The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

COMPETITIVIDADE, INOVAÇÃO E SUSTENTABILIDADE: UMA INTER- RELAÇÃO POR MEIO DA SISTEMATIZAÇÃO DA LITERATURA

The sustainable development growing discussion and the problems inherent to the theme, brings to the fore the companies needs to adapt their processes while maintaining competitiveness. In this search, innovation appears as a key factor, because it enables the  business processes restructuring and the development of new products and technologies. However, the academic understanding of competitiveness, sustainability and innovation has been fragmented. Therefore the aim of this article is to systematize the existing literature in these three areas, seeking to collect evidence of how they are interconnected and encourage  future researches that can investigate deeply the background of these relations. For this, an exploratory qualitative research was conducted through a bibliographic and bibliometric work, which was recorded a total of 379,971 papers in the three areas and their intersections in the period from 1970 to 2015. Among the results, it is observed that, in the short-term, there is a sustainable innovation investment to get competitiveness, either by the benefits of eco-efficiency or the intangible value increase. However, in the long-term, the sustainability problems require investment in radical innovation and how companies could invest in this kind of innovation while maintaining competitiveness should be studied.La creciente discusión acerca del desarrollo sostenible y de los problemas inherentes al tema pone en evidencia la necesidad del entorno corporativo adaptar sus procesos, manteniendo al mismo tiempo la competitividad. En esta búsqueda, la innovación aparece como un factor clave, una vez que permite la reestructuración de los procesos de negocio, y el desarrollo de nuevos productos y tecnologías. Todavía, la comprensión académica de la competitividad, la sostenibilidad y la innovación se presenta fragmentada. El objetivo de este artículo es sistematizar la bibliografía existente en estas tres áreas, tratando de reunir evidencias de la manera como están interconectadas, afín de proponer futuras investigaciones que analicen más profundamente estas relaciones. Con este afán, fue realizada una investigación cualitativa exploratoria, través de un trabajo bibliográfico y bibliométrico, que registró un total de 379.971 trabajos en las tres áreas y sus intersecciones, en el periodo de 1970 hasta 2015. Entre los resultados, se observa que, en el corto plazo, hay un movimiento de inversión en la innovación sostenible como manera de obtener competitividad, sea través de los beneficios del eco eficiencia o del aumento del valor intangible. Sin embargo, en el longo plazo, los problemas presentados por la sostenibilidad exigen inversiones en innovación radical, estableciendo la necesidad de estudios sobre como las empresas podrían invertir en innovación radical al mismo tiempo en que mantienen la competitividad. A crescente discussão a respeito do desenvolvimento sustentável e os problemas inerentes à temática trazem à tona a necessidade do meio corporativo adaptar seus processos, simultaneamente à manutenção da competitividade. Nessa busca, a inovação se mostra como um fator essencial, pois ela permite a reestruturação de processos organizacionais, além do desenvolvimento de novos produtos, tecnologias e processos. Porém, o entendimento acadêmico da competitividade, sustentabilidade e inovação tem sido fragmentado. Portanto o objetivo deste artigo consiste em sistematizar a literatura existente nessas três áreas, buscando levantar evidências de como estão interligadas, para a proposição de pesquisas futuras, que investiguem a fundo tais relações. Para isso, foi realizada uma pesquisa qualitativa exploratória, por meio de um trabalho bibliográfico e bibliométrico, onde foi contabilizado um total de 379.971 trabalhos nas três áreas e suas interseções, no período de 1970 a 2015. Dentre os resultados, observa-se que, em curto prazo, há um movimento de investimento em inovação sustentável para obter competitividade, seja através dos benefícios da ecoeficiência ou do aumento do valor intangível. Porém, em longo prazo, os problemas da sustentabilidade exigem investimento em inovação radical, devendo-se estudar como as empresas poderiam investir em inovação radical, ao mesmo tempo em que mantém a competitividade

HRM practices in a process of organisational change: A contextualist perspective

This paper explores the interactions between HRM practices and contextual factors in a process of organisational change. We first present a typology of HRM models, in line with Mintzberg's organisational configurations. We then develop a contingent view on HRM issues-highlighting the influence of some contextual factors-followed by a more political view which reveals the power games between the different stakeholders, each of them enacting specific contextual factors. Finally, we give a more concrete understanding of the contextualist framework discussing its application to a case study in the alimentary sector