Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules.

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

Additive functions in boolean models of gene regulatory network modules.

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity and solution space, thus making it easier to investigate.

ExpressionView--an interactive viewer for modules identified in gene expression data.

SUMMARY: ExpressionView is an R package that provides an interactive graphical environment to explore transcription modules identified in gene expression data. A sophisticated ordering algorithm is used to present the modules with the expression in a visually appealing layout that provides an intuitive summary of the results. From this overview, the user can select individual modules and access biologically relevant metadata associated with them. AVAILABILITY: http://www.unil.ch/cbg/ExpressionView. Screenshots, tutorials and sample data sets can be found on the ExpressionView web site.

Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome.

The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes.

Modules d'endo-permutation

Dans la th´eorie des repr´esentations modulaires des groupes finis, les modules d?endo-permutation occupent une place importante. En e_et, c?est le r?ole jou´e par ces modules dans l?analyse de la structure de certains modules simples pour des groupes finis p-nilpotents, qui a amen´e E. Dade `a en introduire le concept, en 1978. Quelques ann´ees plus tard, L. Puig a d´emontr´e que la source de n?importe quel module simple pour un groupe fini p-r´esoluble quelconque est un module d?endo-permutation. Plus r´ecemment, on s?est rendu compte que ces modules interviennent aussi dans l?analyse locale des cat´egories d´eriv´ees et dans l?´etude des syst`emes de fusion. La situation que l?on consid`ere est la suivante. On se donne un nombre premier p, un p-groupe fini P, un corps alg´ebriquement clos k de caract´eristique p et on veut d´eterminer tous les kP-modules d?endo-permutation couverts ind´ecomposables de type fini, c?est-`a-dire tous les kP-modules ind´ecomposables de type fini, tels que leur alg`ebre d?endomorphismes est un kP-module de permutation ayant un facteur direct trivial. On d´efinit une relation d?´equivalence sur l?ensemble de ces kP-modules et le produit tensoriel des modules induit une structure de groupe ab´elien sur l?ensemble des classes d?´equivalence. On appelle ce groupe, le groupe de Dade de P. Ainsi, classifier les modules d?endo-permutation couverts revient `a d´eterminer le groupe de Dade de P. Le groupe de Dade d?un p-groupe fini arbitraire est encore inconnu, bien qu?E. Dade, en 1978, ´etait d´ej`a parvenu `a la classification dans le cas o`u P est ab´elien. La premi`ere partie de ce travail de th`ese est consacr´ee au probl`eme de la classification dans le cas g´en´eral et r´esoud la question dans le cas de deux familles de p-groupes finis, `a savoir celle des p-groupes m´etacycliques, pour un nombre premier p impair, et celle des 2-groupes extrasp´eciaux, de la forme D8 _ · · · _ D8. Ces deux choix ont ´et´e motiv´es par le fait que ces groupes sont "presque" ab´eliens. De plus, certains r´esultats sur la structure du groupe de Dade d?un p-groupe fini quelconque rendent le groupe de Dade des groupes de ces deux familles plus simple `a ´etudier. Dans un deuxi`eme temps, nous nous sommes int´eress´es `a deux occurrences de ces modules dans la th´eorie de la repr´esentation des groupes finis, c?est-`a-dire `a deux raisons qui motivent leur ´etude. Ainsi, nous avons r´ealis´e des modules d?endo-permutation comme sources de modules simples. En particulier, il s?av`ere que, dans le cas d?un nombre premier p impair, tout module d?endo-permutation ind´ecomposable dont la classe est un ´el´ement de torsion dans le groupe de Dade est la source d?un module simple. Finalement, nous avons d´etermin´e, parmi tous les modules d?endo-permutation connus actuellement, lesquels poss`edent une r´esolution de permutation endo-scind´ee. Nous sommes arriv´es `a la conclusion que les seuls modules d?endo-permutation qui n?ont pas de r´esolution de permutation endo-scind´ee sont les modules "exceptionnels" apparaissant pour un 2-groupe de quaternions g´en´eralis´es.<br/><br/>In modular representation theory, endo-permutation modules occupy an important position. Indeed, the role that these modules play, in the analysis of the structure of some particular simple modules for finite p-nilpotent groups, induced E. Dade, in 1978, to give them their current name. A few years later, L. Puig proved that the source of any simple module for any finite psolvable group is an endo-permutation module. More recently, the occurrence of endo-permutation modules has also been noticed in the local analysis of splendid equivalences between derived categories and in the study of fusion systems. We consider the following situation. Given a prime number p, a finite pgroup P and an algebraically closed field k of characteristic p, we are looking for all finitely generated indecomposable capped endo-permutation kP-modules. That is, all finitely generated indecomposable kP-modules such that their endomorphism algebra is a permutation kP-module having a trivial direct summand. Then, we define an equivalence relation on the set of all isomorphism classes of such modules, and it turns out that the tensor product (over k) induces a structure of abelian group on this set. We call this group the Dade group of P. Hence, classifying all indecomposable finitely generated capped endo-permutation kPmodules is equivalent to determining the Dade group of P. At present, the Dade group of an arbitrary finite p-group is still unknown. However, E. Dade computed the Dade group of all finite abelian p-groups, in 1978 already. The first part of this doctoral thesis is concerned with the problem of the classification in the general case and solve it in the case of two families of finite p-groups, namely the metacyclic p-groups, for an odd prime number p, and the extraspecial 2-groups of the shape D8 _· · ·_D8. These two choices have been motivated by the fact that these groups are not far from being abelian. Moreover, some general results concerning the Dade group of arbitrary finite p-groups suggest that the Dade group of the groups belonging to these two families is easier to study. In the second part of this thesis, we have been looking at two particular occurrences of these modules in representation theory of finite groups which motivate the interest of their classification. Thus, we realised endo-permutation modules as sources of simple modules. In particular, it turns out that, in case p is an odd prime, any indecomposable module whose class in the Dade group is a torsion element is the source of some simple module. Finally, we considered all the modules we know at present and determined which ones have an endo-split permutation resolution. We could then conclude that all but the "exceptionnal" modules occurring in the generalized quaternion case have an endo-split permutation resolution.<br/><br/>"Module d?endo-permutation" n?est pas le nom d?une maladie exotique contagieuse (du moins pas `a ma connaissance), comme vous pourriez peut-?etre l?imaginer si vous faites partie des personnes qui croient que le titre de docteur n?est destin´e qu?aux m´edecins. Dans ce cas, il se peut que le sujet dont il est question ici vous cause quelques naus´ees et r´eveille de douloureux souvenirs d?´ecole, car un module d?endo-permutation est un objet math´ematique, alg´ebrique, plus pr´ecis´ement. Ce concept a ´et´e introduit il y a un quart de si`ecle, de l?autre c?ot´e de l?Atlantique, et il s?est r´ev´el´e su_samment int´eressant pour qu?aujourd?hui il ait franchi bien des fronti`eres, celles de l?alg`ebre y compris. Mais de quoi s?agit-il ? Si vous entendez le terme "endo-permutation" probablement pour la premi`ere fois, ce n?est certainement pas le cas pour celui de "module". Cependant, sa d´efinition dans le pr´esent contexte ne co¨ýncide avec aucune de celles figurant dans les dictionnaires ordinaires. Les personnes qui ont d´ej`a entendu parler de Frobenius, Burnside, Schur, ou encore Brauer, pourront vous dire qu?un module est une repr´esentation. "De quoi ?" vous demanderezvous. "Un spectacle de marionnettes, peut-?etre ?" Bien s?ur que non ! Un module d?endo-permutation est une repr´esentation particuli`ere de certains groupes finis, o`u un groupe n?est pas un groupe de rock, comme vous pouvez vous en douter, mais d´esigne un objet math´ematique connu par tous les ´etudiants en sciences au terme de leur premi`ere ann´ee universitaire (en th´eorie, du moins). La "popularit´e" de la notion de groupe, fini ou non, est due au fait que les groupes sont fr´equemment utilis´es, aussi bien dans le domaine abstrait des math´ematiques, que dans le monde r´eel des physiciens, chimistes et autres biologistes (pour ne citer qu?eux). "Mais comment peut-on utiliser concr`etement ces objets invisibles ?" vous demanderez-vous alors. Et bien, justement, en les consid´erant par l?interm´ediaire de leurs repr´esentations, c?est-`a-dire en leur associant des matrices, de fa¸con plus ou moins naturelle. Or, comme il y a "beaucoup trop" de matrices pour un groupe donn´e, elles sont classifi´ees selon certaines de leurs propri´et´es, ce qui permet de les r´epertorier dans diverses familles (celle des modules d?endo-permutation, par exemple). Un groupe est ainsi rendu "concret", car les donn´ees matricielles sont manipulables par tous les scienti- fiques (et leurs ordinateurs), qui peuvent alors les utiliser dans leurs recherches, afin de contribuer au progr`es de la science. En toute franchise, c?est bien loin de ces soucis terre-`a-terre que ce travail de th`ese sur la classification des modules d?endo-permutation a ´et´e accompli. En fait, quitte `a choquer certaines ?ames sensibles, sa r´ealisation est surtout due au caract`ere ´epicure de son auteur, qui, avouons-le, en a ´et´e pleinement satisfait !

Establishment of a Developmental Compartment Requires Interactions between Three Synergistic Cis-regulatory Modules.

The subdivision of cell populations in compartments is a key event during animal development. In Drosophila, the gene apterous (ap) divides the wing imaginal disc in dorsal vs ventral cell lineages and is required for wing formation. ap function as a dorsal selector gene has been extensively studied. However, the regulation of its expression during wing development is poorly understood. In this study, we analyzed ap transcriptional regulation at the endogenous locus and identified three cis-regulatory modules (CRMs) essential for wing development. Only when the three CRMs are combined, robust ap expression is obtained. In addition, we genetically and molecularly analyzed the trans-factors that regulate these CRMs. Our results propose a three-step mechanism for the cell lineage compartment expression of ap that includes initial activation, positive autoregulation and Trithorax-mediated maintenance through separable CRMs.

Flippase (FLP) recombinase-mediated marker recycling in the dermatophyte Arthroderma vanbreuseghemii.

Biological processes can be elucidated by investigating complex networks of relevant factors and genes. However, this is not possible in species for which dominant selectable markers for genetic studies are unavailable. To overcome the limitation in selectable markers for the dermatophyte Arthroderma vanbreuseghemii (anamorph: Trichophyton mentagrophytes), we adapted the flippase (FLP) recombinase-recombination target (FRT) site-specific recombination system from the yeast Saccharomyces cerevisiae as a selectable marker recycling system for this fungus. Taking into account practical applicability, we designed FLP/FRT modules carrying two FRT sequences as well as the flp gene adapted to the pathogenic yeast Candida albicans (caflp) or a synthetic codon-optimized flp (avflp) gene with neomycin resistance (nptII) cassette for one-step marker excision. Both flp genes were under control of the Trichophyton rubrum copper-repressible promoter (PCTR4). Molecular analyses of resultant transformants showed that only the avflp-harbouring module was functional in A. vanbreuseghemii. Applying this system, we successfully produced the Ku80 recessive mutant strain devoid of any selectable markers. This strain was subsequently used as the recipient for sequential multiple disruptions of secreted metalloprotease (fungalysin) (MEP) or serine protease (SUB) genes, producing mutant strains with double MEP or triple SUB gene deletions. These results confirmed the feasibility of this system for broad-scale genetic manipulation of dermatophytes, advancing our understanding of functions and networks of individual genes in these fungi.

Can a targeted psychological intervention be effective for young people following a first manic episode? Results from an 18-month pilot study.

Aim: There is a scarce literature describing psychological interventions for a young, first-episode cohort who have experienced psychotic mania. This study aimed to assess whether a manualized psychological intervention could be effective in reducing symptomatology and relapse, and improve functional outcome in this population. Methods: The study was an open-label design, drawn from a larger pharmacotherapy trial. All participants in the pharmacotherapy trial were offered a manualized psychological intervention in addition to case management. Inclusion in the psychotherapy group was based on participant's choice, and on completion of four or more of the eight modules offered. All clinical files were audited to ensure accuracy of group allocation. Forty young people aged 15 to 25 years old who had experienced a manic episode with psychotic features were recruited into the study, with 20 people in the combined treatment as usual plus psychotherapy group (P+TAU), and an equal number of matched control participants who received treatment as usual (TAU) within the same service. All participants were prescribed antipsychotic and mood-stabilizing medication. Symptomatic, functional and relapse measures were taken both at baseline and at 18-month follow-up. Results: Manic symptoms improved significantly for both groups, with no differences between groups. Depression scores and overall symptom severity were significantly lower in the P + TAU group. No differences were evident between groups with regard to numbers or type of relapse. The P + TAU group had significantly better social and occupational functioning after 18 months. Conclusion: This study suggests that a manualized psychological intervention targeted to a first-episode population can be effective in reducing depression and overall symptom severity, and can improve functional outcome following a first episode of psychotic mania.

Programme de remédiation cognitive pour patients présentant une schizophrénie ou un trouble associé (Recos) : résultats préliminaires [Cognitive remediation program for individuals living with schizophrenia (Recos): preliminary results].

BACKGROUND: Nowadays, cognitive remediation is widely accepted as an effective treatment for patients with schizophrenia. In French-speaking countries, techniques used in cognitive remediation for patients with schizophrenia have been applied from those used for patients with cerebral injury. As cognitive impairment is a core feature of schizophrenia, the Département de psychiatrie du CHUV in Lausanne (DP-CHUV) intended to develop a cognitive remediation program for patients with a schizophrenia spectrum disease (Recos-Vianin, 2007). Numerous studies show that the specific cognitive deficits greatly differ from one patient to another. Consequently, Recos aims at providing individualized cognitive remediation therapy. In this feasibility trial, we measured the benefits of this individualized therapy for patients with schizophrenia. Before treatment, the patients were evaluated with a large battery of cognitive tests in order to determine which of the five specific training modules - Verbal memory, visuospatial memory and attention, working memory, selective attention, reasoning - could provide the best benefit depending on their deficit. OBJECTIVES: The study was designed to evaluate the benefits of the Recos program by comparing cognitive functioning before and after treatment. METHOD: Twenty-eight patients with schizophrenia spectrum disorders (schizophrenia [n=18], schizoaffective disorder [n=5], schizotypal disorder [n=4], schizophreniform disorder [n=1], DSM-IV-TR) participated in between one and three of the cognitive modules. The choice of the training module was based on the results of the cognitive tests obtained during the first evaluation. The patients participated in 20 training sessions per module (one session per week). At the end of the training period, the cognitive functioning of each patient was reevaluated by using the same neuropsychological battery. RESULTS: The results showed a greater improvement in the cognitive functions, which were specifically trained, compared to the cognitive functions, which were not trained. However, an improvement was also observed in both types of cognitive functions, suggesting an indirect cognitive gain. CONCLUSION: In our view, the great heterogeneity of the observed cognitive deficits in schizophrenia necessitates a detailed neuropsychological investigation as well as an individualized cognitive remediation therapy. These preliminary results need to be confirmed with a more extended sample of patients.

Cardiac expression of ms1/STARS, a novel gene involved in cardiac development and disease, is regulated by GATA4.

Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease.

Traitement individualisé des déficits cognitifs de la schizophrénie

Quatre-vingt pour-cent des personnes souffrant de schizophrénie présentent des déficits cognitifs dans le domaine de la mémoire, de l'attention et des fonctions exécutives. Tous les patients ne présentent cependant pas les mêmes déficits et plusieurs recherches ont tenté d'identifier les différents profils cognitifs observés dans cette pathologie. Dans la même volonté de cibler les déficits cognitifs de manière spécifique, nous avons développé depuis plusieurs années un programme de remédiation cognitive. Le programme de remédiation cognitive pour patients présentant une schizophrénie ou un trouble associé (RECOS) propose ainsi d'entraîner la mémoire verbale, la mémoire et l'attention visuospatiales, la mémoire de travail, l'attention sélective et le raisonnement. Au-delà des modules d'entraînement proposés, le programme vise à adapter le traitement en fonction des ressources et difficultés observées chez chacun des participants durant les séances de remédiation. Les aspects de transfert et de généralisation de l'apprentissage sont également traités en priorité par le programme RECOS. Une étude de cas permet d'illustrer notre manière d'intervenir de manière individualisée, et de comprendre l'articulation entre le travail en séance et les objectifs très concrets de réinsertion professionnelle. En conclusion, nous soulignons l'importance d'intégrer la remédiation cognitive dans une prise en charge considérée dans sa globalité.

Involvement of PPARβ/δ in mesenchymal-epidermal interactions during skin wound healing

SUMMARY : Skin wound repair is a complex and highly coordinated process, where a variety of cell types unite to regenerate the damaged tissue. Several works have elucidated cellular and molecular mechanisms, in which mesenchymal-epidermal interactions play an essential role for the regulation of skin homeostasis and repair. Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily. Three related isotypes (PPARα, PPARß/δ and PPARγ) have been found, which exhibit distinct tissue distribution and specific physiological functions. PPARß/δ was identified as a crucial player of skin homeostasis. In the mouse skin, PPARß/δ has been described to control proliferation-differentiation state, adhesion and migration, and survival of the keratinocytes during healing. PPARß/δ has been implicated as well in the development of the hair follicles, in which mesenchymal-secreted hepatocyte growth factor (HGF) is involved. These data suggest that the biological activity of PPARß/δ is modulated by mesenchymal-epidermal interactions and that, in turn, PPARß/δ also modulates some of these signals. The aim of the present work was to elucidate the nature of the signals exchanged between the epidermis and dermis compartments, and more particularly those which are under the control of PPARß/δ. In the first part of the study, we showed that PPARß/8 in dermal fibroblasts down-regulates the mitotic activity of keratinocytes by inhibiting the IL-1 signalling pathway via the production of secreted IL-1 receptor antagonist (sIL-1Ra), a natural antagonist of this signalling. The regulation of IL-1 signalling by PPARß/δ is required for anon-pathological skin wound repair. These findings provide evidence for a novel homeostatic control of keratinocyte proliferation and differentiation mediated by the regulation of IL-1 signalling via dermal PPARß/δ fibroblasts. Proteolysis of the extracellular matrix (ECM) is a key process involved in wound repair and modifications in its activity are often associated with an alteration óf the wound closure. This process implies specific proteinases, as matrix metalloproteinases (MMPs), which are finely modulated by IL-1 signalling. In line with the first results, the second part of the work showed that MMP8 and MMP13, which are two important collagenases involved in mouse skin wound repair, are regulated by PPARß/δ. Their expression is indirectly down-regulated by dermal PPARß/δ, via the production of sIL-1Ra, resulting in the inhibition of IL-1 signalling, known to regulate the expression of numerous MMPs. We suggest that, in absence of PPARß/δ, the positive regulation of these two collagenases could participate to the delay of skin wound healing, which has been observed in mice deleted for PPARßlS. The potential therapeutic role of PPARß/b could be as well extending to inflammatory and hyperproliferative skin diseases involving IL-1 signalling, such as psoriasis or skin cancers. Quite interestingly, MMP1 (analogue of mouse MMP13) plays an essential role in human photoaging, suggesting that PPARß/δ could as well be an attractive target for photoprotection. RESUME : La cicatrisation est un processus complexe et extrêmement organisé, impliquant un grand nombre de cellules qui s'unissent pour régénérer le tissu endommagé. De nombreux travaux nous ont éclairés sur les mécanismes cellulaires et moléculaires, dans lesquels les interactions épidermo-mésenchymateuses détiennent un rôle capital à la fois dans la régulation de l'homéostasie et dans la réparation de la peau. PPAR (Peroxisome proliferatar-activated receptor), qui appartient à la superfamille des récepteurs nucléaires, se définit comme un facteur de transcription activé par des ligands très spécifiques. Trois isotypes (PPARa, PPARß/δ et PPARy) ont été décrits et sont caractérisés par une distribution tissulaire et des fonctions physiologiques clairement définies. PPARß/δ a été identifié comme étant un important acteur dans l'homéostasie de la peau. Chez la souris, il a été décrit comme contrôlant l'état de prolifération et de différenciation, le processus d'adhésion et de migration, ainsi que la survie des kératinocytes au cours de la cicatrisation. PPARßIS a également été défini comme contrôlant le développement des follicules pileux, impliquant la sécrétion par le mésenchyme du facteur de croissance HGF. Ces données suggèrent que l'activité biologique de PPARß/δ est modulée par des interactions épidermo-mésenchymateuses, et qu'en retour, il possède la capacité de moduler certains de ces signaux. L`objectif de ce travail a été d'élucider la nature des signaux échangés entre les compartiments épidermique et dermique, et plus particulièrement ceux qui sont sous le contrôle de PPARß/δ. Dans la première partie de l'étude, nous avons montré que les fibroblastes exprimant PPARß/δ réduisent l'activité mitotique des kératinocytes en inhibant la voie de signalisation IL-1, via la production de sIL-1Ra (secreted IL-1 receptor antagonist), défini comme un antagoniste naturel de cette voie de signalisation. La régulation de cette dernière par PPARß/δ est donc nécessaire pour une cicatrisation de type non pathologique. Ces résultats offrent donc une nouvelle preuve du contrôle de l'homéostasie et de l'état de prolifération/différenciation des kératinocytes par les fibroblastes exprimant PPARß/δ, en régulant la voie de signalisation IL-1. Le mécanisme de dégradation de la matrice extracellulaire (MEC) est une étape essentielle lors du processus de cicatrisation. Ainsi des modifications de cette activité protéolytïque sont souvent associées à une altération de la fermeture de la plaie. Ce processus implique des protéinases, comme les MMPs, qui sont finement modulés par la voie de signalisation IL-1. En accord avec les premiers résultats, la seconde partie des nos travaux a montré que les collagénases MMP8 et MMP13, connues pour être d'importantes molécules impliquées lors de la réparation tissulaire chez la souris, sont modulées par l'activité de PPARß/δ. Leurs expressions sont indirectement régulées par PPARß/δ, via la production. de sIL-1 Ra, entraînant ainsi l'inhibition de la voie de signalisation IL-1, décrite pour réguler l'expression de nombreuses MMPs, Nous suggérons donc qu'en absence de PPARß/δ, la régulation de ces deux collagénases pourrait être impliquée dans le retard de cicatrisation, observé chez les souris déficientes pour PPARß/δ. L'activité biologique de PPARß/δ pourrait être ainsi étendue à des maladies hyperproliferatives et inflammatoires de la peau, impliquant la voie de signalisation IL-1, comme le psoriasis ou certains cancers de la peau, et ce à des fins thérapeutiques. Il est aussi intéressant de relever que chez l'homme, MMP1 (présenté comme l'analogue de MMP13 de la souris} joue un rôle primordial dans le photo-vieillissement, nous suggérons donc que PPARß/δ pourrait ainsi être une cible attrayante concernant la photoprotection.

White matter maturation reshapes structural connectivity in the late developing human brain.

From toddler to late teenager, the macroscopic pattern of axonal projections in the human brain remains largely unchanged while undergoing dramatic functional modifications that lead to network refinement. These functional modifications are mediated by increasing myelination and changes in axonal diameter and synaptic density, as well as changes in neurochemical mediators. Here we explore the contribution of white matter maturation to the development of connectivity between ages 2 and 18 y using high b-value diffusion MRI tractography and connectivity analysis. We measured changes in connection efficacy as the inverse of the average diffusivity along a fiber tract. We observed significant refinement in specific metrics of network topology, including a significant increase in node strength and efficiency along with a decrease in clustering. Major structural modules and hubs were in place by 2 y of age, and they continued to strengthen their profile during subsequent development. Recording resting-state functional MRI from a subset of subjects, we confirmed a positive correlation between structural and functional connectivity, and in addition observed that this relationship strengthened with age. Continuously increasing integration and decreasing segregation of structural connectivity with age suggests that network refinement mediated by white matter maturation promotes increased global efficiency. In addition, the strengthening of the correlation between structural and functional connectivity with age suggests that white matter connectivity in combination with other factors, such as differential modulation of axonal diameter and myelin thickness, that are partially captured by inverse average diffusivity, play an increasingly important role in creating brain-wide coherence and synchrony.

Dihydroaeruginoic acid synthetase and pyochelin synthetase, products of the pchEF genes, are induced by extracellular pyochelin in Pseudomonas aeruginosa.

The siderophore pyochelin of Pseudomonas aeruginosa is derived from one molecule of salicylate and two molecules of cysteine. Two cotranscribed genes, pchEF, encoding peptide synthetases have been identified and characterized. pchE was required for the conversion of salicylate to dihydroaeruginoate (Dha), the condensation product of salicylate and one cysteine residue and pchF was essential for the synthesis of pyochelin from Dha. The deduced PchE (156 kDa) and PchF (197 kDa) proteins had adenylation, thiolation and condensation/cyclization motifs arranged as modules which are typical of those peptide synthetases forming thiazoline rings. The pchEF genes were coregulated with the pchDCBA operon, which provides enzymes for the synthesis (PchBA) and activation (PchD) of salicylate as well as a putative thioesterase (PchC). Expression of a translational pchE'-'lacZ fusion was strictly dependent on the PchR regulator and was induced by extracellular pyochelin, the end product of the pathway. Iron replete conditions led to Fur (ferric uptake regulator)-dependent repression of the pchE'-'lacZ fusion. A translational pchD'-'lacZ fusion was also positively regulated by PchR and pyochelin and repressed by Fur and iron. Thus, autoinduction by pyochelin (or ferric pyochelin) and repression by iron ensure a sensitive control of the pyochelin pathway in P. aeruginosa.

3D gait assessment in young and elderly subjects using foot-worn inertial sensors.

This study describes the validation of a new wearable system for assessment of 3D spatial parameters of gait. The new method is based on the detection of temporal parameters, coupled to optimized fusion and de-drifted integration of inertial signals. Composed of two wirelesses inertial modules attached on feet, the system provides stride length, stride velocity, foot clearance, and turning angle parameters at each gait cycle, based on the computation of 3D foot kinematics. Accuracy and precision of the proposed system were compared to an optical motion capture system as reference. Its repeatability across measurements (test-retest reliability) was also evaluated. Measurements were performed in 10 young (mean age 26.1±2.8 years) and 10 elderly volunteers (mean age 71.6±4.6 years) who were asked to perform U-shaped and 8-shaped walking trials, and then a 6-min walking test (6MWT). A total of 974 gait cycles were used to compare gait parameters with the reference system. Mean accuracy±precision was 1.5±6.8cm for stride length, 1.4±5.6cm/s for stride velocity, 1.9±2.0cm for foot clearance, and 1.6±6.1° for turning angle. Difference in gait performance was observed between young and elderly volunteers during the 6MWT particularly in foot clearance. The proposed method allows to analyze various aspects of gait, including turns, gait initiation and termination, or inter-cycle variability. The system is lightweight, easy to wear and use, and suitable for clinical application requiring objective evaluation of gait outside of the lab environment.