Alternative Splicing Regulation During C. elegans Development: Splicing Factors as Regulated Targets

Alternative splicing generates protein diversity and allows for post-transcriptional gene regulation. Estimates suggest that 10% of the genes in Caenorhabditis elegans undergo alternative splicing. We constructed a splicing-sensitive microarray to detect alternative splicing for 352 cassette exons and tested for changes in alternative splicing of these genes during development. We found that the microarray data predicted that 62/352 (∼18%) of the alternative splicing events studied show a strong change in the relative levels of the spliced isoforms (>4-fold) during development. Confirmation of the microarray data by RT-PCR was obtained for 70% of randomly selected genes tested. Among the genes with the most developmentally regulated alternatively splicing was the hnRNP F/H splicing factor homolog, W02D3.11 – now named hrpf-1. For the cassette exon of hrpf-1, the inclusion isoform comprises 65% of hrpf-1 steady state messages in embryos but only 0.1% in the first larval stage. This dramatic change in the alternative splicing of an alternative splicing factor suggests a complex cascade of splicing regulation during development. We analyzed splicing in embryos from a strain with a mutation in the splicing factor sym-2, another hnRNP F/H homolog. We found that approximately half of the genes with large alternative splicing changes between the embryo and L1 stages are regulated by sym-2 in embryos. An analysis of the role of nonsense-mediated decay in regulating steady-state alternative mRNA isoforms was performed. We found that 8% of the 352 events studied have alternative isoforms whose relative steady-state levels in embryos change more than 4-fold in a nonsense-mediated decay mutant, including hrpf-1. Strikingly, 53% of these alternative splicing events that are affected by NMD in our experiment are not obvious substrates for NMD based on the presence of premature termination codons. This suggests that the targeting of splicing factors by NMD may have downstream effects on alternative splicing regulation

Routine Outcomes Monitoring to Support Improving Care for Schizophrenia: Report from the VA Mental Health QUERI

In schizophrenia, treatments that improve outcomes have not been reliably disseminated. A major barrier to improving care has been a lack of routinely collected outcomes data that identify patients who are failing to improve or not receiving effective treatments. To support high quality care, the VA Mental Health QUERI used literature review, expert interviews, and a national panel process to increase consensus regarding outcomes monitoring instruments and strategies that support quality improvement. There was very good consensus in the domains of psychotic symptoms, side-effects, drugs and alcohol, depression, caregivers, vocational functioning, and community tenure. There are validated instruments and assessment strategies that are feasible for quality improvement in routine practice

Noncanonical Compensation of Zygotic X Transcription in Early Drosophila melanogaster Development Revealed through Single-Embryo RNA-Seq

Mmany genes from the X chromosome are expressed at the same level in female and male embryos during early Drosophila development, prior to the establishment of MSL-mediated dosage compensation, suggesting the existence of a novel mechanism

Comprehensive Analysis Reveals Dynamic and Evolutionary Plasticity of Rab GTPases and Membrane Traffic in Tetrahymena thermophila

Cellular sophistication is not exclusive to multicellular organisms, and unicellular eukaryotes can resemble differentiated animal cells in their complex network of membrane-bound structures. These comparisons can be illuminated by genome-wide surveys of key gene families. We report a systematic analysis of Rabs in a complex unicellular Ciliate, including gene prediction and phylogenetic clustering, expression profiling based on public data, and Green Fluorescent Protein (GFP) tagging. Rabs are monomeric GTPases that regulate membrane traffic. Because Rabs act as compartment-specific determinants, the number of Rabs in an organism reflects intracellular complexity. The Tetrahymena Rab family is similar in size to that in humans and includes both expansions in conserved Rab clades as well as many divergent Rabs. Importantly, more than 90% of Rabs are expressed concurrently in growing cells, while only a small subset appears specialized for other conditions. By localizing most Rabs in living cells, we could assign the majority to specific compartments. These results validated most phylogenetic assignments, but also indicated that some sequence-conserved Rabs were co-opted for novel functions. Our survey uncovered a rare example of a nuclear Rab and substantiated the existence of a previously unrecognized core Rab clade in eukaryotes. Strikingly, several functionally conserved pathways or structures were found to be associated entirely with divergent Rabs. These pathways may have permitted rapid evolution of the associated Rabs or may have arisen independently in diverse lineages and then converged. Thus, characterizing entire gene families can provide insight into the evolutionary flexibility of fundamental cellular pathways

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Facilitators and barriers to the active participation of clients with serious mental illnesses in medication decision making: the perceptions of young adult clients

The active participation of young adults with serious mental illnesses (SMI) in making decisions about their psychotropic medications is beneficial to their care quality and overall health. Many however report not expressing treatment preferences to psychiatrists. Qualitative methods were used to interview 24 young adults with SMI about their experiences making medication decisions with their psychiatrists. An inductive analytic approach was taken to identifying conceptual themes in the transcripts. Respondents reported that the primary facilitators to active participation were the psychiatrist\u27s openness to the client\u27s perspective, the psychiatrist\u27s availability outside of office hours, the support of other mental health providers, and personal growth and self-confidence of the young adults. The primary barriers to active participation reported were the resistance of the psychiatrist, the lack of time for consultations, and limited client self-efficacy. Young adults with SMI can be active participants in making decisions about their psychiatric treatment

Job satisfaction of Department of Veterans Affairs peer mental health providers

OBJECTIVES: Department of Veterans Affairs (VA) peer specialists and vocational rehabilitation specialists are Veterans employed in mental health services to help other Veterans with similar histories and experiences. Study objectives were to (a) examine job satisfaction among these employees, (b) compare them to other VA mental health workers, and (c) identify factors associated with job satisfaction across the 3 cohorts. METHODS: The study sample included 152 VA-employed peer specialists and 222 vocational rehabilitation specialists. A comparison group included 460 VA employees from the same job categories. All participants completed the Job Satisfaction Index (11 aspects and overall satisfaction ratings). Linear regression was used to compare job satisfaction and identify its predictors among the 3 cohorts. RESULTS: Job satisfaction was fairly high, averaging somewhat satisfied to very satisfied in 6 (peer specialists) and 9 (vocational rehabilitation specialists) of the 11 aspects and overall job ratings. Adjusting for length of employment, age and gender resulted in no significant group differences with 2 exceptions: White peer specialists were less satisfied with pay and promotion opportunities than vocational rehabilitation specialists and comparison-group employees. Across all cohorts, shorter length of time employed in the job was associated with higher job satisfaction. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The high job satisfaction levels among the 2 peer cohorts suggest support for the policy of hiring peer specialists in the VA. Furthermore, the results are consistent with those of the nonveteran samples, indicating that integrating peer providers into mental health care is possible in VA and non-VA settings