O turismo e a percepção dos seus impactes pela comunidade local: o caso da Ilha do Sal, Cabo Verde

A análise tradicional do turismo visando apenas a sua dimensão económica tem-se mostrado redutora e insuficiente para explicar as inúmeras e versáteis alterações que pode provocar a nível social, cultural, político e ambiental. A complexidade da actividade turística e a carência de instrumentos ajustados para avaliar e tornar mensuráveis os seus impactes constituem terreno fértil à emergência de mitos e de juízos de valor em torno dos efeitos por ele causado nos países receptores. A linha orientadora da investigação parte do pressuposto que a actividade turística só faz sentido e se torna viável se proporcionar uma experiência qualitativa aos principais agentes envolvidos: os turistas e os residentes. A tentativa de compreender a forma como os impactes do turismo são percepcionados pela comunidade receptora da ilha do Sal em Cabo Verde está intimamente associado à convicção que um turismo de qualidade e sustentável só é possível auscultando a população e envolvendo-a no planeamento, gestão e monitorização da actividade. A análise da percepção dos impactes da actividade turística por parte da comunidade desemboca indirectamente no conhecimento dos níveis de satisfação da comunidade em relação à forma como se tem realizado o desenvolvimento turístico na ilha. No âmbito do trabalho de investigação foram realizados duzentos e trinta e um questionários cujos resultados da investigação levam a acreditar que a comunidade local salense possui uma clara consciência dos impactes do turismo no seu quotidiano. Verifica-se que a percepção dos impactes económicos e sociais negativos reúnem maior consenso que os impactes positivos. Os impactes culturais e ambientais são ainda pouco perceptíveis por parte dos inquiridos. Por outro lado, os inquiridos na sua generalidade não se sentem envolvidos no planeamento da actividade turística, embora haja elevadas expectativas em relação à actividade como forma de melhoria das condições de vida da população. A inexistência de um comportamento linear dos impactes da actividade turística no destino e de um modelo de desenvolvimento turístico perfeito e ajustável a todas as realidades obriga a que sejam delineados por parte dos países receptores políticas de planeamento visando a sustentabilidade e condições para a monitorização e mitigação dos seus impactes.

O turismo e a percepção dos seus impactes pela comunidade local : o caso da Ilha do Sal, Cabo Verde

The traditional analysis of tourism, having in mind only its economic impacts has been shown to be reductive and insufficient to explain the numerous and versatile modifications these can and will stimulate in a society at many levels, e.g. socially, culturally, politically and in the environment. The complexity of touristic activities and the insufficient measuring instruments that can provide exact data about these, gives terrain to the emergence of myths and value judgments around the effects in countries where tourism is a reality. This study aims at understanding how the impacts of tourism are grasped by the local community in Sal island – Cape Verde – convinced as we are that a quality and sustainable touristic offer can only be done by trialing the population, and involving them in the planning, managing and monitoring processes. The analysis of the perception of the impacts of touristic activities by the population tells us a lot about the levels of satisfaction of such communities towards the way in which the touristic development has been carried out in their surroundings. This study has been made through the inquiry of 231 locals, by means of a questionnaire, that showed that the population in this island has a very clear conscience of the impacts of tourism in their day-to-day lives. Conclusions drawn are that the negative economic and social impacts are greater than the positive; the cultural and environmental impacts are not so significant, and that the people feel that their voice has not been heard in what planning touristic activities is concerned. Nevertheless, they have high expectations regarding tourism as a way of ameliorating their life conditions. The inexistence of a linear behavior of impacts of touristic activities in the receptive countries and a perfect and adjustable model for tourism development make these countries delineate new politics aiming at the sustainability and the creation of conditions that help them monitor and mitigate its negative impacts.

Predicting the evolution of Kaposi sarcoma, in the highly active antiretroviral therapy era.

BACKGROUND: The outcome of Kaposi sarcoma varies. While many patients do well on highly active antiretroviral therapy, others have progressive disease and need chemotherapy. In order to predict which patients are at risk of unfavorable evolution, we established a prognostic score. METHOD: The survival analysis (Kaplan-Meier method; Cox proportional hazards models) of 144 patients with Kaposi sarcoma prospectively included in the Swiss HIV Cohort Study, from January 1996 to December 2004, was conducted. OUTCOME ANALYZED: use of chemotherapy or death. VARIABLES ANALYZED: demographics, tumor staging [T0 or T1 (16)], CD4 cell counts and HIV-1 RNA concentration, human herpesvirus 8 (HHV8) DNA in plasma and serological titers to latent and lytic antigens. RESULTS: Of 144 patients, 54 needed chemotherapy or died. In the univariate analysis, tumor stage T1, CD4 cell count below 200 cells/microl, positive HHV8 DNA and absence of antibodies against the HHV8 lytic antigen at the time of diagnosis were significantly associated with a bad outcome.Using multivariate analysis, the following variables were associated with an increased risk of unfavorable outcome: T1 [hazard ratio (HR) 5.22; 95% confidence interval (CI) 2.97-9.18], CD4 cell count below 200 cells/microl (HR 2.33; 95% CI 1.22-4.45) and positive HHV8 DNA (HR 2.14; 95% CI 1.79-2.85).We created a score with these variables ranging from 0 to 4: T1 stage counted for two points, CD4 cell count below 200 cells/microl for one point, and positive HHV8 viral load for one point. Each point increase was associated with a HR of 2.26 (95% CI 1.79-2.85). CONCLUSION: In the multivariate analysis, staging (T1), CD4 cell count (<200 cells/microl), positive HHV8 DNA in plasma, at the time of diagnosis, predict evolution towards death or the need of chemotherapy.

Social preferences: Some simple tests and a new model

Departures from pure self interest in economic experiments have recently inspired models of "social preferences". We conduct experiments on simple two-person and three-person games with binary choices that test these theories more directly than the array of games conventionally considered. Our experiments show strong support for the prevalence of "quasi-maximin" preferences: People sacrifice to increase the payoffs for all recipients, but especially for the lowest-payoff recipients. People are also motivated by reciprocity: While people are reluctant to sacrifice to reciprocate good or bad behavior beyond what they would sacrifice for neutral parties, they withdraw willingness to sacrifice to achieve a fair outcome when others are themselves unwilling to sacrifice. Some participants are averse to getting different payoffs than others, but based on our experiments and reinterpretation of previous experiments we argue that behavior that has been presented as "difference aversion" in recent papers is actually a combination of reciprocal and quasi-maximin motivations. We formulate a model in which each player is willing to sacrifice to allocate the quasi-maximin allocation only to those players also believed to be pursuing the quasi-maximin allocation, and may sacrifice to punish unfair players.

O realismo na escrita poética de Manuel Lopes

O realismo apresenta em Cabo Verde particularidades próprias. Se em Portugal e noutros países foi um movimento literário e idiológico-político empenhado em soluções transformadoras da sociedade pela via da função social da arte, pela desmistificação da consciência e pela oposição ao capitalista e ao burguês, em Cabo Verde, por razões naturais, geográficas e sociais contextualiza-se assumindo outras preocupações. Manuel Lopes, com o tempo, sem esquecer o plano subjectivo, envereda por uma escrita poética com implicações objectivistas tematizando os problemas crioulos mais prementes: seca, isolamento, fome, emigração. A objectividade e a subjectividade são, por isso, duas características do realismo cabo-verdiano. Os paradigmas, São Vicente-Mar (urbanidade) e Santo Antão-terra (ruralidade) e ainda a dinâmica de oposição entre o partir/ficar informam decisivamente a sua poesia.

Wild bids. Gambling for resurrection in procurement contracts

This paper analyzes the problem of abnormally low tenders in theprocurement process. Limited liability causes firms in a bad financialsituation to bid more aggressively than good firms in the procurementauction. Therefore, it is more likely that the winning firm is a firm infinancial difficulties with a high risk of bankruptcy. The paper analyzesthe different regulatory practices to face this problem with a specialemphasis on surety bonds used e.g. in the US. We characterize the optimalsurety bond and show that it does not coincide with the current USregulation. In particular we show that under a natural assumption the USregulation is too expensive and provides overinsurance to the problem ofabnormally low tenders.

Expertise and finance: Mergers motivated by technological change

This paper argues that a large technological innovation may lead to a merger wave by inducing entrepreneurs to seek funds from technologically knowledgeable firms -experts. When a large technological innovation occurs, the ability of non-experts (banks) to discriminate between good and bad quality projects is reduced. Experts can continue to charge a low rate of interest for financing because their expertise enables them to identify good quality projects and to avoid unprofitable investments. On the other hand, non-experts now charge a higher rate of interest in order to screen bad projects. More entrepreneurs, therefore, disclose their projects to experts to raise funds from them. Such experts are, however, able to copy the projects and disclosure to them invites the possibility of competition. Thus the entrepreneur and the expert may merge so as to achieve product market collusion. As well as rationalizing mergers, the model can also explain various forms of venture financing by experts such as corporate investors and business angels.

Socio-economic inequalities in health in Catalonia

In this paper we measure the degree of income related inequality in mental health as measured by the GHQ instrument and general health as measured by the EQOL-5D instrument for the Catalan population. We find that income is the main contributor to inequality, although the share of inequality in mental health that can be explained by income is much greater than the corresponding share of inequality in general health. We also find that the variation in demographic structure reduces income related inequality in mental health but increases income related inequality in general health. The regional variations in both instruments for health are striking, with the Barcelona districts faring relatively bad with respect to the rest of geographical areas and Lleida being the health region where, all else held equal, the population reports the greatest level of health. A big share of inequality in the two health measures, but specially mental health, is due to the favourable position in both health and income of those who enjoy an indefinite contract with respect to the rest of individuals. We also find that risky working conditions affect both health measures and are able to explain an important share of socio-economic inequality.

The use of derivatives in the Spanish mutual fund industry

We study the use of derivatives in the Spanish mutual fund industry. The picture that emerges from our analysis is rather negative. In general, the use of derivatives does not improve the performance of the funds. In only one out of eight categories we find some (very weak and not robust) evidence of superior performance. In most of the cases users significantly underperform non users. Furthermore, users do not seem to exhibit superior timing or selectivity skills either, but rather the contrary. This bad performance is only partially explained by the larger fees funds using derivatives charge. Moreover,we do not find evidence of derivatives being used for hedging purposes. We do find evidence of derivatives being used for speculation. But users in only one category exhibit skills as speculators. Finally, we find evidence of derivatives being used to manage the funds cash inflows and outflows more efficiently.

Expression of apoptosis and survival genes in human memory T cell populations

RESUME Introduction: Les cellules T mémoires humaines sont classées en trois sous-populations sur la base de l'expression d'un marqueur de surface cellulaire, CD45RA, et du récepteur aux chimiokines, CCR7. Ces sous-populations, nommées cellules mémoires centrales (TcM), mémoires effectrices (TEM) et mémoires effectrices terminales (ITEM), ont des rôles fonctionnels distincts, ainsi que des capacités de prolifération et de régénération différentes. Cependant, la génération de ces différences reste encore mal comprise et on ignore les mécanismes moléculaires impliqués. Matériaux et Méthodes: Des cellules mononucléaires humaines du sang périphérique ont été séparées par cytométrie de flux selon leur expression de CD4, CD8, CD45RA et CCR7 en sous-populations de cellules CD4+ ou CD8+ naïves, TcM, TEM ou ITEM. Dans chacune de ces sous-populations, 14 gènes impliqués dans l'apoptose, la survie ou la capacité proliférative des cellules T ont été quantifiés par RT-PCR en temps réel, relativement à l'expression d'un gène de référence endogène. L'ARN provenant de 450 cellules T a été utilisé par gène et par sous-population. Les gènes analysés (cibles) comprenaient des gènes de survie (BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα, IL-7Rα), des gènes anti-apoptotiques (Bcl-2, BclxL, FLIP), des gènes pro-apoptotiques (Bad, Bax, Fast) et le gène anti-prolifératif, Tob. A l'aide de la méthode comparative delta-delta-CT, le taux d'expression des gènes cibles de chaque sous-population des cellules T mémoires CD4+ et CD8+, à été comparée à leur taux d'expression dans les cellules T naïves CD4+ et CD8+. Résultats: Dans les cellules CD8+, les gènes pro-apoptotiques Bax et Fast étaient surexprimés dans toutes les sous-populations mémoires, tandis que l'expression des facteurs anti-apoptotiques et de survie comme Bcl-2, APRIL et BAFF-R, étaient diminués. Ces deux tendances étaient particulièrement accentuées dans les sous-groupes des cellules mémoires TEM et TTEM. A noter que malgré le fait que leur expression était également diminuée dans les autres cellules mémoires, le facteur de survie IL-7Ra, était sélectivement surexprimé dans la sous-population de cellules TcM et l'expression d'IL-15Ra était sélectivement augmentée dans les TEM. Dans les cellules CD4+, le taux d'expression des gènes analysés était plus variable entre les sujets étudiés que dans les cellules CD8+, ne permettant pas de définir un profil d'expression spécifique. L'expression du gène de survie BAFF par contre, a été significativement augmentée dans toutes les sous-populations mémoire CD4+. Il en va de même pour l'expression d' APRIL et de BAFF-R, bien que dans moindre degré. A remarquer que l'expression du facteur anti-apoptotique Fast a été observée uniquement dans la souspopulation des TTEM. Discussion et Conclusions: Cette étude montre une nette différence entre les cellules CD8+ et CD4+, en ce qui concerne les profils d'expression des gènes impliqués dans la survie et l'apoptose des cellules T mémoires. Ceci pourrait impliquer une régulation cellulaire homéostatique distincte dans ces deux compartiments de cellules T mémoires. Dans les cellules CD8+ l'expression d'un nombre de gènes impliqués dans la survie et la protection de l'apoptose semblerait être diminuée dans les populations TEM et TTEM en comparaison à celle des sous-populations naïves et TEM, tandis que l'expression des gènes pro-apoptotiques semblerait être augmentée. Comme ceci paraît être plus accentué dans les TTEM, cela pourrait indiquer une plus grande disposition à l'apopotose dans les populations CCR7- (effectrices) et une perte de survie parallèlement à l'acquisition de capacités effectrices. Ceci parlerait en faveur d'un modèle de différentiation linéaire dans les cellules CD8+. De plus, l'augmentation sélective de l'expression d'IL-7Ra observée dans le sous-groupe de cellules mémoires TEM, et d'IL-15Ra dans celui des TEM, pourrait indiquer un moyen de sélection pour des réponses immunitaires mémoires à long terme par une réponse distincte à ces cytokines. Dans les cellules CD4+ par contre, aucun profil d'expression n'a pu être déterminé; les résultats suggèrent même une résistance relative à l'apoptose de la part des cellules mémoires. Ceci pourrait favoriser l'existence d'un modèle de différentiation plus flexible avec des possibilités d'interaction multiples. Ainsi, la surexpression sélective de BAFF, APRIL et BAFF-R dans les sous-populations individuelles des cellules mémoires pourrait être un indice de l'interaction de ces sous-groupes avec des cellules B. ABSTRACT Introduction: Based on their surface expression of the CD45 isoform and of the CCR7 chemokine receptor, memory T cells have been divided into the following three subsets: central memory (TAM), effector memory (TEM) and terminal effector memory (ITEM). Distinct functional roles and different proliferative and regenerative capacities have been attributed to each one of these subpopulations. The molecular mechanisms underlying these differences; however, remain poorly understood. Materials and Methods: According to their expression of CD4, CD8, CD45RA and CCR7, human peripheral blood mononuclear cells were sorted by flow-cytometry into CD4+ or CD8+ naïve, TAM, TEM and ITEM subsets. Using real-time PCR, the expression of 14 genes known to be involved in apoptotis, survival or proliferation of T cells was quantified separately in each individual subset, relative to an endogenous reference gene. The RNA equivalent of 450 T cells was used for each gene and subset. The target gene panel included the survival genes BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα and IL-7Rα, the anti-apoptotic genes Bcl2, Bcl-xL and FLIP, the pro-apoptotic genes Bad, Bax and Fast, as well as the antiproliferative gene Tob. Using the comparative CT-method, the expression of the target genes in the three memory T cell subsets of both CD4+ and CD8+ T cell populations was compared to their expression in the naïve T cells. Results: In CD8+ cells, the pro-apoptotic factors Bax and Fast were found to be upregulated in all memory T cell subsets, whereas the survival and anti-apoptotic factors Bcl-2, APRIL and BAFF-R were downregulated. These tendencies were most accentuated in TEM and TTEM subsets. Even though the survival factor IL-7Rα was also downregulated in these subsets, interestingly, it was selectively upregulated in the CD8+ TAM subset. Similarly, IL-15Rαexpression was shown to be selectively upregulated in the CD8+ TEM subset. In CD4+ cells, the expression levels of the analyzed genes showed a greater inter-individual variability than in CD8+ cells, thus suggesting the absence of any particular expression pattern for CD4+ memory T cells. However, the survival factor BAFF was found to be significantly upregulated in all CD4+ memory T cell subsets, as was also the expression of APRIL and BAFF-R, although to a lesser extent. Furthermore, it was noted that the pro-apoptotic gene Fast was only expressed in the TTEM CD4+ subset. Discussion and Conclusions: Genes involved in apoptosis and survival in human memory T cells have been shown to be expressed differently in CD8+ cells as compared to CD4+ cells, suggesting a distinct regulation of cell homeostasis in these two memory T cell compartments. The present study suggests that, in CD8+ T cells, the expression of various survival and antiapoptotic genes is downregulated in TEM and TTEM subsets, while the expression of proapoptotic genes is upregulated in comparison to the naïve and the TAM populations. These characteristics, potentially translating to a greater susceptibility to apoptosis in the CCR7- (effector) memory populations, are accentuated in the TTEM population, suggesting a loss of survival in parallel to the acquisition of effector capacities. This speaks in favour of a linear differentiation model in CD8+ T memory cells. Moreover, the observed selectively increased expression of IL-7Rα in CD8+ TAM cells - as that of IL-15Rα in CD8+ TEM cells -suggest that differential responsiveness to cytokines could confer a selection bias for distinct long-term memory cell responses. Relative to the results for CD8+ T cells, those for CD4+ T cells seem to indicate a certain resistance of the memory subsets to apoptosis, suggesting the possibility of a more flexible differentiation model with multiple checkpoints and potential interaction of CD4+ memory cells with other cells. Thus, the selective upregulation of BAFF, APRIL and BAFF-R in individual memory subsets could imply an interaction of these subsets with B cells.

Behavioral assumptions and management ability

The paper explores the consequences that relying on different behavioral assumptions intraining managers may have on their future performance. We argue that training with anemphasis on the standard assumptions used in economics (rationality and self-interest) is goodfor technical posts but may also lead future managers to rely excessively on rational and explicitsafeguarding, crowding out instinctive relational heuristics and signaling a bad human type topotential partners. In contrast, human assumptions used in management theories, because oftheir diverse, implicit and even contradictory nature, do not conflict with the innate set ofcooperative tools and may provide a good training ground for such tools. We present tentativeconfirmatory evidence by examining how the weight given to behavioral assumptions in the corecourses of the top 100 business schools influences the average salaries of their MBA graduates.Controlling for the self-selected average quality of their students and some other schools characteristics, average salaries are seen to be significantly greater for schools whose core MBAcourses contain a higher proportion of management courses as opposed to courses based oneconomics or technical disciplines.

La société sénégalaise et les enfants de la rue : approche socio-anthropologique des dynamiques d'exclusion et de survie : étude de cas à Dakar

Résumé : La société sénégalaise traverse une crise profonde qui touche tous les secteurs de la vie. Cette crise à la fois structurelle et conjoncturelle crée à son tour une sorte de société de la crise qui touche les populations les plus vulnérables. Le phénomène des enfants de la rue est l'expression parfaite de cette société de la crise. Le rythme dans lequel il se développe est la traduction de la dynamique d'exclusion qui sévit en milieu urbain sénégalais en général et dans la région de Dakar en particulier. Dans cette région, l'urbanisation s'est accompagnée de la montée des inégalités qui placent la société dans une sorte de dualisation entre centre et périphérie. A la ville de Dakar qui s'est constituée selon les normes de la planification urbaine, s'oppose les principales banlieues de Pikine, Guédiawaye et Rufisque qui offrent le visage de marges sociales urbaines. D'une certaine manière, la montée des inégalités remet en cause les politiques sociales, de la bonne gouvernance et de la redistribution des richesses. Ces banlieues constituent les principaux milieux d'accueil de la masse de migrants ruraux qui fuient la misère des villages. D'une part, l'hétérogénéité sociale de ces banlieues ne favorise pas l'émergence d'une conscience collective fondée sur l'appartenance à un fonds historique commun. Par contre, elle renforce l'anonymat et l'indifférence propres à la ville. D'autre part, les difficultés économiques et la précarité des conditions de vie conjuguées à l'explosion démographique et ses conséquences affaiblissent les systèmes de solidarité entraînant ainsi la montée de l'individualisme et la philosophie du chacun pour soi. Ce qui met en cause l'éducation des enfants qui devient difficile pour les parents d'assumer. En outre, la place importante accordée à l'imaginaire social dans la société sénégalaise explique le recours aux forces surnaturelles par l'intercession des marabouts, sorciers, devins, etc. D'autre part, la place accordée aux offrandes et aux sacrifices de même que le "besoin de donner" alimente et pérennise la pratique de la mendicité en général et celle des enfants en particulier. En outre, l'instrumentalisation de la mendicité par certains marabouts qui se traduit par une sorte de "business talibé" ou de "marché de l'aumône", rapproche les enfants de l'univers de là rue qui devient pour eux une sorte d'échappatoire face aux conditions de vie que leur imposent ces marabouts. Ainsi, pour eux, la rue remplit une fonction de socialisation. En effet, dans cet univers social, les enfants se forgent une personnalité, développent des compétences et des activités qui leur permettent de survivre, créent des repères et des codes collectifs qui leur permettent de mener une existence que la société assimile strictement à la déviance. Mots clé : crise, école, éducation, enfants de la rue, exclusion, inégalités, migration, pauvreté, socialisation, stratégies de survie, uibanisation.

ARE PPARS NOVEL THERAPEUTIC TARGETS TO IMPROVE MELANOMA TREATMENT ?

Cutaneous melanoma is an aggressive malignant tumor of melanocytes, the pigment- producing cells of the epidermis, with a high incidence in developed countries. Despite some major clinical breakthroughs in the last few years, efficient therapies for metastatic melanoma, which portends a very bad prognosis, are still lacking. Among the potential therapeutic targets that have been attracting at-tention in melanoma are the peroxisome proliferator-activated receptors (PPARs). These members - a, ß and 7 - of the nuclear hormone receptor family, which are ligand-gated transcription factors endowed with a multitude of functions besides metabolism homeostasis, have displayed promising antitumor properties in a wide range of cancer cells, including melanoma. However, our knowledge of PPARs' functions in this skin cancer is far from complete, making the usefulness of any of the a, ß or 7 isotype as a therapeutic target uncertain. In this work, we showed that all three PPAR isotypes are expressed in normal melanocytes, in most melanoma cell lines and in primary and metastatic melanomas, and that PPAR/3 and 7 display transcriptional activity in normal melanocytes and melanoma cells. We also showed that the PPAR7 agonist rosiglitazone had anti-melanoma properties largely independent of PPAR7 expression, which was widely varying across the different cell lines and melanoma biopsies we evaluated and was not correlated with cell line stage. Consistent with the general view of PPAR7 as a tumor suppressor gene, we found that, in human samples, PPAR7 was less expressed in melanoma than in normal skin. Transcriptornic profiling of metastatic melanoma cells in which PPAR7 was pharmacologically modulated revealed an association with epithelial-to-mesenchymal transition, though the functional relevance of this finding remains to be determined. Collectively, our results suggests that PPAR7 activity in melanoma is highly complex and that a straightforward picture of PPAR7's role in this skin cancer is difficult to draw. In this study, we also provided compelling evidence that thioredoxin interacting protein (TXNIP) is, in melanoma, a bona fide PPAR7 target gene, the expression of which is repressed by PPAR7 activation. Although TXNIP is mostly known as an inhibitor of the major antioxidant thioredoxin, it has demonstrated a range of biological functions and is generally considered as a tumor suppressor gene. Consistently, we found that TXNIP expression is associated with growth arrest of melanoma cells in vitro and that forced expression of TXNIP strongly impairs cell proliferation. Interestingly, we also discovered that TXNIP favors melanoma cell migration while it diminishes their adhesion. Finally, we provided several lines of evidence that TXNIP may regulate these processes at the transcriptional level as well as by direct protein-protein interactions in the plasma membrane. Altogether, our findings suggest that the PPAR7 target TXNIP may be a double-edged sword in melanoma, hindering tumor growth but promoting invasion and dissemination. Experiments to evaluate the net biological outcome of TXNIP modulation in vivo are ongoing. -- Le mélanome cutané est une tumeur maligne agressive des mélanocytes, cellules de l'épiderme qui produisent la mélanine. Ce cancer présente un taux d'incidence élevé dans les pays développés et est grevé d'un pronostic très sombre une fois qu'il a disséminé. Malgré les importants progrès réalisés ces dernières années, aucune thérapie lie s'est encore montrée véritablement efficace contre le mélanome métastatique. Parmi les cibles thérapeutiques potentielles, nombre de groupes de recherche se sont penchés sur les peroxisome proliferator-activated receptors (PPARs). Ces récepteurs - a, ß et 7 - font partie de la famille des récepteurs nucléaires aux hormones, des facteurs de transcription activés par des ligands et dotés d'une multitude de fonctions en sus de la régulation du métabolisme. Ces protéines ont démontré des propriétés anti-tumorales prometteuses dans une large gamme de cellules cancéreuses, y compris le mélanome. Cependant, nous connaissons encore très mal les fonctions des PPARs dans ce cancer de la peau, rendant l'utilité thérapeutique de l'un des isotypes a, ß ou 7 incertaine. Dans ce travail, nous avons montré que les trois isotypes sont exprimés dans les mélanocytes normaux, dans la plupart des lignées de mélanome ainsi que dans des mélanomes primaires et métastatiques; nous avons aussi montré que PPAR/3 et 7 sont actifs sur le plan transcriptionnel dans les mélanocytes normaux et les cellules de mélanome. La rosiglitazone, un agoniste de PPAR7, a démontré des propriétés anti-mélanome essentiellement indépendantes de l'expression de PPAR7, qui semble très variable dans les lignées et les biopsies que nous avons évaluées; de plus, l'expression de PPAR7 n'est pas corrélée avec le stade de la lignée. En accord avec la vision communément admise de PPAR7 comme étant un gène suppresseur de tumeur, nous avons observé dans des échantillons humains que PPAR7 est moins exprimé dans les mélanomes que dans la peau normale. Une étude transcrip- tomique de cellules de mélanome métastatique a révélé que la modulation phar-macologique de PPAR7 est associée avec la transition épithélio-mésenchymateuse, même si la pertinence fonctionnelle de cette trouvaille reste à déterminer. Collec-tivement, ces résultats suggèrent que l'activité de PPAR/y dans le mélanome est hautement complexe et qu'une image claire du rôle de PPAR7 dans ce cancer est difficile à dessiner. Dans cette étude, nous avons également fourni de solides preuves que la thiore-doxin interacting protein (TXNIP) est, dans le mélanome, un gène cible bona fide de PPAR7 dont l'expression est réprimée par l'activation de PPAR7. Bien que TXNIP soit surtout connu comme un inhibiteur de la thiorédoxine -un anti-oxydant majeur - cette protéine a démontré une large gamme de fonctions biologiques et est généralement considérée comme un gène suppresseur de tumeur. En accord avec cette conception, nous avons trouvé que l'expression de TXNIP est associée avec l'arrêt de croissance des cellules de mélanome in vitro et que l'expression forcée de TXNIP freine considérablement la prolifération cellulaire. Nous avons aussi découvert que TXNIP favorise la migration des cellules de mélanome alors qu'elle diminue leur adhésion. Enfin, nous avons obtenu plusieurs preuves que TXNIP pourrait réguler ces processus tant au niveau transcriptionnel que par des interactions protéine-protéine au sein de la membrane plasmique. En conclusion, nos résultats suggèrent que la cible de PPAR7 TXNIP pourrait être une épée à double tranchant dans le mélanome, freinant la croissance tumorale mais favorisant l'invasion et la dissémination. Des expériences permettant d'évaluer l'effet biologique net de la modulation de TXNIP in vivo sont en cours.

Neurobiologia, coscienza e neuroetica. Ricerche filosofiche in margine al dialogo tra G.P. CHANGEUX e P. RICOEUR

Le neuroscienze occupano oggi un ruolo essenziale nel dibattito scientifico e filosofico, nonché in quello delle scienze umane. Esse costituiscono la sfida più seria al sapere fin qui elaborato intorno ai fondamenti dell'esperienza di coscienza, poiché si propongono come capaci di rispondere alla domanda di origine e funzionamento della coscienza. Le neuroscienze cognitive stanno, oggi, rivoluzionando la nostra concezione della mente e delle sue funzioni. Ci forniscono nuovi dati sulla natura delle sensazioni, della memoria, della percezione e dei processi di astrazione. L'epistemologia è rientrata così pienamente nell'ambito di una disciplina sperimentale, come diversi filosofi (da Hume a Quine) hanno auspicato. È, alla fine, evoluta nell'esperienza odierna della cosiddetta "epistemologia sperimentale", luogo che coniuga il rigore sperimentale della scienza con la profondità e la sofisticazione argomentativa della tradizione filosofica. Come arriviamo a conoscere? Quali vincoli poniamo a quello che deve essere conosciuto? Perché seguiamo certe vie invece di altre? Come arriviamo a formulare giudizi e a prendere decisioni? Che valore ha la conoscenza già acquisita nell'elaborazione di nuove esperienze? In particolare, che peso hanno le aspettative e i ricordi in questo processo? Qual è il rapporto fra esperienza, conoscenza e memoria? Come si fissano e come si richiamano i ricordi? Qual è il rapporto fra coscienza e memoria? Sono alcune delle domande che l'autore si pone in questa ottica e alle quali cerca di rispondere, a partire dall'analisi e valutazione del dialogo-dibattito fra J.-P. Changeux e P. Ricoeur, per apprenderne il linguaggio, capire i problemi sollevati, adattarsi alla complessità della materia. Nel contesto della filosofia della mente, la "lettura" della discussione ripercorre i relativi percorsi attraverso l'analisi delle loro opere, da un lato quelle dello scienziato (sulla struttura e dinamica del cervello, la teoria dell'epigenesi e stabilizzazione selettiva, le speculazioni sull'uomo neuronale e i rilievi antropologici, le teorie della conoscenza e della coscienza, oltre che sulla conoscenza matematica, gli argomenti di estetica ed etica); dall'altro lato quelle del filosofo (dal Cogito riflessivo alla scoperta dell'ermeneutica, dalle eterogenee riflessioni sul Conflitto delle interpretazioni alla grande teoria sulla creatività del linguaggio, le conclusioni teoriche sull'ermeneutica del sé e l'ontologia dell'agire). Il punto di arrivo è la determinazione delle relative posizioni: quella di Changeux tra i neuroscienziati che si occupano di questioni filosofiche, epistemologiche ed etiche, e quella di Ricoeur tra i filosofi che si occupano di neuroscienze. La conclusione della tesi si svolge in un approfondimento teoretico che dalla nozione di "traccia" porta all'esperienza della "memoria", al fine di intrecciare i fili della discussione ripercorsa ed offrire una sponda non forzata al dibattito più ampio. Il tema della memoria è privilegiato per ragioni intrinseche, poiché si tratta di uno dei temi precipui delle neuroscienze, della filosofia della mente e della fenomenologia. A un primo livello viene instaurato su questo punto un confronto epistemologico tra la proposta della neurofenomenologia (Varala, ad esempio) e la posizione tenuta in particolare da Ricoeur rispetto ad essa e al suo "progetto unificante", posizione defilata e, per certi aspetti, criticamente dubbiosa sul fatto che si possa davvero giungere a un "terzo discorso". Si riferisce poi del largo interesse e dei risultati più significativi della riflessione fenomenologica antica e moderna sulla memoria. A un secondo livello vengono illustrati i programmi di ricerca recenti della neurofenomenologia su questo argomento all'interno delle scienze cognitive e si dà conto dei risultati più significativi. Ad un terzo e conclusivo livello, si approfondisce il significato teologico della memoria. Les neurosciences ont aujourd'hui un rôle essentiel dans le débat scientifique et philosophique, ainsi que dans celui des sciences humaines. Elles constituent le défi le plus sérieux aux savoir qu'on a construit jusqu'ici sur les fondements de l'expérience de conscience, attendu qu'elles-mêmes se considèrent capables de répondre à la demande sur l'origine e le fonctionnement de la conscience. Les neurosciences cognitives sont aujourd'hui en train de révolutionner notre conception de l'esprit et des ses fonctions. Elles nous offrent des nouvelles données au sujet de la nature de nos sensations, mémoire, perception et procédés d'abstraction. Aussi l'épistémologie est rentrée pleinement dans le domaine d'une discipline expérimentale, comme plusieurs philosophes (de Hume à Quine) l'ont souhaité. Elle s'est enfin adressée, dans l'expérience actuelle, vers la soi-disant "épistémologie expérimentale", lieu qui met en accord la rigueur expérimentale de la science avec la profondeur et la sophistiquée finesse argumentative de la tradition philosophique. Comment en arrivons-nous à connaître? Quels liens mettons-nous à ce qu'on doit être connu? Pourquoi suivons-nous certaines vois au lieu d'autres? Comment en arrivons-nous à formuler des opinions et à prendre des décisions? Quelle valeur a la connaissance qu'on a déjà acquise par l'élaboration des nouvelles expériences? En particulier, quelle est l'importance des attentes et des souvenirs dans cette évolution? Quel est le rapport entre expérience, connaissance e mémoire? Comment fixons et rappelons-nous nos souvenirs? Quel est le rapport entre conscience et mémoire? Ces sont quelques-unes des questions que l'auteur se pose dans cette perspective et aux quelles essaie de répondre a partir de l'analyse et l'évaluation du dialogue-débat entre fra J.-P. Changeux et P. Ricoeur, pour en apprendre le langage, comprendre les problèmes soulevés, s'adapter à la complexité du sujet. Dans le contexte de la philosophie du cerveau, la "lecture" du dialogue reparcourt les parcours des deux interlocuteurs par l'analyse de leur ouvrages, d'une part celles du savant (sur la structure et la dynamique du cerveau, la théorie de l'épigenèse et stabilisation sélective; les spéculations sur l'homme neuronal et les commentaires anthropologiques; les théories de la connaissance et de la conscience, de même que sur la connaissance de la mathématique, les sujets d'esthétique et étique; d'autre part celles du philosophe (du Cogito réflexif à la découverte de l'herméneutique, de les hétérogènes réflexions sur le Conflit des interprétations à la grande théorie sur la créativité du langage, les conclusions théoriques sur l'herméneutique du soi et l'ontologie de l'agir). L'issue est la determination des relatives positions: celle de Changeux parmi les neuro-scientifiques qui s'occupent de questions philosophiques, épistémologiques et éthiques, et celle de Ricoeur parmi les philosophes qui s'occupent de neurosciences. La conclusion de la thèse se développe dans un approfondissement théorétique que de la notion de "trace" à l'expérience de la "mémoire", à l'effet de nouer les fils de la discussion passée en revue et d'assurer un appui pas forcé au débat plus vaste. Le thème de la mémoire a été choisi pour des raisons intrinsèques, puisqu'il est un des thèmes principaux des neurosciences, de la philosophie de l'esprit et de la phénoménologie. Sur un premier plan épistémologique il est établi une comparaison entre la proposition de la neurophénoménologie (Varala, par exemple) et la position soutenue en particulier par Ricoeur au sujet de ce courant phénoménologique et de son "projet unifiant", position défilée et, à certains égards, critiquement hésitante sur le fait qu'on puisse vraiment en venir à un "troisième discours". On rend compte du grand intérêt et des résultats les plus significatifs de la réflexion phénoménologique ancienne et moderne sur la mémoire. Sur un second plan neurophénoménologique on illustre des plans de recherche récents sur cet argument au-dedans des sciences cognitives et on rend compte des résultats les plus distinctives. Sur un troisième et conclusif plan on approfondit le sens théologique de la mémoire.

Irreversible investment in stochastically cyclical markets

This paper presents a new framework for studying irreversible (dis)investment whena market follows a random number of random-length cycles (such as a high-tech productmarket). It is assumed that a firm facing such market evolution is always unsure aboutwhether the current cycle is the last one, although it can update its beliefs about theprobability of facing a permanent decline by observing that no further growth phasearrives. We show that the existence of regime shifts in fluctuating markets suffices for anoption value of waiting to (dis)invest to arise, and we provide a marginal interpretationof the optimal (dis)investment policies, absent in the real options literature. Thepaper also shows that, despite the stochastic process of the underlying variable has acontinuous sample path, the discreteness in the regime changes implies that the samplepath of the firm s value experiences jumps whenever the regime switches all of a sudden,irrespective of whether the firm is active or not.