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

Transfer of knowledge in international strategic alliances: A structural approach.

Through the examination and partial integration of concurrent, theoretical approaches (transaction cost and organizational learning) and advances from the research on strategic alliances and joint ventures, this dissertation develops a conceptualization and empirical verification of how firms learn and transfer marketing as well as technological competencies in the context of international strategic alliances. A latent model of knowledge transfer is derived, where motivation to learn, capacity to learn, partner protectiveness and ambiguity of the competency represent direct effects on learning. Indirect effects are also postulated through a series of hypothesized relationships between these endogenous variables and secondary, explanatory variables (market uncertainty, technology uncertainty, opportunism, tacitness, complexity, specificity, experience, cultural distance and organizational distance). These theoretical constructs are carefully operationalized through multiple perceptual indicators. The proposed conceptual model is tested under a triangulation approach between LISREL and PLS structural equation techniques, both in a confirmatory and exploratory fashion. A comprehensive questionnaire from a mail survey, filled out by 153 top executives from large, American, high-tech companies, constitutes the basis of the data sample for both the marketing and the technology sides of the study. The quality of the measurement model and the significance of relationships between the latent variables of the structural model are reported and assessed for marketing and technology related know-how sub-samples. Complementary field research in Europe and Japan, based on personal interviews of 35 executives representing 16 American, European and Japanese companies, reconciles the statistical findings and inconsistencies with clinical evidence. The confirmatory analysis shows that motivation to learn, capacity to learn and ambiguity of the competency are significant determinants of learning, while tacitness and opportunism have a significant effect on ambiguity and partner protectiveness respectively. Marginal effects from the confirmatory approach and alternative results from the exploratory analysis offer some additional insights on the behavior of the model, critical at this early stage of theory building. Likewise, this research, driven by the close interplay between theory, statistical analysis and clinical evidence offers a reference point and basis of comparison for the operationalization of latent variables which often lack explicit and reliable measures.Ph.D.Business administrationManagementMarketingSocial SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128776/2/9135694.pd

Description of the Thermodynamic Properties of Aqueous Ionic Solutions within the Mean Spherical Approximation

The thermodynamic properties of ionic solutions are described within the mean spherical approximation (MSA). The original MSA and binding MSA (BiMSA) have been supplemented so as to include solvation effects. The model is shown to be capable of representing ionic solution thermodynamics in a wide range of concentration, generally up to saturation, in the case of strong and associating electrolytes. It constitutes an interesting alternative to the Pitzer model

Reweaving the Silk Road through outsourcing and offshoring: The need for an externalisation theory

The reweaving and repaving of the modern Silk Road passes through outsourcing and offshoring activities that have a profound impact on both global business psyche and landscape. Firms, in particular, and their global value chain are being shaped and reshaped through a complex concoction of vertical integration and disintegration. The boundary of the firm and the firm/market interface has been of interest to students of organisation and economics for some time. It has provided the context for Internalisation Theory. Within the new economy, the twin trends of globalisation and advancing technologies are giving rise to a hitherto unknown “worldwide market for market transactions? and increased opportunities for international expansion by firms via market-based modes of organisation. We describe these trends and offer an early modeling approach for explaining why some firm’s externalise the marginal transaction in the so-called new economy. The paper further draws attention on the need to articulate an “Externalisation Theory? that adequately accounts for the firm’s offshoring and outsourcing activities, and that parallels as well as complement “Internalisation Theory? for a full explanation of today’s firms behaviour