Toward a rational design of combination therapy in cancer.

By merging computational systems modeling and experimental approaches, we have uncovered treatments reprogramming pro-angiogenic monocytes present in breast tumor into immunologically potent cells capable of mediating an anti-tumor immune response. The unraveled pathways and ligands which underlie monocyte pro-angiogenic activity have a strong predictive value for breast cancer patient relapse - free survival.

Las relaciones constituyen las unidades sociales basicas: En la muerte de Charles Tilly

Esta nota necrológica es una adaptación para la RIS del comentario publicado por Salvador Aguilar en la página web de la Editorial Hacer con motivo del fallecimiento de Charles Tilly. Esta editorial, uno de cuyos editores es Salvador Aguilar, ha publicado o está en vías de hacerlo cinco obras mayores del sociólogo norteamericano desaparecido el 29 de abril de 2008 a los 78 años. Salvador Aguilar es Profesor Titular de Estructura y Cambio Social (Universidad de Barcelona).

Effect of humeral stem design on humeral position and range of motion in reverse shoulder arthroplasty.

PURPOSE: The impacts of humeral offset and stem design after reverse shoulder arthroplasty (RSA) have not been well-studied, particularly with regard to newer stems which have a lower humeral inclination. The purpose of this study was to analyze the effect of different humeral stem designs on range of motion and humeral position following RSA. METHODS: Using a three-dimensional computer model of RSA, a traditional inlay Grammont stem was compared to a short curved onlay stem with different inclinations (155°, 145°, 135°) and offset (lateralised vs medialised). Humeral offset, the acromiohumeral distance (AHD), and range of motion were evaluated for each configuration. RESULTS: Altering stem design led to a nearly 7-mm change in humeral offset and 4 mm in the AHD. Different inclinations of the onlay stems had little influence on humeral offset and larger influence on decreasing the AHD. There was a 10° decrease in abduction and a 5° increase in adduction between an inlay Grammont design and an onlay design with the same inclination. Compared to the 155° model, the 135° model improved adduction by 28°, extension by 24° and external rotation of the elbow at the side by 15°, but led to a decrease in abduction of 9°. When the tray was placed medially, on the 145° model, a 9° loss of abduction was observed. CONCLUSIONS: With varus inclination prostheses (135° and 145°), elevation remains unchanged, abduction slightly decreases, but a dramatic improvement in adduction, extension and external rotation with the elbow at the side are observed.

Las Herramientas de comunicación social en la red y las relaciones personales : el caso de los universitarios chinos

Se expone una breve evolución histórica del surgimiento de las nuevas herramientas de comunicación social en la red de la República Popular China, incidiendo en los incesantes avances de la evolución tecnológica y las tendencias de desarrollo que han experimentado los servicios de redes sociales. Se hace un análisis de las consecuencias que conlleva el uso de las redes sociales en las relaciones personales de los universitarios chinos. Se investiga los motivos y la frecuencia de uso de las redes sociales, así como las implicaciones de las interacciones virtuales en la forma de relacionarse con el entorno social. Así mismo, se profundiza en las influencias positivas y negativas que provoca la expansión de las redes sociales en la vida universitaria china.

Design and physicochemical stability studies of paediatric oral formulations of sildenafil

Abstract Personalized medicine is a challenging research area in paediatric treatments. Elaborating new paediatric formulations when no commercial forms are available is a common practice in pharmacy laboratories; among these, oral liquid formulations are the most common. But due to the lack of specialized equipment, frequently studies to assure the efficiency and safety of the final medicine cannot be carried out. Thus the purpose of this work was the development, characterization and stability evaluation of two oral formulations of sildenafil for the treatment of neonatal persistent pulmonary hypertension. After the establishment of a standard operating procedure (SOP) and elaboration, the physicochemical stability parameters appearance, pH, particle size, rheological behaviour and drug content of formulations were evaluated at three different temperatures for 90 days. Equally, prediction of long term stability, as well as, microbiological stability was performed. Formulations resulted in a suspension and a solution slightly coloured exhibiting fruity odour. Formulation I (suspension) exhibited the best physicochemical properties including Newtonian behaviour and uniformity of API content above 90% to assure an exact dosification process.

Handbook of life design : from practice to theory and from theory to practice

Our lives and careers are becoming ever more unpredictable. The "life-design paradigm" described in detail in this ground-breaking handbook helps counselors and others meet people's increasing need to develop and manage their own lives and careers. Life-design interventions, suited to a wide variety of cultural settings, help individuals become actors in their own lives and careers by activating, stimulating, and developing their personal resources. This handbook first addresses life-design theory, then shows how to apply life designing to different age groups and with more at-risk people, and looks at how to train life-design counselors

The octagon, the hendecagon and the approximation of pi: the geometric design of the clypeus in the enclosure of Imperial cult in Tarraco

The ancient temple dedicated to the Roman Emperor Augustus on the hilltop of Tarraco (today’s Tarragona), was the main element of the sacred precinct of the Imperial cult. It was a two hectare square, bordered by a portico with an attic decorated with a sequence of clypeus (i.e. monumental shields) made with marble plates from the Luni-Carrara’s quarries. This contribution presents the results of the analysis of a three-dimensional photogrammetric survey of one of these clipeus, partially restored and exhibited at the National Archaeological Museum of Tarragona. The perimeter ring was bounded by a sequence of meanders inscribed in a polygon of 11 sides, a hendecagon. Moreover, a closer geometric analysis suggests that the relationship between the outer meander rim and the oval pearl ring that delimited the divinity of Jupiter Ammon can be accurately determined by the diagonals of an octagon inscribed in the perimeter of the clypeus. This double evidence suggests a combined layout, in the same design, of an octagon and a hendecagon. Hypothetically, this could be achieved by combining the octagon with the approximation to Pi used in antiquity: 22/7 of the circle’s diameter. This method allows the drawing of a hendecagon with a clearly higher precision than with other ancient methods. Even the modelling of the motifs that separate the different decorative stripes corroborates the geometric scheme that we propose.

Structure-Based, Rational Design of T Cell Receptors.

Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157-165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8(+) T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, K D = ∼1 - 5 μM. Beyond the affinity threshold at K D < 1 μM we observed an attenuation in cellular function, in line with the "half-life" model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method to predict this orientation and successfully assessed it using all non-redundant TCR-pMHC crystal structures available. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of stage IV melanoma.

Design of flywheel generator for a diesel hybrid working machine

The aim of this work is to design a flywheel generator for a diesel hybrid working machine. In this work we perform detailed design of a generator. Mobile machines are commonly used in industry: road building machines, three harvesting machines, boring machines, trucks and other equipment. These machines work with a hydraulic drive system. This system provides good service property and high technical level. Manufacturers of mobile machines tend to satisfy all requirements of customers and modernized drive system. In this work also a description of the frequency inverter is present. Power electronics system is one of the basic parts for structures perform in the project.

Del Estado-nación al Estado-marca. El rol de la diplomacia pública y la marca de país en el nuevo escenario de las relaciones internacionales

El establecimiento de relaciones entre países en un entorno global parece requerir nuevas estrategias que trascienden la tradicional diplomacia de Estado. La diplomacia pública deviene una renovada estrategia de proyección internacional, donde la marca de país ejerce un importante papel a modo de dispositivo aglutinador y de transmisión de identidades nacionales. De este modo, el nuevo “poder blando” de la representación geográfica parece transcurrir en el seno del debilitamiento del Estado-nación y en claro beneficio de una nueva forma de comunicar la identidad de un país más próxima a la intervención de diferentes agentes sociales que a la firma de tratados internacionales de competencia gubernamental. A partir de una revisión de la literatura existente, este artículo presenta un estado del arte relacionado con las nuevas estrategias de representatividad internacional llevadas a cabo por países y naciones.

Acción educativa para la prevención y el tratamiento de la neglicencia parental en el barrio de Can Rull del municipio de Sabadell

Este trabajo se inscribe en el ámbito de la prevención de la negligencia parental. Basado en un proceso teórico-práctico, el programa de intervención está sujeto a la línea de los programas de formación de padres, por lo que sigue una dinámica psico-educativa y comunitaria. Para la realización del trabajo se ha partido de la idea que la familia es la base del desarrollo personal de los humanos y que el buen desarrollo de los menores dependerá en gran parte de las relaciones intrafamiliares. Se establece como objetivo principal ofrecer un servicio específico, estable y continuo, vinculado a los servicios de atención a la infancia y a la familia, que trabaje con el fin de conseguir un cambio conductual en aquellas familias en las que se presente una dinámica parental negligente. La metodología utilizada ha combinado diferentes técnicas de investigación. Para el trabajo de documentación se ha realizado una búsqueda bibliográfica alrededor del concepto de negligencia parental, se han analizado las acciones que se llevan a cabo a nivel institucional y se ha establecido el marco conceptual en el que se incluye tanto los aspectos legal de las diferentes áreas de la administración como aquellos conceptos que forman la estructura de una intervención en el ámbito de la infancia y la familia. También se ha tenido en cuenta la comunicación directa con algunos profesionales del ámbito social, sanitario y educativo como parte importante y determinante del proceso de ejecución del programa. El diseño del programa sigue la metodología del planeamiento estratégico e incluye un diagnóstico preliminar, un plan de acción detallado de las diferentes fases de implementación de la propuesta de intervención, la previsión de mecanismos de evaluación y un presupuesto detallado. En la primera parte del trabajo se refleja la gravedad y el impacto que tiene la negligencia parental en nuestra sociedad, observando la evolución histórica del concepto y la visualización de la problemática a la que va asociado. También se expone la necesidad de crear programas destinados a trabajar esta problemática y una revisión del marco legal que regula la atención a la infancia por parte de las administraciones públicas. En una segunda parte, se propone un programa específico destinado a trabajar la negligencia parental desde una perspectiva de reeducación y cambio conductual. Este proyecto de intervención se ubica en el barrio de Can Rull en Sabadell, del cual se detallan sus especificidades socioeconómicas y su realidad institucional.

Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies.

We have designed and validated a novel generic platform for production of tetravalent IgG1-like chimeric bispecific Abs. The VH-CH1-hinge domains of mAb2 are fused through a peptidic linker to the N terminus of mAb1 H chain, and paired mutations at the CH1-CL interface mAb1 are introduced that force the correct pairing of the two different free L chains. Two different sets of these CH1-CL interface mutations, called CR3 and MUT4, were designed and tested, and prototypic bispecific Abs directed against CD5 and HLA-DR were produced (CD5xDR). Two different hinge sequences between mAb1 and mAb2 were also tested in the CD5xDR-CR3 or -MUT4 background, leading to bispecific Ab (BsAbs) with a more rigid or flexible structure. All four Abs produced bound with good specificity and affinity to CD5 and HLA-DR present either on the same target or on different cells. Indeed, the BsAbs were able to efficiently redirect killing of HLA-DR(+) leukemic cells by human CD5(+) cytokine-induced killer T cells. Finally, all BsAbs had a functional Fc, as shown by their capacity to activate human complement and NK cells and to mediate phagocytosis. CD5xDR-CR3 was chosen as the best format because it had overall the highest functional activity and was very stable in vitro in both neutral buffer and in serum. In vivo, CD5xDR-CR3 was shown to have significant therapeutic activity in a xenograft model of human leukemia.

Escuelas, famílias y resultados académicos. Un nuevo modelo de análisis de las relaciones entre docentes y progenitores para el éxito de todo el alumnado

En este artículo se presenta un modelo de análisis de las relaciones entre docentes y familias basada en cuatro elementos: a) La metáfora de la escuela como país; b) El análisis crítico de los modelos actuales de relaciones entre escuela y progenitores de los alumnos; c) La centralidad de las desigualdades y la lucha contra el fracaso escolar en el análisis de este ámbito educativo; y d) La creciente relevancia, contrastada internacionalmente, de la relación entre cómo se dan los vínculos entre escuela y familia y los resultados académicos de los alumnos/as. Así, el modelo propuesto, resitúa las relaciones entre docentes y familias en el centro de la tarea cotidiana del maestro/a y de su identidad docente. Y lo hace con una propuesta basada en: la inclusión de todas las familias; en la centralidad de un buen vínculo con todas ellas; en la lucha contra la reproducción de las desigualdades sociales; y por el éxito escolar de todo el alumnado. Esta propuesta se fundamenta en la responsabilidad y la capacidad docente en ese envite, así como en el modelo de la corresponsabilidad educativa en la relación con todas las familias.