Variants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients

in Journal of Clinical Medicine (2019)

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD ... [more ▼]

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. [less ▲]

A quoi rêvent les hommes? Les imaginaires du Minitel

Speeches/Talks (2019)

« À quoi rêvent les hommes ? »… sur les murs des villes françaises s’affichent cette question et cette publicité pour le 3615 Ulla, lancé en 1987 par le groupe AGL. L’analyse des imaginaires du Minitel ne ... [more ▼]

« À quoi rêvent les hommes ? »… sur les murs des villes françaises s’affichent cette question et cette publicité pour le 3615 Ulla, lancé en 1987 par le groupe AGL. L’analyse des imaginaires du Minitel ne se réduit toutefois ni à ceux du Minitel rose, ni à l’imaginaire masculin. Bien sûr ces messageries dites conviviales ont contribué à nourrir l’image parfois sulfureuse du Minitel et sont devenues un des symboles des usages de la petite boîte beige. Mais, du mythe de la fin de la civilisation du papier à la question de la neutralité des technologies et intermédiaires, en passant par des thèmes tels que la fracture générationnelle et le « retard français » dans l’Internet et le Web à cause du Minitel, bien d’autres représentations et imaginaires de cette « enfance numérique » peuvent être mis en avant. Ce parcours se propose de les retracer depuis les premiers pas du vidéotex à la fin des années 1970 jusqu’au retour en grâce du Minitel à la faveur de sa disparition en 2012, accompagnée d’un soupçon de nostalgie et de vintage. [less ▲]

Understanding Alpha Decay

Scientific Conference (2019, December 16)

Localization Performance of 1-Bit Passive Radars in NB-IoT Applications

in IEEE International Workshop on Computational Advances in Multi-Sensor Adaptive Processing (CAMSAP) (2019, December 14)

Location-based services form an important use-case in emerging narrowband Internet-of-Things (NB-IoT) networks. Critical to this offering is an accurate estimation of the location without overlaying the ... [more ▼]

Location-based services form an important use-case in emerging narrowband Internet-of-Things (NB-IoT) networks. Critical to this offering is an accurate estimation of the location without overlaying the network with additional active sensors. The massive number of devices, low power requirement, and low bandwidths restrict the sampling rates of NB-IoT receivers. In this paper, we propose a novel low-complexity approach for NB-IoT target delay estimation in cases where one-bit analog-to-digital-converters (ADCs) are employed to sample the received radar signal instead of high-resolution ADCs. This problem has potential applications in the design of inexpensive NB-IoT radar and sensing devices. We formulate the target estimation as a multivariate fractional optimization problem and solve it via Lasserre's semi-definite program relaxation. Numerical experiments suggest feasibility of the proposed approach yielding high localization accuracy with a very low number of 1-bit samples. [less ▲]

A professional development course in translanguaging: Teachers’ stance, design, and shifts

Scientific Conference (2019, December 14)

The school population in Luxembourg is highly socially, culturally, and linguistically diverse. The new law in 2017 has declared multilingual early education mandatory, with the focus not only on the ... [more ▼]

The school population in Luxembourg is highly socially, culturally, and linguistically diverse. The new law in 2017 has declared multilingual early education mandatory, with the focus not only on the development of Luxemburgish, but also familiarizing children with French and valuing their home languages. Thus, our project aims to: (1) offer a professional development (PD) course in translanguaging to preschool teachers, (2) involve children’s families to reinforce home-school collaboration, and (3) foster children’s cognitive, linguistic, and socio-emotional engagement in the classroom. With teachers, we use focus groups, questionnaires, and language portraits, with parents, we employ questionnaires and interviews, and with children, a test in early literacy and numeracy in school and home language and video observations. Translanguaging is the use of a full linguistic repertoire to make meaning (Otheguy, García, & Reid, 2015). Translanguaging pedagogy is the main topic of our 22 hour PD course (June – December 2019) for 40 teachers. In the focus groups, the teachers shared their negative translanguaging stance towards the use of children’s home languages in the classroom, convinced that it hindered the development of Luxembourgish. Teachers, however, in some instances incorporated a translanguaging design (e.g. multilingual stories, morning greetings) and translanguaging shift (e.g. translations by older children). The project addresses these negative translanguaging stances through practical activities and a close collaboration with parents, children and organisational stakeholders. The preliminary results from parent questionnaires and tests with children will provide a bigger picture of the effect of translanguaging pedagogy from our PD course on all the actors involved. References Otheguy, R., García, O., & Reid, W. (2015). Clarifying translanguaging and deconstructing named languages: A perspective from linguistics. Applied Linguistic Review, 6(3), 281–307. [less ▲]

Gouverner, intégrer, participer. Le duché de Luxembourg sous les princes bourguignons et habsbourgeois (milieu XVe – début XVIe s.)

Doctoral thesis (2019)

Architectures of bureaucracy: An architectural and political history of ministerial offices in Belgium, 1915-1940

Doctoral thesis (2019)

Consolidating Observation of Land and Sea Level Changes around South Georgia Island

Poster (2019, December 13)

With its mid-ocean location in the Southern Atlantic Ocean South Georgia Island is in a key position for the oceanic and geodetic global monitoring networks. Since 2013 the tide gauge at King Edward Point ... [more ▼]

With its mid-ocean location in the Southern Atlantic Ocean South Georgia Island is in a key position for the oceanic and geodetic global monitoring networks. Since 2013 the tide gauge at King Edward Point (KEP) with GLOSS ID 187 has been monitored using a GNSS station nearby on Brown Mountain. By accurately geo-referencing the tide gauge and monitoring any vertical land movements, a continuous record of its datum within the Permanent Service for Mean Sea Level (PSMSL) can be established, which in turn makes the recorded and averaged sea levels useful for long-term studies and satellite altimetry calibrations. In 2014 another GNSS station was installed at KEP after local subsidence was sus-pected and later on three additional GNSS stations came to service at the periphery of the main island, making it possible to monitor uplift/subsidence wider afield. Further-more, together with four precise levelling campaigns of the KEP benchmark network in 2013, 2014 and two in 2017, it has also been possible to investigate the very local character of the vertical motions near KEP, i.e. the stability of the jetty upon which the tide gauge is mounted. In this study, we will present the results from the GNSS and precise levelling meas-urements, and will discuss their impact on the sea level record from the KEP tide gauge and nearby satellite altimetry sea surface heights. This study comes at a timely manner as during the Austral Summer 2019/2020 the jetty will be stabilized and en-larged, and consequently the current tide gauge will be replaced by a new one. Our measurements show that uplift is observed all over South Georgia Island while the ar-ea at KEP and particularly the jetty with tide gauge are subsiding relative to the rest of the island. In contrast, results for the tide gauge record show a lower magnitude of ob-served sea level rise than expected from nearby satellite altimetry. We will revisit all geodetic and oceanic observations in an attempt to improve the agreement between these measurements to summarize the status before the work at the jetty begins. [less ▲]

DEVELOPING INDIVIDUAL-BASED GUT MICROBIOME METABOLIC MODELS FOR THE INVESTIGATION OF PARKINSON’S DISEASE-ASSOCIATED INTESTINAL MICROBIAL COMMUNITIES

Doctoral thesis (2019)

The human phenotype is a result of the interactions of environmental factors with genetic ones. Some environmental factors such as the human gut microbiota composition and the related metabolic functions ... [more ▼]

The human phenotype is a result of the interactions of environmental factors with genetic ones. Some environmental factors such as the human gut microbiota composition and the related metabolic functions are known to impact human health and were put in correlation with the development of different diseases. Most importantly, disentangling the metabolic role played by these factors is crucial to understanding the pathogenesis of complex and multifactorial diseases, such as Parkinson’s Disease. Microbial community sequencing became the standard investigation technique to highlight emerging microbial patterns associated with different health states. However, even if highly informative, such technique alone is only able to provide limited information on possible functions associated with specific microbial communities composition. The integration of a systems biology computational modeling approach termed constraint-based modeling with sequencing data (whole genome sequencing, and 16S rRNA gene sequencing), together with the deployment of advanced statistical techniques (machine learning), helps to elucidate the metabolic role played by these environmental factors and the underlying mechanisms. The first goal of this PhD thesis was the development and deployment of specific methods for the integration of microbial abundance data (coming from microbial community sequencing) into constraint-based modeling, and the analysis of the consequent produced data. The result was the implementation of a new automated pipeline, connecting all these different methods, through which the study of the metabolism of different gut microbial communities was enabled. Second, I investigated possible microbial differences between a cohort a Parkinson’s disease patients and controls. I discovered microbial and metabolic changes in Parkinson’s disease patients and their relative dependence on several physiological covariates, therefore exposing possible mechanisms of pathogenesis of the disease.Overall, the work presented in this thesis represents method development for the investigation of before unexplored functional metabolic consequences associated with microbial changes of the human gut microbiota with a focus on specific complex diseases such as Parkinson’s disease. The consequently formulated hypothesis could be experimentally validated and could represent a starting point to envision possible clinical interventions. [less ▲]

IMPROVEMENT OF THE LOAD-BEARING CAPACITY OF DRY-STACKED MASONRY

Doctoral thesis (2019)

Mortar bonded masonry is one of the oldest construction technics traditionally used around the world. However, dry-stacked masonry (DSM) is a competitive system that confers significant assets to masonry ... [more ▼]

Mortar bonded masonry is one of the oldest construction technics traditionally used around the world. However, dry-stacked masonry (DSM) is a competitive system that confers significant assets to masonry in the sense that, concisely, it saves construction time, requires less skill labourers and ease the construction as well as the de-construction. Despite all this major benefits, the current use of DSM is hindered by the geometric imperfections of the block units and the lack of adapted design codes. Indeed, the block geometric imperfections, i.e. the bed-joint roughness and the height difference, cause a significant uneven load-distribution in DSM, which generally leads to a premature cracking and a drop of the wall compressive strength. On the other hand, the lack of adapted design codes entail significant safety hazards in the construction of such masonry walls. In view of the foregoing, through systematic numerical, experimental and analytical investigations, the present thesis aims to analyse the impacts of the block bed-joint imperfections on the mechanical response of DSM axially loaded. Furthermore, the current thesis aims to develop a strategy to overcome the block geometric imperfections and alleviate its impacts on the load-bearing capacity of DSM. Finally, the present thesis intends to develop a design model for predicting the load-bearing capacity of DSM, while taking into account the effects of the block geometric imperfections for a safe design. First of all, at the beginning of the research project, a new dry-stacked masonry block is designed and labelled ‘M-Block’. The impact of the bed-joint roughness and the block height variation on the stress distribution in a DSM is analysed through numerical modelling. It is shown that the block height difference yields five potential load cases that block units may suffer upon the axial compression of a DSM wall. Accordingly, it is also shown that a nominal DSM wall can exhibit different load percolation paths and different damages. Further, a strategy is presented to overcome the bed-joint imperfections, increase the actual contact area in the bed-joints and ultimately improve the load-bearing capacity of DSM, by adding a material layer (the ‘contact layer’) on the raw DSMb. The capacity of the contact layer to increase the actual contact and level the stress distribution was first investigated through numerical models then evidenced through experimental tests on masonry triplets. The contact layer was also investigated for improving the load-bearing capacity of dry-stacked masonry, with satisfactory results obtained on wallets tested in the lab. As the finite element modelling is cumbersome and the experimental investigations onerous and laborious, an analytical model has then been developed for predicting the load-bearing capacity of DSM. A statistical modelling has been developed for determining a factor δh, which stands for the reduction of the nominal section of a DSM generated by the block height variation. Experimental tests were also performed on masonry triplets for measuring the ultimate actual contact in the bed-joints and defining a factor δr, which stands for the reduction of the nominal contact area generated by the block bed-joint roughness. The two defined parameters were then exploited to establish the design model that takes into account the block imperfections in the prediction of the load-bearing capacity of DSM. The design model was shown quite well capable of predicting the load-bearing capacity of DSM with a mean accuracy of 93% - 106% and a standard deviation of 12% - 10%. [less ▲]