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We investigated the role of cue weighting, second language (L2) proficiency, and L2 daily exposure in L2 learning of suprasegmentals different from the first language (L1), using eye-tracking. Spanish monolinguals, English-Spanish learners, and Mandarin--Spanish learners saw a paroxytone and an oxytone verb (e.g., "FIRma-firMÓ" "s/he signs-signed"), listened to a sentence containing one of the verbs, and chose the one that they heard. The three languages have contrastive lexical stress, but suprasegmentals have a greater functional load in Mandarin than in English. Monolinguals predicted suffixes accurately with both stress conditions and favored oxytones, but learners predicted suffixes accurately only with oxytones, the condition activating fewer lexical competitors. Monolinguals predicted suffixes accurately sooner but at a slower rate than did learners. L2 proficiency, but not L1 or L2 exposure, facilitated L2 predictions. In conclusion, learners of a contrastive-stress L1 rely on L2 suprasegmentals to the same extent as monolinguals, regardless of their L1. Lower L2 proficiency and higher cognitive load (more lexical competitors) reduce learners' reliance on suprasegmentals.

Abstract Acquired perforating dermatosis (APD) is a disorder of transepidermal elimination of keratin, collagen or elastic fibers. APD is mainly associated with diabetes mellitus and chronic kidney disease. We present the case of a 66‐year‐old male, poorly controlled diabetic with peripheral arterial disease, obesity, arterial hypertension, Cushing's syndrome and chronic kidney disease requiring hemodialysis who develops an acquired perforating dermatosis. Due to the patient's comorbidities, treatment with corticosteroids, cyclosporine and phototherapy is not possible. He does not respond to gabapentinoids or allopurinol. The outbreaks of skin lesions and pruritus were accentuated in situations of renal function deterioration; however, hemodialysis did not improve her dermatosis, causing a great deterioration of her quality of life. It was decided to start treatment with dupilumab with the dosage used in atopic dermatitis, achieving a complete response of both pruritus and skin lesions. With this case, we want to show how dupilumab can be an effective tool to treat acquired perforating dermatosis.

This work contributes to the improvement of novel medical technologies for the prevention and treatment of diseases. Electrical impedance tomography (EIT) has gained attention as a valuable tool for non-invasive monitoring providing real-time insights. The purpose of this work is to develop and validate a novel portable EIT system with a small form factor for respiratory monitoring. The device uses a 16-electrode architecture with adjacent stimulation and measurement patterns, an integrated circuit current source and a single high-speed ADC operating with multiplexers to stimulate and measure across all electrodes. Tests were conducted on 25 healthy subjects who performed a pulmonary function test with a flowmeter while using the EIT device. The results showed a good performance of the device, which was able to recognize all respirations correctly, and from the EIT signals and images, correlations of 96.7% were obtained for instantaneous respiratory rate and 96.1% for tidal volume prediction. These results validate the preliminary technical feasibility of the EIT system and demonstrates its potential as a reliable tool for non-invasive respiratory assessment. The significance of this work lies in its potential to democratize advanced respiratory monitoring technologies, making them accessible to a wider population, including those in remote or underserved areas.

Summary: Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.

According to the World Health Organization (WHO), major depressive disorder (MDD) is the fourth leading cause of disability worldwide and the second most common disease after cardiovascular events. Approximately 280 million people live with MDD, with incidence varying by age and gender (female to male ratio of approximately 2:1). Although a variety of antidepressants are available for the different forms of MDD, there is still a high degree of individual variability in response and tolerability. Given the complexity and clinical heterogeneity of these disorders, a shift from “canonical treatment” to personalized medicine with improved patient stratification is needed. OPADE is a non-profit study that researches biomarkers in MDD to tailor personalized drug treatments, integrating genetics, epigenetics, microbiome, immune response, and clinical data for analysis. A total of 350 patients between 14 and 50 years will be recruited in 6 Countries (Italy, Colombia, Spain, The Netherlands, Turkey) for 24 months. Real-time electroencephalogram (EEG) and patient cognitive assessment will be correlated with biological sample analysis. A patient empowerment tool will be deployed to ensure patient commitment and to translate patient stories into data. The resulting data will be used to train the artificial intelligence/machine learning (AI/ML) predictive tool.

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4+ T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as “immune inadequate responders”, “immunodiscordant responders” or “immune nonresponders (INR)”. The molecular mechanisms underlying poor CD4+ T-cell recovery are still unclear. In this sense, the use of omics sciences has shed light on possible factors involved in the activity and metabolic dysregulation of immune cells during the failure of CD4+ T-cell recovery in INR. Moreover, identification of key molecules by omics approaches allows for the proposal of potential biomarkers or therapeutic targets to improve CD4+ T-cell recovery and the quality of life of these patients. Hence, this review aimed to summarize the information obtained through different omics concerning the molecular factors and pathways associated with the INR phenotype to better understand the complexity of this immunological status in HIV infection.

El aprendizaje-servicio (ApS) se ha integrado en los procesos enseñanza-aprendizaje a todos los niveles. Su aplicación, acercándose a la realidad sin tamices, contrasta con lo equidistante de una educación neutra, al margen de toda ideología. No obstante, este oxímoron conlleva un aprendizaje limitante para repensar nuestras creencias personales, que son a su vez las carencias sociales de nuestro tiempo. Particularmente, cuando la innovación se promueve con aprendizaje-servicio y enfoque geográfico se posibilita que desde lo local se reconozca la perversidad manifiesta en la globalización. Este es el objetivo del proyecto de sensibilización desarrollado: reformular el sentido de la educación. ¿El servicio? Dar voz a quién se le oprime. Sin necesidad de eludir el currículo establecido, a través del método epistémico, o método humano, queda demostrado el potencial de la escuela para sensibilizar sobre problemáticas sociales, actuando en este caso desde el entorno más inmediato en la opinión pública, a nivel comunitario y social, en concreto, sobre la cuestión migratoria.

Previous studies attest that early bilinguals can modify their perceptual identification according to the fine-grained phonetic detail of the language they believe they are hearing. Following Gonzales et al. (2019), we replicate the double phonemic boundary effect in late learners (LBs) using conceptual-based cueing. We administered a forced choice identification task to 169 native English adult learners of Spanish in two sessions. In both sessions, participants identified the same /b/-/p/ voicing continuum, but language context was cued conceptually using the instructions. The data were analyzed using Bayesian multilevel regression. Learners categorized the continuum in a similar manner when they believed they were hearing English. However, when they believed they were hearing Spanish, "voiceless" responses increased as a function of L2 proficiency. This research demonstrates the double phonemic boundary effect can be conceptually cued in LBs and supports accounts positing selective activation of independent perception grammars in L2 learning.

Abstract A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound (-)-epicatechin, isolated from Theobroma cacao, effectively inhibited FGFR3’s downstream signaling pathways. Transcriptomic analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3 Y367C/+ ) of ACH, we showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily subcutaneous injections of (-)-epicatechin to Fgfr3 Y367C/+ mice increased bone elongation and rescued the primary cilium defects observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a potential drug for the treatment of ACH.

Summary: Inhibition of the heterodimeric amino acid carrier SLC7A5/SLC3A2 (LAT1/CD98) has been widely studied in tumor biology but its role in physiological conditions remains largely unknown. Here we show that the SLC7A5/SLC3A2 heterodimer is constitutively present at different stages of erythroid differentiation but absent in mature erythrocytes. Administration of erythropoietin (EPO) further induces SLC7A5/SLC3A2 expression in circulating reticulocytes, as it also occurs in anemic conditions. Although Slc7a5 gene inactivation in the erythrocyte lineage does not compromise the total number of circulating red blood cells (RBCs), their size and hemoglobin content are significantly reduced accompanied by a diminished erythroblast mTORC1 activity. Furthermore circulating Slc7a5-deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.

Abstract Patients with morbid obesity frequently present non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) associated with pro-atherogenic alterations. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for weight reduction, and for the remission of hepatic alterations. Using 1H-nuclear magnetic resonance (1H-NMR), we investigated the effects of LSG on lipoprotein and glycoprotein profile in patients with morbid obesity and liver disease. We included 154 patients with morbid obesity (49 non-NASH, 54 uncertain NASH, 51 definite NASH). A blood sample was obtained before surgery and, in patients with definite NASH, one year after surgery. Patients with NASH had increased concentrations of medium and small VLDL particles, VLDL and IDL cholesterol concentrations, IDL, LDL, and HDL triglyceride concentrations, and elevated glycoprotein levels. These changes were more marked in patients with type 2 diabetes mellitus. LSG produced significant decreases in the concentration of VLDL particles, VLDL cholesterol and triglycerides, an increase in the concentration LDL particles and LDL cholesterol concentrations, and a decrease in protein glycation. We conclude that patients with obesity and NASH had significant alterations in circulating levels of lipoproteins and glycoproteins that were associated with the severity of the disease. Most of these changes were reversed post-LSG.

The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug–drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.

The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.

Most cases of invasive aspergillosis are caused by Aspergillus fumigatus, whose conidia are ubiquitous in the environment. Additionally, in indoor environments, such as houses or hospitals, conidia are frequently detected too. Hospital-acquired aspergillosis is usually associated with airborne fungal contamination of the hospital air, especially after building construction events. A. fumigatus strain typing can fulfill many needs both in clinical settings and otherwise. The high incidence of aspergillosis in COVID patients from our hospital, made us wonder if they were hospital-acquired aspergillosis. The purpose of this study was to evaluate whether the hospital environment was the source of aspergillosis infection in CAPA patients, admitted to the Hospital Universitario Central de Asturias, during the first and second wave of the COVID-19 pandemic, or whether it was community-acquired aspergillosis before admission. During 2020, sixty-nine A. fumigatus strains were collected for this study: 59 were clinical isolates from 28 COVID-19 patients, and 10 strains were environmentally isolated from seven hospital rooms and intensive care units. A diagnosis of pulmonary aspergillosis was based on the ECCM/ISHAM criteria. Strains were genotyped by PCR amplification and sequencing of a panel of four hypervariable tandem repeats within exons of surface protein coding genes (TRESPERG). A total of seven genotypes among the 10 environmental strains and 28 genotypes among the 59 clinical strains were identified. Genotyping revealed that only one environmental A. fumigatus from UCI 5 (box 54) isolated in October (30 October 2020) and one A. fumigatus isolated from a COVID-19 patient admitted in Pneumology (Room 532-B) in November (24 November 2020) had the same genotype, but there was a significant difference in time and location. There was also no relationship in time and location between similar A. fumigatus genotypes of patients. The global A. fumigatus, environmental and clinical isolates, showed a wide diversity of genotypes. To our knowledge, this is the first study monitoring and genotyping A. fumigatus isolates obtained from hospital air and COVID-19 patients, admitted with aspergillosis, during one year. Our work shows that patients do not acquire A. fumigatus in the hospital. This proves that COVID-associated aspergillosis in our hospital is not a nosocomial infection, but supports the hypothesis of “community aspergillosis” acquisition outside the hospital, having the home environment (pandemic period at home) as the main suspected focus of infection.

Recently, the relationship between nutrients and health is becoming since natural dietary products as polyphenols are being considered by their potential for the management of several diseases. We aimed to investigate the capacity of Lippia citriodora compounds to modulate AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model. HPLC semi-preparative purification method and reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) were used to obtain de compounds from L. citriodora extract. AMPK activity was measured on the hypertrophic 3T3-L1 adipocyte model by immunofluorescence microscopy. Four compounds of 29 total compounds have been tentatively identified in L. citriodora for the first time by HPLC-ESI-TOF-MS. Phenylpropanoids (verbascoside), iridoids (gardoside) and flavonoids (luteolin-7-diglucoronide) were the best candidates to account for activating AMPK capacity. The combination of specific polyphenols from L. citriodora, which showed strong activating AMPK capacity, could be an alternative in the management of obesity-associated diseases.

The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss. In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma. To assess the effect of surgically induced weight loss, we requested paired plasma samples from 44 patients undergoing laparoscopic sleeve gastrectomy one year after the procedure. Oxylipins were measured using ultra-high-pressure liquid chromatography coupled to a triple quadrupole mass spectrometer via semi-targeted lipidomics. Cytokines and markers of interorgan crosstalk were measured using enzyme-linked immunosorbent assays. We observed significantly elevated levels of circulating fatty acids and oxylipins in patients with severe obesity compared to their metabolically healthier overweight/obese counterparts. Our findings indicated that sex and liver disease were not confounding factors, but we observed weak correlations in plasma with circulating adipokines, suggesting the influence of adipose tissue. Importantly, while weight loss restored the balance in circulating fatty acids, it did not fully normalize the oxylipin profile. Before surgery, oxylipins derived from lipoxygenase activity, such as 12-HETE, 11-HDoHE, 14-HDoHE, and 12-HEPE, were predominant. However, one year following laparoscopic sleeve gastrectomy, we observed a complex shift in the oxylipin profile, favoring species from the cyclooxygenase pathway, particularly proinflammatory prostanoids like TXB2, PGE2, PGD2, and 12-HHTrE. This transformation appears to be linked to a reduction in adiposity, underscoring the role of lipid turnover in the development of metabolic disorders associated with severe obesity. Despite the reduction in fatty acid levels associated with weight loss, the oxylipin profile shifts towards a predominance of more proinflammatory species. These observations underscore the significance of seeking mechanistic approaches to address severe obesity and emphasize the importance of closely monitoring the metabolic adaptations after weight loss. [ABSTRACT FROM AUTHOR]

El artículo propone una tipología de áreas de mercado turístico a partir del análisis de la accesibilidad a los principales activos turísticos de Castilla-La Mancha. El objetivo es profundizar en la búsqueda de explicaciones lógicas sobre el impacto que tiene la accesibilidad en el desarrollo turístico de los territorios. Especialmente en áreas rurales donde la dotación diferencial de infraestructuras de transporte ha generado desequilibrios notables. Su comprensión, desde la lógica estructural origen-enlace-destino que adoptan muchos de los sistemas territoriales, supone un avance en el complejo proceso de planificación territorial del turismo. Los resultados obtenidos y trasladados a la escala supramunicipal ponen de relieve potencialidades y desventajas a considerar en las estrategias de los espacios rurales.

Este trabajo pone en conexión el patrimonio natural con la red de itinerarios nacionales del Programa Caminos Naturales , en los que se integran las popularmente conocidas Vías Verdes , manteniendo un enfoque territorial adecuado para destacar el potenc ial de esta infraestructura al posibilitar el acceso al ocio y la recreación en extensas zonas rurales y naturales, a la vez que evidenciamos su escasa valoración y desuso para fines turísticos. El objetivo es poner en valor estos itinerarios en rela ción con el patrimonio territorial, a nivel regional, utilizándolos como iniciativa vehicular para la dinamización turística de los espacios rurales. De este modo, proponemos la definición de un producto de ecoturismo tomando como caso los Caminos Naturale s del Tajo y del Guadiana en Castilla - La Mancha. La metodología aplicada se basa en el uso de los S istemas de Información Geográfica (SIG) como herramienta de análisis, posibilitando la integración de variables de interés en la planificación territori al del turismo , así como la mejor comunicabilidad de los resultados. Concluimos destacando las ventajas de adoptar una visión geográfica capaz de dotar de territorialidad a la oferta turística, así como de coordinar su articulación bajo un marco de des arrollo sostenible e integral, a escala comarcal, en torno a una infraestructura útil para la cohesión territorial.

En el presente artículo aportamos una visión práctica del uso de las hipótesis de transición dentro del ámbito de la Educación Ambiental. Concreta mente ejemplificamos la utilidad de esta herramienta didáctica al desarrollar su uso en el ámbito de la Educación Ambi ental dentro de la temática del agua . Las hipótesis de transición permiten dar coherencia al tratamiento de los problemas socioambie ntales asociados, facilita el manejo de los contenidos, así como la inclusión de las ideas y concepciones de los participantes.

La resolución de problemas matemáticos provoca frustración en los alumnos y preocupación en los docentes debido a su complejidad y dificultad. Se constata la necesidad de llevar a cabo un cambio metodológico que solvente esas dificultades.En este trabajo presentamos una metodología aplicada en el aula para dar respuesta a esas dificultades y mejorar el rendimiento de nuestros alumnos en este ámbito de las matemáticas.Planteamos un estudio relacionando las dificultades que tienen los alumnos en el lenguaje, dificultades como la comprensión lectora, la verbalización del problema, la identificación de los datos relevantes, la identificación de la pregunta y la expresión de la solución, y su repercusión en la resolución de problemas.La metodología que se presenta consta de una parte de desarrollo de competencia lingüística, donde se trabaja la comprensión del lenguaje y el razonamiento lingüístico, y otra parte matemática formada por cinco fases: completar problemas, inventar la pregunta a un enunciado dado, inventar enunciados, inventar problemas y resolver problemas.Posteriormente a la aplicación metodológica se lleva a cabo un estudio estadístico en un curso de tercero de Educación Primaria del ceip Romero Peña de La Solana (Ciudad Real), con un grupo experimental, al cual se le ha aplicado la metodología propuesta, y un grupo de control, que ha seguido la metodología tradicional usando su libro de texto. El análisis estadístico revela que las dificultades en la resolución de problemas matemáticos disminuyen notablemente tras la aplicación de la metodología planteada, constatando que el tratamiento de las dificultades del lenguaje repercute positivamente en la resolución de problemas matemáticos.

Hepatic biopsy is the gold standard for staging nonalcoholic fatty liver disease (NAFLD). Unfortunately, accessing the liver is invasive, requires a multidisciplinary team and is too expensive to be conducted on large segments of the population. NAFLD starts quietly and can progress until liver damage is irreversible. Given this complex situation, the search for noninvasive alternatives is clinically important. A hallmark of NAFLD progression is the dysregulation in lipid metabolism. In this context, recent advances in the area of machine learning have increased the interest in evaluating whether multi-omics data analysis performed on peripheral blood can enhance human interpretation. In the present review, we show how the use of machine learning can identify sets of lipids as predictive biomarkers of NAFLD progression. This approach could potentially help clinicians to improve the diagnosis accuracy and predict the future risk of the disease. While NAFLD has no effective treatment yet, the key to slowing the progression of the disease may lie in predictive robust biomarkers. Hence, to detect this disease as soon as possible, the use of computational science can help us to make a more accurate and reliable diagnosis. We aimed to provide a general overview for all readers interested in implementing these methods.

By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the “energy barriers” separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells.

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.

Introducción: El acceso vascular supone un pilar fundamental en el tratamiento dialítico de los pacientes renales. El empleo de catéteres se ha incrementado en los últimos años. Caso clínico: Varón de 49 años que inició tratamiento de hemodiálisis a sus 32 años. Presentó 7 accesos registrados (tiempo medio de uso: 64 días) hasta el primer trasplante y otros 15 accesos (tiempo medio de uso: 162 días) y 11 infecciones por el germen Staphylococcus Epidermidis, hasta recibir el segundo trasplante, que perdió a los 5 días por infarto renal isquémico masivo, volviendo a hemodiálisis con la colocación de un catéter venoso central tunelizado femoral izquierdo, que dura hasta la actualidad sin complicaciones destacables, gracias al diagnóstico posterior de la mutación heterocigótica del factor V de Leiden (que provoca un trastorno de hipercoagulabilidad), comenzando anticoagulación oral con acenocumarol de forma domiciliaria y heparina de bajo peso molecular intradiálisis desde ese momento. Discusión: Tras comenzar el sellado del catéter con Citrato + Heparina sódica (inicialmente incluía también Taurolidina pero se eliminó debido a intolerancia), no presentó más infecciones. Debido al diagnóstico de la mutación heterocigótica del factor V de Leiden, nos planteamos la posibilidad de que los fracasos de los accesos anteriores sean debidos al desconocimiento de esta mutación. Ante la situación demográfica de España se pone de manifiesto la necesidad de equipos multidisciplinares más amplios e incluir un control y seguimiento del acceso tunelizado para reducir sus pérdidas y evitar situaciones altamente invasivas.

Peripheral artery disease (PAD) is a common disease affecting 20–25% of population over 60 years old. Early diagnosis is difficult because symptoms only become evident in advanced stages of the disease. Inflammation, impaired metabolism, and mitochondrial dysfunction predispose to PAD, which is normally associated with other highly prevalent and related conditions, such as diabetes, dyslipidemia, and hypertension. We have measured energy-balance-associated metabolite concentrations in the plasma of PAD patients segregated by the severity of the disease and in plasma of healthy volunteers using a quantitative and targeted metabolomic approach. We found relevant associations between several metabolites (3-hydroxybutirate, aconitate, (iso)citrate, glutamate, and serine) with markers of oxidative stress and inflammation. Metabolomic profiling also revealed that (iso)citrate and glutamate are metabolites with high ability to discriminate between healthy participants and PAD patients without symptoms. Collectively, our data suggest that metabolomics provide significant information on the pathogenesis of PAD and useful biomarkers for the diagnosis and assessment of progression.

The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy.

Background: Imbalances in the functional binding of fibroblast growth factors (FGFs) to their receptors (FGFRs) have consequences for cell proliferation and differentiation that in chondrocytes may lead to degraded cartilage. The toxic, proinflammatory, and oxidative response of cytokines and FGFs can be mitigated by dietary polyphenols. Objective: We explored the possible effects of polyphenols in the management of osteoarticular diseases using a model based on the transduction of a mutated human FGFR3 (G380R) in murine chondrocytes. This mutation is present in most cases of skeletal dysplasia and is responsible for the overexpression of FGFR3 that, in the presence of its ligand, FGF9, results in toxic effects leading to altered cellular growth. Design: Different combinations of dietary polyphenols derived from plant extracts were assayed in FGFR3 (G380R) mutated murine chondrocytes, exploring cell survival, chloride efflux, extracellular matrix (ECM) generation, and grade of activation of mitogen-activated protein kinases. Results: Bioactive compounds from Hibiscus sabdariffa reversed the toxic effects of FGF9 and restored normal growth, suggesting a probable translation to clinical requests in humans. Indeed, these compounds activated the intracellular chloride efflux, increased ECM generation, and stimulated cell proliferation. The inhibition of mitogen-activated protein kinase phosphorylation was interpreted as the main mechanism governing these beneficial effects. Conclusions: These findings support the rationale behind the encouragement of the development of drugs that repress the overexpression of FGFRs and suggest the dietary incorporation of supplementary nutrients in the management of degraded cartilage.

En este trabajo se describe y analiza el cambio en las concepciones sobre la evaluación en Ciencias de la Naturaleza que experimentan estudiantes del Grado de Maestro de Educación Primaria en la Universidad de Sevilla, que participaron en un curso de formación inicial para aprender a enseñar ciencias en Primaria. Los 347 participantes se organizaron en 92 equipos distribuidos en cinco aulas dirigidas por cinco formadores distintos que compartían el mismo programa formativo. Se analizan las producciones escritas de evaluación elaboradas por estos equipos al inicio y al final del curso. Los resultados revelan que, mayoritariamente, hay un cambio en su conocimiento de la evaluación en las tres categorías estudiadas (sentido, instrumentos y contenido de la evaluación), aunque no se logra un predominio del enfoque formativo de la misma. Describimos los diferentes niveles de progresión sobre la evaluación que pueden servir de referencia en la formación inicial.

Paraoxonase-1 (PON1) is an intra-cellular antioxidant enzyme found also in the circulation associated with high-density lipoproteins. The activity of this enzyme has been shown to be decreased in breast cancer (BC) patients. The aims of our study were to investigate the changes produced by radiotherapy (RT) on activity and concentration of serum PON1 in BC patients, and to evaluate the observed variations in relation to clinical and pathological characteristics of patients and tumors, and the response to treatment. We studied 200 women with BC who were scheduled to receive RT following excision of the tumor. Blood for analyses was obtained before and after the irradiation procedure. The control group was composed of 200 healthy women. Relative to control, BC patients had significantly lower serum PON1 activities pre-RT, while PON1 concentrations were at similar levels. RT was associated with a significant increase in serum PON1 activities and concentrations. We observed significant differences in serum PON1 concentrations post-RT between patients with luminal A or luminal B tumors. Serum PON1 concentration post-RT was markedly lower in BC patients with metastases. We conclude that benefit from RT accrues to the BC patients not only through its direct effect on cancer cells but also indirectly by improving the organism's anti-oxidant defense mechanisms. In addition, our preliminary evidence suggests that the measurement of serum PON1 concentration post-RT could be an efficient prognostic biomarker, and may be used as an index of the efficacy of the RT.

En el present article hem realitzat un estudi que abordi els aspectes teòrics i pràctics relacionats amb les hipòtesis de transició dins l'àmbit de l'educació ambiental. Per això exposem l'evolució seguida fins arribar al propi concepte d'hipòtesis de transició, tant en la nomenclatura utilitzada com en el significat intern d'aquests termes. A més exemplifiquem la utilitat d'aquesta eina didàctica al desenvolupar el seu possible ús en l'àmbit de l'Educació Ambiental dins de la temàtica de l'energia i de l'aigua.

The consumption of polyphenols has frequently been associated with low incidence of degenerative diseases. Most of these natural antioxidants come from fruits, vegetables, spices, grains and herbs. For this reason, there has been increasing interest in identifying plant extract compounds. Polymeric tannins and monomeric flavonoids, such as catechin and epicatechin, in pine bark and green tea extracts could be responsible for the higher antioxidant activities of these extracts. The aim of the present study was to characterize the phenolic compounds in pine bark and green tea concentrated extracts using high-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC–ESI-QTOF-MS). A total of 37 and 35 compounds from pine bark and green tea extracts, respectively, were identified as belonging to various structural classes, mainly flavan-3-ol and its derivatives (including procyanidins). The antioxidant capacity of both extracts was evaluated by three complementary antioxidant activity methods: Trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC). Higher antioxidant activity values by each method were obtained. In addition, total polyphenol and flavan-3-ol contents, which were determined by Folin–Ciocalteu and vanillin assays, respectively, exhibited higher amounts of gallic acid and (+)-catechin equivalents.

Cocoa (Theobroma cacao) is a major, economically important, international crop and has been associated with several nutritional benefits including high antioxidant capacity. The aim of the present study was to isolate, characterize and quantify phenolic compounds of T. cacao extract using HPLC-MSESI-QTOF. A total of 61 compounds were identified and quantified in the T. cacao extract and fractions belonging to various structural classes such as flavan-3-ol and derivatives (including procyanidins), flavonols, N-phenylpropenoyl-L-amino acids, and other compounds. These compounds were isolated by semi-preparative HPLC. Afterwards, the composition of each fraction was established by the detailed HPLC-DAD and HPLC-MSESI-QTOF method. The relationship between the chemical structure of flavonoids and their radical-scavenging activities was analyzed. In addition, T. cacao extract and fractions show antioxidant activity (by TEAC, FRAP and ORAC methods) decreasing the generation of reactive oxygen species.

En condiciones fisiológicas el abdomen actúa como una cavidad cerrada cuya presión aumenta de forma proporcional al volumen que contiene. El valor normal de la presión hidrostática intraperitoneal está alrededor de 0 y en pacientes en diálisis peritoneal con volúmenes intraperitoneales de 2 litros puede estar en torno a 12±2 cmH2O. Realizamos un estudio multicéntrico cuantitativo, descriptivo, longitudinal y prospectivo, que incluía a 42 pacientes en programa de diálisis peritoneal con el fin de examinar la presión intraperitoneal y la ultrafiltración conseguida al infundir diferentes volúmenes de líquido de diálisis. Se hicieron dos intercambios consecutivos el primero con 2500 ml y el segundo con 1500 ml con líquido de diálisis con glucosa 2,3% y permanencia de 120 minutos en cada intercambio. De los 42 pacientes el 71,5% eran hombres, con una edad de 59.31±12.23 años y con un índice de masa corporal de 27.01±4.46. La presión intraperitoneal con volumen intraperitoneal 0 fue de 8.2±4.1; con volumen intraperitoneal 2500 ml la presión fue de 13.8±4.4 y la ultrafiltración de 131±206; con volumen intraperitoneal de 1500 ml la presión fue de 11.2±4.2 y la ultrafiltración de 192±145. La ultrafiltración con respecto a la infusión fue del 5,2%±8,2% con volumen de 2500 ml y del 12,8%±9,6% con volumen de 1500 ml. Podemos describir un aumento de la presión intraperitoneal al aumentar el volumen intraperitoneal, al mismo tiempo hemos observado una mayor ultrafiltración con volúmenes más bajos que implicaban a su vez cifras menores de presión.

Postprandial lipemia can lead to an accumulation of atherogenic lipoproteins in the circulation associated with systemic low-grade inflammation and an increased risk of cardiovascular disease. Lifestyle and pharmacological treatments are usually prescribed for prevention. Vitamin D3 (cholecalciferol), as an anti-atherogenic agent, is being taken into consideration due to its potential beneficial effects in lipid metabolism and its anti-inflammatory potency. To assess the effects of vitamin D3 in the postprandial lipid profile in obese, vitamin D-deficient women, a non-targeted lipidomics approach using liquid chromatography coupled to a quadrupole time-of flight mass spectrometer was used to identify and quantitate a wide-range of circulating lipid species, including diglycerides, lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The most important changes were found in plasmatic sphingomyelin levels, which experience a decrease after vitamin D3 intake. Our results suggest a turnover of sphingomyelins, probably due to an increased activity of neutral sphingomyelinases, and, therefore, with implications in the clearance of chylomicrons, LDL and VLDL, decreasing postprandial inflammation and macrophage adherence to endothelia, potentially improving cardiovascular disease risk.

En el presente artículo se aborda el problema de conocer los procesos de construcción del conocimiento significativo en alumnos y alumnas de 1º de Bachillerato de un centro de secundaria de la ciudad de Sevilla en relación con la temática del agua. Para ello se realizó una experiencia educativa durante tres meses donde se aplicó una programación didáctica cuyos principios básicos fueron: la perspectiva constructivista del aprendizaje, la perspectiva epistemológica de la complejidad y la investigación del alumnado. Dentro del proceso de construcción del conocimiento se realizó un especial esfuerzo en identificar cuáles eran las transiciones más dificultosas para el alumnado dentro del sistema de cuatro categorías propuesto.

O artigo traz reflexões sobre o legado das seis primeiras e o futuro das conferências especializadas sobre o Direito Internacional Privado no âmbito da Organização dos Estados Americanos. Sugere que os países latino-americanos, que são a maioria na OEA, podem aproveitar este foro, que tem servido para modernizar seus sistemas de DIPr, parabuscar denominadores comuns em cada um dos distintos setores do DIPr. Ressaltando que o dia que a integração latino-americana chegar nos encontrará com os mecanismos jurídicos já preparados. Estabelecendo mecanismos práticos a fim de fixar posições comuns paradentro e para fora da Organização.

Prevention of the metabolic consequences of a chronic energy-dense/high-fat diet (HFD) represents a public health priority. Metformin is a strong candidate to be incorporated in alternative therapeutic approaches. We used a targeted metabolomic approach to assess changes related to the multi-faceted metabolic disturbances provoked by HFD. We evaluated the protective effects of metformin and explored how pro-inflammatory and metabolic changes respond when mice rendered obese, glucose-intolerant and hyperlipidemic were switched to diet reversal with or without metformin. Mice treated with metformin and diet-reversal showed a dramatically improved protection against HFD-induced hepatic steatosis, a beneficial effect that was accompanied by a lowering of liver-infiltrating pro-inflammatory macrophages and lower release of pro-inflammatory cytokines. Metformin combined with diet reversal promoted effective weight loss along with better glucose control, lowered levels of circulating cholesterol and triglycerides, and reduced adipose tissue content. Our findings underscored the ability of metformin to target the contribution of branched chain amino acids to adipose tissue metabolism while suppressing mitochondrial-dependent biosynthesis in hepatic tissue. The relationship between adipose tissue and liver might provide clinical potential for combining metformin and dietary modifications to protect against the metabolic damage occurring upon excessive dietary fat intake.