The Internet of Simulation: Enabling Agile Model Based Systems Engineering for Cyber-Physical Systems

The expansion of the Internet of Things (IoT) has resulted in a complex cyber-physical system of systems that is continually evolving. With ever more complex systems being developed and changed there has been an increasing reliance on simulation as a vital part of the design process. There is also a growing need for simulation integration and co-simulation in order to analyse the complex interactions between system components. To this end we propose that the Internet of Simulation (IoS) as an extension of IoT can be used to meet these needs. The IoS allows for multiple heterogeneous simulations to be integrated together for co-simulation. It's effect on the engineer process is to facilitate agile practices without sacrificing rigour. An Industry 4.0 example case study is provided showing how IoS could be utilized

Differential Proteoglycan Expression in Atherosclerosis Alters Platelet Adhesion and Activation

\ua9 2024 by the authors.Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced (p < 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen (p < 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis

Real time dynamic strain monitoring of optical links using the backreflection of live PSK data.

A major cause of faults in optical communication links is related to unintentional third party intrusions (normally related to civil/agricultural works) causing fiber breaks or cable damage. These intrusions could be anticipated and avoided by monitoring the dynamic strain recorded along the cable. In this work, a novel technique is proposed to implement real-time distributed strain sensing in parallel with an operating optical communication channel. The technique relies on monitoring the Rayleigh backscattered light from optical communication data transmitted using standard modulation formats. The system is treated as a phase-sensitive OTDR (ΦOTDR) using random and non-periodical non-return-to-zero (NRZ) phase-shift keying (PSK) pulse coding. An I/Q detection unit allows for a full (amplitude, phase and polarization) characterization of the backscattered optical signal, thus achieving a fully linear system in terms of ΦOTDR trace coding/decoding. The technique can be used with different modulation formats, and operation using 4 Gbaud single-polarization dual PSK and 4 Gbaud dual-polarization quadrature PSK is demonstrated. As a proof of concept, distributed sensing of dynamic strain with a sampling of 125 kHz and a spatial resolution of 2.5 cm (set by the bit size) over 500 m is demonstrated for applied sinusoidal strain signals of 500 Hz. The limitations and possibilities for improvement of the technique are also discussed.This work was supported by the European Research Council through Starting Grant UFINE (Grant no. 307441), the Spanish MINECO through project TEC2013-45265-R, PCIN-2015- 219, and the regional program SINFOTON-CM: S2013/MIT-2790. HFM acknowledges EU funding through the FP7 ITN ICONE program, gr. #608099. SML acknowledges funding from the Spanish MINECO through a “Ramon y Cajal” contract. UK EPSRC funding through project EP/J008842/1

Enantiopure and racemic radical-cation salts of B(malate)2−anions with BEDT-TTF

We have synthesized the first examples of radical-cation salts of BEDT-TTF with chiral borate anions, [B(malate)2]−, prepared from either enantiopure or racemic bidentate malate ligands. In the former case only one of two diastereoisomers of the borate anion is incorporated, while for the hydrated racemic salt one racemic pair of borate anions containing a R and a S malate ligand is incorporated. Their conducting and magnetic properties are reported. The tight-binding band calculation indicates that the chiral salt has an effective half-filled flat band, which is likely to be caused by the chiral structural feature

New semiconducting radical-cation salts of chiral bis(2-hydroxylpropylthio)ethylenedithio TTF

Electrocrystallisations of the chiral donor molecule S,S-bis(2-hydroxylpropylthio)ethylenedithiotetrathiafulvalene have produced a series of 1 : 1 semiconducting radical-cation salts with anions bromide, chloride, perchlorate and hexafluorophosphate. The flexibility and hydrogen bonding ability of the donor's chiral side chains lead to three quite different packing arrangements of donor cation pairs. Conductivity is maintained despite significant separations of donor cation pairs in some cases

How and why DNA barcodes underestimate the diversity of microbial eukaryotes

Background: Because many picoplanktonic eukaryotic species cannot currently be maintained in culture, direct sequencing of PCR-amplified 18S ribosomal gene DNA fragments from filtered sea-water has been successfully used to investigate the astounding diversity of these organisms. The recognition of many novel planktonic organisms is thus based solely on their 18S rDNA sequence. However, a species delimited by its 18S rDNA sequence might contain many cryptic species, which are highly differentiated in their protein coding sequences. Principal Findings: Here, we investigate the issue of species identification from one gene to the whole genome sequence. Using 52 whole genome DNA sequences, we estimated the global genetic divergence in protein coding genes between organisms from different lineages and compared this to their ribosomal gene sequence divergences. We show that this relationship between proteome divergence and 18S divergence is lineage dependant. Unicellular lineages have especially low 18S divergences relative to their protein sequence divergences, suggesting that 18S ribosomal genes are too conservative to assess planktonic eukaryotic diversity. We provide an explanation for this lineage dependency, which suggests that most species with large effective population sizes will show far less divergence in 18S than protein coding sequences. Conclusions: There is therefore a trade-off between using genes that are easy to amplify in all species, but which by their nature are highly conserved and underestimate the true number of species, and using genes that give a better description of the number of species, but which are more difficult to amplify. We have shown that this trade-off differs between unicellular and multicellular organisms as a likely consequence of differences in effective population sizes. We anticipate that biodiversity of microbial eukaryotic species is underestimated and that numerous ''cryptic species'' will become discernable with the future acquisition of genomic and metagenomic sequences

Immuno-oncology combinations: raising the tail of the survival curve.

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis.

Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD

In Vitro Primary-Indirect Genotoxicity in Bronchial Epithelial Cells Promoted by Industrially Relevant Few-Layer Graphene

Few-layer graphene (FLG) has garnered much interest owing to applications in hydrogen storage and reinforced nanocomposites. Consequently, these engineered nanomaterials (ENMs) are in high demand, increasing occupational exposure. This investigation seeks to assess the inhalation hazard of industrially relevant FLG engineered with: (i) no surface functional groups (neutral), (ii) amine, and (iii) carboxyl group functionalization. A monoculture of human lung epithelial (16HBE14o-) cells is exposed to each material for 24-h, followed by cytotoxicity and genotoxicity evaluation using relative population doubling (RPD) and the cytokinesis-blocked micronucleus (CBMN) assay, respectively. Neutral-FLG induces the greatest (two-fold) significant increase (p 1 µm diameter). The findings of the present study have demonstrated the capability of neutral-FLG and amine-FLG to induce genotoxicity in 16HBE14o- cells through primary indirect mechanisms, suggesting a possible role for carboxyl groups in scavenging radicals produced via oxidative stress