Refining Protein Subcellular Localization

The study of protein subcellular localization is important to elucidate protein function. Even in well-studied organisms such as yeast, experimental methods have not been able to provide a full coverage of localization. The development of bioinformatic predictors of localization can bridge this gap. We have created a Bayesian network predictor called PSLT2 that considers diverse protein characteristics, including the combinatorial presence of InterPro motifs and protein interaction data. We compared the localization predictions of PSLT2 to high-throughput experimental localization datasets. Disagreements between these methods generally involve proteins that transit through or reside in the secretory pathway. We used our multi-compartmental predictions to refine the localization annotations of yeast proteins primarily by distinguishing between soluble lumenal proteins and soluble proteins peripherally associated with organelles. To our knowledge, this is the first tool to provide this functionality. We used these sub-compartmental predictions to characterize cellular processes on an organellar scale. The integration of diverse protein characteristics and protein interaction data in an appropriate setting can lead to high-quality detailed localization annotations for whole proteomes. This type of resource is instrumental in developing models of whole organelles that provide insight into the extent of interaction and communication between organelles and help define organellar functionality

Design, Implementation, and Evaluation of a Pharmacist-Led Outpatient Benzodiazepine-Tapering Clinic

Background Benzodiazepines are commonly used among older adults, despite well-known risks. Clinical pharmacists can lead tapering efforts, leveraging their clinical expertise and relieving time-pressured primary care providers. Objectives The objective of this study is to describe the design, implementation, and evaluation of an outpatient pharmacist-led benzodiazepine-tapering clinic. Practice description The clinic is based within a community medical group associated with a large academic health system in Los Angeles, California. Practice innovation The clinic is staffed by clinical pharmacists and supervised by a psychiatrist. The initial visit consists of patient education, design of patient-driven tapering schedule, and medical history review. Follow-up phone/video visits are used to monitor withdrawal symptoms and provide support. Evaluation methods We used chart review to assess tapering status among those enrolled in the tapering clinic versus those who did not enroll. We compared outcomes across the 2 groups using bivariate statistics. Results From March 2017 to May 2019, 176 patients were referred to the clinic; 17 were deemed ineligible. Of the 159 patients contacted, 62 patients enrolled in the clinic; 97 patients did not enroll. Among patients in the clinic, 13 (27%) of patients were tapered down, 29 (60%) completely tapered off, 6 (13%) were unable to taper, and 14 (23%) were in the process of tapering. In contrast, among patients who did not enroll, 3 (4%) of patients were tapered down, 15 (20%) completely tapered off, 57 (76%) were unable to taper, and 22 (22%) were in the process of tapering. Ninety percent of patients had at least some benzodiazepine tapering when enrolled in the clinic compared to 41% among not enrolled in the clinic (P\u3c0.001). Conclusion A pharmacist-led benzodiazepine-tapering clinic can be an effective way to engage patients motivated to taper down. Lessons learned include the importance of ensuring referring providers adequately counsel patients prior to referral

Inducing Partner Preference in Mice by Chemogenetic Stimulation of CA2 Hippocampal Subfield

Social recognition is fundamental for social decision making and the establishment of long-lasting affiliative behaviors in behaviorally complex social groups. It is a critical step in establishing a selective preference for a social partner or group member. C57BL/6J lab mice do not form monogamous relationships, and typically do not show prolonged social preferences for familiar mice. The CA2 hippocampal subfield plays a crucial role in social memory and optogenetic stimulation of inputs to the dorsal CA2 field during a short memory acquisition period can enhance and extend social memories in mice. Here, we show that partner preference in mice can be induced by chemogenetic selective stimulation of the monosynaptic projections from the hypothalamic paraventricular nucleus (PVN) to the CA2 during the cohabitation period. Specifically, male mice spend more time in social contact, grooming and huddling with the partner compared to a novel female. Preference was not induced by prolonging the cohabitation period and allowing more time for social interactions and males to sire pups with the familiar female. These results suggest that PVN-to-CA2 projections are part of an evolutionarily conserved neural circuitry underlying the formation of social preference and may promote behavioral changes with appropriate stimulation

Variation in abundance, diversity and composition of coral reef fishes with increasing depth at a submerged shoal in the northern Great Barrier Reef

Coral reef fishes often exhibit specific or restricted depth distributions, but the factors (biotic or abiotic) that influence patterns of depth use are largely unknown. Given inherent biological gradients with depth (i.e. light, nutrients, habitat, temperature), it is expected that fishes may exploit certain depths within their environment to seek out more favourable conditions. This study used baited remote underwater video (BRUV) systems to document variation in the taxonomic and functional (trophic and size) structure of a fish assemblage along a shallow to upper-mesophotic depth gradient (13–71 m) at a submerged, offshore shoal in the northern Great Barrier Reef. BRUVs were deployed during two separate time periods (February and August 2017), to separately examine patterns of depth use. Both the relative abundance and diversity of reef fishes declined with depth, and there were pronounced differences in the taxonomic and functional structure of the fish assemblage across the depth gradient. In shallow habitats ( 30 m) was dominated by piscivores and mobile invertivores. Depth and habitat type were also strong predictors for important fisheries species such as coral trout (Plectropomus spp.), emperors (Lethrinus spp.) and trevallies (Carangid spp.). We found limited evidence of temporal changes in depth and habitat use by fishes (including fisheries target species), although recorded temperatures were 4 °C higher in February 2017 compared to August 2017

Drink driving among Aboriginal and Torres Strait Islander Australians: what has been done and where to next?

The Australian Government will set the direction for addressing road safety over the next decade with its 2021–2030 National Road Safety Strategy. This road map will detail objectives and goals agreed upon by all Australian states and territories. Similar to previous national strategies, Aboriginal and Torres Strait Islander (Indigenous) Australians are a high priority population. Indigenous Australians are over-represented in serious injury and fatal road crashes, with alcohol a leading factor. Therapeutic and educational programs are a major strategy among the suite of measures designed to reduce and prevent drink driving in Australia. The release of this new strategy provides a timely opportunity to reflect on what is known about drink driving among Indigenous Australians and to consider the suitability of existing therapeutic and educational drink driving programs for Indigenous Australian contexts. Here, we summarise factors that contribute to drink driving in this population and identify outstanding knowledge gaps. Then, we present an overview of drink driving programs available for Indigenous Australians along with suggestions for why tailored programs are needed to suit local contexts. The response to address drink driving among Indigenous Australians has been fragmented Australia-wide. A coordinated national response, with ongoing monitoring and evaluation, would improve policy effectiveness and inform more efficient allocation of resources. Together this information can help create suitable and effective drink driving programs for Indigenous drivers and communities Australia-wide

Associations between atrial cardiopathy and cerebral amyloid: The ARIC-PET study

Background Atrial fibrillation (AF) is a risk factor for cognitive decline, possibly from silent brain infarction. Left atrial changes in structure or function (atrial cardiopathy) can lead to AF but may impact cognition independently. It is unknown if AF or atrial cardiopathy also acts on Alzheimer disease-specific mechanisms, such as deposition of β-amyloid. Methods and Results A total of 316 dementia-free participants from the ARIC (Atherosclerosis Risk in Communities) study underwent florbetapir positron emission tomography, electrocardiography, and 2-dimensional echocardiography. Atrial cardiopathy was defined as ≥1: (1) left atrial volume index \u3e34 mL/

Global profiling of alternative RNA splicing events provides insights into molecular differences between various types of hepatocellular carcinoma

Protein families encoded by transcripts that are differentially spliced in various types of HCC. Table S2. Bioinformatical prediction of functional changes caused by some of ASEs identified. Table S3. List of tumor suppressors for which AS is dysregulated in various types of HCC. Table S4. List of oncogenes for which AS is dysregulated in various types of HCC. Table S5. List of kinases for which AS is dysregulated in various types of HCC. Table S6. List of transcription factors for which AS is dysregulated in various types of HCC. Table S7. List of genes for which AS is dysregulated in all types of HCC. Table S8. List of genes uniquely dysregulated in HBV-associated HCC. Table S9. List of genes uniquely dysregulated in HCV-associated HCC. Table S10. List of genes uniquely dysregulated in HBV&HCV-associated HCC. Table S11. List of genes uniquely dysregulated in virus-free HCC. Figure S1. Characterization of splicing mysregulation in HCC. Figure S2. Characterization of ASEs that are modified in HBV- and HCV-associated HCC. Figure S3. AS modifications in transcripts encoded by kinases and transcriptions factores in HBV- and HCV-associated HCC. Figure S4. Global profiling of ASE modifications in both HBV&HCV-associated HCC and virus-free-associated HCC. Figure S5. RNA splicing factors in HCC. Figure S6. Modifications to AS of 96 transcripts in response to knockdown of splicing factors with specific siRNAs (PDF 6675 kb

Development stage-specific proteomic profiling uncovers small, lineage specific proteins most abundant in the Aspergillus Fumigatus conidial proteome

Background The pathogenic mold Aspergillus fumigatus is the most frequent infectious cause of death in severely immunocompromised individuals such as leukemia and bone marrow transplant patients. Germination of inhaled conidia (asexual spores) in the host is critical for the initiation of infection, but little is known about the underlying mechanisms of this process. Results To gain insights into early germination events and facilitate the identification of potential stage-specific biomarkers and vaccine candidates, we have used quantitative shotgun proteomics to elucidate patterns of protein abundance changes during early fungal development. Four different stages were examined: dormant conidia, isotropically expanding conidia, hyphae in which germ tube emergence has just begun, and pre-septation hyphae. To enrich for glycan-linked cell wall proteins we used an alkaline cell extraction method. Shotgun proteomic resulted in the identification of 375 unique gene products with high confidence, with no evidence for enrichment of cell wall-immobilized and secreted proteins. The most interesting discovery was the identification of 52 proteins enriched in dormant conidia including 28 proteins that have never been detected in the A. fumigatus conidial proteome such as signaling protein Pil1, chaperones BipA and calnexin, and transcription factor HapB. Additionally we found many small, Aspergillus specific proteins of unknown function including 17 hypothetical proteins. Thus, the most abundant protein, Grg1 (AFUA_5G14210), was also one of the smallest proteins detected in this study (M.W. 7,367). Among previously characterized proteins were melanin pigment and pseurotin A biosynthesis enzymes, histones H3 and H4.1, and other proteins involved in conidiation and response to oxidative or hypoxic stress. In contrast, expanding conidia, hyphae with early germ tubes, and pre-septation hyphae samples were enriched for proteins responsible for housekeeping functions, particularly translation, respiratory metabolism, amino acid and carbohydrate biosynthesis, and the tricarboxylic acid cycle. Conclusions The observed temporal expression patterns suggest that the A. fumigatus conidia are dominated by small, lineage-specific proteins. Some of them may play key roles in host-pathogen interactions, signal transduction during conidial germination, or survival in hostile environments

Disk Detective: Discovery of New Circumstellar Disk Candidates through Citizen Science

The Disk Detective citizen science project aims to find new stars with 22 micron excess emission from circumstellar dust using data from NASA's WISE mission. Initial cuts on the AllWISE catalog provide an input catalog of 277,686 sources. Volunteers then view images of each source online in 10 different bands to identify false-positives (galaxies, background stars, interstellar matter, image artifacts, etc.). Sources that survive this online vetting are followed up with spectroscopy on the FLWO Tillinghast telescope. This approach should allow us to unleash the full potential of WISE for finding new debris disks and protoplanetary disks. We announce a first list of 37 new disk candidates discovered by the project, and we describe our vetting and follow-up process. One of these systems appears to contain the first debris disk discovered around a star with a white dwarf companion: HD 74389. We also report four newly discovered classical Be stars (HD 6612, HD 7406, HD 164137, and HD 218546) and a new detection of 22 micron excess around a previously known debris disk host star, HD 22128.Comment: 50 pages, accepted for publication in the Astrophysical Journa