Tnfa signaling through Tnfr2 protects skin against oxidative stress-induced inflammation

14 páginas, 8 figuras.-- Sergio Candel ... et al.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disordersThis work was supported by the Spanish Ministry of Science and Innovation (grants BIO2011-23400 and CSD2007-00002 to VM, and PhD fellowship to SC, all co-funded with Fondos Europeos de Desarrollo Regional/European Regional Development Funds), the Fundación Séneca-Murcia (grant 04538/GERM/06 to VM and PhD fellowship to RE-P), Fundação para a Ciência e Tecnologia (PhD fellowship to SdO, SFRH/BD/62674/2009), a Medical Research Council Senior Clinical fellowship to SAR (G0701932), and the European 7th Framework Initial Training Network FishForPharma (PhD fellowship to SDT, PITG-GA-2011-289209).Peer reviewe

Flame Describing Function analysis of spinning and standing modes in an annular combustor and comparison with experiments

This article reports a numerical analysis of combustion instabilities coupled by a spinning mode or a standing mode in an annular combustor. The method combines an iterative algorithm involving a Helmholtz solver with the Flame Describing Function (FDF) framework. This is applied to azimuthal acoustic coupling with combustion dynamics and is used to perform a weakly nonlinear stability analysis yielding the system response trajectory in the frequency-growth rate plane until a limit cycle condition is reached. Two scenarios for mode type selection are tentatively proposed. The first is based on an analysis of the frequency growth rate trajectories of the system for different initial solutions. The second consid- ers the stability of the solutions at limit cycle. It is concluded that a criterion combining the stability analysis at the limit cycle with the trajectory analysis might best define the mode type at the limit cy- cle. Simulations are compared with experiments carried out on the MICCA test facility equipped with 16 matrix burners. Each burner response is represented by means of a global FDF and it is considered that the spacing between burners is such that coupling with the mode takes place without mutual interac- tions between adjacent burning regions. Depending on the nature of the mode being considered, two hypotheses are made for the FDFs of the burners. When instabilities are coupled by a spinning mode, each burner features the same velocity fluctuation level implying that the complex FDF values are the same for all burners. In case of a standing mode, the sixteen burners feature different velocity fluctua- tion amplitudes depending on their relative position with respect to the pressure nodal line. Simulations retrieve the spinning or standing nature of the self-sustained mode that were identified in the exper- iments both in the plenum and in the combustion chamber. The frequency and amplitude of velocity fluctuations predicted at limit cycle are used to reconstruct time resolved pressure fluctuations in the plenum and chamber and heat release rate fluctuations at two locations. For the pressure fluctuations, the analysis provides a suitable estimate of the limit cycle oscillation and suitably retrieves experimental data recorded in the MICCA setup and in particular reflects the difference in amplitude levels observed in these two cavities. Differences in measured and predicted amplitudes appear for the heat release rate fluctuations. Their amplitude is found to be directly linked to the rapid change in the FDF gain as the velocity fluctuation level reaches large amplitudes corresponding to the limit cycle, underlying the need of FDF information at high modulation amplitudes

On the Exact Solution of a Class of Homogeneous Strongly Coupled Mixed Parabolic Problems

[EN] In this paper an exact series solution for homogeneous parabolic coupled systems is constructed using a projection method. An illustrative example is given.This work has been supported by Spanish Ministerio de Economía y Competitividad and the European Regional Development Fund (ERDF) TIN2014-59294-P.Defez Candel, E.; Soler Basauri, V.; Romero Vivó, S.; Verdoy González, JA. (2019). On the Exact Solution of a Class of Homogeneous Strongly Coupled Mixed Parabolic Problems. Filomat. 33(3):897-915. https://doi.org/10.2298/FIL1903897DS89791533

Risk factors for sexual and erectile dysfunction in HIV-infected men: the role of protease inhibitors

Objectives: To determine the prevalence of erectile dysfunction in a cohort of HIV-infected men in a stable clinical state, the effect of exposure to antiretroviral therapy on sexual dysfunction and to identify the risk factors.Design: This is a cross-sectional, observational study.Methods: HIV-infected men without hepatitis C virus coinfection were included if they were antiretroviral therapy-naive (naive group), on current treatment with an enhanced protease inhibitor (protease inhibitor group) or on current treatment with two to three nucleoside reverse transcriptase inhibitors along with one nonnucleoside reverse transcriptase inhibitor and never having received treatment with protease inhibitor (nonnucleoside reverse transcriptase inhibitor group). Erectile dysfunction was defined as an ejection fraction of 25 or less (International Index of Erectile Function-15).Results: Ninety patients were included, with an age of 42 +/- 8.2 years and CD4 cell count of 465 cells/microl [P25-75 361-676]: 18.9% in Centers for Disease Control and Prevention class C and 72.2% with undetectable viral load. Seventy-six patients (84.4%) were receiving antiretroviral therapy, 39 (43.3%) in the protease inhibitor group. The prevalence of lipodystrophy was 31.5%. Forty-seven (53.4%) patients had an erectile dysfunction. Multivariate logistic regression analysis confirmed that there was an independent association between the patients' age (per decade; odds ratio 2.2, 95% confidence interval 1.04-4.5, P = 0.04) and greater duration of exposure to protease inhibitor (per year; odds ratio 1.6, 95% confidence interval 1.12-2.4, P = 0.01). Older age, depression and lipodystrophy, combined with the duration of exposure to protease inhibitor, determined a lower score on various sexual dysfunction domains (P < 0.05).Conclusion: There is a high prevalence of erectile dysfunction in HIV-infected men, with age and the duration of exposure to protease inhibitor being the only identifiable risk factors

TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response.

TNFα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNFα in certain viral infections

Caracterización del papel de los receptores de TNF en inflamación usando el pez cebra como modelo= Modelling the impact of TNF receptors in inflammation using the zebrafish.

INTRODUCTION: La psoriasis es una enfermedad inflamatoria crónica de la piel que afecta a millones de personas. Aunque en ratón no existen modelos de psoriasis, la facilidad para obtener muestras de piel de pacientes ha facilitado el estudio de las vías de señalización implicadas en la enfermedad, mostrando la importancia del sistema inmune en su desarrollo. Algunas terapias que utilizan anticuerpos específicos contra varias citoquinas, incluyendo TNFα, IL-23 y IL-17, son prometedoras, pero son caras y presentan efectos secundarios. Numerosos estudios han mostrado la aparición de nuevos casos de psoriasis después del tratamiento con antagonistas del TNFα en pacientes con Inflammatory Bowel Disease. Aunque esos datos indican un papel ambiguo del TNFα en psoriasis, su papel, y especialmente la contribución de sus receptores, en la regulación de la inflamación en piel han sido escasamente estudiados. OBJECTIVES: (1) Caracterización del papel de Tnfa y sus receptores (Tnfr1 y Tnfr2) en la función y distribución de los neutrófilos en larvas de pez cebra; (2) Caracterización de las vías de señalización de Tnfr1 y Tnfr2 involucradas en la homeostasis de la piel en larvas de pez cebra; (3) Caracterización del papel de Tnfa y sus receptores en inflamación crónica en piel en larvas de pez cebra; (4) Evaluación de las larvas de pez cebra como posible modelo para estudiar enfermedades inflamatorias crónicas humanas. METHODOLOGY: Líneas transgénicas de pez cebra y las ventajas de trabajar con sus embriones en in vivo imaging y cell tracking han sido utilizadas para estudiar los patrones de distribución de los neutrófilos. Además, la inflamación en la piel causada por la depleción de Tnfa o Tnfr2, pero no Tnfr1, ha sido estudiada mediante la inhibición genética (morpholinos y formas dominantes negativas) y farmacológica (DPI) de Duox1. La expresión de moléculas pro-inflamatorias ha sido medida mediante RT-qPCR, Neutrófilos y queratinocitos han sido aislados de larvas control y deficientes en Tnfr2 usando FACS-sorting. Sondas específicas para H2O2 han sido usadas para detectar su producción. RESULTS AND CONCLUSIONS: La depleción de Tnfa o Tnfr2, pero no de Tnfr1, causa inflamación en la piel a través de la activación de un bucle inflamatorio de retroalimentación positiva que implica a H2O2/NF-κB/Duox1. Tanto la inhibición genética como farmacológica de Duox1 revierten completamente la inflamación en piel, situando al H2O2 derivado de Duox1 aguas arriba de la activación de NF-κB. Extraemos las siguientes conclusiones: (1) La inhibición genética de Tnfa o Tnfr2, pero no de Tnfr1, resulta en la movilización de los neutrófilos desde la CHT hasta la piel; (2) El silenciamiento de Tnfa o Tnfr2 provoca la inducción en la piel de la expresión de genes que codifican para moléculas pro-inflamatorias; (3) La ausencia de señalización de Tnfa a través del receptor Tnfr2 desencadena la producción local de H2O2 por la enzima Duox1 en la piel; (4) La inhibición genética de Tnfa o Tnfr2 resultada en la activación del regulador maestro de la inflamación NF-кB en la piel, aguas abajo de la producción de H2O2; (5) La señalización de Tnfa a través del receptor Tnfr2 es indispensable para el mantenimiento de la homeostasis de la piel; (6) La inducción de DUOX1 y/o la consiguiente producción de H2O2 en la piel de pacientes con psoriasis, podrían ser nuevas dianas para terapias farmacológicas y genéticas para el tratamiento de la psoriasis. Estas nuevas estrategias podrían ser también aplicables para otras enfermedades inflamatorias crónicas; (7) El pez cebra puede utilizarse como organismo modelo para estudiar la psoriasis y otras enfermedades inflamatorias crónicas. INTRODUCTION: Psoriasis is a chronic, debilitating skin disease that affects millions of people worldwide. Although there is no mouse model that accurately reproduces all facets of the psoriasis, the accessibility of skin tissue from patients has facilitated the elucidation of some pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. Recently developed antibodies that selectively target several cytokines, including TNFα, IL-23 and IL-17, have shown promising results in early-phase clinical trials. However, these treatments are extremely expensive and show important side effects. Importantly, numerous studies have reported new-onset psoriasis following TNFα antagonist therapy in adult inflammatory bowel disease patients. Despite these clinical data pointing to an ambiguous function of TNFα in psoriasis, the role of TNFα, and in particular the contribution of each TNFR, in the regulation of skin inflammation has scarcely been studied. OBJECTIVES: Taking that into consideration, the objectives of the present work are: (1) Characterization of the role played by Tnfa and its receptors (Tnfr1 and Tnfr2) in the neutrophil function and distribution patterns in zebrafish larvae; (2) Characterization of the Tnfr1 and Tnfr2 signaling pathways involved in skin homeostasis in zebrafish larvae; (3) Characterization of the role played by Tnfa and its receptors in chronic inflammation in the skin in zebrafish larvae; (4) Evaluation of the zebrafish larvae as a potential model for the study of human chronic inflammatory diseases. METHODOLOGY: Some zebrafish transgenic lines and the unique advantage of the zebrafish embryo for in vivo imaging and cell tracking have been used for the study of the neutrophil distribution patterns. Furthermore, the skin inflammation caused by the depletion of Tnfa or Tnfr2, but not of Tnfr1, has been studied using both genetic (morpholinos and dominant negative forms) and pharmacological (DPI) inhibition of Duox1. The expression of pro-inflammatory molecules has been measured by RT-qPCR, while neutrophils and keratinocytes have been FACS-sorted from controls and Tnfr2-deficient larvae. H2O2-specific probes have been used in order to detect the production of that compound. RESULTS AND CONCLUSIONS: We found that depletion of Tnfa or Tnfr2, but not of Tnfr1, caused skin inflammation through the activation of an H2O2/NF-κB/Duox1 positive feedback inflammatory loop. Moreover, both genetic and pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of the positive feedback inflammatory loop. Thus, these results lead us to the next conclusions: (1) Genetic inhibition of Tnfa or Tnfr2, but not of Tnfr1, results in neutrophil mobilization from the CHT to the skin, where they get infiltrated; (2) Target gene silencing of Tnfa or Tnfr2 results in the induction of the expression of genes encoding pro-inflammatory mediators in the skin; (3) The absence of Tnfa signaling through Tnfr2 triggers the local production of H2O2 by Duox1; (4) Genetic inhibition of Tnfa or Tnfr2 results in the activation of the master regulator of inflammation NF-кB in the skin, downstream the production of H2O2; (5) Tnfa signaling through Tnfr2 is critically required for skin homeostasis; (6) DUOX1 induction and/or the subsequent production of H2O2 in the skin of psoriasis patients, may be new targets for pharmacologic and genetic therapies for the treatment of psoriasis. These new strategies could be applicable to other chronic inflammatory diseases as well; (7) Zebrafish can be used as a model organism for the study of psoriasis and other inflammatory chronic diseases

Diseño, desarrollo e implementación de una herramienta informática, para la mejora del rendimiento y la eficiencia del sistema productivo de una empresa del sector del papel

[ES] El presente TFG es fruto del trabajo desarrollado a lo largo de 12 meses en las que el alumno ha estado realizando prácticas en la empresa CDI Lean Manufacturing (consultora de producción). Dicha empresa decide iniciar al presente TFG a partir de la necesidad de obtener datos de producción de sus clientes. Los clientes de la consultoría parten de la necesidad de mejorar su proceso productivo aplicando técnicas de mejora de procesos. La primera fase en el proceso de mejora de la producción de los clientes de CDI, se centra en la obtención de datos de rendimiento, calidad y productividad, obteniendo de esta forma el indicador OEE el cual explicamos en los anexos del presente TFG. Para ello, primero necesitamos poder recopilar dichos datos y obtener los OEE de las diferentes líneas de producción. La necesidad, aparece en un primer momento en un cliente del sector del papel, que será la pionera a la hora de crear y testar una posible solución.Candel Hernandis, S. (2016). Diseño, desarrollo e implementación de una herramienta informática, para la mejora del rendimiento y la eficiencia del sistema productivo de una empresa del sector del papel. http://hdl.handle.net/10251/70460.TFG

Participatory video and visual literacy: Challenges and opportunities for social and educational change

This article addresses from a theoretical perspectiveparticipatory video as a tool for education innew digital media, reviewing some precedents andexamples. Participatory video is an educommunicativeaction connected to the contexts in which itis practiced, as a form of democratic experimentalismthat questions the uni-directionality of theteaching-learning processes. In participatory video,two aspects converge that pose a challenge tocurrent education, namely, the need for visual andmedia literacy and the understanding of schooland educational processes as scenarios for socialtransformation.Este artículo aborda, desde una perspectivateórica, el video participativo como herramientapara la educación en los nuevos mediosdigitales, revisando algunos precedentes yejemplos. El video participativo es una acciónde tipo educomunicativo conectada a los contextosen los que se practica, como forma deexperimentalismo democrático que cuestionala unidireccionalidad de los procesos de enseñanza-aprendizaje. En el video participativoconvergen dos aspectos que suponen un retopara la educación actual, a saber, la necesidadde la alfabetización visual y mediática y la comprensiónde la escuela y los procesos educativoscomo escenarios para la transformaciónsocial

Md1 and Rp105 regulate innate immunity and viral resistance in zebrafish

11 páginas, 7 figuras, 2 tablasTLR4 was the first TLR family member identified in mammals and is responsible for the activation of the immune response by bacterial LPS. Later, MD1 and RP105 were shown to form complexes that directly interact with the MD2-TLR4 complex, acting as physiological negative regulators of LPS signaling. Despite the general conservation of various TLR families from fish to mammals, several differences can be appreciated, such as the high tolerance of fish to LPS, the absence of the crucial accessory molecules Md2 and Cd14 for Tlr4 signaling in fish, the absence of Tlr4 in some fish species, and the confirmation that LPS does not signal through Tlr4 in zebrafish. The present study has identified the Rp105 and Md1 homologs in zebrafish, confirming (i) Rp105 and Tlr4 evolved from a common ancestor before the divergence between fish and tetrapods and (ii) the presence of Md1 in teleost fish and the lack of Md2, suggesting that the divergence of these accessory molecules occurred in the tetrapod lineage. Biochemical and functional studies indicate that Md1 binds both Rp105 and Tlr4 in zebrafish. Genetic inhibition of zebrafish Md1 and Rp105 reveals that Md1 or Rp105 deficiency impairs the expression of genes encoding pro-inflammatory and antiviral molecules, leading to increased susceptibility to viral infection. These results shed light on the evolutionary history of Md1 and Rp105 and uncover a previously unappreciated function of these molecules in the regulation of innate immunityThis work was supported by the Spanish Ministry of Science and Innovation (grants BIO2011-23400 and CSD2007-00002 to VM, and PhD fellowship to SC, all co-funded with Fondos Europeos de Desarrollo Regional/European Regional Development Funds), the Fundación Séneca-Murcia (PhD fellowship to RE-P), the European 7th Framework Initial Training Network FishForPharma (PhD fellowship to SDT, PITG-GA-2011-289209), and Fundação para a Ciência e Tecnologia (PhD fellowship to SdO, SFRH/BD/62674/2009)Peer reviewe

The nasopharyngeal microbiome in COVID-19

The development of novel culture-independent techniques of microbial identification has allowed a rapid progress in the knowledge of the nasopharyngeal microbiota and its role in health and disease. Thus, it has been demonstrated that the nasopharyngeal microbiota defends the host from invading pathogens that enter the body through the upper airways by participating in the modulation of innate and adaptive immune responses. The current COVID-19 pandemic has created an urgent need for fast-track research, especially to identify and characterize biomarkers to predict the disease severity and outcome. Since the nasopharyngeal microbiota diversity and composition could potentially be used as a prognosis biomarker for COVID-19 patients, which would pave the way for strategies aiming to reduce the disease severity by modifying such microbiota, dozens of research articles have already explored the possible associations between changes in the nasopharyngeal microbiota and the severity or outcome of COVID-19 patients. Unfortunately, results are controversial, as many studies with apparently similar experimental designs have reported contradictory data. Herein we put together, compare, and discuss all the relevant results on this issue reported to date. Even more interesting, we discuss in detail which are the limitations of these studies, that probably are the main sources of the high variability observed. Therefore, this work is useful not only for people interested in current knowledge about the relationship between the nasopharyngeal microbiota and COVID-19, but also for researchers who want to go further in this field while avoiding the limitations and variability of previous works