Role and Regulation of the Actin-Regulatory Protein Hs1 in Tcr Signaling

Numerous aspects of T cell function, including TCR signaling, migration, and execution of effector functions, depend on the actin cytoskeleton. Cytoskeletal rearrangements are driven by the action of actin-regulatory proteins, which promote or antagonize the assembly of actin filaments in response to external cues. In this work, we have examined the regulation and function of HS1, a poorly-understood actin regulatory protein, in T cells. This protein, which becomes tyrosine phosphorylated upon T cell activation, is thought to function primarily by stabilizing existing branched actin filaments. Loss of HS1 results in unstable actin responses upon TCR engagement and defective Ca2+ responses, leading to poor activation of the IL2 promoter. TCR engagement leads to phosphorylation of HS1 at Tyr 378 and Tyr 397, creating binding sites for SH2 domain-containing proteins, including Vav1 and Itk. Phosphorylation at these residues is required for Itk-dependent recruitment of HS1 to the IS, Vav1 IS localization, and HS1-dependent actin reorganization and IL2 production. Therefore, in addition to directly interacting with branched actin filaments, HS1 regulation of Vav1 localization provides another mechanism by which HS1 signals to the actin cytoskeleton. Analysis of Ca2+ responses in HS1-/- T cells reveals that the defect in these cells lies at the level of release from intracellular stores. Phosphorylated HS1 interacts with PLCγ1, and mediates its association with the cytoskeleton and regulates microcluster dynamics. Although HS1 is clearly important for signaling downstream of the TCR, HS1-/- mice exhibit normal T cell development and normal peripheral populations. Surprisingly, HS1 is not required for T cell homing to lymphoid organs, for TCR endocytosis or for CD8+ T cell effector function. However, T cells from HS1-/- mice produce reduced amounts of Ifnγ, and are subsequently less likely to become Ifnγ-producing TH1 effector cells. These data demonstrate that HS1 functions as a cytoskeletal adaptor protein and plays specific roles downstream of TCR engagement

Use of nfsB, encoding nitroreductase, as a reporter gene to determine the mutational spectrum of spontaneous mutations in Neisseria gonorrhoeae

<p>Abstract</p> <p>Background</p> <p>Organisms that are sensitive to nitrofurantoin express a nitroreductase. Since bacterial resistance to this compound results primarily from mutations in the gene encoding nitroreductase, the resulting loss of function of nitroreductase results in a selectable phenotype; resistance to nitrofurantoin. We exploited this direct selection for mutation to study the frequency at which spontaneous mutations arise (transitions and transversions, insertions and deletions).</p> <p>Results</p> <p>A nitroreductase- encoding gene was identified in the <it>N. gonorrhoeae </it>FA1090 genome by using a bioinformatic search with the deduced amino acid sequence derived from the <it>Escherichia coli </it>nitroreductase gene, <it>nfsB</it>. Cell extracts from <it>N. gonorrhoeae </it>were shown to possess nitroreductase activity, and activity was shown to be the result of NfsB. Spontaneous nitrofurantoin-resistant mutants arose at a frequency of ~3 × 10^-6- 8 × 10^-8among the various strains tested. The <it>nfsB </it>sequence was amplified from various nitrofurantoin-resistant mutants, and the nature of the mutations determined. Transition, transversion, insertion and deletion mutations were all readily detectable with this reporter gene.</p> <p>Conclusion</p> <p>We found that <it>nfsB </it>is a useful reporter gene for measuring spontaneous mutation frequencies. Furthermore, we found that mutations were more likely to arise in homopolymeric runs rather than as base substitutions.</p

Método para el análisis del proceso : “Alquiler de maquinaria” utilizando BPM y BI

La estandarización de un proceso en una empresa es importante, pues la orientación del mismo sirve para entender el funcionamiento de su negocio. Por esto aplicó este concepto a INGECONS, empresa dedicada a la construcción que presta el servicio de alquiler de maquinaria, actualmente se lleva un proceso manual donde su información no es usada para análisis, no se efectúan controles sobre el flujo de dinero para insumos y solo una persona tiene conocimiento sobre la ejecución de este proceso, implicando desconocimiento para la empresa e ineficiencias dentro del mismo. Inicialmente se realiza la modelación de la situación actual del proceso de alquiler de maquinaria se analizan las actividades actuales y se simula con un tiempo establecido de 999 días con 24 horas cada día para todo el proceso. Posterior a esto, se proponen mejoras en la trazabilidad de información y gestión, orientación del servicio al cliente y productividad que agreguen valor tomando por ejemplo medidas de acuerdo a los resultados de los gráficos de control de ACPM, formularios e indicadores para la correcta toma de decisiones. Adicionalmente se realiza un análisis sobre los costos que incurren en la ejecución del proceso haciendo cambios en la asignación de actividades. Después de analizar el proceso, se obtienen mejoras en las tres categorías, por ejemplo, se tiene un tiempo del proceso inicial de 102 días y se logra reducir a 62 días mejoras en tiempos de respuesta al cliente e.t.c.Se concluye que la falta de control sobre el proceso hace que los flujos de dinero efectivo para el consumo de ACPM por tipo de maquina tenga una variabilidad alta y la única manera de reducirá es implementar estas medidas de control y seguimiento de la información.The standardization of a process in a company is important, since its orientation is used to understand the performance of the company. This is the reason this concept was applied at INGECONS, a company focused on construction that offers machinery for rent as a service, currently there is a manual process where the information is not used for analysis, there is no control over cash flow for supplies and only one person has knowledge over the execution of this process, this means the company is ignorant of the process and the it is inefficient. Initially, the current machinery rent process situation is modeled, and the current activities are analyzed. It is simulated with a stablished time of 999 days with 24 hours each day for the entire process. After this, improvements are proposed in information traceability and management, orientation to customer service y productivity that add value such as actions according to results from diesel fuel control graphics, forms and indicators for appropriate decision making. Additionally, an analysis about the cost regarding the execution of the process is made making changes in activities assignations. After analyzing the results there are improvements in the three categories, such as, the duration of the initial process was 102 days and it was reduced to 62 days, improvement in reply timing for customers, etc. It is concluded that the lack of control over the process results in cash flows for the consumption of diesel fuel for each machine have high variability and that the only way to reduce it is to implement these actions and information traceability.Ingeniero (a) IndustrialPregrad

Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy.

Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy

Relationship between D90 and D100 with Biochemical and Local Failure in Low-risk Prostate Cancer Treated with Low-rate Brachytherapy (LDR)

Low dose rate brachytherapy (LDR) is an accepted, effective treatment with few local side effects, used as monotherapy in patients with low-risk prostate cancer (PC). The aim of this paper is to analyse 245 patients treated with LDR in the Radiation Oncology Department of the Hospital Gómez Ulla, from 2004 to 2016, evaluating the relationship of dosimetric parameters with biochemical and local recurrence as well as genitourinary and gastrointestinal toxicity derived from the technique. The results obtained show a clear relationship between the dose used and biochemical and local failure

Educación pública digna y prestigiosa en Colombia : ¿sueño alcanzable?

En 2010 Martín Carvajal Chamorro obtuvo el mejor puntaje del departamento de Bolívar en las Pruebas Saber 11. Pese a su corta edad, a este bachiller costeño «le gusta leer clásicos europeos... [apreciar] arte del Renacimiento, practicar el violín, [y] escuchar música clásica de Piotr Ilich Tchaikovsky» (Mineducación, 2010). ¿Qué profesión elige un bachiller con el perfil de Martín? Literatura, en la Universidad de los Andes. En 2011 Jorge Pérez Alvarino también obtuvo el mayor puntaje de Bolívar en las Pruebas Saber 11, y manifestó en una nota de prensa que «soy de los que piensa que los demás son mejores que tú, en la medida que tú permites que lo sean. Siempre pensaba que yo podía estar entre los mejores y ¿si los demás podían, por qué yo no?.» (Mineducación, 2011). Este joven de actitud ganadora decidió estudiar Ingeniería Civil en la Universidad de los AndesIncluye referencias bibliográficas (página 277)

Tras la excelencia docente. Cómo mejorar la calidad de la educación para todos los colombianos

Otros autores: Darío Maldonado, Guillermo Perry, Catherine Rodríguez y Juan Esteban SaavedraTítulo del número: Educación: El reto de la calidad en Colombia. Sección: Investigación"Este artículo resume el estudio Tras la excelencia docente. Cómo mejorar la calidad de la educación para todos los colombianos, impulsado y financiado por la Fundación Compartir, y realizado por investigadores de la Universidad de los Andes, la Universidad del Rosario y la Universidad de Southern California. Se trata de una propuesta sistémica que, de implementarse, logrará transformar la calidad educativa a través de la excelencia del componente escolar más importante para el aprendizaje: los docentes...

Behind teaching excellence: How to improve the quality of education for all Colombians

La educación conjuntamente con las ventajas geográficas, la riqueza natural y la madurez institucional es uno de los factores más importantes para el progreso económico regional y nacional (Barro, 1991; Mankiw, Romer y Weil, 1992; Gennaioli et. al, 2013). Aunque la cantidad de educación medida en años promedio de escolaridad de la fuerza de trabajo, por ejemploincide en la productividad y el crecimiento económico de una nación, varios estudios han encontrado que el impacto de la calidad educativa sobre esas variables es mucho mayor (Hanushek y Kimko, 2000; Hanusek y Woessmann, 2012; Hanushek, 2013). Ahora bien, es natural que en etapas iniciales de procesos de desarrollo económico, las políticas educativas de los países se centren en mejorar indicadores de cobertura, promoción y graduación escolar. Una vez se logran estos hitos, el progreso económico continuado requiere consolidar sectores productivos intensivos en mano de obra calificada que generen alto valor agregado. Para esto, resulta fundamental la calidad educativa. Un énfasis continuo en la calidad le ha permitido, por ejemplo, a Singapur, Finlandia, Canadá (particularmente la provincia de Ontario) y Corea del Sur los cuatro países que hoy tienen el mejor desempeño en pruebas de conocimiento internacionales trascender, en periodos de tiempo relativamente cortos, procesos productivos precarios y de poco valor agregado, hasta convertirse en naciones del conocimiento

Elecciones en el Colegio Mayor de Nuestra Señora del Rosario 1804 - 1805 - ( José Fernardo Madrid)

Expediente de elección de vicerrector y otros cargos celebrada en el colegio mayor del rosario el día 23 de marzo de 1804 a favor Santiago Pérez Valencia y Arroyo (vicerrector), José María Cuero (primer consiliario), José María del Castillo (tercer consiliario), Martín Carrizosa (procurador) Elecciones celebradas en el colegio mayor del rosario el día 8 de enero de 1805 para los cargos de vicerrector y consiliarios a favor de José Agustín Barona (vicerrector), Ramón Bustamante (segundo consiliario), Esteban Quintana (procurador), José Antonio Fernández (maestro de ceremonia

On Extreme Concentrations in Chemical Reaction Networks with Incomplete Measurements

A fundamental problem in the analysis of chemical reactions networks consists of identifying concentration values along time or in steady state which are coherent with the experimental concentration data available. When concentration measurements are incomplete, either because information is missing about the concentration of a species at a particular time instant, or even there is no information at all on the concentration of a species, then the problem becomes ill-defined, and then different concentration curves are compatible with existing data. In this paper we address the problem of finding the extreme (highest and lowest) concentrations under incomplete data measurements; as a byproduct of our approach, the model parameters associated with such extreme concentrations are obtained. These extreme concentrations provide valuable information on the impact that incomplete measurements have on the theoretical reconstruction of concentrations from experimental data. To obtain such concentrations range, mathematical optimization problems are formulated, solvable by a variety of global optimization approaches, such as, for example, the stochastic global optimization method suggested