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.

Triple Modular Redundancy (TMR) is recognized as one of the possible solutions to harden circuits implemented on SRAM-based FPGAs against soft-errors affecting configuration memory and user memory. Several works already showed cross-section figures confirming the soundness of TMR principle, however some faults still escape the TMR's fault masking mechanism. In this work we analyzed by means of extensive fault-injection experiments the TMR architecture. We identified some of the causes that are responsible for the escaped faults, and we proposed possible solutions. In our analyses we considered both the TMR and one of its enhanced version, the XTMR

An Analysis Based on Fault Injection of Hardening Techniques for SRAM-Based FPGAs

Today, many companies are facing the problem of component obsolescence in embedded systems. The incredibly fast growth rate of semiconductor companies is reducing dramatically the time components are available on the market. Twenty years ago, components remained on the market for 5 to 10 years; nowadays, they disappear from the market in less than two years. Developers of safety- or mission-critical systems are particularly sensitive to the obsolescence problem as their systems are expected to remain operative for very long periods (e.g., 30 years or more), and maintaining them fully operative is becoming difficult as the needed components may no longer be available. A possible solution for this problem may be the implementation of the needed components using FPGAs. The purpose of this paper is to provide an overview of the different possibilities designers have to face when developing such dependability-oriented solution. Also, a design flow is presented, describing its applicability to the implementation of processor cores, to be employed as a replacement of obsolete parts in safety- or mission-critical applications. Results show that there is a strong dependence of the reliability of the design with the specific application. The scrubbing process can also be optimized using the related technique.

Coping With the Obsolescence of Safety- or Mission-Critical Embedded Systems Using FPGAs

Estimating the impact of single event effects (SEEs) on SRAM-based FPGA devices is a major issue in order to adopt them in radiation environments such as space or high altitude. Among the available approaches, we proposed an analytical method to predict SEE effects based on the analysis of the circuit the FPGA implements, which does not require either simulation or fault injection. In this paper we provide an experimental validation of this approach, by comparing the results it provides with those coming from accelerated testing. We adopted our analytical method for computing the error cross section of a design implemented on SRAM-based FPGA devices. We then compared the obtained figure with that obtained by accelerated testing. Experimental analysis demonstrated that accelerated testing closely match the figures the analytical method provides.

Experimental Validation of a Tool for Predicting the Effects of Soft Errors in SRAM-Based FPGAs

A methodology for characterization of Propagation Induced Pulse Broadening (PIPB) effects concerning the Single Event Transients (SETs) propagation within logic and routing resources of Flash-based Field Programmable Gate Arrays (FPGAs) is presented. Electrical-based fault injection was performed on the FPGA board and at the electrical model. Experimental results matched the electrical simulations, which validate the effectiveness of the method.

An Analytical Model of the Propagation Induced Pulse Broadening (PIPB) Effects on Single Event Transient in Flash-Based FPGAs

Advanced digital circuits are increasingly sensitive to single event transients (SETs) phenomena. Technology scaling has resulted in a greater sensitivity to single event effects (SEEs) and more in particular to SET propagation, since transients may be generated and propagated through the circuit logic, leading to behavioral errors of the affected circuit. When circuits are implemented on Flash-based FPGAs, SETs generated in the combinational logic resources are the main source of critical behavior. In this paper, we developed a technique based on electrical pulse injection for the analysis of SETs propagation within logic resources of Flash-based FPGAs. We outline logic schematic that allows the injection of different SET pulses. We performed several experimental analyses. We characterized the basic logic gates used by circuits implemented on Flash-based FPGAs evaluating the effect on logic-chains of real lengths. Additionally, we performed an effective analysis evaluating the SET propagation through microprocessor logic paths. Results demonstrated the possibility of mitigating SET-broadening effects by acting on physical place and route constraints.

Luca Sterpone

Papers

An Analysis Based on Fault Injection of Hardening Techniques for SRAM-Based FPGAs

Coping With the Obsolescence of Safety- or Mission-Critical Embedded Systems Using FPGAs

Experimental Validation of a Tool for Predicting the Effects of Soft Errors in SRAM-Based FPGAs

An Analytical Model of the Propagation Induced Pulse Broadening (PIPB) Effects on Single Event Transient in Flash-Based FPGAs

Analysis of SET Propagation in Flash-Based FPGAs by Means of Electrical Pulse Injection