Heterogeneous T-cell response to MAGE-A10(254-262): high avidity-specific cytolytic T lymphocytes show superior antitumor activity.

MAGE-encoded antigens, which are expressed by tumors of many histological types but not in normal tissues, are suitable candidates for vaccine-based immunotherapy of cancers. Thus far, however, T-cell responses to MAGE antigens have been detected only occasionally in cancer patients. In contrast, by using HLA/peptide fluorescent tetramers, we have observed recently that CD8(+) T cells specific for peptide MAGE-A10(254-262) can be detected frequently in peptide-stimulated peripheral blood mononuclear cells from HLA-A2-expressing melanoma patients and healthy donors. On the basis of these results, antitumoral vaccination trials using peptide MAGE-A10(254-262) have been implemented recently. In the present study, we have characterized MAGE-A10(254-262)-specific CD8(+) T cells in polyclonal cultures and at the clonal level. The results indicate that the repertoire of MAGE-A10(254-262)-specific CD8(+) T cells is diverse both in terms of clonal composition, efficiency of peptide recognition, and tumor-specific lytic activity. Importantly, only CD8(+) T cells able to recognize the antigenic peptide with high efficiency are able to lyse MAGE-A10-expressing tumor cells. Under defined experimental conditions, the tetramer staining intensity exhibited by MAGE-A10(254-262)-specific CD8(+) T cells correlates with efficiency of peptide recognition so that "high" and "low" avidity cells can be separated by FACS. Altogether, the data reported here provide evidence for functional diversity of MAGE-A10(254-262)-specific T cells and will be instrumental for the monitoring of peptide MAGE-A10(254-262)-based clinical trials.

Incentivising Investment in the UKCS: a Response to Supporting Investment: a Consultation on the North Sea Fiscal Regime

NORTH SEA STUDY OCCASIONAL PAPER No. 111

Pyelonephritic Escherichia coli expressing P fimbriae decrease immune response of the mouse kidney.

P fimbriae are proteinaceous appendages on the surface of Escherichia coli bacteria that mediate adherence to uroepithelial cells. E. coli that express P fimbriae account for the majority of ascending urinary tract infections in women with normal urinary tracts. The hypothesis that P fimbriae on uropathic E. coli attach to renal epithelia and may regulate the immune response to establish infection was investigated. The polymeric Ig receptor (pIgR), produced by renal epithelia, transports IgA into the urinary space. Kidney pIgR and urine IgA levels were analyzed in a mouse model of ascending pyelonephritis, using E. coli with (P+) and without (P-) P fimbriae, to determine whether P(+) E. coli regulate epithelial pIgR expression and IgA transport into the urine. (P+) E. coli establish infection and persist to a greater amount than P(-) E. coli. P(+)-infected mice downregulate pIgR mRNA and protein levels compared with P(-)-infected or PBS controls at > or =48 h. The decrease in pIgR was associated with decreased urinary IgA levels in the P(+)-infected group at 48 h. pIgR mRNA and protein also decline in P(+) E. coli-infected LPS-hyporesponsive mice. These studies identify a novel virulence mechanism of E. coli that express P fimbriae. It is proposed that P fimbriae decrease pIgR expression in the kidney and consequently decrease IgA transport into the urinary space. This may explain, in part, how E. coli that bear P fimbriae exploit the immune system of human hosts to establish ascending pyelonephritis.

Response of photosynthetic organisms to global change: an approach based on marker pigments

Report for the scientific sojourn carried out at the Department of Freshwater Ecology, National Environmetal Research Institute, Denmark, from 2006 to 2008. The main objective of the project was to reconstruct photosynthetic organism community composition using pigmentbased methods and to study their response to natural (e.g. climate) or anthropogenic (e.g. eutrophication) perturbations that took place in the system over time. We performed a study in different locations and at different temporal scales. We analysed the pigment composition in a short sediment record (46 cm sediment depth) of a volcanic lake (Lake Furnas) in the Azores Archipelago (Portugal). The lake has been affected during the last century by successive fish introductions. The specific objective was to reconstruct the lake’s trophic state history and to assess the role of land-use, climate and fish introductions in structuring the lake community. Results obtained suggested that whereas trophic cascade and changes in nutrient concentrations have some clear effects on algal and microbial assemblages, interpreting the effects of changes in climate are not straightforward. This is probably related with the rather constant precipitation in the Azores Islands during the studied period. We also analysed the pigment composition in a long sediment record (1800 cm sediment depth) of Lake Aborre (Denmark) covering ca. 8kyr of lake history. The specific objective was to describe changes in lake primary production and lake trophic state over the Holocene and to determine the photosynthetic organisms involved. Results suggested that external forcing (i.e. land use changes) was responsible of erosion and nutrient run off to the lake that contributed to the reported changes in lake primary production along most of the Holocene.

Inseguridad ciudadana subjetiva/miedo al delito: límites para la viabilidad de la transferencia de políticas de seguridad

Proyecto de investigación realizado a partir de una estancia en el Centre of Criminology de la University of Toronto, Canadà, entre 2006 y 2008. El miedo al delito como ámbito temático lleva 40 años de andadura y cuenta con cientos de investigaciones en su acervo. Dicha subdisciplina ha utilizado la expresión “miedo al delito” para referirse a un conjunto de conceptos académicos que ella misma va desarrollando, así como a lo que considera una experiencia subjetiva que pretende estudiar. Tanto el concepto como la experiencia han sido vagamente catalogados de respuesta emocional frente al delito o imágenes asociadas a éste. A pesar de los estudios más empíricos y de las teorías más positivistas, que tratan el miedo al delito como un fenómeno que puede ser medido y a cuyo conocimiento nos podemos ir aproximando cada vez con mayor precisión, con el trabajo de este proyecto se puede concluir que el miedo al delito constituye un elemento semántico-conceptual de las categorías académica y popular de delito. Los enfoques culturalistas o hermenéuticos han apuntado esta cuestión pero, simultáneamente, han seguido admitiendo la complementariedad entre enfoques. En principio, admitir el valor constitutivo del miedo al delito en la noción de delito parece que no excluye la necesidad de conocer si los temores a ser víctima de un delito han aumentado en nuestra ciudad, ni el saber por qué ello ha sido así. Apropiarse de tales saberes tal vez sea la única forma de aislar factores discretos que puedan ser manipulados en políticas públicas para erradicar el temor cuyo incremento se supone verificado con las mediciones. Sin embargo, puesto que lo registrado han sido actitudes cognitivas y no emociones, los eventuales programas de intervención deberían ser ideados en el mejor de los casos, con la misma complejidad que la propia formación de creencias lo que lo haría inoperativo. Acción bianual.

Kaposi sarcoma herpes virus antibody response and viremia following highly active antiretroviral therapy in the Swiss HIV Cohort study.

OBJECTIVE: To describe the effect of HAART on Kaposi sarcoma herpes virus (KSHV) antibody response and viremia among HIV-positive MSM. DESIGN: A follow-up study of 272 HIV-positive MSM (including 22 with Kaposi sarcoma) who first initiated HAART between January 1996 and July 2004 in the Swiss HIV Cohort Study. METHODS: For each individual, two serum samples, one at HAART initiation and another 24 months later, were tested for latent and lytic KSHV antibodies using immunofluorescence assays, and for KSHV viremia using PCR. Factors associated with changes in KSHV antibody titers and viremia were evaluated. RESULTS: At HAART initiation, 69.1 and 75.0% of patients were seropositive to latent and lytic KSHV antibodies, respectively. Seropositivity was associated with the presence of Kaposi sarcoma, older age, lower CD8 cell count and higher CD4/CD8 ratio. Prevalence of KSHV viremia at HAART initiation was 6.4%, being significantly higher among patients with Kaposi sarcoma (35.0%), and those with HIV viral loads 100 000 copies/ml (11.7%) or higher. At 24-month follow-up, geometric mean titers (GMTs) among KSHV seropositive patients increased and antibody seroprevalence was higher. Having Kaposi sarcoma and/or CD4 cell counts less than 50 cells/microl at HAART initiation was associated both with higher probability for antibody titers to increase (including seroconversion) and larger increases in GMTs. Only one of 17 viremic patients at HAART initiation had viremia at 24-month follow-up. CONCLUSION: HAART increases KSHV-specific humoral immune response and clearance of viremia among HIV-infected MSM, consistent with the dramatic protection offered by HAART against Kaposi sarcoma.

Complexity and Bounded Rationality in Individual Decision Problemsing.

I develop a model of endogenous bounded rationality due to search costs, arising implicitly from the problems complexity. The decision maker is not required to know the entire structure of the problem when making choices but can think ahead, through costly search, to reveal more of it. However, the costs of search are not assumed exogenously; they are inferred from revealed preferences through her choices. Thus, bounded rationality and its extent emerge endogenously: as problems become simpler or as the benefits of deeper search become larger relative to its costs, the choices more closely resemble those of a rational agent. For a fixed decision problem, the costs of search will vary across agents. For a given decision maker, they will vary across problems. The model explains, therefore, why the disparity, between observed choices and those prescribed under rationality, varies across agents and problems. It also suggests, under reasonable assumptions, an identifying prediction: a relation between the benefits of deeper search and the depth of the search. As long as calibration of the search costs is possible, this can be tested on any agent-problem pair. My approach provides a common framework for depicting the underlying limitations that force departures from rationality in different and unrelated decision-making situations. Specifically, I show that it is consistent with violations of timing independence in temporal framing problems, dynamic inconsistency and diversification bias in sequential versus simultaneous choice problems, and with plausible but contrasting risk attitudes across small- and large-stakes gambles.

Measuring Tax Complexity

This paper critically examines a number of issues relating to the measurement of tax complexity. It starts with an analysis of the concept of tax complexity, distinguishing tax design complexity and operational complexity. It considers the consequences/costs of complexity, and then examines the rationale for measuring complexity. Finally it applies the analysis to an examination of an index of complexity developed by the UK Office of Tax Simplification (OTS).

Pathology and immune response of the blue mussel (Mytilus edulis L.) after an exposure to the harmful dinoflagellate Prorocentrum minimum

The harmful dinoflagellate Prorocentrum minimum has different effects upon various species of grazing bivalves, and these effects also vary with life-history stage. Possible effects of this dinoflagellate upon mussels have not been reported; therefore, experiments exposing adult blue mussels, Mytilus edulis, to P. minimum were conducted. Mussels were exposed to cultures of toxic P. minimum or benign Rhodomonas sp. in glass aquaria. After a short period of acclimation, samples were collected on day 0 (before the exposure) and after 3, 6, and 9 days of continuous-exposure experiment. Hemolymph was extracted for flow-cytometric analyses of hemocyte, immune-response functions, and soft tissues were excised for histopathology. Mussels responded to P. minimum exposure with diapedesis of hemocytes into the intestine, presumably to isolate P. minimum cells within the gut, thereby minimizing damage to other tissues. This immune response appeared to have been sustained throughout the 9-day exposure period, as circulating hemocytes retained hematological and functional properties. Bacteria proliferated in the intestines of the P. minimum-exposed mussels. Hemocytes within the intestine appeared to be either overwhelmed by the large number of bacteria or fully occupied in the encapsulating response to P. minimum cells; when hemocytes reached the intestine lumina, they underwent apoptosis and bacterial degradation. This experiment demonstrated that M. edulis is affected by ingestion of toxic P. minimum; however, the specific responses observed in the blue mussel differed from those reported for other bivalve species. This finding highlights the need to study effects of HABs on different bivalve species, rather than inferring that results from one species reflect the exposure responses of all bivalves.

The response of the external finance premium in Asian corporate bond markets to financial characteristics, financial constraints and two financial crises

Empirical investigation of the external finance premium has been conducted on the margin between internal finance and bank borrowing or equities but little attention has been given to corporate bonds, especially for the emerging Asian market. In this paper, we hypothesize that balance sheet indicators of creditworthiness could affect the external finance premium for bonds as they do for premia in other markets. Using bond-specific and firm-specific data for China, Hong Kong, Indonesia, Korea, Philippines, Singapore and Thailand during 1995-2009 we find that firms with better financial health face lower external finance premia in all countries. When we introduce firm-level heterogeneity, we show that financial variables appear to be both statistically and quantitatively more important for financially constrained firms. Finally, when we examine the effects of the 1997-98 Asian crisis and the 2007-09 global financial crisis, we find that the sensitivity of the premium is greater for constrained firms during the Asian crisis compared to other times.

Cell mediated immunity in Chagas' disease: Trypanosoma cruzi antigens induce suppression of the in vitro proliferative response of mononuclear cells

The partial suppression of the cell-mediated immune response by Trypanosoma cruzi antigens in patients with Chagas' disease is demonstrated in a costimulation assay with T. cruzi antigens and Mycobacterium tuberculosis purified protein derivative (PPD) or Tetanus toxoid (TT). ononuclear cells from 13 patients with chagasic infection without evidence of heart disease, 10 patients with chagasic cardiomyopathy and 7 healthy blood donors were stimulated with antigen A (autoclaved epimastigotes), PPD, TT, PPD + A, PPD + TT and TT + A. The average percentage of suppression induced by costimulation of mononuclear cells with PPD and antigen A was 47.1% in patients with chagasic infection without heart disease (INF), 38.8% in patients with chagasic cardiomyopathy (CDM) and 23.3% in healthy controls. Similar values were observed when living trypomastigotes were used. A costimulatory study with PPD and TT, PPD and A and TT and A was carried out in 8 patients with chagasic infection, in order to evaluate the possibility that this difference could be due to a nonspecific inhibitory effect. The mean suppression induced by TT + PPD was -8.9, with TT + A was 52.7 and with PPD + A was 50.1. The data reported show that T. cruzi antigens induce a specific suppression of the proliferative responseof mononuclear cells, that might be relevant to the persistence of the parasite in the host.

Cellular immune response of humans to the circumsporozoite protein of Plasmodium vivax

The cellular immune response to the circumsporozoite (CS) protein of plasmodium vivax of individuals from malaria-endemic areas of Brazil was studied. We examined the in vitro proliferative response of the peripheral blood mononuclear cells (PBMC) of 22 individuals when stimulated with a CS recombinant protein (rPvCS-2) and two other synthetic peptides based on the sequenceof the P. vivax CS protein. Seven of the individuals from malaria-endemic area displayed an antigen specific in vitro proliferative responseto the recombinant protein PvCS-2 and one out of 6, proliferative response to the peptide 308-320. In contrast, none of the individuals displayed a proliferative reponse when stimulated with the D/A peptide which represent some of the repeated units present in this CS protein. Our study, therefore, provides evidence for the presence, withinthe major surface antigen of P. vivax sporozoites, of epitopes capble to induce proliferation of human PBMC.