Tox21Enricher-Shiny: an R Shiny application for toxicity functional annotation analysis

Inference of toxicological and mechanistic properties of untested chemicals through structural or biological similarity is a commonly employed approach for initial chemical characterization and hypothesis generation. We previously developed a web-based application, Tox21Enricher-Grails, on the Grails framework that identifies enriched biological/toxicological properties of chemical sets for the purpose of inferring properties of untested chemicals within the set. It was able to detect significantly overrepresented biological (e.g., receptor binding), toxicological (e.g., carcinogenicity), and chemical (e.g., toxicologically relevant chemical substructures) annotations within sets of chemicals screened in the Tox21 platform. Here, we present an R Shiny application version of Tox21Enricher-Grails, Tox21Enricher-Shiny, with more robust features and updated annotations. Tox21Enricher-Shiny allows users to interact with the web application component (available at http://hurlab.med.und.edu/Tox21Enricher/) through a user-friendly graphical user interface or to directly access the application’s functions through an application programming interface. This version now supports InChI strings as input in addition to CASRN and SMILES identifiers. Input chemicals that contain certain reactive functional groups (nitrile, aldehyde, epoxide, and isocyanate groups) may react with proteins in cell-based Tox21 assays: this could cause Tox21Enricher-Shiny to produce spurious enrichment analysis results. Therefore, this version of the application can now automatically detect and ignore such problematic chemicals in a user’s input. The application also offers new data visualizations, and the architecture has been greatly simplified to allow for simple deployment, version control, and porting. The application may be deployed onto a Posit Connect or Shiny server, and it uses Postgres for database management. As other Tox21-related tools are being migrated to the R Shiny platform, the development of Tox21Enricher-Shiny is a logical transition to use R’s strong data analysis and visualization capacities and to provide aesthetic and developmental consistency with other Tox21 applications developed by the Division of Translational Toxicology (DTT) at the National Institute of Environmental Health Sciences (NIEHS)

Genome-Wide RNAi Screen Identifies Regulators of Cardiomyocyte Necrosis

Regulation of cellular death is central to nearly all physiological routines and is dysregulated in virtually all diseases. Cell death occurs by two major processes, necrosis which culminates in a pervasive inflammatory response and apoptosis which is largely immunologically inert. As necrosis has long been considered an accidental, unregulated form of cellular death that occurred in response to a harsh environmental stimulus, it was largely ignored as a clinical target. However, recent elegant studies suggest that certain forms of necrosis can be reprogrammed. However, scant little is known about the molecules and pathways that orchestrate calcium-overload-induced necrosis, a main mediator of ischemia/reperfusion (IR)-induced cardiomyocyte cell death. To rectify this critical gap in our knowledge, we performed a novel genome-wide siRNA screen to identify modulators of calcium-induced necrosis in human muscle cells. Our screen identified multiple molecular circuitries that either enhance or inhibit this process, including lysosomal calcium channel TPCN1, mitophagy mediatorTOMM7, Ran-binding protein RanBP9, Histone deacetylase HDAC2, chemokine CCL11, and the Arp2/3 complex regulator glia maturation factor-γ(GMFG). Notably, a number of druggable enzymes were identified, including the proteasome β5 subunit (encoded by PSMB5 gene), which controls the proteasomal chymotrypsin-like peptidase activity. Such findings open up the possibility for the discovery of pharmacological interventions that could provide therapeutic benefits to patients affected by myriad disorders characterized by excessive (or too little) necrotic cell loss, including but not limited to IR injury in the heart and kidney, chronic neurodegenerative disorders, muscular dystrophies, sepsis, and cancers

NO PLIF Visualizations of the Orion Capsule in LENS-I

Planar laser-induced fluorescence (PLIF) of nitric oxide (NO) was used to visualize the interaction of reaction-control-system (RCS) jet flows in the wake of a hypersonic capsule reentry vehicle. The tests were performed at the Calspan University at Buffalo Research Center's (CUBRC) LENS-I reflected shock tunnel facility. This was the first application of PLIF to study RCS jets in a large-scale pulsed hypersonic facility. The LENS-I facility allowed RCS jet flows to be studied while varying the flow enthalpy, Reynolds number, angle of attack and jet configuration. The interaction of pitch and roll jets with the flowfield was investigated. Additionally, thin film sensors were used to monitor heat transfer on the surface of the model to detect any localized heating resulting from the firing of the RCS jets. Tests were conducted with the model held at angles of attack of 18deg and 22deg. The nominal Mach number in all tests was 8, while Reynolds number based on model diameter ranged from 2.2x10(exp 6) - 1.5x10(exp 7). Images were processed using the Virtual Diagnostics Interface (ViDI) system developed at NASA Langley Research Center to provide a three-dimensional display of the experimental data

Workplace Contextual Supports for LGBT Employees: A Review, Meta‐Analysis, and Agenda for future Research

The past decade has witnessed a rise in the visibility of the lesbian, gay, bisexual, and transgender (LGBT) community. This has resulted in some organizational researchers focusing their attention on workplace issues facing LGBT employees. While empirical research has been appropriately focused on examining the impact of workplace factors on the work lives of LGBT individuals, no research has examined these empirical relationships cumulatively. The purpose of this study was to conduct a comprehensive review and meta‐analysis of the outcomes associated with three workplace contextual supports (formal LGBT policies and practices, LGBT‐supportive climate, and supportive workplace relationships) and to compare the relative influence of these workplace supports on outcomes. Outcomes were grouped into four categories: (a) work attitudes, (b) psychological strain, (c) disclosure, and (d) perceived discrimination. Results show that supportive workplace relationships were more strongly related to work attitudes and strain, whereas LGBT supportive climate was more strongly related to disclosure and perceived discrimination compared to the other supports. Our findings also revealed a number of insights concerning the measurement, research design, and sample characteristics of the studies in the present review. Based on these results, we offer an agenda for future research

Adipose Tissue Serves as a Reservoir for Recrudescent Rickettsia prowazekii Infection in a Mouse Model

Brill-Zinsser disease, the relapsing form of epidemic typhus, typically occurs in a susceptible host years or decades after the primary infection; however, the mechanisms of reactivation and the cellular reservoir during latency are poorly understood. Herein we describe a murine model for Brill-Zinsser disease, and use PCR and cell culture to show transient rickettsemia in mice treated with dexamethasone >3 months after clinical recovery from the primary infection. Treatment of similarly infected mice with cyclosporine failed to produce recrudescent bacteremia. Therapy with doxycycline for the primary infection prevented recrudescent bacteremia in most of these mice following treatment with dexamethasone. Rickettsia prowazekii (the etiologic agent of epidemic typhus) was detected by PCR, cell culture, and immunostaining methods in murine adipose tissue, but not in liver, spleen, lung, or central nervous system tissues of mice 4 months after recovery from the primary infection. The lungs of dexamethasone-treated mice showed impaired expression of β-defensin transcripts that may be involved in the pathogenesis of pulmonary lesions. In vitro, R. prowazekii rickettsiae infected and replicated in the murine adipocyte cell line 3T3-L1. Collectively these data suggest a role for adipose tissue as a potential reservoir for dormant infections with R. prowazekii

Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice

Pit1 null (Snell dwarf) and Proph1 null (Ames dwarf) mutant mice lack GH, PRL and TSH. Snell and Ames dwarf mice also exhibit reduced IGF-I, resistance to cancer and a longer lifespan than control mice. Endogenous glucose production during fasting is reduced in Snell dwarf mice compared to fasting control mice. In view of cancer cell dependence on glucose for energy, low endogenous glucose production may provide Snell dwarf mice with resistance to cancer. We investigated whether endogenous glucose production is lower in Snell dwarf mice during feeding. Inhibition of endogenous glucose production by glucose injection was enhanced in 12 to 14 month-old female Snell dwarf mice. Thus, we hypothesize that lower endogenous glucose production during feeding and fasting reduces cancer cell glucose utilization providing Snell dwarf mice with resistance to cancer. The elevation of circulating adiponectin, a hormone produced by adipose tissue, may contribute to the suppression of endogenous glucose production in 12 to 14 month-old Snell dwarf mice. We compared the incidence of cancer at time of death between old Snell dwarf and control mice. Only 18% of old Snell dwarf mice had malignant lesions at the time of death compared to 82% of control mice. The median ages at death for old Snell dwarf and control mice were 33 and 26 months, respectively. By contrast, previous studies showed a high incidence of cancer in old Ames dwarf mice at the time of death. Hence, resistance to cancer in old Snell dwarf mice may be mediated by neuroendocrine factors that reduce glucose utilization besides elevated adiponectin, reduced IGF-I and a lack of GH, PRL and TSH, seen in both Snell and Ames dwarf mice. Proteomics analysis of pituitary secretions from Snell dwarf mice confirmed the absence of GH and PRL, the secretion of ACTH and elevated secretion of Chromogranin B and Secretogranin II. Radioimmune assays confirmed that circulating Chromogranin B and Secretogranin II were elevated in 12 to 14 month-old Snell dwarf mice. In summary, our results in Snell dwarf mice suggest that the pituitary gland and adipose tissue are part of a neuroendocrine loop that lowers the risk of cancer during aging by reducing the availability of glucose

Intensity modulated radiotherapy (IMRT) in the treatment of children and Adolescents - a single institution's experience and a review of the literature

<p>Abstract</p> <p>Background</p> <p>While IMRT is widely used in treating complex oncological cases in adults, it is not commonly used in pediatric radiation oncology for a variety of reasons. This report evaluates our 9 year experience using stereotactic-guided, inverse planned intensity-modulated radiotherapy (IMRT) in children and adolescents in the context of the current literature.</p> <p>Methods</p> <p>Between 1999 and 2008 thirty-one children and adolescents with a mean age of 14.2 years (1.5 - 20.5) were treated with IMRT in our department. This heterogeneous group of patients consisted of 20 different tumor entities, with Ewing's sarcoma being the largest (5 patients), followed by juvenile nasopharyngeal fibroma, esthesioneuroblastoma and rhabdomyosarcoma (3 patients each). In addition a review of the available literature reporting on technology, quality, toxicity, outcome and concerns of IMRT was performed.</p> <p>Results</p> <p>With IMRT individualized dose distributions and excellent sparing of organs at risk were obtained in the most challenging cases. This was achieved at the cost of an increased volume of normal tissue receiving low radiation doses. Local control was achieved in 21 patients. 5 patients died due to progressive distant metastases. No severe acute or chronic toxicity was observed.</p> <p>Conclusion</p> <p>IMRT in the treatment of children and adolescents is feasible and was applied safely within the last 9 years at our institution. Several reports in literature show the excellent possibilities of IMRT in selective sparing of organs at risk and achieving local control. In selected cases the quality of IMRT plans increases the therapeutic ratio and outweighs the risk of potentially increased rates of secondary malignancies by the augmented low dose exposure.</p

Patient involvement in improving the evidence base on mental health inpatient care: the PERCEIVE programme

BackgroundDespite the movement towards care in the community, 40% of the NHS budget on mental health care is still attributed to inpatient services. However, long before the Francis Report highlighted grave shortcomings in inpatient care, there were reports by service user groups on the poor quality of these services in mental health. The programme provides a particular focus on the inclusion of the patient’s perspective in the development and evaluation of evidence.ObjectivesTo understand how changes to inpatient care affect the perceptions of the ward by service users and staff by using stakeholder participatory methods.DesignThe programme consisted of four work packages (WPs). (1) Lasting Improvements for Acute Inpatient SEttings (LIAISE): using participatory methods we developed two new scales [Views On Therapeutic Environment (VOTE) for staff and Views On Inpatient CarE (VOICE) for service users]. (2) Client Services Receipt Inventory – Inpatient (CITRINE): working with nurses and service users we developed a health economic measure of the amount of contact service users have with staff. The self-report measure records interactions with staff as well as the number of therapeutic activities attended. (3) Delivering Opportunities for Recovery (DOORWAYS): a stepped-wedge randomised controlled trial to test if training ward nurses to deliver therapeutic group activities would improve the perception of the ward by service users and staff. A total of 16 wards were progressively randomised and we compared the VOICE, VOTE and CITRINE measures before and after the intervention. A total of 1108 service users and 539 staff participated in this trial. (4) Bringing Emergency TreatmenT to Early Resolution (BETTER PATHWAYS) was an observational study comparing two service systems. The first was a ‘triage’ system in which service users were admitted to the triage ward and then either transferred to their locality wards or discharged back into the community within 7 days. The second system was routine care. We collected data from 454 service users and 284 nurses on their perceptions of the wards.Main outcome measuresThe main outcomes for the DOORWAYS and BETTER project were service user and staff perceptions of the ward (VOICE and VOTE, respectively) and the health economic measure was CITRINE. All were developed in WPs 1 and 2.ResultsWe developed reliable and valid measures of (1) the perceptions of inpatient care from the perspectives of service users and nurses (VOICE and VOTE) and (2) costs of interactions that were valued by service users (CITRINE). In the DOORWAYS project, after adjusting for legal status, we found weak evidence for benefit (standardised effect of –0.18, 95% CI 0.38 improvement to 0.01 deterioration; p = 0.062). There was only a significant benefit for involuntary patients following the staff training (N582, standardised effect of –0.35, 95% CI –0.57 to –0.12; p = 0.002; interaction p-value 0.006). VOTE scores did not change over time (standardised effect size of 0.04, 95% CI –0.09 to 0.18; p = 0.54). We found no evidence of an improvement in cost-effectiveness (estimated effect of £33, 95% CI –£91 to £146; p = 0.602), but resource allocation did change towards patient-perceived meaningful contacts by an average of £12 (95% CI –£76 to £98; p = 0·774). There were no significant differences between the triage and routine models of admission in terms of better perceptions by service users (estimated effect 0.77-point improvement in VOICE score on the triage ward; p = 0.68) or nurses (estimated effect of 1.68-point deterioration in VOTE on the triage ward; p = 0.38) or in terms of the cost of the length of care provided (£391 higher on triage; p = 0.77).Strengths and limitationsWe have developed measures using methods involving both service users and staff from mental health services. The measures were developed specifically for acute inpatient services and, therefore, cannot be assumed to be useful for other services. For instance, extensions of the measures are under construction for use in mother and baby units. The strength of the BETTER PATHWAYS and DOORWAYS projects is the large-scale data collection. However, we were testing specific services based in inner city areas and stretching to inner urban areas. It may be that different effects would be found in more rural communities or in different types of inpatient care.Future workOur database will be used to develop an understanding of the mediating and moderating factors for improving care quality.Trial registrationCurrent Controlled Trials ISRCTN06545047.FundingThis project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 6, No. 7. See the NIHR Journals Library website for further project information

Are High Performance Work Practices (HPWPs) enabling or disabling? Exploring the relationship between selected HPWPs and work-related disability disadvantage

We develop the organizational characteristics element of Stone and Colella’s (1996) framework by drawing on the Ability-Motivation-Opportunity (AMO) model to assess the relationship between High Performance Work Practices (HPWPs) and work-related disability disadvantage. We develop competing ‘enabling’ and ‘disabling’ hypotheses concerning the influence of selected HPWPs (competency testing, performance appraisal, individual performance-related pay, teamworking and functional flexibility) on disabled relative to nondisabled employees. An empirical assessment of these competing hypotheses using matched employer-employee data from the nationally representative British Workplace Employment Relations Study 2011 reveals a negative relationship between these HPWPs when used in combination and the proportion of disabled employees at the workplace, although this relationship disappears in workplaces with a wide range of disability equality practices. Although disabled employees report lower work-related well-being than their non-disabled counterparts we find limited evidence that this is associated with the presence of HPWPs