In vivo metabolic profiling of glioma-initiating cells using proton magnetic resonance spectroscopy at 14.1 Tesla.

In the last decade, evidence has emerged indicating that the growth of a vast majority of tumors including gliomas is sustained by a subpopulation of cancer cells with stem cell properties called cancer initiating cells. These cells are able to initiate and propagate tumors and constitute only a fraction of all tumor cells. In the present study, we showed that intracerebral injection of cultured glioma-initiating cells into nude mice produced fast growing tumors showing necrosis and gadolinium enhancement in MR images, whereas gliomas produced by injecting freshly purified glioma-initiating cells grew slowly and showed no necrosis and very little gadolinium enhancement. Using proton localized spectroscopy at 14.1 Tesla, decreasing trends of N-acetylaspartate, glutamate and glucose concentrations and an increasing trend of glycine concentration were observed near the injection site after injecting cultured glioma-initiating cells. In contrast to the spectra of tumors grown from fresh cells, those from cultured cells showed intense peaks of lipids, increased absolute concentrations of glycine and choline-containing compounds, and decreased concentrations of glutamine, taurine and total creatine, when compared with a contralateral non-tumor-bearing brain tissue. A decrease in concentrations of N-acetylaspartate and γ-aminobutyrate was found in both tumor phenotypes after solid tumor formation. Further investigation is needed to determine the cause of the dissimilarities between the tumors grown from cultured glioma-initiating cells and those from freshly purified glioma-initiating cells, both derived from human glioblastomas.

Selective integration of auditory-visual looming cues by humans.

An object's motion relative to an observer can confer ethologically meaningful information. Approaching or looming stimuli can signal threats/collisions to be avoided or prey to be confronted, whereas receding stimuli can signal successful escape or failed pursuit. Using movement detection and subjective ratings, we investigated the multisensory integration of looming and receding auditory and visual information by humans. While prior research has demonstrated a perceptual bias for unisensory and more recently multisensory looming stimuli, none has investigated whether there is integration of looming signals between modalities. Our findings reveal selective integration of multisensory looming stimuli. Performance was significantly enhanced for looming stimuli over all other multisensory conditions. Contrasts with static multisensory conditions indicate that only multisensory looming stimuli resulted in facilitation beyond that induced by the sheer presence of auditory-visual stimuli. Controlling for variation in physical energy replicated the advantage for multisensory looming stimuli. Finally, only looming stimuli exhibited a negative linear relationship between enhancement indices for detection speed and for subjective ratings. Maximal detection speed was attained when motion perception was already robust under unisensory conditions. The preferential integration of multisensory looming stimuli highlights that complex ethologically salient stimuli likely require synergistic cooperation between existing principles of multisensory integration. A new conceptualization of the neurophysiologic mechanisms mediating real-world multisensory perceptions and action is therefore supported.

Multiple causes of the evolution of dispersal in metapopulations

Abstract This work investigates the outcome of the interaction of the multiple causes of selection acting on dispersal in metapopulations. Dispersal, defined here as the ability of individuals to move out of their natal population to reproduce in an other one, has three main causes. First, population variability, as caused by random population extinctions, induces high incentives to disperse through the probability to recolonize an empty population and thus to escape competition for space. This adds to the second cause, kin competition avoidance where individuals in a crowded patch will benefit from the release of competition with relatives caused by dispersal. Dispersal may thus be viewed as an altruistic act. Third, dispersal might evolve as a strategy of avoiding inbred matings which are expected to bear fitness costs due to the presence of a mutation load. The interaction of inbreeding avoidance and kin competition is explored in chapter 2. Conditions conducive to the establishment of a high relatedness within population are expected to induce high dispersal through both kin competition avoidance and inbreeding avoidance. However, the dynamics of inbreeding depression is bound to depend on the level of gene flow as well as on the deleterious mutation parameters. Mutations more prone to settle a high level of inbreeding depression will select for increased dispersal. Chapter 3 investigates the effect of the mating system on the joint dynamics of dispersal and inbreeding depression. Higher inbreeding rates as those found in various mating systems lead to a more efficient purge of the deleterious mutations. However, this decrease in the costs of inbreeding are usually accompanied by a higher within deme relatedness which balances the decreased effect of inbreeding avoidance on the evolution of dispersal. Finally, population turnover, as found in most natural populations has a dual effect on dispersal. Indeed, it increases dispersal by the increased probability of winning a breeding slot in extinct demes it creates but, on the other hand, it counter-selects for dispersal through the slow establishment of unsaturated demic conditions which contribute to lower the local competition for space. Résumé Ce travail se propose d'étudier les effets conjoints des multiples causes de l'évolution de la dispersion en métapopulation. La dispersion, définie ici comme étant la capacité de quitter sa population d'origine pour se reproduire dans une antre population, possède trois principales causes. Premièrement, l'extinction aléatoire de populations sélectionne pour plus de dispersion car elle augmente la Probabilité de recoloniser un patch éteint et donc d'échapper à la compétition locale. La seconde cause, l'évitement de la compétition de parentèle, sélectionne pour plus de dispersion par les bénéfices qu'elle apporte par diminution de la compétition entre individus apparentés. Troisièmement, la dispersion évolue "comme stratégie d'évitement de la dépression de consanguinité présente dans des petites populations isolées. L'interaction entre l'évitement de la consanguinité et de la compétition de parentèle est étudiée dans le chapitre 2. Les conditions conduisant à l'établissement d'un fort apparentement à l'intérieur des populations sont celles qui génèrent le plus de sélection pour la dispersion. Cependant, la dynamique de la dépression de consanguinité est dépendante de la dispersion entre populations ainsi que des paramètres des mutations délétères. Les mutations créant le plus de dépression de consanguinité sont celles qui sélectionneront le plus pour de la dispersion. Le chapitre 3 s'intéresse aux effets du système de reproduction sur la dynamique conjointe du fardeau de mutation et de la dispersion. La purge des mutations délétère étant plus sévère dans des conditions de forte consanguinité, elle diminue les coûts de la consanguinité mais est habituellement accompagné par une augmentation de l'apparentement et donc l'effet peut être neutre sur la dispersion. Finalement, le turnover de populations a un effet dual sur la dispersion. La dispersion est sélectionnée par l'augmentation de la probabilité de gagner une place de reproduction dans des patchs éteints mais elle est également contre sélectionnée par la désaturation des patchs causée par l'extinction et la diminution de la compétition pour l'espace qui intervient dans ce cas.

Identification of pharmaceutical tablets by Raman spectroscopy and chemometrics

Raman spectroscopy has become an attractive tool for the analysis of pharmaceutical solid dosage forms. In the present study it is used to ensure the identity of tablets. The two main applications of this method are release of final products in quality control and detection of counterfeits. Twenty-five product families of tablets have been included in the spectral library and a non-linear classification method, the Support Vector Machines (SVMs), has been employed. Two calibrations have been developed in cascade: the first one identifies the product family while the second one specifies the formulation. A product family comprises different formulations that have the same active pharmaceutical ingredient (API) but in a different amount. Once the tablets have been classified by the SVM model, API peaks detection and correlation are applied in order to have a specific method for the identification and allow in the future to discriminate counterfeits from genuine products. This calibration strategy enables the identification of 25 product families without error and in the absence of prior information about the sample. Raman spectroscopy coupled with chemometrics is therefore a fast and accurate tool for the identification of pharmaceutical tablets.

Ecologia e rappresentazione dello spazio: Saviano, Tournier, DeLillo

Résumé: Great traveller and tireless observer, the Sicilian poet and writer Bartolo Cattafi was trying to escape from his land for his whole life, which was conducted paradoxically autour de sa chambre, but also travelling through islands and continents, where he found inspiration for his poetry and prose. For this reason, his literary contribution, which never betrayed his poetic nature and reporter character, gives an added value to the modern ulyssic dimension. The latter considers travelling as an essential life step and it is closely related to the concept of attachment to its own land. These two perspectives, often met in his different «isole lontane», define the career of this singular migrant figure. Initially he moves to Milan to fulfil the need to find a job. Later he will find in his own Sicily the harmony and the serenity he has been looking for in the course of his travels. The writings collected in 2008 and object of this study reveal interesting affinities to those published in the "Mondadori" series edited by his good friend Vittorio Sereni and that explain part of the works belonging to the Sicilian author, clarifying his topoi and obsessions.

PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients.

The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8(+) T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8(+) T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8(+) T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8(+) T cells, NY-ESO-1-specific CD8(+) T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8(+) T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines. Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1(+) APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8(+) T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8(+) T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8(+) T cell numbers and functions, increasing the likelihood of tumor regression.

Preliminary beta spectrum measurements using a magnetic spectrometer.

We report the performances of a double focusing magnetic beta spectrometer. The energy resolution was measured using conversion peaks of Cs-137 and Ba-133 at 0.73% for 624 keV, and 1.33% for 124 keV. The counting efficiency as a function of the energy was estimated using a P-32 source and was used to correct the measured spectra of Cs-137. The result was compared with the theoretical spectrum and we found a good agreement.

Analyse comparée de régimes institutionnels de gestion des réseaux urbains de l'eau en station touristique de montagne : les cas de Crans-Montana (Suisse) et de Morzine-Avoriaz (France)

La station touristique représente un espace urbain consacré principalement au tourisme, tout en comprenant également une population résidente permanente. Du point de vue de la gestion des réseaux urbains de l'eau, cette caractéristique induit pour ce type de lieu des usages propres à tout espace urbain mais également des spécificités liées à la forte fluctuation saisonnière de la population résidente ou encore à la présence d'usages particuliers tels que l'irrigation des golfs, la production de neige artificielle ou le thermalisme. Dès lors, la planification de l'approvisionnement est délicate et peu prévisible. Ces difficultés sont renforcées par le fait que les concentrations temporelles de la demande coïncident généralement avec des périodes de stress hydrique notable. Dans le cas de stations balnéaires, les pics de fréquentation interviennent en général durant l'été lorsque la ressource en eau est peu disponible. Le problème est similaire dans les stations touristiques de montagne où l'eau est généralement indisponible car stockée sous forme de neige durant les mois de forte fréquentation. De plus, ces difficultés sont souvent renforcées par la localisation géographique des stations touristiques, fréquemment situées dans des espaces sensibles du point de vue de la ressource en eau, avec des situations de pénuries temporelles, voire structurelles. Ces problématiques propres à la plupart des stations touristiques mènent souvent à de fortes rivalités entre, d'une part, les différents usages touristiques de la ressource, et d'autre part, les usages autochtones et touristiques. Les particularités liées au tourisme tendent ainsi à renforcer les rivalités entre différents types de secteurs d'activité (approvisionnement en eau potable, tourisme, hydroélectricité, enneigement artificiel, irrigation, etc.). Ces différents usages de la ressource mis en concurrence nécessitent dès lors la mise en oeuvre de réglementations structurées à travers des politiques publiques ainsi que des droits de propriété et selon des composantes nationales, régionales et locales ; soit un cadre institutionnel que nous proposons d'appeler Régime Institutionnel de Ressource (RIR) (Knoepfel et al. 2001, 2007). A travers cette thèse de doctorat, nous répondons à différentes questions de recherche. Nous tentons d'abord de comprendre comment ces différents RIR sont-ils mis en oeuvre dans le cadre d'espaces touristiques ? Comment ceux-ci sont-ils concrétisés par les acteurs et quels sont leurs effets en termes de durabilité technique, environnementale, sociale et économique des réseaux urbains de l'eau ? Nous questionnons ensuite les effets du tourisme sur la gestion des infrastructures de réseau à l'échelle de la station touristique et de son bassin versant et nous interrogeons sur les effets du tourisme en termes de gestion des eaux urbaines. Nous portons notre attention sur deux stations touristiques situées dans deux contextes institutionnels différents (Crans-Montana en Suisse et Morzine-Avoriaz en France) et y étudions trois types de régimes institutionnels en particulier : la régie directe (gestion publique), l'affermage (gestion déléguée) et la gestion privée des infrastructures. Les résultats de cette thèse de doctorat indiquent tout d'abord dans quelle mesure le tourisme modifie de façon significative la perception et les modalités de gestion de la ressource en eau et des infrastructures. Ils montrent ensuite que l'espace fonctionnel de la gestion de ces infrastructures correspond rarement aux limites du réseau hydrographique naturel et quelles en sont les implications en termes de durabilité. Enfin, la comparaison de différents régimes institutionnels révèle les forces et les faiblesses de chaque modèle de gestion dans le cas spécifique des stations touristiques et également les différentes solutions adoptées localement pour la mise en oeuvre d'un arrangement institutionnel permettant un usage plus ou moins durable des infrastructures de réseau et du réseau hydrographique naturel. - Tourism resort represents an urban area mainly dedicated to tourism while including at the same time a permanent residential population. From the point of view of urban water networks, this characteristic induces a strong seasonal fluctuation of residential population and involves special water uses such as golf irrigation, production of artificial snow or functioning of thermal baths. Therefore, water supply planning can be tricky and difficult to predict. These difficulties are reinforced by the fact that temporary concentrations of water demand coïncidé generally with periods of water stress. In the case of seaside resorts, frequenting peaks arise in general during summer when water resource is less available. The problem is similar in mountainous tourist resorts where water is generally unavailable as it is stored as snow during months of highest frequenting. Furthermore, these difficulties are often reinforced by resorts' geographical localisations, which are often situated in sensitive areas in terms of temporary or structural water shortages. These problematic issues often lead to strong rivalries between tourists' water uses on the one hand, and between locals and tourists uses on the other hand. Thus, features of tourism tend to reinforce rivalries between different sectors of activity (supply of drinking water, tourism, hydroelectricity, artificial snow, irrigation, etc.). These different and competing water uses need the implementation of rules structured through public policies and property rights and through national, regional and local legal components; We propose to call this framework as an Institutional Resource Regime (IRR) (Knoepfel et al. 2001, 2007, 2009). Through this PhD thesis, we answer different research questions. We firstly aim to understand how those different IRR are implemented within tourism spaces? How do actors materialize them and what are their effects in term of technical, environmental, social and economical sustainability of urban water networks? We then, investigate effects of tourism on water networks infrastructures' management at the scale of the tourist resort and its river basin. We focus our attention on two tourist resorts situated within two different institutional contexts (Crans-Montana, Switzerland and Morzine-Avoriaz, France) and study three types of institutional regime in particular: public, delegated and private management of infrastructures. Results of this PhD thesis indicate firstly how tourism modifies in a significant way the perception and management modalities of water resource and infrastructures. Results also show that functional space of infrastructures management rarely matches with the limits of the natural river basin and indicates what it means in terms of sustainability. Finally, the comparison of different institutional regimes reveals the strengths and weakness of each management model in the specific case of tourist resorts and shows the different solutions in locally implementing an institutional arrangement for a more or less sustainable management of network infrastructures and natural water system.

Effect of immune pressure on hepatitis C virus evolution: insights from a single-source outbreak.

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts.

Angiogenesehemmung in der Neuroonkologie. Eine vielversprechende Therapiestrategie gegen maligne Gliome [Angiogenesis inhibition in neurooncology. A very promising therapy strategy for malignant glioma]

The application of angiogenesis inhibitors in neurooncology is increasing. Initially, these drugs seemed to be very promising because of the surprisingly high neuroradiological response rates that were observed in first clinical trials. Meanwhile, this enthusiasm is waning, as the high response rates did not translate into substantial improvements in progression-free and overall survival. Tumor progression during or after antiangiogenic therapy is often associated with rapid clinical neurological deterioration and sometimes even with diffuse infiltrative gliomatosis-like neuroradiological phenotypes. Thus, the characterization and understanding of escape mechanisms are needed. The identification of criteria for defining the personalized use of angiogenesis inhibitors remains a challenge.

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In so-called unisexual teleost fishes, a broad spectrum of evolutionaty stages with varying amounts of sexual elements has evolved. These range from pure sperm-dependent parthenogenesis (gynogenesis) without or with different amounts of paternal leakage to hybridogenesis with hemiclonal diploid gametogenesis or genome elimination folowed by meiosis (meiotic hybridogenesis). All of these phenomena are hybrid origin. Many of these fish form complexes which involve the coexistence of one or more sexually reproducing species with derived all-female forms that have various ploidy levels and reproductive modes, including gynogenesis, (meiotic) hybridogenesis nnd sexual reproduction. In teleosts, parthenogenetic reproduction is strictly dependent on sperm to initate embryonic development. As opposed to true parthenogenesis, sperm-dependent parthenogenetic teleost lineages must primarily coexist with their "sperm donor", usually males from a parental sexual lineage or from a related sexual species. In some systems, gynogens were able to escape from their initial sperm donors ("host switch") and therefore, to enlarge their ranges and ecological niches. Sperm donors normally do not contribue genetically to the next generation. However, paternal leakage is observed in many systems contributing differing amounts of genetic material (from microchromosomes to entire chromosome sets) allowing interaction between genomes of different origin. Hybridogenesis is similar to gynogenesis in depending upon coexisence with sexual species but incorporates recombined genetic material by true fertilizazion. While hybridogens usually form clonal gametes, some triploids are capable of genome elimination followed by a normal diploid meiosis. Sperm-dependent parthenogenesis and hybridogenesis combine disadvantages and advantages from both sexuality and asexuality. Here, we give an overview of sperm-dependent breeding complexes in fishes, discuss the evolutionary consequences of paternal leakage, and speculate about the evolutionary significance of intergenomic (re)combination.

Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease.

Variation in the 3' untranslated region (3'UTR) of the HLA-C locus determines binding of the microRNA Hsa-miR-148a, resulting in lower cell surface expression of alleles that bind miR-148a relative to those alleles that escape its binding. The HLA-C 3'UTR variant was shown to associate with HIV control, but like the vast majority of disease associations in a region dense with causal candidates, a direct effect of HLA-C expression level on HIV control was not proven. We demonstrate that a MIR148A insertion/deletion polymorphism associates with its own expression levels, affecting the extent to which HLA-C is down-regulated, the level of HIV control, and the risk of Crohn disease only among those carrying an intact miR-148a binding site in the HLA-C 3'UTR. These data illustrate a direct effect of HLA-C expression level on HIV control that cannot be attributed to other HLA loci in linkage disequilibrium with HLA-C and highlight the rich complexity of genetic interactions in human disease.

Synorogenic extension in the Tethyan Himalaya documented by structural studies and the Kubler index, Lachung La area, NW India

Tectonic observations in the Tethyan Himalaya reveal an important extensional event that succeeds the emplacement of SW-verging nappes. A major thrust, called the Kum Tso Thrust, has been backfolded and reactivated by normal faulting associated with this event. Measurements of the Kubler index, coupled with characterization of clay-size paragenesis show the effect of normal faulting on the regional metamorphic zonation and indicate that important extension zones, like the Sarchu-Lachung La Normal Fault Zone (SLFZ), exist within the Tethyan Himalaya. Diagenetic limestones from within the SLFZ are characterized by the occurrence of mixed-layered clay phases, kaolinite and an illite with a 001 peak >0.4 Delta degrees2 theta. This zone is bordered by two anchizonal-to-epizonal zones, where illite peaks become narrower. Further to the NE the successive appearance of biotite, chloritoid, garnet and garnet-staurolite-kyanite assemblapes testifies to an increase in metamorphic grade. The cataclastic samples from the normal faults contain kaolinite, smectite and a `broad' illite, indicating that extension occurs under diagenetic conditions.

Two waves of recombinase gene expression in developing thymocytes.

During T cell development in the thymus, T cell receptor (TCR) alpha, beta, gamma, and delta genes are rearranged and expressed. TCR rearrangement strictly depends upon the coordinate activity of two recombinase activating genes, Rag-1 and Rag-2. In this study we have followed the expression of these genes at different stages of intrathymic development. The results indicate that there are two periods of high Rag-1 and Rag-2 mRNA expression. The first wave peaks early at the CD25+CD4-CD8-CD3- stage of development and coincides with the initial appearance of transcripts derived from fully rearranged TCR beta, gamma, and delta genes, whereas the second wave occurs later at the CD4+CD8+ stage coincident with full-length TCR alpha mRNA expression. Active downregulation of Rag-1 and Rag-2 mRNA expression appears to occur in vivo between the two peaks of recombinase activity. This phenomenon can be mimicked in vitro in response to artificial stimuli such as phorbol myristate acetate and calcium ionophore. Collectively our data suggest that recombinase expression is actively regulated during early thymus development independently of cell surface expression of a mature heterodimeric TCR protein complex.

Transforming growth factor beta 1 production by CD4+ CD25+ regulatory T cells in peripheral blood mononuclear cells from healthy subjects stimulated with Leishmania guyanensis.

Transforming growth factor beta (TGF-beta) has been shown to be a central immunomodulator used by leishmaniae to escape effective mechanisms of protection in human and murine infections with these parasites. However, all the information is derived from studies of established infection, while little is known about TGF-beta production in response to Leishmania stimulation in healthy subjects. In this study, TGF-beta1 production was demonstrated in peripheral blood mononuclear cells from healthy subjects never exposed to leishmaniae in response to live Leishmania guyanensis, and the TGF-beta1-producing cells were described as a distinct subpopulation of CD4(+) CD25(+) regulatory T cells. The suppressive properties of CD4(+) CD25(+) T cells were demonstrated in vitro by their inhibition of production of interleukin 2 (IL-2) and IL-10 by CD4(+) CD25(-) T cells in the presence of either anti-CD3 or L. guyanensis. Although neutralization of TGF-beta1 did not reverse the suppressive activity of CD4(+) CD25(+) T cells activated by anti-CD3, it reversed the suppressive activity of CD4(+) CD25(+) T cells activated by L. guyanensis. Altogether our data demonstrated that TGF-beta1 is involved in the suppressive activity of L. guyanensis-stimulated CD4(+) CD25(+) T cells from healthy controls.