Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor.

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

p21 as a Transcriptional Co-Repressor of S-Phase and Mitotic Control Genes

It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes.

Una aproximación a los entornos 1x1,«Un Ordenador Por Niño», desde las experiencias y las percepciones de los estudiantes de Educación Secundaria en el marco de la Sociedad Informacional

El presente trabajo emerge de la ejecución en Catalunya del proyecto"Las políticas de un «un laptop por niño» en España. Visiones y prácticas del profesorado en el Escuela 2.0 programa. Un análisis comparado entre comunidades autónomas, EDU2010-17037". Financiado en el marco del Plan Nacional I+D+i del Ministerio de Ciencia e Innovación. Se trata del primer estudio realizado en España que busca explorar los efectos e impactos que ha tenido la entrada masiva de las tecnologías en las aulas y escuelas del país, hecho impulsado en la actualidad por programa como el Escuela 2.0. Si bien la investigación se focaliza en la práctica y visión del profesorado, durante la ejecución del proyecto hemos podido conocer las vivencias y perspectivas de otros actores involucrados en la ejecución de este programa, entre ellos las del propio estudiantado. Con el fin de desarrollar esta dimensión, hemos centrado este artículo en desarrollar la siguiente pregunta. En el marco de los entornos 1x1, ¿Cual es la visión de los estudiantes de Educación Secundaria Obligatoria (ESO) ante la utilización de un ordenador en el aula, en el proceso de enseñanza /aprendizaje?

Elearning y la educación postmoderna: trayectorias y experiencias del estudiantado virtual

La emergencia y dinámica del Elearning, en los actuales escenarios de educación superior, evidencia una importante transformación acontecida en el marco de la sociedad de la información: la utilización de las TIC en los procesos de construcción del conocimiento. Este cambio ha ido de la mano, en primer lugar, de la mejora en la calidad y la oferta formativa existente, una oferta que ha buscado ser más inclusiva y representativa de las actuales demandas sociales. Y en segundo lugar, se trata de una modalidad que ha intentado adaptarse a las actuales características del estudiantado digital y del digitalizado (Prensky, 2006), cuyo rol en los proceso de enseñanza, tiende a ser más activo que en los modelos de formación tradicional. El presente artículo, se focaliza en esta segunda dimensión, analizando como el Elearning intenta ser un elemento de mediación entre las transformaciones actuales que se dan en la educación superior y la emergencia de un nuevo estudiantado virtual, cada vez más activo y autónomo.

The El Masnou Infralittoral sedimentary environment (Barcelona province, NW Mediterranean Sea): morphology and Holocene seismic stratigraphy

A detailed analysis of the morphology and the Holocene seismic and sequence stratigraphy and architecture of the infralittoral sedimentary environment of the El Masnou coast (Catalonia, NW Mediterranean Sea) was carried out using multibeam bathymetry and GeoPulse seismic data. This environment extends down to 26-30 m water depth, and is defined morphologically by two depositional wedges whose seafloor is affected by erosive furrows, slides, fields of large- and small-scale wavy bedforms, and dredging trenches and pits. Erosive terraces are also identified in the transition domain toward the inner continental shelf. The Holocene stratigraphy of the infralittoral environment is defined by two major seismic sequences (lower and upper), each one formed by internal seismic units. The sequences and units are characterised by downlapping surfaces made up of deposits formed by progradation of coastal lithosomes. The stratigraphy and stratal architecture, displaying a retrogradational arrangement with progradational patterns of minor order, were controlled by different sea-level positions. The stratigraphic division represents the coastal response to the last fourth-order transgressive and highstand conditions, modulated by small-scale sea-level oscillations (≈1-2 m) of fith to sixth order. This study also highlights the advantage of an integrated analysis using acoustic/seismic methods for practical assessment of the anthropogenic effects on infralittoral domains based on the association of marine geological observations.

Pandemic influença A (H1N1) infection in pregnant and nonpregnant women in Spain (2009-2010)

The present study aimed to compare the main features of infection with pandemic influenza A virus in pregnant and nonpregnant women admitted to hospitals in Spain during the first waves of the 2009-2010 influenza pandemic. This was a prospective (November 2009 to June 2010), multicenter observational study. All cases were women of reproductive age who had not been vaccinated against seasonal or pandemic influenza A. Influenza infection was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). The sociodemographic and clinical data of all cases were reviewed. A total of 219 inpatients, including 49 pregnant women and 170 nonpregnant women, were enrolled in the study upon admission to participating hospitals. The most substantially different symptoms between the groups were respiratory distress and unilobar consolidation, both of which were more frequent among nonpregnant women. Antibiotics and systemic corticosteroids were more frequently used in nonpregnant women; however, there were no differences in the rates of treatment with antivirals. Our findings indicated that the compared with nonpregnant women, pregnant women in this study did not have significantly different symptoms and were not at increased risk of complications from pandemic influenza virus infection.

Suggestion of a national diagnostic reference level for 18F-FDG/PET scans in adult cancer patients in Brazil

Objective To suggest a national value for the diagnostic reference level (DRL) in terms of activity in MBq.kg–1, for nuclear medicine procedures with fluorodeoxyglucose (18F-FDG) in whole body positron emission tomography (PET) scans of adult patients. Materials and Methods A survey on values of 18F-FDG activity administered in Brazilian clinics was undertaken by means of a questionnaire including questions about number and manufacturer of the installed equipment, model and detector type. The suggested DRL value was based on the calculation of the third quartile of the activity values distribution reported by the clinics. Results Among the surveyed Brazilian clinics, 58% responded completely or partially the questionnaire; and the results demonstrated variation of up to 100% in the reported radiopharmaceutical activity. The suggested DRL for 18F-FDG/PET activity was 5.54 MBq.kg–1 (0.149 mCi.kg–1). Conclusion The present study has demonstrated the lack of standardization in administered radiopharmaceutical activities for PET procedures in Brazil, corroborating the necessity of an official DRL value to be adopted in the country. The suggested DLR value demonstrates that there is room for optimization of the procedures and 18F-FDG/PET activities administered in Brazilian clinics to reduce the doses delivered to patients. It is important to highlight that this value should be continually revised and optimized at least every five years.

Headspace needle-trap analysis of priority volatile organic compounds from aqueous samples: application to the analysis of natural and waste waters

Combining headspace (HS) sampling with a needle-trap device (NTD) to determine priority volatile organic compounds (VOCs) in water samples results in improved sensitivity and efficiency when compared to conventional static HS sampling. A 22 gauge stainless steel, 51-mm needle packed with Tenax TA and Carboxen 1000 particles is used as the NTD. Three different HS-NTD sampling methodologies are evaluated and all give limits of detection for the target VOCs in the ng L−1 range. Active (purge-and-trap) HS-NTD sampling is found to give the best sensitivity but requires exhaustive control of the sampling conditions. The use of the NTD to collect the headspace gas sample results in a combined adsorption/desorption mechanism. The testing of different temperatures for the HS thermostating reveals a greater desorption effect when the sample is allowed to diffuse, whether passively or actively, through the sorbent particles. The limits of detection obtained in the simplest sampling methodology, static HS-NTD (5 mL aqueous sample in 20 mL HS vials, thermostating at 50 °C for 30 min with agitation), are sufficiently low as to permit its application to the analysis of 18 priority VOCs in natural and waste waters. In all cases compounds were detected below regulated levels

Les personificacions instrumentals locals: estat de la qüestió

En la primera part d"aquest article s"analitza el fenomen de les personificacions instrumentals locals (PIL), tant de les funcionals (organismes autònoms, entitats públiques empresarials i societats mercantils locals), com de les cooperatives (mancomunitats, consorcis i societats mercantils constituïdes per diversos ens locals). L"estudi inclou dues dimensions: la quantitativa, que centra el seu objectiu en determinar el nombre de personificacions existents i classificar-les; i la qualitativa, en la qual l"anàlisi persegueix descriure i caracteritzar el fenomen i explicar els seus problemes i dificultats de funcionament, com també els criteris de funcionalitat i les alternatives a la seva constitució. La segona part del treball revela com s"ha invertit la tendència al creixement que havia caracteritzat el fenomen de les PIL. L"estudi dels projectes de llei aprovats el mes de juliol de 2013 pels governs estatal (de Racionalidad y Sostenibilidad de la Administración Local) i català (de governs locals de Catalunya) mostra que les propostes normatives contenen limitacions severes a la creació d"aquestes personificacions i d"altres ens vinculats a les entitats locals, així com un conjunt de mesures restrictives tendents al redimensionament del sector públic local, que, si s"aproven finalment, constituiran una manifestació més del declinar de l"auge de les PIL.

Resurrecting Disney: Tracing Walt Disney‘s ever-present spirit in feature animated films of the Michael Eisner era (1984-2004)

El treball Ressuscitant a Disney: Rastrejant el sempre present esperit de Walt Disney en els llargmetratges animats de l'era Michael Eisner (1984-2004) pretén definir i analitzar les característiques, tant respecte al procés creatiu com en la definició de contingut, integrades en els clàssics originals de Disney per, a continuació, demostrar que aquestes van ser recuperades i implementades de nou després de la mort de Walt Disney -amb lleus adaptacions- per donar lloc a una segona edat d'or de l'animació

rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids

Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrodinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net/

Urbanités marchandes : le commerce dans la production de la qualité urbaine et ses régulations : le cas de Lausanne

While collective identity markers are constantly evolving in today's city, the hyper-consumption society has allowed retail, even though greatly transformed, to remain a community hub for socialization. Society's commodification takes shape precisely within the public realm and the urban scene: sprawling analogous drivable retail-only suburbs and turning city centers into bland, soulless and undefined places displaying homogeneous frontages characterized by the same retail storefronts worldwide. More than ever, urban policies on retail oriented servicescapes seem crucial to urban and regional planning from a sustainable perspective. Thorough the study case of Lausanne, our research focuses on how the urban planning model and its policies could set into place spatial strategies to enhance urban quality and to reorganize retail centralities without succumbing to the prevailing commodification of the public realm. -- Les indicateurs d'identité collective se reformulent dans la ville actuelle, mais la société de l'hyperconsommation a permis au commerce, aussi transformé soit-il, de rester un lieu d'échange et de brassage social. La marchandisation de la société prend des formes précises dans l'espace et a un impact certain sur le paysage urbain : multipliant les espaces marchands périphériques monofonctionnels ou encore transformant nos centres-villes en paysages anodins, présentant des vitrines semblables quel que soit le pays où elles se situent. Plus que jamais, une régulation des espaces de consommation semble incontournable pour l'aménagement du territoire et l'urbanisme dans une perspective de durabilité. À travers le cas lausannois, cette thèse s'interroge sur la façon dont les modèles urbanistiques de régulation des jeux d'acteurs privés peuvent participer à la mise en place de stratégies de qualification urbaine et d'organisation des centralités commerciales sans céder à la tentation de la marchandisation des espaces publics.

Método Melhorado para Calcular a Leitura Infinita de Cinéticas de Primeira Ordem

Infinity readings for first order kinetics can be calculated from any three measurements (triads) of a physical property l at three equallyspaced times. Accurate results can be obtained from time intervals aslow as 0.4 half-life. Calculation of infinity readings l¥ from severaltriads at increasing values of time gives an insight into the deviation of the first order kinetics when parallel, consecutive or other spurious reactions occur along with the main first order reaction, not allowing direct measurements or calculation of l¥. The proposed method is more sensitive in distinguishing between first and second order kinetics than the Guggenheim and Kezdy-Swinbourne methods.

Recomendaciones de manipulación doméstica de frutas y hortalizas para preservar su valor nutritivo

El beneficio para la salud del consumo diario de al menos 5 raciones entre frutas y hortalizas está bien documentado. En España no se alcanzan los 600 gramos por persona y día que recomienda la Organización Mundial de la Salud (OMS) en sus objetivos de salud pública, por lo que es importante mejorar el acceso a estos alimentos, aprovechar su potencial nutritivo y salvar las barreras para su consumo. Los objetivos de este documento son: facilitar la toma de decisiones responsables con la salud; aprovechar al máximo el valor nutritivo de frutas y hortalizas; ayudar a salvar las barreras para su consumo e informar sobre cómo afecta la conservación, manipulación y cocinado domésticos a su valor nutritivo. Para minimizar la pérdida de nutrientes y mejorar su biodisponibilidad durante la manipulación de frutas y hortalizas, la Asociación para la promoción del consumo de frutas y hortalizas"5 al día" (España) recomienda: evitar almacenamientos prolongados en el refrigerador; aprovechar las capas y hojas exteriores; pelar y/o cortar el alimento justo antes de consumirlo; lavar las piezas enteras y trocearlas posteriormente; controlar el tiempo de remojo de las piezas cortadas; preferir técnicas de cocinado que no requieran contacto directo con el agua; a menor tiempo de cocción, menor pérdida de nutrientes; la fritura correcta conserva muy bien los nutrientes, aunque no debe abusarse de esta técnica; añadir un chorrito de vinagre o de zumo de limón al agua de cocción; aprovechar el agua de los vegetales cocidos para elaborar otros alimentos (ej.: salsas, sopas, purés, etc.), excepto la de acelgas, espinacas o remolacha. La Asociación"5 al día" recomienda aumentar el consumo de frutas y hortalizas, y considera que la pérdida de nutrientes durante su manipulación doméstica no debe entenderse como una barrera para su consumo.

Feature selection for automatic analysis of emotional response based on nonlinear speech modeling suitable for diagnosis of Alzheimer׳s disease

Alzheimer׳s disease (AD) is the most common type of dementia among the elderly. This work is part of a larger study that aims to identify novel technologies and biomarkers or features for the early detection of AD and its degree of severity. The diagnosis is made by analyzing several biomarkers and conducting a variety of tests (although only a post-mortem examination of the patients’ brain tissue is considered to provide definitive confirmation). Non-invasive intelligent diagnosis techniques would be a very valuable diagnostic aid. This paper concerns the Automatic Analysis of Emotional Response (AAER) in spontaneous speech based on classical and new emotional speech features: Emotional Temperature (ET) and fractal dimension (FD). This is a pre-clinical study aiming to validate tests and biomarkers for future diagnostic use. The method has the great advantage of being non-invasive, low cost, and without any side effects. The AAER shows very promising results for the definition of features useful in the early diagnosis of AD.