Down Regulation of Genes Involved in T Cell Polarity and Motility during the Induction of Heart Allograft Tolerance by Allochimeric MHC I

BACKGROUND:The allochimeric MHC class I molecule [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells. METHODOLOGY/PRINCIPAL FINDINGS:To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs). CONCLUSIONS:These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation

A fully soft generator with embedded conditioning circuitry

This letter presents a fully soft dielectric elastomer generator (DEG) based on a capacitive kinetic-energy-harvesting mechanism. First, using the principle of a passive charge pump, a self-cycling conditioning circuit topology is proposed. Through the electrical reciprocity of a cyclically deforming DEG and another capacitor in series with it, the generated charge can be continuously supplied to the load, via a bilateral conditioning bridge. The antagonistic dual-DEG scheme not only produces a larger potential to drive more charge in the flow but also provides a basic solution to soften the whole device. A further measure is to replace the bridge diodes with special dielectric elastic switches (DESs), which can be embedded into the DEG and synchronously deformed with the latter to control the on/off state of the circuit branches. The intrinsic physical mechanism and characteristics of the change in the resistance of the DES as a function of stretch and electric fields are investigated. We tested and compared the diode-bridge and DES-bridge schemes under different electrical loads and tensile strokes. The results indicate that under certain conditions, the DES-bridge circuit can achieve comparable performance with that of a conventional scheme, which suggests that a fully soft DEG system is possible. We experimentally evaluated and discussed its reliability in practice.Published versio

Capacitive energy harvesting using soft dielectric elastomers: Design, testing and impedance matching optimization

Energy harvesting based on dielectric elastomeric materials, in nature, embodies a capacitive kinetic energy conversion mechanism where the soft DE generator (DEG) interactively cooperates with conditioning circuits. Based on the principle of passive charge pump, this paper proposes a design concept for a self-cycling energy harvesting circuit driven by DEG cyclic deformation, with its essential behavioral mode laid on the electrical reciprocity between the DEG intrinsic capacitor and another capacitor connected in series. By detailed simulation experiments, the working process and dynamic characteristics of the proposed system, as well as the influence of circuital, operating, and load parameters on system performance are quantitatively investigated, with intensive discussions for the time delay behaviors caused by changes of load resistance, along with the different impacts of its value regions. Then, the theoretical analyses are effectively validated by experimental tests for a specially-designed annular DEG prototype. Under the global optimization framework based on impedance matching, this paper presents some guidelines for circuit design, e.g., the selection criteria of the capacitance and load resistance. In addition, the potential of this emerging technology is also demonstrated by experiments

Significance and suppression of redundant IL17 responses in acute allograft rejection by bioinformatics based drug repositioning of fenofibrate.

Despite advanced immunosuppression, redundancy in the molecular diversity of acute rejection (AR) often results in incomplete resolution of the injury response. We present a bioinformatics based approach for identification of these redundant molecular pathways in AR and a drug repositioning approach to suppress these using FDA approved drugs currently available for non-transplant indications. Two independent microarray data-sets from human renal allograft biopsies (n = 101) from patients on majorly Th1/IFN-y immune response targeted immunosuppression, with and without AR, were profiled. Using gene-set analysis across 3305 biological pathways, significant enrichment was found for the IL17 pathway in AR in both data-sets. Recent evidence suggests IL17 pathway as an important escape mechanism when Th1/IFN-y mediated responses are suppressed. As current immunosuppressions do not specifically target the IL17 axis, 7200 molecular compounds were interrogated for FDA approved drugs with specific inhibition of this axis. A combined IL17/IFN-y suppressive role was predicted for the antilipidemic drug Fenofibrate. To assess the immunregulatory action of Fenofibrate, we conducted in-vitro treatment of anti-CD3/CD28 stimulated human peripheral blood cells (PBMC), and, as predicted, Fenofibrate reduced IL17 and IFN-γ gene expression in stimulated PMBC. In-vivo Fenofibrate treatment of an experimental rodent model of cardiac AR reduced infiltration of total leukocytes, reduced expression of IL17/IFN-y and their pathway related genes in allografts and recipients' spleens, and extended graft survival by 21 days (p<0.007). In conclusion, this study provides important proof of concept that meta-analyses of genomic data and drug databases can provide new insights into the redundancy of the rejection response and presents an economic methodology to reposition FDA approved drugs in organ transplantation

An Interval-Valued Intuitionistic Fuzzy Bow-Tie Model (IVIF-BT) for the Effectiveness Evaluation of Safety Barriers in Natural Gas Storage Tank

Safety barriers (SBs) are important means of reducing failure risks of process systems. As barriers vary in type and function, their effectiveness needs to be evaluated in order to find a more reasonable configuration strategy. However, in practice, there is often a lack of accurate and complete data relating to SBs, which poses a significant challenge in quantitatively assessing their effectiveness. To address this issue, in this study, we propose a semi-quantitative approach for evaluating the effectiveness of both preventive and protective barriers in process systems by integrating expert elicitation, interval-valued intuitionistic fuzzy numbers (IVIFNs), and a bow-tie model. In this approach, the bow-tie model is first applied to describe the system failure scenarios and the action phases of the barriers, and then IVIFNs with expert judgment are introduced to obtain the failure probabilities of basic events and the effects of SBs. Subsequently, the effectiveness of each barrier is measured by comparing the relative change in failure risk due to the addition of the barrier. To verify the feasibility of this approach, a natural gas storage tank with some barriers was analyzed. The results show that the regular inspection of the deformation or damage of the storage tank has the highest effectiveness, followed by the installation and regular maintenance of safety electrical equipment. Furthermore, compared to a single barrier, multiple barriers can significantly reduce the system risk