Structure and kinematics of the Jungfrau syncline, Faflertal (Valais, Alps), and its regional significance

The formation and structural evolution of the jungrau syncline is described, based on excellent outcrops occurring in the lotschental, in the central alps of switzerland. the quality of the outcrops allows us to demonstrate that the external massifs of the swiss alps have developed due to internal folding. The jungfrau suncline, which separates the autochtonous gastern dome from the aar massif basement gneiss folds, is composed of slivers of basement rocks with their mesozoic sedimentary cover. in the inner faflertal, a side valley of the lotschental, the 200 m thick syncline cp, roses fpir imots, the gastern massif with a reduced mesozoic sedimentary cover in a normal stratigraphic succession, two units of overturned basement rocks with their mesozoic sedimentary cover, and the overturned lower limn of the tschingelhorn gneiss fold of the aar massif with lenses of its sedimentary cover. stratigraphy shows that the lower units, related to the gastern massis, are condensed and that the upper units, deposited farther away from a gastern paleo-high, form a more complete sequence, linked to the doldenhorn meso-cneozoic basin fill. the integration of these local observations with published regional data leads to the following model. on the northern margin of the doldenhorn hbasin, at the northern fringe of the alpine tethuys, the pre-triassic crystalline basement and its mesozoic sedimentary cover were folded by ductile deformation at temperatures above 300 degrees C and in the presence of high fluid pressures, as the helveti c and penninic nappes were overthrusted towards the northwest during the main alpine deformation phase, the visosity contrast between the basement gneisses and the sediments caused the formation of large basement anticlines and tight sedimentary sunclines (mullion-type structures). The edges of basement blocks bounded buy pre-cursor se-dipping normal faults at the northwestern border of the doldenhorn basin were deformed bu simple shear, creating overturned slices of crystalline rocks with their sedimentary cover in what now forms the hungfrau syncline. the localisation of ductile deformation in the vicinity of pre-existing se-dipping faults is thought to have been helped by the circulation of fluids along the faults; these fluids would have been released from the mesozoic sediments by metamorphic dehydration reactions accompanied by creep and dynamic recrystallisation of quartz at temperatures above 300 degrees C. Quantification of the deformation suggests an strain ellipsoid with a ratio (1 + e(1)/+ e(3)) of approximately 1000. The jungfrau suncline was deformed bu more brittle nw-directed shear creating well-developed shear band cleavages at a late stage, after cooling by uplift and erosion. It is suggested that the external massifs of the apls are basement gneiss folds created at temperatures of 300 degrees C by detachment through ductile deformation of the upper crust of the european plate as it was underthrusted below the adriatic plate.

Peroxisome proliferator activated receptor BETA/DELTA as a central player in the skin response to ultra-violets radiation

Previous studies in the lab of Dr. Liliane Michalik, have shown thai the nuclear hormone receptor Peroxisome Proliferator Activated Receptor beta/delta (PPARß/ö) is an important regulator of skin homeostasis, being involved in the regulation of keratinocyte differentiation, inflammation, apoptosis, arid mouse skin wound healing. Studies of PPARß/ö knock out mice have suggested a possible role for this receptor in cancer. However, contradictory observations of the role for PPARß/ö on tumor growth have been published, depending on cellular contexts and biological models. Given the controversial role of PPARß/ö in skin carcinoma development, the main aim of this PhD work has been to further explore the implication of PPARß/ö in skin response to UV and skin tumor growth. This PhD dissertation is divided in four chapters. The first chapter describes the core part of the project, where I explored the changes in miRNA expression in the skin upon chronic UV irradiation of PPARß/ö wild type and knock-out mice. This analysis shed light on a miRNA- PPARß/ö signature and also predicted thai miR-21-3p (previously named miR-21*) is a key regulator of the PPARß/ö-dependent UV response in the pre-lesiona! skin. Using mice acutely UV-irradiated, ! further demonstrated that miR-21-3p is indirectly regulated by PPARß/ö through activation of Transforming Growth Factor (TGFß)-1 under UV exposure. I also show that miR-21-3p is deregulated in human cutaneous squamous celi carcinoma. In cultured keratinocytes, application of a miR-21 -3p mimic oligonucleotide sequence leads to the regulation of lipid metabolism-related pathway. In the second chapter, I demonstrate that the usage of an mRNA/miRNA combined bioinformatics analysis leads to the discovery of important pathways involved in the PPARß/ö-miRNA response of the skin to chronic UV irradiation, indeed, I validated angiogenesis and lipid metabolism as important functions regulated by PPARß/ö in this context. In the third chapter, we demonstrate that PPARß/5 knockout mice have decreased cutaneous squamous cell carcinomas incidence compared to wild type mice and that PPARß/5 directly activates the cSrc kinase gene. In the last chapter, we review novel insights into PPAR functions in keratinocytes and liver, with emphasis on PPARß/ö but also on PPARa. In summary, this PhD study shows that i) PPARß/5 is able to regulate biological function through regulation of miRNAs, and specifically through miR-21-3p, the passenger miRNA of the oncomiR miR-21, and that ii) the PPARß/5-dependent skin response to UV involves the regulation of angiogenesis and lipid metabolism. Furthermore, the bioinformatics study highlights the relevance of performing integrated mRNA and miRNA genome-wide studies in order to better screen mRNAs and/or miRNAs of interest in the biological context of diseases. - Des études préalables dans le laboratoire du Dr. Liliane Michalik ont démontré que le récepteur nucléaire PPARß/5 est un régulateur important de l'homéostasie de la peau, étant impliqué dans la régulation de la différenciation des keratinocytes, dans l'inflammation, dans l'apoptose et dans la cicatrisation de la peau chez !a souris. L'étude de souris knock-out pour le gène PPARß/5, ont suggérées un rôle possible de ce récepteur dans le cancer. Cependant, des observations opposées ont été publiées suggérant un rôle pro- ou anti- cancer selon le tissue impliqué et le type- cellulaire. En considérant cette controverse autour du rôle de PPARß/5 dans le développement des cancers de la peau, le but principal de mon projet de recherche aura été d'approfondir l'exploration du rôle de PPARß/5 dans la réponse de la peau aux UVs et dans le développement du cancer. Cette dissertation de thèse est divisée en quatre parties. Une première partie, représentant le coeur de mon travail de recherche, décrit la découverte de l'implication des microRNAs (rniRNAs) dans la réponse aux UVs de PPARß/ö et plus spécifiquement l'implication du miRNA miR- 21 -3p (précédemment nommé miR-21*). En étudiant un modèle de souris irradiées de manière aigüe aux UVs, nous montrons que ia régulation de miR-21-3p est PPARß/ö-däpenaante et que cette régulation à lieu par l'intermédiaire du facteur de transcription TGFß-1. Dans des cultures de keratinocytes Humains, la transfecticn d'une séquence oligonucléotidique similaire à celle de miR-21-3p (mimic), montre l'implication de rniR-21-3p dans des fonctions importantes pour le développement des cancers telles que le métabolisme des lipides. Dans un second chapitre, nous montrons que l'usage d'une méthode bioinformatique combinant l'expression des ARN messagers et des miRNAs permet de mettre en évidence des fonctions biologiques importantes lors de ia réponse de PPARß/ö à l'irradiation chronique. L'angiogenèse, le stress oxydatif et le métabolisme des lipides font partie de ces fonctions régulées par PPARß/5 dans la peau irradiée aux UVs. Nous mettons également en évidence la régulation du gène LpcatS par PPARß/5 dans la peau irradiée aux UV ainsi que dans des keratinocytes humains suggérant un rôle pour PPARß/5 dans le remodelage des lipides membranaires. Dans une troisième partie, nous établissons un lien entre la régulation de l'oncogène Src et l'activation de PPARß/5 dans les carcinomes spinocellulaires de la peau. Finalement dans un quatrième chapitre, nous faisons une revue des dernières recherches portées sur le rôle de PPARß/5 et de PPARa dans le foie et ia peau. En résumé ce projet de thèse représente un avancement pour la recherche sur rimplication de PPARß/5 dans la réponse aux UVs de la peau. Pour la première fois, un lien est établi entre ce facteur de transcription et la régulation de microRNAs dans le cadre du carcinome spinocellulare. Jusqu'alors resté dans l'ombre de rniR-21-5p, miR-21-3p est en fait fortement augmenté à la fois dans un modèle de souris d'irradiation aux UVs ainsi que dans ie carcinome spinocellulare chez i'humain. De nouvelles fonctions biologiques pour PPARß/5 ont été également mises en évidence dans ce travail, comme la régulation de l'angiogenèse ou du métabolisme des lipides dans Sa peau. De plus cette dissertation valorise l'intérêt d'une association entre le travail de laboratoire et celui de la bioinformatique.

Phylogeography and Pleistocene refugia of the adder (Vipera berus) as inferred from mitochondrial DNA sequence data.

In order to contribute to the debate about southern glacial refugia used by temperate species and more northern refugia used by boreal or cold-temperate species, we examined the phylogeography of a widespread snake species (Vipera berus) inhabiting Europe up to the Arctic Circle. The analysis of the mitochondrial DNA (mtDNA) sequence variation in 1043 bp of the cytochrome b gene and in 918 bp of the noncoding control region was performed with phylogenetic approaches. Our results suggest that both the duplicated control region and cytochrome b evolve at a similar rate in this species. Phylogenetic analysis showed that V. berus is divided into three major mitochondrial lineages, probably resulting from an Italian, a Balkan and a Northern (from France to Russia) refugial area in Eastern Europe, near the Carpathian Mountains. In addition, the Northern clade presents an important substructure, suggesting two sequential colonization events in Europe. First, the continent was colonized from the three main refugial areas mentioned above during the Lower-Mid Pleistocene. Second, recolonization of most of Europe most likely originated from several refugia located outside of the Mediterranean peninsulas (Carpathian region, east of the Carpathians, France and possibly Hungary) during the Mid-Late Pleistocene, while populations within the Italian and Balkan Peninsulas fluctuated only slightly in distribution range, with larger lowland populations during glacial times and with refugial mountain populations during interglacials, as in the present time. The phylogeographical structure revealed in our study suggests complex recolonization dynamics of the European continent by V. berus, characterized by latitudinal as well as altitudinal range shifts, driven by both climatic changes and competition with related species.

Functional compensation of motor function in pre-symptomatic Huntington's disease.

Involuntary choreiform movements are a clinical hallmark of Huntington's disease. Studies in clinically affected patients suggest a shift of motor activations to parietal cortices in response to progressive neurodegeneration. Here, we studied pre-symptomatic gene carriers to examine the compensatory mechanisms that underlie the phenomenon of retained motor function in the presence of degenerative change. Fifteen pre-symptomatic gene carriers and 12 matched controls performed button presses paced by a metronome at either 0.5 or 2 Hz with four fingers of the right hand whilst being scanned with functional magnetic resonance imaging. Subjects pressed buttons either in the order of a previously learnt 10-item finger sequence, from left to right, or kept still. Error rates ranged from 2% to 7% in the pre-symptomatic gene carriers and from 0.5% to 4% in controls, depending on the condition. No significant difference in task performance was found between groups for any of the conditions. Activations in the supplementary motor area (SMA) and superior parietal lobe differed with gene status. Compared with healthy controls, gene carriers showed greater activations of left caudal SMA with all movement conditions. Activations correlated with increasing speed of movement were greater the closer the gene carriers were to estimated clinical diagnosis, defined by the onset of unequivocal motor signs. Activations associated with increased movement complexity (i.e. with the pre-learnt 10-item sequence) decreased in the rostral SMA with nearing diagnostic onset. The left superior parietal lobe showed reduced activation with increased movement complexity in gene carriers compared with controls, and in the right superior parietal lobe showed greater activations with all but the most demanding movements. We identified a complex pattern of motor compensation in pre-symptomatic gene carriers. The results show that preclinical compensation goes beyond a simple shift of activity from premotor to parietal regions involving multiple compensatory mechanisms in executive and cognitive motor areas. Critically, the pattern of motor compensation is flexible depending on the actual task demands on motor control.

T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension.

This article introduces a new interface for T-Coffee, a consistency-based multiple sequence alignment program. This interface provides an easy and intuitive access to the most popular functionality of the package. These include the default T-Coffee mode for protein and nucleic acid sequences, the M-Coffee mode that allows combining the output of any other aligners, and template-based modes of T-Coffee that deliver high accuracy alignments while using structural or homology derived templates. These three available template modes are Expresso for the alignment of protein with a known 3D-Structure, R-Coffee to align RNA sequences with conserved secondary structures and PSI-Coffee to accurately align distantly related sequences using homology extension. The new server benefits from recent improvements of the T-Coffee algorithm and can align up to 150 sequences as long as 10,000 residues and is available from both http://www.tcoffee.org and its main mirror http://tcoffee.crg.cat.