Identification of Small-Molecule Inhibitors against Meso-2, 6-Diaminopimelate Dehydrogenase from Porphyromonas gingivalis

Species-specific antimicrobial therapy has the potential to combat the increasing threat of antibiotic resistance and alteration of the human microbiome. We therefore set out to demonstrate the beginning of a pathogen-selective drug discovery method using the periodontal pathogen Porphyromonas gingivalis as a model. Through our knowledge of metabolic networks and essential genes we identified a “druggable” essential target, meso-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a high-throughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivaliswas first expressed and purified in Escherichia coli then characterized for enzymatic inhibitor screening studies. Several inhibitors with similar structural scaffolds containing a sulfonamide core and aromatic substituents showed dose-dependent inhibition. These compounds were further assayed showing reasonable whole-cell activity and the inhibition mechanism was determined. We conclude that the establishment of this target and screening strategy provides a model for the future development of new antimicrobials

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Towards a better future for Canadians with bipolar disorder:principles and implementation of a community-based participatory research model

The Collaborative RESearch Team to study psychosocial factors in bipolar disorder (CREST.BD) is a multidisciplinary network dedicated to advancing science and practice around psychosocial issues associated with bipolar disorder (BD), improving the care and wellness of people living with bipolar disorder, and strengthening services and supports for these individuals. CREST.BD specializes in community-based participatory research, in which research is conducted as a partnership between researchers and community members. This article describes the evolution of the CREST.BD network and CREST.BD’s commitment to community-based participatory research in bipolar disorder research. Examples of CREST.BD projects using community-based participatory research to study stigma, quality of life, psychosocial interventions, and creativity in bipolar disorder are highlighted, and opportunities and challenges of engaging in community-based participatory research in bipolar disorder specifically and the mental health field more broadly are discussed. This article demonstrates how CBPR can be used to enhance the relevance of research practices and products through community engagement, and how community-based participatory research can enrich knowledge exchange and mobilization

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Brief Report

Dysregulation of microRNA-21 (miR-21) is independently associated with HIV infection, pulmonary arterial hypertension (PAH), and hepatitis C virus (HCV) infection. To assess the expression of miR-21 in these overlapping comorbidities, we measured plasma miR-21 in HIV with and without PAH and then stratified by concomitant HCV infection. MiR-21 was increased in HIV and HIV-PAH versus uninfected subjects, but it did not differ between these groups. HIV/HCV coinfection correlated with even higher miR-21 levels within the HIV-infected population. These data reveal specific regulation of plasma miR-21 in HIV, HIV/HCV coinfection, and PAH and suggest that miR-21 may integrate complex disease-specific signaling in the setting of HIV infection

Do salivary bypass tubes lower the incidence of pharyngocutaneous fistula following total laryngectomy? A retrospective analysis of predictive factors using multivariate analysis

Salivary bypass tubes (SBT) are increasingly used to prevent pharyngocutaneous fistula (PCF) following laryngectomy and pharyngolaryngectomy. There is minimal evidence as to their efficacy and literature is limited. The aim of the study was to determine if SBT prevent PCF. The study was a multicentre retrospective case control series (level of evidence 3b). Patients who underwent laryngectomy or pharyngolaryngectomy for cancer or following cancer treatment between 2011 and 2014 were included in the study. The primary outcome was development of a PCF. Other variables recorded were age, sex, prior radiotherapy or chemoradiotherapy, prior tracheostomy, type of procedure, concurrent neck dissection, use of flap reconstruction, use of prophylactic antibiotics, the suture material used for the anastomosis, tumour T stage, histological margins, day one post-operative haemoglobin and whether a salivary bypass tube was used. Univariate and multivariate analysis were performed. A total of 199 patients were included and 24 received salivary bypass tubes. Fistula rates were 8.3% in the SBT group (2/24) and 24.6% in the control group (43/175). This was not statistically significant on univariate (p value 0.115) or multivariate analysis (p value 0.076). In addition, no other co-variables were found to be significant. No group has proven a benefit of salivary bypass tubes on multivariate analysis. The study was limited by a small case group, variations in tube duration and subjects given a tube may have been identified as high risk of fistula. Further prospective studies are warranted prior to recommendation of salivary bypass tubes following laryngectomy

Using theatre to address mental illness stigma: a knowledge translation study in bipolar disorder

Publisher's version/PDFBackground: Reduction of the stigma of mental illness is an international priority; arts- and contact-based approaches represent a promising mode of intervention. This project was designed to explore the impact of a one-woman theatrical performance on attitudes towards bipolar disorder (BD) on people with BD and healthcare providers. Methods: A playwright and actress who lives with BD developed a stage performance - ‘That’s Just Crazy Talk’ - targeting stigmatizing attitudes towards BD. Prospective, longitudinal and sequential mixed methods were used to assess the impact of the performance on people with BD (n = 80) and healthcare providers (n = 84). Qualitative interviews were conducted with 33 participants (14 people with BD and 19 healthcare providers). Results and Discussion: Quantitatively, healthcare providers showed significantly improved attitudes immediately post-performance, but this change was not maintained over time; people with BD showed little quantitative change. Qualitatively, both people with BD and BD healthcare providers showed enduring and broadly positive changes. A theatrical presentation designed to reduce stigma produced immediate impact on healthcare providers quantitatively and significant qualitative impact on people with BD and healthcare providers. Additionally, the utility of using mixed-method approaches in mental health research was demonstrated

Immune cell deconvolution reveals possible association of γδ T cells with poor survival in head and neck squamous cell carcinoma

(1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and rare immune cell subtypes and survival outcomes in HNSCC. (2) Methods: In this cohort study, we utilized a deconvolution approach based on the CIBERSORT algorithm and the LM22 signature matrix to infer proportions of immune cell subtypes from 517 patients with untreated HPV-negative HNSCC from The Cancer Genome Atlas. We performed univariate and multivariable survival analysis, integrating immune cell proportions with clinical, pathologic, and genomic data. (3) Results: We reliably deconvolved 22 immune cell subtypes in most patients and found that the most common immune cell types were M0 macrophages, M2 macrophages, and memory resting CD4 T cells. In the multivariable analysis, we identified advanced N stage and the presence of γδ T cells as independently predictive of poorer survival. (4) Conclusions: We uncovered that γδ T cells in the tumor microenvironment were a negative predictor of survival among patients with untreated HNSCC. Our findings underscore the need to better understand the role of γδ T cells in HNSCC, including potential pro-tumorigenic mechanisms, and whether their presence may predict the need for alternative therapy approaches

Minimum information and guidelines for reporting a Multiplexed Assay of Variant Effect

Multiplexed Assays of Variant Effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines has led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs