Comparison Between Expression Microarrays and RNA-Sequencing Using UKBEC Dataset Identified a trans-eQTL Associated with MPZ Gene in Substantia Nigra

In recent years, the advantages of RNA-sequencing (RNA-Seq) have made it the platform of choice for measuring gene expression over traditional microarrays. However, RNA-Seq comes with bioinformatical challenges and higher computational costs. Therefore, this study set out to assess whether the increased depth of transcriptomic information facilitated by RNA-Seq is worth the increased computation over microarrays, specifically at three levels: absolute expression levels, differentially expressed genes identification, and expression QTL (eQTL) mapping in regions of the human brain. Using the United Kingdom Brain Expression Consortium (UKBEC) dataset, there is high agreement of gene expression levels measured by microarrays and RNA-seq when quantifying absolute expression levels and when identifying differentially expressed genes. These findings suggest that depending on the aims of a study, the relative ease of working with microarray data may outweigh the computational time and costs of RNA-Seq pipelines. On the other, there was low agreement when mapping eQTLs. However, a number of eQTLs associated with genes that play important roles in the brain were found in both platforms. For example, a trans-eQTL was mapped that is associated with the MPZ gene in the substantia nigra. These eQTLs that we have highlighted are extremely promising candidates that merit further investigation

Status of complete proteome analysis by mass spectrometry: SILAC labeled yeast as a model system

BACKGROUND: Mass spectrometry has become a powerful tool for the analysis of large numbers of proteins in complex samples, enabling much of proteomics. Due to various analytical challenges, so far no proteome has been sequenced completely. O'Shea, Weissman and co-workers have recently determined the copy number of yeast proteins, making this proteome an excellent model system to study factors affecting coverage. RESULTS: To probe the yeast proteome in depth and determine factors currently preventing complete analysis, we grew yeast cells, extracted proteins and separated them by one-dimensional gel electrophoresis. Peptides resulting from trypsin digestion were analyzed by liquid chromatography mass spectrometry on a linear ion trap-Fourier transform mass spectrometer with very high mass accuracy and sequencing speed. We achieved unambiguous identification of more than 2,000 proteins, including very low abundant ones. Effective dynamic range was limited to about 1,000 and effective sensitivity to about 500 femtomoles, far from the subfemtomole sensitivity possible with single proteins. We used SILAC (stable isotope labeling by amino acids in cell culture) to generate one-to-one pairs of true peptide signals and investigated if sensitivity, sequencing speed or dynamic range were limiting the analysis. CONCLUSION: Advanced mass spectrometry methods can unambiguously identify more than 2,000 proteins in a single proteome. Complex mixture analysis is not limited by sensitivity but by a combination of dynamic range (high abundance peptides preventing sequencing of low abundance ones) and by effective sequencing speed. Substantially increased coverage of the yeast proteome appears feasible with further development in software and instrumentation

Preference uncertainty accounts for developmental effects on susceptibility to peer influence in adolescence.

Adolescents are prone to social influence from peers, with implications for development, both adaptive and maladaptive. Here, using a computer-based paradigm, we replicate a cross-sectional effect of more susceptibility to peer influence in a large dataset of adolescents 14 to 24 years old. Crucially, we extend this finding by adopting a longitudinal perspective, showing that a within-person susceptibility to social influence decreases over a 1.5 year follow-up time period. Exploiting this longitudinal design, we show that susceptibility to social influences at baseline predicts an improvement in peer relations over the follow-up period. Using a Bayesian computational model, we demonstrate that in younger adolescents a greater tendency to adopt others' preferences arises out of a higher uncertainty about their own preferences in the paradigmatic case of delay discounting (a phenomenon called 'preference uncertainty'). This preference uncertainty decreases over time and, in turn, leads to a reduced susceptibility of one's own behaviour to an influence from others. Neuro-developmentally, we show that a measure of myelination within medial prefrontal cortex, estimated at baseline, predicts a developmental decrease in preference uncertainty at follow-up. Thus, using computational and neural evidence, we reveal adaptive mechanisms underpinning susceptibility to social influence during adolescence

Do topical repellents divert mosquitoes within a community? Health equity implications of topical repellents as a mosquito bite prevention tool.

OBJECTIVES: Repellents do not kill mosquitoes--they simply reduce human-vector contact. Thus it is possible that individuals who do not use repellents but dwell close to repellent users experience more bites than otherwise. The objective of this study was to measure if diversion occurs from households that use repellents to those that do not use repellents. METHODS: The study was performed in three Tanzanian villages using 15%-DEET and placebo lotions. All households were given LLINs. Three coverage scenarios were investigated: complete coverage (all households were given 15%-DEET), incomplete coverage (80% of households were given 15%-DEET and 20% placebo) and no coverage (all households were given placebo). A crossover study design was used and coverage scenarios were rotated weekly over a period of ten weeks. The placebo lotion was randomly allocated to households in the incomplete coverage scenario. The level of compliance was reported to be close to 100%. Mosquito densities were measured through aspiration of resting mosquitoes. Data were analysed using negative binomial regression models. FINDINGS: Repellent-users had consistently fewer mosquitoes in their dwellings. In villages where everybody had been given 15%-DEET, resting mosquito densities were fewer than half that of households in the no coverage scenario (Incidence Rate Ratio [IRR]=0.39 (95% confidence interval [CI]: 0.25-0.60); p<0.001). Placebo-users living in a village where 80% of the households used 15%-DEET were likely to have over four-times more mosquitoes (IRR=4.17; 95% CI: 3.08-5.65; p<0.001) resting in their dwellings in comparison to households in a village where nobody uses repellent. CONCLUSIONS: There is evidence that high coverage of repellent use could significantly reduce man-vector contact but with incomplete coverage evidence suggests that mosquitoes are diverted from households that use repellent to those that do not. Therefore, if repellents are to be considered for vector control, strategies to maximise coverage are required

The Association between serum cytokines and damage to large and small nerve fibers in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism

The simulation of action disorganisation in complex activities of daily living

Action selection in everyday goal-directed tasks of moderate complexity is known to be subject to breakdown following extensive frontal brain injury. A model of action selection in such tasks is presented and used to explore three hypotheses concerning the origins of action disorganisation: that it is a consequence of reduced top-down excitation within a hierarchical action schema network coupled with increased bottom-up triggering of schemas from environmental sources, that it is a more general disturbance of schema activation modelled by excessive noise in the schema network, and that it results from a general disturbance of the triggering of schemas by object representations. Results suggest that the action disorganisation syndrome is best accounted for by a general disturbance to schema activation, while altering the balance between top-down and bottom-up activation provides an account of a related disorder - utilisation behaviour. It is further suggested that ideational apraxia (which may result from lesions to left temporoparietal areas and which has similar behavioural consequences to action disorganisation syndrome on tasks of moderate complexity) is a consequence of a generalised disturbance of the triggering of schemas by object representations. Several predictions regarding differences between action disorganisation syndrome and ideational apraxia that follow from this interpretation are detailed

Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention

Background: A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders.&lt;p&gt;&lt;/p&gt; Aims: To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students.&lt;p&gt;&lt;/p&gt; Method: Students were recruited online (n = 1047, age: M = 21.8, SD = 4.2) and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n = 519) or a control intervention (n = 528) using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225). Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9) and Generalised Anxiety Disorder Scale (GAD7). Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes.&lt;p&gt;&lt;/p&gt; Results: Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (p&#60;.001, 95%CI [5.19, 1.98]) and anxiety scores by 2.87 (p = .018, 95%CI [1.31, 4.43]) in students at high risk. In high-risk students, between group effect sizes were 0.58 (depression) and 0.42 (anxiety). In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating.&lt;p&gt;&lt;/p&gt; Conclusions This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a promising way of preventing common mental disorders with a low-intensity intervention

Protein-DNA interactions define the mechanistic aspects of circle formation and insertion reactions in IS2 transposition

<p>Abstract</p> <p>Background</p> <p>Transposition in IS<it>3</it>, IS<it>30</it>, IS<it>21 </it>and IS<it>256 </it>insertion sequence (IS) families utilizes an unconventional two-step pathway. A figure-of-eight intermediate in Step I, from asymmetric single-strand cleavage and joining reactions, is converted into a double-stranded minicircle whose junction (the abutted left and right ends) is the substrate for symmetrical transesterification attacks on target DNA in Step II, suggesting intrinsically different synaptic complexes (SC) for each step. Transposases of these ISs bind poorly to cognate DNA and comparative biophysical analyses of SC I and SC II have proven elusive. We have prepared a native, soluble, active, GFP-tagged fusion derivative of the IS<it>2 </it>transposase that creates fully formed complexes with single-end and minicircle junction (MCJ) substrates and used these successfully in hydroxyl radical footprinting experiments.</p> <p>Results</p> <p>In IS2, Step I reactions are physically and chemically asymmetric; the left imperfect, inverted repeat (IRL), the exclusive recipient end, lacks donor function. In SC I, different protection patterns of the cleavage domains (CDs) of the right imperfect inverted repeat (IRR; extensive <it>in cis</it>) and IRL (selective <it>in trans</it>) at the single active cognate IRR catalytic center (CC) are related to their donor and recipient functions. In SC II, extensive binding of the IRL CD <it>in trans </it>and of the abutted IRR CD <it>in cis </it>at this CC represents the first phase of the complex. An MCJ substrate precleaved at the 3' end of IRR revealed a temporary transition state with the IRL CD disengaged from the protein. We propose that in SC II, sequential 3' cleavages at the bound abutted CDs trigger a conformational change, allowing the IRL CD to complex to its cognate CC, producing the second phase. Corroborating data from enhanced residues and curvature propensity plots suggest that CD to CD interactions in SC I and SC II require IRL to assume a bent structure, to facilitate binding <it>in trans</it>.</p> <p>Conclusions</p> <p>Different transpososomes are assembled in each step of the IS<it>2 </it>transposition pathway. Recipient versus donor end functions of the IRL CD in SC I and SC II and the conformational change in SC II that produces the phase needed for symmetrical IRL and IRR donor attacks on target DNA highlight the differences.</p

Fear and Courage in Children: Two Sides of the Same Coin?

This study further investigated the construct of courage in children. Children aged 8–13 years (n = 51) were interviewed about the most courageous action that they had ever performed during their life, and to retrospectively rate their level of fear and courage experienced during that event. On a separate occasion, children also completed the Courage Measure for Children (CM-C) as an index of children’s general level of personal courage, as well as scales for assessing anxiety symptoms and sensation seeking. Results indicated that almost all children (i.e., 94%) indicated that they had carried out a courageous action at some point during their life, although the levels of fear and courage associated with these acts varied considerably. Further, there was no relation between fear and courage reported for the courageous action, but these variables were significantly correlated with respectively anxiety symptoms and personal courage as indexed by the CM-C. Finally, a significant positive correlation was observed between sensation seeking and personal courage, indicating that children who are more thrill and adventure seeking are generally also more courageous. It is concluded that fear and courage in children are largely unrelated and not just two sides of the same coin. The implications of these results for the etiology and treatment of childhood anxiety problems are discussed