From trained immunity in allergy to trained immunity‐based allergen vaccines.

Innate immune cells experience long lasting metabolic and epigenetic changes after an encounter with specific stimuli. This facilitates enhanced immune responses upon secondary exposition to both the same and unrelated pathogens, a process termed trained immunity. Trained immunity- based vaccines (TIbV) are vaccines able to induce innate immune memory, thus conferring heterologous protection against a broad range of pathogens. While trained immunity has been well documented in the con-text of infections and multiple immune- mediated diseases, the role of innate immune memory and its contribution to the initiation and maintenance of chronic allergic dis-eases remains poorly understood. Over the last years, different studies attempting to uncover the role of trained immunity in allergy have emerged. Exposition to en-vironmental factors impacting allergy development such as allergens or viruses in-duces the reprogramming of innate immune cells to acquire a more pro-inflammatory phenotype in the context of asthma or food allergy. Several studies have convincingly demonstrated that prevention of viral infections using TIbV contributes to reduce wheezing attacks in children, which represent a high- risk factor for asthma develop-ment later in life. Innate immune cells trained with specific stimuli might also acquire anti- inflammatory features and promote tolerance, which may have important impli-cations for chronic inflammatory diseases such as allergies. Recent findings showed that allergoid- mannan conjugates, which are next generation vaccines for allergen- specific immunotherapy (AIT), are able to reprogram monocytes into tolerogenic den-dritic cells by mechanisms depending on metabolic and epigenetic rewiring. A better understanding of the underlying mechanisms of trained immunity in allergy will pave the way for the design of novel trained immunity- based allergen vaccines as potential alternative strategies for the prevention and treatment of allergic diseases

Buenas prácticas de atención y educación en la primera infancia en Centroamérica y República Dominicana

This study presents evidence-based best practices in early childhood care and education. The results are derived from a literature review used to build a conceptual framework for this regional study, which was carried out by the Central American and Caribbean Early Literacy Network (RedLEI). The evidence is organized into eight dimensions: 1) political and financial environment; 2) supervision, monitoring, and support; 3) teaching and learning: (curriculum); 4) staff capacity, leadership, and management; 5) socio-emotional relationships; 6) classroom design, environment, and safety; 7) families and communities; and 8) health and nutrition.Este artículo presenta las buenas prácticas basadas en la evidencia en la atención y educación de la primera infancia. Los hallazgos provienen de la revisión de la literatura relevante para construir el marco conceptual de la investigación de la Red para la Lectoescritura Inicial en Centroamérica y el Caribe (RedLEI). Las evidencia investigativa identificadas se organizan en ocho dimensiones: 1) ambiente político y financiero, 2) supervisión, monitoreo y acompañamiento, 3) enseñanza-aprendizaje: (currículo), 4) capacidad del personal, liderazgo y gestión, 5) relaciones socio afectivas, 6) diseño de ambiente y seguridad del aula, 7) familia y comunidades y 8) salud y nutrición

Evaluation of humoral immunity profiles to identify heart recipients at risk for development of severe infections: a multicenter prospective study

[Abstract] BACKGROUND: New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. METHODS: We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. RESULTS: During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection. CONCLUSION: Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.Instituto de Salud Carlos III; FIS081430Instituto de Salud Carlos III; FIS1101323Instituto de Salud Carlos III; FIS150147

Sinergismo entre 3,4-dihidroxifenilglicol e hidroxitirosol sobre biomarcadores cardiovasculares, estrés oxidativo y nitrosativo en un modelo experimental de Diabetes Mellitus tipo 1.

Resumen Póster: Objetivo El objetivo de este estudio fue evaluar el efecto sinérgico de dos polifenoles del aceite de oliva virgen extra, 3,4,-dihidroxifenilglicol (DHPG) e hidroxitirosol (HT), sobre biomarcadores cardiovasculares en un modelo experimental de Diabetes Mellitus tipo 1. Material y Métodos Se estudiaron siete grupos de animales: (1) ratas no diabéticas (NDR), (2) ratas diabéticas (DR), (3) DR tratadas con HT (5 mg/kg/día), (4) DR tratadas con DHPG (0,5 mg/kg/día), (5) DR tratadas con DPHG (1 mg/kg/día), (6) DR tratadas con HT + DHPG (0,5 mg/kg/día), y (7) DR tratadas con HT + DHPG (1 mg/kg/día). Se analizaron algunos biomarcadores cardiovasculares (agregación plaquetaria, tromboxano B2, prostaciclina, mieloperoxidasa y VCAM-1, variables de estrés oxidativo (peroxidación lipídica, glutatión, actividad antioxidante total, 8-isoprostanos, 8-hidroxi-2-deoxiguanosina y LDL oxidada), y estrés nitrosativo (3-nitrotirosina). Resultados Los animales diabéticos mostraron un desequilibrio en todas las variables analizadas. HT ejerció un efecto regulador a la baja sobre los biomarcadores protrombóticos y antioxidantes, al tiempo que frenó el descenso de prostaciclina. DHPG presentó un perfil similar, pero cuantitativamente inferior. HT y DHPG mostraron un efecto sinérgico en la reducción de la agregación plaquetaria, la producción de prostaciclina, mieloperoxidasa, VCAM-1 y del estrés oxidativo y nitrosativo. Conclusiones Se demuestra sinergismo entre 3,4-dihidroxifenilglicol e hidroxitirosol. Este sinergismo podría ser importante para el desarrollo de aceites funcionales, enriquecidos con estos dos polifenoles en la proporción utilizada en este estudio, para la prevención de la enfermedad cardiovascular.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells

14 p.-8 fig.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.The authors’ laboratories were supported by grants FEI 16_60 from Art.83 4154605 (138/2012)(24/2013), SAF-2017-84978-R from MINECO (Spain) and PID2020-114396RB-I00 from Ministerio de Ciencia e Innovación (Spain) to OP and PID2021-123781OB-C22 to FJC funded by MCIN/AEI/10.13039/501100011033 (Spain) and RTC-2015-3805-1 from MINECO to Inmunotek SL.Peer reviewe

Sustracción internacional de menores y violencia de género

[ES]La sustracción internacional de menores es el traslado de un menor a un país donde no reside llevado a cabo de forma ilícita dentro de un contexto de crisis familiar; además, constituye un delito tipificado en el artículo 225 bis del Código Penal, a cuyos efectos la sustracción puede tener una doble consideración: 1. Traslado ilícito del menor: uno de los progenitores traslada al menor a un lugar diferente al de su residencia sin consentimiento del progenitor con quien convive (otras personas o una institución, en su caso, a quien se confía su guarda o custodia). El fin de este traslado es obtener una resolución judicial que capacite al progenitor que lleva a cabo la sustracción a convivir legalmente con su hijo. 2. Retención ilícita del menor: se trata del supuesto en que el progenitor sustractor retiene al menor en un Estado diferente al de la residencia de los hijos

Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury

Creación de una web del Grupo de Investigación: avances en Salud Oral

Memoria ID-0135. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2015-2016

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017- 86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/ FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018- 024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/ A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/ EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.S

Effects of luteectomy in early pregnancy on the maintenance of gestation and plasma progesterone concentrations in the viviparous temperate lizard Barisia imbricata imbricata

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that the corpus luteum is the principal source of progesterone during the gravidity period in reptiles; however, its participation in the maintenance of gestation in the viviparous squamata is in dispute. The effects of ovariectomy or luteectomy vary according to the species and the time at which the procedure is performed. In this paper, we describe the effects of luteectomy during early pregnancy on the maintenance of gestation and progesterone concentrations in the temperate Mexican viviparous lizard <it>Barisia imbricata imbricata.</it></p> <p>Methods</p> <p>Twenty-four lizards were subjected to three different treatments: luteectomy, sham luteectomy or non-surgical treatment, and blood samples were obtained before and after surgical treatment at different stages of gestation to determine the effects of luteectomy on the maintenance of gestation and progesterone concentrations.</p> <p>Results</p> <p>Spontaneous abortion was not observed in any of the females. However, luteectomy provoked abnormal parturition and a significant reduction in the number of young born alive. Parturition was normal in untreated females as well as those submitted to sham luteectomy. The surgical treatment also caused a significant reduction in progesterone concentrations in luteectomised females during early and middle gestation. However, no significant differences in hormone concentrations were observed among the three groups during late gestation or immediately post-parturition.</p> <p>Conclusions</p> <p>Our observations indicate that the presence of the corpus luteum is not necesary for the maintenance of gestation, but that it does participate in parturition control. Moreover, the corpus luteum of the viviparous lizard <it>B. i. imbricata</it> produces progesterone, at least during the first half of pregnancy, and that an extra-ovarian source of progesterone must maintain gestation in the absence of luteal tissue.</p