In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

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Biological properties of extracellular vesicles and their physiological functions

Within the past decade, extracellular vesicles have emerged as important mediators of intercellular communication, being involved in the transmission of biological signals between cells in both prokaryotes and higher eukaryotes to regulate a diverse range of biological processes. In addition, pathophysiological roles for extracellular vesicles are beginning to be recognized in diseases including cancer, infectious diseases and neurodegenerative disorders, highlighting potential novel targets for therapeutic intervention. Moreover, both unmodified and engineered extracellular vesicles are likely to have applications in macromolecular drug delivery. Here, we review recent progress in understanding extracellular vesicle biology and the role of extracellular vesicles in disease, discuss emerging therapeutic opportunities and consider the associated challenges.

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Extracellular vesicles: biology and emerging therapeutic opportunities

MicroRNAs in Stress Signaling and Human Disease

The shear-responsive transcription factor Kruppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs) post-transcriptionally control gene expression in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 in endothelial cells. KLF2 binds to the promoter and induces a significant upregulation of the miR-143/145 cluster. Interestingly, miR-143/145 has been shown to control smooth muscle cell (SMC) phenotypes; therefore, we investigated the possibility of transport of these miRNAs between endothelial cells and SMCs. Indeed, extracellular vesicles secreted by KLF2-transduced or shear-stress-stimulated HUVECs are enriched in miR-143/145 and control target gene expression in co-cultured SMCs. Extracellular vesicles derived from KLF2-expressing endothelial cells also reduced atherosclerotic lesion formation in the aorta of ApoE(-/-) mice. Combined, our results show that atheroprotective stimuli induce communication between endothelial cells and SMCs through an miRNA- and extracellular-vesicle-mediated mechanism and that this may comprise a promising strategy to combat atherosclerosis.

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Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs.

State-of-the-art on use of insects as animal feed.

Single Event Latchup (SEL) in Gate Arrays MG2 Radiation Hardened Atmel technology is examined with respect to strike of heavy ions Radiation tests, performed at GANIL radiation facility, have been executed at high temperature by monitoring current absorption and analyzing the functionalities of the MSDRX ASIC implemented using MG2RT technology part of a TAS-I transponder core A drastic improvement of the device SEL sensitivity is observed for high power supply voltages In this paper, we describe the performed experiments, the experimental setup and we provide an accurate investigation of the obtained results

Experimental analysis of SEL sensitiveness on Atmel MG2RT technology

Selective mitigation or selective hardening is an effective technique to obtain a good trade-off between the improvements in the overall reliability of a circuit and the hardware overhead induced by the hardening techniques. Selective mitigation relies on preferentially protecting circuit instances according to their susceptibility and criticality. However, ranking circuit parts in terms of vulnerability usually requires computationally intensive fault-injection simulation campaigns. This paper presents a new methodology which uses machine learning clustering techniques to group flip-flops with similar expected contributions to the overall functional failure rate, based on the analysis of a compact set of features combining attributes from static elements and dynamic elements. Fault simulation campaigns can then be executed on a per-group basis, significantly reducing the time and cost of the evaluation. The effectiveness of grouping similar sensitive flip-flops by machine learning clustering algorithms is evaluated on a practical example.Different clustering algorithms are applied and the results are compared to an ideal selective mitigation obtained by exhaustive fault-injection simulation.

Machine Learning Clustering Techniques for Selective Mitigation of Critical Design Features

Reconfigurable compute fabrics (RCFs) are cellular architectures in which an array of computing elements and a configurable interconnection fabric are combined with a general-purpose processor. RCFs can play an important role in safety- or mission-critical applications, provided that a clear understanding of their dependability is available. In this paper, we report an evaluation of the effects induced by transient faults within the resources of an RCF Motorola MRC6011 and we resorted to extensive fault injection to investigate the effects of transient faults.

Dependability evaluation of transient fault effects in reconfigurable compute fabric devices

The recent trends for nanoelectronic computing systems include machine-to-machine communication in the era of Internet-of-Things (IoT) and autonomous systems, complex safety-critical applications, extreme miniaturization of implementation technologies and intensive interaction with the physical world. These set tough requirements on mutually dependent extra-functional design aspects. The H2020 MSCA ITN project RESCUE is focused on key challenges for reliability, security and quality, as well as related electronic design automation tools and methodologies. The objectives include both research advancements and cross-sectoral training of a new generation of interdisciplinary researchers. Notable interdisciplinary collaborative research results for the first half-period include novel approaches for test generation, soft-error and transient faults vulnerability analysis, cross-layer fault-tolerance and error-resilience, functional safety validation, reliability assessment and run-time management, HW security enhancement and initial implementation of these into holistic EDA tools.

RESCUE: Interdependent Challenges of Reliability, Security and Quality in Nanoelectronic Systems

Single Event Transients (SETs) are one of the major concern for Flash-based Field Programmable Gate Arrays (FPGAs). In this paper, we propose a new analysis to characterize the SET phenomena within Flash-based FPGAs.

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Luca Sterpone

Papers

Experimental analysis of SEL sensitiveness on Atmel MG2RT technology

Machine Learning Clustering Techniques for Selective Mitigation of Critical Design Features

Dependability evaluation of transient fault effects in reconfigurable compute fabric devices

RESCUE: Interdependent Challenges of Reliability, Security and Quality in Nanoelectronic Systems

Effective Characterization of Radiation-induced SET on Flash-based FPGAs