Model Predictive Controlled Active NPC Inverter for Voltage Stress Balancing among the Semiconductor Power Switches

© Published under licence by IOP Publishing Ltd. This paper presents a model predictive controlled three-level three-phase active neutral-point-clamped (ANPC) inverter for distributing the voltage stress among the semiconductor power switches as well as balancing the neutral-point voltage. The model predictive control (MPC) concept uses the discrete variables and effectively operates the ANPC inverter by avoiding any linear controller or modulation techniques. A 4.0 kW three-level three-phase ANPC inverter is developed in the MATLAB/Simulink environment to verify the effectiveness of the proposed MPC scheme. The results confirm that the proposed model predictive controlled ANPC inverter equally distributes the voltage across all the semiconductor power switches and provides lowest THD (0.99%) compared with the traditional NPC inverter. Moreover, the neutral-point voltage balancing is accurately maintained by the proposed MPC algorithm. Furthermore, this MPC concept shows the robustness capability against the parameter uncertainties of the system which is also analyzed by MATLAB/Simulink

A novel method to detect translation of membrane proteins following microvesicle intercellular transfer of nucleic acids

© 2016 The Authors. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. Microvesicles (MVs) serve as vectors of nucleic-acid dissemination and are important mediators of intercellular communication. However, the functionality of packaged nucleic acids on recipient cells following transfer of MV cargo has not been clearly elucidated. This limitation is attributed to a lack of methodology available in assessing protein translation following homotypic intercellular transfer of nucleic acids. Using surface peptide shaving we have demonstrated that MVs derived from human leukaemic cells transfer functional P-glycoprotein transcripts, conferring drug-efflux capacity to recipient cells. We demonstrate expression of newly synthesized protein using Western blot. Furthermore, we show functionality of translated P-gp protein in recipient cells using Calcein-AM dye exclusion assays on flow cytometry. Newly synthesized 170 kDa P-gp was detected in recipient cells after coculture with shaven MVs and these proteins were functional, conferring drug efflux. This is the first demonstration of functionality of transferred nucleic acids between human homotypic cells as well as the translation of the cancer multidrug-resistance protein in recipient cells following intercellular transfer of its transcript. This study supports the significant role of MV's in the transfer of deleterious traits in cancer populations and describes a new paradigm in mechanisms governing the acquisition of traits in cancer cell populations

The role of CD44 and ERM proteins in expression and functionality of P-glycoprotein in breast cancer cells

© 2016 by the authors. Multidrug resistance (MDR) is often attributed to the over-expression of P-glycoprotein (P-gp), which prevents the accumulation of anticancer drugs within cells by virtue of its active drug efflux capacity. We have previously described the intercellular transfer of P-gp via extracellular vesicles (EVs) and proposed the involvement of a unique protein complex in regulating this process. In this paper, we investigate the role of these mediators in the regulation of P-gp functionality and hence the acquisition of MDR following cell to cell transfer. By sequentially silencing the FERM domain-binding proteins, Ezrin, Radixin and Moesin (ERM), as well as CD44, which we also report a selective packaging in breast cancer derived EVs, we have established a role for these proteins, in particular Radixin and CD44, in influencing the P-gp-mediated MDR in whole cells. We also report for the first time the role of ERM proteins in the vesicular transfer of functional P-gp. Specifically, we demonstrate that intercellular membrane insertion is dependent on Ezrin and Moesin, whilst P-gp functionality is governed by the integrity of all ERM proteins in the recipient cell. This study identifies these candidate proteins as potential new therapeutic targets in circumventing MDR clinically

Proteome analysis of multidrug-resistant, breast cancer-derived microparticles

© 2014 Deep Pokharel et al. Cancer multidrug resistance (MDR) occurswhen cancer cells evade the cytotoxic actions of chemotherapeutics through the active efflux of drugs from within the cells. Our group have previously demonstrated that multidrug-resistant breast cancer cells spontaneously shed microparticles (MPs) and that these MPs can transfer resistance to drug-responsive cells and confer MDR on those cells in as little as 4 h. Furthermore, we also showed that, unlike MPs derived from leukaemia cells, breast cancer-derived MPs display a tissue selectivity in the transfer of P-glycoprotein (P-gp), transferring the resistance protein only to malignant breast cells. This study aims to define the proteome of breast cancer-derived MPs in order to understand the differences in protein profiles between those shed from drug-resistant versus drug-sensitive breast cancer cells. In doing so, we detail the protein cargo required for the intercellular transfer of MDR to drug-sensitive recipient cells and the factors governing the transfer selectivity to malignant breast cells. We describe the first proteomic analysis of MPs derived from human breast cancer cells using SDS PAGE and liquid chromatography-tandem mass spectrometry (LC/MS/MS), in which we identify 120 unique proteins found only in drug-resistant, breast cancer-derived MPs. Our results demonstrate that the MP-mediated transfer of P-gp to recipient cells occurs alongside CD44; the Ezrin, Radixin and Moesin protein family (ERM); and cytoskeleton motor proteins within the MP cargo

Recovering probabilities for nucleotide trimming processes for T cell receptor TRA and TRG V-J junctions analyzed with IMGT tools

<p>Abstract</p> <p>Background</p> <p>Nucleotides are trimmed from the ends of variable (V), diversity (D) and joining (J) genes during immunoglobulin (IG) and T cell receptor (TR) rearrangements in B cells and T cells of the immune system. This trimming is followed by addition of nucleotides at random, forming the N regions (N for nucleotides) of the V-J and V-D-J junctions. These processes are crucial for creating diversity in the immune response since the number of trimmed nucleotides and the number of added nucleotides vary in each B or T cell. IMGT^®sequence analysis tools, IMGT/V-QUEST and IMGT/JunctionAnalysis, are able to provide detailed and accurate analysis of the final observed junction nucleotide sequences (tool "output"). However, as trimmed nucleotides can potentially be replaced by identical N region nucleotides during the process, the observed "output" represents a <it>biased </it>estimate of the "true trimming process."</p> <p>Results</p> <p>A probabilistic approach based on an analysis of the standardized tool "output" is proposed to infer the probability distribution of the "true trimmming process" and to provide plausible biological hypotheses explaining this process. We collated a benchmark dataset of TR alpha (TRA) and TR gamma (TRG) V-J rearranged sequences and junctions analysed with IMGT/V-QUEST and IMGT/JunctionAnalysis, the nucleotide sequence analysis tools from IMGT^®, the international ImMunoGeneTics information system^®, <url>http://imgt.cines.fr</url>. The standardized description of the tool output is based on the IMGT-ONTOLOGY axioms and concepts. We propose a simple first-order model that attempts to transform the observed "output" probability distribution into an estimate closer to the "true trimming process" probability distribution. We use this estimate to test the hypothesis that Poisson processes are involved in trimming. This hypothesis was not rejected at standard confidence levels for three of the four trimming processes: TRAV, TRAJ and TRGV.</p> <p>Conclusion</p> <p>By using trimming of rearranged TR genes as a benchmark, we show that a probabilistic approach, applied to IMGT^®standardized tool "outputs" opens the way to plausible hypotheses on the events involved in the "true trimming process" and eventually to an exact quantification of trimming itself. With increasing high-throughput of standardized immunogenetics data, similar probabilistic approaches will improve understanding of processes so far only characterized by the "output" of standardized tools.</p

Anisotropic crack propagation and deformation in dentin observed by four-dimensional X-ray nano-computed tomography

Understanding the cracking behaviour of biological composite materials is of practical importance. This paper presents the first study to track the interplay between crack initiation, microfracture and plastic deformation in three dimensions (3D) as a function of tubule and collagen fibril arrangement in elephant dentin using in situ X-ray nano-computed tomography (nano-CT). A nano-indenter with a conical tip has been used to incrementally indent three test-pieces oriented at 0°, 45° and 70° to the long axis of the tubules (i.e. radial to the tusk). For the 0° sample two significant cracks formed, one of which linked up with microcracks in the axial-radial plane of the tusk originating from the tubules and the other one occurred as a consequence of shear deformation at the tubules. The 70° test-piece was able to bear the greatest loads despite many small cracks forming around the indenter. These were diverted by the microstructure and did not propagate significantly. The 45° test-piece showed intermediate behaviour. In all cases strains obtained by digital volume correlation were well in excess of the yield strain (0.9%), indeed some plastic deformation could even be seen through bending of the tubules. The hoop strains around the conical indenter were anisotropic with the smallest strains correlating with the primary collagen orientation (axial to the tusk) and the largest strains aligned with the hoop direction of the tusk

The p.V37I Exclusive Genotype Of GJB2: A Genetic Risk-Indicator of Postnatal Permanent Childhood Hearing Impairment

Postnatal permanent childhood hearing impairment (PCHI) is frequent (0.25%–0.99%) and difficult to detect in the early stage, which may impede the speech, language and cognitive development of affected children. Genetic tests of common variants associated with postnatal PCHI in newborns may provide an efficient way to identify those at risk. In this study, we detected a strong association of the p.V37I exclusive genotype of GJB2 with postnatal PCHI in Chinese Hans (P = 1.4×10−10; OR 62.92, 95% CI 21.27–186.12). This common genotype in Eastern Asians was present in a substantial percentage (20%) of postnatal PCHI subjects, and its prevalence was significantly increased in normal-hearing newborns who failed at least one newborn hearing screen. Our results indicated that the p.V37I exclusive genotype of GJB2 may cause subclinical hearing impairment at birth and increases risk for postnatal PCHI. Genetic testing of GJB2 in East Asian newborns will facilitate prompt detection and intervention of postnatal PCHI

Can disordered mobile phone use be considered a behavioral addiction? An update on current evidence and a comprehensive model for future research

Despite the many positive outcomes, excessive mobile phone use is now often associated with potentially harmful and/or disturbing behaviors (e.g., symptoms of deregulated use, negative impact on various aspects of daily life such as relationship problems, and work intrusion). Problematic mobile phone use (PMPU) has generally been considered as a behavioral addiction that shares many features with more established drug addictions. In light of the most recent data, the current paper reviews the validity of the behavioral addiction model when applied to PMPU. On the whole, it is argued that the evidence supporting PMPU as an addictive behavior is scarce. In particular, it lacks studies that definitively show behavioral and neurobiological similarities between mobile phone addiction and other types of legitimate addictive behaviors. Given this context, an integrative pathway model is proposed that aims to provide a theoretical framework to guide future research in the field of PMPU. This model highlights that PMPU is a heterogeneous and multi-faceted condition

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON