Le Large Area Telescope à bord du satellite Fermi, lancé le 11 juin 2008, est un télescope spatial observant l'univers des hautes énergies. L'instrument couvre l'intervalle en énergie de 20MeV à 300 GeV avec une sensibilité nettement améliorée et la capacité de localiser des sources ponctuelles. Il détecte les photons gamma par leur conversion en paire électron-positron, et mesure leur direction et leur énergie grâce à un trajectographe et un calorimètre. Cette thèse présente les courbes de lumières et les mesures spectrales résolues en phase des pulsars radio et gamma détectés par le LAT. La mesure des paramètres spectraux (flux, indice spectral, et énergie de coupure) dépend des fonctions de réponse de l'instrument (IRFs). Une méthode développée pour la validation en orbite de la surface ecace est présentée en utilisant le pulsar de Vela. Les efficacités des coupures entre les données du LAT et les données simulées sont comparées à chaque niveau de la rejection du fond. Les résultats de cette analyse sont propagés vers les IRFs pour évaluer les systématiques des mesures spectrales. La dernière partie de cette thèse présente les découvertes de nouveaux pulsars individuels tels que PSR J0205+6449, J2229+6114, et J1048-5832 à partir des données du LAT et des éphémérides radio et X. Des analyses temporelles et spectrales sont investies dans le but de contraindre les modèles d'émission gamma. Finalement, nous discutons les propriétés d'une large population de pulsars gamma détectés par le LAT, incluant les pulsars normaux et les pulsars milliseconde.

Galaxy clusters are the most massive bound systems known in the Universe and are believed to have formed through large scale structure formation. They host relativistic cosmic-ray (CR) populations and are gravitationally bound by large amounts of Dark Matter (DM), both providing conditions in which high-energy gamma rays may be produced either via CR interactions with the intracluster medium or through the annihilation or decay of DM particles. Prior to the launch of the Fermi satellite, predictions were optimistic that these sources would be established as γ-ray-bright objects by observations through its prime instrument, the Large Area Telescope (LAT). Yet, despite numerous efforts, even a single firm cluster detection is still pending. This thesis presents a number of studies based on data taken by the LAT over its now seven year mission aiming to discover these γ rays. Using a joint likelihood technique, we study the γ-ray spectra of a sample of nearby clusters searching for a CR-induced signal due to hadronic interactions in the intracluster medium. While we find excesses in some individual targets, we attribute none to the cluster. Hence, we constrain the maximum injection efficiency of hadrons being accelerated in structure formation shocks and the fraction of CR-to-thermal pressure. We also perform a refined search targeting the Coma cluster specifically due to its large variety of existing observations in other wavebands. In the latter case we find weak indications of an excess which however falls below the detection threshold. Because the cluster emission we consider is inherently extended, we need to take into account the imperfect modeling of the foreground emission, which may be particularly difficult such as is the case with the Virgo cluster. Here, we assess the systematics associated with the foreground uncertainties and derive limits based on an improved background model of the region. For the first time we derive limits on the γ-ray flux from CR and DM-interactions in which we take into account the dynamical state of the system. For DM we also include the contribution from substructure. The DM domain is further explored by searching for line-like features as they arise from the annihilation of DM into two photons in a large sample of clusters, including Virgo and Coma. Finding no evidence for γ-ray lines, we derive limits on the DM annihilation cross section that are roughly a factor 10 (100) above that derived from observations of the galactic center assuming an optimistic (conservative) scenario regarding the boost due to DM substructure. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Submitted.</p>

京都大学 / 新制・課程博士 / 博士(医科学) / 甲第23110号 / 医科博第121号 / 新制||医科||8(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 濵﨑 洋子, 教授 竹内 理, 教授 上野 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Yes / ‘Living apart together’ – that is being in an intimate relationship with a partner who lives somewhere else – is increasingly recognised and accepted as a specific way of being in a couple. On the face of it, this is a far cry from the ‘traditional’ version of couple relationships, where co-residence in marriage was placed at the centre and where living apart from one's partner would be regarded as abnormal, and understandable only as a reaction to severe external constraints. Some commentators regard living apart together as a historically new family form where LATs can pursue a ‘both/and’ solution to partnership – they can experience both the intimacy of being in a couple, and at the same time continue with pre-existing commitments. LATs may even de-prioritize couple relationships and place more importance on friendship. Alternatively, others see LAT as just a ‘stage’ on the way to cohabitation and marriage, where LATs are not radical pioneers moving beyond the family, but are cautious and conservative, and simply show a lack of commitment. Behind these rival interpretations lies the increasingly tarnished spectre of individualisation theory. Is LAT some sort of index for a developing individualisation in practice? In this paper we take this debate further by using information from the 2006 British Social Attitudes Survey. We find that LATs have quite diverse origins and motivations, and while as a category LATs are often among the more liberal in family matters, as a whole they do not show any marked ‘pioneer’ attitudinal position in the sense of leading a radical new way, especially if age is taken into account. / ESRC

no / Drawing on a 2011 national survey and 50 semi-structured interviews, we explore the differing ways in which those in living apart together (LAT) relationships discuss and experience notions of commitment. We found that sexual exclusivity in LAT relationships is expected by the large majority, regardless of their reasons for living apart. The majority of the interviewees also expressed a high degree of commitment to their partner in terms of love, care and intimacy, alongside an appreciation of the increased freedom and autonomy that living apart has to offer. Respondents were divided into four groups according to their perceived commitment: 1. Autonomous commitment, 2. Contingent commitment, 3. Ambivalent commitment, and 4. Limited commitment. Despite differing degrees of commitment, however, the overall finding was that the importance of relating and making relational decisions was central, even in the lives of those living in such unconventional relationship styles.

Yes / This article explores how people who live apart from their partners in Britain describe and understand ‘family’. It investigates whether, and how far, non-cohabiting partners, friends, ‘blood’ and legal ties are seen as ‘family’, and how practices of care and support, and feelings of closeness are related to these constructions. It suggests that people in LAT relationships creatively draw and re-draw the boundaries of family belonging in ways that involve emotionally subjective understandings of family life, and that also refer to normative constructions of what ‘family’ ought to be, as well as to practical recognitions of lived family ‘realities’. This often involves handling uncertainties about what constitutes ‘family’.

Une réponse immunitaire efficace contre un large spectre de pathogènes ou contre des cellules tumorales nécessite l’activation des lymphocytes T CD4+. L’engagement du récepteur T par un peptide antigénique apprêté sur les produits de classe-II du complexe majeur d’histocompatibilité (peptide-CMH, pCMH) portés par une cellules présentatrices d’antigène (CPAg), conduit à de nombreux remaniements du lymphocyte T. Il s’établit notamment à l’interface entre le lymphocyte T et la CPAg, une structure spécialisée qui est la synapse immunologique (ou synapse immune). La synapse est le siège d’événements de signalisation intenses où diverses molécules de signalisation nécessaires l’amplification et la diversification du signal provenant du TCR sont recrutées. Ces évènements de signalisation sont régulés par l’adaptateur transmembranaire LAT (« Linker for Activation of T cells ») qui est présent à la membrane plasmique ainsi que dans des compartiments intracellulaires. La fraction intracellulaire de LAT est recrutée à la synapse immune et il est proposé que ces compartiments vésiculaires participent à la signalisation lymphocytaire T. L’objectif de ce travail de thèse a été de déterminer les voies de trafic intracellulaire nécessaires au recrutement de la fraction intracellulaire de LAT à la synapse immunologique et de comprendre le rôle de ce transport dans l’activation et la réponse lymphocytaire T. Par des approches d’extinction de l’expression de différentes molécules de transport intracellulaires dans les cellules T Jurkat ou des lymphocytes T CD4+ primaires humains ou par l’utilisation de souris Knock-Out (KO), nous avons mis en évidence plusieurs voies de transport impliquées dans le transport de LAT. Nous avons ainsi mis en évidence que le recrutement de LAT à la synapse immunologique nécessite une voie de sécrétion dépendante de la protéine SNARE vésiculaire VAMP7. L’analyse plus avant du transport de LAT a par ailleurs permis de montrer que LAT est présente dans des compartiments de recyclage alors que VAMP7 est principalement localisée dans l’appareil de Golgi. L’étude de la petite GTPase Rab6 et de la protéine t-SNARE syntaxine-16 qui sont impliquées dans des voies de transport rétrograde entre les endosomes de recyclage et l’appareil de Golgi, a permis de dévoiler que cette voie de transport est requise dans le recrutement de LAT à la synapse immunologique, ainsi qu’à la réponse lymphocytaire T in vitro, ex vivo et in vivo. Enfin, le rôle de la protéine de transport intraflagellaire IFT20, qui a déjà été mis en cause dans le transport du TCR, a été analysé chez la souris et a également montré des défauts de recrutement de LAT à la synapse et dans l’activation lymphocytaire T ex vivo et in vivo. Nos résultats mettent ainsi en évidence que la régulation du transport intracellulaire dans les lymphocytes T joue un rôle crucial dans l’activation lymphocytaire T. Nous proposons ainsi un modèle dans lequel LAT est constitutivement internalisé depuis la membrane plasmique et poursuit une voie de recyclage dépendante de l’appareil de Golgi qui contient la machinerie de sécrétion associé à VAMP7. Cette voie de transport intracellulaire, conditionnerait la resécrétion polarisée de LAT à la synapse immunologique dans les conditions d’activation et une réponse lymphocytaire T robuste. / The immune response against a broad spectrum of pathogens or against tumor cells requires the CD4 + T lymphocytes activation. The triggering of T Cell Receptor (TCR) by peptide-MHC through antigen-presenting cells (APC) leads to numerous T-cell remodeling and the establishment of a specialized structure at the interface between the T lymphocyte and the APC: the immunological synapse. The synapse is the site of intense signaling events where various signaling molecules are recruited in order to amplify and diversify the signal initiated by the TCR. These signaling events are regulated by the transmembrane adapter LAT ("Linker for activation of T cells") which is present at the plasma membrane as well as in intracellular compartments. The intracellular fraction of LAT is recruited at the immune synapse and it is proposed that these vesicular compartments participate in T lymphocyte signaling. The objective of this thesis work was to determine the intracellular trafficking pathways required for the recruitment of the intracellular pool of LAT to the immunological synapse and understand the role of this transport in T cell activation and response. By silencing the expression of different intracellular transport molecules in Jurkat T cells or primary human CD4 + T lymphocytes, or by using Knock-Out (KO) mice, we have highlighted several trafficking pathways involved in the transport of LAT to the immune synapse. We have demonstrated that the recruitment of LAT to TCR activation sites requires a secretion pathway dependent on the vesicular SNARE protein VAMP7. Further analysis of the transport of LAT showed that LAT is present in recycling compartments whereas VAMP7 is mainly located in the Golgi apparatus. The study of the small GTPase Rab6 and the t-SNARE syntaxin-16 protein that are involved in the retrograde transport pathways between the recycling endosomes and the Golgi apparatus, demonstrated that this route of transport is required for the recruitment of LAT to the immunological synapse and for T lymphocyte response in vitro, ex vivo and in vivo as well. Finally, the role of intraflagellar transport protein IFT20, which has already been implicated in the transport of TCR, was analyzed in mice and also showed defects in LAT recruitment to synapse and T lymphocyte activation ex vivo and in vivo. Our results thus show that the regulation of intracellular transport plays a crucial role in T lymphocyte activation. We thus propose a model in which LAT is constitutively internalized from the plasma membrane and pursues a Golgi-dependent recycling pathway that contains the secretion machinery associated with VAMP7. This intracellular transport pathway would thus allow the polarized LAT re-secretion to the immunological synapse under activation conditions and a robust T lymphocyte response.

Herpes simplex virusas sukelia recidyvuojančią burnos-veido ir lytinių organų infekciją. Latentinėje būklėje šis virusas glūdi sensoriniuose ganglijuose. Latencijos metu visi HSV genai yra supresuoti, išskyrus su latencija susijusį geną (LAT). Tyrimais nustatyta, kad tarp HSV LAT promotoriaus mutantų reaktyvacijos dažnis laboratorinių gyvūnėlių modeliuose yra mažesnis nei laukinių virusų. Nėra atlikta tyrimų, kurie nagrinėtų LAT promotoriaus sekų variaciją herpes simplex virusuose, išskirtuose iš žmonių klinikinių mėginių. Šio tyrimo tikslas buvo įvertinti herpes simplex viruso LAT promotoriaus sekų įvairovę molekulinės diagnostikos metodais bei palyginti su infekcijos klinikiniais požymiais. Tuo tikslu buvo sukurtas PGR metodas HSV LAT promotoriaus analizei atlikti. Buvo ištirta Lietuvos ir Švedijos klinikiniuose odos-gleivinių bei cerebrospinalinio skysčio mėginiuose rasto herpes simplex viruso promotoriaus DNR sekų įvairovė. Tyrimo metu rasta, kad 2 tipo herpes simplex virusas buvo pagrindinė lytinių organų HSV infekcijos priežastis tarp Lietuvos pacientų. Visuose veido srities bėrimuose rasta 1 tipo HSV. HSV LAT promotoriaus sekos ištirtos 145 klinikiniuose mėginiuose. Nustatyta, kad HSV LAT promotoriaus sekos yra gausios GC ir turi variabilias homopolimerinių nukleotidų sritis, kurios varijuoja tarp viruso padermių ir pačių padermių viduje. Ši variacija gali turėti įtakos baltymų sintezei, o drauge ir fenotipo pokyčiams. Nenustatytas ryšys tarp HSV LAT promotoriaus... [toliau žr. visą tekstą] / Herpes simplex virusas sukelia recidyvuojančią burnos-veido ir lytinių organų infekciją. Latentinėje būklėje šis virusas glūdi sensoriniuose ganglijuose. Latencijos metu visi HSV genai yra supresuoti, išskyrus su latencija susijusį geną (LAT). Tyrimais nustatyta, kad tarp HSV LAT promotoriaus mutantų reaktyvacijos dažnis laboratorinių gyvūnėlių modeliuose yra mažesnis nei laukinių virusų. Nėra atlikta tyrimų, kurie nagrinėtų LAT promotoriaus sekų variaciją herpes simplex virusuose, išskirtuose iš žmonių klinikinių mėginių. Šio tyrimo tikslas buvo įvertinti herpes simplex viruso LAT promotoriaus sekų įvairovę molekulinės diagnostikos metodais bei palyginti su infekcijos klinikiniais požymiais. Tuo tikslu buvo sukurtas PGR metodas HSV LAT promotoriaus analizei atlikti. Buvo ištirta Lietuvos ir Švedijos klinikiniuose odos-gleivinių bei cerebrospinalinio skysčio mėginiuose rasto herpes simplex viruso promotoriaus DNR sekų įvairovė. Tyrimo metu rasta, kad 2 tipo herpes simplex virusas buvo pagrindinė lytinių organų HSV infekcijos priežastis tarp Lietuvos pacientų. Visuose veido srities bėrimuose rasta 1 tipo HSV. HSV LAT promotoriaus sekos ištirtos 145 klinikiniuose mėginiuose. Nustatyta, kad HSV LAT promotoriaus sekos yra gausios GC ir turi variabilias homopolimerinių nukleotidų sritis, kurios varijuoja tarp viruso padermių ir pačių padermių viduje. Ši variacija gali turėti įtakos baltymų sintezei, o drauge ir fenotipo pokyčiams. Nenustatytas ryšys tarp HSV LAT promotoriaus... [to full text]

Herpes simplex virus (HSV) causes recurrent orofacial and genital infections and establishes latent infection in sensory neurons. During latency all virus genes are supressed except the latency associated transcripts which are transcribed from latency associated gene (LAT). It is established that HSV LAT promoter mutants have lower levels of spontaneous reactivation rates in small animal models compared to wild virus. However, the variation in the LAT promoter has not been studied in viruses from clinical samples in humans. The aim of the sudy was to evaluate the sequence variation in herpes simplex virus latency associated gene promoter from clinical samples by developing and applying molecular methods and correlate with herpes infection clinical features. In this study a new PCR method specific for HSV LAT promoter was developed and HSV LAT promoter DNA sequences from Lithuanian and Swedish mucocutaneous and cerebrospinal fluid clinical samples were analyzed. HSV type 2 was found to be the main cause of genital herpes in the population of the Lithuanian patients. All cases of orofacial herpes simplex infection were caused by HSV type 1. The structure of the LAT promoter region was studied in 145 HSV clinical samples. HSV LAT promoter was found to be G+C rich and contained variable homopolimer tracts. An inter- and intrastrain variability of homopolimer tracts in the promoter region was detected, potentially giving rise to a large variation at the protein level, leading to... [to full text] / Herpes simplex virusas sukelia recidyvuojančią burnos-veido ir lytinių organų infekciją. Latentinėje būklėje šis virusas glūdi sensoriniuose ganglijuose. Latencijos metu visi HSV genai yra supresuoti, išskyrus su latencija susijusį geną (LAT). Tyrimais nustatyta, kad tarp HSV LAT promotoriaus mutantų reaktyvacijos dažnis laboratorinių gyvūnėlių modeliuose yra mažesnis nei laukinių virusų. Nėra atlikta tyrimų, kurie nagrinėtų LAT promotoriaus sekų variaciją herpes simplex virusuose, išskirtuose iš žmonių klinikinių mėginių. Šio tyrimo tikslas buvo įvertinti herpes simplex viruso LAT promotoriaus sekų įvairovę molekulinės diagnostikos metodais bei palyginti su infekcijos klinikiniais požymiais. Tuo tikslu buvo sukurtas PGR metodas HSV LAT promotoriaus analizei atlikti. Buvo ištirta Lietuvos ir Švedijos klinikiniuose odos-gleivinių bei cerebrospinalinio skysčio mėginiuose rasto herpes simplex viruso promotoriaus DNR sekų įvairovė. Tyrimo metu rasta, kad 2 tipo herpes simplex virusas buvo pagrindinė lytinių organų HSV infekcijos priežastis tarp Lietuvos pacientų. Visuose veido srities bėrimuose rasta 1 tipo HSV. HSV LAT promotoriaus sekos ištirtos 145 klinikiniuose mėginiuose. Nustatyta, kad HSV LAT promotoriaus sekos yra gausios GC ir turi variabilias homopolimerinių nukleotidų sritis, kurios varijuoja tarp viruso padermių ir pačių padermių viduje. Ši variacija gali turėti įtakos baltymų sintezei, o drauge ir fenotipo pokyčiams. Nenustatytas ryšys tarp HSV LAT promotoriaus... [toliau žr. visą tekstą]