The few genetically informative studies to examine post-traumatic stress disorder (PTSD) and alcohol dependence (AD), all of which are based on a male veteran sample, suggest that the co-morbidity ...between PTSD and AD may be attributable in part to overlapping genetic influences, but this issue has yet to be addressed in females.MethodData were derived from an all-female twin sample (n=3768) ranging in age from 18 to 29 years. A trivariate genetic model that included trauma exposure as a separate phenotype was fitted to estimate genetic and environmental contributions to PTSD and the degree to which they overlap with those that contribute to AD, after accounting for potential confounding effects of heritable influences on trauma exposure.
Additive genetic influences (A) accounted for 72% of the variance in PTSD; individual-specific environmental (E) factors accounted for the remainder. An AE model also provided the best fit for AD, for which heritability was estimated to be 71%. The genetic correlation between PTSD and AD was 0.54.
The heritability estimate for PTSD in our sample is higher than estimates reported in earlier studies based almost exclusively on an all-male sample in which combat exposure was the precipitating traumatic event. However, our findings are consistent with the absence of evidence for shared environmental influences on PTSD and, most importantly, the substantial overlap in genetic influences on PTSD and AD reported in these investigations. Additional research addressing potential distinctions by gender in the relative contributions of genetic and environmental influences on PTSD is merited.
Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two ...computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.
Magnesium hydride has been studied extensively for applications as a hydrogen storage material owing to the favourable cost and high gravimetric and volumetric hydrogen densities. However, its high ...enthalpy of decomposition necessitates high working temperatures for hydrogen desorption while the slow rates for some processes such as hydrogen diffusion through the bulk create challenges for large-scale implementation. The present paper reviews fundamentals of the Mg–H system and looks at the recent advances in the optimisation of magnesium hydride as a hydrogen storage material through the use of catalytic additives, incorporation of defects and an understanding of the rate-limiting processes during absorption and desorption.
Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and ...meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.
Dam removal: Listening in Foley, M. M.; Bellmore, J. R.; O'Connor, J. E. ...
Water resources research,
July 2017, 2017-07-00, 20170701, Volume:
53, Issue:
7
Journal Article
Peer reviewed
Open access
Dam removal is widely used as an approach for river restoration in the United States. The increase in dam removals—particularly large dams—and associated dam‐removal studies over the last few decades ...motivated a working group at the USGS John Wesley Powell Center for Analysis and Synthesis to review and synthesize available studies of dam removals and their findings. Based on dam removals thus far, some general conclusions have emerged: (1) physical responses are typically fast, with the rate of sediment erosion largely dependent on sediment characteristics and dam‐removal strategy; (2) ecological responses to dam removal differ among the affected upstream, downstream, and reservoir reaches; (3) dam removal tends to quickly reestablish connectivity, restoring the movement of material and organisms between upstream and downstream river reaches; (4) geographic context, river history, and land use significantly influence river restoration trajectories and recovery potential because they control broader physical and ecological processes and conditions; and (5) quantitative modeling capability is improving, particularly for physical and broad‐scale ecological effects, and gives managers information needed to understand and predict long‐term effects of dam removal on riverine ecosystems. Although these studies collectively enhance our understanding of how riverine ecosystems respond to dam removal, knowledge gaps remain because most studies have been short (< 5 years) and do not adequately represent the diversity of dam types, watershed conditions, and dam‐removal methods in the U.S.
Key Points
Dam removal is an increasingly common approach to river restoration in the United States
Dam‐removal studies provide insights on key controls influencing the physical and ecological responses to dam removal
Although many aspects of physical and ecological systems react quickly to dam removal, overall response trajectories depend on how and where dams are removed and overall watershed conditions
Riboswitches are structural RNA elements that are generally located in the 5' untranslated region of messenger RNA. During regulation of gene expression, ligand binding to the aptamer domain of a ...riboswitch triggers a signal to the downstream expression platform. A complete understanding of the structural basis of this mechanism requires the ability to study structural changes over time. Here we use femtosecond X-ray free electron laser (XFEL) pulses to obtain structural measurements from crystals so small that diffusion of a ligand can be timed to initiate a reaction before diffraction. We demonstrate this approach by determining four structures of the adenine riboswitch aptamer domain during the course of a reaction, involving two unbound apo structures, one ligand-bound intermediate, and the final ligand-bound conformation. These structures support a reaction mechanism model with at least four states and illustrate the structural basis of signal transmission. The three-way junction and the P1 switch helix of the two apo conformers are notably different from those in the ligand-bound conformation. Our time-resolved crystallographic measurements with a 10-second delay captured the structure of an intermediate with changes in the binding pocket that accommodate the ligand. With at least a 10-minute delay, the RNA molecules were fully converted to the ligand-bound state, in which the substantial conformational changes resulted in conversion of the space group. Such notable changes in crystallo highlight the important opportunities that micro- and nanocrystals may offer in these and similar time-resolved diffraction studies. Together, these results demonstrate the potential of 'mix-and-inject' time-resolved serial crystallography to study biochemically important interactions between biomacromolecules and ligands, including those that involve large conformational changes.
Background
Vitamin D has immune‐modulating effects. We determined whether vitamin D supplementation during pregnancy and infancy prevents aeroallergen sensitization and primary care respiratory ...illness presentations.
Methods
A randomized, double‐blind, placebo‐controlled parallel‐group trial. We assigned pregnant women, from 27‐week gestation to birth, and then their infants, from birth to 6 months, to placebo or one of two dosages of daily oral vitamin D. Woman/infant pairs were randomized to: placebo/placebo, 1000 IU/400 IU or 2000 IU/800 IU. When the children were 18 months old, we measured serum‐specific IgE antibodies and identified acute primary care visits described by the doctor to be due to a cold, otitis media, an upper respiratory infection, croup, asthma, bronchitis, bronchiolitis, a wheezy lower respiratory infection or fever and cough.
Results
Specific IgE was measured on 185 of 260 (71%) enrolled children. The proportion of children sensitized differed by study group for four mite antigens: Dermatophagoides farinae (Der‐f1, Der‐f2) and Dermatophagoides pteronyssinus (Der‐p1, Der‐p2). With results presented for placebo, lower dose, and higher dose vitamin D, respectively (all P < 0.05): Der‐f1 (18%, 10%, 2%), Der‐f2 (14%, 3%, 2%), Der‐p1 (19%, 14%, 3%) and Der‐p2 (12%, 2%, 3%). There were study group differences in the proportion of children with primary care visits described by the doctor as being for asthma (11%, 0%, 4%, P = 0.002), but not for the other respiratory diagnoses.
Conclusions
Vitamin D supplementation during pregnancy and infancy reduces the proportion of children sensitized to mites at age 18 months. Preliminary data indicate a possible effect on primary care visits where asthma is diagnosed.
Each B-cell receptor consists of a pair of heavy and light chains. High-throughput sequencing can identify large numbers of heavy- and light-chain variable regions (V(H) and V(L)) in a given B-cell ...repertoire, but information about endogenous pairing of heavy and light chains is lost after bulk lysis of B-cell populations. Here we describe a way to retain this pairing information. In our approach, single B cells (>5 × 10(4) capacity per experiment) are deposited in a high-density microwell plate (125 pl/well) and lysed in situ. mRNA is then captured on magnetic beads, reverse transcribed and amplified by emulsion V(H):V(L) linkage PCR. The linked transcripts are analyzed by Illumina high-throughput sequencing. We validated the fidelity of V(H):V(L) pairs identified by this approach and used the method to sequence the repertoire of three human cell subsets-peripheral blood IgG(+) B cells, peripheral plasmablasts isolated after tetanus toxoid immunization and memory B cells isolated after seasonal influenza vaccination.
The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very ...early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 2.5‐4.4 versus 1.6 1.5‐1.8). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)
Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone ...affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.
We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.
Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68;
= 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23-3.16;
= 0.005.
Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.
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