New AMP-forming acid:CoA ligases from Streptomyces lividans, some of which are posttranslationally regulated by reversible lysine acetylation

In nature, organic acids are a commonly used source of carbon and energy. Many bacteria use AMP‐forming acid:CoA ligases to convert organic acids into their corresponding acyl‐CoA derivatives, which can then enter metabolism. The soil environment contains a broad diversity of organic acids, so it is not surprising that bacteria such as Streptomyces lividans can activate many of the available organic acids. Our group has shown that the activity of many acid:CoA ligases is posttranslationally controlled by acylation of an active‐site lysine. In some cases, the modification is reversed by deacylases of different types. We identified eight new acid:CoA ligases in S. lividans TK24. Here, we report the range of organic acids that each of these enzymes can activate, and determined that two of the newly identified CoA ligases were under NAD⁺‐dependent sirtuin deacylase reversible lysine (de)acetylation control, four were not acetylated by two acetyltransferases used in this work, and two were acetylated but not deacetylated by sirtuin. This work provides insights into the broad organic‐acid metabolic capabilities of S. lividans, and sheds light into the control of the activities of CoA ligases involved in the activation of organic acids in this bacterium

Terrainbento 1.0: a Python package for multi-model analysis in long-term drainage basin evolution

Models of landscape evolution provide insight into the geomorphic history of specific field areas, create testable predictions of landform development, demonstrate the consequences of current geomorphic process theory, and spark imagination through hypothetical scenarios. While the last 4 decades have brought the proliferation of many alternative formulations for the redistribution of mass by Earth surface processes, relatively few studies have systematically compared and tested these alternative equations. We present a new Python package, terrainbento 1.0, that enables multi-model comparison, sensitivity analysis, and calibration of Earth surface process models. Terrainbento provides a set of 28 model programs that implement alternative transport laws related to four process elements: hillslope processes, surface-water hydrology, erosion by flowing water, and material properties. The 28 model programs are a systematic subset of the 2048 possible numerical models associated with 11 binary choices. Each binary choice is related to one of these four elements &ndash; for example, the use of linear or nonlinear hillslope diffusion. Terrainbento is an extensible framework: base classes that treat the elements common to all numerical models (such as input/output and boundary conditions) make it possible to create a new numerical model without reinventing these common methods. Terrainbento is built on top of the Landlab framework such that new Landlab components directly support the creation of new terrainbento model programs. Terrainbento is fully documented, has 100 % unit test coverage including numerical comparison with analytical solutions for process models, and continuous integration testing. We support future users and developers with introductory Jupyter notebooks and a template for creating new terrainbento model programs. In this paper, we describe the package structure, process theory, and software implementation of terrainbento. Finally, we illustrate the utility of terrainbento with a benchmark example highlighting the differences in steady-state topography between five different numerical models.</p

Arid3b Is Critical for B Lymphocyte Development

Arid3a and Arid3b belong to a subfamily of ARID (AT-rich interaction domain) transcription factors. The Arid family is involved in regulating chromatin accessibility, proliferation, and differentiation. Arid3a and Arid3b are closely related and share a unique REKLES domain that mediates their homo- and hetero-multimerization. Arid3a was originally isolated as a B cell transcription factor binding to the AT rich matrix attachment regions (MARS) of the immunoglobulin heavy chain intronic enhancer. Deletion of Arid3a results in a highly penetrant embryonic lethality with severe defects in erythropoiesis and hematopoietic stem cells (HSCs). The few surviving Arid3a-/- (<1%) animals have decreased HSCs and early progenitors in the bone marrow, but all mature lineages are normally represented in the bone marrow and periphery except for B cells. Arid3b-/- animals die around E7.5 precluding examination of hematopoietic development. So it is unclear whether the phenotype of Arid3a loss on hematopoiesis is dependent or independent of Arid3b. In this study we circumvented this limitation by also examining hematopoiesis in mice with a conditional allele of Arid3b. Bone marrow lacking Arid3b shows decreased common lymphoid progenitors (CLPs) and downstream B cell populations while the T cell and myeloid lineages are unchanged, reminiscent of the adult hematopoietic defect in Arid3a mice. Unlike Arid3a-/- mice, HSC populations are unperturbed in Arid3b-/- mice. This study demonstrates that HSC development is independent of Arid3b, whereas B cell development requires both Arid3a and Arid3b transcription factors

Implementation of an e-Learning course in physical activity and sedentary behavior for pre- and in-service early childhood educators: Evaluation of the TEACH pilot study

Background: Childcare-based physical activity (PA) and sedentary behavior (SB) interventions have traditionally used in-person training to supplement early childhood educators’ (ECEs) knowledge and confidence to facilitate physically active programming for the children in their care. However, this method of delivery is resource-intensive and unable to reach a high number of ECEs. The purpose of the Training pre-service EArly CHildhood educators in PA (TEACH) pilot study was to test the implementation (e.g., fidelity, feasibility, acceptability) of an e-Learning course targeting PA and SB among a sample of pre-service (i.e., post-secondary students) and in-service (i.e., practicing) ECEs in Canada. Methods: A pre-/post-study design was adopted for this pilot study, and implementation outcomes were assessed cross-sectionally at post-intervention. Pre-service ECEs were purposefully recruited from three Canadian colleges and in-service ECEs were recruited via social media. Upon completing the e-Learning course, process evaluation surveys (n = 32 pre-service and 121 in-service ECEs) and interviews (n = 3 pre-service and 8 in-service ECEs) were completed to gather ECEs’ perspectives on the e-Learning course. Fidelity was measured via e-Learning course metrics retrieved from the web platform. Descriptive statistics were calculated for quantitative data, and thematic analysis was conducted to analyze qualitative data. Results: Moderate-to-high fidelity to the TEACH study e-Learning course was exhibited by pre-service (68%) and in-service (63%) ECEs. Participants reported that the course was highly acceptable, compatible, effective, feasible, and appropriate in complexity; however, some ECEs experienced technical difficulties with the e-Learning platform and noted a longer than anticipated course duration. The most enjoyed content for pre- and in-service ECEs focused on outdoor play (87.5% and 91.7%, respectively) and risky play (84.4% and 88.4%, respectively). Conclusions: These findings demonstrate the value of e-Learning for professional development interventions for ECEs. Participant feedback will be used to make improvements to the TEACH e-Learning course to improve scalability of this training

Change in pre- and in-service early childhood educators’ knowledge, self-efficacy, and intentions following an e-learning course in physical activity and sedentary behaviour: a pilot study

Background: Early childhood educators (ECEs) are the primary daytime role models for many young children, and are responsible for facilitating physical activity (PA) opportunities and minimizing sedentary behaviour (SB) in childcare. However, they have reportedly received little related education in their pre-service training. The purpose of the Training pre-service EArly CHildhood educators in physical activity (TEACH) pilot study was to explore changes in pre- and in-service ECEs’ knowledge, self-efficacy, behavioural intention, and perceived behavioural control following the TEACH e-Learning course in PA and SB. Methods: Pre-service ECEs were purposefully recruited from three Canadian colleges, while in-service ECEs were recruited via social media. A pre-post study design was used. ECEs completed two online surveys; one prior to, and one immediately following the completion of the TEACH e-Learning course (~ 5 h). Descriptive statistics were reported, and McNemar Chi-Square tests and paired samples t-tests were used to examine changes in ECEs’ question-specific, and total knowledge scores, respectively. Wilcoxon Signed Ranks tests were employed to examine changes in self-efficacy, behavioural intention, and perceived behavioural control. Results: Both pre- (n = 32) and in-service (n = 121) ECEs significantly increased their total knowledge scores from pre- to post-course completion (p \u3c.05*). Significant positive changes in self-efficacy (p \u3c.025*), behavioural intention (p \u3c.007*), and perceived behavioural control (p \u3c.007*) were demonstrated by in-service ECEs following course completion, while only select composite scores within these tools were significant among pre-service ECEs. Conclusions: These findings provide preliminary evidence of the potential efficacy of the e-Learning course at improving ECEs’ knowledge, self-efficacy, behavioural intention, and perceived behavioural control to support PA and minimize SB in childcare. Following the success of the pilot study, testing the effectiveness of the TEACH e-Learning course on a larger scale, with a comparison group, is warranted prior to recommending broader dissemination of the training in pre-service ECE programs and for in-service ECE professional learning

Training Pre-Service Early Childhood Educators in Physical Activity (TEACH): Protocol for a Quasi-Experimental Study

Background: Early childhood educators (ECEs) influence young children’s early uptake of positive health behaviours in childcare settings and serve as important daytime role models. As such, it is imperative that post-secondary early childhood education programs provide students with the foundational knowledge and professional training required to confidently facilitate quality active play opportunities for young children. The primary objective of the Training pre-service EArly CHildhood educators in physical activity (TEACH) study is to develop and implement an e-Learning course in physical activity and sedentary behaviour to facilitate improvements in: pre-service ECEs’ self-efficacy and knowledge to lead physical activity and outdoor play opportunities and minimize sedentary behaviours in childcare. This study will also explore pre-service ECEs’ behavioural intention and perceived control to promote physical activity and outdoor play, and minimize sedentary behaviour in childcare, and the implementation of the e-Learning course. Methods/Design: A mixed-methods quasi-experimental design with three data collection time points (baseline, post-course completion, 3-month follow-up) will be employed to test the e-Learning course in early childhood education programs (n = 18; 9 experimental, 9 comparison) across Canada. Pre-service ECEs enrolled in colleges/universities assigned to the experimental group will be required to complete a 4-module e-Learning course, while programs in the comparison group will maintain their typical curriculum. Pre-service ECEs’ self-efficacy, knowledge, as well as behavioural intention and perceived behavioural control will be assessed via online surveys and module completion rates will be documented using website metrics. Group differences across timepoints will be assessed using linear mixed effects modelling and common themes will be identified through thematic analysis. Discussion: The TEACH study represents a novel, evidence-informed approach to address the existing gap in physical activity and sedentary behaviour-related education in Canadian post-secondary early childhood education programs. Moreover, e-Learning platforms, can be employed as an innovative, standardized, and scalable way to provide ECEs with consistent training across jurisdictions

Implementation Science for the Prevention and Treatment of HIV among Adolescents and Young Adults in Sub-Saharan Africa: A Scoping Review.

Despite many evidence-based adolescent and young adult (AYA) HIV interventions, few are implemented at scale in sub-Saharan Africa (SSA). A growing implementation science literature provides important context for scaling up AYA HIV interventions in this high HIV-burden region. This scoping review examined the use of implementation research in AYA HIV studies conducted in SSA. We searched five databases and included articles which focused on AYA (10-24 years old), addressed HIV prevention or treatment, were conducted exclusively in SSA countries, and included an implementation science outcome. We included 44 articles in 13 SSA countries. Most were in East (52.3%) and South Africa (27.3%), and half focused exclusively on HIV prevention components of the care continuum. Acceptability and feasibility were the most cited implementation science outcomes. Only four articles used an established implementation science framework. The findings informed our recommendations to guide the design, implementation, and dissemination of further studies and health policymaking

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

A Neutralizing Monoclonal Antibody Targeting the Acid-Sensitive Region in Chikungunya Virus E2 Protects from Disease.

The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV