Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

Cultural adaptation of Alzheimer’s disease assessment scale–cognitive subscale for use in India and validation of the Tamil version for South Indian population

Objective: Currently no standardized tools are available in the Indian languages to assess changes in cognition. Our objectives are to culturally adapt the Alzheimer’s disease Assessment Scale–Cognitive Subscale (ADAS-Cog) for use in India and to validate the Tamil version in an urban Tamil-speaking older adult population. / Methods: Two panels of key stakeholders and a series of qualitative interviews informed the cultural and linguistic adaptation of the ADAS-Cog-Tamil. Issues related to levels of literacy were considered during the adaptation. Validation of the ADAS-Cog-Tamil was completed with 107 participants − 54 cases with a confirmed diagnosis of mild-moderate dementia, and 53 age, gender and education matched controls. Concurrent validity was examined with the Vellore Screening Instrument for Dementia (VSID) in Tamil. Internal consistency using Cronbach’s alpha, sensitivity and specificity data using the Area under the Receiver Operating Characteristics (AUROC) curve values were computed. Inter-rater reliability was established in a subsample. / Results: The ADAS-Cog-Tamil shows good internal consistency (α = 0.91), inter-rater reliability and concurrent validity (with VSID-Patient version: r = –0.84 and with VSID-Caregiver version: r = –0.79). A cut-off score of 13, has a specificity of 89% and sensitivity of 90% for the diagnosis of dementia. / Conclusion: ADAS-Cog-Tamil, derived from a rigorous, replicable linguistic and cultural adaptation process involving service users and experts, shows good psychometric properties despite the limitations of the study. It shows potential for use in clinical settings with urban Tamil speaking populations. The English version of the tool derived from the cultural adaptation process could be used for further linguistic adaptation across South Asia

The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index : a mendelian randomisation study

Objective: Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information. Methods: 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA. Results: In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10−7). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA. Conclusions: Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA

A coupling matrix vision for mobile filtering devices with micro-acoustic wave technologies. A systematic approach

Con el espectro radioeléctrico cada vez más saturado, los filtros y duplexores son elementos claves de la tecnología en el mercado de dispositivos discretos para la telefonía móvil. El segmento de usuario de los sistemas de comunicaciones inalámbricas aprovecha las destacadas propiedades de los dispositivos filtrantes basados en resonadores acústicos. Generalmente, el diseño de dispositivos de onda acústica ha sido asumido por técnicas de optimización debido a las restrictivas limitaciones impuestas por la viabilidad tecnológica de los resonadores SAW y BAW, así como las exigentes especificaciones eléctricas. Una respuesta de transmisión muy restrictiva y factores tecnológicos muy limitantes conducen a hacer el diseño más y más complejo y una tarea muy desafiante. El objetivo del trabajo está enfocado en facilitar el diseño de filtros/duplexores y hacerlo más eficiente. En consecuencia, la formulación inicial del problema se ha centrado en la viabilidad tecnológica para implementar filtros de onda acústica. Proporcionar una metodología sistemática es útil para acelerar la curva de aprendizaje de nuevos diseñadores. Los filtros de microondas con elevada selectividad son posibles si sus funciones de transferencia incorporan ceros de transmisión finitos. La introducción de nodos no-resonantes (NRN) da la posibilidad de diseñar filtros con el máximo número de ceros de transmisión finitos sin tener que implementar acoplamientos directos entre la fuente y la carga. Además, las configuraciones en línea con NRN permiten la extracción de los elementos analíticamente. La típica configuración de filtro ladder presenta similitudes características de acuerdo con las redes de prototipo en línea con nodos resonantes y no-resonantes, que son las propiedades de modularidad, para controlar los ceros de transmisión con resonadores independientes, y respuestas completamente canonícas sin acoplamiento fuente-carga directo. Los elementos de la red pasobanda son dados por ecuaciones explícitas en términos de aquellos en los prototipos en línea con NRN que pueden ser sintetizados analíticamente. Como consecuencia, es posible definir una metodología de síntesis directa para obtener los parámetros pasobanda eléctricos de un filtro RF general que está basado en resonadores acústicos. Este trabajo presenta una metodología que proporciona un procedimiento de síntesis sistemático para diseñar filtros y duplexores ladder basados en resonadores de onda micro-acústica. La metodología de diseño utiliza un enfoque nodal basado en NRN y nodos resonantes. La representación de la red mediante una matriz de acoplamiento mixta de nodos resonantes y no resonantes es capaz de gestionar de forma eficiente las restricciones tecnológicas. El procedimiento es eficiente en tiempo, preciso en los resultados y proporciona un profundo entendimiento de las particulares interacciones que se producen entre las restricciones tecnológicas y el funcionamiento del dispositivo. Un completo paquete de software, con un simulador rápido, preciso y de fácil uso, ha sido desarrollado, permitiendo obtener diseños de primera etapa exitosos. Como resultado de la metodología sistemática, hemos desarrollado un método de diseño que combina y sistemáticamente gestiona redes filtrantes compuestas de bloques de polo extraído con bloques de resonadores acoplados, es decir, celdas ladder con secciones CRF. Además, la metodología has sido extendida exitosamente para tener en cuenta el diseño de divisores de potencia con respuesta filtrante por medio de dos topologías diferentes: la configuración ladder y las secciones CRF. La metodología propuesta ofrece una solución que combina el completo cumplimiento de las máscaras de espectro con topologías preparadas para acomodar las restricciones tecnológicas de la tecnología micro-acústica. La metodología ha sido desarrollada orientada nativamente a gestionar la tecnología, como es el ajuste de la limitación en el acoplo electromagnético, y basada en fundamentos de síntesis rigurosos.With a spectrum more and more overcrowded, filters and duplexers are drivers of the technology in the discrete device mobile market. The user segment of wireless communication systems takes profit of the outstanding performance of filtering devices based on acoustic resonators. Usually, the design of acoustic wave devices have been mainly entrusted to optimization techniques because the stringent constraints imposed by the technological feasibility of SAW and BAW resonators and the challenging electrical specifications. A stringent transmission response and very restrictive technological factors lead the design to a more and more complex and challenging task. The aim of the work is focused on easing the filters/duplexers designs and making it more efficient. Consequently, the initial formulation of the problem was focused on the technological feasibility of acoustic wave filters. Providing a systematic methodology is useful to accelerate the learning curve of new entrant designers. Microwave filters with high selectivity are possible if their transfer functions incorporates finite transmission zeros. The inclusion of non-resonant nodes gives the possibility of designing filters with the maximum number of finite transmission zeros without implementing direct couplings between source and load. Furthermore, inline configuration with NRN allows the extraction of the elements analytically. The common ladder filter configuration exhibits characteristic similarities regarding inline prototype networks with resonant and non-resonant nodes, which are the property of modularity, to control transmission zeros by independent resonators, and fully canonical response without a direct source-load coupling. The elements of the lowpass prototype are given by explicit equations in terms of those in in-line prototypes with non-resonating nodes that can be synthesized analytically. As a consequence it is possible to define a direct synthesis methodology to obtain the bandpass electric parameters of a general RF filter that is based on acoustic resonators. This work presents a methodology that provides a systematic synthesis procedure for designing ladder filters and duplexers based on acoustic wave resonators. The methodology uses a nodal approach based on resonating and non-resonating nodes. The coupling matrix representation with a mix of different nature nodes, resonant and non-resonant, is able to efficiently manage the technological restrictions. The procedure is time efficient, precise in the outcomes and provides a deep understanding of the particular interactions between technological constraints and device performance. A complete software package with fast, accurate and easy-to-use simulator has been developed, enabling starting point design success. As a result of the systematic methodology, we have developed a design method that combines and systematically manages a filtering network composed of extracted-pole blocks with coupling resonators blocks, so it is ladder cells with CRF sections. Moreover, the methodology has been successfully extended to take into consideration filtering power dividers by means of two different topologies: ladder configuration and CRF sections. The proposed methodology offers a solution that combines a complete spectrum fulfillment with topologies ready to accommodate technological constraints of micro-acoustics technologies. The methodology has been developed natively oriented to manage with the technology, such as accommodating electromechanical coupling constraints, leveraged in rigorous synthesis foundations

Johnson-Kendall-Roberts theory applied to living cells

Johnson-Kendall-Roberts (JKR) theory is an accurate model for strong adhesion energies of soft slightly deformable material. Little is known about the validity of this theory on complex systems such as living cells. We have addressed this problem using a depletion controlled cell adhesion and measured the force necessary to separate the cells with a micropipette technique. We show that the cytoskeleton can provide the cells with a 3D structure that is sufficiently elastic and has a sufficiently low deformability for JKR theory to be valid. When the cytoskeleton is disrupted, JKR theory is no longer applicable

Progression of lumbar disc degeneration over a decade: a heritability study

Lumbar disc degeneration (LDD) is prevalent, age-related and contributes to low back pain. Cross-sectional LDD as determined by MRI scan is known to be highly heritable. The authors postulated that the rate of progression might also be controlled by genetic factors

Analog Computer Research

Contains reports on two research projects

Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action

Background Patterns of food intake and prevalent osteoarthritis of the hand, hip, and knee were studied using the twin design to limit the effect of confounding factors. Compounds found in associated food groups were further studied in vitro. Methods Cross-sectional study conducted in a large population-based volunteer cohort of twins. Food intake was evaluated using the Food Frequency Questionnaire; OA was determined using plain radiographs. Analyses were adjusted for age, BMI and physical activity. Subsequent in vitro studies examined the effects of allium-derived compounds on the expression of matrix-degrading proteases in SW1353 chondrosarcoma cells. Results Data were available, depending on phenotype, for 654-1082 of 1086 female twins (median age 58.9 years; range 46-77). Trends in dietary analysis revealed a specific pattern of dietary intake, that high in fruit and vegetables, showed an inverse association with hip OA (p = 0.022). Consumption of 'non-citrus fruit' (p = 0.015) and 'alliums' (p = 0.029) had the strongest protective effect. Alliums contain diallyl disulphide which was shown to abrogate cytokine-induced matrix metalloproteinase expression. Conclusions Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action