Cellular responses to the DNA damaging Cytolethal Distending Toxin

Cytolethal distending toxin (CDT) is a genotoxin, which belongs to a group of bacterial protein toxins called cyclomodulins. These are characterized by their interference with the eukaryotic cell cycle. CDT causes DNA damage, which induces cell cycle arrest and apoptosis. The active holotoxin consists of three subunits CdtA, CdtB and CdtC, where CdtB is the active subunit and has structural and functional similarities with DNase I. We demonstrated that CDT uses the same internalization pathway as several other bacterial toxins do, such as cholera toxin and Shiga toxin. The binding on the plasma membrane is dependent on cholesterol. The toxin is internalized via the Golgi complex, and retrogradely transported to the endoplasmic reticulum (ER) and found in the nucleoplasmic reticulum. The translocation from the ER to the nucleus does not require either the ER-associated (ERAD) pathway or the Derlin-1 protein. Additionally, we showed that CDT is not farnesylated, a modification known to occur in the cytosol. In contrast, to other AB toxins, CdtB was demonstrated to have heat-stable properties and is not degraded by the 20S proteasome. All these evidence suggest that the toxin is translocated directly from the ER to the nucleus. In adherent cells the cellular response to the CDT-induced DNA damage involved activation of the RhoA GTPase. We showed that the RhoA-specific Guanine nucleotide exchange factor (GEF) Net1 is dephosphorylated and translocated from the nucleus to the cytosol upon DNA damage. Knock down of Net1 by RNAi prevents RhoA activation, inhibits the formation of stress fibers, and enhances cell death. This indicates that Net1 activation is required for RhoAmediated response to genotoxic stress. The Net1 and the RhoA dependent signals converge the activation of mitogen-activated protein kinase p38 (p38 MAPK) and its downstream target MAPK-activated protein kinase 2 (MK2). To further investigate this novel cell survival pathway in response to CDT we screened a yeast deletion library for CdtB-sensitive strains. Approximately 4500 yeast deletion strains were transformed with a plasmid containing CdtB. The screen shows that 78 mutated strains were hypersensitive to CdtB. Twenty of the human ortholog genes were found to interact with the actin cytoskeleton regulation network. Our analysis focused on TSG101, FEN1 and Vinculin (VCL). We demonstrated that they are all required to induce actin stress fiber formation in response to DNA damage. FEN1 and VCL also regulate the RhoA GTPase and p38 MAPK activation, and delay cell death in response to CDT intoxication. In response to DNA damage, Ataxia-telangiectasia mutated (ATM) and ATM and Rad-3-related kinases (ATR) are activated and orchestrate DNA damage response. The transcription factor Myc has multi-functions such as inducing apoptosis in response to DNA damage. The Mycregulated effectors acting upstream of the mitochorial apoptotic pathway are still unknown. We demonstrated that Myc is required for activation of the ATM-dependent DNA damage checkpoint response in cells exposed to ionizing radiation or CDT. Activation of ATM effectors, such as histone H2AX and the nuclear foci formation of the Nijmegen Berakage Syndrome (Nbs)1 protein, were abolished in the absence of Myc. The cellular response to UV irradiation, known to activate an ATR-dependent checkpoint, was not delayed in the absent of the Myc expression. This data demonstrate that Myc is required for activation of the ATM-dependent pathway. Our studies highlight the importance of understanding the CDT biology and its mode of action. This knowledge could provide new tools to elucidate the putative involvement of bacteria in carcinogenesis

Conforto térmico em instalações para processamento úmido de café

Este estudio tuvo como objetivo evaluar el confort térmico para trabajadores, en tres edificaciones de procesamiento húmedo de café en Colombia, utilizando el índice WBGT, y análisis de temperatura y humedad relativa a través de mapeo. Los límites recomendados del WBGT fueron excedidos en la actividad de abastecimiento de combustible de la secadora en la Edificación 3. Las tres edificaciones presentaron variabilidad higrotérmica espacial debida a la secadora de café, y a problemas con la ventilación, volumen de control y resistencia térmica de materiales en los edificios 2 y 3. Para favorecer la transferencia de calor de la secadora al ambiente exterior, y hacer más homogéneo el ambiente térmico de las edificaciones, se recomienda instalar puentes térmicos alrededor de esta zona, y para hacer más eficiente la evacuación de vapor y calor, aumentar el área de ventilación natural en las edificaciones 2 y 3, e instalar claraboyas de ventilación sobre la secadora

Por la transparencia parlamentaria : propuesta de modelo de comunicación online para acercar la gestión parlamentaria de los partidos políticos a la ciudadanía

La comunicación política está concebida para establecer una relación entre las instituciones políticas (partidos, entidades públicas, politicos, etc) con la ciudadanía, con el fin de mantener un contacto constante informando sobre sus actuaciones políticas de forma transparente y concreta. Sin embargo, a pesar de que este es el deber ser de la comunicación política, en algunas ocasiones no se cumple el objetivo. Por esta razón, el producto final de este trabajo busca acercar al ciudadano el proceso legislativo y de control político que realizan los partidos políticos en el Parlamento de Andalucía, mediante un modelo de comunicación online (página web) que recopile algunas de las actuaciones de los grupos parlamentarios hasta la fecha, con el fin de dar una herramienta para ejercer control político sobre las actuaciones de los parlamentarios, su gestión parlamentaria. Se pretende, además, sentar las bases de una comunicación política integradora con la ciudadanía para que entienda los procesos de toma de decisiones de Andalucía y que en las próximas elecciones su voto sea producto de un conocimiento previo, ayudado por las herramientas que los partidos políticos aportan. Y si no son los partidos políticos quienes tengan la iniciativa, que sean los ciudadanos quienes se empoderen, porque en la información está el poder.Universidad de Sevilla. Máster en Comunicación Institucional y Política de la Facultad de Comunicació

A novel mode of translocation for cytolethal distending toxin

Thermal instability in the toxin catalytic subunit may be a common property of toxins that exit the endoplasmic reticulum (ER) by exploiting the mechanism of ER-associated degradation (ERAD). The Haemophilus ducreyi cytolethal distending toxin (HdCDT) does not utilize ERAD to exit the ER, so we predicted the structural properties of its catalytic subunit (HdCdtB) would differ from other ER-translocating toxins. Here, we document the heat-stable properties of HdCdtB which distinguish it from other ER-translocating toxins. Cell-based assays further suggested that HdCdtB does not unfold before exiting the ER and that it may move directly from the ER lumen to the nucleoplasm. These observations suggest a novel mode of ER exit for HdCdtB. (c) 2008 Elsevier B.V. All rights reserved

La flexibilización salarial : ¿"estrategia legal" para combatir el desempleo?

Abogado (a)Pregrad

Maria Theresa de Medeiros Pacheco: notas biográficas sobre a primeira médica legista do Brasil

Este artigo discute o pioneirismo da médica alagoana que chegou à Bahia em 1948 para ingressar na Faculdade de Medicina da Bahia e se formou em 1953 e, daí por diante, atuou nas conhecidas Maternidades da época, como a Climério de Oliveira e Nita Costa e nos hospitais Aristides Maltez e Santa Isabel. Em 1954, por sua experiência nos serviços de ginecologia e obstetrícia, foi convidada pelo Prof. Estácio de Lima para periciar as vítimas de atentados sexuais: crianças, adolescentes e mulheres, no Instituto Médico Legal Nina Rodrigues, na especialidade Sexologia Forense. Especializou-se nesta área, tornando-se a primeira mulher médica-legista do Brasil e, dentro do referido Instituto, conquistou o mérito de ter sido a primeira diretora de um Instituto Médico Legal no mundo. Na condição de professora da Faculdade de Medicina da Bahia, tornou-se pioneira enquanto mulher, ao assumir a cátedra titular de Medicina Legal

Manejo exitoso de vía aérea con dispositivo King Visión en un niño con síndrome de Morquio: reporte de caso.

Morquio syndrome also called type IV mucopolysaccharidosis, is a condition produced by lysosomal deposit. Morquio syndrome have several implications in the airway management because is characterized by C1-C2, instability, short height, cervical spine instability, odontoid hypoplasia, and Pectus carinatum, this, in addition to airway anatomy distortion. Case summary: This is a case report of successful airway management with video laryngoscopy of a child whit anticipated difficult airway whit Morquio syndrome. Conclusion: The video laryngoscopes are a good choice for management of anticipated difficult airway in child patients.El síndrome de Morquio, mucopolisacaridosis tipo IV, es un trastorno poco frecuente, secundario a la acumulación de depósitos lisosomales, representa un gran reto para el manejo de vía aérea por inestabilidad atlanto axial, estatura corta, inestabilidad de cordón medular, hipoplasia odontoidea, Peptus carinatum y distorsión de la anatomía de la vía aérea. Se presenta un caso de manejo de vía aérea exitosa por grupo de vía aérea difícil, con videolaringoscopia y estabilización cervical en línea de un paciente de 10 años con síndrome de Morquio. El uso de videolaringoscopia es de utilidad en el manejo de los pacientes con vía aérea difícil anticipada en pediatría

Successful airway management with King Vision device in a child with Morquio syndrome: case report

Morquio syndrome also called type IV mucopolysaccharidosis, is a condition produced by lysosomal deposit. Morquio syndrome have several implications in the airway management because is characterized by C1-C2, instability, short height, cervical spine instability, odontoid hypoplasia, and Pectus carinatum, this, in addition to airway anatomy distortion. Case summary: This is a case report of successful airway management with video laryngoscopy of a child whit anticipated difficult airway whit Morquio syndrome. Conclusion: The video laryngoscopes are a good choice for management of anticipated difficult airway in child patients