Lysosomal Degradation of Junctional Proteins

Epithelial cells develop tight junctions (TJs) and cell polarity. Both properties are sensitive to environmental signals such as the epidermal growth factor (EGF) and the cardiotonic steroid ouabain. EGF is regarded as the main protector against injuries in epithelia, and ouabain is a hormone that regulates blood pressure, natriuresis, cell survival, and cell adhesion. After treatment with epidermal growth factor or ouabain, epithelial dog kidney MDCK cells undergo a drastic remodeling that includes changes in the transcription, translation, localization, and degradation of cell junction proteins. Degradation of these proteins involves selective and nonselective autophagy as well as endocytic lysosomal and proteasomal routes. The remodeling mechanism of tight junction’s proteins includes the activation of Src and ERK1/ERK2 kinases, the phosphorylation and translocation into the nucleus of the transcription factor STAT3, the activation of PKC to induce the endocytosis of claudin-2, and the delivery of this protein to the lysosomes. Whole communicating junctions and desmosomes are internalized by one cell and sent to degradation by nonselective autophagy. Nonselective and selective autophagies in epithelial cells are very context dependent; nevertheless, it is clear that, together with endocytic lysosomal and proteasomal degradation, they play a key role in the remodeling and functioning of cell junctions

El cerro de la Judería de Atienza: primera aproximación arqueológica

The archaeological excavations carried out in the medieval Jewish quarter of Atienza (Guadalajara) in 2022 constitute the first comprehensive approach to the archaeological site of the walled quarter in which this religious minority resided. Although there are numerous reports from written sources of the presence of an important Jewish community in Atienza during the late medieval centuries, until now there had only been a few superficial approaches to its archaeological remains. The planned archaeological excavation summarised here, carried out as part of a wider territorial study project, has documented a 13th and 14th century domestic context in the central sector of the Jewish quarter. The analysis of the exhumed structures and the archaeological materials found in context, especially ceramics and archaeozoology, allows us to establish relevant considerations regarding the processes of occupation and abandonment of the quarter and about the central question of the archaeological identification of the late medieval Jewish communities. The site is also an exceptional space for the collection of archaeobiological samples, whose potential for advancing the study of the relationship between these medieval communities and the natural environment has barely been glimpsed.Las excavaciones arqueológicas realizadas en la judería medieval de Atienza (Guadalajara) en 2022 constituyen la primera aproximación integral al conjunto arqueológico del barrio amurallado en el que residió esa minoría religiosa. A pesar de que son numerosas las noticias procedentes de las fuentes escritas que informan de la presencia de una importante comunidad judía en Atienza durante los siglos bajomedievales, hasta ahora apenas se habían hecho algunas aproximaciones superficiales a sus restos arqueológicos. La excavación arqueológica programada que aquí se sintetiza, realizada en el marco de un proyecto de estudio territorial más amplio, ha documentado un espacio doméstico de los siglos XIII y XIV del sector central de la judería. El análisis de las estructuras exhumadas y de los materiales arqueológicos hallados en contexto, especialmente cerámicos y arqueozoológicos, permite establecer consideraciones relevantes en lo relativo a los procesos de ocupación y abandono del barrio y en lo que respecta a la cuestión central de la identificación arqueológica de las comunidades judías bajomedievales. El yacimiento, además, se convierte en un excepcional espacio para la obtención de muestras arqueobiológicas, cuyo potencial para avanzar en el estudio de la relación de estas comunidades medievales y el medio natural apenas se vislumbra

Multidisciplinary management of head and neck cancer: First expert consensus using Delphi methodology from the Spanish Society for Head and Neck Cancer (part 2)

Head and neck cancer is one of the most frequent malignances worldwide. Despite the site-specific multimodality therapy, up to half of the patients will develop recurrence. Treatment selection based on a multidisciplinary tumor board represents the cornerstone of head and neck cancer, as it is essential for achieving the best results, not only in terms of outcome, but also in terms of organ-function preservation and quality of life. Evidence-based international and national clinical practice guidelines for head and neck cancer not always provide answers in terms of decision-making that specialists have to deal with in their daily practice. This is the first Expert Consensus on the Multidisciplinary Approach for Head and Neck Squamous Cell Carcinoma (HNSCC) elaborated by the Spanish Society for Head and Neck Cancer and based on a Delphi methodology. It offers a number of specific recommendations based on the available evidence and the expertise of our specialists to facilitate decision-making of all health-care specialists involved.Also, special thanks to Ainhoa Torres and the Merck Health Foundation for funding and promoting the project and development of the Article.Peer Reviewe

Bone metabolism and inflammatory biomarkers in radiographic and non-radiographic axial spondyloarthritis patients: a comprehensive evaluation

IntroductionAxial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients.MethodsA cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay.ResultsR-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others.ConclusionAltogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation

Pb(II) Induces Scramblase Activation and Ceramide-Domain Generation in Red Blood Cells

The mechanisms of Pb(II) toxicity have been studied in human red blood cells using confocal microscopy, immunolabeling, fluorescence-activated cell sorting and atomic force microscopy. The process follows a sequence of events, starting with calcium entry, followed by potassium release, morphological change, generation of ceramide, lipid flip-flop and finally cell lysis. Clotrimazole blocks potassium channels and the whole process is inhibited. Immunolabeling reveals the generation of ceramide-enriched domains linked to a cell morphological change, while the use of a neutral sphingomyelinase inhibitor greatly delays the process after the morphological change, and lipid flip-flop is significantly reduced. These facts point to three major checkpoints in the process: first the upstream exchange of calcium and potassium, then ceramide domain formation, and finally the downstream scramblase activation necessary for cell lysis. In addition, partial non-cytotoxic cholesterol depletion of red blood cells accelerates the process as the morphological change occurs faster. Cholesterol could have a role in modulating the properties of the ceramide-enriched domains. This work is relevant in the context of cell death, heavy metal toxicity and sphingolipid signaling.AGA was a predoctoral student supported by the Basque Government and later by the University of the Basque Country (UPV/EHU). This work was also supported in part by grants from the Spanish Government (FEDER/MINECO BFU 2015-66306-P to F.M.G. and A.A.) and the Basque Government (IT849-13 to F.M.G. and IT838-13 to A.A.), and by the Swiss National Science Foundation

Prospective Latin American cohort evaluating outcomes of patients with COVID-19 and abnormal liver tests on admission

Introduction & objectives: The independent effect of liver biochemistries as a prognostic factor in patients with COVID-19 has not been completely addressed. We aimed to evaluate the prognostic value of abnormal liver tests on admission of hospitalized patients with COVID-19. Materials & methods: We performed a prospective cohort study including 1611 hospitalized patients with confirmed SARS-CoV-2 infection from April 15, 2020 through July 31, 2020 in 38 different Hospitals from 11 Latin American countries. We registered clinical and laboratory parameters, including liver function tests, on admission and during hospitalization. All patients were followed until discharge or death. We fit multivariable logistic regression models, further post-estimation effect through margins and inverse probability weighting. Results: Overall, 57.8% of the patients were male with a mean age of 52.3 years, 8.5% had chronic liver disease and 3.4% had cirrhosis. Abnormal liver tests on admission were present on 45.2% (CI 42.7–47.7) of the cohort (n = 726). Overall, 15.1% (CI 13.4–16.9) of patients died (n = 244). Patients with abnormal liver tests on admission presented higher mortality 18.7% (CI 15.9–21.7), compared to those with normal liver biochemistries 12.2% (CI 10.1–14.6); P 30. Conclusions: The presence of abnormal liver tests on admission is independently associated with mortality and severe COVID-19 in hospitalized patients with COVID-19 infection and may be used as surrogate marker of inflammation.Fil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Anders, Margarita. Hospital Aleman; ArgentinaFil: Silveyra, María Dolores. Sanatorio Anchorena; ArgentinaFil: Torre, Aldo. Centro Médico ABC; MéxicoFil: Montes, Pedro. Hospital Nacional Daniel A. Carrión; PerúFil: Urzúa, Alvaro. Hospital Clínico de la Universidad de Chile; ChileFil: Pages, Josefina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Toro, Luis G.. Hospitales de San Vicente Fundación de Medellín y Rionegro; ColombiaFil: Díaz, Javier. Hospital Nacional Edgardo Rebagliati Martins; PerúFil: Gonzalez Ballerga, Esteban. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Miranda Zazueta, Godolfino. Instituto Nacional de Ciencias Médicas y Nutrición; MéxicoFil: Peralta, Mirta. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Gutiérrez, Isabel. Centro Médico ABC; MéxicoFil: Michelato, Douglas. Hospital Especializado en Enfermedades Infecciosas Instituto Couto Maia; BrasilFil: Venturelli, Maria Grazia. Hospital Nacional Guillermo Almenara Irigoyen; PerúFil: Varón, Adriana. Fundación Cardio-Infantil; ColombiaFil: Vera Pozo, Emilia. Hospital Regional Dr. Teodoro Maldonado Carbo; EcuadorFil: Tagle, Martín. Clínica Anglo-Americana; PerúFil: García, Matías. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Tassara, Alfredo. Hospital Aleman; ArgentinaFil: Brutti, Julia. Sanatorio Anchorena; ArgentinaFil: Ruiz García, Sandro. Hospital de Víctor Lazarte Echegaray; PerúFil: Bustios, Carla. Clínica Delgado; PerúFil: Escajadillo, Nataly. Hospital Nacional Almanzor Aguinaga Asenjo; PerúFil: Macias, Yuridia. No especifíca;Fil: Higuera de la Tijera, Fátima. Hospital General de México “Dr. Eduardo Liceaga"; MéxicoFil: Gómez, Andrés J.. Hospital Universitario Fundación Santa Fé de Bogotá; ColombiaFil: Dominguez, Alejandra. Hospital Padre Hurtado; ChileFil: Castillo Barradas, Mauricio. Hospital de Especialidades del Centro Médico Nacional La Raza; MéxicoFil: Contreras, Fernando. No especifíca;Fil: Scarpin, Aldana. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Schinoni, Maria Isabel. Hospital Alianza; BrasilFil: Toledo, Claudio. Universidad Austral de Chile; ChileFil: Girala, Marcos. Universidad Nacional de Asunción; ParaguayFil: Mainardi, Victoria. Hospital Central De las Fuerzas Armadas; UruguayFil: Sanchez, Abel. Hospital Roosevelt; GuatemalaFil: Bessone, Fernando. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Rubinstein, Fernando Adrian. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Silva, Marcelo Oscar. Universidad Austral. Hospital Universitario Austral; Argentin

Sexual Relationships in Hispanic Countries: a Literature Review

This is a pre-print of an article published in Current Sexual Health Reports. The final authenticated version is available online at: https://doi.org/10.1007/s11930-020-00272-6Purpose of Review: Sexuality is a complex dimension for which culture seems to play an important role, particularly in countries that are more traditional. This review summarizes the knowledge about sexual relationships in Hispanic countries, considering sexual debut, attitudes, behaviors, and satisfaction. Recent Findings: In line with the literature reviewed, the sexual double standard seems to be continuing to influence sexual relationships. Some countries show more open expressions of sexuality based on the level of gender inequality or sexualized context, and within countries, variables such as religious commitment, family characteristics, and access to resources may play important roles in sexuality. Summary: Future research, policies, and interventions should consider these specific characteristics, including these forms of expression of sexuality, in the adjustment of cross-cultural and cross-national strategies

The Pierre Auger Observatory III: Other Astrophysical Observations

Astrophysical observations of ultra-high-energy cosmic rays with the Pierre Auger ObservatoryComment: Contributions to the 32nd International Cosmic Ray Conference, Beijing, China, August 201