Activity

JABFM seeks to widely disseminate its peer-reviewed publications, increasing article visibility for the purpose of advancing scientific knowledge. We describe the journal’s approach to dissemination and recommend a number of strategies for authors to implement, including press releases and social media. Providing the article’s digital object identifier (DOI) is most useful, compared with links that can break, or attaching the article PDF, which will depress reader metrics. All JABFM articles are freely accessible online worldwide. © Copyright 2020 by the American Board of Family Medicine.Family physician researchers continue to provide assistance to improve family medicine care. Commentaries on social determinants of health lead off this issue. Next, we have several papers on successful interventions by clinicians and/or patients to improve diabetes control, and then other provide information on other practice interventions that make a difference in overall care. Drug advertising continues to mislead. There is costly and nonproductive overuse of specific types of care. Herein is also a Scoping Review of possible indices for determining timely initiation of advance care planning. The issue’s clinical reviews on use of transgender care, cervical myelopathy, and inhaled steroids for chronic obstructive pulmonary disease are pertinent, thorough, and timely. © Copyright 2020 by the American Board of Family Medicine.Cells and tissues sense, respond to and translate mechanical forces into biochemical signals through mechanotransduction, which governs individual cell responses that drive gene expression, metabolic pathways and cell motility, and determines how cells work together in tissues. Mechanotransduction often depends on cytoskeletal networks and their attachment sites that physically couple cells to each other and to the extracellular matrix. One way that cells associate with each other is through Ca2+-dependent adhesion molecules called cadherins, which mediate cell-cell interactions through adherens junctions, thereby anchoring and organizing the cortical actin cytoskeleton. This actin-based network confers dynamic properties to cell sheets and developing organisms. However, these contractile networks do not work alone but in concert with other cytoarchitectural elements, including a diverse network of intermediate filaments. This Review takes a close look at the intermediate filament network and its associated intercellular junctions, desmosomes. Bobcat339 clinical trial We provide evidence that this system not only ensures tissue integrity, but also cooperates with other networks to create more complex tissues with emerging properties in sensing and responding to increasingly stressful environments. We will also draw attention to how defects in intermediate filament and desmosome networks result in both chronic and acquired diseases. © 2020. Published by The Company of Biologists Ltd.Over recent years, a plethora of new genetic tools has transformed conditional engineering of the malaria parasite genome, allowing functional dissection of essential genes in the asexual and sexual blood stages that cause pathology or are required for disease transmission, respectively. Important challenges remain, including the desirability to complement conditional mutants with a correctly regulated second gene copy to confirm that observed phenotypes are due solely to loss of gene function and to analyse structure-function relationships. To meet this challenge, here we combine the dimerisable Cre (DiCre) system with the use of multiple lox sites to simultaneously generate multiple recombination events of the same gene. We focused on the Plasmodium falciparum cGMP-dependent protein kinase (PKG), creating in parallel conditional disruption of the gene plus up to two allelic replacements. We use the approach to demonstrate that PKG has no scaffolding or adaptor role in intraerythrocytic development, acting solely at merozoite egress. We also show that a phosphorylation-deficient PKG is functionally incompetent. Our method provides valuable new tools for analysis of gene function in the malaria parasite. © 2020 Koussis et al.The function of Dicer’s helicase domain has been enigmatic since its discovery. Why do only some Dicers require ATP, despite a high degree of sequence conservation in their helicase domains? We discuss evolutionary considerations based on differences between vertebrate and invertebrate antiviral defense, and how the helicase domain has been co-opted in extant organisms as the binding site for accessory proteins. Many accessory proteins are double-stranded RNA binding proteins, and we propose models for how they modulate Dicer function and catalysis. © 2019 Hansen et al.; Published by Cold Spring Harbor Laboratory Press.Plant endogenous small RNAs (sRNAs) are important regulators of gene expression. There are two broad categories of plant sRNAs microRNAs (miRNAs) and endogenous short interfering RNAs (siRNAs). MicroRNA loci are relatively well-annotated but compose only a small minority of the total sRNA pool; siRNA locus annotations have lagged far behind. Here, we used a large data set of published and newly generated sRNA sequencing data (1333 sRNA-seq libraries containing more than 20 billion reads) and a uniform bioinformatic pipeline to produce comprehensive sRNA locus annotations of 47 diverse plants, yielding more than 2.7 million sRNA loci. The two most numerous classes of siRNA loci produced mainly 24- and 21-nucleotide (nt) siRNAs, respectively. Most often, 24-nt-dominated siRNA loci occurred in intergenic regions, especially at the 5′-flanking regions of protein-coding genes. In contrast, 21-nt-dominated siRNA loci were most often derived from double-stranded RNA precursors copied from spliced mRNAs. Genic 21-nt-dominated loci were especially common from disease resistance genes, including from a large number of monocots. Individual siRNA sequences of all types showed very little conservation across species, whereas mature miRNAs were more likely to be conserved. We developed a web server where our data and several search and analysis tools are freely accessible. © 2020 Lunardon et al.; Published by Cold Spring Harbor Laboratory Press.RNA-binding proteins (RNA-BPs) play critical roles in development and disease to regulate gene expression. However, genome-wide identification of their targets in primary human cells has been challenging. Here, we applied a modified CLIP-seq strategy to identify genome-wide targets of the FMRP translational regulator 1 (FMR1), a brain-enriched RNA-BP, whose deficiency leads to Fragile X Syndrome (FXS), the most prevalent inherited intellectual disability. We identified FMR1 targets in human dorsal and ventral forebrain neural progenitors and excitatory and inhibitory neurons differentiated from human pluripotent stem cells. In parallel, we measured the transcriptomes of the same four cell types upon FMR1 gene deletion. We discovered that FMR1 preferentially binds long transcripts in human neural cells. FMR1 targets include genes unique to human neural cells and associated with clinical phenotypes of FXS and autism. Integrative network analysis using graph diffusion and multitask clustering of FMR1 CLIP-seq and transcriptional targets reveals critical pathways regulated by FMR1 in human neural development. Our results demonstrate that FMR1 regulates a common set of targets among different neural cell types but also operates in a cell type-specific manner targeting distinct sets of genes in human excitatory and inhibitory neural progenitors and neurons. By defining molecular subnetworks and validating specific high-priority genes, we identify novel components of the FMR1 regulation program. Our results provide new insights into gene regulation by a critical neuronal RNA-BP in human neurodevelopment. © 2020 Li et al.; Published by Cold Spring Harbor Laboratory Press.OBJECTIVE To compare the treatment effect on lifestyle-related risk factors (LRFs) in older (≥65 years) versus younger ( less then 65 years) patients with coronary artery disease (CAD) in The Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists 2 (RESPONSE-2) trial. METHODS The RESPONSE-2 trial was a community-based lifestyle intervention trial (n=824) comparing nurse-coordinated referral with a comprehensive set of three lifestyle interventions (physical activity, weight reduction and/or smoking cessation) to usual care. In the current analysis, our primary outcome was the proportion of patients with improvement at 12 months follow-up (n=711) in ≥1 LRF stratified by age. RESULTS At baseline, older patients (n=245, mean age 69.2±3.9 years) had more adverse cardiovascular risk profiles and comorbidities than younger patients (n=579, mean age 53.7±6.6 years). There was no significant variation on the treatment effect according to age (p value treatment by age=0.45, OR 1.67, 95% CI 1.22 to 2.31). However, older patients were more likely to achieve ≥5% weight loss (OR old 5.58, 95% CI 2.77 to 11.26 vs OR young 1.57, 95% CI 0.98 to 2.49, p=0.003) and younger patients were more likely to show non-improved LRFs (OR old 0.38, 95% CI 0.22 to 0.67 vs OR young 0.88, 95% CI 0.61 to 1.26, p=0.01). CONCLUSION Despite more adverse cardiovascular risk profiles and comorbidities among older patients, nurse-coordinated referral to a community-based lifestyle intervention was at least as successful in improving LRFs in older as in younger patients. Higher age alone should not be a reason to withhold lifestyle interventions in patients with CAD. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.This review focuses on the available data regarding the utility of advanced left ventricular (LV) imaging in aortic stenosis (AS) and its potential impact for optimising the timing of aortic valve replacement. Ejection fraction is currently the only LV parameter recommended to guide intervention in AS. The cut-off value of 50%, recommended for decision-making in asymptomatic patients with AS, is currently under debate. Several imaging parameters have emerged as predictors of disease progression and clinical outcomes in this setting. Global longitudinal LV strain by speckle tracking echocardiography is useful for risk stratification of asymptomatic patients with severe AS and preserved LV ejection fraction. Its prognostic value was demonstrated in these patients, but further work is required to define the best thresholds to aid the decision-making process. The assessment of myocardial fibrosis is the most studied application of cardiac magnetic resonance in AS. The detection of replacement fibrosis by late gadolinium enhancement offers incremental prognostic information in these patients. Clinical implementation of this technique to optimise the timing of aortic valve intervention in asymptomatic patients is currently tested in a randomised trial. The use of T1 mapping techniques can provide an assessment of interstitial myocardial fibrosis and represents an expanding field of interest. However, convincing data in patients with AS is still lacking. All these imaging parameters have substantial potential to influence the management decision in patients with AS in the future, but data from randomised clinical trials are awaited to define their utility in daily practice. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.