The nidogen-domain protein DEX-1 is necessary for the Caenorhabditis elegans dauer morphology and behavior

The ability to modify a given phenotype to adapt to the external environment (i.e. phenotypic plasticity) is a critical component of an organism’s ability to survive unfavorable conditions. The free-living nematode, Caenorhabditis elegans is an excellent example of phenotypic plasticity. When exposed to unfavorable conditions, C. elegans halts reproductive development and enters an alternative developmental stage called dauer. Dauer larvae undergo extensive tissue remodeling, including changes to the outer cuticle, muscle, and nervous system. Although several morphological and behavioral traits of the dauer larvae have been described, the molecular mechanisms underlying dauer-specific tissue remodeling have remained poorly understood. This work provides evidence that the nidogen domain-containing protein DEX-1 facilitates the stage-specific tissue remodeling observed during dauer morphogenesis. DEX-1 was previously shown to function as a secreted extracellular matrix protein that regulates sensory dendrite formation during embryogenesis. However, we found an alternative developmental role for DEX-1. Specifically, we show that DEX-1 is also required for remodeling of the stem-cell like hypodermal seam cells and formation of the cuticular lateral alae. Further, we found that DEX-1 is necessary for proper dauer mobility, and may function as a component of the neuromuscular system to facilitate dauer locomotion behaviors. We show that dex-1 is secreted from the seam cells, but functions locally in a cell-autonomous manner to facilitate dauer morphogenesis. dex-1 expression during dauer is also regulated through DAF-16/FOXO-mediated transcriptional activation. Finally, we show that dex-1 genetically interacts with a family of zona pellucida-domain genes to regulate seam cell remodeling and alae formation. Taken together, this work shows that DEX-1 is an extracellular matrix component that plays a critical role in C. elegans tissue plasticity during dauer formation

The nidogen-domain protein DEX-1 is necessary for the Caenorhabditis elegans dauer morphology and behavior

The ability to modify a given phenotype to adapt to the external environment (i.e. phenotypic plasticity) is a critical component of an organism’s ability to survive unfavorable conditions. The free-living nematode, Caenorhabditis elegans is an excellent example of phenotypic plasticity. When exposed to unfavorable conditions, C. elegans halts reproductive development and enters an alternative developmental stage called dauer. Dauer larvae undergo extensive tissue remodeling, including changes to the outer cuticle, muscle, and nervous system. Although several morphological and behavioral traits of the dauer larvae have been described, the molecular mechanisms underlying dauer-specific tissue remodeling have remained poorly understood. This work provides evidence that the nidogen domain-containing protein DEX-1 facilitates the stage-specific tissue remodeling observed during dauer morphogenesis. DEX-1 was previously shown to function as a secreted extracellular matrix protein that regulates sensory dendrite formation during embryogenesis. However, we found an alternative developmental role for DEX-1. Specifically, we show that DEX-1 is also required for remodeling of the stem-cell like hypodermal seam cells and formation of the cuticular lateral alae. Further, we found that DEX-1 is necessary for proper dauer mobility, and may function as a component of the neuromuscular system to facilitate dauer locomotion behaviors. We show that dex-1 is secreted from the seam cells, but functions locally in a cell-autonomous manner to facilitate dauer morphogenesis. dex-1 expression during dauer is also regulated through DAF-16/FOXO-mediated transcriptional activation. Finally, we show that dex-1 genetically interacts with a family of zona pellucida-domain genes to regulate seam cell remodeling and alae formation. Taken together, this work shows that DEX-1 is an extracellular matrix component that plays a critical role in C. elegans tissue plasticity during dauer formation

Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane

Plantazolicin (PZN) is a ribosomally synthesized and post-translationally modified natural product from Bacillus methylotrophicus FZB42 and Bacillus pumilus. Extensive tailoring to 12 of the 14 amino acid residues in the mature natural product endows PZN with not only a rigid, polyheterocyclic structure, but also antibacterial activity. Here we report the remarkably discriminatory activity of PZN toward Bacillus anthracis, which rivals a previously described gamma (γ) phage lysis assay in distinguishing <i>B. anthracis</i> from other members of the Bacillus cereus group. We evaluate the underlying cause of this selective activity by measuring the RNA expression profile of PZN-treated <i>B. anthracis</i>, which revealed significant up-regulation of genes within the cell envelope stress response. PZN depolarizes the <i>B. anthracis</i> membrane like other cell envelope-acting compounds but uniquely localizes to distinct foci within the envelope. Selection and whole-genome sequencing of PZN-resistant mutants of <i>B. anthracis</i> implicate a relationship between the action of PZN and cardiolipin (CL) within the membrane. Exogenous CL increases the potency of PZN in wild type <i>B. anthracis</i> and promotes the incorporation of fluorescently tagged PZN in the cell envelope. We propose that PZN localizes to and exacerbates structurally compromised regions of the bacterial membrane, which ultimately results in cell lysis

The structural and social determinants of Alzheimer\u27s disease related dementias

INTRODUCTION: The projected growth of Alzheimer\u27s disease (AD) and AD-related dementia (ADRD) cases by midcentury has expanded the research field and impelled new lines of inquiry into structural and social determinants of health (S/SDOH) as fundamental drivers of disparities in AD/ADRD. METHODS: In this review, we employ Bronfenbrenner\u27s ecological systems theory as a framework to posit how S/SDOH impact AD/ADRD risk and outcomes. RESULTS: Bronfenbrenner defined the macrosystem as the realm of power (structural) systems that drive S/SDOH and that are the root cause of health disparities. These root causes have been discussed little to date in relation to AD/ADRD, and thus, macrosystem influences, such as racism, classism, sexism, and homophobia, are the emphasis in this paper. DISCUSSION: Under Bronfenbrenner\u27s macrosystem framework, we highlight key quantitative and qualitative studies linking S/SDOH with AD/ADRD, identify scientific gaps in the literature, and propose guidance for future research. HIGHLIGHTS: Ecological systems theory links structural/social determinants to AD/ADRD. Structural/social determinants accrue and interact over the life course to impact AD/ADRD. Macrosystem is made up of societal norms, beliefs, values, and practices (e.g., laws). Most macro-level determinants have been understudied in the AD/ADRD literature

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London