Membrane localization of the NlpC/P60 family protein EGL-26 correlates with regulation of vulval cell morphogenesis in Caenorhabditis elegans

AbstractVulval morphogenesis in Caenorhabditis elegans generates a stack of toroidal cells enclosing a tubular lumen. Mutation of egl-26 is associated with malformation of vulF, the most dorsal toroid in the stack, resulting in a blocked lumen and an egg-laying defect. Here we present evidence that vulF retains the expected gene expression pattern, functions in signaling to the uterus and retains proper polarity when egl-26 is mutated, all suggesting that mutation of egl-26 specifically results in aberrant morphogenesis as opposed to abnormal fate specification. Recent computational analysis indicates that EGL-26, which was previously characterized as novel, belongs to the LRAT (lecithin retinol acyltransferase) subfamily of the NlpC/P60 superfamily of catalytic proteins. Via site-directed mutagenesis, we demonstrate a requirement of the putative catalytic residues for EGL-26 function in vivo. We also show that mutation of conserved serine 275 perturbs the apical membrane localization and the function of the EGL-26 protein. Additional mutagenesis of this residue suggests that EGL-26 attains its membrane localization via a mechanism distinct from that of LRAT

Morphogenesis of the vulva and the vulval-uterine connection

The C. elegans hermaphrodite vulva is an established model system to study mechanisms of cell fate specification and tissue morphogenesis. The adult vulva is a tubular shaped organ composed of seven concentric toroids that arise from selective fusion between differentiated vulval progeny. The dorsal end of the vulval tubule is connected to the uterus via a multinucleate syncytium utse (uterine-seam) cell. The vulval tubule and utse are formed as a result of changes in morphogenetic processes such as cell polarity, adhesion, and invagination. A number of genes controlling these processes are conserved all the way up to human and function in similar developmental contexts. This makes it possible to extend the findings to other metazoan systems. Gene expression studies in the vulval and uterine cells have revealed the presence of regulatory networks specifying distinct cell fates. Thus, these two cell types serve as a good system to understand how gene networks confer unique cell identities both experimentally and computationally. This chapter focuses on morphogenetic processes during the formation of the vulva and its connection to uterus

An unexpectedly high degree of specialization and a widespread involvement in sterol metabolism among the C. elegans putative aminophospholipid translocases

<p>Abstract</p> <p>Background</p> <p>P-type ATPases in subfamily IV are exclusively eukaryotic transmembrane proteins that have been proposed to directly translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from the exofacial to the cytofacial monolayer of the plasma membrane. Eukaryotic genomes contain many genes encoding members of this subfamily. At present it is unclear why there are so many genes of this kind per organism or what individual roles these genes perform in organism development.</p> <p>Results</p> <p>We have systematically investigated expression and developmental function of the six, <it>tat-1 </it>through <it>6</it>, subfamily IV P-type ATPase genes encoded in the <it>Caenorhabditis elegans </it>genome. <it>tat-5 </it>is the only ubiquitously-expressed essential gene in the group. <it>tat-6 </it>is a poorly-transcribed recent duplicate of <it>tat-5</it>. <it>tat-2 </it>through <it>4 </it>exhibit tissue-specific developmentally-regulated expression patterns. Strong expression of both <it>tat-2 </it>and <it>tat-4 </it>occurs in the intestine and certain other cells of the alimentary system. The two are also expressed in the uterus, during spermatogenesis and in the fully-formed spermatheca. <it>tat-2 </it>alone is expressed in the pharyngeal gland cells, the excretory system and a few cells of the developing vulva. The expression pattern of <it>tat-3 </it>is almost completely different from those of <it>tat-2 </it>and <it>tat-4</it>. <it>tat-3 </it>expression is detectable in the steroidogenic tissues: the hypodermis and the XXX cells, as well as in most cells of the pharynx (except gland), various tissues of the reproductive system (except uterus and spermatheca) and seam cells. Deletion of <it>tat-1 </it>through <it>4 </it>individually interferes little or not at all with the regular progression of organism growth and development under normal conditions. However, <it>tat-2 </it>through <it>4 </it>become essential for reproductive growth during sterol starvation.</p> <p>Conclusion</p> <p><it>tat-5 </it>likely encodes a housekeeping protein that performs the proposed aminophospholipid translocase function routinely. Although individually dispensable, <it>tat-1 </it>through <it>4 </it>seem to be at most only partly redundant. Expression patterns and the sterol deprivation hypersensitivity deletion phenotype of <it>tat-2 </it>through <it>4 </it>suggest that these genes carry out subtle metabolic functions, such as fine-tuning sterol metabolism in digestive or steroidogenic tissues. These findings uncover an unexpectedly high degree of specialization and a widespread involvement in sterol metabolism among the genes encoding the putative aminophospholipid translocases.</p

Morphogenesis of the vulva and the vulval-uterine connection

The C. elegans hermaphrodite vulva is an established model system to study mechanisms of cell fate specification and tissue morphogenesis. The adult vulva is a tubular shaped organ composed of seven concentric toroids that arise from selective fusion between differentiated vulval progeny. The dorsal end of the vulval tubule is connected to the uterus via a multinucleate syncytium utse (uterine-seam) cell. The vulval tubule and utse are formed as a result of changes in morphogenetic processes such as cell polarity, adhesion, and invagination. A number of genes controlling these processes are conserved all the way up to human and function in similar developmental contexts. This makes it possible to extend the findings to other metazoan systems. Gene expression studies in the vulval and uterine cells have revealed the presence of regulatory networks specifying distinct cell fates. Thus, these two cell types serve as a good system to understand how gene networks confer unique cell identities both experimentally and computationally. This chapter focuses on morphogenetic processes during the formation of the vulva and its connection to uterus

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men