AimsPathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-b1 (TGF-b1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-b1 by inducing a conformational change in the latent complex. The mesenchymal integrins avb5 and avb3 are expressed in the heart, but their role in the activation of TGF-b1 remains elusive. Here, we test whether targeting avb5 and avb3 integrins reduces latent TGF-b1 activation by cardiac fibroblasts with the goal to prevent the formation of a-smooth muscle actin (a-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis. Methods and resultsUsing a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins avb5 and avb3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-b1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-b1 activation by cardiac fibroblast contraction and loss of a-SMA expression, which is restored by adding active TGF-b1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-b1 activation and induction of a-SMA expression. ConclusionsIntegrins avb5 and avb3 both control myofibroblast differentiation by activating latent TGF-b1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-b1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.--

The ability of cardiac fibroblasts to sense and control the mechanical properties of the extracellular matrix is essential to adapt the heart tissue to mechanical load, such as in conditions of hypertension and to repair injuries after myocardial infarct. Aberrant mechanosensing and/or persistent stress results in the chronic activation of cardiac fibroblasts and other progenitors into myofibroblasts. Myofibroblasts drive the development of fibrosis by excessive collagen secretion and contraction of the neo-matrix into scar tissue. Stiff fibrotic tissue impairs heart distensibility, pumping and valve function, contributes to diastolic and systolic dysfunction, and affects myocardial electrical transmission, leading to arrhythmia and ultimately heart failure. To explore novel therapeutic strategies that specifically target the myofibroblasts in heart fibrosis, we here elaborate on the common factors that control myofibroblast activation from different precursor cells in the heart. At least two factors are pivotal for myofibroblast activation and function: mechanical stress, manifested in disease as a stiff extracellular matrix, and active TGF-β1. Because of uncontrollable side effects, global TGF-β1 inhibition has failed in clinical trials to treat fibrosis but preventing TGF-β1 activation in a myofibroblastspecific manner has promising perspectives.

The article gives the picture of initiation and development of two European digital libraries, their projects and successes and reports on the steps and results of the RSL’s participation and partnership in the European Library activities.

Cooperation between the Russian State Library and the European Library, as well as national libraries of Europe continues to develop.

In the modern digital society, innovative technologies are coming to the fore in the activities of libraries; with their help the libraries can focus on the value of their role in culture and education, meet information needs in the context of digital transformation. At the same time, libraries try to facilitate the work of their employees as much as possible and simplify the efforts of readers in obtaining the necessary literature. This can be achieved by automation of the process of delivery and return of library materials ordered by users within the premises of the library. As a rule, for such purposes there is used telelift — an automated monorail handling system designed for the delivery of goods up to 50 kg (documents, books, magazines, etc.) inside buildings and premises. Telelift is installed in many large libraries, including national libraries in many countries. In addition to telelifts, national libraries use some other document delivery systems. So, the national library of the Netherlands, which is located in one building, has three reading rooms and several storages in the same building, uses the automated storage and retrieval systems of Swisslog company. The article is based on studying the materials of websites of the national libraries, the appeals to the library virtual reference services Ask a Librarian, correspondence with employees of the departments of storage and library and information services of national libraries, as well as additional questionnaire surveys of libraries on the issues related to the storage of library materials. The questionnaire covered the following topics: conducting complete or partial audit, types of audit, use of RFID tags, delivery of material to reading rooms, including, from the remote repositories, the preferred format for issuing a document to the user if this document has a copy (microfilm, microfiche, electronic copy, etc.), as well as statistics of binding and restoration work, ordering necessary materials by readers, etc. The article presents the questionnaire survey responses of the national libraries of Switzerland, Korea, the Royal Library of Netherlands, the British Library, as well as the the Library and Archives of Canada.