A three-level signature by graph for Reverse Engineering of mechanical assemblies

Several approaches exist to provide Reverse Engineering solutions on mechanical parts. Mechanical assemblies and the expertise information retrieved at the same time with the model geometry are not really taken into account in the literature. Thus, the main challenge of this contribution is to propose a methodology to retrieve the Digital Mock-Up of a mechanical assembly from its meshed data (from digitalization). The output DMU consists of expertise information and parameterized CAD models. The methodology proposed relies on a signature by a three-level graph. It enables to provide an adequate level of details by identifying the corresponding functional surfaces in meshed data. The first-level graph is a connectivity graph; the intermediate level is the same as the first with the geometric type of face added to each node (plane, cylinder and sphere) and the deepest level corresponds to a precedence graph. This one provides information such as functional surfaces and position between them (perpendicularity, coaxiality etc.). The solutions developed and the results are presented in this paper. The methodology is illustrated thanks to an industrial use-case with a scan of an assembly with a connecting rod and a piston. The conclusion and perspectives will complete this paper

Towards new processes to reverse engineering digital mock-ups from a set of heterogeneous data

Reverse-Engineering techniques are commonly used to generate or update the CAD model of a single physical object. However, the reverse engineering of a whole assembly is still very tedious and time-consuming. This is mainly due to the fact that the complete definition of the final digital mock-up relies on the integration of multiple sources of heterogeneous data, such as point clouds, images, schemes or any type of digital representations which are not yet fully supported by actual software. Thus, having new methods and tools to better process and integrate those multi-representations would speed up the reconstruction process which could therefore become adapted to the reconstruction of large mechanical assemblies such as in automotive field. This paper addresses such a difficult problem. Actually, starting from an analysis of three different use-cases, we first highlight the lack of software solutions for the considered problematic. Then, the proposed process-workflow is introduced together with the advanced mechanisms involved in the reconstruction. In our approach, the signatures of the components play a key role in the identification of the relationships and matching procedures between the heterogeneous data. This process-workflow is illustrated on an example in the automotive domain

A three-level signature by graph for Reverse Engineering of mechanical assemblies

Several approaches exist to provide Reverse Engineering solutions on mechanical parts. Mechanical assemblies and the expertise information retrieved at the same time with the model geometry are not really taken into account in the literature. Thus, the main challenge of this contribution is to propose a methodology to retrieve the Digital Mock-Up of a mechanical assembly from its meshed data (from digitalization). The output DMU consists of expertise information and parameterized CAD models. The methodology proposed relies on a signature by a three-level graph. It enables to provide an adequate level of details by identifying the corresponding functional surfaces in meshed data. The first-level graph is a connectivity graph; the intermediate level is the same as the first with the geometric type of face added to each node (plane, cylinder and sphere) and the deepest level corresponds to a precedence graph. This one provides information such as functional surfaces and position between them (perpendicularity, coaxiality etc.). The solutions developed and the results are presented in this paper. The methodology is illustrated thanks to an industrial use-case with a scan of an assembly with a connecting rod and a piston. The conclusion and perspectives will complete this paper

Mechanisms of congenital heart disease caused by NAA15 haploinsufficiency

Rationale: NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Étude de la spécification des lignées cellulaires lors du développement péri-implantatoire humain

The human embryo develops as a result of the fusion of the ovocyte and the spermatozoon. ln just a few days, the embryo develops from a single cell into a complex, three-dimensional, asymmetric, multicellular structure whose development and regulation mechanisms are still largely unknown. This lack of knowledge is particularly lacking in assited reproductive technologies (ART) for infertile couples, where pregnancy rates are less than 30%. ln order to better understand how the human embryo develops, we conducted a multidisciplinary research project combining bioinformatics, hospital expertise, and fundamental research in developmental biology. We have reconstructed the transcriptomic continuum of the human embryo cells during its first days of development. We show that the emergence of the inner cell mass (ICM, future fetus) and the trophectoderm (TE, future placenta) takes place shortly after the formation of the blastocyst, and not at the morula stage as in the mouse. We also show that the trophectoderm matures faster on the polar side, where it implants in the uterus. Finally, we present new markers of the cell lineages of the embryo before and after its implantation in vitro. This collaborative work opens new research perspectives in the study of human development, ART, and regenerative medicine.L'embryon humain se développe suite à la fusion de l'ovocyte et du spermatozoïde. En quelque jours seulement, l'embryon passe d'une cellule unique à une structure multicellulaire complexe en trois dimensions, asymétrique, et dont les mécanismes de développement et de régulation sont encore largement méconnus. Ce manque de connaissance fait notamment défaut en procréation médicalement assistée (AMP) pour les couples infertiles, où les taux de grossesse sont de moins de 30%. Afin de mieux comprendre comment l'embryon humain se développe, nous avons mené un , projet de recherche pluridisciplinaire mêlant bio informatique, expertise hospitalière, et recherche fondamentale en biologie du développement. Nous avons reconstitué le continuum transcriptomique des cellules de l'embryon humain au cours de ses premiers jours de développement. Nous montrons que l'émergence de la masse cellulaire interne (ICM, futur fœtus) et du trophectoderme (TE, futur placenta) a lieu peu après la formation du blastocyste, et non au stade morula comme chez la souris. Nous montrons également que le trophectoderme mature plus vite du côté polaire, côté où il s'implante dans l'utérus. Enfin, nous présentons de nouveaux marqueurs des lignées cellulaires de l'embryon avant et après son implantation in vitro. Ce travail collaboratif ouvre de nouvelles perspectives de recherche dans l'étude du développement humain, de l'AMP, et la médecine régénérative

Study of cell lineage specification occuring during human peri-implantation development

L'embryon humain se développe suite à la fusion de l'ovocyte et du spermatozoïde. En quelque jours seulement, l'embryon passe d'une cellule unique à une structure multicellulaire complexe en trois dimensions, asymétrique, et dont les mécanismes de développement et de régulation sont encore largement méconnus. Ce manque de connaissance fait notamment défaut en procréation médicalement assistée (AMP) pour les couples infertiles, où les taux de grossesse sont de moins de 30%. Afin de mieux comprendre comment l'embryon humain se développe, nous avons mené un , projet de recherche pluridisciplinaire mêlant bio informatique, expertise hospitalière, et recherche fondamentale en biologie du développement. Nous avons reconstitué le continuum transcriptomique des cellules de l'embryon humain au cours de ses premiers jours de développement. Nous montrons que l'émergence de la masse cellulaire interne (ICM, futur fœtus) et du trophectoderme (TE, futur placenta) a lieu peu après la formation du blastocyste, et non au stade morula comme chez la souris. Nous montrons également que le trophectoderme mature plus vite du côté polaire, côté où il s'implante dans l'utérus. Enfin, nous présentons de nouveaux marqueurs des lignées cellulaires de l'embryon avant et après son implantation in vitro. Ce travail collaboratif ouvre de nouvelles perspectives de recherche dans l'étude du développement humain, de l'AMP, et la médecine régénérative.The human embryo develops as a result of the fusion of the ovocyte and the spermatozoon. ln just a few days, the embryo develops from a single cell into a complex, three-dimensional, asymmetric, multicellular structure whose development and regulation mechanisms are still largely unknown. This lack of knowledge is particularly lacking in assited reproductive technologies (ART) for infertile couples, where pregnancy rates are less than 30%. ln order to better understand how the human embryo develops, we conducted a multidisciplinary research project combining bioinformatics, hospital expertise, and fundamental research in developmental biology. We have reconstructed the transcriptomic continuum of the human embryo cells during its first days of development. We show that the emergence of the inner cell mass (ICM, future fetus) and the trophectoderm (TE, future placenta) takes place shortly after the formation of the blastocyst, and not at the morula stage as in the mouse. We also show that the trophectoderm matures faster on the polar side, where it implants in the uterus. Finally, we present new markers of the cell lineages of the embryo before and after its implantation in vitro. This collaborative work opens new research perspectives in the study of human development, ART, and regenerative medicine

New metal-catalyzed methodologies for C-C and C-heteroatom bond-forming reactions : Application to the synthesis of Hsp90 inhibitors and Lectine A ligands.

Les travaux rapportés dans ce mémoire concernent le développement de nouvelles réactions métallo-catalysées pour la création de liaison carbone-hétéroatome et carbone-carbone ainsi que leurs applications à la synthèse de produits biologiquement actifs. La première partie de ce manuscrit est consacrée à l'étude de la réactivité des sucres dans les couplages organométalliques. Des conditions ont été développées pour la création de la liaison C-S entre glycosyl thiols et partenaires arylés. De plus, la création de la liaison carbone azote de glycosyl amines avec des acides boroniques a été étudiée. Les produits synthétisés dans cette première partie ont été évalués pour leur potentiel d'inhibition de la Lectine A chez Pseudomonas aeruginosa, impliquée dans de sévères infections pulmonaires.La seconde partie de ce travail est dédiée à la création d'une série inédite d'analogues du 6BrCaQ, inhibiteurs de la Hsp90 ainsi que leur évaluation biologique. Cette nouvelle série est obtenue grâce à une nouvelle méthodologie de synthèse basée sur l'activation C-H entre un hétérocycle halogéné et son partenaire C-H activable. L'activité antiproliférative et l'inhibition de la Hsp90 ont été évaluées et seront présentées dans ce manuscrit.The work reported in this dissertation concerns the development of new metal-catalyzed reactions for the creation of carbon-heteroatom and carbon-carbon bonds as well as their applications to the synthesis of biologically active products.The first part of this manuscript is devoted to the study of the reactivity of sugars as nucleophiles in organometallic couplings. Conditions were developed for the creation of the C-S bond between glycosyl thiols and aryl partners. Moreover, the creation of the nitrogen carbon bond of glycosyl amine with boronic acids was studied. The products synthesized in this first part have been evaluated for their potential to inhibit the lectin A, in Pseudomonas aeruginosa related lung infections.The second part of this work is dedicated to the creation of a new series of 6BrCaQ analogues as Hsp90 inhibitors and their biological evaluation. This new series was synthetized through a new CH activation methodology. The antitumoral potential was evaluated and will be presented in this manuscript