Hematopoiesis under telomere attrition at the single-cell resolution

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance

An overview of using small punch testing for mechanical characterization of MCrAlY bond coats

Considerable work has been carried out on overlay bond coats in the past several decades because of its excellent oxidation resistance and good adhesion between the top coat and superalloy substrate in the thermal barrier coating systems. Previous studies mainly focus on oxidation and diffusion behavior of these coatings. However, the mechanical behavior and the dominant fracture and deformation mechanisms of the overlay bond coats at different temperatures are still under investigation. Direct comparison between individual studies has not yet been achieved due to the fragmentary data on deposition processes, microstructure and, more apparently, the difficulty in accurately measuring the mechanical properties of thin coatings. One of the miniaturized specimen testing methods, small punch testing, appears to have the potential to provide such mechanical property measurements for thin coatings. The purpose of this paper is to give an overview of using small punch testing to evaluate material properties and to summarize the available mechanical properties that include the ductile-to-brittle transition and creep of MCrAlY bond coat alloys, in an attempt to understand the mechanical behavior of MCrAlY coatings over a broad temperature range

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

Early clay technologies: studies in Early Neolithic clay usage from the Central Zagros

The advent of clay usage for portable material culture in the Central Zagros is first evidenced by small, unfired tokens from the 10th millennium BC. Over the course of the next three millennia, the production of clay objects proliferated, permeating symbolic and functional realms. The malleability of clay, the ready availability of the resource and its relative durability opened up the possibility for utilisation by all, with little skill or training, to craft functional and symbolic objects with minimal investment. This paper examines the role of clay usage through case studies in the Central Zagros and outlines potential future directions for the study of clay in the Neolithic

Hospitalization of HIV positive patients: Significant demand affecting all hospital sectors

Position du problème Dans un contexte d’évolution des morbidités sévères chez les sujets vivant avec le VIH (PVVIH), l’objectif de cette étude était de décrire les motifs d’hospitalisation et les modes de prise en charge des sujets ayant recours à une hospitalisation. Méthodes Toutes les hospitalisations (≥24h) de PVVIH survenues au sein de 10 hôpitaux du sud de Paris (COREVIH Ile-de-France Sud) entre le 01/01/2011 et 31/12/2011 ont été identifiées. Les données hospitalières et la base de la file active du service référent VIH ont été croisées dans chaque hôpital. Un retour au dossier clinique individuel a été réalisé sur un échantillon aléatoire de sujets (65 % des patients hospitalisés identifiés au cours de cette année) pour recueillir des données cliniques et biologiques détaillées. Résultats Au total, 3013 hospitalisations (1489 patients) ont été enregistrées au cours de l’année 2011. Le taux estimé de patients hospitalisés sur les 10105 PVVIH régulièrement suivis dans le COREVIH Ile-de-France Sud en 2011 était d’environ 8 %. La majorité (58,5 %) de ces hospitalisations ont eu lieu hors secteur VIH. Les infections non classant SIDA représentaient la première cause d’admission (16,4 %), suivies des pathologies liées au VIH (15,6 %), des maladies hépatiques/gastro-intestinales (12,0 %) et des maladies cardiovasculaires (10,3 %). La durée médiane d’hospitalisation était de 5jours (IQR : 2–11), elle était plus longue pour les patients hospitalisés dans le service référent VIH que dans les autres services. Les patients hospitalisés avaient une infection par le VIH ancienne (>10ans) pour 61,4 % d’entre eux, souvent des comorbidités associées (co-infection VHC/VHB 40,5 %, tabac 45,8 %, hypertension artérielle 33,4 %, dyslipidémie 28,8 %, diabète 14,8 %). Les sujets âgés de plus de 60 ans représentaient 15 % des patients hospitalisés, étaient virologiquement contrôlés sous traitement antirétroviral pour la majorité d’entre eux, et les pathologies cardiovasculaires étaient leur principale raison d’admission. Conclusion Le recours à l’hospitalisation chez les PVVIH reste important, avec une grande variété de lieux et de causes d’admission mobilisant tous les secteurs de l’hôpital. Il est primordial de prévenir les comorbidités pour réduire ces recours et de conserver un lien entre le suivi devenu ambulatoire de ces patients et le recours spécialisé dans les hôpitaux