Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function.

Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often of too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel of sequence-optimized HLA-A(*)0201/NY-ESO-1(157-165)-specific TCR variants with affinities lying within physiological boundaries to preserve antigenic specificity and avoid cross-reactivity, as well as two outliers (i.e., a very high- and a low-affinity TCR). Primary human CD8 T cells transduced with these TCRs demonstrated robust correlations between binding measurements of TCR affinity and avidity and the biological response of the T cells, such as TCR cell-surface clustering, intracellular signaling, proliferation, and target cell lysis. Strikingly, above a defined TCR-peptide-MHC affinity threshold (K(D) < approximately 5 muM), T cell function could not be further enhanced, revealing a plateau of maximal T cell function, compatible with the notion that multiple TCRs with slightly different affinities participate equally (codominantly) in immune responses. We propose that rational design of improved self-specific TCRs may not need to be optimized beyond a given affinity threshold to achieve both optimal T cell function and avoidance of the unpredictable risk of cross-reactivity.

A Percepção da População Local Sobre os Impactos Económicos do Turismo na Ilha de São Vicente

A actividade turística só faz sentido, e torna-se viável, quando se proporciona uma experiência qualitativa aos principais agentes envolvidos, isto é, quando haja a optimização da experiência turística, a conservação ambiental e cultural e a inclusão social, pela participação activa das comunidades locais. Assim, esta monografia debruça-se sobre a análise de um desses pilares, mais concretamente, a população local, e como tal, objectiva-se analisar a sua percepção sobre os impactos económicos do turismo no desenvolvimento da ilha de São Vicente. Contudo, para dar uma resposta coerente à problemática deste estudo, que é identificar os impactos económicos do turismo percebido pelos residentes, recorreu-se à uma abordagem económica do turismo, tendo em conta as nomenclaturas desenvolvidas no âmbito da Conta Satélite do Turismo. Na avaliação dos impactos, fez-se a aplicação de um inquérito por questionário, dirigido aos residentes das zonas de Norte Baía, Ribeira de Calhau, São Pedro e o Centro da Cidade. Definiu-se uma amostra representativa de 200 indivíduos, analisando a relação entre o turismo e um conjunto de variáveis económicas tais como o emprego, o rendimento, as receitas governamentais, as infra-estruturas, a sazonalidade, os investimentos, e a inflação. Pelos resultados obtidos, concluiu-se que o turismo contribui positivamente para aumentar o emprego, o rendimento, melhorar a qualidade de vida, o aparecimento de novas empresas, o aumento do Produto Interno Bruto e ainda contribui para o desenvolvimento económico da ilha. Contudo, os resultados permitiram concluir que a ilha não depende, do ponto de vista económico, exclusivamente do turismo. Touristic activity only makes sense and becomes profitable when it brings a qualitative experience to the parties involved, i.e. when it results in an improvement of the touristic experience, with an environmental and cultural protection and social inclusion, through the active participation of the local communities, we developed this monograph based on the analysis of the people´s perception about the economic impact of the tourism in the development of São Vicente island. However, in order to have a coherent answer to the issues this document is concerned with, i.e to identify the economic impact of the tourism on people´s live, we went through an economic approach of the tourism, taking in consideration the nomenclature developed in the sphere of Tourism Satellite Account. For the evaluation of the impact we resorted to an enquiry to the residents of Norte Baía, Ribeira de Calhau, São Pedro, and Mindelo. A representative sample of 200 individuals has been defined, to analyze the relationship between the tourism itself and several economic targets, such as: employment, profits, infrastructure, season, investment, inflation. According to the analysis we concluded that the tourism has positively contributed to the uprising of new enterprise, to the increasing of the gross domestic product, to rise up the employment rate, to increase family´s incomes and consequently a better life quality and also to the economic development of São Vicente Island. Nevertheless we also concluded that economically São Vicente does not depend only on the tourism incomes.

Effect of genetic convergence on phylogenetic inference.

Phylogenetic reconstructions are a major component of many studies in evolutionary biology, but their accuracy can be reduced under certain conditions. Recent studies showed that the convergent evolution of some phenotypes resulted from recurrent amino acid substitutions in genes belonging to distant lineages. It has been suggested that these convergent substitutions could bias phylogenetic reconstruction toward grouping convergent phenotypes together, but such an effect has never been appropriately tested. We used computer simulations to determine the effect of convergent substitutions on the accuracy of phylogenetic inference. We show that, in some realistic conditions, even a relatively small proportion of convergent codons can strongly bias phylogenetic reconstruction, especially when amino acid sequences are used as characters. The strength of this bias does not depend on the reconstruction method but varies as a function of how much divergence had occurred among the lineages prior to any episodes of convergent substitutions. While the occurrence of this bias is difficult to predict, the risk of spurious groupings is strongly decreased by considering only 3rd codon positions, which are less subject to selection, as long as saturation problems are not present. Therefore, we recommend that, whenever possible, topologies obtained with amino acid sequences and 3rd codon positions be compared to identify potential phylogenetic biases and avoid evolutionarily misleading conclusions.

Institutional support of the firm: A theory of business registries

Registering originative business contracts allows entrepreneurs and creditors to choose, andcourts to enforce market-friendly contract rules that protect innocent third parties whenadjudicating disputes on subsequent contracts. This reduces information asymmetry for thirdparties, which enhances impersonal trade. It does so without seriously weakening property rights,because it is rightholders who choose or activate the legal rules and can, therefore, minimize thecost of any possible weakening. Registries are essential not only to make the chosen rules publicbut to ensure rightholders commitment and avoid rule-gaming, because independent registriesmake rightholders choices verifiable by courts. The theory is supported by comparative andhistorical analyses.

Molecular basis of odor detection in insects.

Olfactory systems are evolutionarily ancient, underlying the common requirement for all animals to sense and respond to diverse volatile chemical signals in their environment. Odor detection is mediated by odorant receptors (ORs) that, in most olfactory systems, comprise large families of divergent G protein-coupled receptors. Here, I discuss our and others' recent investigations of ORs in the fruit fly, Drosophila melanogaster, which have revealed insights into the distinct evolutionary origin and molecular function of insect ORs. I also describe a bioinformatics strategy that we developed to identify molecules that function with these insect-specific receptors in odor detection.

Subjective theories of gynaecologists discussing sexuality in consultations

Objectives: This study aims to explore subjectives theories (Flick, 1991) concerning sexualityamong gynaecologists. Methods: We conducted 27 deepened semi-structured interviews withmen and women gynaecologists, in the French part of Switzerland. A thematic contentanalysis was applied to the entire corpus. Results: We observe that discourse on sexualityissues can be source of discomfort during consultation with patients. Our analysis highlightsdisparities among levels of knowledge, attitudes and practices in gynaecologists. We observedthat their knowledges on sexuality seem to be constructed mainly on a profane knowledgebased on the common sense and/or their personal experiences. Furthermore, our findingsshow sex differences among physicians, especially on theoretical perspectives underlying theirdiscourse, and the time they allow themselves to spend with a patient. Conclusion: Nowadays,gynaecologists come across sexuality issues that go beyond anatomical and physiologicalconsiderations and for which they are not necessarily qualified. Our research suggests toanalyse both the role and the limits of gynaecologists as well as the motivations guiding theircurrent practice.

Integrating sexuality into gynaecological consultations: gynaecologists' perspectives

There are currently few studies exploring doctors' personal perspectives on integrating sexuality into medical consultations. This study focuses on the views of gynaecologists on introducing, or not introducing, sexuality into their work. A total of 30 semistructured interviews were conducted with gynaecologists in the French-speaking part of Switzerland. The thematic content analysis and computer-assisted lexical analysis (Alceste) on the interview transcripts highlighted four categories: perceptions and description of sexuality, patient's sexological history, training in sexology and perceived difficulties. It is observed that, above all, the 'medical dimension' characterises gynaecologists' perceptions. Of greater interest is our observation of disparities in gynaecologists' discussion of their practice, which is often the product of lay knowledge based on common sense and/or personal experience. Finally, the decision to integrate questions relating to sexuality seems to depend on non-medical factors such as the personal experience, interest or gender of the doctor.

Libertad de cátedra del profesor universitario. Contenido y amenazas en el contexto actual de reforma del modelo de universidad pública

[spa] Asistimos, desde hace algunos años, a un proceso de profundos cambios en la Universidad. Reformas que no sólo están afectando, entre otros, a su financiación, a su gobierno y gestión o a la estructura de las enseñanzas que en ella se imparten. También, y de forma muy especial e intensa, se están proyectando en su profesorado modificando su proceso de selección y transformando su función docente. Precisamente, en relación con ésta última, el papel que está llamado a desempeñar el docente está garantizado por la Constitución que les reconoce el derecho fundamental a la libertad de cátedra. La proclamación al más alto nivel normativo de este derecho del profesor ha obligado a conjugarla con otros derechos, igualmente fundamentales, presentes en el sistema educativo, en especial, el de la educación, y con otras potestades que se encomiendan a poderes públicos y universidades derivadas de la concepción de la educación como un servicio público. No obstante, en la actualidad las amenazas que plantean las nuevas exigencias derivadas del EEES pueden suponer un paso más allá actuando en la misma esencia de contenido de la libertad de cátedra perdiendo su sentido originario y condicionando su ejercicio a límites no permitidos por el propio texto constitucional.

Influencia de los medios de comunicación y de los grupos sociales en la percepción de la imagen corporal en pacientes con anorexia neviosa

La anorexia nerviosa es un trastorno de la conducta alimentaria que se caracteriza por unapérdida de peso superior al saludablemente recomendado, conductas para perder peso y evitarel aumento de peso, miedo a la obesidad y distorsión de la imagen corporal. Tanto la incidenciacomo la prevalencia de este tipo de trastornos ha aumentado considerablemente en las últimasdécadas, son varios los estudios que afirman que hay una estrecha relación entre la influencia delos factores socioculturales y el grado de distorsión de la imagen corporal en este tipo depacientes.El objetivo de este estudio es analizar la influencia que ejercen los medios de comunicación ylos grupos sociales en la distorsión de la imagen corporal de pacientes con anorexia nerviosa.Para lograr este objetivo se realizará un estudio fenomenológico con pacientes de 16 a 21 añosque se visiten en un hospital de día de trastornos de la conducta alimentaria. Los datos serecogerán mediante de una entrevista semiestructurada basada en los ítems del cuestionario deinfluencia de los modelos estéticos corporales (CIMEC). El análisis de los datos obtenidos serápor edición, transcribiendo la entrevista, identificando los segmentos significativos paraposteriormente poderlos analizar.En relación con las consideraciones finales, es un estudio que dentro de la subjetividad podríaser realmente útil para conocer desde el punto de vista del paciente cómo influyen los medios decomunicación y las relaciones sociales en la anorexia nerviosa, permitiendo la propuesta deacciones futuras que ayuden a estos adolescentes y adultos jóvenes a hacer frente a la presiónque ejerce la sociedad.

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In this book, the authors present current research in the study of health behavior. Topics discussed include the role of fitness classes in the development of eating disorders among women; first year university female students' lifestyles and attitudes towards health risk and preventive measures; an examination of the extensive cross-sectional and longitudinal evidence that links traditional screen-time to pediatric obesity; gender issue implications on health; and health promotion messages used to inform the population about important health issues and to motivate individuals to adopt healthy behaviors and avoid unhealthy behaviors. (Imprint: Novinka)

Comunicar con los visitantes: una nueva faceta profesional para los conservadores-restauradores

Heritage resources are more exposed than ever to visitors. For this reason, the transmission of cultural content is not enough: the present situation demands the inclusion of some messages able to foment a sustainable relation between the visitor and the resource. And this can best be achieved with the Preventive Difusion, a sensitizing strategy to inform and persuade visitors about the extreme fragility of the heritage resources. In addition, this strategy is a magnificent tool at the service of the corporate identity of the heritage resources and of the conservators: usually, preventive conservation actions and policies are not clear to visitors. But if they are included into the visit discourse, the public receive an accurate vi-sion of the efforts done in that sense, and it allows them to have a clear idea of these efforts, leading to the image that they have about the resource in question and, by extension, of their conservators.

Quelle organisation des soins pour le patient polymorbide? [How should we organize health care for multimorbidity patients?].

Polymorbidity affects an increasing number of patients of all ages as demonstrated by a recent epidemiological study and represents a real challenge for the organization of health care. Appropriate management of polymorbid patients requires an interdisciplinary approach associating generalist and specialist physicians, but also nurses, other health professionals and social workers. An improvement in transition care between the community and the hospital is necessary in both directions. Prioritizing the treatment objectives is essential to allow patient adherence and avoid cumulative drug interactions and adverse effects. Those objectives are difficult to attain in the context of our present health care organization. This paper attempts to identify the difficulties involved in caring for polymorbid patients and propose ways to improve it.

Narration und Diagrammatik. Eine Vorüberlegung und sieben Thesen

[Narrative and the Diagrammatic. Preliminary Thoughts and Seven Theses.] This article proposes a view of narrative that does not depend on the traditional perspective of temporal sequence but emphasizes the spatial structure of literary narrative. Contrary to the prevalent treatment of space in narrative theory, the notion of spatiality in this context refers not to the space that is represented by the narrative (e.g. the setting and other spatial elements of the fictional world) but to the space that represents it: first, the graphic surface of the text; second, the (quasi-)spatial mental representation of its content that is produced in the process of reception. It is argued that these conditions form the primary ontological mode of narrative, whereas the temporal development of a story is an aesthetic illusion that has been specifically stimulated by the narrative conventions of approximately the past three centuries and must thus be considered a secondary effect. The diagrammatic, as a way of both depicting data and perceiving relations through spatial representation, thus forms a more adequate methodological approach to understanding narrative structure than approaches that are implicitly derived from the 'grammar' of narrative in the structuralist sense and its sequential logic.

Three essays in dynamic corporate finance

The three essays constituting this thesis focus on financing and cash management policy. The first essay aims to shed light on why firms issue debt so conservatively. In particular, it examines the effects of shareholder and creditor protection on capital structure choices. It starts by building a contingent claims model where financing policy results from a trade-off between tax benefits, contracting costs and agency costs. In this setup, controlling shareholders can divert part of the firms' cash ows as private benefits at the expense of minority share- holders. In addition, shareholders as a class can behave strategically at the time of default leading to deviations from the absolute priority rule. The analysis demonstrates that investor protection is a first order determinant of firms' financing choices and that conflicts of interests between firm claimholders may help explain the level and cross-sectional variation of observed leverage ratios. The second essay focuses on the practical relevance of agency conflicts. De- spite the theoretical development of the literature on agency conflicts and firm policy choices, the magnitude of manager-shareholder conflicts is still an open question. This essay proposes a methodology for quantifying these agency conflicts. To do so, it examines the impact of managerial entrenchment on corporate financing decisions. It builds a dynamic contingent claims model in which managers do not act in the best interest of shareholders, but rather pursue private benefits at the expense of shareholders. Managers have discretion over financing and dividend policies. However, shareholders can remove the manager at a cost. The analysis demonstrates that entrenched managers restructure less frequently and issue less debt than optimal for shareholders. I take the model to the data and use observed financing choices to provide firm-specific estimates of the degree of managerial entrenchment. Using structural econometrics, I find costs of control challenges of 2-7% on average (.8-5% at median). The estimates of the agency costs vary with variables that one expects to determine managerial incentives. In addition, these costs are sufficient to resolve the low- and zero-leverage puzzles and explain the time series of observed leverage ratios. Finally, the analysis shows that governance mechanisms significantly affect the value of control and firms' financing decisions. The third essay is concerned with the documented time trend in corporate cash holdings by Bates, Kahle and Stulz (BKS,2003). BKS find that firms' cash holdings double from 10% to 20% over the 1980 to 2005 period. This essay provides an explanation of this phenomenon by examining the effects of product market competition on firms' cash holdings in the presence of financial constraints. It develops a real options model in which cash holdings may be used to cover unexpected operating losses and avoid inefficient closure. The model generates new predictions relating cash holdings to firm and industry characteristics such as the intensity of competition, cash flow volatility, or financing constraints. The empirical examination of the model shows strong support of model's predictions. In addition, it shows that the time trend in cash holdings documented by BKS can be at least partly attributed to a competition effect.

Anatomy of liver arteries for interventional radiology.

The availability of intra-arterial hepatic therapies (radio and/or chemo-embolisation, intra-arterial hepatic chemotherapy) has convinced radiologists to perfect their knowledge of the anatomy of the liver arteries. These sometimes, complex procedures most often require selective arterial catheterization. Knowledge of the different arteries in the liver and the peripheral organs is therefore essential to optimize the procedure and avoid eventual complications. This paper aims to describe the anatomy of the liver arteries and the variants, applying it to angiography images, and to understand the implications of such variations in interventional radiological procedures.