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.

Flash-based Field Programmable Gate Arrays (Flash-based FPGAs) are becoming more and more interesting for safety critical applications due to their re-programmability features while being non-volatile. However, Single Event Transients (SETs) in combinational logic represent their primary source of critical errors since they can propagate and change their shape traversing combinational paths and being broadened and amplified before sampled by sequential Flip-Flops. In this paper the SET sensitivity of circuits implemented in Flash-based FPGAs is mitigated with respect to the working frequency and different FPGA routing architecture. We outline a parametric routing scheme and placement and routing tools based on an iterative partitioning algorithm able to generate high performance circuits by reducing the wires delay and reducing the SET sensitivity. The efficiency of the proposed tools has been evaluated on a Microsemi Flash-based FPGA implementing different benchmark circuits including a RISC microprocessor. Experimental results demonstrated the reduction of SET sensitivity of more than 30% on the average versus state-of-the-art mitigation solutions and a performance improvement of about 10% of the nominal working frequency.

SET-PAR: Place and Route Tools for the Mitigation of Single Event Transients on Flash-Based FPGAs

A comparative radiation analysis of reconfigurable memory technologies: FinFET versus bulk CMOS

Static RAM modules are widely adopted in high performance systems. Single Event Effects (SEEs) resilient memories are required in many embedded systems applied in automotive and aerospace applications to increase their overall resiliency against SEEs. The current SEE resilient SRAM modules are obtained by applying radiation-hardened by design solutions which leads to elevated area overhead and difficulty to tune the resiliency capability with respect to the particle's radiation profile. To overcome these limitations, we propose a methodology for the analysis and mitigation of embedded SRAMs generated by the OpenRAM memory compiler. A technology-oriented radiation analysis tool is presented to support the interaction of the charged radiation particles with the SRAM layout and depict the sensitive transistors of the SRAM memory. A selective duplication of the sensitive transistors has been applied to the 6T-SRAM cell designed at the layout level. The designed cell is included in the OpenRAM compiler and used to generate a mitigated 8Kb SRAM-bank. We evaluated the SEEs sensitivity by comparative simulation-based radiation analysis observing a reduction more than 6 times with respect to the original 6T-SRAM cell for the SEE sensitivity at high energy heavy ions particles, with negligible degradation of operations margins and power consumption and area overhead of less than $\sim$ 4%.

On the Evaluation of SEEs on Open-Source Embedded Static RAMs

DNA microarray technologies are an essential part of modern biomedical research. The analysis of DNA microarray images allows the identification of gene expressions in order to drawn biologically meaningful conclusions for applications that ranges from the genetic profiling to the diagnosis of oncology diseases. Unfortunately, DNA microarray technology has a high variation of data quality. Therefore, in order to obtain reliable results, complex and extensive image analysis algorithms should be applied before actual DNA microarray information can be used for biomedical purpose. In this paper, we present a novel hardware acceleration architecture specifically designed to process DNA microarray images. The proposed architecture uses several units working in a single instruction-multiple data fashion managed by a microprocessor core. An FPGA-based prototypal implementation of the developed architecture is presented. Experimental results on several realistic DNA microarray images show a reduction of the computation time of one order of magnitude if compared with previously developed software-based approach.

A new hardware architecture for performing the gridding of DNA microarray images

General-purpose graphics processing units (GPGPUs) are extensively used in high-performance computing. However, it is well known that these devices’ reliability may be limited by the rising of faults at the hardware level. This work introduces a flexible solution to detect and mitigate permanent faults affecting the execution units in these parallel devices. The proposed solution is based on adding some spare modules to perform two in-field operations: detecting and mitigating faults. The solution takes advantage of the regularity of the execution units in the device to avoid significant design changes and reduce the overhead. The proposed solution was evaluated in terms of reliability improvement and area, performance, and power overhead costs. For this purpose, we resorted to a micro-architectural open-source GPGPU model (FlexGripPlus). Experimental results show that the proposed solution can extend the reliability by up to 57%, with overhead costs lower than 2% and 8% in area and power, respectively.

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Luca Sterpone

Papers

SET-PAR: Place and Route Tools for the Mitigation of Single Event Transients on Flash-Based FPGAs

A comparative radiation analysis of reconfigurable memory technologies: FinFET versus bulk CMOS

On the Evaluation of SEEs on Open-Source Embedded Static RAMs

A new hardware architecture for performing the gridding of DNA microarray images

DYRE: a DYnamic REconfigurable solution to increase GPGPU’s reliability