Identification of a Core Amino Acid Motif within the α Subunit of GABAARs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures

The fidelity of inhibitory neurotransmission is dependent on the accumulation of γ-aminobutyric acid type A receptors (GABAARs) at the appropriate synaptic sites. Synaptic GABAARs are constructed from α(1-3), β(1-3), and γ2 subunits, and neurons can target these subtypes to specific synapses. Here, we identify a 15-amino acid inhibitory synapse targeting motif (ISTM) within the α2 subunit that promotes the association between GABAARs and the inhibitory scaffold proteins collybistin and gephyrin. Using mice in which the ISTM has been introduced into the α1 subunit (Gabra1-2 mice), we show that the ISTM is critical for axo-axonic synapse formation, the efficacy of GABAergic neurotransmission, and seizure sensitivity. The Gabra1-2 mutation rescues seizure-induced lethality in Gabra2-1 mice, which lack axo-axonic synapses due to the deletion of the ISTM from the α2 subunit. Taken together, our data demonstrate that the ISTM plays a critical role in promoting inhibitory synapse formation, both in the axonic and somatodendritic compartments

The impact of junior doctors’ worktime arrangements on their fatigue and well-being

Objective Many doctors report working excessively demanding schedules that comply with the European Working Time Directive (EWTD). We compared groups of junior doctors working on different schedules in order to identify which features of schedule design most negatively affected their fatigue and well-being in recent weeks.Methods Completed by 336 doctors, the questionnaires focused on the respondents\u27 personal circumstances, work situation, work schedules, sleep, and perceptions of fatigue, work-life balance and psychological strain. Results Working 7 consecutive nights was associated with greater accumulated fatigue and greater work life interference, compared with working just 3 or 4 nights. Having only I rest day after working nights was associated with increased fatigue. Working a weekend on-call between 2 consecutive working weeks was associated with increased work-life interference. Working frequent on-calls (either on weekends or during the week) was associated with increased work-life interference and psychological strain. Inter-shift intervals o

Quantitative Analysis of Survivin Protein Expression and Its Therapeutic Depletion by an Antisense Oligonucleotide in Human Lung Tumors

RNA-directed antisense and interference therapeutics are a promising treatment option for cancer. The demonstration of depletion of target proteins within human tumors in vivo using validated methodology will be a key to the application of this technology. Here, we present a flow cytometric-based approach to quantitatively determine protein levels in solid tumor material derived by fiber optic brushing (FOB) of non-small cell lung cancer (NSCLC) patients. Focusing upon the survivin protein, and its depletion by an antisense oligonucleotide (ASO) (LY2181308), we show that we can robustly identify a subpopulation of survivin positive tumor cells in FOB samples, and, moreover, detect survivin depletion in tumor samples from a patient treated with LY2181308. Survivin depletion appears to be a result of treatment with this ASO, because a tumor treated with conventional cytotoxic chemotherapy did not exhibit a decreased percentage of survivin positive cells. Our approach is likely to be broadly applicable to, and useful for, the quantification of protein levels in tumor samples obtained as part of clinical trials and studies, facilitating the proof-of-principle testing of novel targeted therapies

Further Sunyaev-Zel'dovich observations of two Planck ERCSC clusters with the Arcminute Microkelvin Imager

We present follow-up observations of two galaxy clusters detected blindly via the Sunyaev-Zel'dovich (SZ) effect and released in the Planck Early Release Compact Source Catalogue. We use the Arcminute Microkelvin Imager, a dual-array 14-18 GHz radio interferometer. After radio source subtraction, we find a SZ decrement of integrated flux density -1.08+/-0.10 mJy toward PLCKESZ G121.11+57.01, and improve the position measurement of the cluster, finding the centre to be RA 12 59 36.4, Dec +60 04 46.8, to an accuracy of 20 arcseconds. The region of PLCKESZ G115.71+17.52 contains strong extended emission, so we are unable to confirm the presence of this cluster via the SZ effect.Comment: 4 tables, 3 figures, revised after referee's comments and resubmitted to MNRA

Measuring service quality of international tennis coach education courses

Customer satisfaction with the quality of sport services contributes significantly to the sustained competitiveness of sport organisations, and customer retention. This study measured the perceived service quality of the International Tennis Federation (ITF) Starter-Beginner coach education courses. A purposive sample of four courses and 56 tennis coaches was drawn. A precourse and post course SERVQUAL questionnaire together with a biographical questionnaire were administered. The findings of the current study suggest that tennis coaches are dissatisfied with four of the five SERVQUAL dimensions of service quality namely the reliability of the services, the responsiveness of the ITF as service provider, the tangibles of the course as well as the empathy of the ITF. Tennis coaches expressed overall satisfaction in the service dimension of assurance of service users. Satisfaction with service quality differed across the four different geographical course locations suggesting dissatisfaction with personal interaction between head tutors and participants. This study should be regarded as exploratory research in the area of tennis coach education service quality. Further research should determine the reliability and validity of the SERVQUAL instrument in sport coach education contexts.http://www.ajol.info/journal_index.php?jid=153&ab=ajpherd2016-03-30am201

Non-equilibrium states of a photon cavity pumped by an atomic beam

We consider a beam of two-level randomly excited atoms that pass one-by-one through a one-mode cavity. We show that in the case of an ideal cavity, i.e. no leaking of photons from the cavity, the pumping by the beam leads to an unlimited increase in the photon number in the cavity. We derive an expression for the mean photon number for all times. Taking into account leaking of the cavity, we prove that the mean photon number in the cavity stabilizes in time. The limiting state of the cavity in this case exists and it is independent of the initial state. We calculate the characteristic functional of this non-quasi-free non-equilibrium state. We also calculate the energy flux in both the ideal and open cavity and the entropy production for the ideal cavity.Comment: Corrected energy production calculations and made some changes to ease the readin

Explaining the variation in the management of lifestyle risk factors in primary health care: a multilevel cross sectional study

BackgroundDespite evidence for the effectiveness of interventions to modify lifestyle behaviours in the primary health care (PHC) setting, assessment and intervention for these behaviours remains low in routine practice. Little is known about the relative importance of various determinants of practice.This study aimed to examine the relative importance of provider characteristics and attitudes, patient characteristics and consultation factors in determining the rate of assessment and intervention for lifestyle risk factors in PHC.MethodsA prospective audit of assessment and intervention for lifestyle risk factors was undertaken by PHC nurses and allied health providers (n = 57) for all patients seen (n = 732) over a two week period. Providers completed a survey to assess key attitudes related to addressing lifestyle issues. Multi-level logistic regression analysis of patient audit records was undertaken. Associations between variables from both data sources were examined, together with the variance explained by patient and consultation (level 1) and provider (level 2) factors.ResultsThere was significant variance between providers in the assessment and intervention for lifestyle risk factors. The consultation type and reason for the visit were the most important in explaining the variation in assessment practices, however these factors along with patient and provider variables accounted for less than 20% of the variance. In contrast, multi-level models showed that provider factors were most important in explaining the variance in intervention practices, in particular, the location of the team in which providers worked (urban or rural) and provider perceptions of their effectiveness and accessibility of support services. After controlling for provider variables, patients\u27 socio-economic status, the reason for the visit and providers\u27 perceptions of the \u27appropriateness\u27 of addressing risk factors in the consultation were all significantly associated with providing optimal intervention. Together, measured patient consultation and provider variables accounted for most (80%) of the variation in intervention practices between providers.ConclusionThe findings highlight the importance of provider factors such as beliefs and attitudes, team location and work context in understanding variations in the provision of lifestyle intervention in PHC. Further studies of this type are required to identify variables that improve the proportion of variance explained in assessment practices

An exploration of how clinician attitudes and beliefs influence the implementation of lifestyle risk factor management in primary healthcare: a grounded theory study

BackgroundDespite the effectiveness of brief lifestyle intervention delivered in primary healthcare (PHC), implementation in routine practice remains suboptimal. Beliefs and attitudes have been shown to be associated with risk factor management practices, but little is known about the process by which clinicians\u27 perceptions shape implementation. This study aims to describe a theoretical model to understand how clinicians\u27 perceptions shape the implementation of lifestyle risk factor management in routine practice. The implications of the model for enhancing practices will also be discussed.MethodsThe study analysed data collected as part of a larger feasibility project of risk factor management in three community health teams in New South Wales (NSW), Australia. This included journal notes kept through the implementation of the project, and interviews with 48 participants comprising 23 clinicians (including community nurses, allied health practitioners and an Aboriginal health worker), five managers, and two project officers. Data were analysed using grounded theory principles of open, focused, and theoretical coding and constant comparative techniques to construct a model grounded in the data.ResultsThe model suggests that implementation reflects both clinician beliefs about whether they should (commitment) and can (capacity) address lifestyle issues. Commitment represents the priority placed on risk factor management and reflects beliefs about role responsibility congruence, client receptiveness, and the likely impact of intervening. Clinician beliefs about their capacity for risk factor management reflect their views about self-efficacy, role support, and the fit between risk factor management ways of working. The model suggests that clinicians formulate different expectations and intentions about how they will intervene based on these beliefs about commitment and capacity and their philosophical views about appropriate ways to intervene. These expectations then provide a cognitive framework guiding their risk factor management practices. Finally, clinicians\u27 appraisal of the overall benefits versus costs of addressing lifestyle issues acts to positively or negatively reinforce their commitment to implementing these practices.ConclusionThe model extends previous research by outlining a process by which clinicians\u27 perceptions shape implementation of lifestyle risk factor management in routine practice. This provides new insights to inform the development of effective strategies to improve such practices