Transcriptome-wide expression profiling in skin fibroblasts of patients with joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type

Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients

Gamma-spectrometric measurement of radioactivity in agricultural soils of the Lombardia region, northern Italy

Abstract This work is part of a wider monitoring project of the agricultural soils in Lombardia, which aims to build a database of topsoil properties and the potentially toxic elements, organic pollutants and gamma emitting radionuclides that the topsoils contain. A total of 156 agricultural soils were sampled according to the LUCAS (Land Use/Cover Area frame statistical Survey) standard procedure. The aim was to provide a baseline to document the conditions present at the time of sampling. The results of the project concerning soil radioactivity are presented here. The aim was to assess the content of 238U, 232Th, 137Cs and 40K by measuring soil samples by gamma spectrometry. 238U, 232Th and 40K activities range 24–231, 20–70, and 242–1434 Bq kg−1 respectively. The geographic distribution of 238U reflects the geophysical framework of the Lombardia region: the soils with high content of uranium are distributed for the most part in the South Alpine belt, where the presence of magmatic rocks is widespread. These soils show an higher activity of 238U than of 232Th. The 238U activities become lower than 232Th when soils are located in the plain, originating from basic sedimentary rocks. 137Cs activity ranges 0.4–86.8 kBq m−2. The lowest activity of 137Cs is in the plain, whereas the highest is in the North on soils kept as lawn or pasture. The 137Cs activity of some samples suggests the presence of accumulation processes that lead to 137Cs enriched soils. This is the first survey of gamma emitting radionuclides in Lombardia that is based on the LUCAS standard sampling. The results from this monitoring campaign are important for the human radiation exposure and provide the zero point, which will be useful for assessing future effects due to external factors such as human activities

Autonomous metabolic reprogramming and oxidative stress characterize endothelial dysfunction in acute myocardial infarction

Background: Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction underlying acute coronary syndrome. However, unveiling the underlying metabolic determinants has been hampered by the scarcity of appropriate cell models to address cell-autonomous mechanisms of ED dysfunction. Methods: We have generated endothelial cells derived from thrombectomy specimens from patients affected with acute myocardial infarction (AMI) and conducted phenotypical and metabolic characterization, focused on central carbon metabolism. Results: AMI-derived endothelial cells (AMIECs), but not control healthy coronary endothelial cells, display impaired growth, migration and tubulogenesis. Metabolically, AMIECs displayed augmented reactive oxygen species (ROS) and glutathione intracellular content, along with a diminished glucose consumption coupled to high lactate production. Consistent with diminished glycolysis in AMIECs, the protein levels of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase type 3, PFKFB3, were downregulated. In contrast, PFKFB4 levels were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway (PPP), supported by upregulation in AMIECs of G6PD, the key enzyme in the oxidative branch of the PPP. Further, the glutaminolytic enzyme GLS was upregulated in AMIECs, providing a mechanistic explanation for the observed increase in glutathione content. Finally, AMIECs displayed a significantly higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggest a highly coupled mitochondrial activity in patient ECs. Conclusions: We suggest high mitochondrial proton coupling underlies the abnormally high production of ROS, balanced by PPP- and glutaminolysis-driven synthesis of glutathione, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI. Funding: European Commission Horizon 2020; CIBER- Carlos III National Institute of Health, Spain; Ministerio de Economia y Competitividad (MINECO) and Ministerio de Ciencia e Innovación, Spain; Generalitat de Catalunya-AGAUR, Catalonia; Plataforma Temática Interdisciplinar Salud Global (PTI-SG), Spain; British Heart Foundation, UK. </p

repeat assessed values model for housing price index

Abstract This study proposes an innovative methodology, named Repeat Appraised Price Model (RAV), useful for determining the price index numbers for real estate markets and the corresponding index numbers of hedonic prices of main real estate characteristics in the case of a lack of data. The methodological approach proposed in this paper aims to appraise the time series of price index numbers. It integrates the principles of the method of repeat sales with the peculiarities of the Hedonic Price Method, overcoming the problem of an almost total absence of repeat sales for the same property in a given time range; on the other hand, the technique aims to overcome the limitation of the repeat sales technique concerning the inability to take into account the characteristics of individual properties

Protein network analyses of pulmonary endothelial cells in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a vascular disease characterized by the presence of organized thromboembolic material in pulmonary arteries leading to increased vascular resistance, heart failure and death. Dysfunction of endothelial cells is involved in CTEPH. The present study describes for the first time the molecular processes underlying endothelial dysfunction in the development of the CTEPH. The advanced analytical approach and the protein network analyses of patient derived CTEPH endothelial cells allowed the quantitation of 3258 proteins. The 673 differentially regulated proteins were associated with functional and disease protein network modules. The protein network analyses resulted in the characterization of dysregulated pathways associated with endothelial dysfunction, such as mitochondrial dysfunction, oxidative phosphorylation, sirtuin signaling, inflammatory response, oxidative stress and fatty acid metabolism related pathways. In addition, the quantification of advanced oxidation protein products, total protein carbonyl content, and intracellular reactive oxygen species resulted increased attesting the dysregulation of oxidative stress response. In conclusion this is the first quantitative study to highlight the involvement of endothelial dysfunction in CTEPH using patient samples and by network medicine approach

Metabolic alterations in cardiopulmonary vascular dysfunction

Cardiovascular diseases (CVD) are the leading cause of death worldwide. CVD comprise a range of diseases affecting the functionality of the heart and blood vessels, including acute myocardial infarction (AMI) and pulmonary hypertension (PH). Despite their different causative mechanisms, both AMI and PH involve narrowed or blocked blood vessels, hypoxia, and tissue infarction. The endothelium plays a pivotal role in the development of CVD. Disruption of the normal homeostasis of endothelia, alterations in the blood vessel structure, and abnormal functionality are essential factors in the onset and progression of both AMI and PH. An emerging theory proposes that pathological blood vessel responses and endothelial dysfunction develop as a result of an abnormal endothelial metabolism. It has been suggested that, in CVD, endothelial cell metabolism switches to higher glycolysis, rather than oxidative phosphorylation, as the main source of ATP, a process designated as the Warburg effect. The evidence of these alterations suggests that understanding endothelial metabolism and mitochondrial function may be central to unveiling fundamental mechanisms underlying cardiovascular pathogenesis and to identifying novel critical metabolic biomarkers and therapeutic targets. Here, we review the role of the endothelium in the regulation of vascular homeostasis and we detail key aspects of endothelial cell metabolism. We also describe recent findings concerning metabolic endothelial cell alterations in acute myocardial infarction and pulmonary hypertension, their relationship with disease pathogenesis and we discuss the future potential of pharmacological modulation of cellular metabolism in the treatment of cardiopulmonary vascular dysfunction. Although targeting endothelial cell metabolism is still in its infancy, it is a promising strategy to restore normal endothelial functions and thus forestall or revert the development of CVD in personalized multi-hit interventions at the metabolic level

Teoría política posfundacional. Presupuestos, métodos, apuestas

Las notas que presentamos a continuación sintetizan el trabajo de una comunidad abierta que ha intentado hacer de la política un lugar de pensamiento. Notas preliminares de una indagación inacabada que buscan precisar las dificultadescon las que nos hemos encontrado a lo largo de varios años. Al mismo tiempo, presentamos ciertos resultados provisorios, ciertas respuestas que hemos encontrado para tratar de definir una aproximación singular a la política; especificando los presupuestos, los métodos y las apuestas que constituyen una perspectiva específica.Fil: Biset, Emmanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: Martínez, Natalia María. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; ArgentinaFil: Soria, Ana Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: Aznarez Carini, Gala. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: Lorio, Natalia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Humanidades. Universidad Nacional de Córdoba. Instituto de Humanidades; ArgentinaFil: Moyano, Manuel Ignacio. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; ArgentinaFil: Llao, Marina Ivana. Universidad Nacional de Córdoba; ArgentinaFil: Romero, María Aurora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: Salamanca Agudelo, Katherine. Universidad Nacional de Córdoba. Centro de Estudios Avanzados; ArgentinaFil: Sosa, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: Vargas, Maria de Las Mercedes. Universidad Nacional de Santiago del Estero; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Farrán, Roque. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; Argentin

GLUT10-Lacking in Arterial Tortuosity Syndrome-Is Localized to the Endoplasmic Reticulum of Human Fibroblasts.

GLUT10 belongs to a family of transporters that catalyze the uptake of sugars/polyols by facilitated diffusion. Loss-of-function mutations in the SLC2A10 gene encoding GLUT10 are responsible for arterial tortuosity syndrome (ATS). Since subcellular distribution of the transporter is dubious, we aimed to clarify the localization of GLUT10. In silico GLUT10 localization prediction suggested its presence in the endoplasmic reticulum (ER). Immunoblotting showed the presence of GLUT10 protein in the microsomal, but not in mitochondrial fractions of human fibroblasts and liver tissue. An even cytosolic distribution with an intense perinuclear decoration of GLUT10 was demonstrated by immunofluorescence in human fibroblasts, whilst mitochondrial markers revealed a fully different decoration pattern. GLUT10 decoration was fully absent in fibroblasts from three ATS patients. Expression of exogenous, tagged GLUT10 in fibroblasts from an ATS patient revealed a strict co-localization with the ER marker protein disulfide isomerase (PDI). The results demonstrate that GLUT10 is present in the ER

Metabolic Alterations in Cardiopulmonary Vascular Dysfunction

Cardiovascular diseases (CVD) are the leading cause of death worldwide. CVD comprise a range of diseases affecting the functionality of the heart and blood vessels, including acute myocardial infarction (AMI) and pulmonary hypertension (PH). Despite their different causative mechanisms, both AMI and PH involve narrowed or blocked blood vessels, hypoxia, and tissue infarction. The endothelium plays a pivotal role in the development of CVD. Disruption of the normal homeostasis of endothelia, alterations in the blood vessel structure, and abnormal functionality are essential factors in the onset and progression of both AMI and PH. An emerging theory proposes that pathological blood vessel responses and endothelial dysfunction develop as a result of an abnormal endothelial metabolism. It has been suggested that, in CVD, endothelial cell metabolism switches to higher glycolysis, rather than oxidative phosphorylation, as the main source of ATP, a process designated as the Warburg effect. The evidence of these alterations suggests that understanding endothelial metabolism and mitochondrial function may be central to unveiling fundamental mechanisms underlying cardiovascular pathogenesis and to identifying novel critical metabolic biomarkers and therapeutic targets. Here, we review the role of the endothelium in the regulation of vascular homeostasis and we detail key aspects of endothelial cell metabolism. We also describe recent findings concerning metabolic endothelial cell alterations in acute myocardial infarction and pulmonary hypertension, their relationship with disease pathogenesis and we discuss the future potential of pharmacological modulation of cellular metabolism in the treatment of cardiopulmonary vascular dysfunction. Although targeting endothelial cell metabolism is still in its infancy, it is a promising strategy to restore normal endothelial functions and thus forestall or revert the development of CVD in personalized multi-hit interventions at the metabolic level