The major transcription initiation site of the SV40 late promoter is a potent thyroid hormone response element

Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily, which act as transcription factors upon binding to specific DNA sequences called thyroid hormone (T3) response elements (TREs). Such elements are found in the upstream regulatory region of promoters as well as in intragenic sequences of T3-responsive genes. In this report, we demonstrate that SV40 late (SVL) promoter activity is strongly down-regulated by TR in the absence of ligand. Addition of T3 releases this repression, but does not further induce SVL promoter activity. Electrophoretic mobility shift analyses reveal a TR binding element that overlaps with the SV40 major late transcription initiation site. This element closely fits the consensus TRE, formed of two hexanucleotides organized in a tandem repeat separated by 4 nt, and is able to confer T3 responsiveness on a heterologous promoter. We further show that, although the presence of TR leads to quantitatively modified expression of an SVL-driven reporter gene, neither displacement of the site of transcription initiation nor modification of the splicing pattern of the primary transcripts occu

Variants of the human PPARG locus and the susceptibility to chronic periodontitis

Apart from its regulatory function in lipid and glucose metabolism, peroxisome proliferator-activated receptor (PPAR)γ has impact on the regulation of inflammation and bone metabolism. The aim of the study was to investigate the association of five polymorphisms (rs10865710, rs2067819, rs3892175, rs1801282, rs3856806) within the PPARG gene with chronic periodontitis. The study population comprised 402 periodontitis patients and 793 healthy individuals. Genotyping of the PPARG gene polymorphisms was performed by PCR and melting curve analysis. Comparison of frequency distribution of genotypes between individuals with periodontal disease and healthy controls for the polymorphism rs3856806 showed a P-value of 0.04 but failed to reach significance after correction for multiple testing (P  0.90). A 3-site analysis (rs2067819-rs1801282-rs3856860) revealed five haplotypes with a frequency of ≥1% among cases and controls. Following adjustment for age, gender and smoking, none of the haplotypes was significantly different between periodontitis and healthy controls after Bonferroni correction. This study could not show a significant association between PPARG gene variants and chronic periodontitis

Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function.

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes (α, β/δ and γ) have been identified, among which PPARβ/δ is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPARβ/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPARβ/δ-interacting corepressor or coactivator complexes and PPARβ/δ protein post-translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPARβ/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPARβ/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding

Impaired musculoskeletal response to age and exercise in PPARβ(-/-) diabetic mice.

Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes in which the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARβ(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARβ(-/-) mice and investigated both the mechanism behind those changes with age as well as their response to exercise. Compared with their wild type, PPARβ(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation, and increased resorption. In addition, mesenchymal cells from PPARβ(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARγ, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARβ(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARβ controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARβ deficiency leads to glucose intolerance, decreased muscle function, and reduced bone strength. On a molecular level, PPARβ appears to regulate myostatin and PPARγ expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances

Peroxisome Proliferator-Activated Receptor β/δ in the Brain: Facts and Hypothesis

peroxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressed in the brain and its deletion in mice induces a brain developmental defect. Nevertheless, exploration of PPARβ action in the central nervous system remains sketchy. The lipid content alteration observed in PPARβ null brains and the positive action of PPARβ agonists on oligodendrocyte differentiation, a process characterized by lipid accumulation, suggest that PPARβ acts on the fatty acids and/or cholesterol metabolisms in the brain. PPARβ could also regulate central inflammation and antioxidant mechanisms in the damaged brain. Even if not fully understood, the neuroprotective effect of PPARβ agonists highlights their potential benefit to treat various acute or chronic neurological disorders. In this perspective, we need to better understand the basic function of PPARβ in the brain. This review proposes different leads for future researches

Functions of peroxisome proliferator-activated receptors (PPAR) in skin homeostasis

The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor family. Three isotypes (PPARα, PPARβ or δ, and PPARγ) with distinct tissue distributions and cellular functions have been found in vertebrates. All three PPAR isotypes are expressed in rodent and human skin. They were initially investigated for a possible function in the establishment of the permeability barrier in skin because of their known function in lipid metabolism in other cell types. In vitro studies using specific PPAR agonists and in vivo gene disruption approaches in mice indeed suggest an important contribution of PPARα in the formation of the epidermal barrier and in sebocyte differentiation. The PPARγ isotype plays a role in stimulating sebocyte development and lipogenesis, but does not appear to contribute to epidermal tissue differentiation. The third isotype, PPARβ, regulates the late stages of sebaceous cell differentiation, and is the most effective isotype in stimulating lipid production in these cells, both in rodents and in humans. In addition, PPARβ activation has pro-differentiating effects in kera-tinocytes under normal and inflammatory conditions. Finally, preliminary studies also point to a potential role of PPAR in hair follicle growth and in melanocyte differentiation. By their diverse biological effects on cell proliferation and differentiation in the skin, PPAR agonists or antagonists may offer interesting oppotunities for the treatment of various skin disorders characterized by inflammation, cell hyperproliferation, and aberrant differentiatio

Polymacromonomères. Synthèse-Diffusion de Neutrons aux Petits Angles- Rhéologie. De l'architecture ramifiée à la conformation: étoiles et cylindres chevelus au repos et sous écoulement.

Polymacromonomers (PMs) are well-defined branched polymers resulting from macromonomer polymerisation. The PM investigated in this work have been prepared using anionic and ring-opening metathesis polymerizations, which can be carried out under ?living? conditions. Our final PMs (polystyrene (PS) branches and polynorbornene backbone) show a regular and narrow branch distribution. Our aim was to describe in a quantitative way the PM conformation. SANS was a key technique has it allowed us to label PMs without modifying their architecture. Different geometric models have been applied to fit experimental form factors, measured by SANS, such as form factors of micelles with spherical or cylindrical cores, for PMs in solution as well as in the melt. Architecture has been shown to strongly influence the PM conformation and their interactions with the environment. Furthermore, pure entropic demixion induced by the structure of PM has been evidenced under specific conditions in PM ? linear PS blends. Besides, rheological investigation has been performed to define dynamics of the PM relaxation, which strongly differs from that of linear polymers. Branches are responsible for the specific response of our PMs. Further understanding has been provided by investigating the relaxation of the chain conformation after a quick elongation step of PM/linear blends films using SANS. The relaxation rate and process appear to differ depending on the scale investigated, from the statistical unit to the global size. Complex interpretation of the spectra has been carried out using a modified micelle form factor (combination of an ellipsoidal core with the phantom model applied to describe the branches conformation).Les polymacromonomers (PMs) sont des polymères ramifiés bien définis issus de la polymérisation de macromonomères. Les méthodes de synthèse utilisées ici (polymérisation anionique et polymérisation procédant par métathèse et ouverture de cycle) nous ont permis de travailler dans les conditions d?une polymérisation ?vivante? et d?obtenir des PMs (branches de polystyrène (PS) et tronc de polynorbornène) possédant une distribution régulière et élevée de branches. La DNPA s?est avéré idéale pour décrire de façon quantitative la conformation des PMs, en offrant la possibilité de marquer nos polymères sans altérer leur architecture grâce au marquage sélectif. Différents modèles géométriques, tels que des modèles de micelles à c?ur sphérique ou cylindrique, ont été ajustés aux facteurs de forme expérimentaux mesurés par DNPA, en solution comme en fondus. Nous avons démontré que l?architecture influence directement la conformation des PMs et leurs interactions avec le milieu environnant. Notamment, sous certaines conditions apparaît une démixtion purement entropique, due à la structure intrinsèque de PMs dans les mélanges PMs ? PS linéaire. Par ailleurs, les propriétés mécaniques et le comportement dynamique des PMs sont fortement modifiés par la structure ramifiée des PMs. Nous avons mené une étude en rhéologie oscillatoire et comparé la réponse viscoélastique des PMs à celle du PS linéaire. Afin d?établir de façon précise la dynamique de relaxation des PMs, des films étirés puis relaxés ont été étudiés par DNPA. L?interprétation des résultats obtenus est complexe et s?est faite à l?aide d?un modèle de micelle modifié (combinant un c?ur ellipsoïdal et des branches modélisées par le modèle de réseau fantôme)

Etude des résonateurs MEMS à ondes de Lamb - Application au filtrage en fréquence intermédiaire dans les récepteurs de radiotélécommunication

Dans l'optique d'améliorer les performances des récepteurs et émetteurs radio-fréquences (RF) en termes de consommation et d'intégration, les Systèmes Micro-Electro-Mécaniques (MEMS) sont de très bons candidats pour remplacer les composants classiques tels que les commutateurs RF, les résonateurs et les filtres. Un des axes de recherche est actuellement concentré sur la réalisation de résonateurs intégrables sur puce pour les fréquences intermédiaires (FI) dans le but de remplacer les classiques résonateurs et filtres SAW non intégrables. Les résonateurs piézoélectriques à ondes de Lamb (LWR) ont des caractéristiques particulièrement adaptées à cette problématique. Premièrement, ces dispositifs offrent des facteurs de qualité supérieurs à 2000. Deuxièmement, leur intégration est réalisable sur puces et est compatible avec la technologie BAW exploitée par les résonateurs et filtres RF. Troisièmement, les filtres constitués de LWR offrent des impédances d'adaptation (1-2 kΩ) favorables à la très faible consommation. La première partie de cette thèse a donc été focalisée sur la conception de ces dispositifs : étude technologique, modélisation des résonateurs et des filtres, conception des masques et réalisation basée sur la technologie du LETI. Les résonateurs ainsi obtenus atteignent des facteurs de qualité de 2300 (mesure dans l'air). De plus, nous avons réalisé les premiers filtres à couplage acoustique (LCRF) exploitant un guide d'onde entre LWR pour contrôler la bande passante. La seconde partie de la thèse a été orientée vers l'implémentation d'un LWR dans une architecture de réception à convertisseur ΣΔ passe-bande à temps continu. Nous avons ainsi montré qu'ils pouvaient remplacer avantageusement les résonateurs à réseau LC ou à transconductance GmC.To improve performances of radiofrequency (RF) transceivers in terms of power consumption and integration level, Micro-Electro-Mechanical Systems (MEMS) are great candidate to replace standard components such as RF switches, resonators and filters. One of main researches is focused on above-IC intermediate frequency (IF) resonators to replace standard off-chip components such as LC-tank and SAW resonators. Lamb wave resonators (LWR) have several advantages which correspond to the problematic. First, LWRs offer high quality factors (>2000). Second, they are above-IC and suitable for a co-integration with BAW technology used for RF antenna filter. Third, Lamb wave filters, composed of LWR, have high impedances (1-2 kΩ) adapted to ultra low power consumption. The first part on this thesis is focused on the design of Lamb wave resonators and filters: technology optimization, modeling, layout and manufacturing based on LETI technology. In this way, quality factors of 2300 have been obtained for LWR. Moreover, the first filter (LCRF) using a periodic guide to control filter bandwidth have been realized and measured. The second part of this work is focused on implementation of LWRs in continuous-time bandpass ΔΣ modulator (CT BP ΔΣ modulator). LWRs should replace LC-tank and Gm-C transconductor to improve modulator performances

Integrating nuclear receptor mobility in models of gene regulation

The mode of action of nuclear receptors in living cells is an actively investigated field but much remains hypothetical due to the lack, until recently, of methods allowing the assessment of molecular mechanisms in vivo. However, these last years, the development of fluorescence microscopy methods has allowed initiating the dissection of the molecular mechanisms underlying gene regulation by nuclear receptors directly in living cells or organisms. Following our analyses on peroxisome proliferator activated receptors (PPARs) in living cells, we discuss here the different models arising from the use of these tools, that attempt to link mobility, DNA binding or chromatin interaction, and transcriptional activity

The Master and the Slave. A glance at the social life of molecules

Low energy interactions induce the formation of molecular assemblies that can display a large variety of sizes and shapes such as dimers, oligomers, colloids, gels, helices, cylinders, etc. These grouping modes mimic human relationships, as people generally flock together according to their affinities. Moreover, chemical reactions, undergone under strong energy interactions, that result in bond breaking and formation of new compounds, can also be compared to human behaviour. The fables usually involve animals but rarely molecules to play the role of human beings. In this article, we report a molecular tale where two different 9-substituted anthracene derivatives compete in a photochemical reaction, simulating the behaviour of a master and a slave, respectivel