ON THE ORIGIN OF THE NEAR-INFRARED EMISSION FROM THE NEUTRON-STAR LOW-MASS X-RAY BINARY GX 9+1

We have determined an improved position for the luminous persistent neutron-star low-mass X-ray binary and atoll source GX 9+1 from archival Chandra X-ray Observatory data. The new position significantly differs from a previously published Chandra position for this source. Based on the revised X-ray position we have identified a new near-infrared (NIR) counterpart to GX 9+1 in K[subscript s]-band images obtained with the PANIC and FourStar cameras on the Magellan Baade Telescope. NIR spectra of this K[subscript s]=16.5 ± 0.1 mag star, taken with the FIRE spectrograph on the Baade Telescope, show a strong Br γ emission line, which is a clear signature that we discovered the true NIR counterpart to GX 9+1. The mass donor in GX 9+1 cannot be a late-type giant, as such a star would be brighter than the estimated absolute Ks magnitude of the NIR counterpart. The slope of the dereddened NIR spectrum is poorly constrained due to uncertainties in the column density NH and NIR extinction. Considering the source's distance and X-ray luminosity, we argue that NH likely lies near the high end of the previously suggested range. If this is indeed the case, the NIR spectrum is consistent with thermal emission from a heated accretion disk, possibly with a contribution from the secondary. In this respect, GX 9+1 is similar to other bright atolls and the Z sources, whose NIR spectra do not show the slope that is expected for a dominant contribution from optically thin synchrotron emission from the inner regions of a jet

Discovery of the near-infrared counterpart to the luminous neutron-star low-mass X-ray binary GX 3+1

Using the High Resolution Camera onboard the Chandra X-ray Observatory, we have measured an accurate position for the bright persistent neutron-star X-ray binary and atoll source GX 3+1. At a location that is consistent with this new position we have discovered the near-infrared (NIR) counterpart to GX 3+1 in images taken with the PANIC and FourStar cameras on the Magellan Baade Telescope. The identification of this K_s=15.8+-0.1 mag star as the counterpart is based on the presence of a Br-gamma emission line in a NIR spectrum taken with the FIRE spectrograph on the Baade Telescope. The absolute magnitude derived from the best available distance estimate to GX 3+1 indicates that the mass donor in the system is not a late-type giant. We find that the NIR light in GX 3+1 is likely dominated by the contribution from a heated outer accretion disk. This is similar to what has been found for the NIR flux from the brighter class of Z sources, but unlike the behavior of atolls fainter (Lx ~ 1e36 to 1e37 erg/s) than GX 3+1, where optically-thin synchrotron emission from a jet probably dominates the NIR flux.Comment: Accepted for publication in Ap

A Brave New Internet: Hacking the Narrative of Mark Zuckerberg’s 2021 Introduction of the Metaverse

We are entering an era of ‘techlash’: increasing unease with the hold of large technology companies over our lives, driven by fatalistic feelings of loss of agency. Neither attempts by these companies to address such concerns, such as appointing ethical committees and ombudsmen, nor grassroot initiatives aimed at user empowerment, seem effective in addressing this. This context remains unacknowledged in Mark Zuckerberg’s introduction of the Metaverse on 28 October 2021. We will show, however, that it is still implicitly addressed through its narrative. A far-reaching transformation of the way in which we use the internet is presented as desirable and unescapable, employing an epic narrative mode which values constancy of the individual and their mastery over their surroundings. However, this future is shaped by Zuckerberg and his company: promising agency for all, it is remarkable how little agency is given to the user. We juxtapose this smooth future vision with a counternarrative using the same narrative building stones, but told in a narrative mode distributing agency more equally. Thus, we engage in strategic analysis, exploring how to resist narratives such as the Metaverse’s. We call this method hacking the narrative

Breaks in the 45S rDNA Lead to Recombination-Mediated Loss of Repeats

rDNA repeats constitute the most heavily transcribed region in the human genome. Tumors frequently display elevated levels of recombination in rDNA, indicating that the repeats are a liability to the genomic integrity of a cell. However, little is known about how cells deal with DNA double-stranded breaks in rDNA. Using selective endonucleases, we show that human cells are highly sensitive to breaks in 45S but not the 5S rDNA repeats. We find that homologous recombination inhibits repair of breaks in 45S rDNA, and this results in repeat loss. We identify the structural maintenance of chromosomes protein 5 (SMC5) as contributing to recombination-mediated repair of rDNA breaks. Together, our data demonstrate that SMC5-mediated recombination can lead to error-prone repair of 45S rDNA repeats, resulting in their loss and thereby reducing cellular viability

Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins

Willingness to participate in a lifestyle intervention program of patients with type 2 diabetes mellitus: a conjoint analysis

Background: Several studies suggest that lifestyle interventions can be effective for people with, or at risk for, diabetes. The participation in lifestyle interventions is generally low. Financial incentives may encourage participation in lifestyle intervention programs. Objetive: The main aim of this exploratory analysis is to study empirically potential effects of financial incentives on diabetes patients' willingness to participate in lifestyle interventions. One financial incentive is negative ("copayment") and the other incentive is positive ("bonus"). The key part of this research is to contrast both incentives. The second aim is to investigate the factors that influence participation in a lifestyle intervention program. Methods: Conjoint analysis techniques were used to empirically identify factors that influence willingness to participate in a lifestyle intervention. For this purpose diabetic patients received a questionnaire with descriptions of various forms of hypothetical lifestyle interventions. They were asked if they would be willing to participate in these hypothetical programs. Results: In total, 174 observations were rated by 46 respondents. Analysis showed that money was an important factor independently associated with respondents' willingness to participate. Receiving a bonus seemed to be associated with a higher willingness to participate, but having to pay was negatively associated with participation in the lifestyle intervention. Conclusion: Conjoint analysis results suggest that financial considerations may influence willingness to participate in lifestyle intervention programs. Financial disincentives in the form of copayments might discourage participation. Although the positive impact of bonuses is smaller than the negative impact of copayments, bonuses could still be used to encourage willingness to participate

Chapter Genetics of Amyotrophic Lateral Sclerosis

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Genetics of Amyotrophic Lateral Sclerosis

La sclérose latérale amyotrophique (SLA) est la maladie des neurones moteurs la plus fréquente, affectant 4-6 individus par 100,000 habitants à l’échelle mondiale. La maladie se caractérise par une faiblesse et une atrophie musculaire suite à la dégénérescence des neurones du cortex moteur, tronc cérébral et moelle épinière. Les personnes atteintes développent les premiers symptômes à l’âge adulte et la maladie progresse sur une période de trois à cinq ans. Il a été répertorié qu’environ 10% des patients ont une histoire familiale de SLA; 90% des gens affectés le sont donc de façon sporadique. La découverte il y a 19 ans de mutations dans le gène zinc/copper superoxide dismutase (SOD1), présentes dans 15-20% des cas familiaux de SLA et environ 2% du total des individus affectés, a été l’événement déclencheur pour la découverte de variations génétiques responsables de la maladie. La recherche sur la génétique de la SLA a connu une progression rapide ces quatre dernières années avec l’identification de mutations dans de nouveaux gènes. Toutefois, même si certains de ces gènes ont été démontrés comme réellement liés à la maladie, la contribution d’autres gènes demeure incertaine puisque les résultats publiés de ceux-ci n’ont pas, à ce jour, été répliqués. Une portion substantielle de cas reste cependant à être génétiquement expliquée, et aucun traitement à ce jour n’a été démontré comme étant efficace pour remédier, atténuer ou prévenir la maladie. Le but du projet de recherche de doctorat était d’identifier de nouveaux gènes mutés dans la SLA, tout en évaluant la contribution de gènes nouvellement identifiés chez une importante cohorte multiethnique de cas familiaux et sporadiques. Les résultats présentés sont organisés en trois sections différentes. Dans un premier temps, la contribution de mutations présentes dans le gène FUS est évaluée chez les patients familiaux, sporadiques et juvéniles de SLA. Précisément, de nouvelles mutations sont rapportées et la proportion de mutations retrouvées chez les cas familiaux et sporadiques de SLA est évaluée. De plus, une nouvelle mutation est rapportée dans un cas juvénile de SLA; cette étude de cas est discutée. Dans un deuxième temps, de nouvelles avenues génétiques sont explorées concernant le gène SOD1. En effet, une nouvelle mutation complexe est rapportée chez une famille française de SLA. De plus, la possibilité qu’une mutation présente dans un autre gène impliqué dans la SLA ait un impact sur l’épissage du gène SOD1 est évaluée. Finalement, la dernière section explique la contribution de nouveaux gènes candidats chez les patients atteints de SLA. Spécifiquement, le rôle des gènes OPTN, SIGMAR1 et SORT1 dans le phénotype de SLA est évalué. Il est souhaité que nos résultats combinés avec les récents développements en génétique et biologie moléculaire permettent une meilleure compréhension du mécanisme pathologique responsable de cette terrible maladie tout en guidant le déploiement de thérapies suite à l’identification des cibles appropriées.Amyotrophic lateral sclerosis (ALS) is the most common of motor neuron diseases, affecting 4-6 individuals per 100,000 individuals worldwide. ALS is characterized by muscle weakness and atrophy caused by the degeneration of neurons located in the motor cortex, brain stem and spinal cord. This fatal disease generally has an adult onset and progresses over a three to five year period. While 10% of patients affected have a family history of the disease, 90% of cases do not and are considered sporadic. The finding of mutations in the zinc/copper superoxide dismutase gene (SOD1) gene 19 years ago in about 15-20% of familial ALS (FALS) patients and approximately 2% of overall cases developed the interest of identifying rare genetics variants causing the disease. The ALS research field experienced a rapid progression during the last four years as mutations in new genes have been identified. While mutations in some of those new genes have been clearly linked to ALS, the role of others is still questionable and so far has not been positively replicated in other populations. Importantly, a significant portion of cases still need to be genetically explained and, unfortunately, there is still no effective treatment to cure, attenuate or prevent the disease. The aim of this Ph.D research project was to identify new ALS mutated genes while analysing the causative role of other newly identified genes in a large familial and sporadic ALS cohort of different origins. The results presented here are categorized into three different sections. First, the contribution of FUS mutations to familial, sporadic and juvenile ALS is analysed. Specifically, new FUS mutations are reported in ALS cases and the proportions of variants present in the tested familial and sporadic ALS cohorts are assessed. In addition, a new mutation is reported in a juvenile ALS patient, and this interesting case is discussed. Second, new genetic avenues are explored for the SOD1 gene. Precisely, a new and complex SOD1 mutation is reported in a French ALS family. Moreover, the possibility that other ALS mutated genes influence SOD1 splicing events is evaluated. Third, the contribution of new candidate genes is evaluated. Precisely, the contribution of OPTN, SIGMAR1 and SORT1 genes to the ALS phenotype is assessed. Hopefully, our different findings combined with recent developments in genetics and molecular biology will permit a better understanding of the pathological mechanisms involved in the disease and will lead to the identification of the right targets in order to develop appropriate therapeutics for ALS patients