Structure of the PII signal transduction protein of Neisseria meningitidis at 1.85 Ȃ resolution

Copyright @ 2006 International Union of CrystallographyThe PII signal transduction proteins GlnB and GlnK are implicated in the regulation of nitrogen assimilation in Escherichia coli and other enteric bacteria. PII-like proteins are widely distributed in bacteria, archaea and plants. In contrast to other bacteria, Neisseria are limited to a single PII protein (NMB 1995), which shows a high level of sequence identity to GlnB and GlnK from Escherichia coli (73 and 62%, respectively). The structure of the PII protein from N. meningitidis (serotype B) has been solved by molecular replacement to a resolution of 1.85 Ȃ. Comparison of the structure with those of other PII proteins shows that the overall fold is tightly conserved across the whole population of related proteins, in particular the positions of the residues implicated in ATP binding. It is proposed that the Neisseria PII protein shares functions with GlnB/GlnK of enteric bacteria.This study is funded by the Medical Research Council UK and Europe (SPINE) consortium (European Commission Grant No. QLG2-CT-2002-00988)

A One Health Framework for the Evaluation of Rabies Control Programmes: A Case Study from Colombo City, Sri Lanka

<div><p>Background</p><p>One Health addresses complex challenges to promote the health of all species and the environment by integrating relevant sciences at systems level. Its application to zoonotic diseases is recommended, but few coherent frameworks exist that combine approaches from multiple disciplines. Rabies requires an interdisciplinary approach for effective and efficient management.</p><p>Methodology/Principal Findings</p><p>A framework is proposed to assess the value of rabies interventions holistically. The economic assessment compares additional monetary and non-monetary costs and benefits of an intervention taking into account epidemiological, animal welfare, societal impact and cost data. It is complemented by an ethical assessment. The framework is applied to Colombo City, Sri Lanka, where modified dog rabies intervention measures were implemented in 2007. The two options included for analysis were the control measures in place until 2006 (“baseline scenario”) and the new comprehensive intervention measures (“intervention”) for a four-year duration. Differences in control cost; monetary human health costs after exposure; Disability-Adjusted Life Years (DALYs) lost due to human rabies deaths and the psychological burden following a bite; negative impact on animal welfare; epidemiological indicators; social acceptance of dogs; and ethical considerations were estimated using a mixed method approach including primary and secondary data. Over the four years analysed, the intervention cost US $1.03 million more than the baseline scenario in 2011 prices (adjusted for inflation) and caused a reduction in dog rabies cases; 738 DALYs averted; an increase in acceptability among non-dog owners; a perception of positive changes in society including a decrease in the number of roaming dogs; and a net reduction in the impact on animal welfare from intermediate-high to low-intermediate.</p><p>Conclusions</p><p>The findings illustrate the multiple outcomes relevant to stakeholders and allow greater understanding of the value of the implemented rabies control measures, thereby providing a solid foundation for informed decision-making and sustainable control.</p></div

Chapter 7: Grading a Body of Evidence on Diagnostic Tests

10.1007/s11606-012-2021-9Journal of General Internal Medicine27SUPPL.1S47-S55JGIM

Membrane interaction and structure of the transmembrane domain of influenza hemagglutinin and its fusion peptide complex

<p>Abstract</p> <p>Background</p> <p>To study the organization and interaction with the fusion domain (or fusion peptide, FP) of the transmembrane domain (TMD) of influenza virus envelope glycoprotein for its role in membrane fusion which is also essential in the cellular trafficking of biomolecules and sperm-egg fusion.</p> <p>Results</p> <p>The fluorescence and gel electrophoresis experiments revealed a tight self-assembly of TMD in the model membrane. A weak but non-random interaction between TMD and FP in the membrane was found. In the complex, the central TMD oligomer was packed by FP in an antiparallel fashion. FP insertion into the membrane was altered by binding to TMD. An infrared study exhibited an enhanced membrane perturbation by the complex formation. A model was built to illustrate the role of TMD in the late stages of influenza virus-mediated membrane fusion reaction.</p> <p>Conclusion</p> <p>The TMD oligomer anchors the fusion protein in the membrane with minimal destabilization to the membrane. Upon associating with FP, the complex exerts a synergistic effect on the membrane perturbation. This effect is likely to contribute to the complete membrane fusion during the late phase of fusion protein-induced fusion cascade. The results presented in the work characterize the nature of the interaction of TMD with the membrane and TMD in a complex with FP in the steps leading to pore initiation and dilation during virus-induced fusion. Our data and proposed fusion model highlight the key role of TMD-FP interaction and have implications on the fusion reaction mediated by other type I viral fusion proteins. Understanding the molecular mechanism of membrane fusion may assist in the design of anti-viral drugs.</p

Membrane interaction and structure of the transmembrane domain of influenza hemagglutinin and its fusion peptide complex

<p>Abstract</p> <p>Background</p> <p>To study the organization and interaction with the fusion domain (or fusion peptide, FP) of the transmembrane domain (TMD) of influenza virus envelope glycoprotein for its role in membrane fusion which is also essential in the cellular trafficking of biomolecules and sperm-egg fusion.</p> <p>Results</p> <p>The fluorescence and gel electrophoresis experiments revealed a tight self-assembly of TMD in the model membrane. A weak but non-random interaction between TMD and FP in the membrane was found. In the complex, the central TMD oligomer was packed by FP in an antiparallel fashion. FP insertion into the membrane was altered by binding to TMD. An infrared study exhibited an enhanced membrane perturbation by the complex formation. A model was built to illustrate the role of TMD in the late stages of influenza virus-mediated membrane fusion reaction.</p> <p>Conclusion</p> <p>The TMD oligomer anchors the fusion protein in the membrane with minimal destabilization to the membrane. Upon associating with FP, the complex exerts a synergistic effect on the membrane perturbation. This effect is likely to contribute to the complete membrane fusion during the late phase of fusion protein-induced fusion cascade. The results presented in the work characterize the nature of the interaction of TMD with the membrane and TMD in a complex with FP in the steps leading to pore initiation and dilation during virus-induced fusion. Our data and proposed fusion model highlight the key role of TMD-FP interaction and have implications on the fusion reaction mediated by other type I viral fusion proteins. Understanding the molecular mechanism of membrane fusion may assist in the design of anti-viral drugs.</p

Library 2.0: the effectiveness of social media as a marketing tool for libraries in educational institutions

In an attempt to market their services and connect with potential users, and particularly young people, many libraries are opening accounts on social media platforms. Research suggests a contradiction between the advice relating to marketing and that regarding the use of social media in libraries, with the former emphasising the importance of the user at the centre of all considerations and the latter placing library staff as central to decisions. In this work we attempt to re-address this imbalance by surveying the current state of library activity on Twitter and, by means of questionnaires, investigate the experiences and motivations of librarians (n=58) in using social media and whether students (n=498) are willing to engage with the library in this manner and why. Our findings confirm that libraries in the sector are indeed struggling to foster interest in their social media activities and go some way to understanding why this is so, leading to a number of conclusions and recommendations for practitioners

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Adaptação do inventário parental “Language Use Inventory (LUI)” para crianças entre 18 e 47 meses para o português europeu : estudo piloto

Language acquisition and development takes in account the child’s interaction with the surrounding environment. Daily social interactions with people and communication with others allow the child to acquire language being pragmatics considered a system of rules that support the communicative use of language. Identification and assessment of children at risk for language disorders are crucial in order to carry out an effective early intervention. This study was carried out taking into account first, the relevance of pragmatics as a component of language, and second the lack of assessment tools in Portugal to assess these abilities. Therefore, the aim of this study consists on the translation, adaptation and validation of the inventory “Language Use Inventory” (LUI), to European Portuguese. The LUI is a standardized parent report measure designed to assess pragmatic language development in children within 18- to 47-month-old.Objetivo: A aquisição e o desenvolvimento da linguagem resultam da interação da criança com o meio ambiente. As interações sociais cotidianas com as pessoas e a comunicação com outros permitem que a criança adquira linguagem, sendo a pragmática o sistema de regras que suporta o uso comunicativo da linguagem. A identificação e a avaliação de crianças em risco de desenvolverem transtornos de linguagem são cruciais, tendo em vista a intervenção precoce eficaz. Tendo em vista a relevância da pragmática como componente da linguagem e a escassez, em Portugal, de instrumentos de avaliação da linguagem validados para idades precoces, a finalidade deste estudo consistiu na tradução, adaptação e validação do instrumento Language Use Inventory (LUI), para o português europeu. O LUI é um inventário parental que avalia o desenvolvimento da pragmática entre os 18 e os 47 meses. Métodos: Foram adotados todos os procedimentos recomendados pelas diretrizes internacionais sobre a adaptação de testes, culminando em estudo piloto com uma amostra de 120 inventários, respondidos pelos pais/cuidadores de crianças portuguesas da referida faixa etária. Resultados: Os coeficientes de consistência interna (Alfa de Cronbach) para a versão portuguesa do LUI situaram-se em 0,97 para a escala total e entre 0,71 e 0,96 para as subescalas. Conclusão: Os resultados preliminares dos estudos de adaptação e de validação do LUI-Pt para crianças portuguesas são promissores e asseguram a validade interna desta escala em termos da sua dimensionalidade e consistência interna

Implementing and evaluating a regional strategy to improve testing rates in VA patients at risk for HIV, utilizing the QUERI process as a guiding framework: QUERI Series

<p>Abstract</p> <p>Background</p> <p>We describe how we used the framework of the U.S. Department of Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) to develop a program to improve rates of diagnostic testing for the Human Immunodeficiency Virus (HIV). This venture was prompted by the observation by the CDC that 25% of HIV-infected patients do not know their diagnosis – a point of substantial importance to the VA, which is the largest provider of HIV care in the United States.</p> <p>Methods</p> <p>Following the QUERI steps (or process), we evaluated: 1) whether undiagnosed HIV infection is a high-risk, high-volume clinical issue within the VA, 2) whether there are evidence-based recommendations for HIV testing, 3) whether there are gaps in the performance of VA HIV testing, and 4) the barriers and facilitators to improving current practice in the VA.</p> <p>Based on our findings, we developed and initiated a QUERI step 4/phase 1 pilot project using the precepts of the Chronic Care Model. Our improvement strategy relies upon electronic clinical reminders to provide <it>decision support</it>; audit/feedback as a <it>clinical information system</it>, and appropriate changes in <it>delivery system design</it>. These activities are complemented by academic detailing and social marketing interventions to achieve <it>provider activation</it>.</p> <p>Results</p> <p>Our preliminary formative evaluation indicates the need to ensure leadership and team buy-in, address facility-specific barriers, refine the reminder, and address factors that contribute to inter-clinic variances in HIV testing rates. Preliminary unadjusted data from the first seven months of our program show 3–5 fold increases in the proportion of at-risk patients who are offered HIV testing at the VA sites (stations) where the pilot project has been undertaken; no change was seen at control stations.</p> <p>Discussion</p> <p>This project demonstrates the early success of the application of the QUERI process to the development of a program to improve HIV testing rates. Preliminary unadjusted results show that the coordinated use of audit/feedback, provider activation, and organizational change can increase HIV testing rates for at-risk patients. We are refining our program prior to extending our work to a small-scale, multi-site evaluation (QUERI step 4/phase 2). We also plan to evaluate the durability/sustainability of the intervention effect, the costs of HIV testing, and the number of newly identified HIV-infected patients. Ultimately, we will evaluate this program in other geographically dispersed stations (QUERI step 4/phases 3 and 4).</p