DTM driven by geomagnetic indices with a 60 minute cadence (denoted Hp60) rather than 3-hourly Kp indices (and corresponding ap indices). The development of the Hp60 index, and the Hp30 and Hp90 indices, which are similar to Hp60 but with 30 minute and 90 minute cadences, respectively, is described, as is the development and testing of neural network and other machine learning methods applied to the forecast of geomagnetic indices.European Union Horizon 202

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.

Measurement of the W+W−W^+W^- Production Cross Section and Search for Anomalous WWγWW\gamma and WWZWWZ Couplings in ppˉp \bar p Collisions at s=1.96\sqrt{s} = 1.96 TeV

This Letter describes the current most precise measurement of the $W$ boson pair production cross section and most sensitive test of anomalous $WW\gamma$ and $WWZ$ couplings in $p \bar p$ collisions at a center-of-mass energy of 1.96 TeV. The $WW$ candidates are reconstructed from decays containing two charged leptons and two neutrinos, where the charged leptons are either electrons or muons. Using data collected by the CDF II detector from 3.6 fb$^{-1}$ of integrated luminosity, a total of 654 candidate events are observed with an expected background contribution of $320 \pm 47$ events. The measured total cross section is $\sigma (p \bar p \to W^+ W^- + X) = 12.1 \pm 0.9 \textrm{(stat)} ^{+1.6}_{-1.4} \textrm{(syst)}$ pb, which is in good agreement with the standard model prediction. The same data sample is used to place constraints on anomalous $WW\gamma$ and $WWZ$ couplings.Comment: submitted to Phys. Rev. Let