Miracle-dz/UniFAR-FTUs huggingface dataset:
Cavβ3 Regulates Ca2+ Signaling and Insulin Expression in Pancreatic β-Cells in a Cell-Autonomous Manner

Voltage-gated Ca2+ (Cav) channels consist of a pore-forming Cavα1 subunit and auxiliary Cavα2-δ and Cavβ subunits. In fibroblasts, Cavβ3, independent of its role as a Cav subunit, reduces the sensitivity to low concentrations of inositol-1,4,5-trisphosphate (IP3). Similarly, Cavβ3 could affect cytosolic calcium concentration ([Ca2+]) in pancreatic β-cells. In this study, we deleted the Cavβ3-encoding gene Cacnb3 in insulin-secreting rat β-(Ins-1) cells using CRISPR/Cas9. These cells were used as controls to investigate the role of Cavβ3 on Ca2+ signaling, glucose-induced insulin secretion (GIIS), Cav channel activity, and gene expression in wild-type cells in which Cavβ3 and the IP3 receptor were coimmunoprecipitated. Transcript and protein profiling revealed significantly increased levels of insulin transcription factor Mafa, CaMKIV, proprotein convertase subtilisin/kexin type-1, and nitric oxide synthase-1 in Cavβ3-knockout cells. In the absence of Cavβ3, Cav currents were not altered. In contrast, CREB activity, the amount of MAFA protein and GIIS, the extent of IP3-dependent Ca2+ release and the frequency of Ca2+ oscillations were increased. These processes were decreased by the Cavβ3 protein in a concentration-dependent manner. Our study shows that Cavβ3 interacts with the IP3 receptor in isolated β-cells, controls IP3-dependent Ca2+-signaling independently of Cav channel functions, and thereby regulates insulin expression and its glucose-dependent release in a cell-autonomous manner.
Cortactin knockdown results in disruption of basal TBCs and alters turnover of Sertoli cell ESs in Rattus norvegicus

Abstract Here we explore the prediction that long-term knockdown of cortactin (CTTN), a component of tubulobulbar complexes (TBCs), disrupts TBCs in Sertoli cells and alters the turnover of basal ectoplasmic specializations (ESs). In rats, intratesticular injections of siRNA targeting CTTN (siCTTN) in one testis and nontargeting siRNA (siControl) in the contralateral testis were done on days 0, 2, 4, 6, and 8. The experiment was terminated on day 9 and testes were analyzed by either western blotting, or by stimulated emission depletion (STED), electron and/or conventional fluorescence microscopy. Levels of CTTN were successfully knocked down in experimental testes compared to controls. When cryo-sections were labeled for actin filaments, or CTTN, and oxysterol binding protein–related protein 9 (ORP9) and analyzed by STED microscopy, TBCs were “less distinct” than in tubules of the same stages from control testes. When analyzed by electron microscopy, redundant clumps of basal actin filament containing ESs were observed in experimental sections. Using labeling of actin filaments in ESs, thresholding techniques were used to calculate the number of pixels above threshold per unit length of tubule wall in seminiferous tubules at Stage VII. Median values were higher in experimental testes relative to controls in the four animals analyzed. Although we detected subtle differences in ES turnover, we were unable to demonstrate changes in spermatocyte translocation or in the levels of junction proteins at the sites. Our results are the first to demonstrate that perturbation of basal TBCs alters the turnover of actin-related junctions (ESs). Summary sentence Cortactin knockdown disrupts basal TBCs and perturbs basal ES turnover. Graphical Abstract
C–X–C motif chemokine ligand 12: a potential therapeutic target in Duchenne muscular dystrophy

ABSTRACT Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by a mutant dystrophin protein. DMD patients undergo gradual progressive paralysis until death. Chronic glucocorticoid therapy remains one of the main treatments for DMD, despite the significant side effects. However, its mechanisms of action remain largely unknown. We used bioinformatics tools to identify pathogenic genes involved in DMD and glucocorticoid target genes. Two gene expression profiles containing data from DMD patients and healthy controls (GSE38417 and GSE109178) were downloaded for further analysis. Differentially expressed genes (DEGs) between DMD patients and controls were identified using GEO2R, and glucocorticoid target genes were predicted from the Pharmacogenetics and Pharmacogenomics Knowledge Base. Surprisingly, only one gene, CXCL12 (C–X–C motif chemokine ligand 12), was both a glucocorticoid target and a DEG. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, Gene Ontology term enrichment analysis, and gene set enrichment analysis were performed. A protein–protein interaction network was constructed and hub genes identified using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape. Enriched pathways involving the DEGs, including CXCL12, were associated with the immune response and inflammation. Levels of CXCL12 and its receptor CXCR4 (C–X–C motif chemokine receptor 4) were increased in X-linked muscular dystrophy (mdx) mice (DMD models) but became significantly reduced after prednisone treatment. Metformin also reduced the expression of CXCL12 and CXCR4 in mdx mice. In conclusion, the CXCL12–CXCR4 pathway may be a potential target for DMD therapy.
From “Homegrown” to Research-Ready: Converting an Existing Practitioner-Developed Violence Prevention Intervention Into an Evaluable Intervention

There is an increased call for research on promising prevention programs already embedded in communities (“homegrown interventions”). Unfortunately, there is limited guidance to help researchers prepare these types of interventions for rigorous evaluation. To address this need, this article presents our team’s process for revising a promising community-based sexual violence prevention intervention for rigorous research. Our extensive and iterative process of reviewing and revising the intervention was guided by evaluability assessment (EA) approaches, implementation science, and a close collaboration with our community partners. Our EA process allowed us to specify the intervention’s core components and develop a “research ready” standardized curriculum with implementation fidelity assessments. We offer four lessons learned from our process: (1) even with existing materials and an extensive history of community-based delivery, community-developed programs are not necessarily research-ready; (2) close collaboration and a trusting relationship between researchers and community partners throughout the revision process ensures the integrity of core program components are maintained and implementation in diverse community settings is feasible; (3) observations of program implementation are a crucial part of the revision process; and (4) it is important to budget adequate time and resources for such revisions.
Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I

Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re‐evaluated the NF1 gene variants found in the period 2000–2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2–11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non‐homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5′ end of NF1 had a lower age‐related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5′ end of the NF1 gene although not significant at the multivariate analysis.
Proline-rich Extensin-like Receptor Kinases PERK5 and PERK12 are involved in Pollen Tube Growth

Background Cell wall integrity plays an essential role during polarized cell growth typical of pollen tubes and root hairs. Proline-rich Extensin-like Receptor Kinases (PERK) belong to the hydroxyproline-rich glycoprotein (HRGP) superfamily of cell surface glycoproteins. Results Here, we identified two PERKs from Arabidopsis thaliana, PERK5 and PERK12 highly expressed in mature pollen. Pollen tube growth was impaired in the single and double perk5-1 perk12-1 loss of function mutants, with a moderate impact on seed production. When the segregation of self- and reciprocal-crosses of the perk5-1, perk5-2 and perk12-1 single mutants, and reciprocal-crosses of the perk5-1 perk12-1 double mutant were carried out, a male gametophytic defect was found, indicating that perk5-1 and perk12-1 mutants carry defective pollen tubes, resulting in deficient pollen transmission. Furthermore, double perk5-1 perk12-1 mutants show excessive accumulation of pectins and cellulose at the cell wall pollen of the tube tip. In addition, an upregulation of cytoplasmic ROS levels were detected by using 2,7-dichlorofluorescein diacetate probe (H2DCF-DA), and in agreement, similar results were obtained with HyPer, a genetically encoded YFP-based radiometric sensor, which is used to follow the production of hydrogen peroxide (H2O2). Single and double perk5-1 perk12-1 mutants show higher levels of cytoplasmic H2O2 in their pollen tube tips. Conclusions Taken together, our results suggest that PERK5 and PERK12 are necessary for proper pollen tube growth highlighting their role on cell wall assembly and ROS homeostasis.
A cross-sectional study to determine the normal corneal epithelial thickness in Indian population using 9-mm wide optical coherence tomography scans

Purpose: To study the corneal epithelial thickness with 9-mm scans of optical coherence tomography in normal Indians with appropriate representation of all age groups. Methods: This was a cross-sectional observational study. 263 patients were divided into the age groups 5–20 years, 21–35 years, 36–50 years and more than 51 years were recruited for the study. All patients underwent a detailed ophthalmic examination. Patients found to have any ocular surface or intraocular disease condition (except cataract and refractive error), or who had undergone any ophthalmic surgery in the past, or had corneal topography changes suggestive of corneal ectasias (screened in patients with astigmatism more than 3 diopters) or had been continuously using any topical medication in either eye for a period of 3 months or more with the last instillation being within 1 month of inclusion in the study were excluded. All subjects underwent corneal epithelial thickness measurement with anterior segment optical coherence tomography (AS-OCT) on the Avanti OCT (Model RTVueXR1002, Optovue, USA). The corneal epithelial thickness (CET) data from 25 sectors in each eye were analyzed. Results: 263 right and left eyes of 263 patients were analyzed in the study. Mean CETs in the central 2 mm zone were 54.13 ± 4.51 μm and 54.37 ± 3.75 μm for the right and left eyes, respectively. The superior peripheral sectors and inferior paracentral sectors were the thinnest and the thickest sectors, respectively, in both eyes. Conclusion: CET parameters for Indian eyes are comparable to those reported from racially distinct and geographically distant study subjects.
Musculoskeletal Pain and Cardiovascular Risk in Hispanic/Latino Meatpacking Workers

Background Most meatpacking workers have pain affecting their back, arms, and/or wrists from work-related repetitive motions, forceful exertion, and awkward positioning. Chronic musculoskeletal pain is associated with obesity, hypertension, type II diabetes, heart attack, and stroke. Hispanic/Latino workers in the meatpacking industry are a vulnerable population; limited English, lack of health insurance, and fear of deportation often deter them from seeking care where preventable cardiovascular risks might be detected. The purpose of this study was to examine perceived health and actual cardiovascular risk among Hispanic/Latino meatpacking workers with musculoskeletal pain in Nebraska. Methods Structured interviews were used to examine perceived health, awareness of cardiometabolic risk, and capacity for health self-management. Body mass index (BMI), lipids, blood pressure, Hemoglobin A1c (HbA1c), and cardiorespiratory fitness (step test) were used to examine cardiovascular risk. Findings Of those interviewed (n = 39), musculoskeletal pain affected usual life activities in 64% (n = 25) of participants. Of those tested (n = 30), 93% (n = 28) had a BMI > 30 kg/m2, 86% (n = 26) had at least one lipid abnormality, 50% (n = 15) had blood pressure > 120/80 mm Hg, and 43% (n = 13) had an HbA1c > 5.7%. Males had greater fitness than females (p = .03), but also greater lifetime risk of heart attack or stroke compared with females (p = .02). Conclusion/Application to Practice In this sample, cardiovascular risk exceeded that found in the general Hispanic population in the United States. Occupational health nurses can assist workers to be aware of their risk by measuring and providing culturally and linguistically appropriate education on blood pressure, BMI, cholesterol, and HbA1c.
Professional Development, Shifting Perspectives, and Instructional Change among Community College Anatomy and Physiology Instructors

This paper presents community college (CC) instructors’ responses to the Community College Anatomy and Physiology Educational Research (CAPER) project, a professional development program focused on active learning and educational research. We engage with conceptual change theory to better understand why and how CC instructors shifted their perspectives toward active learning. Qualitative data indicate that the participating CC instructors experienced pedagogical discontentment, leading to increased positive beliefs about active learning and educational research. In addition, we find that CC instructors have continued their pursuit of pedagogical change and educational research through communities of practice, which provide positive learning environments.
Idiopathic primary intraventricular hemorrhage and cerebral small vessel disease

Background Although primary intraventricular hemorrhage is frequently due to trauma or vascular lesions, the etiology of idiopathic primary intraventricular hemorrhage (IP-IVH) is not defined. Aims Herein, we test the hypothesis that cerebral small vessel diseases (cSVD) including hypertensive cSVD (HTN-cSVD) and cerebral amyloid angiopathy are associated with IP-IVH. Methods Brain magnetic resonance imaging from consecutive patients (January 2011 to September 2019) with non-traumatic intracerebral hemorrhage from a single referral center were reviewed for the presence of HTN-cSVD (defined by strictly deep or mixed-location intracerebral hemorrhage/cerebral microbleeds) and cerebral amyloid angiopathy (applying modified Boston criteria). Results Forty-six (4%) out of 1276 patients were identified as having IP-IVH. Among these, the mean age was 74.4 ± 12.2 years and 18 (39%) were females. Forty (87%) had hypertension, and the mean initial blood pressure was 169.2 ± 40.4/88.8 ± 22.2 mmHg. Of the 35 (76%) patients who received a brain magnetic resonance imaging, two (6%) fulfilled the modified Boston criteria for possible cerebral amyloid angiopathy and 10 (29%) for probable cerebral amyloid angiopathy. Probable cerebral amyloid angiopathy was found at a similar frequency when comparing IP-IVH patients to the remaining patients with primary intraparenchymal hemorrhage (P-IPH) (27%, p = 0.85). Furthermore, imaging evidence for HTN-cSVD was found in 8 (24%) patients with IP-IVH compared to 209 (28%, p = 0.52) patients with P-IPH. Conclusions Among IP-IVH patients, cerebral amyloid angiopathy was found in approximately one-third of patients, whereas HTN-cSVD was detected in 23%—both similar rates to P-IPH patients. Our results suggest that both cSVD subtypes may be associated with IP-IVH.
Proximity and High Density of Convenience Stores Was Associated With Obesity in Children of a Rural Community of Mexico: Using a Geographic Information System Approach

Background: Food environment (FE) has been linked to obesity in urban areas, but there is limited information in rural areas, particularly in developing countries, where prevalence of obesity is high. Objective: To determine the association between FE and childhood obesity using Geographic Information Systems (GIS). Methods: A total of 218 (8-10 years) children participated in a cross-sectional study. Weight, height, and body fat were measured. Geolocation of convenience stores (CS) and participants’ households was collected, and the amount of processed food (PF) in the stores was measured. The proximity to the nearest CS and the number of CS within a 250-m buffer from each participant’s household was calculated using GIS. Linear regression models between obesity measurements and FE were performed. Results: The combined prevalence of overweight and obesity was 32%. A total of 91% of the children had access to a CS within 250 m. On average, 48% of the shelf-space of the CS were occupied with PF. A positive association between the density of CS with body fat % (β = .145; 95% CI, 0.048-0.241, P = .004), abdominal fat % (β = .206; 95% CI, 0.048-0.241, P = .003), and body mass index (BMI)-for-age z-score (BMIz; β = .028; 95% CI, 0.005-0.062, P = .005) was found. Living closer to CS was associated with increases in body fat % (β = −0.009; 95% CI, −0.017 to −0.001, P = 0.025), abdominal fat % (β = −0.012; 95% CI, −0.023 to −0.001, P = 0.033), and BMIz (β = −0.002, 95% CI, −0.004 to −0.001, P = 0.003). Conclusion: In a rural community in Mexico, a high density and low proximity to CS is associated with obesity in school-aged children.
Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial

Introduction Intracerebral hemorrhage is the deadliest form of stroke. Hematoma expansion, growth of the hematoma between the baseline computed tomography scan and a follow-up computed tomography scan at 24 ± 6 h, predicts long-term disability or death. Recombinant factor VIIa (rFVIIa) has reduced hematoma expansion in previous clinical trials with a variable effect on clinical outcomes, with the greatest impact on hematoma expansion and potential benefit when administered within 2 h of symptom onset. Methods Factor VIIa for Hemorrhagic Stroke Treatment at Earliest Possible Time (FASTEST, NCT03496883) is a randomized controlled trial that will enroll 860 patients at ∼100 emergency departments and mobile stroke units in five countries. Patients are eligible for enrollment if they have acute intracerebral hemorrhage within 2 h of symptom onset confirmed by computed tomography, a hematoma volume of 2 to 60 mL, no or small volumes of intraventricular hemorrhage, do not take anticoagulant medications or concurrent heparin/heparinoids (antiplatelet medications are permissible), and are not deeply comatose. Enrolled patients will receive rFVIIa 80 µg/kg or placebo intravenously over 2 min. The primary outcome measure is the distribution of the ordinal modified Rankin Scale at 180 days. FASTEST is monitored by a Data Safety Monitoring Board. Safety endpoints include thrombotic events (e.g. myocardial infarction). Human subjects research is monitored by an external Institutional Review Board in participating countries. Discussion In the US, FASTEST will be first NIH StrokeNet Trial with an Exception from Informed Consent which allows enrollment of non-communicative patients without an immediately identifiable proxy.
Use of Naloxone in 9-1-1 Patients without Respiratory Depression in Los Angeles County, California (USA)

Abstract Introduction: Along with an increase in opioid deaths, there has been a desire to increase the accessibility of naloxone. However, in the absence of respiratory depression, naloxone is unlikely to be beneficial and may be deleterious if it precipitates withdrawal in individuals with central nervous system (CNS) depression due to non-opioid etiologies. Objective: The aim of this study was to evaluate how effective prehospital providers were in administering naloxone. Methods: This is a retrospective study of naloxone administration in two large urban Emergency Medical Service (EMS) systems. The proportion of patients who had a respiratory rate of at least 12 breaths per minute at the time of naloxone administration by prehospital providers was determined. Results: During the two-year study period, 2,580 patients who received naloxone by prehospital providers were identified. The median (interquartile range) respiratory rate prior to naloxone administration was 12 (6-16) breaths per minute. Using an a priori respiratory rate of under 12 breaths per minute to define respiratory depression, only 1,232 (47.8%; 95% CI, 50.3%-54.2%) subjects who received naloxone by prehospital providers had respiratory depression. Conclusion: This study showed that EMS providers in Los Angeles County, California (USA) frequently administered naloxone to individuals without respiratory depression.
Incomplete IgG avidity maturation after seasonal coronavirus infections

In classical viral infections, the avidity of immunoglobulin G (IgG) is low during acute infection and high a few months later. As recently reported, SARS‐CoV‐2 infections are not following this scheme, but they are rather characterized by incomplete avidity maturation. This study was performed to clarify whether infection with seasonal coronaviruses also leads to incomplete avidity maturation.