Single cell analysis reveals similar functional competence of dominant and nondominant CD8 T-cell clonotypes.

Immune protection from infectious diseases and cancer is mediated by individual T cells of different clonal origin. Their functions are tightly regulated but not yet fully characterized. Understanding the contribution of each T cell will improve the prediction of immune protection based on laboratory assessment of T-cell responses. Here we developed techniques for simultaneous molecular and functional assessment of single CD8 T cells directly ex vivo. We studied two groups of patients with melanoma after vaccination with two closely related tumor antigenic peptides. Vaccination induced T cells with strong memory and effector functions, as found in virtually all T cells of the first patient group, and fractions of T cells in the second group. Interestingly, high functionality was not restricted to dominant clonotypes. Rather, dominant and nondominant clonotypes acquired equal functional competence. In parallel, this was also found for EBV- and CMV-specific T cells. Thus, the nondominant clonotypes may contribute similarly to immunity as their dominant counterparts.

Exendin-(9-39) is an inverse agonist of the murine glucagon-like peptide-1 receptor: implications for basal intracellular cyclic adenosine 3',5'-monophosphate levels and beta-cell glucose competence.

The effect of exendin-(9-39), a described antagonist of the glucagon-like peptide-1 (GLP-1) receptor, was evaluated on the formation of cAMP- and glucose-stimulated insulin secretion (GSIS) by the conditionally immortalized murine betaTC-Tet cells. These cells have a basal intracellular cAMP level that can be increased by GLP-1 with an EC50 of approximately 1 nM and can be decreased dose dependently by exendin-(9-39). This latter effect was receptor dependent, as a beta-cell line not expressing the GLP-1 receptor was not affected by exendin-(9-39). It was also not due to the endogenous production of GLP-1, because this effect was observed in the absence of detectable preproglucagon messenger RNA levels and radioimmunoassayable GLP-1. Importantly, GSIS was shown to be sensitive to this basal level of cAMP, as perifusion of betaTC-Tet cells in the presence of exendin-(9-39) strongly reduced insulin secretion. This reduction of GSIS, however, was observed only with growth-arrested, not proliferating, betaTC-Tet cells; it was also seen with nontransformed mouse beta-cells perifused in similar conditions. These data therefore demonstrated that 1) exendin-(9-39) is an inverse agonist of the murine GLP-1 receptor; 2) the decreased basal cAMP levels induced by this peptide inhibit the secretory response of betaTC-Tet cells and mouse pancreatic islets to glucose; 3) as this effect was observed only with growth-arrested cells, this indicates that the mechanism by which cAMP leads to potentiation of insulin secretion is different in proliferating and growth-arrested cells; and 4) the presence of the GLP-1 receptor, even in the absence of bound peptide, is important for maintaining elevated intracellular cAMP levels and, therefore, the glucose competence of the beta-cells.

How does ownership structure invfluence bank risk? Analyzing the role of managerial incentives

This paper analyzes how ownership concentration and managerial incentives influences bank risk for a large sample of US banks over the period 1997-2007. Using 2SLS simultaneous equations models, we show that ownership concentration has a positive total effect on bank risk. This is the result of a positive direct effect, which reflects monitoring and opportunistic behavior, and a negative indirect effect, which works through the design of managerial incentive contracts and reflects shareholder preferences toward risk. Large shareholders reduce bank risk by reducing the sensitivity of CEO wealth to stock volatility (Vega) and by increasing the CEO pay-performance sensitivity (Delta). In addition, we show that the direct and indirect effect of ownership concentration on bank risk depends on the type of the largest shareholder (a family, a bank, a corporation or an institutional investor), as well as, on the total shareholding held by each type as a group. Our results suggest that the positive relation between ownership concentration and risk is not the result of preferences towards more risk. Rather, they point at opportunistic behavior of large shareholders.

Assessment and reuse of contents in the competence-based educational platform InterMediActor

This paper describes a failure alert system and a methodology for content reuse in a new instructional design system called InterMediActor (IMA). IMA provides an environment for instructional content design, production and reuse, and for students’ evaluation based in content specification through a hierarchical structure of competences. The student assessment process and information extraction process for content reuse are explained.

Supporting life-long competence development using the TENCompetence infrastructure: a first experiment

This paper describes an experiment to explore the effects of the TENCompetence infrastructure for supporting lifelong competence development which is now in development. This infrastructure provides structured, multi-leveled access to learning materials, based upon competences. People can follow their own learning path, supported by a listing of competences and their components, by competence development plans attached to competences and by the possibility to mark elements as complete. We expected the PCM to have an effect on (1) control of participants of their own learning, and (2) appreciation of their learning route, (3) of the learning resources, (4) of their competence development, and (5) of the possibilities of collaboration. In the experiment, 44 Bulgarian teachers followed a distance learning course on a specific teaching methodology for six weeks. Part of them used the TENCompetence infrastructure, part used an infrastructure which was similar, except for the characterizing elements mentioned above. The results showed that in the experimental condition, more people passed the final competence assess-ment, and people felt more in control of their own learning. No differences between the two groups were found on the amount and appreciation of collaboration and on further measures of competence development.

Guiding students through competence-based educational material

Student guidance is an always desired characteristic in any educational system, butit represents special difficulty if it has to be deployed in an automated way to fulfilsuch needs in a computer supported educational tool. In this paper we explorepossible avenues relying on machine learning techniques, to be included in a nearfuture -in the form of a tutoring navigational tool- in a teleeducation platform -InterMediActor- currently under development. Since no data from that platform isavailable yet, the preliminary experiments presented in this paper are builtinterpreting every subject in the Telecommunications Degree at Universidad CarlosIII de Madrid as an aggregated macro-competence (following the methodologicalconsiderations in InterMediActor), such that marks achieved by students can beused as data for the models, to be replaced in a near future by real data directlymeasured inside InterMediActor. We evaluate the predictability of students qualifications, and we deploy a preventive early detection system -failure alert-, toidentify those students more prone to fail a certain subject such that correctivemeans can be deployed with sufficient anticipation.

Excess Entry, Ambiguity Seeking, and Competence: An Experimental Investigation

Excess entry refers to the high failure rate of new entrepreneurial ventures. Economic explanations suggest 'hit and run' entrants and risk-seeking behavior. A psychological explanation is that people (entrepreneurs) are overconfident in their abilities (Camerer & Lovallo, 1999). Characterizing entry decisions as ambiguous gambles, we alternatively suggest following Heath and Tversky (1991) that people seek ambiguity when the source of uncertainty is related to their competence. Overconfidence, as such, plays no role. This hypothesis is confirmed in an experimental study that also documents the phenomenon of reference group neglect. Finally, we emphasize the utility that people gain from engaging in activities that contribute to a sense of competence. This is an important force in economic activity that deserves more explicit attention.

The Strategic Impact of Clinical Practice Guidelines in Nursing on the Managerial Function of Supervision

Clinical practice guidelines in nursing (CPG-N) are tools that allow the necessary knowledge that frequently remains specialist-internalised to be made explicit. These tools are a complement to risk adjustment systems (RAS), reinforcing their effectiveness and permitting a rationalisation of healthcare costs. This theoretical study defends the importance of building and using CPG-Ns as instruments to support the figure of the nursing supervisor in order to optimise the implementation of R&D and hospital quality strategies, enabling clinical excellence in nursing processes and cost-efficient reallocation of economic resources through their linear integration with SARs.

The Construction Of Ethical Competence In The Perception Of Primary Care Nurses


The study intended to understand the perception of nurses of Primary Care Services about the construction of ethical competence on their formation and practices. This is a qualitative study, with an interpretative phenomenological approach and interviews with ten nurses of the community health services of Porto Alegre, RS. The results showed that the interviewed professionals had already experienced situations with ethical conflicts and knew what ethical competence means. The central themes point out three fundamental issues in the construction of the ethical competence: personal values, education and practice. Taking into account that ethical competence is in permanent construction, the study shows the importance to promote organizational and educational activities in a transversal manner, as a tool to cope the moral stress and contribute in improving the quality of care in the primary health attention.


Stakeholder Activism, Managerial Entrenchment, and the Congruence of Interests between Shareholders and Stakeholders

We argue that when stakeholder protection is left to the voluntary initiative of managers, concessions to social activists and pressure groups can turn into a self-entrenchment strategy for incumbent CEOs. Stakeholders other than shareholders thus benefit from corporate governance rules putting managers under a tough replacement threat. We show that a minimal amount of formal stakeholder protection, or the introduction of explicit covenants protecting stakeholder rights in the firm charter, may deprive CEOs of the alliance with powerful social activists, thus increasing managerial turnover and shareholder value. These results rationalize a recent trend whereby well-known social activists like Friends of the Earth and active shareholders like CalPERS are showing a growing support for each other s agendas.

Improved immunogenicity against HIV-1 clade C antigens by using NYVAC-C with restored replication competence.

In order to improve the immunogenicity of currently available non-replicating pox virus HIV vaccine vectors, NYVAC was genetically modified through re-insertion of two host range genes (K1L and C7L), resulting in restored replicative capacity in human cells. In the present study these vectors, expressing either a combination of the HIV-1 clade C antigens Env, Gag, Pol, Nef, or a combination of Gal, Pol, Nef were evaluated for safety and immunogenicity in rhesus macaques, which were immunized at weeks 0, 4 and 12 either by scarification (conventional poxvirus route of immunization), intradermal or by intramuscular injection (route used in previous vaccine studies).Replication competent NYVAC-C-KC vectors induced higher HIV-specific responses, as measured by IFN- ELISpot assay, than the replication defective NYVAC-C vectors. Application through scarification only required one immunization to induce maximum HIV-specific immune responses. This method simultaneously induced relatively lower anti-vector responses. In contrast, two to three immunizations were required when the NYVAC-C-KC vectors were given by intradermal or intramuscular injection and this method tended to generate slightly lower responses. Responses were predominantly directed against Env in the animals that received NYVAC-C-KC vectors expressing HIV-1 Env, Gag, Pol, Nef, while Gag responses were dominant in the NYVAC-C-KC HIV-1 Gag, Pol, Nef immunized animals.The current study demonstrates that NYVAC replication competent vectors were well tolerated and showed increased immunogenicity as compared to replication defective vectors. Further studies are needed to evaluate the most efficient route of immunization and to explore the use of these replication competent NYVAC vectors in prime/boost combination with gp120 protein-based vaccine candidates. This studies was performed within the Poxvirus T-cell Vaccine Discovery Consortium (PTVDC) which is part of the CAVD program.

Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells.

T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.

Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

BACKGROUND/AIMS: Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms. METHODS: We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed. RESULTS: Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation. CONCLUSIONS/INTERPRETATION: Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.

Capacité de discernement des adolescents mineurs: étude qualitative sur les représentations en Suisse romande. [Minor adolescent's competence: a qualitative study about representations in Switzerland's French-speaking part]

This exploratory qualitative study run using focus groups investigates the representations in the field of adolescent confidentiality and competence. Four groups of 3 to 8 participants (two of respectively younger and older adolescents, one of parents, one of pediatricians) have participated in a hone hour and a half discussion, than transcribed verbatim and analyzed by main themes. The concept of confidentiality is well known and understood, but the legal framework which underpins it is less well identified, both among young people and adults. Also, while the participants of all four groups agree with the idea that 14 year old youngsters are usually competent, they all admit that there are circumstances in which this statement should be revisited. Physicians report that they do not feel skilled in how to evaluate competence in such specific situations.

Managerial incentives for mergers

We study managerial incentives in a model where managers take notonly product market but also takeover decisions. We show that the optimalcontract includes an incentive to increase the firm's sales, under bothquantity and price competition. This result is in contrast to the previousliterature and hinges on the fact that with a more aggressive manager rivalfirms earn lower profits and are willing to sell out at a lower price. \\However, as a side--effect of such a contract, the manager might take overmore rivals than would be profitable.