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

Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.

AIMS: Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS: CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION: EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation

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

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

Low-cycle behavior of wood screws under alternating bending

Earthquake-resistant timber structures may be designed accounting either for the dissipative or low-dissipative structural behavior, depending on the relevant ductility class. A timber structure belonging to a given ductility class shall meet specific requirements especially in the type and rotational ductility capacity of connections, since the timber members themselves shall be regarded as behaving elastically. In addition, Eurocode 8 prescribes that only materials and mechanical fasteners providing appropriate low-cycle fatigue behavior may be used in joints regarded as dissipative zones. In this context, the properties of dissipative zones may be determined by tests either on single joints, or on whole structures in accordance with EN 12512. At the same time, the appropriate fastener’s low-cycle behavior is currently deemed to be satisfied if the connectors are sufficiently slender with respect to the thickness of the joined members. Nowadays, this assumption may not be sufficiently reliable because of the actual trends in fasteners technology, which consists in providing heavily hardened connectors in order to achieve higher resistances and ease of insertion into timber. The aim of this study is to investigate the low-cycle behavior of modern wood screws by means of three-point alternating bending tests. The paper describes a new testing apparatus, the related test procedure and assessment criteria specifically designed for this purpose. A preliminary investigation of the low-cycle behavior of different wood screws currently on the market is then carried out and the related test results are discussed

Impact performance of thin glass-polycarbonate composite panels

Safety glass is usually the proper designer choice when glazing may be subjected to the impact of a person. In order to avoid people injuries, glass products must comply with appropriate safety practices. Existing technical standards classify safety glass products by mode of breakage and post-breakage behavior. Critical demanding applications in terms of self-weight saving, like high efficiency elevator cars in buildings or aircrafts and other means of transportation interiors in aerospatial and automotive industries, are currently driving the innovation in the development of safety glass. In this framework, glass-polycarbonate composite panels offer a lightweight alternative which is at once able to preserve the aesthetic and safety aspects of traditional laminated safety glass. The aim of this paper is to present an experimental investigation on the performance under impact of thin glass layer with a cellular polycarbonate backing joined together by an auto-adhesive interlayer film. Different coatings (mirror and paint) at the glass-adhesive interface are also taken into account