Disease-Associated Mutations Prevent GPR56-Collagen III Interaction

GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Using the N-terminal fragment of GPR56 (GPR56N) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56N, the ligand binding domain. This domain contains four disease-associated mutations and two N-glycosylation sites. Our study reveals that although glycosylation is not required for ligand binding, each of the four disease-associated mutations completely abolish the ligand binding ability of GPR56. Our data indicates that these four single missense mutations cause BFPP mostly by abolishing the ability of GPR56 to bind to its ligand, collagen III, in addition to affecting GPR56 protein surface expression as previously shown

Outcomes of Invasive and Noninvasive Ventilation in a Haitian Emergency Department

Background: Limited data exist on the outcomes of patients requiring invasive ventilation or noninvasive positive pressure ventilation (NIPPV) in low-income countries. To our knowledge, no study has investigated this topic in Haiti. Objectives: We describe the clinical epidemiology, treatment, and outcomes of patients requiring NIPPV or intubation in an emergency department (ED) in rural Haiti. Methods: This is an observational study utilizing a convenience sample of adult and pediatric patients requiring NIPPV or intubation in the ED at an academic hospital in central Haiti from January 2019–February 2021. Patients were prospectively identified at the time of clinical care. Data on demographics, clinical presentation, management, and ED disposition were extracted from patient charts using a standardized form and analyzed in SAS v9.4. The primary outcome was survival to discharge. Findings: Of 46 patients, 27 (58.7%) were female, mean age was 31 years, and 14 (30.4%) were pediatric (age <18 years). Common diagnoses were cardiogenic pulmonary edema, pneumonia/pulmonary sepsis, and severe asthma. Twenty-three (50.0%) patients were initially treated with NIPPV, with 4 requiring intubation; a total of 27 (58.7%) patients were intubated. Among those for whom intubation success was documented, first-pass success was 57.7% and overall success was 100% (one record missing data); intubation was associated with few immediate complications. Twenty-two (47.8%) patients died in the ED. Of the 24 patients who survived, 4 were discharged, 19 (intubation: 12; NIPPV: 9) were admitted to the intensive care unit or general ward, and 1 was transferred. Survival to discharge was 34.8% (intubation: 22.2%; NIPPV: 52.2%); 1 patient left against medical advice following admission. Conclusions: Patients with acute respiratory failure in this Haitian ED were successfully treated with both NIPPV and intubation. While overall survival to discharge remains relatively low, this study supports developing capacity for advanced respiratory interventions in low-resource settings

Loss of Col3a1, the Gene for Ehlers-Danlos Syndrome Type IV, Results in Neocortical Dyslamination

It has recently been discovered that Collagen III, the encoded protein of the type IV Ehlers-Danlos Syndrome (EDS) gene, is one of the major constituents of the pial basement membrane (BM) and serves as the ligand for GPR56. Mutations in GPR56 cause a severe human brain malformation called bilateral frontoparietal polymicrogyria, in which neurons transmigrate through the BM causing severe mental retardation and frequent seizures. To further characterize the brain phenotype of Col3a1 knockout mice, we performed a detailed histological analysis. We observed a cobblestone-like cortical malformation, with BM breakdown and marginal zone heterotopias in Col3a1−/− mouse brains. Surprisingly, the pial BM appeared intact at early stages of development but starting as early as embryonic day (E) 11.5, prominent BM defects were observed and accompanied by neuronal overmigration. Although collagen III is expressed in meningeal fibroblasts (MFs), Col3a1−/− MFs present no obvious defects. Furthermore, the expression and posttranslational modification of α-dystroglycan was undisturbed in Col3a1−/− mice. Based on the previous finding that mutations in COL3A1 cause type IV EDS, our study indicates a possible common pathological pathway linking connective tissue diseases and brain malformations

Theoretical and experimental foundations for some new ramifications of holography

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33440/1/0000843.pd

Personal Papers (MS 80-0002)

Letter from G. H. Strokes to Daniel W. Kempner enclosing a folder on their newest sprinkle

Tree-Ring Dates from the Navajo Land Claim IV. The Eastern Sector

The Eastern Sector of the Navajo Land Claim is located in the state of New Mexico, and is comprised of areas located across or adjacent to the Continental Divide. Of the 724 specimens processed in the Laboratory, 346 yield tree-ring dates.This item is part of the Tree-Ring Research (formerly Tree-Ring Bulletin) archive. It was digitized from a physical copy provided by the Laboratory of Tree-Ring research at The University of Arizona. For more information about this peer-reviewed scholarly journal, please email the Editor of Tree-Ring Research at [email protected]

Interview no. 544

Former Army Chief of Staff debates with Cleveland\u27s first Black Mayor and NBC Political analyst on defense spending and social programs. Included is a paper written by Kim Vernon based on the debate