<p>The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.</p><p>This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.</p>

Cette th��se propose une nouvelle impl��mentation de "l'approximation de la phase al��atoire avec polarisation contrainte" (constrained Random Phase Approximation, cRPA). Notre impl��mentation repose sur la th��orie de la fonctionnelle de la densit��, d��velopp��e dans une base d'ondes planes augment��es (linearized augmented plane wave, LAPW). Cette m��thode, appliqu��e �� des mat��riaux fortement corr��l��s, permet de calculer de facon r��aliste la matrice d'interaction coulombienne effective, qui pourra ��tre trait��e par la suite au moyen de l'approche �� N-corps souhait��e. En particulier, les valeurs de l'interaction de Hubbard, U , et de l'��change de Hund, J, sont d��termin��es de mani��re ab initio, ainsi que leur d��pendance en fr��quence qui r��sulte des effets dynamiques de l'��crantage. Comme dans la th��orie du groupe de renormalisation de Wilson, l'interaction coulombienne effective d��pend du choix du sous-espace corr��l�� pour lequel est construit un Hamiltonien effectif de basse ��nergie, alors que les valeurs des observables physiques n'en d��pendent pas. Afin de g��n��raliser la cRPA aux mat��riaux dont la structure ��lectronique exhibe des or- bitales corr��l��es et itin��rantes intriqu��es, une m��thode bas��e sur la projection sur le sous-espace corr��l�� est ��galement introduite. Diff��rentes classes de mat��riaux sont envisag��es comme applications : i) pnictures �� base de fer, LaOFeAs et BaFe2As2, et chalcog��nides, FeSe (Chapitre 6), ii) m��taux de transition 3d afin de valider notre m��thode de projection (Chapitre 6), iii) oxydes de m��taux de transition p��rovskites, SrMO3 (M = V, Cr, Mn, Nb, Mo, Tc), et p��rovskites en couches, Sr2MO4 (M = Mo, Tc, Ru, Rh) (Chapitre 7). L'Hamiltonien d'interaction cRPA est ��galement coupl�� �� la th��orie du champ moyen dynamique (LDA+cRPA+DMFT) afin de d��crire l'isolant de Mott induit par le couplage spin-orbite, Sr2IrO4, et le pigment �� base de terre rare, CeSF (Chapitre 8).

Global climate is controlled by two factors, the amount of heat energy received from the sun (solar insolation) and the way that heat is distributed Earth's surface. Solar insolation varies on timescales of 10s to 100s of thousands of years due to changes in the path of Earth's orbit about the sun (Milankovitch cycles). Earth's internal boundary conditions, such as paleogeography, the presence/absence of polar icecaps, atmospheric/oceanic chemistry and sea level, provide distribution and feedback mechanisms for the incoming heat. Variations in these internal boundary conditions may happen abruptly or, as in the case of plate tectonics, take millions of years. We use geochemical and sedimentological techniques to investigate the response of ocean chemistry, regional aridity and atmospheric and oceanic circulation patterns to climate change during both greenhouse and icehouse climates. To explore the connection between orbitally-forced changes in solar insolation, continental aridity and wind, we generated a high-resolution dust record for ~58 Myr old deep-sea sediments from Shatsky Rise. Our data provide the first evidence of a correlation between dust flux to the deep sea and orbital cycles during the Early Paleogene, indicating dust supply (regional aridity) responded to orbital forcing during the last major interval of greenhouse climate. The change in dust flux was comparable to that during icehouse climates implying subtle variations in solar insolation have a similar impact on climate during intervals of over-all warmth as they do during glacial-interglacial states. The Carboniferous Period (359-299 Ma) marks a critical time in Earth's history when a series of tectonic and biological events caused a shift in the mean climate state from a global "greenhouse" to an "icehouse". Geochemical records extracted from sedimentary rocks deposited in shallow epicontinental seaways are increasingly being used to infer relationships between tectonism, carbon cycling and climate and therefore are assumed to reflect global ocean processes. We analyzed radiogenic isotopes in biogenic apatite along a North American transect to constrain the degree of geochemical coupling between the epicontinental seas and the open ocean. Our results argue strongly for decoupling of North American seaways from the open ocean by latest Mississippian time.

The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated. This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.

The building industry makes up a considerable fraction of world&amp / #8217 / s energy consumption. The adverse effects of a growing energy demand such as depletion in fossil fuel reserves and natural resources hassled the building industry to a search for new technologies that result in less energy consumption together with the maximum utilization of natural resources. Energy- and ecology-conscious European countries incorporated the well-being of occupants while conducting research on innovative technologies. In view of the fact that double-skin fa&ccedil / ades offer a healthy and comfortable milieu for the occupants and use natural resources hence consume less energy they became a promising invention for all concerns. The analysis of the performance of the double-skin fa&ccedil / ades and energy consumption is inconclusive at this time. However, based upon thermal performance analysis have been done so far, a double-skin fa&ccedil / ade perform better and provide some energy reduction, particularly on the heating side cycle, from a standard double glazed unit wall. The aim of this study was to examine the relationship between double-skin fa&ccedil / ades and building management systems in intelligent office buildings as they relate to energy efficiency issues thus to find out whether or not the integration of these systems into intelligent buildings provides optimization in energy performance and comfort conditions. The building for the case study, which is an intelligent office building incorporating a double-skin fa&ccedil / ade was selected as one that promises high comfort conditions for the occupants with low energy consumption. The working principles of integrated fa&ccedil / ade systems, together with their advantages and disadvantages were investigated by means of the case study. It was concluded that due to their high initial costs, these systems offer no real advantages for today. However with the inevitable exhaustion of fossil fuels that is foreseen for the future, these systems would become an innovative solution in terms of energy conservation.

Morphine withdrawal increases the HPA axis activity, which is dependent on a hyperactivity of noradrenergic pathways (NTS-A2) innervating the PVN. In this Thesis we found that morphine withdrawal resulted in an increase in ACTH and corticosterone secretion and a neuronal activation in the PVN. Additionally, we found robust increases in CRF and AVP hnRNAs in the PVN, concomitantly with an increase in c-Fos expression. Morphine withdrawal activated ERK1/2 in PVN and NTS, which could be involved in the c-Fos expression. Morphine withdrawal induced an increase in TH mRNA levels in the NTS-A2, total TH protein in the NTS and TH phosphorylation at Ser31 in PVN and NTS-A2, which resulted in an augmentation of TH activity in the PVN. The enhancement in TH phosphorylated at Ser31 was blocked by SL327 in both nuclei. Finally, we have found that adrenalectomy eliminated the hyperactivity of noradrenergic pathways innervating the PVN during morphine withdrawal. / La abstinencia a morfina aumenta la actividad del eje HHA, que depende de la hiperactivación de las vías noradrenérgicas (NTS-A2) que inervan al PVN. En esta Tesis encontramos que la abstinencia a morfina induce la liberación de ACTH y corticosterona y la activación neuronal del PVN. Además, observamos un aumento en los niveles de hnRNA para CRF y AVP en el PVN, concomitantemente con un incremento en la expresión de c-Fos. El síndrome de abstinencia a morfina activó a ERK1/2 en PVN y NTS. También indujo un incremento en el mRNA para TH en el NTS-A2, proteína TH total y fosforilación de TH en su Ser31 en PVN y NTS-A2, que se tradujo en un aumento en su actividad enzimática. El aumento de TH fosforilada en Ser31 fue bloqueado por SL327. Finalmente, la adrenalectomía eliminó la hiperactividad de las vías noradrenérgicas que inervan al PVN durante la abstinencia a morfina.

The goal of this body of research was to elucidate the mechanism by which CD4+ T cells provide help for CD8+ cytotoxic T lymphocyte (CTL) responses in different immunization types. The establishment of diseases, such as chronic infections and cancers, is attributed to severe loss of or dysfunctions of CD4+ T cells. Even in acute infections, CD4+ T cell deficiency leads to poor memory responses. While the role of CD4+ T cells is being increasingly appreciated in these diseases, the timing and nature of CD4+ T help and associated molecular mechanisms are not completely understood. Growing evidence suggests that, depending on the type of infections or immunizations, the requirements of CD4+ T cells can vary for optimal CD8+ CTL responses. In order to understand the modulatory effects of CD4+ T cells for optimal CD8+ CTL responses, two distinct immunization types were chosen. These include: 1) non-inflammatory dendritic cell (DC) immunization, which fails to provide inflammatory/danger signals; and 2) inflammatory adenovirus (AdV) immunization, which provides profound inflammatory/danger signals. This allowed us to study CD4+ T cell’s participation under different inflammatory conditions. The studies described in Chapters 2 and 3 of this thesis were performed to further understand the concept of how CD4+ T cells mediate optimal CD8+ CTL responses. This has been called the “new dynamic model of CD4+ T helper – antigen (Ag)-presenting cells (Th-APCs),” proposed in 2005 by our laboratory. The study described in Chapter 2 shows that Th-APCs participate not only in augmenting CTL-mediated immune responses, perhaps during early phase, but also in regulating cellular immunity, perhaps during a later phase. Through enhanced IL-2, CD80 and CD40L singnaling, and weaker peptideMHC I (pMHC) signaling, Th-APCs stimulated naïve CD8+ T cells to differentiate into effector CTLs, capable of developing into, central memory CTLs. Th-APC-stimulated CD4+ T cells behaved like Th cells in function, augmenting the overall magnitude of CTL responses. In contrast, Th-APCs were able to kill DCs and other Th-APCs, predominantly through perforin-mediated pathway. The experiments described in Chapter 3 revealed a novel co-operative role of cognate Th-CTL interactions, contrary to previously known immune-regulatory mechanisms among Th-Th or CTL-CTL interactions. In our experiments, Th cells, via CD40L, IL-2, and acquired pMHC-I signaling, enhanced CTL survival and transition into functional memory CTLs. Moreover, RT-PCR, flow cytometry and western blot analysis demonstrate that increased survival of Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of FasL and TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (NFATc1, Bcl-10, Casp-3, Casp-4, Casp-7) genes/ molecules. Finally, helped CTLs were also able to induce protection against highly metastasizing tumor challenge, explaining why memory CTLs generated under cognate Th1’s help show survival and recall advantages. The studies in Chapter 4 showed how the precursor frequency (PF) of CD8+ T cells impacts CD4+ T helper requirements for functional CTL responses. At endogenous PF, CD4+ T helper signals were necessary for both primary and memory CTL responses. At increased PF, CD4+ T help, and its CD40L but not IL-2 signal became dispensable for primary CTL responses. In contrast, memory CTL responses required CD4+ T cell signals, largely in the form of IL-2 and CD40L. Thus, these results could impact the development of novel immunotherapy against cancers, since their efficacy would be determined in part by CD4+ T help and CD8+ T cell PF. Finally, the study showed the importance of CD4+ T cells for multiple phases of AdV transgene product-specific CTL responses. These include: a) cognate CD4+ T cells enhanced CTL responses via IL-2 and CD40L signaling during primary, maintenance and memory phases; b) polyclonal CD4+ T environment enhanced the survival of AdV-specific CTL survival, partially explaining protracted CTL contraction phase; and c) during the recall phase, the CD4+ T environment, particularly memory CD4+ T cells, considerably enhanced not only helped, but also unhelped, memory CTL expansion. Thus, these results suggest the participation of both cognate and polyclonal CD4+ T cells for multiple phases of AdV-specific CTLs. Taken together, the current work delineated the critical roles of CD4+ T cells in different stages of CTL responses and in the development of anti-tumor immunity. The results presented here will significantly advance our current understanding of immunity to cancers, autoimmunity and chronic infections, since pathogenesis of these diseases is largely determined by CD4+ T helper functions. As most immunization procedures use the principle that is based on functions of memory cells, the knowledge gained from this work will also have a major impact on designing vaccines against intractable diseases, including cancers and chronic infections. Moreover, in advanced tumors, vaccines developed using this knowledge may act synergistically with other cancer treatments such as irradiation, chemotherapy and microsurgery, minimizing their side effects and prolonging the lives of patients.

Le Limousin (NW du Massif Central) est caractérisé par de larges massifs granitiques mis en place entre 360 et 290 Ma. Ils présentent d'étroites relations spatiales avec de grands accidents ductiles en faille normale et décrochement qui prolongent vers le SE la zone de cisaillement Sud Armoricaine. <br />Le volumineux (~ 10000km3) complexe granitique N-S de Millevaches, limité par des décrochements et failles normales, est un exemple type de granite mis en place dans un contexte tectonique décrochant. <br />Le modèle de mise en place des granites de Millevaches prend en compte l'analyse structurale, microstructurale, magnétique (A.S.M.), gravimétrique et géochronologique (40Ar/39Ar et U/Pb). L'ascension des magmas se fait par des conduits verticaux étroits sous forme d'injections successives qui se relaient le long de l'axe principal N-S des Pradines. Les magmas sont ensuite piégés puis canalisés par la foliation précoce, anisotropie mécanique sub-horizontale majeure de la croûte moyenne. Les magmas syntectoniques du décrochement dextre N-S des Pradines enregistrent des trajectoires de déformation orientées N-S dans la faille et NW-SE de part et d'autre. La poussée du magma au toit du laccolite induit une déformation par aplatissement relaxée par le développement de failles d'échappement sub-horizontales et normales. La mise en place syntectonique des leucogranites du Millevaches, datée à 313 ± 4 Ma est contemporaine du métamorphisme granulitique subi par les roches encaissantes. <br />Le fonctionnement des décrochements du Limousin débute vers 350 Ma et finit vers 300 Ma. Nous proposons que les deux générations de granites (granodiorite-monzogranite et leucogranite) se mettent en place dès 350 Ma, dans une ceinture tectonique résultant d'un contexte en transpression. Les cisaillements ductiles constituent les branches d'un large, long (~700 km), et unique système décrochant lithosphérique analogue à une « pop-up structure » NW-SE dextre allant du Massif Sud Armoricain au Limousin.

科学研究費補助金 研究種目:基盤研究(C)(2) 課題番号:16520205 研究代表者:田所 光男 研究期間:2004-2005年度

The Aegean is a classic setting for studying exhumation of high-pressure (HP) metamorphic rocks. Two end-member models are proposed to explain the uplift of these rocks: core-complex style extension along low-angle normal faults and extrusion-wedge uplift. Extrusion-wedge underplating is the mechanism that exhumed HP rocks on Evia whereas Tinos hosts several detachments varying in age from 30-9 Ma. Andros, situated between them, may be the geological manifestation of the interplay of these processes and provides an opportunity to test these models. Detachments on NW Tinos and on Andros and the enigmatic low-angle Makrotantalon Unit contact on Andros were insufficiently dated prior to this study. Geo- and thermochronometrycombined with structural observations from sampling transects in the transport direction from (1) lower plate Cycladic Blueschist Unit on Andros and Tinos, (2) middle plate Makrotantalon Unit on Andros, and (3) hanging wall Upper Unit address these issues. Maximum depositional ages from detrital zircon U-Pb geochronometry and structures reveal Paleocene-Eocene syn-HP metamorphism thrusting resulted in an inversed-age relationship between the Permian Makrotantalon Unit and the underlying Triassic-Eocene Cycladic Blueschist Unit on Andros. The Makrotantalon Unit has an internal inversed stratigraphy whereas the Cycladic Blueschist Unit on Andros and Tinos appear stratigraphically intact. Structures and zircon and apatite (U-Th)/He ages in transects from NW Tinos (~12-8 Ma) and central Andros Cycladic Blueschist Unit (~13-7 Ma) indicate rapid cooling due to exhumation associated with the Livada Detachment. Older cooling ages (~16-10 Ma) and structures in the Makrotantalon Unit indicate later brittle strain localization on the Makrotantalon Thrust contact is accommodated by rheologically weaker serpentinites and calc-schists, resulting in slivering of the footwall under the Livada Detachment on Andros. Estimated mean cooling slip rates of the Livada Detachment on Andros of ~3.8 (+1.2/-1.3) km/Myr and 2.1 (+0.2/-0.2) km/Myr on NW Tinos resulted in minimum vertical exhumations of 15 km and 4 km, respectively. The NCDS here accommodated ~12-25% of 60 km of HP-rock exhumation from ~30-7 Ma. We present a tectonic model to elucidate the evolution of the Makrotantalon Unit and the magnitude, temporal, and spatial variability of exhumation via detachments on these islands.