Excavación superficial del Shaft por el método de perforación y voladura de la Central Hidroelectrica Chaglla

TesisEl presente informe profesional titulado “Excavación Superficial del Shaft mediante el método de Perforación y Voladura” tiene como objetivo principal dar a conocer el método de excavación del Shaft, por donde descenderán las compuertas que cerrarán el Túnel de Desvío, dando inicio al embalse del Rio Huallaga. El procedimiento seguido fue: 1ero. Las generalidades de la Central Hidroeléctrica Chaglla, tales como su ubicación, accesibilidad, clima, recursos, entre otros. 2do. Se describió la parte correspondiente a la Geología, tanto local como regionalmente; también se señalaron las características geológica y geotécnicas de las estructuras por donde se construirán los túneles de desvío, de vertedero, de aducción y el Shaft. 3ero. Se hizo la descripción del Proyecto de la Central Hidroeléctrica Chaglla, considerándose los accesos provisionales, la presa, el caudal ecológico, los vertederos, los túneles de desvío y aducción, los equipos a utilizar, para finalizar con los aspectos de seguridad y medio ambiente. 4to. Se realizó la descripción del método de excavación Superficial del Shaft, tales como los antecedentes, las operaciones unitarias de la construcción del shaft: perforación, voladura, carguío, sostenimiento e izaje de material. 5to. Finalmente se hizo el detalle de la excavación por el método de perforación y voladura, resultados con registros fotográficos, cronograma de trabajo, costo

Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance

Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native β cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple β cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+ and CD8+ diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+ T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+ and CD8+ T cells

Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing

International audienceHost versus graft reaction is a major impediment to CAR-T cell immune therapy in allogeneic settings. Authors show here that CAR-T cells, engineered to be deficient in MHC I expression but to express the NK inhibitor HLA-E, are resistant to destruction by both T and NK cells of the host. Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. However, realizing these advantages in an allogeneic setting requires universal CAR T-cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Here, we describe the development of a novel immune-evasive universal CAR T-cells scaffold using precise TALEN-mediated gene editing and DNA matrices vectorized by recombinant adeno-associated virus 6. We simultaneously disrupt and repurpose the endogenous TRAC and B2M loci to generate TCR alpha beta- and HLA-ABC-deficient T-cells expressing the CAR construct and the NK-inhibitor named HLA-E. This highly efficient gene editing process enables the engineered T-cells to evade NK cell and alloresponsive T-cell attacks and extend their persistence and antitumor activity in the presence of cytotoxic levels of NK cell in vivo and in vitro, respectively. This scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications