Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling.

Cells rely on the coordinated regulation of lipid phosphoinositides and Rab GTPases to define membrane compartment fates along distinct trafficking routes. The family of disease-related myotubularin (MTM) phosphoinositide phosphatases includes catalytically inactive members, or pseudophosphatases, with poorly understood functions. We found that Drosophila MTM pseudophosphatase Sbf coordinates both phosphatidylinositol 3-phosphate (PI(3)P) turnover and Rab21 GTPase activation in an endosomal pathway that controls macrophage remodeling. Sbf dynamically interacts with class II phosphatidylinositol 3-kinase and stably recruits Mtm to promote turnover of a PI(3)P subpool essential for endosomal trafficking. Sbf also functions as a guanine nucleotide exchange factor that promotes Rab21 GTPase activation associated with PI(3)P endosomes. Of importance, Sbf, Mtm, and Rab21 function together, along with Rab11-mediated endosomal trafficking, to control macrophage protrusion formation. This identifies Sbf as a critical coordinator of PI(3)P and Rab21 regulation, which specifies an endosomal pathway and cortical control

RNA-seq reveals post-transcriptional regulation of Drosophila insulin-like peptide dilp8 and the neuropeptide-like precursor Nplp2 by the exoribonuclease Pacman/XRN1

Ribonucleases are critically important in many cellular and developmental processes and defects in their expression are associated with human disease. Pacman/XRN1 is a highly conserved cytoplasmic exoribonuclease which degrades RNAs in a 5' - 3' direction. In Drosophila, null mutations in pacman result in small imaginal discs, a delay in onset of pupariation and lethality during the early pupal stage. In this paper, we have used RNA-seq in a genome-wide search for mRNAs misregulated in pacman null wing imaginal discs. Only 4.2% of genes are misregulated ±>2-fold in pacman null mutants compared to controls, in line with previous work showing that Pacman has specificity for particular mRNAs. Further analysis of the most upregulated mRNAs showed that Pacman post-transcriptionally regulates the expression of the secreted insulin-like peptide Dilp8. Dilp8 is related to human IGF-1, and has been shown to co-ordinate tissue growth with developmental timing in Drosophila. The increased expression of Dilp8 is consistent with the developmental delay seen in pacman null mutants. Our analysis, together with our previous results, show that the normal role of this exoribonuclease in imaginal discs is to suppress the expression of transcripts that are crucial in apoptosis and growth control during normal development

Meta-analysis of honey bee neurogenomic response links deformed wing virus type A to precocious behavioral maturation

Crop pollination by the western honey bee Apis mellifera is vital to agriculture but threatened by alarmingly high levels of colony mortality, especially in Europe and North America. Colony loss is due, in part, to the high viral loads of Deformed wing virus (DWV), transmitted by the ectoparasitic mite Varroa destructor, especially throughout the overwintering period of a honey bee colony. Covert DWV infection is commonplace and has been causally linked to precocious foraging, which itself has been linked to colony loss. Taking advantage of four brain transcriptome studies that unexpectedly revealed evidence of covert DWV-A infection, we set out to explore whether this effect is due to DWV-A mimicking naturally occurring changes in brain gene expression that are associated with behavioral maturation. Consistent with this hypothesis, we found that brain gene expression profiles of DWV-A infected bees resembled those of foragers, even in individuals that were much younger than typical foragers. In addition, brain transcriptional regulatory network analysis revealed a positive association between DWV-A infection and transcription factors previously associated with honey bee foraging behavior. Surprisingly, single-cell RNA-Sequencing implicated glia, not neurons, in this effect; there are relatively few glial cells in the insect brain and they are rarely associated with behavioral plasticity. Covert DWV-A infection also has been linked to impaired learning, which together with precocious foraging can lead to increased occurrence of infected bees from one colony mistakenly entering another colony, especially under crowded modern apiary conditions. These findings provide new insights into the mechanisms by which DWV-A affects honey bee health and colony survival

Advancing the Entry-Level Practitioner: A Curricular Model of the Professional Occupational Therapy Doctoral Degree

The recent growth of entry-level occupational therapy doctoral (EL-OTD) programs has been met with mixed opinions from both occupational therapy educators and practitioners. These opinions occasionally have been accompanied by uncertainty about the specific curricular components that differentiate the EL-OTD from the entry-level master’s degree. In an effort to address this uncertainty, the purpose of this article is to present one example of an EL-OTD curricular model and describe its distinct educational components. This curricular model integrates recommendations for doctoral education originally proposed by Case-Smith et al. (2014) and is characterized by the following three components: 1) Advanced Coursework; 2) the Doctoral Capstone Project; and 3) the Doctoral Capstone Experience. We share the lessons learned after matriculating three cohorts of EL-OTD students and describe influences from the field of implementation science that have informed the development of our curriculum

The Direct Medical Costs of Undiagnosed Chronic Obstructive Pulmonary Disease

AbstractObjectiveTo estimate the costs of undiagnosed chronic obstructive pulmonary disease (COPD) by describing inpatient, outpatient, and pharmacy utilization in the years before and after the diagnosis.MethodsA total of 6864 patients who were enrolled in the Lovelace Health Plan for at least 12 months during the study period (January 1, 1999 through December 31, 2004) were identified. The first date that utilization was attributed to COPD was considered the first date of diagnosis. Each COPD case was matched to up to three age- and sex-matched controls. All utilization and direct medical costs during the study period were compiled monthly and compared based on the time before and after the initial diagnosis.ResultsTotal costs were higher by an average of $1182 per patient in the 2 years before the initial COPD diagnosis, and$2489 in the 12 months just before the initial diagnosis, compared to matched controls. Most of the higher cost for undiagnosed COPD was attributable to hospitalizations. Inpatient costs did not increase after the diagnosis was made, but approximately one-third of admissions after the diagnosis were attributed to respiratory disease. Outpatient and pharmacy costs did not differ substantially between cases and matched controls until just a few months before the initial diagnosis, but remained 50% to 100% higher than for controls in the 2 years after diagnosis.ConclusionsUndiagnosed COPD has a substantial impact on health-care costs and utilization in this integrated managed care system, particularly for hospitalizations

Experiences and Attitudes of Genome Investigators Regarding Return of Individual Genetic Test Results

Purpose Whether and how to return individual genetic results to study participants is among the most contentious policy issues in contemporary genomic research. Methods: We surveyed corresponding authors of genome-wide association studies (GWAS), identified through the National Human Genome Research Institute's Catalog of Published GWAS, to describe the experiences and attitudes of these stakeholders. Results: Of 357 corresponding authors, 200 (56%) responded. One hundred twenty-six (63%) had been responsible for primary data and sample collection, whereas 74 (37%) had performed secondary analyses. Only 7 (4%) had returned individual results within their index GWAS. Most (69%) believed that return of results to individual participants was warranted under at least some circumstances. Most respondents identified a desire to benefit participants's health (63%) and respect for participants's; desires for information (57%) as major motivations for returning results. Most also identified uncertain clinical utility (76%), the possibility that participants will misunderstand results (74%), the potential for emotional harm (61%), the need to ensure access to trained clinicians (59%), and the potential for loss of confidentiality (51%) as major barriers to return. Conclusion: Investigators have limited experience returning individual results from genome-scale research, yet most are motivated to do so in at least some circumstances