The role of reactive oxygen species in oxidative-induced neoplastic transformation

The generation of reactive oxygen species (ROS) is a normal occurrence in the life of a cell. ROS are derived from both exogenous and endogenous sources and take part in a plethora of normal physiological mechanisms from host immunity to cell cycle regulation. However, ROS also exhibit a deleterious, disruptive character that means they must now be taken seriously as a genuine carcinogenic agent able to alter a variety of pathways leading to the initiation of cancer. The two-sidedness of ROS means that the relationship between ROS and the onset and progression of cancer is hard to determine. ROS and reactive nitrogen species (RNS) are able to initiate cancer through the damage of DNA leading to the genetic instability that drives the early stages of cancer. Simultaneously, they can activate a number of signalling cascades and transcription factors that facilitate uncontrolled cell growth. The production of ROS in neoplastic cells can lead to the production of new blood vessels that provide the machinery for subsequent metastasis and tumour invasion. It is important that the role of ROS in these pathways are fully elucidated in order to provide potential therapies measures

Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and β-interferon production during pseudomonas aeruginosa infection

Bacterial infection can trigger autophagy and inflammasome activation, but the effects of inflammasome activation on autophagy are unknown. We examined this in the context of Pseudomonas aeruginosa macrophage infection, which triggers NLRC4 inflammasome activation. P. aeruginosa induced autophagy via TLR4 and its adaptor TRIF. NLRC4 and caspase-1 activation following infection attenuated autophagy. Caspase-1 directly cleaved TRIF to diminish TRIF-mediated signaling, resulting in inhibition of autophagy and in reduced type I interferon production. Expression of a caspase-1 resistant TRIF mutant enhanced autophagy and type I interferon production following infection. Preventing TRIF cleavage by caspase-1 in an in vivo model of P. aeruginosa infection resulted in enhanced bacterial autophagy, attenuated IL-1β production, and increased bacterial clearance. Additionally, TRIF cleavage by caspase-1 diminished NLRP3 inflammasome activation. Thus, caspase-1 mediated TRIF cleavage is a key event in controlling autophagy, type I interferon production, and inflammasome activation with important functional consequences

Control Twisting con Adaptación Basada en Cruce por Cero para un Sistema de Columna de Agua Oscilante con Generador Sincrónico

Este trabajo presenta el control de un dispositivo de columna de agua oscilante, que incluye un generador sincrónico de imán permanente, para la extracción óptima de potencia. Se diseñan dos controladores de modo deslizante de segundo orden adaptables, que funcionan de manera robusta en modo deslizante real y muestran una notable mejora en la reducción del chattering cuando se los compara con el mismo esquema con ganancias fijas, al ser probados sobre el modelo completo del sistema

Control para maxima extracción de energía undimotriz por Modos Deslizantes de Segundo Orden real con Ganancias Adaptivas

La optimización del aprovechamiento de la energıa de las olas se está desarrollando fuertemente de manera internacional y Argentina tiene gran potencial de este recurso. Entre todos los dispositivos capaces de transformar la energıa undimotriz, los sistemas de Columna de Agua Oscilante han sido los más estudiados y maximizar la extracción de potencia de la ola es el objetivo primordial de los últimos anos. Este trabajo avanza sobre una propuesta inicial de controladores de Modo Deslizante de Segundo Orden, considerando condiciones realistas de funcionamiento para el sistema y una configuración de ganancias adaptivas que reduce el chattering. Los resultados muestran notablemente la mejora esperada, a partir de reducir el esfuerzo de control, manteniendo la robustez ante incertidumbre en los parámetros, dinámica no modelada y perturbaciones

Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy.

The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS-dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy

Public health professionals' perceptions toward provision of health protection in England: a survey of expectations of Primary Care Trusts and Health Protection Units in the delivery of health protection

BACKGROUND: Effective health protection requires systematised responses with clear accountabilities. In England, Primary Care Trusts and the Health Protection Agency both have statutory responsibilities for health protection. A Memorandum of Understanding identifies responsibilities of both parties, but there is a potential lack of clarity about responsibility for specific health protection functions. We aimed to investigate professionals' perceptions of responsibility for different health protection functions, to inform future guidance for, and organisation of, health protection in England. METHODS: We sent a postal questionnaire to all health protection professionals in England from the following groups: (a) Directors of Public Health in Primary Care Trusts; (b) Directors of Health Protection Units within the Health Protection Agency; (c) Directors of Public Health in Strategic Health Authorities and; (d) Regional Directors of the Health Protection Agency RESULTS: The response rate exceeded 70%. Variations in perceptions of who should be, and who is, delivering health protection functions were observed within, and between, the professional groups (a)-(d). Concordance in views of which organisation should, and which does deliver was high (≥90%) for 6 of 18 health protection functions, but much lower (≤80%) for 6 other functions, including managing the implications of a case of meningitis out of hours, of landfill environmental contamination, vaccination in response to mumps outbreaks, nursing home infection control, monitoring sexually transmitted infections and immunisation training for primary care staff. The proportion of respondents reporting that they felt confident most or all of the time in the safe delivery of a health protection function was strongly correlated with the concordance (r = 0.65, P = 0.0038). CONCLUSION: Whilst we studied professionals' perceptions, rather than actual responses to incidents, our study suggests that there are important areas of health protection where consistent understanding of responsibility for delivery is lacking. There are opportunities to clarify the responsibility for health protection in England, perhaps learning from the approaches used for those health protection functions where we found consistent perceptions of accountability

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis

The relationship between chiropractor required and current level of business knowledge

Background: Chiropractors frequently practice within health care systems requiring the business acumen of an entrepreneur. However, some chiropractors do not know the relationship between the level of business knowledge required for practice success and their current level of business knowledge. The purpose of this quantitative study was to examine the relationship between chiropractors’ perceived level of business knowledge required and their perceived level of current business knowledge. Methods: Two hundred and seventy-four participants completed an online survey (Health Care Training and Education Needs Survey) which included eight key business items. Participants rated the level of perceived business knowledge required (Part I) and their current perceived level of knowledge (Part II) for the same eight items. Data was collected from November 27, 2013 to December 18, 2013. Data were analyzed using Spearman’s ranked correlation to determine the statistically significant relationships for the perceived level of knowledge required and the perceived current level of knowledge for each of the paired eight items from Parts I and II of the survey. Wilcoxon Signed Ranks Tests were performed to determine the statistical difference between the paired items. Results: The results of Spearman’s correlation testing indicated a statistically significant (p < 0.01) positive correlation for the perceived level of knowledge required and perceived current level of knowledge for six variables: (a) organizational behavior, (b) strategic management, (c) marketing, (d) legal and ethical, (e) managerial decisions, and (f) operations. Wilcoxon Signed Ranks testing indicated a significant difference for three paired items: strategic management; marketing and; legal and ethical. The results suggest that relationships exist for the majority of business items (6 of 8) however a statistically difference was demonstrated in only three of the paired business items. Conclusion: The implications of this study for social change include the potential to improve chiropractors’ business knowledge and skills, enable practice success, enhance health services delivery and positively influence the profession as a viable career.https://doi.org/10.1186/s12998-017-0134-