Fermi Large Area Telescope observations of PSR J1836+5925

The discovery of the gamma-ray pulsar PSR J1836+5925, powering the formerly unidentified EGRET source 3EG J1835+5918, was one of the early accomplishments of the Fermi Large Area Telescope (LAT). Sitting 25 degrees off the Galactic plane, PSR J1836+5925 is a 173 ms pulsar with a characteristic age of 1.8 million years, a spindown luminosity of 1.1$\times10^{34}$ erg s$^{-1}$, and a large off-peak emission component, making it quite unusual among the known gamma-ray pulsar population. We present an analysis of one year of LAT data, including an updated timing solution, detailed spectral results and a long-term light curve showing no indication of variability. No evidence for a surrounding pulsar wind nebula is seen and the spectral characteristics of the off-peak emission indicate it is likely magnetospheric. Analysis of recent XMM observations of the X-ray counterpart yields a detailed characterization of its spectrum, which, like Geminga, is consistent with that of a neutron star showing evidence for both magnetospheric and thermal emission.Comment: Accepted to Astrophysical Journa

Recruitment of heterosexual couples in public health research: a study protocol

BACKGROUND: Public health research involving social or kin groups (such as sexual partners or family members), rather than samples of unrelated individuals, has become more widespread in response to social ecological approaches to disease treatment and prevention. This approach requires the development of innovative sampling, recruitment and screening methodologies tailored to the study of related individuals. METHODS: In this paper, we describe a set of sampling, recruitment and screening protocols developed to enlist urban, drug-using, heterosexual couples into a public health research study. This population is especially hard to reach because they are engaged in illegal and/or stigmatized behaviors. The protocols were designed to integrate adaptive sampling, street- and referral-based recruitment, and screening procedures to verify study eligibility and relationship status. DISCUSSION: Recruitment of heterosexual couples through one partner, preferably the female, can be an effective enlistment technique. Verification of relationship status is an important component of dyadic research. Comparison of parallel questionnaires administered to each member of a dyad can aid in the assessment of relationship status. However, multiple independent sources of information should be used to verify relationship status when available. Adaptive sampling techniques were effective in reaching drug-using heterosexual couples in an urban setting, and the application of these methods to other groups of related individuals in clinical and public health research may prove to be useful. However, care must be taken to consider potential sources of sampling bias when interpreting and generalizing study results

A novel TLR3 inhibitor encoded by African swine fever virus (ASFV)

African swine fever virus (ASFV) encodes proteins that manipulate important host antiviral mechanisms. Bioinformatic analysis of the ASFV genome revealed ORF I329L, a gene without any previous functional characterization as a possible inhibitor of TLR signaling. We demonstrate that ORF I329L encodes a highly glycosylated protein expressed in the cell membrane and on its surface. I329L also inhibited dsRNA-stimulated activation of NFκB and IRF3, two key players in innate immunity. Consistent with this, expression of I329L protein also inhibited the activation of interferon-β and CCL5. Finally, overexpression of TRIF reversed I329L-mediated inhibition of both NFκB and IRF3 activation. Our results suggest that TRIF, a key MyD88-independent adaptor molecule, is a possible target of this viral host modulation gene. The demonstration of an ASFV host evasion molecule inhibiting TLR responses is consistent with the ability of this virus to infect vertebrate and invertebrate hosts, both of which deploy innate immunity controlled by conserved TLR systems

Structural Insights into TIR Domain Specificity of the Bridging Adaptor Mal in TLR4 Signaling

MyD88 adaptor-like protein (Mal) is a crucial adaptor that acts as a bridge to recruit the MyD88 molecule to activated TLR4 receptors in response to invading pathogens. The specific assembly of the Toll/interleukin-1 receptor (TIR) domains of TLR4, Mal and MyD88 is responsible for proper signal transduction in the TLR4 signaling pathway. However, the molecular mechanism for the specificity of these TIR domains remains unclear. Here, we present the crystal structure of the TIR domain of the human Mal molecule (Mal-TIR) at a resolution of 2.4 Å. Unexpectedly, Mal-TIR exhibits an extraordinarily long AB loop, but no αB helix or BB loop, distinguishing it from other TIR domains. More importantly, the Mal-TIR AB loop is capable of mediating direct binding to the TIR domains of TLR4 and MyD88 simultaneously. We also found that Mal-TIR can form a back-to-back dimer that may resemble the dimeric assembly of the entire Mal molecule. Our data demonstrate the bridge role of the Mal-TIR domain and provide important information about TIR domain specificity

Convergent Evidence from Mouse and Human Studies Suggests the Involvement of Zinc Finger Protein 326 Gene in Antidepressant Treatment Response

OBJECTIVES: The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. METHODS: FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). RESULTS: One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). CONCLUSIONS: The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response

Clinical research without consent in adults in the emergency setting: a review of patient and public views

<p>Abstract</p> <p>Background</p> <p>In emergency research, obtaining informed consent can be problematic. Research to develop and improve treatments for patients admitted to hospital with life-threatening and debilitating conditions is much needed yet the issue of research without consent (RWC) raises concerns about unethical practices and the loss of individual autonomy. Consistent with the policy and practice turn towards greater patient and public involvement in health care decisions, in the US, Canada and EU, guidelines and legislation implemented to protect patients and facilitate acute research with adults who are unable to give consent have been developed with little involvement of the lay public. This paper reviews research examining public opinion regarding RWC for research in emergency situations, and whether the rules and regulations permitting research of this kind are in accordance with the views of those who ultimately may be the most affected.</p> <p>Methods</p> <p>Seven electronic databases were searched: Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews, Philosopher's Index, Age Info, PsychInfo, Sociological Abstracts and Web of Science. Only those articles pertaining to the views of the public in the US, Canada and EU member states were included. Opinion pieces and those not published in English were excluded.</p> <p>Results</p> <p>Considering the wealth of literature on the perspectives of professionals, there was relatively little information about public attitudes. Twelve studies employing a range of research methods were identified. In five of the six questionnaire surveys around half the sample did <it>not </it>agree generally with RWC, though paradoxically, a higher percentage would <it>personally </it>take part in such a study. Unfortunately most of the studies were not designed to investigate individuals' views in any depth. There also appears to be a level of mistrust of medical research and some patients were more likely to accept an experimental treatment 'outside' of a research protocol.</p> <p>Conclusion</p> <p>There are too few data to evaluate whether the rules and regulations permitting RWC protects – or is acceptable to – the public. However, any attempts to engage the public should take place in the context of findings from further basic research to attend to the apparently paradoxical findings of some of the current surveys.</p

Deciphering the universe of RNA structures and trans RNA-RNA interactions of transcriptomes in vivo: from experimental protocols to computational analyses

The last few years have seen an explosion of experimental and computational methods for investigating RNA structures of entire transcriptomes in vivo. Very recent experimental protocols now also allow trans RNA–RNA interactions to be probed in a transcriptome-wide manner. All of the experimental strategies require comprehensive computational pipelines for analysing the raw data and converting it back into actual RNA structure features or trans RNA–RNA interactions. The overall performance of these methods thus strongly depends on the experimental and the computational protocols employed. In order to get the best out of both worlds, both aspects need to be optimised simultaneously. This review introduced the methods and proposes ideas how they could be further improved

Is alcohol consumption a risk factor for prostate cancer? A systematic review and meta-analysis.

Background: Research on a possible causal association between alcohol consumption and risk of prostate cancer is inconclusive. Recent studies on associations between alcohol consumption and other health outcomes suggest these are influenced by drinker misclassification errors and other study quality characteristics. The influence of these factors on estimates of the relationship between alcohol consumption and prostate cancer has not been previously investigated. Methods: PubMed and Web of Science searches were made for case–control and cohort studies of alcohol consumption and prostate cancer morbidity and mortality (ICD–10: C61) up to December 2014. Studies were coded for drinker misclassification errors, quality of alcohol measures, extent of control for confounding and other study characteristics. Mixed models were used to estimate relative risk (RR) of morbidity or mortality from prostate cancer due to alcohol consumption with study level controls for selection bias and confounding. Results: A total of 340 studies were identified of which 27 satisfied inclusion criteria providing 126 estimates for different alcohol exposures. Adjusted RR estimates indicated a significantly increased risk of prostate cancer among low (RR = 1.08, P 1.3, <24 g per day). This relationship is stronger in the relatively few studies free of former drinker misclassification error. Given the high prevalence of prostate cancer in the developed world, the public health implications of these findings are significant. Prostate cancer may need to be incorporated into future estimates of the burden of disease alongside other cancers (e.g. breast, oesophagus, colon, liver) and be integrated into public health strategies for reducing alcohol related disease

Predictive Genes in Adjacent Normal Tissue Are Preferentially Altered by sCNV during Tumorigenesis in Liver Cancer and May Rate Limiting

Background: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. Methodology/Principal Findings: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ~250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance: This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types. © 2011 Lamb et al.published_or_final_versio