MicroRNA133 and microRNA499 exert synergistic effect on cardiac differentiation

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Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-κB activation.

Background: After myocardial infarction, necrotic cardiomyocytes release damage-associated proteins that stimulate innate immune pathways and macrophage tissue infiltration, which drives inflammation and myocardial remodeling. Circulating inflammatory extracellular vesicles play a crucial role in the acute and chronic phases of ischemia, in terms of inflammatory progression. In this study, we hypothesize that the paracrine effect mediated by these vesicles induces direct cytotoxicity in cardiomyocytes. Thus, we examined whether reducing the generation of inflammatory vesicles within the first few hours after the ischemic event ameliorates cardiac outcome at short and long time points. Methods: Myocardial infarction was induced in rats that were previously injected intraperitoneally with a chemical inhibitor of extracellular-vesicle biogenesis. Heart global function was assessed by echocardiography performed at 7, 14 and 28 days after MI. Cardiac outcome was also evaluated by hemodynamic analysis at sacrifice. Cytotoxic effects of circulating EV were evaluated ex-vivo in a Langendorff, system by measuring the level of cardiac troponin I (cTnI) in the perfusate. Mechanisms undergoing cytotoxic effects of EV derived from pro-inflammatory macrophages (M1) were studied in-vitro in primary rat neonatal cardiomyocytes. Results: Inflammatory response following myocardial infarction dramatically increased the number of circulating extracellular vesicles carrying alarmins such as IL-1α, IL-1β and Rantes. Reducing the boost in inflammatory vesicles during the acute phase of ischemia resulted in preserved left ventricular ejection fraction in vivo. Hemodynamic analysis confirmed functional recovery by displaying higher velocity of left ventricular relaxation and improved contractility. When added to the perfusate of isolated hearts, post-infarction circulating vesicles induced significantly more cell death in adult cardiomyocytes, as assessed by cTnI release, comparing to circulating vesicles isolated from healthy (non-infarcted) rats. In vitro inflammatory extracellular vesicles induce cell death by driving nuclear translocation of NF-κB into nuclei of cardiomyocytes. Conclusion: Our data suggest that targeting circulating extracellular vesicles during the acute phase of myocardial infarction may offer an effective therapeutic approach to preserve function of ischemic heart

Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration.

Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of Exo <sup>CXCR4</sup> significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to Exo <sup>CTRL</sup> (p < 0.01). Hemodynamic measurements showed that Exo <sup>CXCR4</sup> improved dp/dt min, as compared to Exo <sup>CTRL</sup> and PBS group. In vitro, Exo <sup>CXCR4</sup> was more bioactive than Exo <sup>CTRL</sup> in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease

Chronic productive cough in young adults is very often due to chronic rhino-sinusitis

Background. Chronic productive cough is a common clinical problem; often potential causes outside the lower respiratory tract are forgotten or ignored. The aim of this study was to make a precise etiopathogenetic diagnosis of chronic productive cough in young adults. Methods. In a clinical setting, 212 subjects (mean age 41±5 years) who had reported chronic productive cough in a previous postal survey of a young adult population underwent within two years clinical and functional investigations following a rational diagnostic approach. Two pulmonologists independently established the diagnosis using a clinically structured interview on nasal and respiratory symptoms, spirometry and other tests when appropriate (bronchodilator test or methacholine bronchial challenge, chest radiography); if rhino-sinusitis was suspected, subjects underwent an ENT examination with nasal endoscopy and/or sinus computed tomography. Results. At the end of the diagnostic procedure, 87 subjects (41%) no longer had chronic productive cough and had normal function. Fifty-eight subjects (27%) had chronic rhino-sinusitis; seventeen subjects (8%) had asthma, and of these fourteen also had chronic rhino-sinusitis; 50 subjects (24%) had COPD stage 0+, of these seven also had chronic rhino-sinusitis. Chronic rhino-sinusitis was more frequent in females than in males (p<0.05). Conclusions. Both in clinical practice and in epidemiological studies, it is important to consider that the origin of chronic productive cough could be frequently outside the lower respiratory tract; a consistent percentage of young adults with persistent productive cough has indeed chronic rhino-sinusitis

Conditioned Medium From Human Amniotic Mesenchymal Stromal Cells Limits Infarct Size and Enhances Angiogenesis

The paracrine properties of human amniotic membrane-derived mesenchymal stromal cells (hAMCs) have not been fully elucidated. The goal of the present study was to elucidate whether hAMCs can exert beneficial paracrine effects on infarcted rat hearts, in particular through cardioprotection and angiogenesis. Moreover, we aimed to identify the putative active paracrine mediators. hAMCs were isolated, expanded, and characterized. In vitro, conditioned medium from hAMC (hAMC-CM) exhibited cytoprotective and proangiogenic properties. In vivo, injection of hAMC-CM into infarcted rat hearts limited the infarct size, reduced cardiomyocyte apoptosis and ventricular remodeling, and strongly promoted capillary formation at the infarct border zone. Gene array analysis led to the identification of 32 genes encoding for the secreted factors overexpressed by hAMCs. Among these, midkine and secreted protein acidic and rich in cysteine were also upregulated at the protein level. Furthermore, high amounts of several proangiogenic factors were detected in hAMC-CM by cytokine array. Our results strongly support the concept that the administration of hAMC-CM favors the repair process after acute myocardial infarction

A Ks-band-selected catalogue of objects in the ALHAMBRA survey

Large scale structure and cosmolog

Cooking pots, tableware, and the changing sounds of sociability in Italy, 1300–1700

This article considers how the sounds produced by the preparation and consumption of meals in Italy changed between around 1300 and 1700. It argues that by focusing on sound, and by using ecological approaches, we can rediscover obscured connections between different categories of material objects. By examining material and textual evidence for three categories of objects associated with cooking and dining – metalwork, ceramics, and glass – the article traces changes in the material cultures of kitchen and table, and the clear impact these changes had on domestic soundscapes. It considers these sound-producing objects as agents of social interaction, exploring the social relationships they constructed, and the role sound played in those relationships. The article then focuses on the practices of cooking and dining, and the way they shaped the sound of objects. Finally, the article situates objects and social practices within the spatial context of the home, tracing an increasing impetus to manage and control specific types of sound in relation to gender. In the discourse on hospitality, noise came to signify a badly-managed, and therefore morally dubious, household, while silence testified to decorous and authoritative domestic management

SEISMIC DESIGN AND EXPERIMENTAL INVESTIGATION OF A NEW TIMBER HOLD-DOWN CONNECTION

Timber connections made with hold-down are usually adopted for timber wall to foundation connection at the edges of the wall to restraint the possible overturning moment (due to rocking) which can occur by applying a horizontal force to the panel (e.g. under seismic action). The main components of the connection are the steel plate fastened to the panel via threaded screws or nails and the anchor system to the concrete foundation. As such, the connection behavior under seismic loading is characterized by the contemporarily contribution of different resistant mechanisms, i.e. (i) laterally loaded timber screws or nails; (ii) axially loaded steel plate; (iii) axially loaded anchor in concrete. The former has been basically neglected in past investigations having anchored the hold-down with steel bolt directly to the strong floor. However, the design of the anchor should be considered as crucial when it comes to capacity design, especially in case of narrow foundations (edge failure) and post-installed anchors when the resistance is highly reduced with respect to steel bolt capacity. Moreover, the overall dissipative performance might be affected by the anchor’s displacement. An innovative hold-down connection has been designed to promote steel failure of the axially loaded plate. The plate’s geometry has been optimized such that capacity design rules according to Eurocode 8 can be applied. Additionally, a target displacement requirement is addressed, and the stretch length is defined accordingly. The whole connection is tested against cyclic loading and results show enhanced performances with respect to standard configuration. In particular, brittle mechanism such as concrete-cone failure of the anchors and splitting of timber are prevented. The paper discusses the experimental results for different type and size of the anchor, also the size of the optimized steel plate is considered as a parameter

Las tramas del sentir : ensayos desde una sociología de los cuerpos y las emociones

Los artículos compilados en esta publicación forman parte de un trabajo de reflexión que los integrantes del Grupo de Estudios sobre Sociología de las Emociones y los Cuerpos del Instituto de Investigaciones Gino Germani de la Universidad de Buenos Aires venimos construyendo desde fines del año 2008 bajo la dirección del Dr. Adrián Scribano. Las tramas del sentir, tal como propone el título de este libro, señalan hacia esos nodos vivenciales/experienciales que configuran las particulares maneras de ser/estar/desear/tener que ponen en juego los sujetos en el fluir de sus interacciones cotidianas. Sentir y sentirse es un acto que compromete y actualiza la dimensión histórico-social de los sentidos, impregnando la materialidad del cuerpo y, al mismo tiempo, valiéndose de ella como plataforma para la incorporación del conjunto de sensibilidades a partir de las cuales la dominación opera creando la ilusión de modos de sentir(se) únicos, propios e individuales