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

Performance improvement by temperature control of an open-cathode PEM fuel cell system

The work presented in this article combines experimental analysis and theoretical studies of temperature effects on the performance of an open-cathode, self-humidified PEM fuel cell system for the design of optimal control strategies. The experimental analysis shows the great potential of improving the system performance by proper thermal management. The most significant temperature dependent parameter of the system under study is the exchange current density. On the one hand it is influenced positively by a temperature increase as this lowers the activation barrier. On the other hand a higher temperature causes a reduction of the electrochemical active sites in the cathode catalyst layer (CCL) due to lower water content in the ionomer and primary pores. Dynamic models for fuel cell temperature, liquid water transport and the related electrochemistry have been developed and validated against the experiment. A cascaded Extremum Seeking control algorithm with a local PI controller is proposed to regulate the temperature to a fuel cell voltage maximum. However, the slow dynamics of the temperature related catalyst-drying effect on performance complicate the optimal thermal management with model-free control strategies.Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señale

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

Diseño y construcción integral de un banco de supercapacitores: del modelado a la estimación del estado de carga

En este trabajo, enmarcado en la línea de investigación de módulos de almacenamiento de energía no convencionales (MANC), se presenta el diseño y la construcción de un banco de supercapacitores (SC), junto con un diseño preliminar de un sistema de observación para el estado de carga (SOC por sus siglas en inglés) utilizando un diferenciador por modo deslizante acoplado con un estimador paramétrico. Hoy en día, numerosos estudios han demostrado la limitación práctica que poseen las energías renovables en cuanto al almacenamiento de energía. Esto último resalta la importancia de los MANC, en un marco de creciente utilización de sistemas híbridos tanto a pequeña como a gran escala, sobre todo debido a su capacidad de manejar grandes niveles de potencia. En particular, la versatilidad de los SC y baterías de Ión-Litio para poder funcionar como módulos de almacenamiento o buffers en un mismo sistema híbrido y su excelente performance en términos de eficiencia, vida útil y densidad de potencia, los convierte en elementos de sumo interés para la comunidad científico-tecnológica en el desarrollo de vehículos eléctricos y sistemas híbridos de energía renovables. Actualmente, los SC son un foco de interés principalmente debido a su gran densidad de potencia, aunque como principal desventaja puede señalarse que estos dispositivos no poseen grandes niveles de densidad de energía y suele ser necesario utilizar los SC junto con otras fuentes de almacenamiento, como baterías de Ión-Litio, o esquemas de almacenamiento basados en hidrógeno [4]. Mas aún, para poder emplear SC en un sistema híbrido es necesario un agrupamiento en serie o serie-paralelo de SC. Estos arreglos son conocidos como ‘Banco de SC’ o ‘Pila de SC’. Para conservar la vida útil de los SC de un banco, es necesario incorporar un sistema de balanceo, que se encargue de mantener igualadas las tensiones de cada SC, asegurando que el banco se mantenga balanceado independientemente de la variabilidad de los parámetros internos de cada dispositivo. También adquiere gran relevancia incorporar técnicas de observación y estimación para el banco de SC, con el objetivo de extraer información de los parámetros internos del mismo, y así mejorar la eficiencia de operación del banco, y del sistema híbrido donde se lo utilice. Emplear técnicas de observación y estimación permite conocer el SOC y predecir la vida útil del banco a través del estado de salud (SOH), obtenidos indirectamente mediante la estimación de las capacidades y resistencias de pérdidas a partir de modelos eléctricos equivalentes. Consecuentemente, adquieren gran relevancia el modelado y la identificación del banco de SC, para lograr una adecuada regulación y control al integrarlo en sistemas de mayor energía. Por último, para resguardar la seguridad del usuario/a, se incorporan módulos externos de monitoreo y protección, los cuales poseen la finalidad de supervisar las variables eléctricas del banco (tensión, corriente y temperatura) con el objetivo de desconectar al banco de su alimentación o descargarlo, según sea pertinente preservando simultáneamente la integridad del mismo.Sección: Electrotecnia.Facultad de Ingenierí

Diseño y construcción integral de un banco de supercapacitores: del modelado a la estimación del estado de carga

En este trabajo, enmarcado en la línea de investigación de módulos de almacenamiento de energía no convencionales (MANC), se presenta el diseño y la construcción de un banco de supercapacitores (SC), junto con un diseño preliminar de un sistema de observación para el estado de carga (SOC por sus siglas en inglés) utilizando un diferenciador por modo deslizante acoplado con un estimador paramétrico. Hoy en día, numerosos estudios han demostrado la limitación práctica que poseen las energías renovables en cuanto al almacenamiento de energía. Esto último resalta la importancia de los MANC, en un marco de creciente utilización de sistemas híbridos tanto a pequeña como a gran escala, sobre todo debido a su capacidad de manejar grandes niveles de potencia. En particular, la versatilidad de los SC y baterías de Ión-Litio para poder funcionar como módulos de almacenamiento o buffers en un mismo sistema híbrido y su excelente performance en términos de eficiencia, vida útil y densidad de potencia, los convierte en elementos de sumo interés para la comunidad científico-tecnológica en el desarrollo de vehículos eléctricos y sistemas híbridos de energía renovables. Actualmente, los SC son un foco de interés principalmente debido a su gran densidad de potencia, aunque como principal desventaja puede señalarse que estos dispositivos no poseen grandes niveles de densidad de energía y suele ser necesario utilizar los SC junto con otras fuentes de almacenamiento, como baterías de Ión-Litio, o esquemas de almacenamiento basados en hidrógeno [4]. Mas aún, para poder emplear SC en un sistema híbrido es necesario un agrupamiento en serie o serie-paralelo de SC. Estos arreglos son conocidos como ‘Banco de SC’ o ‘Pila de SC’. Para conservar la vida útil de los SC de un banco, es necesario incorporar un sistema de balanceo, que se encargue de mantener igualadas las tensiones de cada SC, asegurando que el banco se mantenga balanceado independientemente de la variabilidad de los parámetros internos de cada dispositivo. También adquiere gran relevancia incorporar técnicas de observación y estimación para el banco de SC, con el objetivo de extraer información de los parámetros internos del mismo, y así mejorar la eficiencia de operación del banco, y del sistema híbrido donde se lo utilice. Emplear técnicas de observación y estimación permite conocer el SOC y predecir la vida útil del banco a través del estado de salud (SOH), obtenidos indirectamente mediante la estimación de las capacidades y resistencias de pérdidas a partir de modelos eléctricos equivalentes. Consecuentemente, adquieren gran relevancia el modelado y la identificación del banco de SC, para lograr una adecuada regulación y control al integrarlo en sistemas de mayor energía. Por último, para resguardar la seguridad del usuario/a, se incorporan módulos externos de monitoreo y protección, los cuales poseen la finalidad de supervisar las variables eléctricas del banco (tensión, corriente y temperatura) con el objetivo de desconectar al banco de su alimentación o descargarlo, según sea pertinente preservando simultáneamente la integridad del mismo.Sección: Electrotecnia.Facultad de Ingenierí

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

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-

Autophagy Controls Acquisition of Aging Features in Macrophages

Macrophages provide a bridge linking innate and adaptive immunity. An increased frequency of macrophages and other myeloid cells paired with excessive cytokine production is commonly seen in the aging immune system, known as 'inflamm-aging'. It is presently unclear how healthy macrophages are maintained throughout life and what connects inflammation with myeloid dysfunction during aging. Autophagy, an intracellular degradation mechanism, has known links with aging and lifespan extension. Here, we show for the first time that autophagy regulates the acquisition of major aging features in macrophages. In the absence of the essential autophagy gene Atg7, macrophage populations are increased and key functions such as phagocytosis and nitrite burst are reduced, while the inflammatory cytokine response is significantly increased - a phenotype also observed in aged macrophages. Furthermore, reduced autophagy decreases surface antigen expression and skews macrophage metabolism toward glycolysis. We show that macrophages from aged mice exhibit significantly reduced autophagic flux compared to young mice. These data demonstrate that autophagy plays a critical role in the maintenance of macrophage homeostasis and function, regulating inflammation and metabolism and thereby preventing immunosenescence. Thus, autophagy modulation may prevent excess inflammation and preserve macrophage function during aging, improving immune responses and reducing the morbidity and mortality associated with inflamm-aging. © 2015 S. Karger AG, Basel

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