Répression transcriptionnelle du gène TRH

Les hormones thyroïdiennes (HT : T3, T4) exerçant des effets pléiotropes chez les vertébrés, leur synthèse et leur sécrétion doivent être finement contrôlées. Elles agissent elles-mêmes sur leur production, par un système de rétrocontrôle négatif de l’expression des gènes hypothalamique TRH et hypophysaire TSH. Les fondements moléculaires de cette répression transcriptionnelle des gènes TRH et TSH par l’hormone T3, forme biologiquement la plus active des HT, restent méconnus. Certaines caractéristiques de cette régulation commencent toutefois à être identifiées, notamment le rôle spécifique des isoformes TRβ (versus TRα) des récepteurs des HT. La spécificité fonctionnelle de ces isoformes résiderait principalement dans leur extrémité aminoterminale, qui permettrait une interaction différentielle avec certains comodulateurs. L’objectif, aujourd’hui, est de caractériser ces comodulateurs et d’analyser leur contribution à la régulation transcriptionnelle du gène TRH par l’hormone T3.The synthesis and secretion of thyroid hormones (TH: T3, T4) must be strictly regulated. TH act on their own production via a negative feedback system. The synthesis of thyrotropin-releasing hormone (TRH), produced in the hypothalamus, and thyrotropin (TSH) in the pituitary is inhibited at the transcriptional level by TH. TRH and TSH stimulate production of TH. An outstanding, still open, question is the molecular basis of T3-dependent transcription repression of TRH and TSH genes. However, some regulatory components have been identified, with the β-TH receptor (TRβ) playing a specific regulatory role (versus TRα) in the negative feedback effects of T3 on production of TRH and TSH. Moreover, the N-terminus of TRβ is known to be a key element in this regulation. A hypothesis to explain this isoform specificity could be that TRβ and TRα interact differentially with transcriptional comodulators. Thus, it is critical to characterize these comodulators and to analyse their contribution to the transcription regulation of TRH

A Generic System for Automotive Software Over the Air (SOTA) Updates Allowing Efficient Variant and Release Management

The introduction of Software Over The Air (SOTA) Updates in the automotive industry offers both the Original Equipment Manufacturer and the driver many advantages such as cost savings through inexpensive over the air bug fixes. Furthermore, it enables enhancing the capabilities of future vehicles throughout their life-cycle. However, before making SOTA a reality for safety-critical automotive functions, major challenges must be deeply studied and resolved: namely the related security risks and the required high system safety. The security concerns are primarily related to the attack and manipulation threats of wireless connected and update-capable cars. The functional safety requirements must be fulfilled despite the agility needed by some software updates and the typically high variants numbers. We studied the state of the art and developed a generic SOTA updates system based on a Server-Client architecture and covering main security and safety aspects including a rollback capability. The proposed system offers release and variant management, which is the main novelty of this work. The proof of concept implementation with a server running on a host PC and an exemplary Electric/Electronic network showed the feasibility and the benefits of SOTA updates

Lifecycle Management of Automotive Safety-Critical Over the Air Updates: A Systems Approach

With the increasing importance of Over The Air (OTA) updates in the automotive field, maintaining safety standards becomes more challenging as frequent incremental changes of embedded software are regularly integrated into a wide range of vehicle variants. This necessitates new processes and methodologies with a holistic view on the backend, where the updates are developed and released

A Survey on the State and Future of Automotive Software Release and Configuration Management

In modern vehicles, embedded software is mainly the driving force for the realisation of new functionality. Spread on more than hundred electronic control units, software parts work together in a network to fulfil certain tasks of safety, comfort, energy management and of course vehicle dynamics. Currently, this software is flashed at the end of the assembly line. In regular terms (normally six months), a software baseline of all the electronic control units is released. As a consequence, a distinct variety of releases is deployed on vehicles on the road for each vehicle type. Combined with the alternatives of engines, chassis and customer wishes, the variants of vehicles rise to a number beyond millions. Opening now the chance for over the air updates demands for restrictive and rigorous consistency checks before any update is spread among all the vehicles of one brand or type in the field. In an empirical study based on a survey, we collected and interpreted the answers of participants from different automotive institutions concerning the current state of practice and the faced challenges during release development and management. The outcome of the survey revealed that field updates are getting more and more important due to the rising software part inside vehicles and that over the air communication is an efficient way to realise them in the future. The shortening release and update cycles together with increasing number of variants and the multidisciplinarity in the automotive field were identified as the main challenges in the current development of automotive engineering

Thyroid hormone receptor expression during metamorphosis of Atlantic halibut (Hippoglossus hippoglossus)

Flatfish such as the Atlantic halibut (Hippoglossus hippoglossus) undergo a dramatic metamorphosis that transforms the pelagic, symmetric larva into a benthic, cranially asymmetric juvenile. In common with amphibian metamorphosis, flatfish metamorphosis is under endocrine control with thyroid hormones being particularly important. In this report we confirm that tri-iodothyronine (T3) levels peak at metamorphic climax during halibut metamorphosis. Moreover we have isolated cDNA clones of TR and TR genes and confirmed the presence in halibut of two TR isoforms (representing the products of distinct genes) and two TR isoforms (generated from a single gene by alternative splicing). Real time PCR was used to assess expression of these genes during metamorphosis. TR shows the most dramatic expression profile, with a peak occurring during metamorphic climax.This work has been carried out within the project “Arrested development: The Molecular and Endocrine Basis of Flatfish Metamorphosis” (Q5RS-2002-01192) with financial support from the Commission of the European Communities. However, it does not necessarily reflect the Commission’s views and in no way anticipates its future policy in this area. We thank Heiddis Smáradóttir (Fiskeldi Eyjafjarðar, IS-600 Akureyri, Iceland) for collecting and providing the Atlantic halibut samples, and Karin Pittman and Øystein Sæle (both from the Department of Biology, University of Bergen, Norway) for analysing samples to determine developmental stage. We are also grateful to Marco Campinho for preparing the RNA used in the study

Development and implementation of a multi-scale and multilayer numerical model of skin aging

Avec l’accélération du vieillissement de la population dans les dernières années, l'étude du vieillissement cutané demeure une des problématiques les plus préoccupantes dans les domaines cosmétique et dermatologique. Plusieurs travaux ont montré que l'altération de l'apparence de la peau est directement liée aux changements de sa microstructure et de son comportement mécanique. A ce jour et à notre connaissance, très peu de travaux ont considéré la microstructure de la peau dans l’étude de l’effet du vieillissement sur son comportement mécanique. De plus, aucun de ces travaux ne semble prendre en compte la structure multi-échelle du collagène. L’objectif de cette thèse est de développer un modèle numérique basé sur la méthode des éléments finis décrivant le comportement macroscopique de la peau. Ce modèle considère les différentes couches de la peau (l’épiderme, le derme et l’hypoderme) avec une description multi-échelle de la structure du derme. La finalité étant de fournir un outil permettant d’étudier les effets des changements de la structure de la peau, générés par le vieillissement, sur son comportement mécanique. L’épiderme et l’hypoderme sont décrits par une loi de comportement élastique linéaire avec des propriétés mécaniques spécifiques à chaque couche. Le derme est décrit par une loi de comportement élastique non linéaire, issue d’une modélisation multi-échelle, qui considère sa structure hiérarchique, allant de la triple hélice du collagène au réseau microscopique des fibres de collagène et d’élastine. L'évaluation du comportement macroscopique du derme repose sur la connaissance des paramètres de la microstructure, tels que la densité, les propriétés mécaniques et géométriques du collagène et de l’élastine. La formulation multi-échelle retenue combine un modèle d’homogénéisation linéaire de type Mori-Tanaka à une homogénéisation incrémentale permettant de reproduire le comportement non linéaire de la fibre de collagène. L'anisotropie du derme est prise en compte via une fonction de distribution d'orientation de von Mises. La non linéarité du comportement élastique découle de plusieurs facteurs sur différentes échelles, tels que la réorientation des fibres de collagène au cours de la déformation, leurs déplissages, et la rigidité de la molécule de collagène. Le vieillissement est modélisé via la modulation en fonction de l’âge de paramètres matériaux disponibles dans la littérature Enfin, un algorithme de calcul éléments finis en 2D (déformations planes) et en grandes déformations, décrivant le comportement cutané, a été implémenté sur Matlab. Afin de décrire l’amincissement de la peau en fonction de l’âge, une modélisation de la variation volumique a été introduite en se basant sur la méthode de décomposition multiplicative. L’objectif étant de simuler et prédire la réponse de la peau avec la prise en compte du facteur de l’âge. Dans l’ensemble, les résultats obtenus montrent une modification du comportement élastique non linéaire du derme, avec une différence entre les comportements des dermes papillaire et réticulaire. De plus, le modèle numérique par EF montre une sensibilité à différents paramètres tels que l'élasticité et le volume des couches.With the acceleration of the population’s aging in recent years, the study of skin aging remains one of the most important issues in the cosmetic and dermatological fields. Several studies have shown that the alteration of the skin's appearance is directly linked to changes in its microstructure and mechanical behavior. To date, very few works have considered the microstructure of the skin, in the study of the effect of aging on its mechanical behavior. Moreover, none of these works seems to take into account the multiscale structure of collagen. The objective of this thesis is to develop a numerical model based on the finite element method, describing the macroscopic behavior of the skin. This model considers the different layers of the skin (epidermis, dermis and hypodermis), with a multi-scale consideration for the dermis structure. The aim is to provide a strong tool to study the effects of changes in the skin structure, generated by aging, on its mechanical behavior. The epidermis and hypodermis are described by a linear elastic behavior, with specific mechanical properties for each layer. The dermis is described by a nonlinear elastic behavior, resulting from a multiscale modeling, which considers its hierarchical structure, from the triple helix of collagen to the microscopic network of collagen and elastin fibers. The evaluation of the macroscopic behavior of the dermis relies on the knowledge of the microstructure parameters, such as density, mechanical and geometric properties of collagen and elastin. The multiscale formulation chosen combines a linear homogenization model of the Mori-Tanaka type with an incremental approach, to reproduce the nonlinear behavior of the collagen fiber. The anisotropy of the dermis is taken into account via a von Mises orientation distribution function. The nonlinearity of the elastic behavior is due to several factors on different scales, such as the reorientation of collagen fibers during deformation, their straightening, and the stiffness of the collagen molecule. Finally, a 2D (plane deformations) finite element code for large deformation, describing the skin behavior, has been implemented on Matlab. In order to describe the skin thinning as a function of age, a model of the volumetric variation was introduced based on the multiplicative decomposition method. The objective was to simulate and predict the skin response with consideration of the age factor. Overall, the results obtained show a modification of the nonlinear elastic behavior of the dermis, with a difference between the behavior of the papillary and reticular dermis. Moreover, the FE numerical model shows a sensitivity to different parameters such as elasticity and volume of the layers

MECANISMES MOLECULAIRES DE LA REGULATION TRANSCRIPTIONNELLE PHYSIOLOGIQUE DE LA THYREOLIBERINE HYPOTHALAMIQUE (TRH) (ETUDE IN VIVO CHEZ LA SOURIS)

NOTRE ANALYSE A PORTE SUR LE ROLE DES ISOFORMES DES RECEPTEURS AUX HORMONES THYROIDIENNES (TR), TR ET TR, DANS LA REGULATION NEGATIVE INDUITE PAR LA T, SUR LE GENE DE LA THYREOLIBERINE HYPOTHALAMIQUE (TRH). L'UTILISATION DE LA POLYETHYLENIMINE (PEI) A PERMIS PREMIEREMENT, D'INTRODUIRE UN TRANSGENE CONTENANT LE PROMOTEUR TRH COUPLE AU GENE RAPPORTEUR LUCIFERASE (TRH-LUC) ET DEUXIEMMENT, DE SUREXPRIMER DES TRS DIRECTEMENT DANS L'HYPOTHALAMUS DE SOURIS IN VIVO. NOUS MONTRONS QUE LE TRANSGENE TRH-LUC EST REGULE DE MANIERE PHYSIOLOGIQUE : LA TRANSCRIPTION EST AUGMENTEE CHEZ LES ANIMAUX HYPOTHYROIDIENS ; ET REPRIMEE CHEZ CEUX TRAITES A LA T 3. EN CE QUI CONCERNE LES EFFETS DES TRS, SEULES LES DIFFERENTES ISOFORMES TR (1/2) SUREXPRIMEES DANS L'HYPOTHALAMUS INDUISENT UNE REPRESSION TRANSCRIPTIONNELLE SIGNIFICATIVE DU TRANSGENE TRH-LUC EN PRESENCE DE LA T 3. LA SUREXPRESSION DE TR1, LA BLOQUE. AINSI, TR MAIS NON TR JOUE UN ROLE SPECIFIQUE DANS LA REGULATION PHYSIOLOGIQUE DU GENE TRH. DE PLUS, LES EFFETS TRANSCRIPTIONNELS DES TRS SONT CORRELES AVEC DES EFFETS SUR LA T 4 CIRCULANTE. ENSUITE, NOUS AVONS ANALYSE LA BASE STRUCTURALE DE LA SPECIFICITE DE FONCTION DES TRS DANS CETTE REGULATION. L'UTILISATION DE CHIMERES TR CORRESPONDANT A L'ECHANGE DE DOMAINES A/B, C/D ET E ENTRE LES ISOFORMES TR1 ET 1 DE RAT (, , , ) MONTRE QUE LA REGION N-TERMINALE CONFERE UNE ACTION SPECIFIQUE DE L'ISOFORME TR DANS LA REPRESSION TRANSCRIPTIONNELLE DU GENE TRH PAR LA T 3. EN EFFET, LES CHIMERES AVEC UNE REGION N-TERMINALE (, ) BLOQUENT CETTE REPRESSION ALORS QUE LES CHIMERES AVEC UNE REGION N-TERMINALE (, ) L'INDUISENT. CEPENDANT, L'ANALYSE PAR RETARD SUR GEL MONTRE QUE CETTE SPECIFICITE N'EST PAS TROUVEE POUR LA RECONNAISSANCE D'UN TRE NEGATIF APPARTENANT AU GENE TRH, SUGGERANT QUE LE CONTEXTE CELLULAIRE ET LES INTERACTIONS PROTEINE-PROTEINE IN VIVO SONT IMPLIQUEES DANS CETTE SPECIFICITE. POUR CETTE RAISON, NOUS AVONS CIBLE LE ROLE QUE PEUVENT JOUER LES CO-REPRESSEURS NUCLEAIRES. NCOR ET SMRT DANS LA REGULATION NEGATIVE INDUITE PAR LE LIGAND. NOUS AVONS UTILISE LES TECHNIQUES D'HYBRIDATION IN SITU (HIS) ET DE NORTHERN POUR SUIVRE L'EXPRESSION DES CO-REPRESSEURS DANS L'HYPOTHALAMUS. L'HIS MONTRE DES ARNM NCOR/SMRT DANS LES MEMES REGIONS QUE LES TRS, SUGGERANT UN ROLE GENERAL DE CES CO-REPRESSEURS DANS LES MECANISMES DE TRANSMISSION DU SIGNA INDUITS PAR LES TRS. EN REVANCHE, BIEN QUE LES ARNM NCOR SOIENT EXPRIMES DANS LES NOYAUX PARAVENTRICULAIRES DE L'HYPOTHALAMUS, ILS SONT ABSENTS AU NIVEAU DES NEURONES A TRH. DE PLUS, NOS ETUDES FONCTIONNELLES IN VIVO, MONTRENT QUE NCOR A UN EFFET INHIBITEUR SUR LA REPRESSION DU TRANSGENE TRH-LUC PAR LA T 3. AINSI, NOUS CONCLUONS QUE L'EXPRESSION DU CO-REPRESSEUR NUCLEAIRE NCOR EST INCOMPATIBLE AVEC LA REGULATION PHYSIOLOGIQUE NEGATIVE DU GENE TRH PAR LA T 3.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Acute kidney injury complicating critical forms of COVID-19: risk factors and prognostic impact

This was a retrospective descriptive case/control monocentric study carried out in the medical ICU of Bizerte hospital (a tertiary teaching hospital in north of Tunisia) over a period of 18 months (September 2020-February 2022). This medical ICU is managed by medical intensivists with a novel unit of six beds created for the COVID-19 outbreak. In this study we aimed to assess the incidence, the risk factors and the prognostic impact of AKI complicating critical forms of COVID-19.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

TROPICAL SPRUE: DIAGNOSTIC CHALLENGES OF AN OLD DISEASE BUT UNDERRECOGNIZED. A TUNISIAN CASE REPORT

A tunisian case report of a latent Tropical sprue presented by a visitor of an endemic area Tropical sprue (TS) is a post-infective disease of the small bowel characterized by a malabsorption syndrome affecting tropics inhabitants and visitors. Diagnosis of TS remain challenging since it can be confused with common diarrheal diseases, especially in non-endemic areas.After ruling out other causes of chronic dirrhea, improvement after an optimal management combining rehydration, replacement of micronutrient, folate and vitamin B12 deficiencies as well as a prolonged antibiotic course supports the diagnosis of TS.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

[Transcriptional repression of the TRH gene]

The synthesis and secretion of thyroid hormones (TH: T3, T4) must be strictly regulated. TH act on their own production via a negative feedback system. The synthesis of thyrotropin-releasing hormone (TRH), produced in the hypothalamus, and thyrotropin (TSH) in the pituitary is inhibited at the transcriptional level by TH. TRH and TSH stimulate production of TH. An outstanding, still open, question is the molecular basis of T3-dependent transcription repression of TRH and TSH genes. However, some regulatory components have been identified, with the b-TH receptor (TRb) playing a specific regulatory role (versus TRa) in the negative feedback effects of T3 on production of TRH and TSH. Moreover, the N-terminus of TRb is known to be a key element in this regulation. A hypothesis to explain this isoform specificity could be that TRb and TRa interact differentially with transcriptional comodulators. Thus, it is critical to characterize these comodulators and to analyse their contribution to the transcription regulation of TRH