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

Global Language Justice in the Digital Sphere: The Ethiopic Case

Abstract of paper 0498 presented at the Digital Humanities Conference 2019 (DH2019), Utrecht , the Netherlands 9-12 July, 2019

THE HEGEMONY OF KEYBOARD DEFAULTS

No single tool is more fundamental to writing—and more unexamined—than the computer keyboard. Most of us in the West never consider that the standard QWERTY key layout, i.e. the staggered key design and the selection of keys available, is anything but the received, traditional means of text input. And as such, keyboard/device manufacturers wield a unique form of power: they dictate the kind of words we can create. They further decide, however unconsciously, the motions our fingers take when we write; the staggered layout was necessary for the proper functioning of mechanical typewriters, but has no necessity for computers (let alone mobile devices), yet continues to be replicated, despite the fact that it is responsible for repetitive stress injuries that could be eliminated or reduced with an improved ergonomic design. QWERTY may even shape the meaning of words that we type. Furthermore, considering the global reach of QWERTY against the backdrop of language diversity, and particularly the approximately 300 non-Latin scripts in existence, the hegemony of default QWERTY keyboards hints at the ongoing impacts of the colonial legacy within digital technologies. Thus, to make computing, and the Internet, more equitable and humane, we must reimagine our keyboard layouts, the characters they include, and our modes of human-computer interaction. Our paper presents this case, employing data analyses of hardware and software keyboard usage statistics

QUES, a new Phaseolus vulgaris genotype resistant to common bean weevils, contains the Arcelin-8 allele coding for new lectin-related variants

In common bean (Phaseolus vulgaris L.), the most abundant seed proteins are the storage protein phaseolin and the family of closely related APA proteins (arcelin, phytohemagglutinin and α-amylase inhibitor). High variation in APA protein composition has been described and the presence of arcelin (Arc) has been associated with bean resistance against two bruchid beetles, the bean weevil (Acanthoscelides obtectus Say) and the Mexican bean weevil (Zabrotes subfasciatus Bohemian). So far, seven Arc variants have been identified, all in wild accessions, however, only those containing Arc-4 were reported to be resistant to both species. Although many efforts have been made, a successful breeding of this genetic trait into cultivated genotypes has not yet been achieved. Here, we describe a newly collected wild accession (named QUES) and demonstrate its resistance to both A. obtectus and Z. subfasciatus. Immunological and proteomic analyses of QUES seed protein composition indicated the presence of new Arc and arcelin-like (ARL) polypeptides of about 30 and 27 kDa, respectively. Sequencing of cDNAs coding for QUES APA proteins confirmed that this accession contains new APA variants, here referred to as Arc-8 and ARL-8. Moreover, bioinformatic analysis showed the two proteins are closely related to APA components present in the G12949 wild bean accession, which contains the Arc-4 variant. The presence of these new APA components, combined with the observations that they are poorly digested and remain very abundant in A. obtectus feces, so-called frass, suggest that the QUES APA locus is involved in the bruchid resistance. Moreover, molecular analysis indicated a lower complexity of the locus compared to that of G12949, suggesting that QUES should be considered a valuable source of resistance for further breeding purposes

Field data from 26 sampled bean populations in Mexico.

a<p>m.a.s.l.: meters above sea level.</p>b<p>GPS coordinates (dd: degrees; mm: minutes; ss: seconds).</p><p>“NA” indicates values which could not be computed.</p><p>For each bean population, the State of origin, GPS coordinates (latitude and longitude) and the altitude were recorded. Additionally field infestation levels of <i>Acanthoscelides</i> spp., the most dominant bruchid genus, were computed for each population by dividing the number of emerged beetles by the number of collected seeds. Parasitism rates were calculated for each bean population by dividing the number of emerged parasitoids by the number of potential hosts (sum of bruchids + sum of parasitoids). The mean tibia length ± SD of <i>H. missouriensis</i> females, the most dominant species emerging from field collected seeds, and the mean weight ± SD of <i>Acanthoscelides</i> spp. were measured for each bean population.</p

Correlation between laboratory and field performance of <i>Acanthoscelides</i> beetles.

<p>Asterisks indicate significant values.</p><p>“-“parameters were not tested.</p><p>Spearman rank tests were performed to investigate whether parameters of performance experiments with <i>A. obtectus</i> correlate with field weights of <i>Acanthoscelides</i> spp. males and females and field infestation levels. Data for bean population “ISA” and “QUES” were not included in the analysis since no insects emerged from those seeds. P-values and the Spearman's rank correlation coefficient “rho” are indicated.</p

Performance experiments with <i>A. obtectus</i> on beans of 26 wild bean populations from Mexico.

a<p>degrees of freedom.</p>b<p>Wald Chi squared test.</p><p>Asterisks indicate significant values.</p><p>n.s. indicate not significant values.</p><p>50 eggs were added to each container (N = 8) and for each beetle its sex, weight and developmental time was determined. To half of the containers we added 2 pairs of <i>Dinarmus basalis</i> parasitoids. <i>A. obtectus</i> weight was analysed using an Anova table of the linear mixed effects model (lme) with bruchid weight as dependent variable and the container as random variable. Developmental time was analysed using an Analysis of deviance table (type II test) of the generalized linear mixed model (GLMM) with developmental time as dependent variable and container as random factor. Survival rate of <i>A. obtectus</i> was analysed using an Analysis of deviance table (type II test) of the generalized linear model (GLM). The dependent variable in the model was the number of successful emergences of beetles over the failures and the container was the random variable.</p

Overview of the laboratory performance of <i>Acanthoscelides obtectus</i> on seeds of 26 sampled bean populations from Mexico (N = 5′847).

<p>N =  number of emerged <i>A. obtectus</i> or <i>D. basalis</i> females for each bean population</p><p>“NA” indicates values which could not be computed.</p><p>For each bean population the mean weight of emerged <i>A. obtectus</i>, the mean developmental time and the standard errors were recorded. For the survival rate of <i>A. obtectus</i>, the standard deviation was computed. In the case of <i>Dinarmus basalis,</i> the mean tibia length and the standard error were measured (N = 564). Parasitism rates were computed by dividing the number of emerged parasitoids by the number of potential hosts (sum of bruchids + sum of parasitoids).</p

Résultats de la fécondation in vitro en cycle naturel ou avec une stimulation hormonale minimale

Natural cycle, modified natural cycle and mild stimulation are different protocols which provide some advantages compared to conventional stimulation: lower medication cost, less injections, less invasive, low risk of ovarian hyperstimulation and multiple pregnancy. There main drawback is high cancellation rate due to premature ovulation and lack of egg recovery at the retrieval. When an embryo transfer can be performed, the cumulative pregnancy rate is similar to the results in con- ventional stimulation. Those protocols don't provide any advantage in term of results for woman with normal ovarian reserve, however it might be considered as a therapeutic alternative in poor responders