Role of heme oxygenase-1 in Salmonella iron acquisition within hemophagocytic macrophages

Salmonella enterica serotype Typhimurium (STm) is a Gram-negative bacterial pathogen that causes chronic infection in mammals. During chronic infections, STm preferentially reside in hemophagocytic macrophages (HMs). HMs are a unique type of macrophage that engulf and degrade viable cells of the hematopoietic lineage, such as erythrocytes. Heme, a major component of erythrocyte hemoglobin, is degraded by the host enzyme heme oxygenase-1 (HO-1) resulting in free iron. It is unclear how STm preferentially replicates in HMs, however, we hypothesize that free iron originating from degrading erythrocytes promotes STm replication. To examine if iron promotes STm replication, STm was grown in the presence of degraded erythrocytes and replication was monitored by growth curves. In minimal media, STm replication was augmented in the presence of degraded erythrocytes. Additionally, cell culture assays were utilized to determine STm replication in the presence of added iron, an iron chelator, and an HO-1 inhibitor. Supplementing cell culture non-HMs with free iron increased STm replication, while chelating iron in HMs decreased STm replication. Inhibition of HO-1 activity also decreased STm replication in HMs suggesting that products released from heme breakdown enhance STm replication. Collectively, these results demonstrate that free iron released from HO-1-mediated breakdown of heme contributes to STm replication in HMs (Figure 1)

Betta Less Motivated: Effects of Fluoxetine on Betta Splendens

Previous studies have demonstrated that the selective serotonin reuptake inhibitor (SSRI) Fluoxetine reduces aggression in Siamese fighting fish (Betta splendens). While this finding has been replicated across multiple studies, the behavioral mechanism of Fluoxetine\u27s action upon aggression is not known. Betta splendens are great candidates for Fluoxetine exposure based on their well documented seratonergic activity as well as their choice for agressive opportunities. In particular, Fluoxetine may produce its anti-aggressive effects by altering the motivational component of aggressive responding in Betta splendens or through the sedation of motoric activity. To examine this hypothesis a maze swimming task for access to aggressive oppurtunities was designed. Results from this task indicated that Fluoxetine exposures reduce the appetitive properties of the aggressive encounters and provide evidence for a role of serotonin in the control of motivational processes. The results leave room for discussion of the impacts of antidepressant medications used by humans

We are failing to improve the evidence base for “Exercise Referral”: How a Physical Activity Referral Scheme Taxonomy can help

Abstract not available

Exercise on Referral – Symposium hosted by the Physical Activity Special Interest Group of the Wolfson Research Institute for Health and Wellbeing, Durham University

THE Physical Activity Special Interest Group of the Wolfson Research Insti- tute for Health and Wellbeing (Durham University) hosted a symposium focused on exercise referral schemes (ERS), on 14 October 2016 at the College of St Hild and St Bede, Durham. Exercise referral schemes typically allow health professionals, such as general practitioners, nurses and physiotherapists to refer inactive individuals with long-term health conditions to a third party leisure provider for a supervised exercise programme, with the aim of increasing physical activity levels. The symposium was lively and thought-provoking with pres- entations divided into two core themes: ‘Emerging Evidence for ERS’ and ‘Future Developments for ERS’

Accessing the Curricular Play of Critical and Creative Thinking

A three-year collaborative research project in a K–6 elementary school is underway. The collaboration entails participating educators and their students exploring curricular enactment that embraces critical and creative thinking within its conduct. This article reveals whole-school efforts over Year One to build educators’ and students’ confidence to do so, sustaining such curricular practices. Chronicled as a case study, narrative inquiry fittingly unfolds the particularities encountered within the specifics of the case during Year One. Educators’ belief in the worthiness of curricular play, as well as concretely negotiating critical and creative thinking with their students, arises as a necessary issue to address in order to invest in the research intents over three years. The integral role of participants’ commitments to professional growth through curricular play and experimentation, actively seeking resources, entering wholly into curricular-making efforts, conversing sincerely with colleagues through inquiry conversations, and seeking organizational structures that support and strengthen curricular-making efforts, are found to be key to fostering the pedagogically oriented context needed to grow and sustain project intents

Penalized wavelet monotone regression

In this paper we focus on nonparametric estimation of a constrained regression function using penalized wavelet regression techniques. This results into a convex op- timization problem under linear constraints. Necessary and sufficient conditions for existence of a unique solution are discussed. The estimator is easily obtained via the dual formulation of the optimization problem. In particular we investigate a penalized wavelet monotone regression estimator. We establish the rate of convergence of this estimator, and illustrate its finite sample performance via a simulation study. We also compare its performance with that of a recently proposed constrained estimator. An illustration to some real data is given

A modified Delphi study to gain consensus for a taxonomy to report and classify physical activity referral schemes (PARS)

Background: Physical Activity Referral Schemes (PARS), including exercise referral schemes, are a popular approach to health improvement, but understanding of effectiveness is limited by considerable heterogeneity in reporting and evaluation. We aimed to gain consensus for a PARS taxonomy as a comprehensive method for reporting and recording of such schemes. Methods: We invited 62 experts from PARS policy, research and practice to complete a modified Delphi study. In round one, participants rated the need for a PARS taxonomy, the suitability of three proposed classification levels and commented on proposed elements. In round two, participants rated proposed taxonomy elements on an 11-point Likert scale. Elements scoring a median of ≥7, indicating high agreement, were included in the final taxonomy. Results: Of those invited, 47 (75.8%) participated in round one, with high retention in round two (n = 43; 91.5%). 42 were UK-based, meaning the resultant taxonomy has been scrutinised for fit to the UK context only. The study gained consensus for a three-level taxonomy: Level 1: PARS classification (primary classification, provider, setting, conditions accepted [have or at risk of], activity type and funding). Level 2: scheme characteristics (staff structure, staff qualifications, behaviour change theories, behaviour change techniques, referral source, referrers, referral process, scheme duration, session frequency, session length, session times, session type, exit routes, action in case of non-attendance, baseline assessment, exit assessment, feedback to referrer and exclusion criteria) and Level 3: participant measures (demographics, monitoring and evaluation, and measures of change). Conclusion: Using a modified Delphi method, this study developed UK-based consensus on a PARS classification taxonomy. We encourage PARS practitioners and public health colleagues, especially those working with similar service models internationally, to test, refine and use this taxonomy to inform policy and practice

Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence

Background: Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI. Methods: The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented. Results: The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI. Conclusions: The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit. Clinical Trials Registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II)

Metathesis Cascade Strategies (ROM-RCM-CM): A DOS approach to Skeletally Diverse Sultams

The development of a ring-opening metathesis/ring-closing metathesis/cross metathesis (ROM-RCM-CM) cascade strategy to the synthesis of a diverse collection of bi- and tricyclic sultams is reported. In this study, functionalized sultam scaffolds derived from intramolecular Diels-Alder (IMDA) reactions undergo metathesis cascades to yield a collection tricyclic sultams. Additional appendage based diversity was achieved by utilizing a variety of CM partners

LOCATE: a mammalian protein subcellular localization database

LOCATE is a curated, web-accessible database that houses data describing the membrane organization and subcellular localization of mouse and human proteins. Over the past 2 years, the data in LOCATE have grown substantially. The database now contains high-quality localization data for 20% of the mouse proteome and general localization annotation for nearly 36% of the mouse proteome. The proteome annotated in LOCATE is from the RIKEN FANTOM Consortium Isoform Protein Sequence sets which contains 58 128 mouse and 64 637 human protein isoforms. Other additions include computational subcellular localization predictions, automated computational classification of experimental localization image data, prediction of protein sorting signals and third party submission of literature data. Collectively, this database provides localization proteome for individual subcellular compartments that will underpin future systematic investigations of these regions. It is available at http://locate.imb.uq.edu.au