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.

The continuous scaling of electronic components has led to the development of high-performance microprocessors that are suitable even for safety-critical applications where radiation-induced errors such as Single Event Effects (SEEs) can have a significant impact on the performance and reliability of the system. This work is dedicated to investigating the reliability of systems based on programmable hardware and Real-time operating Systems (RTOS) in the presence of architectural faults induced by soft errors in the configuration memory of the programmable hardware. We performed a proton radiation test campaigned at PSI radiation facility to identify the fault model affecting the configuration memory of Xilinx Zynq-7020 reconfigurable AP-Soc Device. The identified fault model in terms of SEU and MBU clusters has been used to evaluate the impact of proton-induced faults on applications running within FreeRTOS on a Microblaze soft processor. A Single Event Multiple Upset fault model resulting from a proton test is presented, focusing on characteristics such as shape, size, and frequency of observed cluster of errors. We conduct two fault injection campaigns and analyze the results to assess the effect of cluster size on system reliability. Moreover, we discuss software exceptions caused by faults that can affect the hardware structure of the soft processor.

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Exploring the Impact of Soft Errors on the Reliability of Real-Time Embedded Operating Systems

Reconfigurable systems are increasingly used in different domains, due to the advantages they offer in terms of flexibility: reconfigurability can also be used for managing possible faults affecting a circuit, when fault tolerance is the target. In this case the system must be able to (1) detect any possible fault, (2) identify the module (or partition) including it, and (3) take proper actions able to overcome the problem (e.g., by substituting the faulty module with a spare one). In this chapter, we address the point (2) when a Very Long Instruction Word (VLIW) processor is used by resorting to a Software-Based Self-Test (SBST) approach. SBST techniques have shown to represent an effective solution for permanent fault detection and diagnosis, both at the end of the production process, and during the operational phase. When VLIW processors are addressed, SBST techniques can effectively exploit the parallelism intrinsic in these architectures. In this chapter, we propose a new approach that starting from existing detection-oriented programs generates a diagnosis-oriented test program. Moreover, we propose (1) a detailed analysis of the generated equivalence classes and (2) a solution aimed to maximize the diagnosability of the modules composing the VLIW processor under test, thus perfectly suiting the needs of reconfigurable systems. Experimental results gathered on a case study VLIW processor show the effectiveness of the proposed approach: at the end of the presented method, the faulty module is always identified.

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Partition-Based Faults Diagnosis of a VLIW Processor

In recent years, three-dimensional IC (3D IC) has gained much attention as a promising approach to increase IC performance due to their several advantages in terms of integration density, power dissipation and achievable clock frequencies. However, the reliability of 3D ICs regarding soft errors induced by radiation is not investigated yet. In this work, we propose a method for evaluating the sensitivity of 3D ICs to Single Event Transient induced by Heavy Ions. The flow starts with identifying the characteristics of the generated transient pulses with respect to the radiation profile and 3D layout of the design. Secondly, our method provides a Dynamic Error Rate using a Simulation-based Fault Injection environment. Experimental results achieved applying the approach on a 15nm 3D configurable Look-Up-Table (LUT) designed on two tiers demonstrated the feasibility of the method, showing the vulnerability characterization of four different functional configurations using eight different types of heavy ions.

A new Method for the Analysis of Radiation-induced Effects in 3D VLSI Face-to-Back LUTs

SRAM-based FPGAs are widely used in mission critical applications. Due to the increasing working frequency and technology scaling of ultra-nanometer technology, Single Event Transients (SETs) are becoming a major source of errors for these devices. In this paper, we propose an approach for evaluating the Propagation-induced Pulse Broadening (PIPB) effect introduced by the logic resources traversed by transient pulses. The proposed methodology is applicable to any recent technology to provide SET analysis, necessary for an efficient mitigation technology. Experimental results achieved from a set of benchmarks are compared with fault injection experiments executed on a 28 nm SRAM-based FPGA to demonstrate the effectiveness of our technique.

Luca Sterpone

Papers

Exploring the Impact of Soft Errors on the Reliability of Real-Time Embedded Operating Systems

Partition-Based Faults Diagnosis of a VLIW Processor

A new Method for the Analysis of Radiation-induced Effects in 3D VLSI Face-to-Back LUTs

On the Evaluation of the PIPB Effect within SRAM-based FPGAs

On the Reliability of Real-Time Operating System on Embedded Soft Processor for Space Applications