Association Signals Unveiled by a Comprehensive Gene Set Enrichment Analysis of Dental Caries Genome-Wide Association Studies

Gene set-based analysis of genome-wide association study (GWAS) data has recently emerged as a useful approach to examine the joint effects of multiple risk loci in complex human diseases or phenotypes. Dental caries is a common, chronic, and complex disease leading to a decrease in quality of life worldwide. In this study, we applied the approaches of gene set enrichment analysis to a major dental caries GWAS dataset, which consists of 537 cases and 605 controls. Using four complementary gene set analysis methods, we analyzed 1331 Gene Ontology (GO) terms collected from the Molecular Signatures Database (MSigDB). Setting false discovery rate (FDR) threshold as 0.05, we identified 13 significantly associated GO terms. Additionally, 17 terms were further included as marginally associated because they were top ranked by each method, although their FDR is higher than 0.05. In total, we identified 30 promising GO terms, including 'Sphingoid metabolic process,' 'Ubiquitin protein ligase activity,' 'Regulation of cytokine secretion,' and 'Ceramide metabolic process.' These GO terms encompass broad functions that potentially interact and contribute to the oral immune response related to caries development, which have not been reported in the standard single marker based analysis. Collectively, our gene set enrichment analysis provided complementary insights into the molecular mechanisms and polygenic interactions in dental caries, revealing promising association signals that could not be detected through single marker analysis of GWAS data. © 2013 Wang et al

Occupational Therapy Educators\u27 Self-Efficacy to Teach in a Blended Curriculum

In recent years, occupational therapy education has been evolving due to educational trends such as blended learning. Blended learning is a combination of both synchronous and asynchronous learning that occurs online as well as in a brick-and-mortar setting. Little is known regarding occupational therapy educators\u27 self-efficacy to teach in a blended curriculum. It is essential to understand the self-efficacy of these educators, especially related to their skills and capabilities to teach in such an innovative format. The purpose of this qualitative study was to examine the perceptions of occupational therapy educators\u27 self-efficacy teaching in a blended curriculum. The research question for this study focused on how occupational therapy educators view their self-efficacy regarding teaching effectively in a blended curriculum. The conceptual framework for this study was Bandura’s self-efficacy theory. Ten occupational therapy educators who were currently teaching in a blended curriculum were interviewed for this study. Descriptive and in vivo coding were used to analyze the data. Results revealed that personal agency, professional development and mentorship, feedback from colleagues and students, and using coping strategies to manage frustration contributed to an enhanced perception of self-efficacy in occupational therapy educators. This study can facilitate positive social change by informing university administrators and leadership on how to best support faculty teaching future occupational therapy practitioners using a blended curriculum by providing structured professional development and mentoring programs focusing on pedagogy, learning management systems, and educational technology tools

Design de remo seco para áreas externas

Este trabalho de conclusão de curso propõe o desenvolvimento de um equipamento de remo seco para áreas externas no contexto do Design de Produto, explorando as técnicas do esporte remo, assim como o desenvolvimento físico dos usuários a partir do uso de um sistema de resistência. Os objetivos centrais do projeto consistem em compreender as necessidades dos usuários, com base na análise de uso dos equipamentos e questionário, as transformando em requisitos e parâmetros projetuais. Delineou-se como problema projetual a dificuldade de acesso aos esportes e a falta de equipamentos de remo seco que possibilitem a prática da técnica, bem como da geração de força. Busca-se, dessa forma, gerar alternativas e soluções que atendam a estas carências, acatando o escopo definido. O presente trabalho seguiu a metodologia de projeto Platcheck (2012) e foi dividido em quatro etapas: Proposta, Desenvolvimento, Detalhamento e Teste e Otimização. Dados dos equipamentos de remo seco, seus componentes e sistemas de resistência existentes foram levantados através da análise de similares e a biomecânica do esporte foi minuciosamente examinada para que fosse possível compreender da melhor forma a relação do usuário com o equipamento, permitindo uma avaliação ergonômica adequada. Por meio deste projeto, percebeu-se a complexidade de projetos de produtos que se relacionam diretamente com a mobilidade do corpo, devido à amplitude e a grande variedade de movimentos que podem ser executados e como isso pode ser implementado na configuração do produto, que busca ser ergonômico. Apesar das inúmeras adversidades, o desenvolvimento de equipamentos para a prática esportiva é um ramo que está em constante inovação, tornando possível o Design atuar nessa área, contribuindo para que cada vez mais as necessidades reais dos usuários sejam fatores determinantes nos projetos.This final paper proposes the development of indoor rowing equipment for outdoor areas in the context of Product Design, exploring rowing sport techniques, as well as the physical development of users from the use of a resistance system. The central objectives of the project are to understand the needs of users, based on the analysis of the use of equipment and questionnaire, transforming them into requirements and design parameters. It was outlined as a project problem the difficulty of access to sports and the lack of indoor rowing equipment that allows the practice of the technique as well as the generation of strength. In this way, we seek to generate alternatives and solutions that meet these needs, according to the scope that have been set. The present work followed the Platcheck project methodology (2012) and was divided into four stages: Proposal, Development, Detailing and Testing and Optimization. Data from indoor rowing equipment, their existing components and resistance systems were surveyed through similar analysis, and the biomechanics of the sport was thoroughly examined so that it was possible to better understand the user's relationship with the equipment, allowing an adequate ergonomic evaluation . Through this project, the complexity of product designs that are directly related to the mobility of the body, due to the amplitude and the great variety of movements that can be executed and how this can be implemented in the configuration of the product, that aims to be ergonomic. Despite the many adversities, the development of equipment for sports practice is a field that is constantly innovating, making it possible for Design to operate in this area, contributing to the fact that increasingly the real needs of users are determining factors in the projects

Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations

In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6–7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160–167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287–294 cM, including D2), chromosome 5 (p-value < 0.001 for 0–7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7–14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage

Neuromuscular factors related to varus thrust during walking in knee osteoarthritis

BACKGROUND: Up to 37% of people with knee osteoarthritis (OA) present with varus thrust, an abrupt and dynamic worsening of varus alignment during the load-bearing stages of gait. Varus thrust is associated with up to 4-fold increased odds of medial knee OA progression as well as worsening clinical outcomes. While the implications of varus thrust have been well studied, the neuromuscular factors related to varus thrust are still not well understood and many studies report contradictory findings. Additionally, many potential factors remain unstudied. This warrants further efforts to determine associations between neuromuscular factors and varus thrust. The purpose of this study is to investigate knee muscle strength and muscle activation during walking in relation to biomechanical measures of varus thrust. METHODS: Analyses of existing data from participants with and without knee OA recruited at three institutions were used for this study. All participants underwent gait analyses at their self-selected pace while kinematics, kinetics, and surface EMG data were collected. Quadriceps and hamstrings strength was measured using isokinetic dynamometry. Gait data were used to calculate adduction excursion and peak knee adduction velocity as measures of varus thrust. A custom MATLAB code was used to calculate the rate of force development of the quadriceps, and a muscular co-contraction equation was used to calculate co-contraction values for four antagonist muscle pairs (VL-LH, VM-MH, VL-LG, and VM-MG) from surface EMG data during walking. Correlational analyses were performed to assess associations of strength, rate of force development, and muscle co-contraction variables with measures of varus thrust. RESULTS: A total of 183 participants were enrolled, however, a varying number of participants were used for different analyses based on available data. Peak isokinetic quadriceps strength at 60 degrees/second and peak hamstrings strength at both 60 and 120 degrees/second were negatively correlated with knee adduction velocity in people with knee OA. This association was not observed for people without knee OA. VLLH and VMMH co-contraction indices during preactivation were positively correlated with knee adduction excursion. VLLG co-contraction during midstance was positively correlated with peak knee adduction velocity. Association between rate of force development and varus thrust variables was not significant. CONCLUSIONS: Lower isokinetic thigh muscle strength and greater preactivation during walking are related to greater magnitude of varus thrust measured using motion capture. These results advance our understanding of neuromuscular factors related to varus thrust and could inform future interventions to reduce thrust and prevent further progression of OA.2020-06-14T00:00:00

“proyecto para la implementación de plantación de flores tropicales para la exportación y comercialización interna mediante página web”

El proyecto se trata del establecimiento de una plantación de 8 hectáreas de flores tropicales específicamente Heliconias y Gingers, la misma que estará ubicada en el cantón Santo Domingo de los Colorados perteneciente a la provincia de Santo Domingo de los Tsáchilas, Ecuador. La ciudad es conocida por poseer un clima tropical húmedo, óptimo para este tipo de cultivos. La producción en su totalidad será exportada directamente hacia los países de destino para ingresar con un precio más competitivo ya que no se utilizarán intermediarios. Las flores de segunda se destinarán al mercado interno, las que se comercializarán mediante una página web con arreglos florales elaborados. El proyecto conlleva el establecimiento de la plantación, esto incluye la adquisición del terreno, maquinarias, insumos, recurso humano y capital y la comercialización del producto. Los productos que ofreceremos serán flores exóticas de la familia de las Heliconias y Gingers caracterizados por sus formas atractivas y colores peculiares con una calidad muy alta y producida bajo buenas prácticas agrícolas y aplicando avances tecnológicos reduciendo al máximo los riesgos de contaminación y agilizando los procesos. Nuestro mercado objetivo será Estados Unidos principalmente el estado de La Florida. Cabe recalcar que el proyecto tendrá un impacto social positivo en zona ya que para su operación demanda mano de obra directa e indirecta de hombres y mujeres campesinos de entre 18 y 35 años

P19INK4D y su fosforilación secuencial son críticas para el mantenimiento de la integridad del genoma

Las proteínas INK4 (p16INK4a, p15INK4b, p18INK4c, y p19INK4d) componen una familia de inhibidores de quinasas dependientes de ciclinas (CDKs) que funcionan en la fase G1 bloqueando la actividad de las quinasas CDK4 y CDK6. Mientras que comparten similitudes en sus estructuras formadas por repeticiones de motivos ankirina, estas proteínas difieren en sus patrones de expresión durante el desarrollo y en el adulto. Más allá de la aparente redundancia de su función en el control del ciclo celular, algunos de sus miembros han sido involucrados en distintos procesos tales como diferenciación, senescencia y supresión tumoral. En este trabajo demostramos que p19INK4d es inducido por radiación UV en diferentes tipos celulares (células de Leydig MA-10, cultivos primarios de células de Leydig, BHK-21 y WI-38) y que la inducción es específica de este miembro de la familia. Planteamos que la inducción podría implicar una posible participación de p19INK4d en la reparación del ADN. Mediante diversas estrategias, establecimos que p19INK4d efectivamente tiene una función en este proceso. Además, frente a daño genotóxico la disminución en los niveles de p19INK4d aumentó el número de aberraciones cromosómicas, concluyendo que la actividad de p19INK4d afecta el mantenimiento de la integridad del genoma. Sumado a esto, las células con niveles reducidos de p19INK4d resultaron con menor capacidad de sobrevivir al tratamiento con radiación UV. En respuesta al daño al ADN se encienden una serie de cascadas de señales que involucran diversas proteínas quinasas. Estas quinasas activan a su vez diferentes sustratos efectores de la respuesta conduciendo a la reparación, o no, del daño. Habiendo descripto una función de p19 en este proceso el siguiente objetivo consistió en estudiar si p19 formaba parte de este grupo de proteínas efectoras fosforiladas frente al daño. Encontramos que p19 es fosforilada por agentes que inducen diferentes tipos de daño (radiación UV, péptido β-amiloide y cisplatino). Identificamos dos sitios de fosforilación, serina 76 y treonina 141, los cuales son fosforilados en forma secuencial. Los resultados señalan a CDK2 y CDK5 como responsables de la fosforilación en serina 76 y a PKA en treonina 141. La fosforilación de ambos sitios ocurre en el citoplasma y la serina 76 es necesaria para la translocación de p19 al núcleo en esta respuesta. Evaluamos luego la relevancia fisiológica de la fosforilación en estos sitios. Encontramos que tanto la serina 76 como la treonina 141 son estrictamente necesarias para la función de p19 en la reparación del ADN. Sin embargo, mutantes en estos sitios incapaces de ser fosforiladas, mantienen la misma capacidad de inhibir la proliferación del ciclo celular cuando son sobreexpresadas. Esto señala que existe una independencia en la función de reparación respecto de la función inhibitoria de CDK4/CDK6. Por último, iniciamos el estudio referido a las posibles proteínas que interactúan con p19INK4d relacionadas a la función de reparación del ADN. Describimos seis interactores encontrados por análisis de doble híbrido en levaduras que resultan de particular interés porque presentan funciones en procesos comunes a p19INK4d. Estos posibles interactores participan en la reparación del ADN, en la remodelación de la cromatina y en la regulación de factores de transcripción del ciclo celular y la apoptosis. En vista de la participación de p19INK4d en respuesta a diversos agentes genotóxicos, que activan distintos mecanismos de reparación, postulamos que p19INK4d actuaría en la reparación del ADN específicamente en una etapa temprana de la respuesta celular al daño al ADN. El análisis de los potenciales interactores de p19INK4d, luego de la injuria genotóxica, permite sugerir la participación de esta proteína en los complejos remodeladores de la cromatina necesarios para permitir el acceso de las maquinarias de reparación en los sitios de daño.INK4 proteins are members of a family of cyclin-dependent kinase (CDK) inhibitors that function in G1 to block the activity of CDK4 and CDK6. While they share clear structural similarities, numerous studies have shown that INK4 proteins differ in their expression patterns during development and in the adult, and have differing roles in differentiation, senescence and tumor suppression. We demonstrated that p19INK4d is induced in response to UV radiation in different cell types (Leydig MA-10 cell line, primary Leydig cell culture, BHK-21 y WI-38) and that this induction is specific of this family member. We hypothesized that this fact could be related to a role of p19INK4d in DNA repair. Taking advantage of diverse strategies, we found that p19INK4d effectively participates in this process. Adding to this, diminished p19INK4d levels when cells are exposed to genotoxics leads to an increase in the number of chromosomal aberrations. From these facts we concluded that p19INK4d influences the maintenance of genome integrity. Furthermore, cells with reduced p19 expression resulted in a significant decrease of the survival rate upon UV damage. In DNA damage response different pathways are triggered involving the activity of protein kinases. These kinases in turn activate diverse substrates that act as effectors of the response leading or not to DNA repair. Having described a function of p19INK4d in this process, the next aim leaded the study to analize whether p19INK4d is part of the effector proteins phosphorylated after DNA damage. We found out that p19 is phosphorylated by treatment with agents which induce different types of DNA damage (UV light, β-amyloid peptide and cisplatin). We identified two phosphorylation sites, serine 76 and threonine 141, which are sequentially phosphorylated. Our results pointed out CDK2 and CDK5 as responsible kinases to act on serine 76 and PKA as the one acting on threonine 141. Both sites are phosphorylated in the cytoplasmic space but only serine 76 is required for p19INK4d translocation to the nucleus in this response. We investigate the physiological relevance of the phosphorylation process in these sites. We showed that serine 76 and threonine 141 are strictly necessary for p19 function in DNA repair. However, those mutants of p19 not able to be phosphorylated have full capacity for inhibiting cell proliferation when they are overexpressed. This fact indicates the independence of p19INK4d functions. Lastly, we began the study related to potential proteins interacting with p19INK4d linked to DNA repair. We described six interactors found by a yeast two hybrid screening which appear particularly interesting because they have functions in common processes to p19INK4d. These interactors participate in processes such as: DNA repair, chromatin remodelling and regulation of transcription factors of the cell cycle and apoptosis. Taking into account p19INK4d participation in response to diverse genotoxic agents which activate different DNA repair mechanisms, we finally raised the hypothesis that p19 would be taking part in an early step in DNA damage response, specifically in DNA repair. The analysis of potential p19INK4d interactors, after genotoxic injury, suggests that this protein could play a role as a member of chromatin - remodeling complexes necessary for the accessibility of DNA repair machineries to DNA damaged sites.Fil:Marazita, Mariela C.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Methods for detecting gene × gene interaction in multiplex extended pedigrees

Complex diseases are multifactorial in nature and can involve multiple loci with gene × gene and gene × environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene × gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem

An ordered subset approach to including covariates in the transmission disequilibrium test

Clinical heterogeneity of a disease may reflect an underlying genetic heterogeneity, which may hinder the detection of trait loci. Consequently, many statistical methods have been developed that allow for the detection of linkage and/or association signals in the presence of heterogeneity

Methods for detecting gene × gene interaction in multiplex extended pedigrees

Complex diseases are multifactorial in nature and can involve multiple loci with gene × gene and gene × environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene × gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem