Membrane particles from mesenchymal stromal cells reduce the expression of fibrotic markers on pulmonary cells

Background: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options in which the telomere shortening is a strong predictive factor of poor prognosis. Mesenchymal stromal cells (MSC) administration is probed in several experimental induced lung pathologies; however, MSC might stimulate fibrotic processes. A therapy that avoids MSC side effects of transformation would be an alternative to the use of living cells. Membranes particles (MP) are nanovesicles artificially generated from the membranes of MSC containing active enzymes involved in ECM regeneration. We aimed to investigate the anti-fibrotic role of MP derived from MSC in an in vitro model of pulmonary fibrosis. Methods: Epithelial cells (A549) and lung fibroblasts, from IPF patients with different telomere length, were co-cultured with MP and TGF-β for 48h and gene expression of major pro-fibrotic markers were analyzed. Results: About 90% of both types of cells effectively took up MP without cytotoxic effects. MP decreased the expression of profibrotic proteins such as Col1A1, Fibronectin and PAI-1, in A549 cells. In fibroblasts culture, there was a different response in the inhibitory effect of MP on some pro-fibrotic markers when comparing fibroblast from normal telomere length patients (FN) versus short telomere length (FS), but both types showed an inhibition of Col1A1, Tenascin-c, PAI-1 and MMP-1 gene expression after MP treatment

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction

Trasplante de pulmón; Fibrosis pulmonar; Trastornos de los telómerosTrasplantament pulmonar; Fibrosi pulmonar; Trastorns dels telòmersLung transplantation; Pulmonary fibrosis; Telomere disordersIntroduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology. Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life. Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal. Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable.This study was funded by Instituto de Salud Carlos III through project PI18/00367 (Co-funded by European Regional Development Fund, ERDF, a way to build Europe), Spanish Society of Respiratory (SEPAR), Barcelona Respiratory Network (BRN), and Fundació Ramón Pla Armengol. RP laboratory was funded by grants PI20-00335 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds). MM-M was funded by grants PI18/00367 (Fondo de Investigaciones Sanitarias, ISCIII, Spain, supported by FEDER funds), AC19/00006 (Projects of International Programs, ISCIII, Spain, supported by FEDER funds), Cohorte FPI CIBERES-ISCIII, Barcelona Respiratory Network-Fundation Ramon Pla Armengol, Spanish Society of Respiratory (SEPAR), and Catalan Society of Respiratory (SOCAP-FUCAP). CF was funded by Ministerio de Ciencia e Innovación (grant RTC-2017-6471-1; AEI/FEDER, UE), and by Cabildo Insular de Tenerife (CGIEU0000219140)

TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation

TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction

Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology. Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life. Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal. Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable

Internet of things

Manual of Digital Earth / Editors: Huadong Guo, Michael F. Goodchild, Alessandro Annoni .- Springer, 2020 .- ISBN: 978-981-32-9915-3Digital Earth was born with the aim of replicating the real world within the digital world. Many efforts have been made to observe and sense the Earth, both from space (remote sensing) and by using in situ sensors. Focusing on the latter, advances in Digital Earth have established vital bridges to exploit these sensors and their networks by taking location as a key element. The current era of connectivity envisions that everything is connected to everything. The concept of the Internet of Things(IoT)emergedasaholisticproposaltoenableanecosystemofvaried,heterogeneous networked objects and devices to speak to and interact with each other. To make the IoT ecosystem a reality, it is necessary to understand the electronic components, communication protocols, real-time analysis techniques, and the location of the objects and devices. The IoT ecosystem and the Digital Earth (DE) jointly form interrelated infrastructures for addressing today’s pressing issues and complex challenges. In this chapter, we explore the synergies and frictions in establishing an efficient and permanent collaboration between the two infrastructures, in order to adequately address multidisciplinary and increasingly complex real-world problems. Although there are still some pending issues, the identified synergies generate optimism for a true collaboration between the Internet of Things and the Digital Earth

Text Mining the History of Medicine

Historical text archives constitute a rich and diverse source of information, which is becoming increasingly readily accessible, due to large-scale digitisation efforts. However, it can be difficult for researchers to explore and search such large volumes of data in an efficient manner. Text mining (TM) methods can help, through their ability to recognise various types of semantic information automatically, e.g., instances of concepts (places, medical conditions, drugs, etc.), synonyms/variant forms of concepts, and relationships holding between concepts (which drugs are used to treat which medical conditions, etc.). TM analysis allows search systems to incorporate functionality such as automatic suggestions of synonyms of user-entered query terms, exploration of different concepts mentioned within search results or isolation of documents in which concepts are related in specific ways. However, applying TM methods to historical text can be challenging, according to differences and evolutions in vocabulary, terminology, language structure and style, compared to more modern text. In this article, we present our efforts to overcome the various challenges faced in the semantic analysis of published historical medical text dating back to the mid 19th century. Firstly, we used evidence from diverse historical medical documents from different periods to develop new resources that provide accounts of the multiple, evolving ways in which concepts, their variants and relationships amongst them may be expressed. These resources were employed to support the development of a modular processing pipeline of TM tools for the robust detection of semantic information in historical medical documents with varying characteristics. We applied the pipeline to two large-scale medical document archives covering wide temporal ranges as the basis for the development of a publicly accessible semantically-oriented search system. The novel resources are available for research purposes, while the processing pipeline and its modules may be used and configured within the Argo TM platform

GSE4‐loaded nanoparticles a potential therapy for lung fibrosis that enhances pneumocyte growth, reduces apoptosis and DNA damage

Idiopathic pulmonary fibrosis is a lethal lung fibrotic disease, associated with aging with a mean survival of 2-5 years and no curative treatment. The GSE4 peptide is able to rescue cells from senescence, DNA and oxidative damage, inflammation, and induces telomerase activity. Here, we investigated the protective effect of GSE4 expression in vitro in rat alveolar epithelial cells (AECs), and in vivo in a bleomycin model of lung fibrosis. Bleomycin-injured rat AECs, expressing GSE4 or treated with GSE4-PLGA/PEI nanoparticles showed an increase of telomerase activity, decreased DNA damage, and decreased expression of IL6 and cleaved-caspase 3. In addition, these cells showed an inhibition in expression of fibrotic markers induced by TGF-β such as collagen-I and III among others. Furthermore, treatment with GSE4-PLGA/PEI nanoparticles in a rat model of bleomycin-induced fibrosis, increased telomerase activity and decreased DNA damage in proSP-C cells. Both in preventive and therapeutic protocols GSE4-PLGA/PEI nanoparticles prevented and attenuated lung damage monitored by SPECT-CT and inhibited collagen deposition. Lungs of rats treated with bleomycin and GSE4-PLGA/PEI nanoparticles showed reduced expression of α-SMA and pro-inflammatory cytokines, increased number of pro-SPC-multicellular structures and increased DNA synthesis in proSP-C cells, indicating therapeutic efficacy of GSE4-nanoparticles in experimental lung fibrosis and a possible curative treatment for lung fibrotic patients

Cycles of Police Reform in Latin America.

yesOver the last quarter century post-conflict and post-authoritarian transitions in Latin America have been accompanied by a surge in social violence, acquisitive crime, and insecurity. These phenomena have been driven by an expanding international narcotics trade, by the long-term effects of civil war and counter-insurgency (resulting in, inter alia, an increased availability of small arms and a pervasive grammar of violence), and by structural stresses on society (unemployment, hyper-inflation, widening income inequality). Local police forces proved to be generally ineffective in preventing, resolving, or detecting such crime and forms of “new violence”3 due to corruption, frequent complicity in criminal networks, poor training and low pay, and the routine use of excessive force without due sanction. Why, then, have governments been slow to prioritize police reform and why have reform efforts borne largely “limited or nonexistent” long-term results? This chapter highlights a number of lessons suggested by various efforts to reform the police in Latin America over the period 1995-2010 . It focuses on two clusters of countries in Latin America. One is Brazil and the Southern Cone countries (Chile, Argentina, and Uruguay), which made the transition to democracy from prolonged military authoritarian rule in the mid- to late 1980s. The other is Central America and the Andean region (principally El Salvador, Guatemala, Honduras, Peru, and Colombia), which emerged/have been emerging from armed conflict since the mid- 1990s. The chapter examines first the long history of international involvement in police and security sector reform in order to identify long-run tropes and path dependencies. It then focuses on a number of recurring themes: cycles of de- and re-militarization of the policing function; the “security gap” and “democratization dilemmas” involved in structural reforms; the opportunities offered by decentralization for more community-oriented police; and police capacity to resist reform and undermine accountability mechanisms