NMDA receptor genotypes associated with the vulnerability to develop dyskinesia

Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl--aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism

Assessment of effectiveness measures in patients with schizophrenia initiated on risperidone long-acting therapy: the SOURCE study results

<p>Abstract</p> <p>Background</p> <p>To evaluate effectiveness outcomes in a real-world setting in patients with schizophrenia initiating risperidone long-acting therapy (RLAT).</p> <p>Methods</p> <p>This was a 24-month, multicenter, prospective, longitudinal, observational study in patients with schizophrenia who were initiated on RLAT. Physicians could change treatment during the study as clinically warranted. Data were collected at baseline and subsequently every 3 months up to 24 months. Effectiveness outcomes included changes in illness severity as measured by Clinical Global Impression-Severity (CGI-S) scale; functional scores as measured by Personal and Social Performance (PSP) scale, Global Assessment of Functioning (GAF), and Strauss-Carpenter Levels of Functioning (LOF); and health status (Medical Outcomes Survey Short Form-36 [SF-36]). Life-table methodology was used to estimate the cumulative probability of relapse over time. Adverse events were evaluated for safety.</p> <p>Results</p> <p>532 patients were enrolled in the study; 209 (39.3%) completed the 24-month study and 305 (57.3%) had at least 12 months of follow-up data. The mean (SD) age of patients was 42.3 (12.8) years. Most patients were male (66.4%) and either Caucasian (60.3%) or African American (23.7%). All changes in CGI-S from baseline at each subsequent 3-month follow-up visit were statistically significant (<it>p </it>< .0001), indicating improvement in disease severity. Improvements were also noted for the PSP, GAF, and total LOF, indicating improvement in daily functioning and health outcome.</p> <p>Conclusions</p> <p>Patients with schizophrenia who were initiated on RLAT demonstrated improvements in measures of effectiveness within 3 months, which persisted over 24 months.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00246194">NCT00246194</a></p

Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis

© The Author(s) 2018In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants’ inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs.Peer reviewedFinal Published versio

A Functional Gene Array for Detection of Bacterial Virulence Elements

Emerging known and unknown pathogens create profound threats to public health. Platforms for rapid detection and characterization of microbial agents are critically needed to prevent and respond to disease outbreaks. Available detection technologies cannot provide broad functional information about known or novel organisms. As a step toward developing such a system, we have produced and tested a series of high-density functional gene arrays to detect elements of virulence and antibiotic resistance mechanisms. Our first generation array targets genes from Escherichia coli strains K12 and CFT073, Enterococcus faecalis and Staphylococcus aureus. We determined optimal probe design parameters for gene family detection and discrimination. When tested with organisms at varying phylogenetic distances from the four target strains, the array detected orthologs for the majority of targeted gene families present in bacteria belonging to the same taxonomic family. In combination with whole-genome amplification, the array detects femtogram concentrations of purified DNA, either spiked in to an aerosol sample background, or in combinations from one or more of the four target organisms. This is the first report of a high density NimbleGen microarray system targeting microbial antibiotic resistance and virulence mechanisms. By targeting virulence gene families as well as genes unique to specific biothreat agents, these arrays will provide important data about the pathogenic potential and drug resistance profiles of unknown organisms in environmental samples

Dynamic probe selection for studying microbial transcriptome with high-density genomic tiling microarrays

<p>Abstract</p> <p>Background</p> <p>Current commercial high-density oligonucleotide microarrays can hold millions of probe spots on a single microscopic glass slide and are ideal for studying the transcriptome of microbial genomes using a tiling probe design. This paper describes a comprehensive computational pipeline implemented specifically for designing tiling probe sets to study microbial transcriptome profiles.</p> <p>Results</p> <p>The pipeline identifies every possible probe sequence from both forward and reverse-complement strands of all DNA sequences in the target genome including circular or linear chromosomes and plasmids. Final probe sequence lengths are adjusted based on the maximal oligonucleotide synthesis cycles and best isothermality allowed. Optimal probes are then selected in two stages - sequential and gap-filling. In the sequential stage, probes are selected from sequence windows tiled alongside the genome. In the gap-filling stage, additional probes are selected from the largest gaps between adjacent probes that have already been selected, until a predefined number of probes is reached. Selection of the highest quality probe within each window and gap is based on five criteria: sequence uniqueness, probe self-annealing, melting temperature, oligonucleotide length, and probe position.</p> <p>Conclusions</p> <p>The probe selection pipeline evaluates global and local probe sequence properties and selects a set of probes dynamically and evenly distributed along the target genome. Unique to other similar methods, an exact number of non-redundant probes can be designed to utilize all the available probe spots on any chosen microarray platform. The pipeline can be applied to microbial genomes when designing high-density tiling arrays for comparative genomics, ChIP chip, gene expression and comprehensive transcriptome studies.</p

Determining solar effects in Neptune’s atmosphere

Long-duration observations of Neptune’s brightness in two visible wavelengths provide a disk-averaged estimate of its atmospheric aerosol. Brightness variations were previously associated with the 11-year solar cycle, through solar-modulated mechanisms linked with either ultra-violet (UV) or galactic cosmic ray (GCR) effects on atmospheric particles. Here we use a recently extended brightness dataset (1972-2014), with physically realistic modelling to show that rather than alternatives, UV and GCR are likely to be modulating Neptune’s atmosphere in combination. The importance of GCR is further supported by the response of Neptune's atmosphere to an intermittent 1.5 to 1.9 year periodicity, which occurred preferentially in GCR (not UV) during the mid-1980s. This periodicity was detected both at Earth, and in GCR measured by Voyager 2, then near Neptune. A similar coincident variability in Neptune’s brightness suggests nucleation onto GCR ions. Both GCR and UV mechanisms may occur more rapidly than the subsequent atmospheric particle transport

The importance of context: an exploration of factors influencing the adoption of student-centered teaching among chemistry, biology, and physics faculty

Background: Research at the secondary and postsecondary levels has clearly demonstrated the critical role that individual and contextual characteristics play in instructors’ decision to adopt educational innovations. Although recent research has shed light on factors influencing the teaching practices of science, technology, engineering, and mathematics (STEM) faculty, it is still not well understood how unique departmental environments impact faculty adoption of evidence-based instructional practices (EBIPs) within the context of a single institution. In this study, we sought to characterize the communication channels utilized by STEM faculty, as well as the contextual and individual factors that influence the teaching practices of STEM faculty at the departmental level. Accordingly, we collected survey and observational data from the chemistry, biology, and physics faculty at a single large research-intensive university in the USA. We then compared the influencing factors experienced by faculty in these different departments to their instructional practices. Results: Analyses of the survey data reveal disciplinary differences in the factors influencing adoption of EBIPs. In particular, the physics faculty (n = 15) had primarily student-centered views about teaching and experienced the most positive contextual factors toward adoption of EBIPs. At the other end of the spectrum, the chemistry faculty (n = 20) had primarily teacher-centered views and experienced contextual factors that hindered the adoption of student-centered practices. Biology faculty (n = 25) fell between these two groups. Classroom observational data reflected these differences: The physics classrooms were significantly more student-centered than the chemistry classrooms. Conclusions: This study demonstrates that disciplinary differences exist in the contextual factors teaching conceptions that STEM faculty experience and hold, even among faculty within the same institution. Moreover, it shows that these differences are associated to the level of adoption of student-centered teaching practices. This work has thus identified the critical need to carefully characterize STEM faculty’s departmental environment and conceptions about teaching before engaging in instructional reform efforts, and to adapt reform activities to account for these factors. The results of this study also caution the over generalization of findings from a study focused on one type of STEM faculty in one environment to all STEM faculty in any environment

Kinetics of Host Cell Recruitment During Dissemination of Diffuse Malignant Peritoneal Mesothelioma

Diffuse malignant mesothelioma is an aggressive tumor which displays a median survival of 11.2 months and a 5-year survival of less than 5% emphasizing the need for more effective treatments. This study uses an orthotopic model of malignant mesothelioma established in syngeneic, immunocompetent C57Bl/6 mice which produce malignant ascites and solid tumors that accurately replicate the histopathology of the human disease. Host stromal and immune cell accumulation within malignant ascites and solid tumors was determined using immunofluorescent labeling with confocal microscopy and fluorescence-activated cell sorting. An expression profile of cytokines and chemokines was produced using quantitative real-time PCR arrays. Tumor spheroids and solid tumors show progressive growth and infiltration with host stromal and immune cells including macrophages, endothelial cells, CD4+ and CD8+ lymphocytes, and a novel cell type, myeloid derived suppressor cells (MDSCs). The kinetics of host cell accumulation and inflammatory mediator expression within the tumor ascites divides tumor progression into two distinct phases. The first phase is characterized by progressive macrophage and T lymphocyte recruitment, with a cytokine profile consistent with regulatory T lymphocytes differentiation and suppression of T cell function. The second phase is characterized by decreased expression of macrophage chemotactic and T-cell regulating factors, an increase in MDSCs, and increased expression of several cytokines which stimulate differentiation of MDSCs. This cellular and expression profile suggests a mechanism by which host immune cells promote diffuse malignant mesothelioma progression

Increased incidence of rare codon clusters at 5' and 3' gene termini:implications for function

<p>Abstract</p> <p>Background</p> <p>The process of translation can be affected by the use of rare versus common codons within the mRNA transcript.</p> <p>Results</p> <p>Here, we show that rare codons are enriched at the 5' and 3' termini of genes from <it>E. coli </it>and other prokaryotes. Genes predicted to be secreted show significant enrichment in 5' rare codon clusters, but not 3' rare codon clusters. Surprisingly, no correlation between 5' mRNA structure and rare codon usage was observed.</p> <p>Conclusions</p> <p>Potential functional roles for the enrichment of rare codons at terminal positions are explored.</p

A Screen for Spore Wall Permeability Mutants Identifies a Secreted Protease Required for Proper Spore Wall Assembly

The ascospores of Saccharomyces cerevisiae are surrounded by a complex wall that protects the spores from environmental stresses. The outermost layer of the spore wall is composed of a polymer that contains the cross-linked amino acid dityrosine. This dityrosine layer is important for stress resistance of the spore. This work reports that the dityrosine layer acts as a barrier blocking the diffusion of soluble proteins out of the spore wall into the cytoplasm of the ascus. Diffusion of a fluorescent protein out of the spore wall was used as an assay to screen for mutants affecting spore wall permeability. One of the genes identified in this screen, OSW3 (RRT12/YCR045c), encodes a subtilisin-family protease localized to the spore wall. Mutation of the active site serine of Osw3 results in spores with permeable walls, indicating that the catalytic activity of Osw3 is necessary for proper construction of the dityrosine layer. These results indicate that dityrosine promotes stress resistance by acting as a protective shell around the spore. OSW3 and other OSW genes identified in this screen are strong candidates to encode enzymes involved in assembly of this protective dityrosine coat