An ABC transporter containing a forkhead-associated domain interacts with a serine-threonine protein kinase and is required for growth of Mycobacterium tuberculosis in mice

Forkhead-associated (FHA) domains are modular phosphopeptide recognition motifs with a striking preference for phosphothreonine-containing epitopes. FHA domains have been best characterized in eukaryotic signaling pathways but have been identified in six proteins in Mycobacterium tuberculosis, the causative organism of tuberculosis. One of these, coded by gene Rv1747, is an ABC transporter and the only one to contain two such modules. A deletion mutant of Rv1747 is attenuated in a mouse intravenous injection model of tuberculosis where the bacterial load of the mutant is 10-fold lower than that of the wild type in both lungs and spleen. In addition, growth of the mutant in mouse bone marrow-derived macrophages and dendritic cells is significantly impaired. In contrast, growth of this mutant in vitro was indistinguishable from that of the wild type. The mutant phenotype was lost when the mutation was complemented by the wild-type allele, confirming that it was due to mutation of Rv1747. Using yeast two-hybrid analysis, we have shown that the Rv1747 protein interacts with the serine-threonine protein kinase PknF. This interaction appears to be phospho-dependent since it is abrogated in a kinase-dead mutant and by mutations in the presumed activation loop of PknF and in the first FHA domain of Rv1747. These results demonstrate that the protein coded by Rv1747 is required for normal virulent infection by M. tuberculosis in mice and, since it interacts with a serine-threonine protein kinase in a kinase-dependent manner, indicate that it forms part of an important phospho-dependent signaling pathway

Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis

Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation

Proactive and politically skilled professionals: What is the relationship with affective occupational commitment?

The aim of this study is to extend research on employee affective commitment in three ways: (1) instead of organizational commitment the focus is on occupational commitment; (2) the role of proactive personality on affective occupational commitment is examined; and (3) occupational satisfaction is examined as a mediator and political skills as moderator in the relationship between proactive personality and affective occupational commitment. Two connected studies, one in a hospital located in the private sector and one in a university located in the public sector, are carried out in Pakistan, drawing on a total sample of over 400 employees. The results show that proactive personality is positively related to affective occupational commitment, and that occupational satisfaction partly mediates the relationship between proactive personality and affective occupational commitment. No effect is found for a moderator effect of political skills in the relationship between proactive personality and affective occupational commitment. Political skills however moderate the relationship between proactive personality and affective organizational commitment

Policy Coherence in US Tobacco Control: Beyond FDA Regulation

Joshua Yang and Thomas Novotny explore whether the US government can develop and implement a coherent policy agenda to reduce tobacco-related morbidity and mortality

Overcoming barriers to engaging socio-economically disadvantaged populations in CHD primary prevention: a qualitative study

<p><b>Background:</b> Preventative medicine has become increasingly important in efforts to reduce the burden of chronic disease in industrialised countries. However, interventions that fail to recruit socio-economically representative samples may widen existing health inequalities. This paper explores the barriers and facilitators to engaging a socio-economically disadvantaged (SED) population in primary prevention for coronary heart disease (CHD).</p> <p><b>Methods:</b> The primary prevention element of Have a Heart Paisley (HaHP) offered risk screening to all eligible individuals. The programme employed two approaches to engaging with the community: a) a social marketing campaign and b) a community development project adopting primarily face-to-face canvassing. Individuals living in areas of SED were under-recruited via the social marketing approach, but successfully recruited via face-to-face canvassing. This paper reports on focus group discussions with participants, exploring their perceptions about and experiences of both approaches.</p> <p><b>Results:</b> Various reasons were identified for low uptake of risk screening amongst individuals living in areas of high SED in response to the social marketing campaign and a number of ways in which the face-to-face canvassing approach overcame these barriers were identified. These have been categorised into four main themes: (1) processes of engagement; (2) issues of understanding; (3) design of the screening service and (4) the priority accorded to screening. The most immediate barriers to recruitment were the invitation letter, which often failed to reach its target, and the general distrust of postal correspondence. In contrast, participants were positive about the face-to-face canvassing approach. Participants expressed a lack of knowledge and understanding about CHD and their risk of developing it and felt there was a lack of clarity in the information provided in the mailing in terms of the process and value of screening. In contrast, direct face-to-face contact meant that outreach workers could explain what to expect. Participants felt that the procedure for uptake of screening was demanding and inflexible, but that the drop-in sessions employed by the community development project had a major impact on recruitment and retention.</p> <p><b>Conclusion:</b> Socio-economically disadvantaged individuals can be hard-to-reach; engagement requires strategies tailored to the needs of the target population rather than a population-wide approach.</p&gt

GNA11 brain somatic pathogenic variant in an individual with phacomatosis pigmentovascularis

Objective: To describe the findings of histopathology and genotyping studies in affected brain tissue from an individual with phacomatosis pigmentovascularis (PPV). / Methods: A retrospective chart review of a 2-year 10-month-old male with a clinical diagnosis of PPV cesiomarmorata (or type V) was performed. Clinical features, brain imaging and histopathology findings, and genotyping studies in his affected brain tissue are summarized. / Results: The proband had a clinically severe neurologic phenotype characterized by global developmental delay, generalized hypotonia, and recurrent episodes of cardiac asystole in the setting of status epilepticus. A somatic pathogenic variant in GNA11 (c.547C>T, p.Arg183Cys) was detected in his skin tissue but not in blood (previously published). He underwent an urgent left posterior quadrantectomy for his life-threatening seizures. Histopathology of resected brain tissue showed an increase in leptomeningeal melanocytes and abnormal vasculature, and the exact pathogenic variant in GNA11 (c.547C>T, p.Arg183Cys), previously isolated from his skin tissue but not blood, was detected in his resected brain tissue. / Conclusions: The finding of this variant in affected skin and brain tissue of our patient with PPV supports a unifying genetic diagnosis of his neurocutaneous features

Cervical adenocarcinoma presenting as a cardiac tamponade in a 57-year-old woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pericardial effusion as a complication of malignant gynecological disorders is rare. Few cases of endometrial cancer, squamous cell carcinoma of the cervix, ovarian cancer and uterine carcinosarcoma have been previously reported. We report the first case of cardiac tamponade secondary to a cervical adenocarcinoma.</p> <p>Case presentation</p> <p>A 54-year-old Caucasian woman, without any relevant medical history and no gynecological aftercare, was admitted to our hospital emergency room with severe dyspnea. Echocardiography revealed severe pericardial effusion with a swinging heart. An emergency pericardial drainage was performed through a pericardial window, which permitted the draining of 700 mL of bloody fluid and a pericardial biopsy. Cytological examination of the fluid revealed atypical cells, and the biopsy specimen showed tumor emboli suggestive of adenocarcinoma. Magnetic resonance imaging showed a 35 mm cervical lesion indicative of an endocervical tumor. Exploratory laparoscopy revealed diffuse peritoneal lesions and histological examination of cervical curettage showed a poorly differentiated micropapillary adenocarcinoma of the cervix.</p> <p>Conclusion</p> <p>Carcinomatous pericarditis as the first symptom of a malignant gynecological adenocarcinoma has not, to the best of our knowledge, been documented before. This case highlights the extreme severity of pericardial effusion secondary to cervical adenocarcinoma, a sign of advanced disease. Gynecological malignancies have to be considered in cases of neoplastic pericardial effusion.</p

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

Climate model response from the Geoengineering Model Intercomparison Project (GeoMIP)

Solar geoengineering - deliberate reduction in the amount of solar radiation retained by the Earth - has been proposed as a means of counteracting some of the climatic effects of anthropogenic greenhouse gas emissions. We present results from Experiment G1 of the Geoengineering Model Intercomparison Project, in which 12 climate models have simulated the climate response to an abrupt quadrupling of CO2 from preindustrial concentrations brought into radiative balance via a globally uniform reduction in insolation. Models show this reduction largely offsets global mean surface temperature increases due to quadrupled CO2 concentrations and prevents 97% of the Arctic sea ice loss that would otherwise occur under high CO2 levels but, compared to the preindustrial climate, leaves the tropics cooler (-0.3 K) and the poles warmer (+0.8 K). Annual mean precipitation minus evaporation anomalies for G1 are less than 0.2 mm day-1 in magnitude over 92% of the globe, but some tropical regions receive less precipitation, in part due to increased moist static stability and suppression of convection. Global average net primary productivity increases by 120% in G1 over simulated preindustrial levels, primarily from CO2 fertilization, but also in part due to reduced plant heat stress compared to a high CO2 world with no geoengineering. All models show that uniform solar geoengineering in G1 cannot simultaneously return regional and global temperature and hydrologic cycle intensity to preindustrial levels. Key Points Temperature reduction from uniform geoengineering is not uniform Geoengineering cannot offset both temperature and hydrology changes NPP increases mostly due to CO2 fertilization ©2013. American Geophysical Union. All Rights Reserved.BK is supported by the Fund for Innovative Climate and Energy Research. Simulations performed by BK were supported by the NASA High-End Computing (HEC) Program through the NASA Center for Climate Simulation (NCCS) at Goddard Space Flight Center. The Pacific Northwest National Laboratory is operated for the U.S. Department of Energy by Battelle Memorial Institute under contract DE-AC05-76RL01830. AR is supported by US National Science Foundation grant AGS-1157525. JMH and AJ were supported by the joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101). KA, DBK, JEK, UN, HS, and MS received funding from the European Union’s Seventh Framework Programme (FP7/ 2007–2013) under grant agreement 226567-IMPLICC. KA and JEK received support from the Norwegian Research Council’s Programme for Supercomputing (NOTUR) through a grant of computing time. Simulations with the IPSL-CM5 model were supported through HPC resources of [CCT/ TGCC/CINES/IDRIS] under the allocation 2012-t2012012201 made by GENCI (Grand Equipement National de Calcul Intensif). DJ and JCM thank all members of the BNU-ESM model group, as well as the Center of Information and Network Technology at Beijing Normal University for assistance in publishing the GeoMIP data set. The National Center for Atmospheric Research is funded by the National Science Foundation. SW was supported by the Innovative Program of Climate Change Projection for the 21st century, MEXT, Japan. Computer resources for PJR, BS, and JHY were provided by the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under contract DE-AC02-05CH11231