Direct isotopic evidence of biogenic methane production and efflux from beneath a temperate glacier

The base of glaciers and ice sheets provide environments suitable for the production of methane. High pressure conditions beneath the impermeable ‘cap’ of overlying ice promote entrapment of methane reserves that can be released to the atmosphere during ice thinning and meltwater evacuation. However, contemporary glaciers and ice sheets are rarely accounted for as methane contributors through field measurements. Here, we present direct field-based evidence of methane production and release from beneath the Icelandic glacier Sólheimajökull, where geothermal activity creates sub-oxic conditions suited to methane production and preservation along the meltwater flow path. Methane production at the glacier bed (48 tonnes per day, or 39 mM CH4 m−2 day−1), and evasion to the atmosphere from the proglacial stream (41 tonnes per day, or 32 M CH4 m−2 day−1) indicates considerable production and release to the atmosphere during the summer melt season. Isotopic signatures (−60.2‰ to −7.6‰ for δ13CCH4 and −324.3‰ to +161.1‰ for DCH4), support a biogenic signature within waters emerging from the subglacial environment. Temperate glacial methane production and release may thus be a significant and hitherto unresolved contributor of a potent greenhouse gas to the atmosphere

Varicella-Zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line

Post-herpetic neuralgia (PHN) is the most significant complication of herpes zoster caused by reactivation of latent Varicella-Zoster virus (VZV). We undertook a heterologous infection in vitro study to determine whether PHN-associated VZV isolates induce changes in sodium ion channel currents known to be associated with neuropathic pain. Twenty VZV isolates were studied blind from 11 PHN and 9 non-PHN subjects. Viruses were propagated in the MeWo cell line from which cell-free virus was harvested and applied to the ND7/23-Nav1.8 rat DRG x mouse neuroblastoma hybrid cell line which showed constitutive expression of the exogenous Nav 1.8, and endogenous expression of Nav 1.6 and Nav 1.7 genes all encoding sodium ion channels the dysregulation of which is associated with a range of neuropathic pain syndromes. After 72 hrs all three classes of VZV gene transcripts were detected in the absence of infectious virus. Single cell sodium ion channel recording was performed after 72 hr by voltage-clamping. PHN-associated VZV significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas) or vaccine VZV strains ((POka, Merck and GSK). These sodium current increases were unaffected by acyclovir pre-treatment but were abolished by exposure to Tetrodotoxin (TTX) which blocks the TTX-sensitive fast Nav 1.6 and Nav 1.7 channels but not the TTX-resistant slow Nav 1.8 channel. PHN-associated VZV sodium current increases were therefore mediated in part by the Nav 1.6 and Nav 1.7 sodium ion channels. An additional observation was a modest increase in message levels of both Nav1.6 and Nav1.7 mRNA but not Nav 1.8 in PHN virally infected cells

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility

Personalization Paradox in Behavior Change Apps:Lessons from a Social Comparison-Based Personalized App for Physical Activity

Social comparison-based features are widely used in social computing apps. However, most existing apps are not grounded in social comparison theories and do not consider individual differences in social comparison preferences and reactions. This paper is among the first to automatically personalize social comparison targets. In the context of an m-health app for physical activity, we use artificial intelligence (AI) techniques of multi-armed bandits. Results from our user study (n=53) indicate that there is some evidence that motivation can be increased using the AI-based personalization of social comparison. The detected effects achieved small-to-moderate effect sizes, illustrating the real-world implications of the intervention for enhancing motivation and physical activity. In addition to design implications for social comparison features in social apps, this paper identified the personalization paradox, the conflict between user modeling and adaptation, as a key design challenge of personalized applications for behavior change. Additionally, we propose research directions to mitigate this Personalization Paradox

Making it work for me: beliefs about making a personal health record relevant and useable.

BACKGROUND: A Personal Health Record (PHR) is an electronic record that individuals use to manage and share their health information, e.g. data from their medical records and data collected by apps. However, engagement with their record can be low if people do not find it beneficial to their health, wellbeing or interactions with health and other services. We have explored the beliefs potential users have about a PHR, how it could be made personally relevant, and barriers to its use. METHODS: A qualitative design comprising eight focus groups, each with 6-8 participants. Groups included adults with long-term health conditions, young people, physically active adults, data experts, and members of the voluntary sector. Each group lasted 60-90 min, was audio recorded and transcribed verbatim. We analysed the data using thematic analysis to address the question "What are people's beliefs about making a Personal Health Record have relevance and impact?" RESULTS: We found four themes. Making it work for me is about how to encourage individuals to actively engage with their PHR. I control my information is about individuals deciding what to share and who to share it with. My concerns is about individuals' concerns about information security and if and how their information will be acted upon. Potential impact shows the potential benefits of a PHR such as increasing self-efficacy, uptake of health-protective behaviours, and professionals taking a more holistic approach to providing care and facilitating behaviour change. CONCLUSIONS: Our research shows the functionality that a PHR requires in order for people to engage with it. Interactive functions and integration with lifestyle and health apps are particularly important. A PHR could increase the effectiveness of behaviour change apps by specifying evidence-based behaviour change techniques that apps should incorporate. A PHR has the potential to increase health-protective behaviours and facilitate a more person-driven health and social care system. It could support patients to take responsibility for self-managing their health and treatment regimens, as well as helping patients to play a more active role when care transfers across boundaries of responsibility

A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults

Background: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LT alpha) may be important for the development of cerebral malaria (CM) and other SM syndromes

A redox switch in angiotensinogen modulates angiotensin release.

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child

Expression of Human nPTB Is Limited by Extreme Suboptimal Codon Content

Background: The frequency of synonymous codon usage varies widely between organisms. Suboptimal codon content limits expression of viral, experimental or therapeutic heterologous proteins due to limiting cognate tRNAs. Codon content is therefore often adjusted to match codon bias of the host organism. Codon content also varies between genes within individual mammalian species. However, little attention has been paid to the consequences of codon content upon translation of host proteins. Methodology/Principal Findings: In comparing the splicing repressor activities of transfected human PTB and its two tissue-restricted paralogs–nPTB and ROD1–we found that the three proteins were expressed at widely varying levels. nPTB was expressed at 1–3 % the level of PTB despite similar levels of mRNA expression and 74 % amino acid identity. The low nPTB expression was due to the high proportion of codons with A or U at the third codon position, which are suboptimal in human mRNAs. Optimization of the nPTB codon content, akin to the ‘‘humanization’ ’ of foreign ORFs, allowed efficient translation in vivo and in vitro to levels comparable with PTB. We were then able to demonstrate that all three proteins act as splicing repressors. Conclusions/Significance: Our results provide a striking illustration of the importance of mRNA codon content in determining levels of protein expression, even within cells of the natural host species