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Introduction: Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems all over the world. Antibiotics and antifungals are widely used for such infectious diseases, which is linked with microbial resistances and microbiota deleterious effects. The development of novel approaches for genitourinary tract infections (GUTIs) such as trained immunity-based vaccines (TIbV) is therefore highly required. MV140 is a sublingual whole-cell heat-inactivated polybacterial preparation with demonstrated clinical efficacy for RUTIs. The sublingual heat-inactivated Candida albicans vaccine V132 has been developed for RVVCs. We previously showed that the combination of MV140 and V132 promotes potent Th1/Th17 and regulatory T-cell responses against antigens contained in the formulation and unrelated antigens. The specific contribution of each preparation to such effects and the underlying molecular mechanisms remain incompletely understood. Methods: PBMC and monocytes were isolated from healthy donors and in vitro stimulated with V132, MV140 or MV140/V132. After 6 days of resting, cells were reestimulated with LPS and MV140. Analysis of cytokine production by ELISA, Seahorse assays for functional metabolic experiments and chromatin immunoprecipitation assays were performed. BALB/c mice were intraperitoneally and sublingually immunized with V132. Results: We uncover that V132 induces trained immunity in human PBMCs and purified monocytes, significantly increasing the responses triggered by purified monocytes, significantly increasing the responses triggered by subsequent stimulation with MV140. Mechanistically, V132 drives metabolic rewiring towards increased glycolysis and oxidative phosphorylation and induces epigenetic reprogramming that enhances the transcription of the pro-inflammatory genes IL6 and TNFA. Splenocytes and peritoneal cells from V132-immunize mice show increased responses upon in vitro stimulation w, MINECO, The Netherlands Organization for Scientific Research, Netherlands Organization for Scientific Research, ERC Advanced Grant, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

Recurrent respiratory tract infections (RRTIs) are the first leading cause of community- and nosocomial-acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat-inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor-interacting serine/threonine-protein kinase-2 (RIPK2)- and myeloid-differentiation primary-response gene-88 (MyD88)-mediated signalling pathways under the control of IL-10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL-10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections., MINECO, INNPACTO, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

MINECO, Ministerio de Ciencia e Innovación, CDTI, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

Background: Polymerized allergoids conjugated to mannan (PM) are suitable vaccines for allergen-specific immunotherapy (AIT). Alum remains the most widely used adjuvant in AIT, but its way of action is not completely elucidated. The better understanding of the mechanisms underlying alum adjuvanticity could help to improve AIT vaccine formulations. Objective: We sought to investigate the potential influence of alum in the tolerogenic properties imprinted by PM at the molecular level. Methods: Flow cytometry, ELISAs, cocultures, intracellular staining and suppression assays were performed to assess alum and PM effects in human dendritic cells (DCs). BALB/c mice were immunized with PM alone or adsorbed to alum. Allergen-specific antibodies, splenocyte cytokine production and splenic forkhead box P3 (FOXP3)+ regulatory T (Treg) cells were quantified. Metabolic and immune pathways were also studied in human DCs. Results: Alum decreases PD-L1 expression and IL-10 production induced by PM in human DCs and increases pro-inflammatory cytokine production. Alum impairs PM-induced functional FOXP3+ Treg cells and promotes Th1/Th2/Th17 responses. Subcutaneous immunization of mice with PM plus alum inhibits in vivo induction of Treg cells promoted by PM without altering the capacity to induce functional allergen-specific blocking antibodies. Alum inhibits mTOR activation and alters metabolic reprogramming by shifting glycolytic pathways and inhibiting reactive oxygen species (ROS) production in PM-activated DCs, impairing their capacity to generate functional Treg cells. Conclusion: We uncover novel mechanisms by which alum impairs the tolerogenic properties induced by PM, which might well contribute to improve the formulation of novel vaccines for AIT., Ministerio de Economía y Competitividad, Centre for Industrial Technological Development, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

Purpose of Review: Allergic diseases represent a major health problem of increasing prevalence worldwide. In allergy, dendritic cells (DCs) contribute to both the pathophysiology and the induction of healthy immune responses to the allergens. Different studies have reported that some common allergens contain glycans in their structure. C-type lectin receptors (CLRs) expressed by DCs recognize carbohydrate structures and are crucial in allergen uptake, presentation, and polarization of T cell responses. This review summarizes the recent literature regarding the role of CLRs in the regulation of type 2 immune responses to allergens. Recent Findings: In this review, we highlight the capacity of CLRs to recognize carbohydrates in common allergens triggering different signaling pathways involved in the polarization of CD4+ T cells towards specific Th2 responses. Under certain conditions, specific CLRs could also promote tolerogenic responses to allergens, which might well be exploited to develop novel therapeutic approaches of allergen-specific immunotherapy (AIT), the single treatment with potential disease-modifying capacity for allergic disease. At this regard, polymerized allergens conjugated to non-oxidized mannan (allergoid-mannan conjugated) are next-generation vaccines targeting DCs via CLRs that promote regulatory T cells, thus favoring allergen tolerance both in preclinical models and clinical trials. Summary: A better understanding of the role of CLRs in the development of allergy and in the induction of allergen tolerance might well pave the way for the design of novel strategies for allergic diseases., MICINN, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

Functional Tregs play a key role in tumor development and progression, representing a major barrier to anticancer immunity. The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood. Herein, by using NMR, chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses, we demonstrate that the tumoral carbohydrate A10 (Ca10), a cell-surface carbohydrate derived from Ehrlich’s tumor (ET) cells, is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs. Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming, PD-L1, IL-10, and IDO. Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features. In solid ET-bearing mice, we found positive correlations between Ca10 serum levels, tumor size and splenic Treg numbers. Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice. Remarkably, we provide evidence supporting the presence of a circulating human Ca10 counterpart (Ca10H) and show, for the first time, that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals. Of note, these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases. Collectively, we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer. The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment., MINECO, Ministerio de Ciencia e Innovación, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

Las células dendríticas (DCs) son células presentadoras de antígenos profesionales que tienen un papel esencial en la inducción de respuestas inmunitarias adecuadas. Actúan como nexo de unión entre la inmunidad innata y adaptativa. Las DCs exhiben la capacidad dual de promover respuestas inmunitarias frente a patógenos potencialmente dañinos o de generar tolerancia frente a antígenos exógenos inocuos y antígenos propios. Este proceso se encuentra altamente regulado y depende de los antígenos y las señales que se encuentran en el ambiente. Alteraciones en la función de las DCs conducen al desarrollo de enfermedades inmunomediadas tales como infecciones recurrentes, cáncer, autoinmunidad o alergia. Las infecciones y el cáncer constituyen un problema de salud muy importante con un gran impacto socio-económico a nivel mundial. Las infecciones del tracto genitourinario (GUTIs), que incluyen infecciones recurrentes del tracto urinario (RUTIs) y candidiasis vulvovaginales recurrentes (RVVCs), son enfermedades infecciosas bacterianas y fúngicas muy frecuentes. Actualmente, los tratamientos de referencia siguen siendo los antibióticos y antifúngicos, respectivamente. Sin embargo, el uso excesivo de estos fármacos conlleva un aumento de las resistencias microbianas y un efecto perjudicial en la microbiota. Las vacunas basadas en inmunidad entrenada (TIbV) son formulaciones capaces de inducir inmunidad entrenada, lo que confiere protección frente a los antígenos presentes en la vacuna y, además, frente a otros patógenos no contenidos en la preparación. Las TIbV se han propuesto como nuevas estrategias terapéuticas para las infecciones recurrentes. La vacuna sublingual MV140 es una preparación polibacteriana compuesta por bacterias enteras inactivadas por calor: 75% de Gram-negativas (25% Escherichia coli, 25% Proteus vulgaris y 25% Klebsiella pneumoniae) y 25% de Gram-positivas (Enterococcus faecalis). Además, ha mostrado eficacia clínica frente a RUTIs. MV140 activa DCs propo, Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in the orchestration of proper immune responses by linking innate and adaptive immunity. DCs exhibit the dual capacity to promote potent immune responses against potentially dangerous pathogens or to generate tolerance against self- and non-self-innocuous antigens, a process that must be tightly regulated and that strongly depends on the encountered antigens and surrounding environmental signals. Alterations in the regulation of this vital DC’s function might well lead to different immune-mediated diseases such as recurrent infections, cancer, autoimmunity or allergy.Infections and cancer represent major healthcare problems with increasing prevalence and high socio-economic impact worldwide. Genitourinary tract infections (GUTIs), including recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs), are among the most common bacterial and fungal infectious diseases significantly impairing patients’ quality of life. Antibiotics and antifungals remain the mainstay of treatment for these infections, respectively. However, their overuse is associated with microbial resistances and microbiota deleterious effects. Trained immunity-based vaccines (TIbV) are vaccine formulations able to induce trained immunity, thus conferring protection not only against the antigens contained in the vaccine formulation but also against heterologous infections. TIbV have been regarded as potential novel suitable strategies for recurrent infections. Sublingual vaccine MV140 is a whole heat-inactivated polybacterial preparation composed of 75% Gram-negative bacteria (25% Escherichia coli, 25% Proteus vulgaris and 25% Klebsiella pneumoniae) and 25% Gram-positive bacteria (Enterococcus faecalis). MV140 shows clinical efficacy for RUTIs acting on DCs promoting Th1, Th17 and IL-10 immune responses. V132 is a sublingual whole heat-inactivated Candida albicans formulation for RVVCs. G

[ES] Félix Candela (1910-1997) fue uno de los maestros encargados de llevar a cabo una gran variedad de proyectos mediante el uso de cáscaras de hormigón. Durante los años 50 del siglo pasado, Candela calculó y diseño tal tipo de cubiertas a partir de una serie de ecuaciones de índole estática que ofrecían unos resultados que, con el paso del tiempo, han resultado ser bastante aproximados a los obtenidos en la actualidad desarrollados mediante elementos finitos. Apoyándonos en estas evidencias, nuestro trabajo pretende desarrollar una herramienta mediante el software comercial de diseño CAD paramétrico (Rhino-Grasshopper) que permita reproducir en tiempo real el estado de esfuerzos de membrana en paraboloides hiperbólicos, con la geometría parametrizada sometida a cargas tipificadas. Para ello emplearemos la formulación que desarrolló Candela con el objetivo de que esta sirva de apoyo para el diseño de esta tipología de formas con la actualización continua de esfuerzos ante las posibles modificaciones en la búsqueda de la opción idónea. Mediante la programación de este algoritmo se podrán valorar una variedad de opciones en cuanto a proporciones o disposiciones geométricas, visualizando su comportamiento en términos de magnitud y distribución de fuerzas internas., [CA] Félix Candela (1910-1997) va ser un dels mestres encarregats a dur a terme una gran varietat de projectes mitjançant l’ús de corfes de formigó. Al llarg dels anys 50 del segle passat, Candela va calcular i dissenyar aquest tipus de cobertes a partir d’una sèrie d’equacions d’índole estàtica que oferien uns resultats que, amb el pas del temps, han resultat ser prou aproximats als obtinguts en l’actualitat desenvolupats mitjançant elements finits. Tenint en compte aquestes evidències, el nostre treball pretén desenvolupar una eina mitjançant el programari comercial de disseny CAD paramètric (Rhino- Grasshopper) que permeta reproduir en temps real l’estat d’esforços de membrana en paraboloides hiperbòlics, amb la geometria parametritzada sotmesa a càrregues tipificades. Per aquest motiu emprarem la formulació que va desenvolupar Candela amb l’objectiu que aquesta servisca de suport per al disseny d’aquesta tipologia de formes amb l’actualització contínua d’esforços davant les possibles modificacions en la cerca de l’opció idònia. Mitjançant la programació d’aquest algorisme es podran valorar una varietat d’opcions de proporcions o disposicions geomètriques, visualitzant el seu comportament en termes de magnitud i distribució de forces internes, [EN] Félix Candela (1910-1997) was one of the masters in charge of carrying out a wide variety of projects through the use of concrete shells. During the 50s of the 20th century, Candela calculated and designed this type of roof from a series of static nature equations whose results, with time, have been turned out to be quite approximate to those obtained today by using finite elements. Based on this evidence, this project aims to develop a tool with the ultimate purpose of reproducing in real-time the state of membrane stresses in hyperbolic paraboloids, with the parameterized geometry subjected to standardized loads and by using the commercial parametric CAD software (Rhino-Grasshopper). Regarding the main objective, we will employ the formulation developed by Candela as a support for the design of this typology of forms. It will also be considered the continuous updating of efforts to face possible modifications when searching for the ideal option. As a result, by programming, this algorithm, a wide variety of options can be evaluated in terms of proportions or geometric arrangements, which will facilitate the study of their behaviour regarding the magnitude and distribution of internal forces.

Allergy is defined as the unexpected abnormal or exaggerated reaction to an exogenous stimulus (allergen) involving the immune system. Allergic diseases represent a major health problem of increasing prevalence with high socio-economic burden, decreasing the quality of life of many patients. Nowadays, allergen-specific immunotherapy (AIT) is the only treatment with potential long-lasting disease-modifying effects for allergic diseases, and together with biologicals such as monoclonal antibodies (mAbs), represent the most effective therapies for allergic patients when conventional medication is not enough to control the symptoms. However, they still have drawbacks in terms of efficacy, security, long duration or high cost. Therefore, there is an urgent need to develop more effective and safer treatments. Allergoid-mannan conjugates represent next-generation vaccines for AIT targeting dendritic cells (DCs) able to promote the generation of functional regulatory T (Treg) cells. On the other hand, omalizumab, an anti-IgE biological, is approved for the treatment of severe allergic asthma, for chronic spontaneous urticaria (CSU) and for chronic rhinosinusitis with nasal polyps (CRSwNP). Recently, a next-generation anti-IgE mAb (ligelizumab) with significant higher affinity for IgE than omalizumab, has been developed and it is being currently assayed in phase III random clinical trials for CSU...

Allergy is defined as the unexpected abnormal or exaggerated reaction to an exogenous stimulus (allergen) involving the immune system. Allergic diseases represent a major health problem of increasing prevalence with high socio-economic burden, decreasing the quality of life of many patients. Nowadays, allergen-specific immunotherapy (AIT) is the only treatment with potential long-lasting disease-modifying effects for allergic diseases, and together with biologicals such as monoclonal antibodies (mAbs), represent the most effective therapies for allergic patients when conventional medication is not enough to control the symptoms. However, they still have drawbacks in terms of efficacy, security, long duration or high cost. Therefore, there is an urgent need to develop more effective and safer treatments. Allergoid-mannan conjugates represent next-generation vaccines for AIT targeting dendritic cells (DCs) able to promote the generation of functional regulatory T (Treg) cells. On the other hand, omalizumab, an anti-IgE biological, is approved for the treatment of severe allergic asthma, for chronic spontaneous urticaria (CSU) and for chronic rhinosinusitis with nasal polyps (CRSwNP). Recently, a next-generation anti-IgE mAb (ligelizumab) with significant higher affinity for IgE than omalizumab, has been developed and it is being currently assayed in phase III random clinical trials for CSU..., La alergia se define como una reacción exagerada a sustancias externas (alérgenos) mediada por el sistema inmune. Las enfermedades alérgicas constituyen un problema muy importante de salud con una gran carga socioeconómica, disminuyendo la calidad de vida de los pacientes. Actualmente, la inmunoterapia específica de alérgeno (AIT) es el único tratamiento con capacidad potencial para modificar el curso de las enfermedades alérgicas a largo plazo, y junto a los biológicos como los anticuerpos monoclonales (mAbs) dirigidos frente a dianas específicas, representan las terapias más efectivas para los pacientes en los que la medicación convencional no es suficiente para el control de los síntomas. Sin embargo, estos tratamientos aún presentan ciertas limitaciones en cuanto a eficacia, seguridad, larga duración o alto coste, por lo que hay una necesidad urgente de desarrollar tratamientos más efectivos y seguros. Los alergoides conjugados a manano son vacunas de nueva generación para AIT dirigidas frente a células dendríticas (DCs) capaces de inducir células T reguladoras (Treg) funcionales. Por otro lado, omalizumab, un biológico anti-IgE, está aprobado para el tratamiento del asma alérgica grave, de urticaria crónica espontánea (CSU) y de rinosinusitis crónica con pólipos nasales (CRSwNP). Recientemente, se ha desarrollado un nuevo mAb anti-IgE de alta afinidad (ligelizumab) que se encuentra actualmente en fases muy avanzadas para el tratamiento de CSU...

Dendritic cells (DCs) are professional antigen presenting cells that play a key role in the orchestration of immune responses by linking innate and adaptive immunity. The main function of DCs is to capture antigens in the periphery and transport them to the closer lymph nodes. There, they present the processed antigens to naïve T cells, inducing T cell activation and polarization into different phenotypes depending on the antigen, the environmental cues, costimulatory signals and cytokines. Changes in the energetic metabolism of DCs are essential for the regulation of their functional properties. At this regard, several studies have reported the involvement of autophagy, an essential catabolic process, in the control of DC functions. The endocannabinoid system (ECS) is a complex signalling network involved in many physiological processes such as neuronal development, brain plasticity, memory, cell survival, metabolism and immunity. The main components of the ECS include the endocannabinoid ligands, the cannabinoid receptors (CBRs) and the enzymes related to the ligand synthesis or degradation. Several studies showed that cannabinoid compounds display anti-inflammatory properties in different immune-mediated diseases. However, their potential capacity to regulate the orchestration of immune responses is not well understood, specifically in humans. Human DCs express all the components of the ECS. The ability of cannabinoids to immunomodulate the phenotype and function of DCs remain elusive. Considering all these aspects, the main objective of this Doctoral Thesis is to investigate the role and the underlying molecular mechanisms of synthetic cannabinoids in the control of human DC function and their potential implications in preclinical in vitro and in vivo models of immune-mediated diseases as potential novel strategies for the prevention and treatment of inflammatory disorders. In this work, we have developed and validated a novel HU210-Alexa488 fluorescence probe t

Dendritic cells (DCs) are professional antigen presenting cells that play a key role in the orchestration of immune responses by linking innate and adaptive immunity. The main function of DCs is to capture antigens in the periphery and transport them to the closer lymph nodes. There, they present the processed antigens to naïve T cells, inducing T cell activation and polarization into different phenotypes depending on the antigen, the environmental cues, costimulatory signals and cytokines. Changes in the energetic metabolism of DCs are essential for the regulation of their functional properties. At this regard, several studies have reported the involvement of autophagy, an essential catabolic process, in the control of DC functions. The endocannabinoid system (ECS) is a complex signalling network involved in many physiological processes such as neuronal development, brain plasticity, memory, cell survival, metabolism and immunity. The main components of the ECS include the endocannabinoid ligands, the cannabinoid receptors (CBRs) and the enzymes related to the ligand synthesis or degradation. Several studies showed that cannabinoid compounds display anti-inflammatory properties in different immune-mediated diseases. However, their potential capacity to regulate the orchestration of immune responses is not well understood, specifically in humans. Human DCs express all the components of the ECS. The ability of cannabinoids to immunomodulate the phenotype and function of DCs remain elusive. Considering all these aspects, the main objective of this Doctoral Thesis is to investigate the role and the underlying molecular mechanisms of synthetic cannabinoids in the control of human DC function and their potential implications in preclinical in vitro and in vivo models of immune-mediated diseases as potential novel strategies for the prevention and treatment of inflammatory disorders. In this work, we have developed and validated a novel HU210-Alexa488 fluorescence probe t, Las células dendríticas (DCs) son células presentadoras de antígeno profesionales que tienen un papel clave en la inducción de las respuestas inmunes conectando el sistema inmune innato con el adaptativo. La principal función de las DCs es reconocer antígenos en la periferia y transportarlos a los órganos linfoides más próximos. Allí, las DCs presentan los antígenos procesados a las células T vírgenes, induciendo su activación y diferenciación hacia distintos fenotipos dependiendo del antígeno, de las señales encontradas en el ambiente, de las señales co-estimuladoras y de las citoquinas. Cambios en el metabolismo energético de las DCs son esenciales en la regulación de su activación y función. Varios estudios han demostrado la implicación de la autofagia, un proceso catabólico esencial para las células, en el control de la función de las DCs. El sistema endocannabinoide (ECS) es una red compleja de señalización implicada en varios procesos fisiológicos como desarrollo neuronal, plasticidad cerebral, memoria, supervivencia celular, metabolismo e inmunidad. Los principales componentes del ECS son los ligandos endocannabinoides, los receptores de cannabinoides (CBRs) y las enzimas implicadas en la síntesis y degradación de los ligandos. Varios estudios han mostrado que los compuestos cannabinoides presentan propiedades anti-inflamatorias en diferentes enfermedades mediadas por el sistema inmune. Sin embargo, su capacidad para regular las respuestas inmunes no se conoce completamente, especialmente en humanos. Las DCs humanas expresan todos los componentes del ECS. La habilidad de los cannabinoides de inmunomodular el fenotipo y la función de las DCs se desconoce. Teniendo en cuenta estos aspectos, el objetivo de esta Tesis Doctoral es investigar el papel de los cannabinoides sintéticos en la regulación de la función de las DCs humanas, los mecanismos subyacentes y sus posibles implicaciones en modelos preclínicos in vitro e in vivo de enfermedades mediadas por el sist

Las infecciones recurrentes de las vías respiratorias (RRTIs, recurrent respiratory tract infections) y de las vías urinarias (RUTIs, recurrent urinary tract infections) figuran como las enfermedades infecciosas más comunes a nivel mundial con una alta tasa de mortalidad. Por ello, las RRTIs y RUTIs representan un problema de salud global muy serio con un gran impacto socioeconómico. Hasta la fecha, el tratamiento de referencia para combatir estas infecciones consiste en la administración repetida y prolongada de numerosos ciclos de antibióticos. Estos tratamientos han demostrado eficacia clínica en muchos casos pero su uso indiscriminado conlleva una de serie efectos adversos. Entre ellos, cabe destacar el incremento de resistencias a antibióticos asociado a un consumo abusivo de los mismos o su efecto perjudicial en el microbioma, lo que favorece las infecciones por hongos y bacterias. Por ello, según los últimos informes de la Organización Mundial de la Salud (OMS) y otras instituciones competentes existe y urge la necesidad de desarrollar nuevos tratamientos alternativos para prevenir y tratar las RRTIs y RUTIs. En este sentido, las vacunas bacterianas administradas a través de la mucosa sublingual han demostrado una alta eficacia, ya que son capaces de potenciar el sistema inmune asociado a las mucosas de manera local y en órganos distantes, mejorando así los mecanismos de defensa del organismo frente a patógenos que afectan distintos tipos de tejidos. Estudios recientes indican que la inmunización sublingual con MV130 (Bactek®) o MV140 (Uromune®), preparaciones bacterianas polivalentes (PBPs) compuestas por bacterias enteras inactivadas por calor comercializadas por Inmunotek S.L., reducen drásticamente la tasa de infecciones en los pacientes que sufren RRTIs y RUTIs, respectivamente. MV130 está formada por bacterias enteras inactivadas por calor causantes del mayor número de infecciones respiratorias en Europa (90% Gram positivas: 60% Streptococcus pneumoniae, Recurrent respiratory tract infections (RRTIs) and recurrent urinary tract infections (RUTIs) are the most common infections worldwide with a significant mortality rate. RRTIs and RUTIs represent a major health problem with a very high socioeconomic impact. Up to date, antibiotics remain the mainstay of treatment and they show clinical efficacy in many cases. However, RRTIs and RUTIs require repeated and prolonged antibiotic cycles, further increasing the risk to develop antibiotic resistances. Other negative factors associated to the overuse of antibiotics include deleterious effects for the normal microbiome, which favour pathogen invasion and subsequent bacterial and fungal superinfections. Therefore, the last reports from the World Health Organization (WHO) stated that there is an urgent need for new alternative approaches to antibiotics for the prevention and treatment of RRTIs and RUTIs able to overcome the main drawbacks associated to the overuse of antibiotics. At this regard, mucosal bacterial vaccines have demonstrated efficacy in the prevention and treatment of recurrent infections as they can potentiate immune responses both at the site of administration as well as in distant tissues, thus contributing to avoid the pathogen colonization and infection at their natural site of entrance. Recent studies showed that sublingual immunizations with MV130 (Bactek®) and MV140 (Uromune®), polybacterial preparations (PBPs) based on whole inactivated components from Inmunotek S.L., significantly reduced the infection rates in patients suffering from RRTIs and RUTIs, respectively. MV130 is composed of different proportions of whole heat-inactivated Gram-positive and –negative bacteria often present in the respiratory tract and causing the majority of upper and lower respiratory infections in Europe (90% Gram-positive: 60% Streptococcus pneumoniae, 15% Staphylococcus aureus, 15% Staphylococcus epidermidis; 10% Gram-negative: 4% Klebsiella pneumoniae, 3% Moraxella catar

Las infecciones recurrentes de las vías respiratorias (RRTIs, recurrent respiratory tract infections) y de las vías urinarias (RUTIs, recurrent urinary tract infections) figuran como las enfermedades infecciosas más comunes a nivel mundial con una alta tasa de mortalidad. Por ello, las RRTIs y RUTIs representan un problema de salud global muy serio con un gran impacto socioeconómico. Hasta la fecha, el tratamiento de referencia para combatir estas infecciones consiste en la administración repetida y prolongada de numerosos ciclos de antibióticos. Estos tratamientos han demostrado eficacia clínica en muchos casos pero su uso indiscriminado conlleva una de serie efectos adversos. Entre ellos, cabe destacar el incremento de resistencias a antibióticos asociado a un consumo abusivo de los mismos o su efecto perjudicial en el microbioma, lo que favorece las infecciones por hongos y bacterias. Por ello, según los últimos informes de la Organización Mundial de la Salud (OMS) y otras instituciones competentes existe y urge la necesidad de desarrollar nuevos tratamientos alternativos para prevenir y tratar las RRTIs y RUTIs. En este sentido, las vacunas bacterianas administradas a través de la mucosa sublingual han demostrado una alta eficacia, ya que son capaces de potenciar el sistema inmune asociado a las mucosas de manera local y en órganos distantes, mejorando así los mecanismos de defensa del organismo frente a patógenos que afectan distintos tipos de tejidos. Estudios recientes indican que la inmunización sublingual con MV130 (Bactek®) o MV140 (Uromune®), preparaciones bacterianas polivalentes (PBPs) compuestas por bacterias enteras inactivadas por calor comercializadas por Inmunotek S.L., reducen drásticamente la tasa de infecciones en los pacientes que sufren RRTIs y RUTIs, respectivamente. MV130 está formada por bacterias enteras inactivadas por calor causantes del mayor número de infecciones respiratorias en Europa (90% Gram positivas: 60% Streptococcus pneumoniae

This work presents the evolution, over a year, of nitrate content in the groundwater of the western area of La Hoya de Huesca. The observation of 21 water points indicates that the groundwater of the studied area normally exceeds 50 mg/L of nitrate ion. It also confirms the existence of an old problem of diffuse contamination., En este artículo se presenta la evolución, durante un año, del contenido de nitratos en las aguas subterráneas de la zona occidental de la Hoya de Huesca. A partir de 21 puntos de agua se constata que, en general, las aguas subterráneas de la zona estudiada superan los 50 mg/L de ion nitrato. Se comprueba la existencia de un viejo problema de contaminación difusa.

The present article deals with micromechanical composite modeling. Both analytical and computational micromechanics approaches are described as well as micromechanical modeling of damage. Based on micromechanics of failure theory, a user subroutine including a progressive damage algorithm is programmed for finite element analysis. Three theory-experiment correlations of tubes under a three-point bending test have been carried out using the bi-phase material model developed along with this project. These studies include three-ply schedules.