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.

Reconfigurable logic devices such as SRAM-based Field Programmable Gate Arrays (FPGAs) are nowadays increasingly popular thanks to their capability of implementing complex circuits with very short development time and for their high versatility in implementing different kind of applications, ranging from signal processing to the networking. The usage of reconfigurable devices in safety critical fields such as space or avionics require the adoption of specific fault tolerant techniques, like Triple Modular Redundancy (TMR), in order to protect their functionality against radiation effects. While these techniques allow to increase the protection capability against radiation effects, they introduce several penalties to the design particularly in terms of performances. In this paper, we present an innovative placement algorithm able to implement fault tolerant circuits on SRAM-based FPGAs while reducing the performance penalties. This algorithm is based on a model-based topology heuristic that address the arithmetic modules implemented on the FPGA reducing the interconnection delays between their resources. Experimental evaluations performed by means of timing analysis and fault injection on two industrial-like case studies demonstrated that the proposed algorithm is able to improve the running frequency up to the 44% versus standard TMR-based techniques while maintaining complete fault tolerance capabilities.

A new placement algorithm for the optimization of fault tolerant circuits on reconfigurable devices

MicroRNAs (miRNAs) play determinant roles in gene expression and several cellular processes of mammalian. These processes include differentiation, development, apoptosis, and cancer pathomechanisms. In detail, miRNAs are known to regulate the expression of keys genes relevant to cancer and potentially to other diseases [1–3]. MiRNAs are short noncoding RNAs having a central function in gene expression, since miRNAs are involved in cellular differentiation processes [4, 5], organism developments [6], and apoptosis. Furthermore, recent studies provide growing evidence of the contribution of miRNAs in cancer cellular mechanisms. Therefore, the analysis and the correct identification of miRNAs expression levels play a key role for better understanding and classifying cancer and other diseases. In parallel with the drastic growing of interest into the study of miRNAs, the support of systems and tools that allow an efficient and more robust analysis of miRNA’s expression levels become increasing mandatory to have a better disease identification.

Analysis and Clustering of MicroRNA Array: A New Efficient and Reliable Computational Method

Thanks to the immunity against Single Event Upsets in configuration memory, Flash-based FPGA is becoming widely adopted in mission- and safety-critical applications, such as in aerospace field. However, the decreasing of device feature size leads to an increasing of the device sensitivity regarding Single Event Transients (SETs). In this paper, we developed a new workflow to evaluate SET phenomena in a specific convergence case and introduce a new mitigation of SET pulse without introducing any performance penalization to the original netlist.

On the mitigation of single event transients on flash-based FPGAs

Software-Based Self-Test (SBST) approaches have shown to be an effective solution to detect permanent faults, both at the end of the production process, and during the operational phase. However, when Very Long Instruction Word (VLIW) processors are addressed these techniques require some optimization steps in order to properly exploit the parallelism intrinsic in these architectures. In this chapter we present a new method that, starting from previously known algorithms, automatically generates an effective test program able to still reach high fault coverage on the VLIW processor under test, while minimizing the test duration and the test code size. Moreover, using this method, a set of small SBST programs can be generated aimed at the diagnosis of the VLIW processor. Experimental results gathered on a case study show the effectiveness of the proposed approach.

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On the Automatic Generation of Software-Based Self-Test Programs for Functional Test and Diagnosis of VLIW Processors

Flash-based Field Programmable Gate Array (FPGA) devices are nowadays golden cores of many applications especially in space and avionic fields where reliability is becoming an important concern. In particular, for Flash-based FPGAs when adopted in those applications, the main concern is radiation-induced voltage glitched know as Single Event Transient (SET) in the combinational logic. In this work, a new CAD tool has been developed in order to evaluate the sensitivity of the implemented circuit regarding SET and to mitigate their effects. The proposed tool has been applied to an industrial design adopted by the EUCLID space mission including more than ten different modules. The experimental results demonstrated the feasibility and efficiency of proposed tool.

Luca Sterpone

Papers

A new placement algorithm for the optimization of fault tolerant circuits on reconfigurable devices

Analysis and Clustering of MicroRNA Array: A New Efficient and Reliable Computational Method

On the mitigation of single event transients on flash-based FPGAs

On the Automatic Generation of Software-Based Self-Test Programs for Functional Test and Diagnosis of VLIW Processors

SETA: A CAD Tool for Single Event Transient Analysis and Mitigation on Flash-Based FPGAs