The prehistoric sequence of Abittaga cave (Amoroto, Biscay): review of J.M. Barandiarán excavations (1964-1966)

Resumen: El yacimiento de la cueva de Abittaga, excavado por J.M. Barandiarán entre 1964 y 1965, contiene una secuencia arqueológica con ocupaciones del Magdaleniense Superior y de la Prehistoria Reciente. Este yacimiento apenas ha participado en los debates de la prehistoria vasca de los últimos 40 años, fundamentalmente porque el yacimiento había sido estudiado de manera parcial y porque la información estratigráfica resultaba confusa. En este trabajo presentamos la revisión la colección arqueológica de Abittaga (industria lítica, ósea, cerámica, macrofauna y restos humanos). Se presentan además nuevas dataciones para las ocupaciones magdalenienses (nivel VII), y las de la Prehistoria Reciente (niveles I-III), y los resultados de la intervención arqueológica realizada en 2016. Estos resultados proporcionan una visión actualizada de un yacimiento usado con fines sepulcrales en la Edad del Bronce y como campamento ocasional, dentro de una amplia red de emplazamientos en la cuenca del Lea, durante el Magdaleniense Superior.Abstract: The archaeological site of Abittaga cave, excavated by J.M. Barandiarán between 1964 and 1965, has yielded a stratigraphic sequence with Late Magdalenian and Recent Prehistory occupations. For several reasons, this site has barely contributed to the debates about the Basque Prehistory during the last 40 years, debates such as the subsistence strategies and cultural transformations of the last hunter gatherers in the region, or the use of caves by the first farmer communities. This can probably be explained not only by the absence of a complete comprehensive analysis of the site and the archaeological materials, but also because some of the information provided by J.M. Barandiarán about the site, specially about its stratigraphy, was rather confusing. In this work we present the systematic revision of the archaeo-palaeontological collection, and we offer new data about the lithic tools, bone industry, pottery, and faunal and human remains. The analysis of the documentation of the site recorded by J.M. Barandiarán and J.M. Apellániz complemented with the results of the excavation made in 2016 at the site, suggest that the archaeological deposits excavated by J.M. Barandiarán probably correspond with deposits in primary position preserved only by the right wall of the entrance hall of the cave. The analysis of the pottery assemblage suggests different uses of the cave between the III and the I millennium cal BC. The presence of a single human individual buried in levels I-III, directly dated between 1895-1689 cal BC, indicates a funerary use of the cave during the Bronze Age. Levels IV-VI are really poor in archaeological materials and thus very difficult to interpret. Level VII presents the bulk of the archaeological material and it has been dated between 14321-14051 cal BP. In this level, the lithic assemblage is well preserved, with different refitting series. Almost all the lithic artifacts have been knapped using Flysch flint, but there are examples of flint varieties coming from more than 50 km of distance. We have recognized an in situ bladelet production obtained from carinated burins and small blocks, and the production of larger blades outside the cave, that were subsequently carried to Abittaga. The retouched toolkit is composed basically by burins, partially retouched blades and backed bladelets, with a remarkable absence of endscrapers. On the other hand, the bone industry is rich and varied, with bone points, single-row barbed harpoons, and rods. This lithic and bone industry is similar to other coeval sites in the same region such as Santa Catalina or Atxurra. The Late Magdalenian occupation of Abittaga cave is interpreted as a short-term occupation which was part of a wider settlement network that existed at that time in the Lea basin.La intervención y el estudio de materiales antiguos en la cueva de Abittaga, fue autorizada y subvencionada por el Servicio de Patrimonio Cultural de la Diputación Foral de Bizkaia (A013/2016, 72095530YA). AGO ha recibido apoyo de FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación (proyecto PGC2018-093925-B-C33), del Grupo de Investigación IT1418-19 de Eusko Jaurlaritza-Gobierno Vasco y tiene un contrato Ramón y Cajal (RYC-2017-22558). AGS tiene un contrato predoctoral de la UPV/EHU para realizar la tesis en cotutela entre dicha universidad y la Universidad de Burdeos. Iñaki Intxaurbe (UPV/EHU) nos ha proporcionado las coordenadas de los yacimientos reflejadas en el mapa de la Figura 1. Queremos agradecer al Arkeologi Museoa de Bilbao las facilidades concedidas para la consulta de materiales y de documentación anexa, especialmente a Sonia Aníbarro. Encarnación Regalado y Ander Ugarte colaboraron en la excavación de 2016

Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease

[EN] Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of agerelated hepatosteatosis.This work was supported by Ayudas para apoyar grupos de investigación del sistema Universitario Vasco (IT971‐16 to P.A.), MINECO‐FEDER (SAF2017‐87301‐R to M.L.M‐Ch) MCIU/AEI/FEDER, UE (RTI2018‐095134‐B‐100 to P.A. and RTI2018‐099413‐B‐I00 to RN, Asociación Española contra el Cáncer, Canceres raros (M.L.M‐Ch), La Caixa Foundation (to M.L.M‐Ch), Ayudas Fundación BBVA a equipos de Investigación Científica 2018 (to M.L.M‐Ch), Xunta de Galicia (RN: 2015‐CP080 and 2016‐ PG057), Fundación BBVA (RN), and European Foundation for the Study of Diabetes (RN). ISCIII‐FEDER PI17/00535 (to C.G‐M.), ISCIII‐FEDER CP14/00181 and PI16/00823 (to A.G‐ R.), and Francisco Cobos Foundation (to A.G‐R.). CiC bioGUNE thanks MINECO for the Severo Ochoa Excellence Accreditation (SEV‐2016‐ 0644

miR-873-5p targets mitochondrialGNMT-Complex II interface contributing tonon-alcoholic fatty liver disease

Objective:Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolicpathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation andfibrosis.The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, isdownregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression.Methods:miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Differentin vitroandin vivoNAFLD murinemodels were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy.Results:We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria.In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinicalmurine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating withhepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation andfibrosis byenhancing fatty acidb-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment.Conclusion:GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activityin the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment

miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease

Objective: Non-alcoholic fatly liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression. Methods: miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy. Results: We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondria! functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid beta-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment. Conclusion: GNMT participates in the regulation of metabolic pathways and mitochondria! functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment. (C) 2019 The Authors. Published by Elsevier GmbH.This work was supported by grants from NIH (US Department of Health and Human services)-R01AT001576 (to S.C.L., J.M.M., and M.L.M.-C.), Ministerio de Economia, Industria y Competitividad: SAF2017-87301-R (to M.L.M.-C.), SAF2015-64352-R (to P.A.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), Gobierno Vasco-Departamento de Educacion IT-336-10 (to PA), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD (M.L.M.-C.), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), Asociacion Espanola contra el Cancer (to T.C.D., P.F.-T. and M.L.M.-C.), Mitotherapeutix (to M.L.M.-C.), Daniel Alagille award from EASL (to T.C.D), Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.), La Caixa Foundation Program (to M.L.M.-C.), Ayudas Fundacion BBVA a Equipos de Investigacion Cientifica 2019 (to M.L.M.-C.). Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank this work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (to M.V.R.). This work was supported by Fonds National de la Recherche Luxembourg and the Deutsche Forschungsgemeinschaft (C12/BM/3975937, FL/997/7-1, Inter "HepmiRSTAT", to I.B. and F.L.). We thank MINECO for the Severo Ochoa Excellence Accreditation (SEV2016-0644)

Osteopontin: a key regulator of liver lipid metabolism

El contenido de los capítulos C,D,E,F,G e I están sujetos a confidencialidad 78 p. [168 p.]Osteopontin deficiency protects from obesity-related hepatosteatosis and liver fibrosis. Here we have investigated the role of osteopontin as a direct regulator of liver metabolism and whether osteopontin could be a serum-biomarker of liver metabolic dysfunction in non-alcoholic fatty-liver (NAFL) disease patients. We demonstrate that osteopontin regulates the crosstalk between liver cholesterol and phosphatidylcholine metabolism, being the key process the conversion of cholesterol into bile acids, frequently decreased in NAFL. In osteopontin-deficient mice enhanced cholesterogenesis in hepatocytes leads to decreased de novo lipogenesis and in vivo inhibition of cholesterogenesis normalizes liver phosphatidylcholine content. Finally, serum osteopontin levels correlate with liver phosphatidylcholine and cholesterol concentration in non-obese NAFL patients, in whom adipose tissue metabolic deregulation is not evident and conversion of cholesterol into bile acids is decreased. In conclusion, osteopontin is a key regulator of liver lipid metabolism and may be an early serum-biomarker of metabolic de regulation in non-obese NAFL patients

Osteopontin: a key regulator of liver lipid metabolism

El contenido de los capítulos C,D,E,F,G e I están sujetos a confidencialidad 78 p. [168 p.]Osteopontin deficiency protects from obesity-related hepatosteatosis and liver fibrosis. Here we have investigated the role of osteopontin as a direct regulator of liver metabolism and whether osteopontin could be a serum-biomarker of liver metabolic dysfunction in non-alcoholic fatty-liver (NAFL) disease patients. We demonstrate that osteopontin regulates the crosstalk between liver cholesterol and phosphatidylcholine metabolism, being the key process the conversion of cholesterol into bile acids, frequently decreased in NAFL. In osteopontin-deficient mice enhanced cholesterogenesis in hepatocytes leads to decreased de novo lipogenesis and in vivo inhibition of cholesterogenesis normalizes liver phosphatidylcholine content. Finally, serum osteopontin levels correlate with liver phosphatidylcholine and cholesterol concentration in non-obese NAFL patients, in whom adipose tissue metabolic deregulation is not evident and conversion of cholesterol into bile acids is decreased. In conclusion, osteopontin is a key regulator of liver lipid metabolism and may be an early serum-biomarker of metabolic de regulation in non-obese NAFL patients

Osteopontin: a key regulator of liver lipid metabolism

El contenido de los capítulos C,D,E,F,G e I están sujetos a confidencialidad 78 p. [168 p.]Osteopontin deficiency protects from obesity-related hepatosteatosis and liver fibrosis. Here we have investigated the role of osteopontin as a direct regulator of liver metabolism and whether osteopontin could be a serum-biomarker of liver metabolic dysfunction in non-alcoholic fatty-liver (NAFL) disease patients. We demonstrate that osteopontin regulates the crosstalk between liver cholesterol and phosphatidylcholine metabolism, being the key process the conversion of cholesterol into bile acids, frequently decreased in NAFL. In osteopontin-deficient mice enhanced cholesterogenesis in hepatocytes leads to decreased de novo lipogenesis and in vivo inhibition of cholesterogenesis normalizes liver phosphatidylcholine content. Finally, serum osteopontin levels correlate with liver phosphatidylcholine and cholesterol concentration in non-obese NAFL patients, in whom adipose tissue metabolic deregulation is not evident and conversion of cholesterol into bile acids is decreased. In conclusion, osteopontin is a key regulator of liver lipid metabolism and may be an early serum-biomarker of metabolic de regulation in non-obese NAFL patients

Randomized Clinical Trial to Evaluate the Morphological Changes in the Adventitial Vasa Vasorum Density and Biological Markers of Endothelial Dysfunction in Subjects with Moderate Obesity Undergoing a Very Low-Calorie Ketogenic Diet

Weight loss after bariatric surgery decreases the earlier expansion of the adventitial vasa vasorum (VV), a biomarker of early atheromatous disease. However, no data are available regarding weight loss achieved by very low calorie ketogenic diets (VLCKD) on VV and lipid-based atherogenic indices. A randomized clinical trial was performed to examine changes in adventitial VV density in 20 patients with moderate obesity who underwent a 6-month very low calorie ketogenic diet (VLCKD, 600–800 kcal/day), and 10 participants with hypocaloric diet based on the Mediterranean Diet (MedDiet, estimated reduction of 500 kcal on the usual intake). Contrast-enhanced carotid ultrasound was used to assess the VV. Body composition analysis was also used. The atherogenic index of plasma (log (triglycerides to high-density lipoprotein cholesterol ratio)) and the triglyceride-glucose index were calculated. Serum concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured. The impact of weight on quality of life-lite (IWQOL-Lite) questionnaire was administered. Participants of intervention groups displayed a similar VV values. Significant improvements of BMI (−5.3 [−6.9 to −3.6] kg/m2, p < 0.001), total body fat (−7.0 [−10.7 to −3.3] %, p = 0.003), and IWQOL-Lite score (−41.4 [−75.2 to −7.6], p = 0.027) were observed in VLCKD group in comparison with MedDiet group. Although after a 6-months follow-up period VV density (mean, right and left sides) did not change significantly in any group, participants in the VLCKD exhibited a significantly decrease both in their atherogenic index of plasma and serum concentration of sICAM-1. A 6-month intervention with VLCKD do not impact in the density of the adventitial VV in subjects with moderate obesity, but induces significant changes in markers of endothelial dysfunction and CV risk

The role of associations in reducing the emotional and financial impact on parents caring for children with duchenne muscular dystrophy : a cross-cultural study

Abstract: Caregivers’ emotions and finances are affected by the deterioration of functional capacity of patients with Duchenne muscular dystrophy (DMD), both in Mexico and Spain. Patient associations may reduce this impact on caregivers. This study aims to study the role of two models of associations, inspired by two different cultural models, in how the services they provide can help decrease the emotional and financial impact on the caregivers of children with DMD. The sample consisted of 34 caregivers from Mexico and 40 from Spain recruited from Spanish hospitals and rare disease organizations in Spain and Mexico. The instruments used consisted of a sociodemographic and socioeconomic questionnaire, the CarerQol-7D, the PHQ-15, the Zarit Caregiver’s Burden Scale and the SWLS. The results showed that caregivers in Mexico are in better physical and psychological health than caregivers in Spain. They also receive more subsidies than those in Spain. Caregivers in Mexico have a greater well-being and are less affected by the economic impact of the disease due to the associations’ day-to-day work and the fact that they generate a network of health services that they make available to the patient free of charge. These differences may also be attributable to cultural issues and to the fact that Mexico has a deeply established culture of support