The generation of a lactate-rich environment stimulates cell cycle progression and modulates gene expression on neonatal and hiPSC-derived cardiomyocytes

In situ tissue engineering strategies are a promising approach to activate the endogenous regenerative potential of the cardiac tissue helping the heart to heal itself after an injury. However, the current use of complex reprogramming vectors for the activation of reparative pathways challenges the easy translation of these therapies into the clinic. Here, we evaluated the response of mouse neonatal and human induced pluripotent stem cell-derived cardiomyocytes to the presence of exogenous lactate, thus mimicking the metabolic environment of the fetal heart. An increase in cardiomyocyte cell cycle activity was observed in the presence of lactate, as determined through Ki67 and Aurora-B kinase. Gene expression and RNA-sequencing data revealed that cardiomyocytes incubated with lactate showed upregulation of BMP10, LIN28 or TCIM in tandem with downregulation of GRIK1 or DGKK among others. Lactate also demonstrated a capability to modulate the production of inflammatory cytokines on cardiac fibroblasts, reducing the production of Fas, Fraktalkine or IL-12p40, while stimulating IL-13 and SDF1a. In addition, the generation of a lactate-rich environment improved ex vivo neonatal heart culture, by affecting the contractile activity and sarcomeric structures and inhibiting epicardial cell spreading. Our results also suggested a common link between the effect of lactate and the activation of hypoxia signaling pathways. These findings support a novel use of lactate in cardiac tissue engineering, modulating the metabolic environment of the heart and thus paving the way to the development of lactate-releasing platforms for in situ cardiac regeneration.Postprint (published version

IAMCEST secundario a mixoma auricular de morfología inusual.

We present echocardiographic images of an atrial myxoma with a rare location and morphology. This is a clinical case of a woman who begins with symptoms of chest pain, diagnosed with STEMI. Coronary angiography shows coronary arteries without lesions. Echocardiography shows a staghorn, sessile and mobile image, with a differential diagnosis of tumor or thrombus. In transesophagic echocardiographic, the mass implants sessilely in the postero-superior wall of the atrium, close to the mouth of the left pulmonary veins. It has a very irregular, staghorn surface, with multiple long and mobile pedicles, reaching the mitral annulus in diastole, without causing obstruction or insufficiency. The drainage flow from the pulmonary veins was normal. She is scheduled for surgical intervention, which proceeds without complications and finally the pathological diagnosis of atrial myxoma is obtained.Presentamos imágenes ecocardiográficas de un mixoma auricular de localización y morfología poco frecuente. Se trata de un caso clínico de una mujer que comienza con clínica con dolor torácico, diagnosticándose de IAMCEST. Se coronariografía que muestra coronarias sin lesiones. En la ecocardiografía se oserva una imagen coraliforme, sesil y movil, con diagnóstico diferencial de tumor o trombo. En ETE la masa se implanta de forma sésil en la pared postero-superior de la aurícula, próxima a la desembocadura de las venas pulmonares izquierdas. Presenta superficie muy irregular, coraliforme, con múltiples pedículos largos y móviles, llegando al anillo mitral en diástole, sin causar obstrucción ni insuficiencia. El flujo de drenaje de las venas pulmonares era normal. Se programa para intervención quirúrgica, que transcurre sin complicaciones y finalmente se obtiene el diagnóstico anatomopatológico de mixoma auricula

The generation of a lactate-rich environment stimulates cell cycle progression and modulates gene expression on neonatal and hiPSC-derived cardiomyocytes

In situ tissue engineering strategies are a promising approach to activate the endogenous regenerative potential of the cardiac tissue helping the heart to heal itself after an injury. However, the current use of complex reprogramming vectors for the activation of reparative pathways challenges the easy translation of these therapies into the clinic. Here, we evaluated the response of mouse neonatal and human induced pluripotent stem cell-derived cardiomyocytes to the presence of exogenous lactate, thus mimicking the metabolic environment of the fetal heart. An increase in cardiomyocyte cell cycle activity was observed in the presence of lactate, as determined through Ki67 and Aurora-B kinase. Gene expression and RNA-sequencing data revealed that cardiomyocytes incubated with lactate showed upregulation of BMP10, LIN28 or TCIM in tandem with downregulation of GRIK1 or DGKK among others. Lactate also demonstrated a capability to modulate the production of inflammatory cytokines on cardiac fibroblasts, reducing the production of Fas, Fraktalkine or IL-12p40, while stimulating IL-13 and SDF1a. In addition, the generation of a lactate-rich environment improved ex vivo neonatal heart culture, by affecting the contractile activity and sarcomeric structures and inhibiting epicardial cell spreading. Our results also suggested a common link between the effect of lactate and the activation of hypoxia signaling pathways. These findings support a novel use of lactate in cardiac tissue engineering, modulating the metabolic environment of the heart and thus paving the way to the development of lactate-releasing platforms for in situ cardiac regeneration.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved

Isotopic evidence of strong reliance on animal foods and dietary heterogeneity among Early-Middle Neolithic communities of Iberia

Stable carbon and nitrogen isotope research on past populations in the Iberian Neolithic has emphasized the Atlantic and Mediterranean coasts. This study provides the first isotopic insights into the diet and subsistence economy of Early and Middle Neolithic populations from open-air sites in interior north-central Iberia. We present bone collagen carbon (?13C) and nitrogen (?15N) isotope ratios for 44 humans and 33 animals recovered from six cemeteries of the Ebro valley and the northern Iberian Plateau. The results obtained are consistent with the C3 terrestrial diets typical of other contemporary south-western European populations, but the spacing between human and herbivore values from Los Cascajos and Paternanbidea sites is higher than expected, and a significant positive correlation is identified between the ?13C and ?15N human values at both. Moreover, the results clearly differ from those of the Late Neolithic/Early Chalcolithic in the same region, which show significantly lower ?13C and ?15N values. These findings contribute to an understanding of the implementation of an agro-pastoral economy in interior Iberia, suggesting a stronger reliance on animal foods among the first Neolithic groups of inner Iberia than in subsequent periods as well as differential access to some resources (possibly suckling herbivores) in the diet, which may point to the existence of early social or economic inequalities that do not seem to be linked to age and sex parameters or to mortuary treatment.This research was funded by the Basque Government (POS_2013_1_147; POS_2014_2_24; POS_2015_2_ 0001) and the Spanish Ministry of Economy and Competitiveness (project ‘Coastal societies in a changing world: A diachronic and comparative approach to the Prehistory of SWEurope from the late Palaeolithic to the Neolithic (CoChange)’ (HAR2014-51830-P)). The study has also been supported by a Newton International Fellowship funded by the British Academy (NF170854); the Basque Government (IT542/10); the University of the Basque Country (UPV/EHU) (UFI11/09); and the Spanish Ministry of Science and Innovation (projects ‘Los Caminos del Neolítico’ (HAR2009-09027) and ‘Los Caminos del Neolítico II’ (HAR2013-46800-P))

A microphysiological system combining electrospun fibers and electrical stimulation for the maturation of highly anisotropic cardiac tissue

he creation of cardiac tissue models for preclinical testing is still a non-solved problem in drug discovery, due to the limitations related to the in vitro replication of cardiac tissue complexity. Among these limitations, the difficulty of mimicking the functional properties of the myocardium due to the immaturity of the used cells hampers the obtention of reliable results that could be translated into human patients. In vivo models are the current gold standard to test new treatments, although it is widely acknowledged that the used animals are unable to fully recapitulate human physiology, which often leads to failures during clinical trials. In the present work, we present a microfluidic platform that aims to provide a range of signaling cues to immature cardiac cells to drive them towards an adult phenotype. The device combines topographical electrospun nanofibers with electrical stimulation in a microfabricated system. We validated our platform using a co-culture of neonatal mouse cardiomyocytes and cardiac fibroblasts, showing that it allows us to control the degree of anisotropy of the cardiac tissue inside the microdevice in a cost-effective way. Moreover, a 3D computational model of the electrical field was created and validated to demonstrate that our platform is able to closely match the distribution obtained with the gold standard (planar electrode technology) using inexpensive rod-shaped biocompatible stainless-steel electrodes. The functionality of the electrical stimulation was shown to induce a higher expression of the tight junction protein Cx-43, as well as the upregulation of several key genes involved in conductive and structural cardiac properties. These results validate our platform as a powerful tool for the tissue engineering community due to its low cost, high imaging compatibility, versatility, and high-throughput configuration capabilities.Peer ReviewedPostprint (author's final draft

Giant cystic hepatocarcinoma in the absence of cirrhosis.

The diagnosis of hepatocellular carcinoma (HCC) became easier in relation to the improved radiological examinations; however, the neoplasm may occur under atypical presentations mimicking other benign or malignant processes. Several mechanisms for the cystic changes of HCC have been suggested, including arterial thrombosis, inflammation, and rapid tumor growth. This paper reports an uncommon case of a 74-year-old patient, who presented with pain in the upper right abdomen and large cystic mass involving right lobe of the liver. He was diagnosed as cystic HCC, in the absence of cirrhosis, after surgery

Tuning multilayered polymeric self-standing films for controlled release of L-lactate by electrical stimulation

We examine different approaches for the controlled release of L-lactate, which is a signaling molecule that participates in tissue remodeling and regeneration, such as cardiac and muscle tissue. Robust, flexible, and self-supported 3-layers films made of two spin-coated poly(lactic acid) (PLA) layers separated by an electropolymerized poly(3,4-ethylenedioxythiophene) (PEDOT) layer, are used as loading and delivery systems. Films with outer layers prepared using homochiral PLA and with nanoperforations of diameter 146 ± 70 experience more bulk erosion, which also contributes to the release of L-lactic acid, than those obtained using heterochiral PLA and with nanoperforations of diameter 66 ± 24. Moreover, the release of L-lactic acid as degradation product is accelerated by applying biphasic electrical pulses. The four approaches used for loading extra L-lactate in the 3-layered films were: incorporation of L-lactate at the intermediate PEDOT layer as primary dopant agent using (1) organic or (2) basic water solutions as reaction media; (3) substitution at the PEDOT layer of the ClO4- dopant by L-lactate using de-doping and re-doping processes; and (4) loading of L-lactate at the outer PLA layers during the spin-coating process. Electrical stimuli were applied considering biphasic voltage pulses and constant voltages (both negative and positive). Results indicate that the approach used to load the L-lactate has a very significant influence in the release regulation process, affecting the concentration of released L-lactate up to two orders of magnitude. Among the tested approaches, the one based on the utilization of the outer layers for loading, approach (4), can be proposed for situations requiring prolonged and sustained L-lactate release over time. The biocompatibility and suitability of the engineered films for cardiac tissue engineering has also been confirmed using cardiac cellsPostprint (author's final draft

En la ruta occidental del poblamiento de la Península Ibérica

[ES] Tradicionalmente, viene considerándose que el paso de los grupos humanos por los Pirineos resulta dificultoso durante el Paleolítico y existen, efectivamente, datos que contradicen este planteamiento. Incluso podemos valorar como verosímil la existencia de una región paleolítica pirenaica, con rasgos culturales específicos y una serie de yacimientos implicados, especialmente durante el Magdaleniense. La existencia de rutas de tránsito a través de los tramos centrales de los Pirineos no es incompatible, sin embargo, con una mayor preferencia por los pasos occidental y oriental entre la Península Ibérica y el resto del continente europeo. Partiendo de esta hipótesis, nos proponemos explorar la ruta occidental del poblamiento peninsular, la que cruza el País Vasco, a partir de diferentes tipos de registro: la propia dispersión de los yacimientos arqueológicos, la distribución de materias primas líticas, los tecnocomplejos y las similitudes o diferencias en los comportamientos culturales y económicos de los grupos humanos. Para ello, partimos de la reflexión teórica efectuada en el Coloquio de Tarascon (2004), para comprobar la validez de aquella propuesta, desde la perspectiva de doce años.[EU] Sarritan aipatu da Pirinioetako pasatzea zaila izan dela gizakientzako, Paleolitoan zehar, eta ba dira datuak hipotesi hau ezeztatzeko. Batzuk aipatu dute Pirinioetako eremu kultural bat, adierazle kultural oso espezifikoekin, bereziki Magdalen aldian. Pirinioak zeharkatzen dituzten zenbait pasabideen izatea, aldi berean, bateragarria da beste planteamenduarekin, hain zuzen ere, gizataldeek nahiago izaten dituztela Pirinioetako mendebaldeko eta ekialdeko ertzak Iberiar Penintsula eta kontinentearen arteko pasabideak bezala, erosoagoak direlako. Hipotesi hau abiapuntutzat hartuta, mendebaldeko pasabidea (Euskal Herria zeharkatzen duena) zenbait erregistro materialen arabera aztertuko dugu: aztarnategi arkeologikoen sakabanaketa, harrizko lehengaien hornidura eta gizataldeen portaera kultural eta ekonomikoen arteko aldeak eta desberdintasunak. Aspaldian, 2004ko Tarascon-sur-Ariègen izandako kongresuan egin genuen hausnarketa teoretikoa izan da gure oinarria, hamabi urte beranduago hipotesi horren baliokidetza aztertzeko.[EN] It has traditionally been thought that movement of human groups across the Pyrenees would have been difficult in the Palaeolithic, although there are data contradicting this view. It may even be proposed that a Pyrenean region existed in the Palaeolithic with specific cultural traits and a series of sites, especially in the Magdalenian. The existence of routes across the central parts of the Pyrenees is not incompatible, however, with a preference for the western and eastern routes between the Iberian Peninsula and the rest of Europe. With this hypothesis, we propose to explore the western route for the movement of populations, the one that crosses the Basque Country, through different kinds of record: the location of the archaeological sites themselves, the distribution of lithic raw materials, the technocomplexes, and the similarities and differences in the cultural and subsistence behaviour of the human groups. We will retake the theoretical approach proposed at the International Meeting on Prehistorical Pyrenees (Tarascon, 2004), to check its validity, twelve years later.Parcialmente financiado por el Grupo de Investigación Consolidado en Prehistoria de la Universidad del País Vasco (IT-622-13), las redes PALEOPYR y PALMESOPYR de la Comunidad de Trabajo de los Pirineos y el proyecto PALEOGATE del MINECO (HAR2014-53536-P)