Extension and stress during continental breakup: seismic anisotropy of the crust in Northern Afar

Studies that attempt to simulate continental rifting and subsequent breakup require detailed knowledge of crustal stresses, however observational constraints from continental rifts are lacking. In addition, a knowledge of the stress field around active volcanoes can be used to detect sub-surface changes to the volcanic system. Here we use shear wave splitting to measure the seismic anisotropy of the crust in Northern Afar, a region of active, magma-rich continental breakup. We combine shear wave splitting tomography with modelling of gravitational and magmatic induced stresses to propose a model for crustal stress and strain across the rift. Results show that at the Ethiopian Plateau, seismic anisotropy is consistently oriented N–S. Seismic anisotropy within the rift is generally oriented NNW–SSE, with the exception of regions north and south of the Danakil Depression where seismic anisotropy is rift-perpendicular. These results suggest that the crust at the rift axis is characterized by rift-aligned structures and melt inclusions, consistent with a focusing of tectonic extension at the rift axis. In contrast, we show that at regions within the rift where extension rate is minimal the seismic anisotropy is best explained by the gravitationally induced stress field originating from variations in crustal thickness. Seismic anisotropy away from the rift is controlled by a combination of inherited crustal structures and gravitationally induced extension whereas at the Dabbahu region we show that the stress field changes orientation in response to magmatic intrusions. Our proposed model provides a benchmark of crustal stress in Northern Afar which will aid the monitoring of volcanic hazard. In addition we show that gravitational forces play a key role in measurements of seismic anisotropy, and must be considered in future studies. We demonstrate that during the final stages of continental rifting the stress field at the rift axis is primarily controlled by tectonic extension, but that gravitational forces and magmatic intrusions can play a key role in the orientation of the stress field

Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer

BACKGROUND: The transcription factor activator protein-1 (AP-1) has been implicated in a large variety of biological processes including oncogenic transformation. The tyrosine kinases of the epidermal growth factor receptor (EGFR) constitute the beginning of one signal transduction cascade leading to AP-1 activation and are known to control cell proliferation and differentiation. Drug discovery efforts targeting this receptor and other pathway components have centred on monoclonal antibodies and small molecule inhibitors. Resistance to such inhibitors has already been observed, guiding the prediction of their use in combination therapies with other targeted agents such as RNA interference (RNAi). This study examines the use of RNAi and kinase inhibitors for qualification of components involved in the EGFR/AP-1 pathway of ME180 cells, and their inhibitory effects when evaluated individually or in tandem against multiple components of this important disease-related pathway. METHODS: AP-1 activation was assessed using an ME180 cell line stably transfected with a beta-lactamase reporter gene under the control of AP-1 response element following epidermal growth factor (EGF) stimulation. Immunocytochemistry allowed for further quantification of small molecule inhibition on a cellular protein level. RNAi and RT-qPCR experiments were performed to assess the amount of knockdown on an mRNA level, and immunocytochemistry was used to reveal cellular protein levels for the targeted pathway components. RESULTS: Increased potency of kinase inhibitors was shown by combining RNAi directed towards EGFR and small molecule inhibitors acting at proximal or distal points in the pathway. After cellular stimulation with EGF and analysis at the level of AP-1 activation using a β-lactamase reporter gene, a 10–12 fold shift or 2.5–3 fold shift toward greater potency in the IC(50 )was observed for EGFR and MEK-1 inhibitors, respectively, in the presence of RNAi targeting EGFR. CONCLUSION: EGFR pathway components were qualified as targets for inhibition of AP-1 activation using RNAi and small molecule inhibitors. The combination of these two targeted agents was shown to increase the efficacy of EGFR and MEK-1 kinase inhibitors, leading to possible implications for overcoming or preventing drug resistance, lowering effective drug doses, and providing new strategies for interrogating cellular signalling pathways

A study of sertraline in dialysis (ASSertID) : a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis

© 2015 Friedli et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBACKGROUND: The prevalence of depression in people receiving haemodialysis is high with estimates varying between 20 and 40 %. There is little research on the effectiveness of antidepressants in dialysis patients with the few clinical trials suffering significant methodological issues. We plan to carry out a study to evaluate the feasibility of conducting a randomised controlled trial in patients on haemodialysis who have diagnosed Major Depressive Disorder.METHODS/DESIGN: The study has two phases, a screening phase and the randomised controlled trial. Patients will be screened initially with the Beck Depression Inventory to estimate the number of patients who score 16 or above. These patients will be invited to an interview with a psychiatrist who will invite those with a diagnosis of Major Depressive Disorder to take part in the trial. Consenting patients will be randomised to either Sertraline or placebo. Patients will be followed-up for 6 months. Demographic and clinical data will be collected at screening interview, baseline interview and 2 weeks, and every month (up to 6 months) after baseline. The primary outcome is to evaluate the feasibility of conducting a randomised, double blind, placebo pilot trial in haemodialysis patients with depression. Secondary outcomes include estimation of the variability in the outcome measures for the treatment and placebo arms, which will allow for a future adequately powered definitive trial. Analysis will primarily be descriptive, including the number of patients eligible for the trial, drug exposure of Sertraline in haemodialysis patients and the patient experience of participating in this trial.DISCUSSION: There is an urgent need for this research in the dialysis population because of the dearth of good quality and adequately powered studies. Research with renal patients is particularly difficult as they often have complex medical needs. This research will therefore not only assess the outcome of anti-depressants in haemodialysis patients with depression but also the process of running a randomised controlled trial in this population. Hence, the outputs of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the efficacy of anti-depressants in patient on haemodialysis with depression.TRIAL REGISTRATION: ISRCTN registry ISRCTN06146268 and EudraCT reference: 2012-000547-27.Peer reviewedFinal Published versio

First recorded eruption of Nabro volcano, Eritrea, 2011

We present a synthesis of diverse observations of the first recorded eruption of Nabro volcano, Eritrea, which began on 12 June 2011. While no monitoring of the volcano was in effect at the time, it has been possible to reconstruct the nature and evolution of the eruption through analysis of re- gional seismological and infrasound data and satellite remote sensing data, supplemented by petrological analysis of erupted products and brief field surveys. The event is notable for the comparative rarity of recorded historical eruptions in the region and of caldera systems in general, for the prodi- gious quantity of SO2 emitted into the atmosphere and the significant human impacts that ensued notwithstanding the low population density of the Afar region. It is also relevant in understanding the broader magmatic and tectonic signifi- cance of the volcanic massif of which Nabro forms a part and which strikes obliquely to the principal rifting directions in the Red Sea and northern Afar. The whole-rock compositions of Editorial responsibility: G. Giordano the erupted lavas and tephra range from trachybasaltic to trachybasaltic andesite, and crystal-hosted melt inclusions contain up to 3,000 ppm of sulphur by weight. The eruption was preceded by significant seismicity, detected by regional networks of sensors and accompanied by sustained tremor. Substantial infrasound was recorded at distances of hundreds to thousands of kilometres from the vent, beginning at the onset of the eruption and continuing for weeks. Analysis of ground deformation suggests the eruption was fed by a shal- low, NW–SE-trending dike, which is consistent with field and satellite observations of vent distributions. Despite lack of prior planning and preparedness for volcanic events in the country, rapid coordination of the emergency response miti- gated the human costs of the eruption

Maternal common mental disorders and infant development in Ethiopia : the P-MaMiE Birth Cohort

Background: Chronicity and severity of early exposure to maternal common mental disorders (CMD) has been associated with poorer infant development in high-income countries. In low- and middle-income countries (LAMICs), perinatal CMD is inconsistently associated with infant development, but the impact of severity and persistence has not been examined. Methods: A nested population-based cohort of 258 pregnant women was identified from the Perinatal Maternal Mental Disorder in Ethiopia (P-MaMiE) study, and 194 (75.2%) were successfully followed up until the infants were 12 months of age. Maternal CMD was measured in pregnancy and at two and 12 months postnatal using the WHO Self-Reporting Questionnaire, validated for use in this setting. Infant outcomes were evaluated using the Bayley Scales of Infant Development. Results: Antenatal maternal CMD symptoms were associated with poorer infant motor development ( β ^ -0.20; 95% CI: -0.37 to -0.03), but this became non-significant after adjusting for confounders. Postnatal CMD symptoms were not associated with any domain of infant development. There was evidence of a dose-response relationship between the number of time-points at which the mother had high levels of CMD symptoms (SRQ ≥ 6) and impaired infant motor development ( β ^ = -0.80; 95%CI -2.24, 0.65 for ante- or postnatal CMD only, β ^ = -4.19; 95%CI -8.60, 0.21 for ante- and postnatal CMD, compared to no CMD; test-for-trend χ213.08(1), p < 0.001). Although this association became non-significant in the fully adjusted model, the β ^ coefficients were unchanged indicating that the relationship was not confounded. In multivariable analyses, lower socio-economic status and lower infant weight-for-age were associated with significantly lower scores on both motor and cognitive developmental scales. Maternal experience of physical violence was significantly associated with impaired cognitive development. Conclusions: The study supports the hypothesis that it is the accumulation of risk exposures across time rather than early exposure to maternal CMD per se that is more likely to affect child development. Further investigation of the impact of chronicity of maternal CMD upon child development in LAMICs is indicated. In the Ethiopian setting, poverty, interpersonal violence and infant undernutrition should be targets for interventions to reduce the loss of child developmental potential.Peer Reviewe

Crowdsourced mapping of unexplored target space of kinase inhibitors

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome. The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts

A Comprehensive Investigation on Common Polymorphisms in the MDR1/ABCB1 Transporter Gene and Susceptibility to Colorectal Cancer

ATP Binding Cassette B1 (ABCB1) is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC) risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs) that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755) were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (Ptrend = 0.016 and 0.029, respectively), while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (Ptrend = 0.022). We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC

Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (pinteraction= 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Concl