Sharing Data for Public Health Research by Members of an International Online Diabetes Social Network

Background: Surveillance and response to diabetes may be accelerated through engaging online diabetes social networks (SNs) in consented research. We tested the willingness of an online diabetes community to share data for public health research by providing members with a privacy-preserving social networking software application for rapid temporal-geographic surveillance of glycemic control. Methods and Findings: SN-mediated collection of cross-sectional, member-reported data from an international online diabetes SN entered into a software applicaction we made available in a “Facebook-like” environment to enable reporting, charting and optional sharing of recent hemoglobin A1c values through a geographic display. Self-enrollment by 17% (n = 1,136) of n = 6,500 active members representing 32 countries and 50 US states. Data were current with 83.1% of most recent A1c values reported obtained within the past 90 days. Sharing was high with 81.4% of users permitting data donation to the community display. 34.1% of users also displayed their A1cs on their SN profile page. Users selecting the most permissive sharing options had a lower average A1c (6.8%) than users not sharing with the community (7.1%, p = .038). 95% of users permitted re-contact. Unadjusted aggregate A1c reported by US users closely resembled aggregate 2007–2008 NHANES estimates (respectively, 6.9% and 6.9%, p = 0.85). Conclusions: Success within an early adopter community demonstrates that online SNs may comprise efficient platforms for bidirectional communication with and data acquisition from disease populations. Advancing this model for cohort and translational science and for use as a complementary surveillance approach will require understanding of inherent selection and publication (sharing) biases in the data and a technology model that supports autonomy, anonymity and privacy.Centers for Disease Control and Prevention (U.S.) (P01HK000088-01)Centers for Disease Control and Prevention (U.S.) (P01HK000016 )National Institute of Alcohol Abuse and Alcoholism (U.S.) (R21 AA016638-01A1)National Center for Research Resources (U.S.) (1U54RR025224-01)Children's Hospital (Boston, Mass.) (Program for Patient Safety and Quality

Substitution of adeno-associated virus Rep protein binding and nicking sites with human Chromosome 19 sequences

<p>Abstract</p> <p>Background</p> <p>Adeno-associated virus type 2 (AAV2) preferentially integrates its DNA at a ~2 kb region of human chromosome 19, designated <it>AAVS1 </it>(also known as <it>MBS85</it>). Integration at <it>AAVS1 </it>requires the AAV2 replication (Rep) proteins and a DNA sequence within <it>AAVS1 </it>containing a 16 bp Rep recognition sequence (RRS) and closely spaced Rep nicking site (also referred to as a terminal resolution site, or <it>trs</it>). The AAV2 genome is flanked by inverted terminal repeats (ITRs). Each ITR contains an RRS and closely spaced <it>trs</it>, but the sequences differ from those in <it>AAVS1</it>. These ITR sequences are required for replication and packaging.</p> <p>Results</p> <p>In this study we demonstrate that the <it>AAVS1 </it>RRS and <it>trs </it>can function in AAV2 replication, packaging and integration by replacing a 61 bp region of the AAV2 ITR with a 49 bp segment of <it>AAVS1 </it>DNA. Modifying one or both ITRs did not have a large effect on the overall virus titers. These modifications did not detectably affect integration at <it>AAVS1</it>, as measured by semi-quantitative nested PCR assays. Sequencing of integration junctions shows the joining of the modified ITRs to <it>AAVS1 </it>sequences.</p> <p>Conclusions</p> <p>The ability of these <it>AAVS1 </it>sequences to substitute for the AAV2 RRS and <it>trs </it>provides indirect evidence that the stable secondary structure encompassing the <it>trs </it>is part of the AAV2 packaging signal.</p

Parvovirus Minute Virus of Mice Induces a DNA Damage Response That Facilitates Viral Replication

Infection by DNA viruses can elicit DNA damage responses (DDRs) in host cells. In some cases the DDR presents a block to viral replication that must be overcome, and in other cases the infecting agent exploits the DDR to facilitate replication. We find that low multiplicity infection with the autonomous parvovirus minute virus of mice (MVM) results in the activation of a DDR, characterized by the phosphorylation of H2AX, Nbs1, RPA32, Chk2 and p53. These proteins are recruited to MVM replication centers, where they co-localize with the main viral replication protein, NS1. The response is seen in both human and murine cell lines following infection with either the MVMp or MVMi strains. Replication of the virus is required for DNA damage signaling. Damage response proteins, including the ATM kinase, accumulate in viral-induced replication centers. Using mutant cell lines and specific kinase inhibitors, we show that ATM is the main transducer of the signaling events in the normal murine host. ATM inhibitors restrict MVM replication and ameliorate virus-induced cell cycle arrest, suggesting that DNA damage signaling facilitates virus replication, perhaps in part by promoting cell cycle arrest. Thus it appears that MVM exploits the cellular DNA damage response machinery early in infection to enhance its replication in host cells

The Intrinsic Antiviral Defense to Incoming HSV-1 Genomes Includes Specific DNA Repair Proteins and Is Counteracted by the Viral Protein ICP0

Cellular restriction factors responding to herpesvirus infection include the ND10 components PML, Sp100 and hDaxx. During the initial stages of HSV-1 infection, novel sub-nuclear structures containing these ND10 proteins form in association with incoming viral genomes. We report that several cellular DNA damage response proteins also relocate to sites associated with incoming viral genomes where they contribute to the cellular front line defense. We show that recruitment of DNA repair proteins to these sites is independent of ND10 components, and instead is coordinated by the cellular ubiquitin ligases RNF8 and RNF168. The viral protein ICP0 targets RNF8 and RNF168 for degradation, thereby preventing the deposition of repressive ubiquitin marks and counteracting this repair protein recruitment. This study highlights important parallels between recognition of cellular DNA damage and recognition of viral genomes, and adds RNF8 and RNF168 to the list of factors contributing to the intrinsic antiviral defense against herpesvirus infection

Are social norms associated with smoking in French university students? A survey report on smoking correlates

<p>Abstract</p> <p>Background</p> <p>Knowledge of the correlates of smoking is a first step to successful prevention interventions. The social norms theory hypothesises that students' smoking behaviour is linked to their perception of norms for use of tobacco. This study was designed to test the theory that smoking is associated with perceived norms, controlling for other correlates of smoking.</p> <p>Methods</p> <p>In a pencil-and-paper questionnaire, 721 second-year students in sociology, medicine, foreign language or nursing studies estimated the number of cigarettes usually smoked in a month. 31 additional covariates were included as potential predictors of tobacco use. Multiple imputation was used to deal with missing values among covariates. The strength of the association of each variable with tobacco use was quantified by the inclusion frequencies of the variable in 1000 bootstrap sample backward selections. Being a smoker and the number of cigarettes smoked by smokers were modelled separately.</p> <p>Results</p> <p>We retain 8 variables to predict the risk of smoking and 6 to predict the quantities smoked by smokers. The risk of being a smoker is increased by cannabis use, binge drinking, being unsupportive of smoke-free universities, perceived friends' approval of regular smoking, positive perceptions about tobacco, a high perceived prevalence of smoking among friends, reporting not being disturbed by people smoking in the university, and being female. The quantity of cigarettes smoked by smokers is greater for smokers reporting never being disturbed by smoke in the university, unsupportive of smoke-free universities, perceiving that their friends approve of regular smoking, having more negative beliefs about the tobacco industry, being sociology students and being among the older students.</p> <p>Conclusion</p> <p>Other substance use, injunctive norms (friends' approval) and descriptive norms (friends' smoking prevalence) are associated with tobacco use.</p> <p>University-based prevention campaigns should take multiple substance use into account and focus on the norms most likely to have an impact on student smoking.</p

Transcriptional Activation of the Adenoviral Genome Is Mediated by Capsid Protein VI

Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents viral gene expression through the assembly of repressive chromatin remodeling complexes targeting incoming viral genomes. However, it has remained unclear how initial transcriptional activation of the adenoviral genome is achieved. Here we show that Daxx mediated repression of the immediate early Ad E1A promoter is efficiently counteracted by the capsid protein VI. This requires a conserved PPxY motif in protein VI. Capsid proteins from other DNA viruses were also shown to activate the Ad E1A promoter independent of Ad gene expression and support virus replication. Our results show how Ad entry is connected to transcriptional activation of their genome in the nucleus. Our data further suggest a common principle for genome activation of DNA viruses by counteracting Daxx related repressive mechanisms through virion proteins

DNA repair, genome stability and cancer: a historical perspective

The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy

Threatened reef corals of the world

10.1371/journal.pone.0034459PLoS ONE73

Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Emerging roles of ATF2 and the dynamic AP1 network in cancer

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lau, Eric . Burnham Institute for Medical Research; Estados UnidosFil: Ronai, Zeev . Burnham Institute for Medical Research; Estados Unido