Endothelium-Derived Netrin-4 Supports Pancreatic Epithelial Cell Adhesion and Differentiation through Integrins α2β1 and α3β1

BACKGROUND: Netrins have been extensively studied in the developing central nervous system as pathfinding guidance cues, and more recently in non-neural tissues where they mediate cell adhesion, migration and differentiation. Netrin-4, a distant relative of Netrins 1-3, has been proposed to affect cell fate determination in developing epithelia, though receptors mediating these functions have yet to be identified. METHODOLOGY/PRINCIPAL FINDINGS: Using human embryonic pancreatic cells as a model of developing epithelium, here we report that Netrin-4 is abundantly expressed in vascular endothelial cells and pancreatic ductal cells, and supports epithelial cell adhesion through integrins α2β1 and α3β1. Interestingly, we find that Netrin-4 recognition by embryonic pancreatic cells through integrins α2β1 and α3β1 promotes insulin and glucagon gene expression. In addition, full genome microarray analysis revealed that fetal pancreatic cell adhesion to Netrin-4 causes a prominent down-regulation of cyclins and up-regulation of negative regulators of the cell cycle. Consistent with these results, a number of other genes whose activities have been linked to developmental decisions and/or cellular differentiation are up-regulated. CONCLUSIONS/SIGNIFICANCE: Given the recognized function of blood vessels in epithelial tissue morphogenesis, our results provide a mechanism by which endothelial-derived Netrin-4 may function as a pro-differentiation cue for adjacent developing pancreatic cell populations expressing adhesion receptors α2β1 and α3β1 integrins

Typology of adults diagnosed with mental disorders based on socio-demographics and clinical and service use characteristics

<p>Abstract</p> <p>Background</p> <p>Mental disorder is a leading cause of morbidity worldwide. Its cost and negative impact on productivity are substantial. Consequently, improving mental health-care system efficiency - especially service utilisation - is a priority. Few studies have explored the use of services by specific subgroups of persons with mental disorder; a better understanding of these individuals is key to improving service planning. This study develops a typology of individuals, diagnosed with mental disorder in a 12-month period, based on their individual characteristics and use of services within a Canadian urban catchment area of 258,000 persons served by a psychiatric hospital.</p> <p>Methods</p> <p>From among the 2,443 people who took part in the survey, 406 (17%) experienced at least one episode of mental disorder (as per the Composite International Diagnostic Interview (CIDI)) in the 12 months pre-interview. These individuals were selected for cluster analysis.</p> <p>Results</p> <p>Analysis yielded four user clusters: people who experienced mainly anxiety disorder; depressive disorder; alcohol and/or drug disorder; and multiple mental and dependence disorder. Two clusters were more closely associated with females and anxiety or depressive disorders. In the two other clusters, males were over-represented compared with the sample as a whole, namely, substance abuses with or without concomitant mental disorder. Clusters with the greatest number of mental disorders per subject used a greater number of mental health-care services. Conversely, clusters associated exclusively with dependence disorders used few services.</p> <p>Conclusion</p> <p>The study found considerable heterogeneity among socio-demographic characteristics, number of disorders, and number of health-care services used by individuals with mental or dependence disorders. Cluster analysis revealed important differences in service use with regard to gender and age. It reinforces the relevance of developing targeted programs for subgroups of individuals with mental and/or dependence disorders. Strategies aimed at changing low service users' attitude (youths and males) or instituting specialised programs for that particular clientele should be promoted. Finally, as concomitant disorders are frequent among individuals with mental disorder, psychological services and/or addiction programs must be prioritised as components of integrated services when planning treatment.</p

Systems microscopy approaches to understand cancer cell migration and metastasis

Cell migration is essential in a number of processes, including wound healing, angiogenesis and cancer metastasis. Especially, invasion of cancer cells in the surrounding tissue is a crucial step that requires increased cell motility. Cell migration is a well-orchestrated process that involves the continuous formation and disassembly of matrix adhesions. Those structural anchor points interact with the extra-cellular matrix and also participate in adhesion-dependent signalling. Although these processes are essential for cancer metastasis, little is known about the molecular mechanisms that regulate adhesion dynamics during tumour cell migration. In this review, we provide an overview of recent advanced imaging strategies together with quantitative image analysis that can be implemented to understand the dynamics of matrix adhesions and its molecular components in relation to tumour cell migration. This dynamic cell imaging together with multiparametric image analysis will help in understanding the molecular mechanisms that define cancer cell migration

Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines

This article discusses the definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are difficult. Variations in treatment and risk factors influencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely highpowered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP