Mitochondrial Dysfunction and Apoptosis in Cumulus Cells of Type I Diabetic Mice

Impaired oocyte quality has been demonstrated in diabetic mice; however, the potential pathways by which maternal diabetes exerts its effects on the oocyte are poorly understood. Cumulus cells are in direct contact with the oocyte via gap junctions and provide essential nutrients to support oocyte development. In this study, we investigated the effects of maternal diabetes on the mitochondrial status in cumulus cells. We found an increased frequency of fragmented mitochondria, a decreased transmembrane potential and an aggregated distribution of mitochondria in cumulus cells from diabetic mice. Furthermore, while mitochondrial biogenesis in cumulus cells was induced by maternal diabetes, their metabolic function was disrupted as evidenced by lower ATP and citrate levels. Moreover, we present evidence suggesting that the mitochondrial impairments induced by maternal diabetes, at least in part, lead to cumulus cell apoptosis through the release of cytochrome c. Together the deleterious effects on cumulus cells may disrupt trophic and signaling interactions with the oocyte, contributing to oocyte incompetence and thus poor pregnancy outcomes in diabetic females

FEM-based oxygen consumption and cell viability models for avascular pancreatic islets

<p>Abstract</p> <p>Background</p> <p>The function and viability of cultured, transplanted, or encapsulated pancreatic islets is often limited by hypoxia because these islets have lost their vasculature during the isolation process and have to rely on gradient-driven passive diffusion, which cannot provide adequate oxygen transport. Pancreatic islets (islets of Langerhans) are particularly susceptible due to their relatively large size, large metabolic demand, and increased sensitivity to hypoxia. Here, finite element method (FEM) based multiphysics models are explored to describe oxygen transport and cell viability in avascular islets both in static and in moving culture media.</p> <p>Methods</p> <p>Two- and three-dimensional models were built in COMSOL Multiphysics using the convection and diffusion as well as the incompressible Navier-Stokes fluid dynamics application modes. Oxygen consumption was assumed to follow Michaelis-Menten-type kinetics and to cease when local concentrations fell below a critical threshold; in a dynamic model, it was also allowed to increase with increasing glucose concentration.</p> <p>Results</p> <p>Partial differential equation (PDE) based exploratory cellular-level oxygen consumption and cell viability models incorporating physiologically realistic assumptions have been implemented for fully scaled cell culture geometries with 100, 150, and 200 <it>μ</it>m diameter islets as representative. Calculated oxygen concentrations and intra-islet regions likely to suffer from hypoxia-related necrosis obtained for traditional flask-type cultures, oxygen-permeable silicone-rubber membrane bottom cultures, and perifusion chambers with flowing media and varying incoming glucose levels are presented in detail illustrated with corresponding colour-coded figures and animations.</p> <p>Conclusion</p> <p>Results of the computational models are, as a first estimate, in good quantitative agreement with existing experimental evidence, and they confirm that during culture, hypoxia is often a problem for non-vascularised islet and can lead to considerable cell death (necrosis), especially in the core region of larger islets. Such models are of considerable interest to improve the function and viability of cultured, transplanted, or encapsulated islets. The present implementation allows convenient extension to true multiphysics applications that solve coupled physics phenomena such as diffusion and consumption with convection due to flowing or moving media.</p

Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci

Using behavioral and genetic information from the Autism Genetics Resource Exchange (AGRE) data set we developed phenotypes and investigated linkage and association for individuals with and without Autism Spectrum Disorders (ASD) who exhibit expressive language behaviors consistent with a motor speech disorder. Speech and language variables from Autism Diagnostic Interview-Revised (ADI-R) were used to develop a motor speech phenotype associated with non-verbal or unintelligible verbal behaviors (NVMSD:ALL) and a related phenotype restricted to individuals without significant comprehension difficulties (NVMSD:C). Using Affymetrix 5.0 data, the PPL framework was employed to assess the strength of evidence for or against trait-marker linkage and linkage disequilibrium (LD) across the genome. Ingenuity Pathway Analysis (IPA) was then utilized to identify potential genes for further investigation. We identified several linkage peaks based on two related language-speech phenotypes consistent with a potential motor speech disorder: chromosomes 1q24.2, 3q25.31, 4q22.3, 5p12, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and 4p15.2 and 21q22.2 for NVMSD:C. While no compelling evidence of association was obtained under those peaks, we identified several potential genes of interest using IPA. Conclusion: Several linkage peaks were identified based on two motor speech phenotypes. In the absence of evidence of association under these peaks, we suggest genes for further investigation based on their biological functions. Given that autism spectrum disorders are complex with a wide range of behaviors and a large number of underlying genes, these speech phenotypes may belong to a group of several that should be considered when developing narrow, well-defined, phenotypes in the attempt to reduce genetic heterogeneity

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

A forma abreviada da escala posições frente ao diagnóstico de enfermagem: desenvolvimento e avaliação psicométrica

The Positions on Nursing Diagnosis (PND) is a scale that uses the semantic differential technique to measure nurses' attitudes towards the nursing diagnosis concept. The aim of this study was to develop a shortened form of the Spanish version of this scale and evaluate its psychometric properties and efficiency. A double theoretical-empirical approach was used to obtain a short form of the PND, the PND-7-SV, which would be equivalent to the original. Using a cross-sectional survey design, the reliability (internal consistency and test-retest reliability), construct (exploratory factor analysis, known-groups technique and discriminant validity) and criterion-related validity (concurrent validity), sensitivity to change and efficiency of the PND-7-SV were assessed in a sample of 476 Spanish nursing students. The results endorsed the utility of the PND-7-SV to measure attitudes toward nursing diagnosis in an equivalent manner to the complete form of the scale and in a shorter time.El Position on Nursing Diagnosis (PND) es una escala que utiliza la técnica del diferencial semántico para medir las actitudes hacia el concepto diagnóstico enfermero. El estudio objetivó desarrollar una forma abreviada de la versión española de esta escala, evaluar sus propiedades psicométricas y eficiencia. Se utilizó un doble enfoque empírico-teórico para obtener una forma reducida del PND, el PND-7-SV, que fuera equivalente a la original. Mediante un diseño transversal a través de encuesta, se evaluó la fiabilidad (consistencia interna y fiabilidad test-retest), validez de constructo (análisis factorial exploratorio, técnica de grupos conocidos y validez discriminante) y de criterio (validez concurrente), sensibilidad al cambio y eficiencia del PND-7-SV en una muestra de 476 estudiantes de enfermería españoles. Los resultados avalaron la utilidad del PND-7-SV para medir las actitudes hacia el diagnóstico enfermero de manera equivalente a la forma completa de la escala y en un tiempo más reducido

Visualisation automatique, précise et compressée du rayonnement de solutions d'équation de Helmholtz obtenues par éléments de frontière

International audienceWe propose a methodology to generate an accurate and efficient reconstruction of radiated fields based on high order interpolation. As the solution is obtained with the convolution by a smooth but potentially high frequency oscillatory kernel, our basis functions therefore incorporate plane waves. Directional interpolation is shown to be efficient for smart directions. An adaptive subdivision of the domain is established to limit the oscillations of the kernel in each element. The new basis functions , combining high order polynomials and plane waves, provide much better accuracy than low order ones. Finally, as standard visualization softwares are generally unable to represent such fields, a method to have a well-suited visualization of high order functions is used. Several numerical results confirm the potential of the method.Nous proposons une méthodologie pour générer la reconstruction précise et efficace des champs rayonnés à partir d'interpolations d'ordre élevé. Comme la solution est obtenue par convolution avec un noyau régulier mais potentiellement oscillant à hautes fréquences, nos fonctions de base incorporent donc des ondes planes. Nous montrons que l'interpolation directionnelle est efficace pour les bonnes directions. Une subdivision adaptative du domaine est créée afin de limiter les oscillations du noyau dans chaque élément. Les nouvelles fonctions de base, combinant des polynômes d'ordre élevé et des ondes planes, donnent une bien meilleure précision que celles de bas ordre. Enfin, les logiciels de visualisation étant généralement incapables de représenter de telles solutions, une méthode permettant une visualisation correcte des fonctions d'ordre élevé est utilisée. Plusieurs exemples numériques confirment le potentiel de cette méthode