T-Cell Receptors Binding Orientation over Peptide/MHC Class I Is Driven by Long-Range Interactions.

Crystallographic data about T-Cell Receptor - peptide - major histocompatibility complex class I (TCRpMHC) interaction have revealed extremely diverse TCR binding modes triggering antigen recognition. Understanding the molecular basis that governs TCR orientation over pMHC is still a considerable challenge. We present a simplified rigid approach applied on all non-redundant TCRpMHC crystal structures available. The CHARMM force field in combination with the FACTS implicit solvation model is used to study the role of long-distance interactions between the TCR and pMHC. We demonstrate that the sum of the coulomb interactions and the electrostatic solvation energies is sufficient to identify two orientations corresponding to energetic minima at 0° and 180° from the native orientation. Interestingly, these results are shown to be robust upon small structural variations of the TCR such as changes induced by Molecular Dynamics simulations, suggesting that shape complementarity is not required to obtain a reliable signal. Accurate energy minima are also identified by confronting unbound TCR crystal structures to pMHC. Furthermore, we decompose the electrostatic energy into residue contributions to estimate their role in the overall orientation. Results show that most of the driving force leading to the formation of the complex is defined by CDR1,2/MHC interactions. This long-distance contribution appears to be independent from the binding process itself, since it is reliably identified without considering neither short-range energy terms nor CDR induced fit upon binding. Ultimately, we present an attempt to predict the TCR/pMHC binding mode for a TCR structure obtained by homology modeling. The simplicity of the approach and the absence of any fitted parameters make it also easily applicable to other types of macromolecular protein complexes.

An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2.

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen-self-major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced "homeostatic" proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8(+) T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.

Proposta de Implementação do Time-Driven Activity - Based Costing numa Empresa Industrial

O presente trabalho tem como objectivo a apresentação do processo de concepção e implementação de um projecto-piloto de um sistema de custeio baseado em actividades e tempo – TDABC, numa empresa industrial de conserva de pescado, Frescomar, S.A. Mais especificamente o trabalho desenvolveu-se na apuração do custo da área de produção da empresa objecto de estudo. O sistema de custeio Time-Driven Activity-Based Costing (TDABC) representa um modelo alternativo aos sistemas tradicionais da contabilidade de custos, e é uma evolução do Activity-Based Costing (ABC). O sistema ABC surgiu durante a década de 1980 e tem vindo a evoluir desde então. Muitas empresas abandonaram o ABC, pois este método de custeio, além de não conseguir captar a complexidade das suas operações, a sua implementação é demorado, e é muito dispendioso de aplicar e manter. Com o método TDABC encontra-se uma alternativa para dirimir estes problemas. Observou-se a necessidade do desenvolvimento de apenas algumas equações de tempo (time equations) para representar as principais actividades da área de produção. Foram observadas, durante a realização do estudo, vários dos benefícios do TDABC como: a facilidade em modelar actividades complexas por meio das equações de tempo, obtenção rigorosa de gastos e o baixo tempo de desenvolvimento do modelo. Contudo, também foram identificadas algumas limitações como subjectividade no cálculo do tempo de execução das actividades e dificuldade em se estimar as equações de tempo para actividades pouco estruturadas.

Organic matter in upwelling off northern Peru, november 1977

Analiza la cantidad de carbon organico y nitrogeno en las costas del norte del Perú en noviembre de 1977

Vertical distributions of plankton in the upper 35m of the peruvian upwelling zone - application of a shipboard electronic plankton counting system

Analiza el proyecto ICANE y suma modificaciones para estudiar la distribución de zooplancton pequeño

Grazing patterns of copepods in the upwelling system off Peru

Estudio de la cantidad de alimento ingerido para tres generos de copepodos con el fin de determinar la profundidad y la hora del día que se da el máximo y mínimo de actividad alimentaria.

The peruvian anchoveta an its upwelling ecosystem: three decades of change

Analiza los recursos marinos del mar peruano y su manejo responsable.

The peruvian upwelling ecosystem: dynamics and interactions

446 p.

Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor

In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin α(M)β(2)-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fibγ(390-396A)) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α(M)β(2) binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α(M)β(2) blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-α(M)β(2) interactions may provide a novel strategy for DMD treatment.