Thymic selection generates a large T cell pool recognizing a self-peptide in humans.

The low frequency of self-peptide-specific T cells in the human preimmune repertoire has so far precluded their direct evaluation. Here, we report an unexpected high frequency of T cells specific for the self-antigen Melan-A/MART-1 in CD8 single-positive thymocytes from human histocompatibility leukocyte antigen-A2 healthy individuals, which is maintained in the peripheral blood of newborns and adults. Postthymic replicative history of Melan-A/MART-1-specific CD8 T cells was independently assessed by quantifying T cell receptor excision circles and telomere length ex vivo. We provide direct evidence that the large T cell pool specific for the self-antigen Melan-A/MART-1 is mostly generated by thymic output of a high number of precursors. This represents the only known naive self-peptide-specific T cell repertoire directly accessible in humans.

Chemotherapy induces tumor metastasis and dormancy

Chemotherapy is widely used as a systemic treatment modality in cancer patients and provides survival benefits for a significant fraction of treated patients H However, some patients suffer from cancer relapse and rapidly progress to metastasis, suggesting that following chemotherapy their residual tumor developed a more aggressive phenotype 4 5. Although some molecular mechanisms involved in chemo-resistance and chemotherapy-induced metastatic relapse have been reported, more investigations and understanding of these processes are necessary before any translation into the clinic might be considered. By using the syngeneic metastatic 4T1 murine breast cancer model, we observed that chemotherapy treatment and selection of chemotherapy-resistant cancer cells in vitro can induces two opposite phenotypes: a dormant one and a relapsing-metastatic one. Previous studies in our laboratory demonstrated that irradiation of mammary gland promotes tumor metastasis, at least in part, by inducing the recruitment of CD11b+ cells to both the primary tumor and the lungs at a pre-metastatic stage. In this study we found that CD11b+ cells may also play important roles in chemotherapy-induced tumor metastasis and dormancy in vivo. Tumor cells expressing the stem cell marker Sca-1 were enriched by chemotherapy treatment in vitro, as well as in tumor metastasis in vivo. Furthermore, tumor-derived CD11b+ cells were capable to maintain and expand this population in vitro. These results suggest that the expansion of a tumor cell population with stem cell features might be a mechanism by which chemotherapy induces metastasis. On the other hand, the same drug treatment in vitro generated resistant cells with a dormant phenotype. Dormant tumor cells were able to induce an in vivo immune- inflammatory response in the draining lymph node, which is normally absent due to the immunosuppressive effects of tumor-recruited myeloid derived- suppressor cells (MDSCs). Genome-wide gene expression analysis revealed the enrichment of invasion and metastasis-related genes in the relapsing metastatic tumor cells and immune response-related genes in the dormant tumor cells. Interestingly, CD11b+ cells derived from the microenvironment of growing-metastatic tumors, but not CD11b+ cells derived from the spleen of tumor-free mice, were able to instigate outgrowth of dormant tumor cells in vivo. Also, dormant cells formed growing and metastatic tumors when injected into immune-compromised NGS mice. These results point to a role of chemotherapy in enabling treated tumor cells to acquire immune response-inducing capabilities, while impairing the recruitment of CD11b+ cells and their differentiation into an immune-suppressive cell. The molecular mechanisms underneath these effects are being further investigated. In conclusion, results obtained in this model indicate that chemotherapy can induce a dormant phenotype in cancer cells and that this state of dormancy can be broken by MDSCs educated by relapsing tumors. Understanding the mechanism beyond these effects, in particular unraveling the genetic or epigenetic determinants of dormancy vs relapse, might open the way to therapies aimed and maintaining residual cells escaping chemotherapy in a state of sustained dormancy. - La chimiothérapie est un traitement systémique largement utilisé chez les patients cancéreux qui donne un avantage de survie significatif pour une bonne partie de patients traités (1-3). Cependant, certains patients souffrent d'une rechute et progressent ensuite vers la métastase. Ceci suggère que leur tumeur résiduelle a développé un phénotype agressif suite à la chimiothérapie (4-5). Bien que certains mécanismes moléculaires impliqués dans la chimiorésistance et la rechute métastatique ont été identifiés, d'avantage d'études sont nécessaires afin de mieux comprendre ce phénomène et de développer des nouvelles thérapies cliniques. En utilisant un modèle syngénique de cancer du sein métastatique chez la sourie (4T1), nous avons observé que la sélection des cellules cancéreuses résistantes à la chimiothérapie in vitro peut induire deux phénotypes opposés: un phénotype de dormance et un phénotype de progression métastatique. Une étude précédente issue de notre laboratoire a démontré que l'irradiation de la glande mammaire favorise la métastase de tumeurs recourants suite au recrutement de cellules CD11b+ dans la tumeur primaire et dans les poumons pré-métastatiques. Dans notre étude nous avons constaté que les cellules CD11b+ peuvent également jouer un rôle important dans la formation de métastases induites par la chimiothérapie ainsi que dans le maintien de la dormance in vivo. Nous avons également observé un enrichissement de cellules tumorales exprimant le marqueur de cellule souche Sca-1 parmi les cellules tumorales résistantes à la chimiothérapie et dans les cellules qui on formé des métastases in vivo. Des cellules CD11b+ dérivées du microenvironnement tumorale favorisent l'expansion de la population de cellules tumorales Sca-1+ in vitro. Ces résultats suggèrent que l'expansion d'une population de cellules tumorales avec des caractéristiques de cellules souches pourrait constituer un mécanisme par lequel la chimiothérapie induit des métastases dans des tumeurs récurrentes. D'autre part le même traitement de chimiothérapie peut générer des cellules résistantes avec un phénotype dormant. Les expériences in vivo indiquent que les cellules tumorales dormantes induisent une réponse immunitaire inflammatoire dans le ganglion lymphatique de drainage, qui est normalement réprimée par des cellules myéloïdes suppressives de tumeur (MDSC). Une analyse d'expression de gènes a révélé l'enrichissement de gènes liés à l'invasion et à la métastase dans les cellules tumorales récurrentes et des gènes liés à la réponse immunitaire dans les cellules tumorales dormantes. Les cellules CD11b+ issues du microenvironnement des tumeurs récurrents ont incité la croissance des cellules tumorales dormantes in vivo, tandis que les cellules CD11b+ dérivées de la rate de souris non porteuses de tumeur ne l'étaient pas. Les mécanismes moléculaires sous-jacents restent à découvrir. En conclusion, les résultats obtenus dans ce modèle indiquent que la chimiothérapie pourrait favoriser non seulement l'induction d'une dormance cellulaire, mais également que les cellules dormantes seraient adroits de induire une réponse immunitaire capable les maintenir dans un état de dormance prolongé. Un déséquilibre dans cette réponse immunitaire pourrait des lors briser cet état de dormance et induire une progression tumorale. Comprendre les mécanismes responsables de ces effets, en particulier l'identification des déterminants génétiques ou épigénétiques liés à la dormance vs la rechute, pourraient ouvrir la voie à des nouvelles thérapies visant le maintien d'un état de dormance permanente des cellules résiduelles après chimiothérapie.

Strategy selection during exploratory behavior: sex differences

This study was designed to assess sex-related differences in the selection of an appropriate strategy when facing novelty. A simple visuo-spatial task was used to investigate exploratory behavior as a specific response to novelty. The exploration task was followed by a visual discrimination task, and the responses were analyzed using signal detection theory. During exploration women selected a local searching strategy in which the metric distance between what is already known and what is unknown was reduced, whereas men adopted a global strategy based on an approximately uniform distribution of choices. Women's exploratory behavior gives rise to a notion of a secure base warranting a sense of safety while men's behavior does not appear to be influenced by risk. This sex-related difference was interpreted as a difference in beliefs concerning the likelihood of uncertain events influencing risk evaluation. Keywords: exploration, spontaneous strategies, sex differences, decision-making.

Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone

Chloroquine has been the mainstay of malaria chemotherapy for the past five decades, but resistance is now widespread. Pyrimethamine or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chloroquine resistance. Both pyrimethamine and proguanil are dihydrofolate reductase (DHFR) inhibitors, the proguanil acting primarily through its major metabolite cycloguanil. Resistance to these drugs arises due to specific point mutations in the dhfr gene. Cross resistance between cycloguanil and pyrimethamine is not absolute. It is, therefore, important to investigate mutation rates in P. falciparum for pyrimethamine and proguanil so that DHFR inhibitor with less mutation rate is favored in drug combinations. Hence, we have compared mutation rates in P. falciparum genome for pyrimethamine and cycloguanil. Using erythrocytic stages of P. falciparum cultures, progressively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence. Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil. It enhances the degree of genomic polymorphism leading to diversity of natural parasite population which in turn is predisposes the parasites for faster selection of resistance to some other antimalarial drugs.

Public sector rationing and private sector selection [paper accepted and forthcoming in Journal of Public Economic Theory]

We study the interaction between nonprice public rationing and prices in the private market. Under a limited budget, the public supplier uses a rationing policy. A private firm may supply the good to those consumers who are rationed by the public system. Consumers have different amounts of wealth, and costs of providing the good to them vary. We consider two regimes. First, the public supplier observes consumers' wealth information; second, the public supplier observes both wealth and cost information. The public supplier chooses a rationing policy, and, simultaneously, the private firm, observing only cost but not wealth information, chooses a pricing policy. In the first regime, there is a continuum of equilibria. The Pareto dominant equilibrium is a means-test equilibrium: poor consumers are supplied while rich consumers are rationed. Prices in the private market increase with the budget. In the second regime, there is a unique equilibrium. This exhibits a cost-effectiveness rationing rule; consumers are supplied if and only if their costbenefit ratios are low. Prices in the private market do not change with the budget. Equilibrium consumer utility is higher in the cost-effectiveness equilibrium than the means-test equilibrium [Authors]

Le point de vue d'un sociologue de la religion

(Résumé de l'ouvrage) Ce livre a trait ici au ministère pastoral, problème central de la théologie aux yeux du théologien protestant Jean-Louis Leuba. Se joue en effet sur le ministère toute la question de la transmission du credo et de la légitimation de sa vérité aux diverses époques. Jean-Louis Leuba propose en préambule du livre des thèses sur le ministère que ses interlocuteurs - théologiens protestants, catholiques, luthériens, ainsi qu'un sociologue des religions - vont reprendre pour les accueillir avec leurs sensibilités ou les réfuter.

Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro.

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (-0.47 Deltalog(10) CFU/ml. h) which was comparable to that of levofloxacin (-0.49 Deltalog(10) CFU/ml. h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (-1.04 Deltalog(10) CFU/ml. h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (parC and parE) and gyrase (gyrA and gyrB) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.

Conserved non-genic sequences - an unexpected feature of mammalian genomes.

Mammalian genomes contain highly conserved sequences that are not functionally transcribed. These sequences are single copy and comprise approximately 1-2% of the human genome. Evolutionary analysis strongly supports their functional conservation, although their potentially diverse, functional attributes remain unknown. It is likely that genomic variation in conserved non-genic sequences is associated with phenotypic variability and human disorders. So how might their function and contribution to human disorders be examined?

Sound Texture Modelling

In the PhD thesis “Sound Texture Modeling” we deal with statistical modelling or textural sounds like water, wind, rain, etc. For synthesis and classification. Our initial model is based on a wavelet tree signal decomposition and the modeling of the resulting sequence by means of a parametric probabilistic model, that can be situated within the family of models trainable via expectation maximization (hidden Markov tree model ). Our model is able to capture key characteristics of the source textures (water, rain, fire, applause, crowd chatter ), and faithfully reproduces some of the sound classes. In terms of a more general taxonomy of natural events proposed by Graver, we worked on models for natural event classification and segmentation. While the event labels comprise physical interactions between materials that do not have textural propierties in their enterity, those segmentation models can help in identifying textural portions of an audio recording useful for analysis and resynthesis. Following our work on concatenative synthesis of musical instruments, we have developed a pattern-based synthesis system, that allows to sonically explore a database of units by means of their representation in a perceptual feature space. Concatenative syntyhesis with “molecules” built from sparse atomic representations also allows capture low-level correlations in perceptual audio features, while facilitating the manipulation of textural sounds based on their physical and perceptual properties. We have approached the problem of sound texture modelling for synthesis from different directions, namely a low-level signal-theoretic point of view through a wavelet transform, and a more high-level point of view driven by perceptual audio features in the concatenative synthesis setting. The developed framework provides unified approach to the high-quality resynthesis of natural texture sounds. Our research is embedded within the Metaverse 1 European project (2008-2011), where our models are contributting as low level building blocks within a semi-automated soundscape generation system.

Cutting edge: influence of the TCR Vbeta domain on the selection of semi-invariant NKT cells by endogenous ligands.

Invariant Valpha14 (Valpha14i) NKT cells are a murine CD1d-dependent regulatory T cell subset characterized by a Valpha14-Jalpha18 rearrangement and expression of mostly Vbeta8.2 and Vbeta7. Whereas the TCR Vbeta domain influences the binding avidity of the Valpha14i TCR for CD1d-alpha-galactosylceramide complexes, with Vbeta8.2 conferring higher avidity binding than Vbeta7, a possible impact of the TCR Vbeta domain on Valpha14i NKT cell selection by endogenous ligands has not been studied. In this study, we show that thymic selection of Vbeta7(+), but not Vbeta8.2(+), Valpha14i NKT cells is favored in situations where endogenous ligand concentration or TCRalpha-chain avidity are suboptimal. Furthermore, thymic Vbeta7(+) Valpha14i NKT cells were preferentially selected in vitro in response to CD1d-dependent presentation of endogenous ligands or exogenously added self ligand isoglobotrihexosylceramide. Collectively, our data demonstrate that the TCR Vbeta domain influences the selection of Valpha14i NKT cells by endogenous ligands, presumably because Vbeta7 confers higher avidity binding.

Hierarchical conditional random fields for parts based models matching

A parts based model is a parametrization of an object class using a collection of landmarks following the object structure. The matching of parts based models is one of the problems where pairwise Conditional Random Fields have been successfully applied. The main reason of their effectiveness is tractable inference and learning due to the simplicity of involved graphs, usually trees. However, these models do not consider possible patterns of statistics among sets of landmarks, and thus they sufffer from using too myopic information. To overcome this limitation, we propoese a novel structure based on a hierarchical Conditional Random Fields, which we explain in the first part of this memory. We build a hierarchy of combinations of landmarks, where matching is performed taking into account the whole hierarchy. To preserve tractable inference we effectively sample the label set. We test our method on facial feature selection and human pose estimation on two challenging datasets: Buffy and MultiPIE. In the second part of this memory, we present a novel approach to multiple kernel combination that relies on stacked classification. This method can be used to evaluate the landmarks of the parts-based model approach. Our method is based on combining responses of a set of independent classifiers for each individual kernel. Unlike earlier approaches that linearly combine kernel responses, our approach uses them as inputs to another set of classifiers. We will show that we outperform state-of-the-art methods on most of the standard benchmark datasets.

Metal•lúrgia del coure a la prehistòria recent del oest d'Europa.Una mirada des de les anàlisis de composició elemental dels artefactes metàl·lics

L’objecte principal que ha guiat la recerca dels darrers tres anys ha estat la arqueometal•lúrgia. Esta memòria s’estructura en 3 parts: Els objectius inicials, el treball realitzat cada any i els resultats de la meva investigació. Evidentment, és en aquest darrer apartat on s’emfatitza la tasca de recerca i s’exposen els 3 àmbits d’actuació principals. El primer d’ells, necessari, és la formació teòric-metodològica en arqueometal•lúrgia. El segon, l’estudi de la composició elemental de les societats del Ha B2 de l’oest d’Europa. El darrer queda configurat per la recerca en curs en torn a la producció metal•lúrgica argàrica. També s’adjunta una selecció d’annex amb informes i publicacions redactats durant la beca i que ofereixen mirades en detall dels diferents elements que composen la recerca.