HIVsirDB: a database of HIV inhibiting siRNAs.

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Atul Tyagi

Full Text Available Human immunodeficiency virus (HIV is responsible for millions of deaths every year. The current treatment involves the use of multiple antiretroviral agents that may harm patients due to their toxic nature. RNA interference (RNAi is a potent candidate for the future treatment of HIV, uses short interfering RNA (siRNA/shRNA for silencing HIV genes. In this study, attempts have been made to create a database HIVsirDB of siRNAs responsible for silencing HIV genes.HIVsirDB is a manually curated database of HIV inhibiting siRNAs that provides comprehensive information about each siRNA or shRNA. Information was collected and compiled from literature and public resources. This database contains around 750 siRNAs that includes 75 partially complementary siRNAs differing by one or more bases with the target sites and over 100 escape mutant sequences. HIVsirDB structure contains sixteen fields including siRNA sequence, HIV strain, targeted genome region, efficacy and conservation of target sequences. In order to facilitate user, many tools have been integrated in this database that includes; i siRNAmap for mapping siRNAs on target sequence, ii HIVsirblast for BLAST search against database, iii siRNAalign for aligning siRNAs.HIVsirDB is a freely accessible database of siRNAs which can silence or degrade HIV genes. It covers 26 types of HIV strains and 28 cell types. This database will be very useful for developing models for predicting efficacy of HIV inhibiting siRNAs. In summary this is a useful resource for researchers working in the field of siRNA based HIV therapy. HIVsirDB database is accessible at http://crdd.osdd.net/raghava/hivsir/.

Function and anatomy of plant siRNA pools derived from hairpin transgenes

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Lee Kevin AW

2007-11-01

Full Text Available Abstract Background RNA interference results in specific gene silencing by small-interfering RNAs (siRNAs. Synthetic siRNAs provide a powerful tool for manipulating gene expression but high cost suggests that novel siRNA production methods are desirable. Strong evolutionary conservation of siRNA structure suggested that siRNAs will retain cross-species function and that transgenic plants expressing heterologous siRNAs might serve as useful siRNA bioreactors. Here we report a detailed evaluation of the above proposition and present evidence regarding structural features of siRNAs extracted from plants. Results Testing the gene silencing capacity of plant-derived siRNAs in mammalian cells proved to be very challenging and required partial siRNA purification and design of a highly sensitive assay. Using the above assay we found that plant-derived siRNAs are ineffective for gene silencing in mammalian cells. Plant-derived siRNAs are almost exclusively double-stranded and most likely comprise a mixture of bona fide siRNAs and aberrant partially complementary duplexes. We also provide indirect evidence that plant-derived siRNAs may contain a hitherto undetected physiological modification, distinct from 3' terminal 2-O-methylation. Conclusion siRNAs produced from plant hairpin transgenes and extracted from plants are ineffective for gene silencing in mammalian cells. Thus our findings establish that a previous claim that transgenic plants offer a cost-effective, scalable and sustainable source of siRNAs is unwarranted. Our results also indicate that the presence of aberrant siRNA duplexes and possibly a plant-specific siRNA modification, compromises the gene silencing capacity of plant-derived siRNAs in mammalian cells.

MysiRNA-designer: a workflow for efficient siRNA design.

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Mohamed Mysara

Full Text Available The design of small interfering RNA (siRNA is a multi factorial problem that has gained the attention of many researchers in the area of therapeutic and functional genomics. MysiRNA score was previously introduced that improves the correlation of siRNA activity prediction considering state of the art algorithms. In this paper, a new program, MysiRNA-Designer, is described which integrates several factors in an automated work-flow considering mRNA transcripts variations, siRNA and mRNA target accessibility, and both near-perfect and partial off-target matches. It also features the MysiRNA score, a highly ranked correlated siRNA efficacy prediction score for ranking the designed siRNAs, in addition to top scoring models Biopredsi, DISR, Thermocomposition21 and i-Score, and integrates them in a unique siRNA score-filtration technique. This multi-score filtration layer filters siRNA that passes the 90% thresholds calculated from experimental dataset features. MysiRNA-Designer takes an accession, finds conserved regions among its transcript space, finds accessible regions within the mRNA, designs all possible siRNAs for these regions, filters them based on multi-scores thresholds, and then performs SNP and off-target filtration. These strict selection criteria were tested against human genes in which at least one active siRNA was designed from 95.7% of total genes. In addition, when tested against an experimental dataset, MysiRNA-Designer was found capable of rejecting 98% of the false positive siRNAs, showing superiority over three state of the art siRNA design programs. MysiRNA is a freely accessible (Microsoft Windows based desktop application that can be used to design siRNA with a high accuracy and specificity. We believe that MysiRNA-Designer has the potential to play an important role in this area.

siRNA delivery with lipid-based systems

DEFF Research Database (Denmark)

Foged, Camilla

2012-01-01

A key hurdle for the further development of RNA interference (RNAi) therapeutics like small interfering RNA (siRNA) is their safe and effective delivery. Lipids are promising and versatile carriers because they are based on Nature's own building blocks and can be provided with properties which......RNA into more hydrophobic lipoplexes, which promote passage of the siRNA across cellular membrane barriers, especially when lipids are added that facilitate membrane fusion. Despite these attractive features, siRNA delivery vehicles are facing a number of challenges such as the limited delivery efficiency...

Cancer-targeting siRNA delivery from porous silicon nanoparticles.

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Wan, Yuan; Apostolou, Sinoula; Dronov, Roman; Kuss, Bryone; Voelcker, Nicolas H

2014-10-01

Porous silicon nanoparticles (pSiNPs) with tunable pore size are biocompatible and biodegradable, suggesting that they are suitable biomaterials as vehicles for drug delivery. Loading of small interfering RNA (siRNA) into the pores of pSiNPs can protect siRNA from degradation as well as improve the cellular uptake. We aimed to deliver MRP1 siRNA loaded into pSiNPs to glioblastoma cells, and to demonstrate downregulation of MRP1 at the mRNA and protein levels. 50-220 nm pSiNPs with an average pore size of 26 nm were prepared, followed by electrostatic adsorption of siRNA into pores. Oligonucleotide loading and release profiles were investigated; MRP1 mRNA and protein expression, cell viability and cell apoptosis were studied. Approximately 7.7 µg of siRNA was loaded per mg of pSiNPs. Cells readily took up nanoparticles after 30 min incubation. siRNA-loaded pSiNPs were able to effectively downregulate target mRNA (~40%) and protein expression (31%), and induced cell apoptosis and necrosis (33%). siRNA loaded pSiNPs downregulated mRNA and protein expression and induced cell death. This novel siRNA delivery system may pave the way towards developing more effective tumor therapies.

Unconventional uranium transactions

International Nuclear Information System (INIS)

Anderson, S.C.

1981-01-01

The purpose of this paper is to describe some representative unconventional transactions which have been observed in the uranium market; to explain the circumstances giving rise to these transactions; and to describe the benefits resulting from these transactions. Unconventional transactions are usually quite specialized, since they are tailored to meet the particular needs of specific market participants. Nevertheless, most of these transactions fall into the following basic categories: multi-party (back-to-back; bridge); swap (deconversion; nationality); barter; inventory financing (leasing with repurchase obligation; sale with repurchase option). These transactions are explained and discussed. (U.K.)

Transactional Memory

CERN Document Server

Harris, Tim; Rajwar, Ravi

2010-01-01

The advent of multicore processors has renewed interest in the idea of incorporating transactions into the programming model used to write parallel programs.This approach, known as transactional memory, offers an alternative, and hopefully better, way to coordinate concurrent threads. The ACI(atomicity, consistency, isolation) properties of transactions provide a foundation to ensure that concurrent reads and writes of shared data do not produce inconsistent or incorrect results. At a higher level, a computation wrapped in a transaction executes atomically - either it completes successfullyand

New insights into siRNA amplification and RNAi.

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Zhang, Chi; Ruvkun, Gary

2012-08-01

In the nematode Caenorhabditis elegans (C. elegans), gene inactivation by RNA interference can achieve remarkable potency due to the amplification of initial silencing triggers by RNA-dependent RNA polymerases (RdRPs). RdRPs catalyze the biogenesis of an abundant species of secondary small interfering RNAs (siRNAs) using the target mRNA as template. The interaction between primary siRNAs derived from the exogenous double-stranded RNA (dsRNA) trigger and the target mRNA is required for the recruitment of RdRPs. Other genetic requirements for RdRP activities have not been characterized. Recent studies have identified the RDE-10/RDE-11 complex which interacts with the primary siRNA bound target mRNA and acts upstream of the RdRPs. rde-10 and rde-11 mutants show an RNAi defective phenotype because the biogenesis of secondary siRNAs is completely abolished. In addition, the RDE-10/RDE-11 complex plays a similar role in the endogenous RNAi pathway for the biogenesis of a subset of siRNAs targeting recently acquired, duplicated genes.

Pathways of cellular internalisation of liposomes delivered siRNA and effects on siRNA engagement with target mRNA and silencing in cancer cells.

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Alshehri, Abdullah; Grabowska, Anna; Stolnik, Snow

2018-02-28

Design of an efficient delivery system is a generally recognised bottleneck in translation of siRNA technology into clinic. Despite research efforts, cellular processes that determine efficiency of siRNA silencing achieved by different delivery formulations remain unclear. Here, we investigated the mechanism(s) of cellular internalisation of a model siRNA-loaded liposome system in a correlation to the engagement of delivered siRNA with its target and consequent silencing by adopting siRNA molecular beacon technology. Probing of cellular internalisation pathways by a panel of pharmacological inhibitors indicated that clathrin-mediated (dynamin-dependent) endocytosis, macropinocytosis (dynamine independent), and cell membrane cholesterol dependent process(es) (clathrin and caveolea-independent) all play a role in the siRNA-liposomes internalization. The inhibition of either of these entry routes was, in general, mirrored by a reduction in the level of siRNA engagement with its target mRNA, as well as in a reduction of the target gene silencing. A dramatic increase in siRNA engagement with its target RNA was observed on disruption of endosomal membrane (by chloroquine), accompanied with an increased silencing. The work thus illustrates that employing molecular beacon siRNA technology one can start to assess the target RNA engagement - a stage between initial cellular internalization and final gene silencing of siRNA delivery systems.

SiRNA Crosslinked Nanoparticles for the Treatment of Inflammation-induced Liver Injury.

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Tang, Yaqin; Zeng, Ziying; He, Xiao; Wang, Tingting; Ning, Xinghai; Feng, Xuli

2017-02-01

RNA interference mediated by small interfering RNA (siRNA) provides a powerful tool for gene regulation, and has a broad potential as a promising therapeutic strategy. However, therapeutics based on siRNA have had limited clinical success due to their undesirable pharmacokinetic properties. This study presents pH-sensitive nanoparticles-based siRNA delivery systems (PNSDS), which are positive-charge-free nanocarriers, composed of siRNA chemically crosslinked with multi-armed poly(ethylene glycol) carriers via acid-labile acetal linkers. The unique siRNA crosslinked structure of PNSDS allows it to have minimal cytotoxicity, high siRNA loading efficiency, and a stimulus-responsive property that enables the selective intracellular release of siRNA in response to pH conditions. This study demonstrates that PNSDS can deliver tumor necrosis factor alpha (TNF-α) siRNA into macrophages and induce the efficient down regulation of the targeted gene in complete cell culture media. Moreover, PNSDS with mannose targeting moieties can selectively accumulate in mice liver, induce specific inhibition of macrophage TNF-α expression in vivo, and consequently protect mice from inflammation-induced liver damages. Therefore, this novel siRNA delivering platform would greatly improve the therapeutic potential of RNAi based therapies.

siRNAmod: A database of experimentally validated chemically modified siRNAs.

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Dar, Showkat Ahmad; Thakur, Anamika; Qureshi, Abid; Kumar, Manoj

2016-01-28

Small interfering RNA (siRNA) technology has vast potential for functional genomics and development of therapeutics. However, it faces many obstacles predominantly instability of siRNAs due to nuclease digestion and subsequently biologically short half-life. Chemical modifications in siRNAs provide means to overcome these shortcomings and improve their stability and potency. Despite enormous utility bioinformatics resource of these chemically modified siRNAs (cm-siRNAs) is lacking. Therefore, we have developed siRNAmod, a specialized databank for chemically modified siRNAs. Currently, our repository contains a total of 4894 chemically modified-siRNA sequences, comprising 128 unique chemical modifications on different positions with various permutations and combinations. It incorporates important information on siRNA sequence, chemical modification, their number and respective position, structure, simplified molecular input line entry system canonical (SMILES), efficacy of modified siRNA, target gene, cell line, experimental methods, reference etc. It is developed and hosted using Linux Apache MySQL PHP (LAMP) software bundle. Standard user-friendly browse, search facility and analysis tools are also integrated. It would assist in understanding the effect of chemical modifications and further development of stable and efficacious siRNAs for research as well as therapeutics. siRNAmod is freely available at: http://crdd.osdd.net/servers/sirnamod.

Managerial accounting for transaction costs

OpenAIRE

Лабынцев, Николай Тихонович

2015-01-01

Essence and significance of transaction accounting and its basic concepts – transaction and transaction costs – have been determined. Main types of transaction costs and elements of transaction accounting for expenses have been considered. Source documents forms for the purpose of accounting for transaction costs have been worked out.

Thermo-sensitive nanoparticles for triggered release of siRNA.

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Yang, Zheng; Cheng, Qiang; Jiang, Qian; Deng, Liandong; Liang, Zicai; Dong, Anjie

2015-01-01

Efficient delivery of small interfering RNA (siRNA) is crucially required for cancer gene therapy. Herein, a thermo-sensitive copolymer with a simple structure, poly (ethylene glycol) methyl ether acrylate-b-poly (N-isopropylacrylamide) (mPEG-b-PNIPAM) was developed. A novel kind of thermo-sensitive nanoparticles (DENPs) was constructed for the cold-shock triggered release of siRNA by double emulsion-solvent evaporation method using mPEG-b-PNIPAM and a cationic lipid, 3β [N-(N', N'-dimethylaminoethane)-carbamoyl] cholesterol [DC-Chol]. DENPs were observed by transmission electron microscopy and dynamical light scattering before and after 'cold shock' treatment. The encapsulation efficiency (EE) of siRNA in DENPs, which was measured by fluorescence spectrophotometer was 96.8% while it was significantly reduced to be 23.2% when DC-Chol was absent. DENPs/siRNA NPs exhibited a thermo-sensitive siRNA release character that the cumulatively released amount of siRNA from cold shock was approximately 2.2 folds higher after 7 days. In vitro luciferase silencing experiments indicated that DENPs showed potent gene silencing efficacy in HeLa-Luc cells (HeLa cells steadily expressed luciferase), which was further enhanced by a cold shock. Furthermore, MTT assay showed that cell viability with DENPs/siRNA up to 200 nM remained above 80%. We also observed that most of siRNA was accumulated in kidney mediated by DENPs instead of liver and spleen in vivo experiments. Thus, DENPs as a cold shock responsive quick release model for siRNA or hydrophilic macromolecules delivery provide a new way to nanocarrier design and clinic therapy.

High-throughput screening of effective siRNAs using luciferase-linked chimeric mRNA.

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Shen Pang

Full Text Available The use of siRNAs to knock down gene expression can potentially be an approach to treat various diseases. To avoid siRNA toxicity the less transcriptionally active H1 pol III promoter, rather than the U6 promoter, was proposed for siRNA expression. To identify highly efficacious siRNA sequences, extensive screening is required, since current computer programs may not render ideal results. Here, we used CCR5 gene silencing as a model to investigate a rapid and efficient screening approach. We constructed a chimeric luciferase-CCR5 gene for high-throughput screening of siRNA libraries. After screening approximately 900 shRNA clones, 12 siRNA sequences were identified. Sequence analysis demonstrated that most (11 of the 12 sequences of these siRNAs did not match those identified by available siRNA prediction algorithms. Significant inhibition of CCR5 in a T-lymphocyte cell line and primary T cells by these identified siRNAs was confirmed using the siRNA lentiviral vectors to infect these cells. The inhibition of CCR5 expression significantly protected cells from R5 HIV-1JRCSF infection. These results indicated that the high-throughput screening method allows efficient identification of siRNA sequences to inhibit the target genes at low levels of expression.

Albumin-mediated delivery of siRNA

DEFF Research Database (Denmark)

Bienk, Konrad

2015-01-01

. The human body, however, possesses several natural transport mechanisms for active transport of molecules. Amongst these is albumin, which is the most abundant plasma protein and has a circulatory half-life of ~21 days, partially due to engagement and recycling by the neonatal Fc receptor (FcRn). Albumin...... vehicle. This proof of concept silencing showed that siRNA can be used for therapeutic purposes without the use of non-biocompatible polymer or lipid materials. This work, therefore, provides a novel technology platform for the safe delivery of siRNA therapeutics....

Solid nano-in-nanoparticles for potential delivery of siRNA.

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Amsalem, Orit; Nassar, Taher; Benhamron, Sandrine; Lazarovici, Philip; Benita, Simon; Yavin, Eylon

2017-07-10

siRNA-based therapeutics possess great potential to treat a wide variety of genetic disorders. However, they suffer from low cellular uptake and short half-lives in blood circulation; issues that remain to be addressed. This work is, to the best of our knowledge, the first to report the production of solid nano-in-nanoparticles, termed double nano carriers (DNCs) by means of the innovative technology of nano spray drying. DNCs (with a median size of 580-770nm) were produced by spraying at low temperatures (50°C) to prevent damage to heat-sensitive biomacromolecules like siRNA. DNCs consisting of Poly (d,l-lactide-co-glycolide) used as a wall material, encapsulating 20% human serum albumin primary nanoparticles (PNPs) loaded with siRNA, were obtained as a dry nanoparticulate powder with smooth spherical surfaces and a unique inner morphology. Incubation of pegylated or non-pegylated DNCs under sink conditions at 37°C, elicited a controlled release profile of the siRNA for up to 12 or 24h, respectively, with a minimal burst effect. Prolonged incubation of pegylated DNCs loaded with active siRNA (anti EGFR) in an A549 epithelial cell culture monolayer did not induce any apparent cytotoxicity. A slow degradation of the internalized DNCs by the cells was also observed resulting in the progressive release of the siRNA for up to 6days, as corroborated by laser confocal microscopy. The structural integrity and silencing activity of the double encapsulated siRNA were fully preserved, as demonstrated by HPLC, gel electrophoresis, and potent RNAi activity of siRNA extracted from DNCs. These results demonstrate the potential use of DNCs as a nano drug delivery system for systemic administration and controlled release of siRNA and potentially other sensitive bioactive macromolecules. Copyright © 2016 Elsevier B.V. All rights reserved.

[Efficacy of siRNA on feline leukemia virus replication in vitro].

Science.gov (United States)

Lehmann, Melanie; Weber, Karin; Rauch, Gisep; Hofmann-Lehmann, Regina; Hosie, Margaret J; Meli, Marina L; Hartmann, Katrin

2015-01-01

Feline leukemia virus (FeLV) can lead to severe clinical signs in cats. Until now, there is no effective therapy for FeLV-infected cats. RNA interference-based antiviral therapy is a new concept. Specific small interfering RNA (siRNA) are designed complementary to the mRNA of a target region, and thus inhibit replication. Several studies have proven efficacy of siRNAs in inhibiting virus replication. The aim of this study was to evaluate the inhibitory potential of siRNAs against FeLV replication in vitro. siRNAs against the FeLV env gene and the host cell surface receptor (feTHTR1) which is used by FeLV-A for entry as well as siRNA that were not complementary to the FeLV or cat genome, were tested. Crandell feline kidney cells (CrFK cells) were transfected with FeLV-A/Glasgow-1. On day 13, infected cells were transfected with siRNAs. As control, cells were mock-transfected or treated with azidothymidine (AZT) (5 μg/ml). Culture supernatants were analyzed for FeLV RNA using quantitative real-time RT-PCR and for FeLV p27 by ELISA every 24 hours for five days. All siRNAs significantly reduced viral RNA and p27 production, starting after 48 hours. The fact that non-complementary siRNAs also inhibited virus replication may lead to the conclusion that unspecific mechanisms rather than specific binding lead to inhibition.

Functional characterization of endogenous siRNA target genes in Caenorhabditis elegans

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Heikkinen Liisa

2008-06-01

Full Text Available Abstract Background Small interfering RNA (siRNA molecules mediate sequence specific silencing in RNA interference (RNAi, a gene regulatory phenomenon observed in almost all organisms. Large scale sequencing of small RNA libraries obtained from C. elegans has revealed that a broad spectrum of siRNAs is endogenously transcribed from genomic sequences. The biological role and molecular diversity of C. elegans endogenous siRNA (endo-siRNA molecules, nonetheless, remain poorly understood. In order to gain insight into their biological function, we annotated two large libraries of endo-siRNA sequences, identified their cognate targets, and performed gene ontology analysis to identify enriched functional categories. Results Systematic trends in categorization of target genes according to the specific length of siRNA sequences were observed: 18- to 22-mer siRNAs were associated with genes required for embryonic development; 23-mers were associated uniquely with post-embryonic development; 24–26-mers were associated with phosphorus metabolism or protein modification. Moreover, we observe that some argonaute related genes associate with siRNAs with multiple reads. Sequence frequency graphs suggest that different lengths of siRNAs share similarities in overall sequence structure: the 5' end begins with G, while the body predominates with U and C. Conclusion These results suggest that the lengths of endogenous siRNA molecules are consequential to their biological functions since the gene ontology categories for their cognate mRNA targets vary depending upon their lengths.

Dendrimers for siRNA Delivery

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Swati Biswas

2013-02-01

Full Text Available Since the discovery of the “starburst polymer”, later renamed as dendrimer, this class of polymers has gained considerable attention for numerous biomedical applications, due mainly to the unique characteristics of this macromolecule, including its monodispersity, uniformity, and the presence of numerous functionalizable terminal groups. In recent years, dendrimers have been studied extensively for their potential application as carriers for nucleic acid therapeutics, which utilize the cationic charge of the dendrimers for effective dendrimer-nucleic acid condensation. siRNA is considered a promising, versatile tool among various RNAi-based therapeutics, which can effectively regulate gene expression if delivered successfully inside the cells. This review reports on the advancements in the development of dendrimers as siRNA carriers.

Production and processing of siRNA precursor transcripts from the highly repetitive maize genome.

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Christopher J Hale

2009-08-01

Full Text Available Mutations affecting the maintenance of heritable epigenetic states in maize identify multiple RNA-directed DNA methylation (RdDM factors including RMR1, a novel member of a plant-specific clade of Snf2-related proteins. Here we show that RMR1 is necessary for the accumulation of a majority of 24 nt small RNAs, including those derived from Long-Terminal Repeat (LTR retrotransposons, the most common repetitive feature in the maize genome. A genetic analysis of DNA transposon repression indicates that RMR1 acts upstream of the RNA-dependent RNA polymerase, RDR2 (MOP1. Surprisingly, we show that non-polyadenylated transcripts from a sampling of LTR retrotransposons are lost in both rmr1 and rdr2 mutants. In contrast, plants deficient for RNA Polymerase IV (Pol IV function show an increase in polyadenylated LTR RNA transcripts. These findings support a model in which Pol IV functions independently of the small RNA accumulation facilitated by RMR1 and RDR2 and support that a loss of Pol IV leads to RNA Polymerase II-based transcription. Additionally, the lack of changes in general genome homeostasis in rmr1 mutants, despite the global loss of 24 nt small RNAs, challenges the perceived roles of siRNAs in maintaining functional heterochromatin in the genomes of outcrossing grass species.

Investigating the cognitive precursors of emotional response to cancer stress: re-testing Lazarus's transactional model.

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Hulbert-Williams, N J; Morrison, V; Wilkinson, C; Neal, R D

2013-02-01

Lazarus's Transactional Model of stress and coping underwent significant theoretical development through the 1990s to better incorporate emotional reactions to stress with their appraisal components. Few studies have robustly explored the full model. This study aimed to do so within the context of a major life event: cancer diagnosis. A repeated measures design was used whereby data were collected using self-report questionnaire at baseline (soon after diagnosis), and 3- and 6-month follow-up. A total of 160 recently diagnosed cancer patients were recruited (mean time since diagnosis = 46 days). Their mean age was 64.2 years. Data on appraisals, core-relational themes, and emotions were collected. Data were analysed using both Spearman's correlation tests and multivariate regression modelling. Longitudinal analysis demonstrated weak correlation between change scores of theoretically associated components and some emotions correlated more strongly with cognitions contradicting theoretical expectations. Cross-sectional multivariate testing of the ability of cognitions to explain variance in emotion was largely theory inconsistent. Although data support the generic structure of the Transactional Model, they question the model specifics. Larger scale research is needed encompassing a wider range of emotions and using more complex statistical testing. WHAT IS ALREADY KNOWN ON THIS SUBJECT?: • Stress processes are transactional and coping outcome is informed by both cognitive appraisal of the stressor and the individual's emotional response (Lazarus & Folkman, 1984). • Lazarus (1999) made specific hypotheses about which particular stress appraisals would determine which emotional response, but only a small number of these relationships have been robustly investigated. • Previous empirical testing of this theory has been limited by design and statistical limitations. WHAT DOES THIS STUDY ADD?: • This study empirically investigates the cognitive precedents of a

Efficient siRNA delivery system using carboxilated single-wall carbon nanotubes in cancer treatment.

Science.gov (United States)

Neagoe, Ioana Berindan; Braicu, Cornelia; Matea, Cristian; Bele, Constantin; Florin, Graur; Gabriel, Katona; Veronica, Chedea; Irimie, Alexandru

2012-08-01

Several functionalized carbon nanotubes have been designed and tested for the purpose of nucleic acid delivery. In this study, the capacity of SWNTC-COOH for siRNA deliverey were investigated delivery in parallel with an efficient commercial system. Hep2G cells were reverse-transfected with 50 nM siRNA (p53 siRNA, TNF-alphasiRNA, VEGFsiRNA) using the siPORT NeoFX (Ambion) transfection agent in paralel with SWNTC-COOH, functionalised with siRNA. The highest level of gene inhibition was observed in the cases treated with p53 siRNA gene; in the case of transfection with siPort, the NeoFX value was 33.8%, while in the case of SWNTC-COOH as delivery system for p53 siRNA was 37.5%. The gene silencing capacity for VEGF was 53.7%, respectively for TNF-alpha 56.7% for siPORT NeoFX delivery systems versus 47.7% (VEGF) and 46.5% (TNF-alpha) for SWNTC-COOH delivery system. SWNTC-COOH we have been showed to have to be an efficient carrier system. The results from the inhibition of gene expresion for both transfection systems were confirmed at protein level. Overall, the lowest mRNA expression was confirmed at protein level, especially in the case of p53 siRNA and TNF-alpha siRNA transfection. Less efficient reduction protein expressions were observed in the case of VEGF siRNA, for both transfection systems at 24 h; only at 48 h, there was a statistically significant reduction of VEGF protein expression. SWCNT-COOH determined an efficient delivery of siRNA. SWNTC-COOH, combined with suitable tumor markers like p53 siRNA, TNFalpha siRNA or VEGF siRNA can be used for the efficient delivery of siRNA.

Smart Inulin-Based Polycationic Nanodevices for siRNA Delivery.

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Cavallaro, G; Sardo, C; Scialabba, C; Licciardi, M; Giammona, G

2017-01-01

The advances of short interfering RNA (siRNA) mediated therapy provide a powerful option for the treatment of many diseases by silencing the expression of targeted genes including cancer development and progression. Inulin is a very simple and biocompatible polysaccharide proposed by our groups to produce interesting delivery systems for Nucleic Acid Based Drugs (NABDs), such as siRNA, either as polycations able to give polyplexes and polymeric coatings for nanosystems having a metallic core. In this research field, different functionalizing groups were linked to the inulin backbone with specific aims including oligoamine such as Ethylendiammine (EDA), Diethylediamine (DETA), Spermine, (SPM) etc. In this contribution the main Inulin-based nanodevices for the delivery of siRNA have been reported, analysed and compared with particular reference to their chemical design and structure, biocompatibility, siRNA complexing ability, silencing ability. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Overcoming the Challenges of siRNA Delivery: Nanoparticle Strategies.

Science.gov (United States)

Shajari, Neda; Mansoori, Behzad; Davudian, Sadaf; Mohammadi, Ali; Baradaran, Behzad

2017-01-01

Despite therapeutics based on siRNA have an immense potential for the treatment of incurable diseases such as cancers. However, the in vivo utilization of siRNA and also the delivery of this agent to the target site is one of the most controversial challenges. The helpful assistance by nanoparticles can improve stable delivery and also enhance efficacy. More nanoparticle-based siRNA therapeutics is expected to become available in the near future. The search strategy followed the guidelines of the Centre of Reviews and Dissemination. The studies were identified from seven databases (Scopus, Web of Science, Academic Search Premiere, CINAHL, Medline Ovid, Eric and Cochrane Library). Studies was selected based on titles, abstracts and full texts. One hundred twenty nine papers were included in the review. These papers defined hurdles in RNAi delivery and also strategies to overcome these hurdles. This review discussed the existing hurdles for systemic administration of siRNA as therapeutic agents and highlights the various strategies to overcome these hurdles, including lipid-based nanoparticles and polymeric nanoparticles, and we also briefly reviewed chemical modification. Delivery of siRNA to the target site is the biggest challenge for its application in the clinic. The findings of this review confirmed by encapsulation siRNA in the nanoparticles can overcome these challenges. The rapid progress in nanotechnology has enabled the development of effective nanoparticles as the carrier for siRNA delivery. However, our data about siRNA-based therapeutics and also nanomedicine are still limited. More clinical data needs to be completely understood in the benefits and drawbacks of siRNA-based therapeutics. Prospective studies must pay attention to the in vivo safety profiles of the different delivery systems, including uninvited immune system stimulation and cytotoxicity. In essence, the development of nontoxic, biocompatible, and biodegradable delivery systems for

Assorted Processing of Synthetic Trans-Acting siRNAs and Its Activity in Antiviral Resistance.

Science.gov (United States)

Zhao, Mingmin; San León, David; Mesel, Frida; García, Juan Antonio; Simón-Mateo, Carmen

2015-01-01

The use of syn-tasiRNAs has been proposed as an RNA interference technique alternative to those previously described: hairpin based, virus induced gene silencing or artificial miRNAs. In this study we engineered the TAS1c locus to impair Plum pox virus (PPV) infection by replacing the five native siRNAs with two 210-bp fragments from the CP and the 3´NCR regions of the PPV genome. Deep sequencing analysis of the small RNA species produced by both constructs in planta has shown that phased processing of the syn-tasiRNAs is construct-specific. While in syn-tasiR-CP construct the processing was as predicted 21-nt phased in register with miR173-guided cleavage, the processing of syn-tasiR-3NCR is far from what was expected. A 22-nt species from the miR173-guided cleavage was a guide of two series of phased small RNAs, one of them in an exact 21-nt register, and the other one in a mixed of 21-/22-nt frame. In addition, both constructs produced abundant PPV-derived small RNAs in the absence of miR173 as a consequence of a strong sense post-transcriptional gene silencing induction. The antiviral effect of both constructs was also evaluated in the presence or absence of miR173 and showed that the impairment of PPV infection was not significantly higher when miR173 was present. The results show that syn-tasiRNAs processing depends on construct-specific factors that should be further studied before the so-called MIGS (miRNA-induced gene silencing) technology can be used reliably.

Assorted Processing of Synthetic Trans-Acting siRNAs and Its Activity in Antiviral Resistance.

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Mingmin Zhao

Full Text Available The use of syn-tasiRNAs has been proposed as an RNA interference technique alternative to those previously described: hairpin based, virus induced gene silencing or artificial miRNAs. In this study we engineered the TAS1c locus to impair Plum pox virus (PPV infection by replacing the five native siRNAs with two 210-bp fragments from the CP and the 3´NCR regions of the PPV genome. Deep sequencing analysis of the small RNA species produced by both constructs in planta has shown that phased processing of the syn-tasiRNAs is construct-specific. While in syn-tasiR-CP construct the processing was as predicted 21-nt phased in register with miR173-guided cleavage, the processing of syn-tasiR-3NCR is far from what was expected. A 22-nt species from the miR173-guided cleavage was a guide of two series of phased small RNAs, one of them in an exact 21-nt register, and the other one in a mixed of 21-/22-nt frame. In addition, both constructs produced abundant PPV-derived small RNAs in the absence of miR173 as a consequence of a strong sense post-transcriptional gene silencing induction. The antiviral effect of both constructs was also evaluated in the presence or absence of miR173 and showed that the impairment of PPV infection was not significantly higher when miR173 was present. The results show that syn-tasiRNAs processing depends on construct-specific factors that should be further studied before the so-called MIGS (miRNA-induced gene silencing technology can be used reliably.

Nanocapsule-mediated cytosolic siRNA delivery for anti-inflammatory treatment.

Science.gov (United States)

Jiang, Ying; Hardie, Joseph; Liu, Yuanchang; Ray, Moumita; Luo, Xiang; Das, Riddha; Landis, Ryan F; Farkas, Michelle E; Rotello, Vincent M

2018-06-05

The use of nanoparticle-stabilized nanocapsules for cytosolic siRNA delivery for immunomodulation in vitro and in vivo is reported. These NPSCs deliver siRNA directly to the cytosol of macrophages in vitro with concomitant knockdown of gene expression. In vivo studies showed directed delivery of NPSCs to the spleen, enabling gene silencing of macrophages, with preliminary studies showing 70% gene knockdown at a siRNA dose of 0.28 mg/kg. Significantly, the delivery of siRNA targeting tumor necrosis factor-α efficiently silenced TNF-α expression in LPS-challenged mice, demonstrating efficacy in modulating immune response in an organ-selective manner. This research highlights the potential of the NPSC platform for targeted immunotherapy and further manipulation of the immune system. Copyright © 2018 Elsevier B.V. All rights reserved.

Bioreducible poly(amido amine)s for siRNA delivery

NARCIS (Netherlands)

van der Aa, L.J.

2011-01-01

Successes in RNA interference based therapies are still limited due to the lack of efficient delivery of the mediator, small interfering RNA (siRNA), to the targeted site. The key to success can be the delivery of the siRNA molecules by polymer-based carrier systems, since they can be chemically

A novel program to design siRNAs simultaneously effective to highly variable virus genomes.

Science.gov (United States)

Lee, Hui Sun; Ahn, Jeonghyun; Jun, Eun Jung; Yang, Sanghwa; Joo, Chul Hyun; Kim, Yoo Kyum; Lee, Heuiran

2009-07-10

A major concern of antiviral therapy using small interfering RNAs (siRNAs) targeting RNA viral genome is high sequence diversity and mutation rate due to genetic instability. To overcome this problem, it is indispensable to design siRNAs targeting highly conserved regions. We thus designed CAPSID (Convenient Application Program for siRNA Design), a novel bioinformatics program to identify siRNAs targeting highly conserved regions within RNA viral genomes. From a set of input RNAs of diverse sequences, CAPSID rapidly searches conserved patterns and suggests highly potent siRNA candidates in a hierarchical manner. To validate the usefulness of this novel program, we investigated the antiviral potency of universal siRNA for various Human enterovirus B (HEB) serotypes. Assessment of antiviral efficacy using Hela cells, clearly demonstrates that HEB-specific siRNAs exhibit protective effects against all HEBs examined. These findings strongly indicate that CAPSID can be applied to select universal antiviral siRNAs against highly divergent viral genomes.

17 CFR 37.8 - Information relating to transactions on derivatives transaction execution facilities.

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Information relating to transactions on derivatives transaction execution facilities. 37.8 Section 37.8 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES TRANSACTION EXECUTION FACILITIES § 37.8...

Targeted delivery of anti-coxsackievirus siRNAs using ligand-conjugated packaging RNAs.

Science.gov (United States)

Zhang, Huifang M; Su, Yue; Guo, Songchuan; Yuan, Ji; Lim, Travis; Liu, Jing; Guo, Peixuan; Yang, Decheng

2009-09-01

Coxsackievirus B3 (CVB3) is a common pathogen of myocarditis. We previously synthesized a siRNA targeting the CVB3 protease 2A (siRNA/2A) gene and achieved reduction of CVB3 replication by 92% in vitro. However, like other drugs under development, CVB3 siRNA faces a major challenge of targeted delivery. In this study, we investigated a novel approach to deliver CVB3 siRNAs to a specific cell population (e.g. HeLa cells containing folate receptor) using receptor ligand (folate)-linked packaging RNA (pRNA) from bacterial phage phi29. pRNA monomers can spontaneously form dimers and multimers under optimal conditions by base-pairing between their stem loops. By covalently linking a fluorescence-tag to folate, we delivered the conjugate specifically to HeLa cells without the need of transfection. We further demonstrated that pRNA covalently conjugated to siRNA/2A achieved an equivalent antiviral effect to that of the siRNA/2A alone. Finally, the drug targeted delivery was further evaluated by using pRNA monomers or dimers, which carried both the siRNA/2A and folate ligand and demonstrated that both of them strongly inhibited CVB3 replication. These data indicate that pRNA as a siRNA carrier can specifically deliver the drug to target cells via its ligand and specific receptor interaction and inhibit virus replication effectively.

Treating respiratory viral diseases with chemically modified, second generation intranasal siRNAs.

Science.gov (United States)

Barik, Sailen

2009-01-01

Chemically synthesized short interfering RNA (siRNA) of pre-determined sequence has ushered a new era in the application of RNA interference (RNAi) against viral genes. We have paid particular attention to respiratory viruses that wreak heavy morbidity and mortality worldwide. The clinically significant ones include respiratory syncytial virus (RSV), parainfluenza virus (PIV) and influenza virus. As the infection by these viruses is clinically restricted to the respiratory tissues, mainly the lungs, the logical route for the application of the siRNA was also the same, i.e., via the nasal route. Following the initial success of intranasal siRNA against RSV, second-generation siRNAs were made against the viral polymerase large subunit (L) that were chemically modified and screened for improved stability, activity and pharmacokinetics. 2'-O-methyl (2'-O-Me) and 2'-deoxy-2'-fluoro (2'-F) substitutions in the ribose ring were incorporated in different positions of the sense and antisense strands and the resultant siRNAs were tested with various transfection reagents intranasally against RSV. Based on these results, we propose the following consensus for designing intranasal antiviral siRNAs: (i) modified 19-27 nt long double-stranded siRNAs are functional in the lung, (ii) excessive 2'-OMe and 2'-F modifications in either or both strands of these siRNAs reduce efficacy, and (iii) limited modifications in the sense strand are beneficial, although their precise efficacy may be position-dependent.

Delivery systems and local administration routes for therapeutic siRNA.

Science.gov (United States)

Vicentini, Fabiana Testa Moura de Carvalho; Borgheti-Cardoso, Lívia Neves; Depieri, Lívia Vieira; de Macedo Mano, Danielle; Abelha, Thais Fedatto; Petrilli, Raquel; Bentley, Maria Vitória Lopes Badra

2013-04-01

With the increasing number of studies proposing new and optimal delivery strategies for the efficacious silencing of gene-related diseases by the local administration of siRNAs, the present review aims to provide a broad overview of the most important and latest developments of non-viral siRNA delivery systems for local administration. Moreover, the main disease targets for the local delivery of siRNA to specific tissues or organs, including the skin, the lung, the eye, the nervous system, the digestive system and the vagina, were explored.

Managing transaction risks in interdependent supply chains: an extended transaction cost economics perspective

NARCIS (Netherlands)

Wever, M.; Wognum, P.M.; Trienekens, J.H.; Omta, S.W.F.

2012-01-01

The present study examines the management of transaction risks in supply chains. Risk management studies often ignore the wider supply chain context in which individual transactions take place. However, risk management strategies which are suitable to use when only a single transaction is considered

Dendrimers as Carriers for siRNA Delivery and Gene Silencing: A Review

Directory of Open Access Journals (Sweden)

Jiangyu Wu

2013-01-01

Full Text Available RNA interference (RNAi was first literaturally reported in 1998 and has become rapidly a promising tool for therapeutic applications in gene therapy. In a typical RNAi process, small interfering RNAs (siRNA are used to specifically downregulate the expression of the targeted gene, known as the term “gene silencing.” One key point for successful gene silencing is to employ a safe and efficient siRNA delivery system. In this context, dendrimers are emerging as potential nonviral vectors to deliver siRNA for RNAi purpose. Dendrimers have attracted intense interest since their emanating research in the 1980s and are extensively studied as efficient DNA delivery vectors in gene transfer applications, due to their unique features based on the well-defined and multivalent structures. Knowing that DNA and RNA possess a similar structure in terms of nucleic acid framework and the electronegative nature, one can also use the excellent DNA delivery properties of dendrimers to develop effective siRNA delivery systems. In this review, the development of dendrimer-based siRNA delivery vectors is summarized, focusing on the vector features (siRNA delivery efficiency, cytotoxicity, etc. of different types of dendrimers and the related investigations on structure-activity relationship to promote safe and efficient siRNA delivery system.

Dendrimers as Carriers for siRNA Delivery and Gene Silencing: A Review

Science.gov (United States)

Huang, Weizhe; He, Ziying

2013-01-01

RNA interference (RNAi) was first literaturally reported in 1998 and has become rapidly a promising tool for therapeutic applications in gene therapy. In a typical RNAi process, small interfering RNAs (siRNA) are used to specifically downregulate the expression of the targeted gene, known as the term “gene silencing.” One key point for successful gene silencing is to employ a safe and efficient siRNA delivery system. In this context, dendrimers are emerging as potential nonviral vectors to deliver siRNA for RNAi purpose. Dendrimers have attracted intense interest since their emanating research in the 1980s and are extensively studied as efficient DNA delivery vectors in gene transfer applications, due to their unique features based on the well-defined and multivalent structures. Knowing that DNA and RNA possess a similar structure in terms of nucleic acid framework and the electronegative nature, one can also use the excellent DNA delivery properties of dendrimers to develop effective siRNA delivery systems. In this review, the development of dendrimer-based siRNA delivery vectors is summarized, focusing on the vector features (siRNA delivery efficiency, cytotoxicity, etc.) of different types of dendrimers and the related investigations on structure-activity relationship to promote safe and efficient siRNA delivery system. PMID:24288498

Efficient and gentle siRNA delivery by magnetofection

Science.gov (United States)

Ensenauer, R; Hartl, D; Vockley, J; Roscher, AA; Fuchs, U

2015-01-01

Magnetic force combined with magnetic nanoparticles recently has shown potential for enhancing nucleic acid delivery. Achieving effective siRNA delivery into primary cultured cells is challenging. We compared the utility of magnetofection with lipofection procedures for siRNA delivery to primary and immortalized mammalian fibroblasts. Transfection efficiency and cell viability were analyzed by flow cytometry and effects of gene knockdown were quantified by real-time PCR. Lipofectamine 2000 and magnetofection achieved high transfection efficiencies comparable to similar gene silencing effects of about 80%; the cytotoxic effect of magnetofection, however, was significantly less. Magnetofection is a reliable and gentle alternative method with low cytotoxicity for siRNA delivery into difficult to transfect cells such as mammalian fibroblasts. These features are especially advantageous for functional end point analyses of gene silencing, e.g., on the metabolite level. PMID:20297946

Principles of Transactional Memory The Theory

CERN Document Server

Guerraoui, Rachid

2010-01-01

Transactional memory (TM) is an appealing paradigm for concurrent programming on shared memory architectures. With a TM, threads of an application communicate, and synchronize their actions, via in-memory transactions. Each transaction can perform any number of operations on shared data, and then either commit or abort. When the transaction commits, the effects of all its operations become immediately visible to other transactions; when it aborts, however, those effects are entirely discarded. Transactions are atomic: programmers get the illusion that every transaction executes all its operati

Intravenous siRNA of brain cancer with receptor targeting and avidin-biotin technology.

Science.gov (United States)

Xia, Chun-Fang; Zhang, Yufeng; Zhang, Yun; Boado, Ruben J; Pardridge, William M

2007-12-01

The effective delivery of short interfering RNA (siRNA) to brain following intravenous administration requires the development of a delivery system for transport of the siRNA across the brain capillary endothelial wall, which forms the blood-brain barrier in vivo. siRNA was delivered to brain in vivo with the combined use of a receptor-specific monoclonal antibody delivery system, and avidin-biotin technology. The siRNA was mono-biotinylated on either terminus of the sense strand, in parallel with the production of a conjugate of the targeting MAb and streptavidin. Rat glial cells (C6 or RG-2) were permanently transfected with the luciferase gene, and implanted in the brain of adult rats. Following the formation of intra-cranial tumors, the rats were treated with a single intravenous injection of 270 microg/kg of biotinylated siRNA attached to a transferrin receptor antibody via a biotin-streptavidin linker. The intravenous administration of the siRNA caused a 69-81% decrease in luciferase gene expression in the intracranial brain cancer in vivo. Brain delivery of siRNA following intravenous administration is possible with siRNAs that are targeted to brain with the combined use of receptor specific antibody delivery systems and avidin-biotin technology.

BSA Nanoparticles for siRNA Delivery: Coating Effects on Nanoparticle Properties, Plasma Protein Adsorption, and In Vitro siRNA Delivery

Directory of Open Access Journals (Sweden)

Haran Yogasundaram

2012-01-01

Full Text Available Developing vehicles for the delivery of therapeutic molecules, like siRNA, is an area of active research. Nanoparticles composed of bovine serum albumin, stabilized via the adsorption of poly-L-lysine (PLL, have been shown to be potentially inert drug-delivery vehicles. With the primary goal of reducing nonspecific protein adsorption, the effect of using comb-type structures of poly(ethylene glycol (1 kDa, PEG units conjugated to PLL (4.2 and 24 kDa on BSA-NP properties, apparent siRNA release rate, cell viability, and cell uptake were evaluated. PEGylated PLL coatings resulted in NPs with ζ-potentials close to neutral. Incubation with platelet-poor plasma showed the composition of the adsorbed proteome was similar for all systems. siRNA was effectively encapsulated and released in a sustained manner from all NPs. With 4.2 kDa PLL, cellular uptake was not affected by the presence of PEG, but PEG coating inhibited uptake with 24 kDa PLL NPs. Moreover, 24 kDa PLL systems were cytotoxic and this cytotoxicity was diminished upon PEG incorporation. The overall results identified a BSA-NP coating structure that provided effective siRNA encapsulation while reducing ζ-potential, protein adsorption, and cytotoxicity, necessary attributes for in vivo application of drug-delivery vehicles.

Local administration of siRNA through Microneedle: Optimization, Bio-distribution, Tumor Suppression and Toxicity

Science.gov (United States)

Tang, Tao; Deng, Yan; Chen, Jiao; Zhao, Yi; Yue, Ruifeng; Choy, Kwong Wai; Wang, Chi Chiu; Du, Quan; Xu, Yan; Han, Linxiao; Chung, Tony Kwok Hung

2016-07-01

Although RNA interference may become a novel therapeutic approach for cancer treatment, target-site accumulation of siRNA to achieve therapeutic dosage will be a major problem. Microneedle represents a better way to deliver siRNAs and we have evaluated for the first time the capability of a silicon microneedle array for delivery of Gapdh siRNA to the skin in vivo and the results showed that the microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively. For the further study in this field, we evaluated the efficacy of the injectable microneedle device for local delivery of siRNA to the mouse xenograft. The results presented here indicate that local administration of siRNA through injectable microneedle could effectively deliver siRNA into the tumor region, and inhibit tumor progression without major adverse effects.

THE SPECIFICITY OF INTRACOMMUNITY TRANSACTIONS

Directory of Open Access Journals (Sweden)

PALIU-POPA LUCIA

2011-09-01

Full Text Available Considered from the perspective of Romania's accession to the European Union, we can say that starting with 1 January 2007, foreign trade transactions were delimited in relation to the customs borders in intra-Community transactions and international transactions. In this context, the way of conducting these operations is influenced by both the economic and financial features specific to both categories of transactions, that relate to the economic character of the activity, the diversity and specificity of the foreign trade activity, transport of goods, the complexity and regulation of intra-Community and international commercial transactions, and by the specific features of each category of transaction. Starting from the consideration that the economic and financial characteristics of foreign trade activity, specific to intra-Community commercial transactions, have a significant influence in the organization and management of accounting of the entities involved in such transactions, determining in a greater or lesser extent, the way of capitalization of the financial and accounting information in the processes of analysis, decision and control, in this paper we proposed to address the features of intra-Community trade.

Valuation of Transactive Systems

Energy Technology Data Exchange (ETDEWEB)

Hammerstrom, Donald J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Corbin, Charles D. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Fernandez, Nicholas [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Homer, Juliet S. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Makhmalbaf, Atefe [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Pratt, Robert G. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Somani, Abhishek [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Gilbert, Erik I. [Navigant Consulting, Boulder, CO (United States); Chandler, Shawn [Navigant Consulting, Portland, OR (United States); Shandross, Richard [Navigant Consulting, Burlington, MA (United States)

2016-05-12

This is a final report from a project funded by the U.S. Department of Energy to formulate and test a methodology for valuation of systems where transaction-based mechanisms coordinate the exchange of value between the system’s actors. Today, the principal commodity being exchanged is electrical energy, and such mechanisms are called transactive energy systems. The authors strove to lay a foundation for meaningful valuations of transactive systems in general, and transactive energy systems as a special case. The word valuation is used in many different ways. This report proposes a valuation methodology that is inclusive of many types of valuations. Many will be familiar with cost-benefit valuations, in which both costs and benefits are assessed to determine whether the assets are worth their cost. Another set of valuation methods attempt to optimize an outcome using available resources, as is the case with integrated resource planning. In the end, this report’s methodology was most influenced by and most resembles the integrated-resource-planning approach. Regardless, we wish to enforce the premise that all valuations are comparative and should clearly specify a baseline scenario. A long, annotated list of prior valuation studies and valuation methodologies that influenced this report has been appended to this report. Much research is being conducted today concerning transactive systems, but only a handful of transactive system mechanisms have been formulated and field tested. They are found to be quite diverse, and the documentation of the various mechanisms is uneven in breadth and quality. It is therefore not adequate to simply assert that a valuation scenario includes a transactive system; certain characteristics and qualities of the chosen transactive system mechanism must be defined and stated. The report lists and discusses most of the known transactive system mechanisms. It offers a set of questions that may be used to help specify important

The Complexity of Posttranscriptional Small RNA Regulatory Networks Revealed by In Silico Analysis of Gossypium arboreum L. Leaf, Flower and Boll Small Regulatory RNAs.

Directory of Open Access Journals (Sweden)

Hongtao Hu

Full Text Available MicroRNAs (miRNAs and secondary small interfering RNAs (principally phased siRNAs or trans-acting siRNAs are two distinct subfamilies of small RNAs (sRNAs that are emerging as key regulators of posttranscriptional gene expression in plants. Both miRNAs and secondary-siRNAs (sec-siRNAs are processed from longer RNA precursors by DICER-LIKE proteins (DCLs. Gossypium arboreum L., also known as tree cotton or Asian cotton, is a diploid, possibly ancestral relative of tetraploid Gossypium hirsutum L., the predominant type of commercially grown cotton worldwide known as upland cotton. To understand the biological significance of these gene regulators in G. arboreum, a bioinformatics analysis was performed on G. arboreum small RNAs produced from G. arboreum leaf, flower, and boll tissues. Consequently, 263 miRNAs derived from 353 precursors, including 155 conserved miRNAs (cs-miRNAs and 108 novel lineage-specific miRNAs (ls-miRNAs. Along with miRNAs, 2,033 miRNA variants (isomiRNAs were identified as well. Those isomiRNAs with variation at the 3'-miRNA end were expressed at the highest levels, compared to other types of variants. In addition, 755 pha-siRNAs derived 319 pha-siRNA gene transcripts (PGTs were identified, and the potential pha-siRNA initiators were predicted. Also, 2,251 non-phased siRNAs were found as well, of which 1,088 appeared to be produced by so-called cis- or trans-cleavage of the PGTs observed at positions differing from pha-siRNAs. Of those sRNAs, 148 miRNAs/isomiRNAs and 274 phased/non-phased siRNAs were differentially expressed in one or more pairs of tissues examined. Target analysis revealed that target genes for both miRNAs and pha-siRNAs are involved a broad range of metabolic and enzymatic activities. We demonstrate that secondary siRNA production could result from initial cleavage of precursors by both miRNAs or isomiRNAs, and that subsequently produced phased and unphased siRNAs could result that also serve as triggers

The Complexity of Posttranscriptional Small RNA Regulatory Networks Revealed by In Silico Analysis of Gossypium arboreum L. Leaf, Flower and Boll Small Regulatory RNAs.

Science.gov (United States)

Hu, Hongtao; Rashotte, Aaron M; Singh, Narendra K; Weaver, David B; Goertzen, Leslie R; Singh, Shree R; Locy, Robert D

2015-01-01

MicroRNAs (miRNAs) and secondary small interfering RNAs (principally phased siRNAs or trans-acting siRNAs) are two distinct subfamilies of small RNAs (sRNAs) that are emerging as key regulators of posttranscriptional gene expression in plants. Both miRNAs and secondary-siRNAs (sec-siRNAs) are processed from longer RNA precursors by DICER-LIKE proteins (DCLs). Gossypium arboreum L., also known as tree cotton or Asian cotton, is a diploid, possibly ancestral relative of tetraploid Gossypium hirsutum L., the predominant type of commercially grown cotton worldwide known as upland cotton. To understand the biological significance of these gene regulators in G. arboreum, a bioinformatics analysis was performed on G. arboreum small RNAs produced from G. arboreum leaf, flower, and boll tissues. Consequently, 263 miRNAs derived from 353 precursors, including 155 conserved miRNAs (cs-miRNAs) and 108 novel lineage-specific miRNAs (ls-miRNAs). Along with miRNAs, 2,033 miRNA variants (isomiRNAs) were identified as well. Those isomiRNAs with variation at the 3'-miRNA end were expressed at the highest levels, compared to other types of variants. In addition, 755 pha-siRNAs derived 319 pha-siRNA gene transcripts (PGTs) were identified, and the potential pha-siRNA initiators were predicted. Also, 2,251 non-phased siRNAs were found as well, of which 1,088 appeared to be produced by so-called cis- or trans-cleavage of the PGTs observed at positions differing from pha-siRNAs. Of those sRNAs, 148 miRNAs/isomiRNAs and 274 phased/non-phased siRNAs were differentially expressed in one or more pairs of tissues examined. Target analysis revealed that target genes for both miRNAs and pha-siRNAs are involved a broad range of metabolic and enzymatic activities. We demonstrate that secondary siRNA production could result from initial cleavage of precursors by both miRNAs or isomiRNAs, and that subsequently produced phased and unphased siRNAs could result that also serve as triggers of a second

siRNA transfection in larvae of the barnacle Amphibalanus amphitrite

KAUST Repository

Zhang, G.

2015-06-25

RNA interference (RNAi) provides an efficient and specific technique for functional genomic studies. Yet, no successful application of RNAi has been reported in barnacles. In this study, siRNA against p38 MAPK was synthesized and then transfected into A. amphitrite larvae at either the nauplius or cyprid stage, or at both stages. Effects of siRNA transfection on the p38 MAPK level were hardly detectable in the cyprids when they were transfected at the nauplius stage. In contrast, larvae that were transfected at the cyprid stage showed lower levels of p38 MAPK than the blank and reagent controls. However, significantly decreased levels of phosphorylated p38 MAPK (pp38 MAPK) and reduced settlement rates were observed only in ‘double transfections’, in which larvae were exposed to siRNA solution at both the nauplius and cyprid stages. A relatively longer transfection time and more larval cells directly exposed to siRNA might explain the higher efficiency of double transfection experiments.

siRNA transfection in larvae of the barnacle Amphibalanus amphitrite

KAUST Repository

Zhang, G.; He, L.-S.; Wong, Y. H.; Yu, L.; Qian, P.-Y.

2015-01-01

RNA interference (RNAi) provides an efficient and specific technique for functional genomic studies. Yet, no successful application of RNAi has been reported in barnacles. In this study, siRNA against p38 MAPK was synthesized and then transfected into A. amphitrite larvae at either the nauplius or cyprid stage, or at both stages. Effects of siRNA transfection on the p38 MAPK level were hardly detectable in the cyprids when they were transfected at the nauplius stage. In contrast, larvae that were transfected at the cyprid stage showed lower levels of p38 MAPK than the blank and reagent controls. However, significantly decreased levels of phosphorylated p38 MAPK (pp38 MAPK) and reduced settlement rates were observed only in ‘double transfections’, in which larvae were exposed to siRNA solution at both the nauplius and cyprid stages. A relatively longer transfection time and more larval cells directly exposed to siRNA might explain the higher efficiency of double transfection experiments.

Multi-task learning for cross-platform siRNA efficacy prediction: an in-silico study.

Science.gov (United States)

Liu, Qi; Xu, Qian; Zheng, Vincent W; Xue, Hong; Cao, Zhiwei; Yang, Qiang

2010-04-10

Gene silencing using exogenous small interfering RNAs (siRNAs) is now a widespread molecular tool for gene functional study and new-drug target identification. The key mechanism in this technique is to design efficient siRNAs that incorporated into the RNA-induced silencing complexes (RISC) to bind and interact with the mRNA targets to repress their translations to proteins. Although considerable progress has been made in the computational analysis of siRNA binding efficacy, few joint analysis of different RNAi experiments conducted under different experimental scenarios has been done in research so far, while the joint analysis is an important issue in cross-platform siRNA efficacy prediction. A collective analysis of RNAi mechanisms for different datasets and experimental conditions can often provide new clues on the design of potent siRNAs. An elegant multi-task learning paradigm for cross-platform siRNA efficacy prediction is proposed. Experimental studies were performed on a large dataset of siRNA sequences which encompass several RNAi experiments recently conducted by different research groups. By using our multi-task learning method, the synergy among different experiments is exploited and an efficient multi-task predictor for siRNA efficacy prediction is obtained. The 19 most popular biological features for siRNA according to their jointly importance in multi-task learning were ranked. Furthermore, the hypothesis is validated out that the siRNA binding efficacy on different messenger RNAs(mRNAs) have different conditional distribution, thus the multi-task learning can be conducted by viewing tasks at an "mRNA"-level rather than at the "experiment"-level. Such distribution diversity derived from siRNAs bound to different mRNAs help indicate that the properties of target mRNA have important implications on the siRNA binding efficacy. The knowledge gained from our study provides useful insights on how to analyze various cross-platform RNAi data for uncovering

Multi-task learning for cross-platform siRNA efficacy prediction: an in-silico study

Directory of Open Access Journals (Sweden)

Xue Hong

2010-04-01

Full Text Available Abstract Background Gene silencing using exogenous small interfering RNAs (siRNAs is now a widespread molecular tool for gene functional study and new-drug target identification. The key mechanism in this technique is to design efficient siRNAs that incorporated into the RNA-induced silencing complexes (RISC to bind and interact with the mRNA targets to repress their translations to proteins. Although considerable progress has been made in the computational analysis of siRNA binding efficacy, few joint analysis of different RNAi experiments conducted under different experimental scenarios has been done in research so far, while the joint analysis is an important issue in cross-platform siRNA efficacy prediction. A collective analysis of RNAi mechanisms for different datasets and experimental conditions can often provide new clues on the design of potent siRNAs. Results An elegant multi-task learning paradigm for cross-platform siRNA efficacy prediction is proposed. Experimental studies were performed on a large dataset of siRNA sequences which encompass several RNAi experiments recently conducted by different research groups. By using our multi-task learning method, the synergy among different experiments is exploited and an efficient multi-task predictor for siRNA efficacy prediction is obtained. The 19 most popular biological features for siRNA according to their jointly importance in multi-task learning were ranked. Furthermore, the hypothesis is validated out that the siRNA binding efficacy on different messenger RNAs(mRNAs have different conditional distribution, thus the multi-task learning can be conducted by viewing tasks at an "mRNA"-level rather than at the "experiment"-level. Such distribution diversity derived from siRNAs bound to different mRNAs help indicate that the properties of target mRNA have important implications on the siRNA binding efficacy. Conclusions The knowledge gained from our study provides useful insights on how to

Diatomite biosilica nanocarriers for siRNA transport inside cancer cells.

Science.gov (United States)

Rea, Ilaria; Martucci, Nicola M; De Stefano, Luca; Ruggiero, Immacolata; Terracciano, Monica; Dardano, Principia; Migliaccio, Nunzia; Arcari, Paolo; Taté, Rosarita; Rendina, Ivo; Lamberti, Annalisa

2014-12-01

Diatomite is a natural porous biomaterial of sedimentary origin, formed by fragments of diatom siliceous skeletons, called "frustules". Due to large availability in many areas of the world, chemical stability, and non-toxicity, these fossil structures have been widespread used in lot of industrial applications, such as food production, water extracting agent, production of cosmetics and pharmaceutics. However, diatomite is surprisingly still rarely used in biomedical applications. In this work, we exploit diatomite nanoparticles for small interfering ribonucleic acid (siRNA) transport inside human epidermoid cancer cells (H1355). Morphology and composition of diatomite microfrustules (average size lower than 40μm) are investigated by scanning electron microscopy equipped by energy dispersive X-ray spectroscopy, Fourier transform infrared analysis, and photoluminescence measurements. Nanometric porous particles (average size lower than 450nm) are obtained by mechanical crushing, sonication, and filtering of micrometric frustules. siRNA bioconjugation is performed on both micrometric and nanometric fragments by silanization. In-vitro experiments show very low toxicity on exposure of the cells to diatomite nanoparticle concentration up to 300μg/ml for 72h. Confocal microscopy imaging performed on cancer cells incubated with siRNA conjugated nanoparticles demonstrates a cytoplasmatic localization of vectors. Gene silencing by delivered siRNA is also demonstrated. Our studies endorse diatomite nanoparticles as non-toxic nanocarriers for siRNA transport in cancer cells. siRNA is a powerful molecular tool for cancer treatment but its delivery is inefficient due to the difficulty to penetrate the cell membrane. siRNA-diatomite nanoconjugate may be well suited for delivery of therapeutic to cancer cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Networks and Transaction Costs

DEFF Research Database (Denmark)

Henning, Christian; Henningsen, Geraldine; Henningsen, Arne

2011-01-01

Based on the well-known fact that social networks can provide effective mechanisms that help to increase the trust level between two trade partners, we apply a simple game-theoretical framework to derive transaction costs as a high risk of opportunistic behavior in a repeated trade relation...... determined by the density and size of trading networks. In the empirical part of the paper we apply a two stage procedure to estimate the impact of social network structures on farm’s transaction costs observed for different input and output markets. At a first stage we estimate a multiple input...... transaction cost functions for all traded farm inputs and outputs. Estimation results based on a sample of 315 Polish farms imply a significant influence of social network structures on farm’s transaction costs. Moreover, estimated transaction costs correspond to a reasonable amount of farm specific shadow...

Networks and Transaction Costs

DEFF Research Database (Denmark)

Henning, Christian; Henningsen, Geraldine; Henningsen, Arne

2011-01-01

determined by the density and size of trading networks. In the empirical part of the paper we apply a two stage procedure to estimate the impact of social network structures on farm’s transaction costs observed for different input and output markets. At a first stage we estimate a multiple input......Based on the well-known fact that social networks can provide effective mechanisms that help to increase the trust level between two trade partners, we apply a simple game-theoretical framework to derive transaction costs as a high risk of opportunistic behavior in a repeated trade relation...... transaction cost functions for all traded farm inputs and outputs. Estimation results based on a sample of 315 Polish farms imply a significant influence of social network structures on farm’s transaction costs. Moreover, estimated transaction costs correspond to a reasonable amount of farm specific shadow...

Micro-transactions for concurrent data structures

DEFF Research Database (Denmark)

Meawad, Fadi; Iyer, Karthik; Schoeberl, Martin

2013-01-01

implementation of transactional memory that we call micro-transactions. In particular, we argue that hardware support for micro-transactions allows us to efficiently implement certain data structures. Those data structures are difficult to realize with the atomic operations provided by stock hardware and provide......, atomic instructions, and micro-transactions. Our results suggest that transactional memory is an interesting alternative to traditional concurrency control mechanisms....

Transactional Network Platform: Applications

Energy Technology Data Exchange (ETDEWEB)

Katipamula, Srinivas; Lutes, Robert G.; Ngo, Hung; Underhill, Ronald M.

2013-10-31

In FY13, Pacific Northwest National Laboratory (PNNL) with funding from the Department of Energy’s (DOE’s) Building Technologies Office (BTO) designed, prototyped and tested a transactional network platform to support energy, operational and financial transactions between any networked entities (equipment, organizations, buildings, grid, etc.). Initially, in FY13, the concept demonstrated transactions between packaged rooftop air conditioners and heat pump units (RTUs) and the electric grid using applications or "agents" that reside on the platform, on the equipment, on a local building controller or in the Cloud. The transactional network project is a multi-lab effort with Oakridge National Laboratory (ORNL) and Lawrence Berkeley National Laboratory (LBNL) also contributing to the effort. PNNL coordinated the project and also was responsible for the development of the transactional network (TN) platform and three different applications associated with RTUs. This document describes two applications or "agents" in details, and also summarizes the platform. The TN platform details are described in another companion document.

Transactions in domain-specific information systems

Science.gov (United States)

Zacek, Jaroslav

2017-07-01

Substantial number of the current information system (IS) implementations is based on transaction approach. In addition, most of the implementations are domain-specific (e.g. accounting IS, resource planning IS). Therefore, we have to have a generic transaction model to build and verify domain-specific IS. The paper proposes a new transaction model for domain-specific ontologies. This model is based on value oriented business process modelling technique. The transaction model is formalized by the Petri Net theory. First part of the paper presents common business processes and analyses related to business process modeling. Second part defines the transactional model delimited by REA enterprise ontology paradigm and introduces states of the generic transaction model. The generic model proposal is defined and visualized by the Petri Net modelling tool. Third part shows application of the generic transaction model. Last part of the paper concludes results and discusses a practical usability of the generic transaction model.

Transacted Memory for Smart Cards

NARCIS (Netherlands)

Hartel, Pieter H.; Butler, Michael J.; de Jong, Eduard; Longley, Mark; Olivieira, J.N.; Zave, P.

A transacted memory that is implemented using EEPROM technology offers persistence, undoability and auditing. The transacted memory system is formally specified in Z, and refined in two steps to a prototype C implementation / SPIN model. Conclusions are offered both on the transacted memory system

Ternary complexes of folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugate, siRNA and low-molecular-weight polysaccharide sacran as a novel tumor-selective siRNA delivery system.

Science.gov (United States)

Ohyama, Ayumu; Higashi, Taishi; Motoyama, Keiichi; Arima, Hidetoshi

2017-06-01

We previously developed a tumor-selective siRNA carrier by preparing polyamidoamine dendrimer (generation 4, G4) conjugates with α-cyclodextrin and folate-polyethylene glycol (Fol-PαC (G4)). In the present study, we developed ternary complexes of Fol-PαC (G4)/siRNA with low-molecular-weight-sacrans to achieve more effective siRNA transfer activity. Among the different molecular-weight sacrans, i.e. sacran 100, 1000 and 10,000 (MW 44,889Da, 943,692Da and 1,488,281Da, respectively), sacran 100 significantly increased the cellular uptake and the RNAi effects of Fol-PαC (G4)/siRNA binary complex with negligible cytotoxicity in KB cells (folate receptor-α positive cells). In addition, the ζ-potential and particle size of Fol-PαC (G4)/siRNA complex were decreased by the ternary complexation with sacran 100. Importantly, the in vivo RNAi effect of the ternary complex after the intravenous administration to tumor-bearing BALB/c mice was significantly higher than that of the binary complex. In conclusion, Fol-PαC (G4)/siRNA/sacran 100 ternary complex has a potential as a novel tumor-selective siRNA delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

Microfluidic Synthesis of Highly Potent Limit-size Lipid Nanoparticles for In Vivo Delivery of siRNA

Directory of Open Access Journals (Sweden)

Nathan M Belliveau

2012-01-01

Full Text Available Lipid nanoparticles (LNP are the leading systems for in vivo delivery of small interfering RNA (siRNA for therapeutic applications. Formulation of LNP siRNA systems requires rapid mixing of solutions containing cationic lipid with solutions containing siRNA. Current formulation procedures employ macroscopic mixing processes to produce systems 70-nm diameter or larger that have variable siRNA encapsulation efficiency, homogeneity, and reproducibility. Here, we show that microfluidic mixing techniques, which permit millisecond mixing at the nanoliter scale, can reproducibly generate limit size LNP siRNA systems 20 nm and larger with essentially complete encapsulation of siRNA over a wide range of conditions with polydispersity indexes as low as 0.02. Optimized LNP siRNA systems produced by microfluidic mixing achieved 50% target gene silencing in hepatocytes at a dose level of 10 µg/kg siRNA in mice. We anticipate that microfluidic mixing, a precisely controlled and readily scalable technique, will become the preferred method for formulation of LNP siRNA delivery systems.

Targeted delivery of siRNA to macrophages for anti-inflammatory treatment.

Science.gov (United States)

Kim, Sang-Soo; Ye, Chunting; Kumar, Priti; Chiu, Isaac; Subramanya, Sandesh; Wu, Haoquan; Shankar, Premlata; Manjunath, N

2010-05-01

Inflammation mediated by tumor necrosis factor-alpha (TNF-alpha) and the associated neuronal apoptosis characterizes a number of neurologic disorders. Macrophages and microglial cells are believed to be the major source of TNF-alpha in the central nervous system (CNS). Here, we show that suppression of TNF-alpha by targeted delivery of small interfering RNA (siRNA) to macrophage/microglial cells dramatically reduces lipopolysaccharide (LPS)-induced neuroinflammation and neuronal apoptosis in vivo. Because macrophage/microglia express the nicotinic acetylcholine receptor (AchR) on their surface, we used a short AchR-binding peptide derived from the rabies virus glycoprotein (RVG) as a targeting ligand. This peptide was fused to nona-D-arginine residues (RVG-9dR) to enable siRNA binding. RVG-9dR was able to deliver siRNA to induce gene silencing in macrophages and microglia cells from wild type, but not AchR-deficient mice, confirming targeting specificity. Treatment with anti-TNF-alpha siRNA complexed to RVG-9dR achieved efficient silencing of LPS-induced TNF-alpha production by primary macrophages and microglia cells in vitro. Moreover, intravenous injection with RVG-9dR-complexed siRNA in mice reduced the LPS-induced TNF-alpha levels in blood as well as in the brain, leading to a significant reduction in neuronal apoptosis. These results demonstrate that RVG-9dR provides a tool for siRNA delivery to macrophages and microglia and that suppression of TNF-alpha can potentially be used to suppress neuroinflammation in vivo.

Random small interfering RNA library screen identifies siRNAs that induce human erythroleukemia cell differentiation.

Science.gov (United States)

Fan, Cuiqing; Xiong, Yuan; Zhu, Ning; Lu, Yabin; Zhang, Jiewen; Wang, Song; Liang, Zicai; Shen, Yan; Chen, Meihong

2011-03-01

Cancers are characterized by poor differentiation. Differentiation therapy is a strategy to alleviate malignant phenotypes by inducing cancer cell differentiation. Here we carried out a combinatorial high-throughput screen with a random siRNA library on human erythroleukemia K-562 cell differentiation. Two siRNAs screened from the library were validated to be able to induce erythroid differentiation to varying degrees, determined by CD235 and globin up-regulation, GATA-2 down-regulation, and cell growth inhibition. The screen we performed here is the first trial of screening cancer differentiation-inducing agents from a random siRNA library, demonstrating that a random siRNA library can be considered as a new resource in efforts to seek new therapeutic agents for cancers. As a random siRNA library has a broad coverage for the entire genome, including known/unknown genes and protein coding/non-coding sequences, screening using a random siRNA library can be expected to greatly augment the repertoire of therapeutic siRNAs for cancers.

Mesoporous silica nanorods toward efficient loading and intracellular delivery of siRNA

Science.gov (United States)

Chen, Lijue; She, Xiaodong; Wang, Tao; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

2018-02-01

The technology of RNA interference (RNAi) that uses small interfering RNA (siRNA) to silence the gene expression with complementary messenger RNA (mRNA) sequence has great potential for the treatment of cancer in which certain genes were usually found overexpressed. However, the carry and delivery of siRNA to the target site in the human body can be challenging for this technology to be used clinically to silence the cancer-related gene expression. In this work, rod shaped mesoporous silica nanoparticles (MSNs) were developed as siRNA delivery system for specific intracellular delivery. The rod MSNs with an aspect ratio of 1.5 had a high surface area of 934.28 m2/g and achieved a siRNA loading of more than 80 mg/g. With the epidermal growth factor (EGF) grafted on the surface of the MSNs, siRNA can be delivered to the epidermal growth factor receptor (EGFR) overexpressed colorectal cancer cells with high intracellular concentration compared to MSNs without EGF and lead to survivin gene knocking down to less than 30%.

In vivo therapeutic potential of Dicer-hunting siRNAs targeting infectious hepatitis C virus.

Science.gov (United States)

Watanabe, Tsunamasa; Hatakeyama, Hiroto; Matsuda-Yasui, Chiho; Sato, Yusuke; Sudoh, Masayuki; Takagi, Asako; Hirata, Yuichi; Ohtsuki, Takahiro; Arai, Masaaki; Inoue, Kazuaki; Harashima, Hideyoshi; Kohara, Michinori

2014-04-23

The development of RNA interference (RNAi)-based therapy faces two major obstacles: selecting small interfering RNA (siRNA) sequences with strong activity, and identifying a carrier that allows efficient delivery to target organs. Additionally, conservative region at nucleotide level must be targeted for RNAi in applying to virus because hepatitis C virus (HCV) could escape from therapeutic pressure with genome mutations. In vitro preparation of Dicer-generated siRNAs targeting a conserved, highly ordered HCV 5' untranslated region are capable of inducing strong RNAi activity. By dissecting the 5'-end of an RNAi-mediated cleavage site in the HCV genome, we identified potent siRNA sequences, which we designate as Dicer-hunting siRNAs (dh-siRNAs). Furthermore, formulation of the dh-siRNAs in an optimized multifunctional envelope-type nano device inhibited ongoing infectious HCV replication in human hepatocytes in vivo. Our efforts using both identification of optimal siRNA sequences and delivery to human hepatocytes suggest therapeutic potential of siRNA for a virus.

In vitro and in vivo siRNA delivery to hepatocyte utilizing ternary complexation of lactosylated dendrimer/cyclodextrin conjugates, siRNA and low-molecular-weight sacran.

Science.gov (United States)

Hayashi, Yuya; Higashi, Taishi; Motoyama, Keiichi; Jono, Hirofumi; Ando, Yukio; Arima, Hidetoshi

2018-02-01

In this study, we newly developed the ternary complexes consisting of lactosylated dendrimer (generation 3)/α-cyclodextrin conjugate (Lac-α-CDE), siRNA and the anionic polysaccharide sacrans, and evaluated their utility as siRNA transfer carriers. Three kinds of the low-molecular-weight sacrans, i.e. sacran (100) (Mw 44,889Da), sacran (1000) (Mw 943,692Da) and sacran (10,000) (Mw 1,488,281Da) were used. Lac-α-CDE/siRNA/sacran ternary complexes were prepared by adding the low-molecular-weight sacrans to the Lac-α-CDE/siRNA binary complex solution. Cellular uptake of the ternary complex with sacran (100) was higher than that of the binary complex or the other ternary complexes with sacran (1000) and sacran (10,000) in HepG2 cells. Additionally, the ternary complex possessed high serum resistance and endosomal escaping ability in HepG2 cells. High liver levels of siRNA and Lac-α-CDE were observed after the intravenous administration of the ternary complex rather than that of the binary complex. Moreover, intravenous administration of the ternary complex (siRNA 5mg/kg) induced the significant RNAi effect in the liver of mice with negligible change of blood chemistry values. Therefore, a ternary complexation of the Lac-α-CDE/siRNA binary complex with sacran is useful as a hepatocyte-specific siRNA delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

Protection and systemic translocation of siRNA following oral administration of chitosan/siRNA nanoparticles

DEFF Research Database (Denmark)

Gonzalez, Borja Ballarin; Dagnæs-Hansen, Frederik; Fenton, Robert A.

2013-01-01

, gastrointestinal (GI) deposition, and translocation into peripheral tissue of nonmodified siRNA after oral gavage of chitosan/siRNA nanoparticles in mice. In contrast to naked siRNA, retained structural integrity and deposition in the stomach, proximal and distal small intestine, and colon was observed at 1 and 5...... hours for siRNA within nanoparticles. Furthermore, histological detection of fluorescent siRNA at the apical regions of the intestinal epithelium suggests mucoadhesion provided by chitosan. Detection of intact siRNA in the liver, spleen, and kidney was observed 1 hour after oral gavage, with an organ...

Transaction Costs For Innovations Diffusion

Directory of Open Access Journals (Sweden)

Ilya A. Romanov

2012-10-01

Full Text Available The article deals with the analysis of transaction costs of the innovations distribution. The factors, affecting the innovations diffusion in accordance with the clusters, relations, dynamics of the distribution are disclosed. Transaction costs as a result of bounded rationality of economic entities are detected. The inevitability of transaction costs as an objective phenomenon is shown. Their dependence on the quality of economic information and information uncertainty is indicated. Correlative approach for the analysis of these costs is applied. The article justifies that the reduction of transaction costs increases the efficiency of innovations.

Targeted Delivery of siRNA Therapeutics to Malignant Tumors

Directory of Open Access Journals (Sweden)

Qixin Leng

2017-01-01

Full Text Available Over the past 20 years, a diverse group of ligands targeting surface biomarkers or receptors has been identified with several investigated to target siRNA to tumors. Many approaches to developing tumor-homing peptides, RNA and DNA aptamers, and single-chain variable fragment antibodies by using phage display, in vitro evolution, and recombinant antibody methods could not have been imagined by researchers in the 1980s. Despite these many scientific advances, there is no reason to expect that the ligand field will not continue to evolve. From development of ligands based on novel or existing biomarkers to linking ligands to drugs and gene and antisense delivery systems, several fields have coalesced to facilitate ligand-directed siRNA therapeutics. In this review, we discuss the major categories of ligand-targeted siRNA therapeutics for tumors, as well as the different strategies to identify new ligands.

Low-weight polyethylenimine cross-linked 2-hydroxypopyl-ß-cyclodextrin and folic acid as an efficient and nontoxic siRNA carrier for gene silencing and tumor inhibition by VEGF siRNA

Directory of Open Access Journals (Sweden)

Li JM

2013-06-01

Full Text Available Jin-Ming Li, Yuan-Yuan Wang, Wei Zhang, Hua Su, Liang-Nian Ji, Zong-Wan Mao MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, People's Republic of China Background: Targeted delivery of small interfering RNA (siRNA has been regarded as one of the most important technologies for the development of siRNA therapeutics. However, the need for safe and efficient delivery systems is a barrier to further development of RNA interference therapeutics. In this work, a nontoxic and efficient siRNA carrier delivery system of low molecular weight polyethyleneimine (PEI-600 Da cross-linked with 2-hydroxypopyl-β-cyclodextrin (HP-β-CD and folic acid (FA was synthesized for biomedical application. Methods: The siRNA carrier was prepared using a simple method and characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. The siRNA carrier nanoparticles were characterized in terms of morphology, size and zeta potential, stability, efficiency of delivery, and gene silencing efficiency in vitro and in vivo. Results: The siRNA carrier was synthesized successfully. It showed good siRNA binding capacity and ability to protect siRNA. Further, the toxicity of the carrier measured in vitro and in vivo appeared to be negligible, probably because of degradation of the low molecular weight PEI and HP-β-CD in the cytosol. Flow cytometry and confocal microscopy confirmed that the FA receptor-mediated endocytosis of the FA-HP-β-CD-PEI/siRNA complexes was greater than that of the HP-β-CD-PEI/siRNA complexes in FA receptor-enriched HeLa cells. The FA-HP-β-CD-PEI/siRNA complexes also demonstrated excellent gene silencing efficiency in vitro (in the range of 90%, and reduced vascular endothelial growth factor (VEGF protein expression in the presence of 20% serum. FA-HP-β-CD-PEI/siRNA complexes administered via tail vein injection resulted in marked

Transactions Concurrency Control in Web Service Environment

DEFF Research Database (Denmark)

Alrifai, Mohammad; Dolog, Peter; Nejdl, Wolfgang

2006-01-01

an engineering point of view as it does not change the way consumers or clients of web services have to be programmed. Furthermore, it avoids direct communication between transaction coordinators which preserves security by keeping the information about business transactions restricted to the coordinators which......Business transactions in web service environments run with relaxed isolation and atomicity property. In such environments, transactions can commit and roll back independently on each other. Transaction management has to reflect this issue and address the problems which result for example from...... concurrent access to web service resources and data. In this paper we propose an extension to the WS-Transaction Protocol which ensures the consistency of the data when independent business transactions access the data concurrently under the relaxed transaction properties. Our extension is based...

Efficient inhibition of fibroblast proliferation and collagen expression by ERK2 siRNAs

International Nuclear Information System (INIS)

Li, Fengfeng; Fan, Cunyi; Cheng, Tao; Jiang, Chaoyin; Zeng, Bingfang

2009-01-01

Transforming growth factor-β1 and fibroblast growth factor-2 play very important roles in fibroblast proliferation and collagen expression. These processes lead to the formation of joint adhesions through the SMAD and MAPK pathways, in which ERK2 is supposed to be crucial. Based on these assumptions, lentivirus (LV)-mediated small interfering RNAs (siRNAs) targeting ERK2 were used to suppress the proliferation and collagen expression of rat joint adhesion tissue fibroblasts (RJATFs). Among four siRNAs examined, siRNA1 caused an 84% reduction in ERK2 expression (p < 0.01) and was selected as the most efficient siRNA for use in this study. In subsequent experiments, significant downregulation of types I and III collagen were observed by quantitative RT-PCR and Western blot analyses. MTT assays and flow cytometry revealed marked inhibition of RJATF proliferation, but no apoptosis. In conclusion, LV-mediated ERK2 siRNAs may represent novel therapies or drug targets for preventing joint adhesion formation.

CDE-1 affects chromosome segregation through uridylation of CSR-1-bound siRNAs.

Science.gov (United States)

van Wolfswinkel, Josien C; Claycomb, Julie M; Batista, Pedro J; Mello, Craig C; Berezikov, Eugene; Ketting, René F

2009-10-02

We have studied the function of a conserved germline-specific nucleotidyltransferase protein, CDE-1, in RNAi and chromosome segregation in C. elegans. CDE-1 localizes specifically to mitotic chromosomes in embryos. This localization requires the RdRP EGO-1, which physically interacts with CDE-1, and the Argonaute protein CSR-1. We found that CDE-1 is required for the uridylation of CSR-1 bound siRNAs, and that in the absence of CDE-1 these siRNAs accumulate to inappropriate levels, accompanied by defects in both meiotic and mitotic chromosome segregation. Elevated siRNA levels are associated with erroneous gene silencing, most likely through the inappropriate loading of CSR-1 siRNAs into other Argonaute proteins. We propose a model in which CDE-1 restricts specific EGO-1-generated siRNAs to the CSR-1 mediated, chromosome associated RNAi pathway, thus separating it from other endogenous RNAi pathways. The conserved nature of CDE-1 suggests that similar sorting mechanisms may operate in other animals, including mammals.

Identifying Bitcoin users by transaction behavior

Science.gov (United States)

Monaco, John V.

2015-05-01

Digital currencies, such as Bitcoin, offer convenience and security to criminals operating in the black marketplace. Some Bitcoin marketplaces, such as Silk Road, even claim anonymity. This claim contradicts the findings in this work, where long term transactional behavior is used to identify and verify account holders. Transaction timestamps and network properties observed over time contribute to this finding. The timestamp of each transaction is the result of many factors: the desire purchase an item, daily schedule and activities, as well as hardware and network latency. Dynamic network properties of the transaction, such as coin flow and the number of edge outputs and inputs, contribute further to reveal account identity. In this paper, we propose a novel methodology for identifying and verifying Bitcoin users based on the observation of Bitcoin transactions over time. The behavior we attempt to quantify roughly occurs in the social band of Newell's time scale. A subset of the Blockchain 230686 is taken, selecting users that initiated between 100 and 1000 unique transactions per month for at least 6 different months. This dataset shows evidence of being nonrandom and nonlinear, thus a dynamical systems approach is taken. Classification and authentication accuracies are obtained under various representations of the monthly Bitcoin samples: outgoing transactions, as well as both outgoing and incoming transactions are considered, along with the timing and dynamic network properties of transaction sequences. The most appropriate representations of monthly Bitcoin samples are proposed. Results show an inherent lack of anonymity by exploiting patterns in long-term transactional behavior.

Extending Software Transactional Memory in Clojure with Side-Effects and Transaction Control

DEFF Research Database (Denmark)

Jensen, Søren Kejser; Thomsen, Lone Leth

2016-01-01

In conjunction with the increase of multi-core processors the use of functional programming languages has increased in recent years. The functional language Clojure has concurrency as a core feature, and provides Software Transactional Memory (STM) as a substitute for locks. Transactions in Cloju...

Decision, Transaction, Law and Contract

DEFF Research Database (Denmark)

Koch, Carsten Allan

Copy from ”Preface to Post Doctoral Dissertation” ”Decision, transaction, law and contract” The period since 1970 has witnessed an explosion in contributions to what is now often referred to as the new institutional economics. One of the most influential (but also most atypical) of these approaches...... and Hierarchies” from 1975. Since then Williamson has, almost singlehandedly, erected an impressive research program which aims at explaining the institutional structures at the micro-level under which economic transactions take place. A number of different phenomena that were very hard to rationalize given...... further. Compared to earlier contributions, the mode of analysis employed differs in at least three ways. Firstly, the analysis is made in terms of the decision premises for entering a transactional relationship. This is in opposition to traditional transaction cost economics, where the transaction...

Synthesis and characterization of amino acid-functionalized calcium phosphate nanoparticles for siRNA delivery.

Science.gov (United States)

Bakan, Feray; Kara, Goknur; Cokol Cakmak, Melike; Cokol, Murat; Denkbas, Emir Baki

2017-10-01

Small interfering RNAs (siRNA) are short nucleic acid fragments of about 20-27 nucleotides, which can inhibit the expression of specific genes. siRNA based RNAi technology has emerged as a promising method for the treatment of a variety of diseases. However, a major limitation in the therapeutic use of siRNA is its rapid degradation in plasma and cellular cytoplasm, resulting in short half-life. In addition, as siRNA molecules cannot penetrate into the cell efficiently, it is required to use a carrier system for its delivery. In this work, chemically and morphologically different calcium phosphate (CaP) nanoparticles, including spherical-like hydroxyapatite (HA-s), needle-like hydroxyapatite (HA-n) and calcium deficient hydroxyapatite (CDHA) nanoparticles were synthesized by the sol-gel technique and the effects of particle characteristics on the binding capacity of siRNA were investigated. In order to enhance the gene loading efficiency, the nanoparticles were functionalized with arginine and the morphological and their structural characteristics were analyzed. The addition of arginine did not significantly change the particle sizes; however, it provided a significantly increased binding of siRNA for all types of CaP nanoparticles, as revealed by spectrophotometric measurements analysis. Arginine functionalized HA-n nanoparticles showed the best binding behavior with siRNA among the other nanoparticles due to its high, positive zeta potential (+18.8mV) and high surface area of Ca ++ rich "c" plane. MTT cytotoxicity assays demonstrated that all the nanoparticles tested herein were biocompatible. Our results suggest that high siRNA entrapment in each of the three modified non-toxic CaP nanoparticles make them promising candidates as a non-viral vector for delivering therapeutic siRNA molecules to treat cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Nonblocking Scheduling for Web Service Transactions

DEFF Research Database (Denmark)

Alrifai, Mohammad; Balke, Wolf-Tilo; Dolog, Peter

2007-01-01

. In this paper, we propose a novel nonblocking scheduling mechanism that is used prior to the actual service invocations. Its aim is to reach an agreement between the client and all participating providers on what transaction processing times have to be expected, accepted, and guaranteed. This enables service......For improved flexibility and concurrent usage existing transaction management models for Web services relax the isolation property of Web service-based transactions. Correctness of the concurrent execution then has to be ensured by commit order-preserving transaction schedulers. However, local...... schedulers of service providers typically do take into account neither time constraints for committing the whole transaction, nor the individual services' constraints when scheduling decisions are made. This often leads to an unnecessary blocking of transactions by (possibly long-running) others...

Kinetic analysis of the effects of target structure on siRNA efficiency

Science.gov (United States)

Chen, Jiawen; Zhang, Wenbing

2012-12-01

RNAi efficiency for target cleavage and protein expression is related to the target structure. Considering the RNA-induced silencing complex (RISC) as a multiple turnover enzyme, we investigated the effect of target mRNA structure on siRNA efficiency with kinetic analysis. The 4-step model was used to study the target cleavage kinetic process: hybridization nucleation at an accessible target site, RISC-mRNA hybrid elongation along with mRNA target structure melting, target cleavage, and enzyme reactivation. At this model, the terms accounting for the target accessibility, stability, and the seed and the nucleation site effects are all included. The results are in good agreement with that of experiments which show different arguments about the structure effects on siRNA efficiency. It shows that the siRNA efficiency is influenced by the integrated factors of target's accessibility, stability, and the seed effects. To study the off-target effects, a simple model of one siRNA binding to two mRNA targets was designed. By using this model, the possibility for diminishing the off-target effects by the concentration of siRNA was discussed.

Development of a Positive-readout Mouse Model of siRNA Pharmacodynamics

Directory of Open Access Journals (Sweden)

Mark Stevenson

2013-01-01

Full Text Available Development of RNAi-based therapeutics has the potential to revolutionize treatment options for a range of human diseases. However, as with gene therapy, a major barrier to progress is the lack of methods to achieve and measure efficient delivery for systemic administration. We have developed a positive-readout pharmacodynamic transgenic reporter mouse model allowing noninvasive real-time assessment of siRNA activity. The model combines a luciferase reporter gene under the control of regulatory elements from the lac operon of Escherichia coli. Introduction of siRNA targeting lac repressor results in increased luciferase expression in cells where siRNA is biologically active. Five founder luciferase-expressing and three founder Lac-expressing lines were generated and characterized. Mating of ubiquitously expressing luciferase and lac lines generated progeny in which luciferase expression was significantly reduced compared with the parental line. Administration of isopropyl β-D-1-thiogalactopyranoside either in drinking water or given intraperitoneally increased luciferase expression in eight of the mice examined, which fell rapidly when withdrawn. Intraperitoneal administration of siRNA targeting lac in combination with Lipofectamine 2000 resulted in increased luciferase expression in the liver while control nontargeting siRNA had no effect. We believe a sensitive positive readout pharmacodynamics reporter model will be of use to the research community in RNAi-based vector development.

SiRNAs conjugated with aromatic compounds induce RISC-mediated antisense strand selection and strong gene-silencing activity

Energy Technology Data Exchange (ETDEWEB)

Kubo, Takanori, E-mail: kubo-t@yasuda-u.ac.jp [Faculty of Pharmacy, Yasuda Women' s University, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153 (Japan); Yanagihara, Kazuyoshi [Faculty of Pharmacy, Yasuda Women' s University, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153 (Japan); Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Takei, Yoshifumi [Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumi-cho, Showa-ku, Nagoya 466-8550 (Japan); Mihara, Keichiro [Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553 (Japan); Sato, Yuichiro; Seyama, Toshio [Faculty of Pharmacy, Yasuda Women' s University, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153 (Japan)

2012-10-05

Highlights: Black-Right-Pointing-Pointer SiRNAs conjugated with aromatic compounds (Ar-siRNAs) at 5 Prime -sense strand were synthesized. Black-Right-Pointing-Pointer Ar-siRNAs increased resistance against nuclease degradation. Black-Right-Pointing-Pointer Ar-siRNAs were thermodynamically stable compared with the unmodified siRNA. Black-Right-Pointing-Pointer High levels of cellular uptake and cytoplasmic localization were found. Black-Right-Pointing-Pointer Strong gene-silencing efficacy was exhibited in the Ar-siRNAs. -- Abstract: Short interference RNA (siRNA) is a powerful tool for suppressing gene expression in mammalian cells. In this study, we focused on the development of siRNAs conjugated with aromatic compounds in order to improve the potency of RNAi and thus to overcome several problems with siRNAs, such as cellular delivery and nuclease stability. The siRNAs conjugated with phenyl, hydroxyphenyl, naphthyl, and pyrenyl derivatives showed strong resistance to nuclease degradation, and were thermodynamically stable compared with unmodified siRNA. A high level of membrane permeability in HeLa cells was also observed. Moreover, these siRNAs exhibited enhanced RNAi efficacy, which exceeded that of locked nucleic acid (LNA)-modified siRNAs, against exogenous Renilla luciferase in HeLa cells. In particular, abundant cytoplasmic localization and strong gene-silencing efficacy were found in the siRNAs conjugated with phenyl and hydroxyphenyl derivatives. The novel siRNAs conjugated with aromatic compounds are promising candidates for a new generation of modified siRNAs that can solve many of the problems associated with RNAi technology.

Rethinking Ethiopian Secured Transactions Law through ...

African Journals Online (AJOL)

Various countries have reformed their secured transaction laws recognizing the significance of modern secured transactions law in enhancing access to credit and economic development. Ethiopia has not undertaken comprehensive secured transactions law reform, despite the demonstrable mismatch between the legal ...

Improved nucleic acid descriptors for siRNA efficacy prediction.

Science.gov (United States)

Sciabola, Simone; Cao, Qing; Orozco, Modesto; Faustino, Ignacio; Stanton, Robert V

2013-02-01

Although considerable progress has been made recently in understanding how gene silencing is mediated by the RNAi pathway, the rational design of effective sequences is still a challenging task. In this article, we demonstrate that including three-dimensional descriptors improved the discrimination between active and inactive small interfering RNAs (siRNAs) in a statistical model. Five descriptor types were used: (i) nucleotide position along the siRNA sequence, (ii) nucleotide composition in terms of presence/absence of specific combinations of di- and trinucleotides, (iii) nucleotide interactions by means of a modified auto- and cross-covariance function, (iv) nucleotide thermodynamic stability derived by the nearest neighbor model representation and (v) nucleic acid structure flexibility. The duplex flexibility descriptors are derived from extended molecular dynamics simulations, which are able to describe the sequence-dependent elastic properties of RNA duplexes, even for non-standard oligonucleotides. The matrix of descriptors was analysed using three statistical packages in R (partial least squares, random forest, and support vector machine), and the most predictive model was implemented in a modeling tool we have made publicly available through SourceForge. Our implementation of new RNA descriptors coupled with appropriate statistical algorithms resulted in improved model performance for the selection of siRNA candidates when compared with publicly available siRNA prediction tools and previously published test sets. Additional validation studies based on in-house RNA interference projects confirmed the robustness of the scoring procedure in prospective studies.

Emerging RNA-based drugs: siRNAs, microRNAs and derivates.

Science.gov (United States)

Pereira, Tiago Campos; Lopes-Cendes, Iscia

2012-09-01

An emerging new category of therapeutic agents based on ribonucleic acid has emerged and shown very promising in vitro, animal and pre-clinical results, known as small interfering RNAs (siRNAs), microRNAs mimics (miRNA mimics) and their derivates. siRNAs are small RNA molecules that promote potent and specific silencing of mutant, exogenous or aberrant genes through a mechanism known as RNA interference. These agents have called special attention to medicine since they have been used to experimentally treat a series of neurological conditions with distinct etiologies such as prion, viral, bacterial, fungal, genetic disorders and others. siRNAs have also been tested in other scenarios such as: control of anxiety, alcohol consumption, drug-receptor blockage and inhibition of pain signaling. Although in a much earlier stage, miRNAs mimics, anti-miRs and small activating RNAs (saRNAs) also promise novel therapeutic approaches to control gene expression. In this review we intend to introduce clinicians and medical researchers to the most recent advances in the world of siRNA- and miRNA-mediated gene control, its history, applications in cells, animals and humans, delivery methods (an yet unsolved hurdle), current status and possible applications in future clinical practice.

siRNAs Targeting Viral Protein 5: The Major Capsid Protein of ...

African Journals Online (AJOL)

Purpose: To investigate whether siRNA targeting viral protein 5 (VP5) can become a new treatment for herpes simplex virus type 1 (HSV-1). Methods: Flow cytometry was performed to determine the ratio of siRNA and lipo2000 to reach the highest transfection efficiency. Western blot and q-PCR were performed to determine ...

Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis

Directory of Open Access Journals (Sweden)

Fatima Khaja

2016-01-01

Full Text Available Since its discovery, small interfering RNA (siRNA has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA not easily accessed by conventional drugs. Hence, RNA interference (RNAi therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs. This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF, an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP, showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases.

Private benefits in corporate control transactions

DEFF Research Database (Denmark)

Poulsen, Thomas

This paper presents an analytical framework from which it can be inferred whether sellers or buyers in corporate control transactions value private benefits highest. I am thus able to suggest an answer to the question: Are blocks of shares traded because the buyer is a more efficient monitor...... with high security benefits, or because the buyer has high private benefits from the control rights that come with the shares? Using voting rights as the vehicle for private benefits, I find that the selling shareholders in block transactions attach more value to private benefits than the buyers. In tender...... offer transactions, the answer is that private benefits are insignificant to both sides of the transaction. As an alternative measure of the transaction premium, I calculate the abnormal return premium. This represents the stock market's valuation of the transaction. I find that the stock market puts...

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence.

Science.gov (United States)

Gavrilov, Kseniya; Seo, Young-Eun; Tietjen, Gregory T; Cui, Jiajia; Cheng, Christopher J; Saltzman, W Mark

2015-12-01

Canonical siRNA design algorithms have become remarkably effective at predicting favorable binding regions within a target mRNA, but in some cases (e.g., a fusion junction site) region choice is restricted. In these instances, alternative approaches are necessary to obtain a highly potent silencing molecule. Here we focus on strategies for rational optimization of two siRNAs that target the junction sites of fusion oncogenes BCR-ABL and TMPRSS2-ERG. We demonstrate that modifying the termini of these siRNAs with a terminal G-U wobble pair or a carefully selected pair of terminal asymmetry-enhancing mismatches can result in an increase in potency at low doses. Importantly, we observed that improvements in silencing at the mRNA level do not necessarily translate to reductions in protein level and/or cell death. Decline in protein level is also heavily influenced by targeted protein half-life, and delivery vehicle toxicity can confound measures of cell death due to silencing. Therefore, for BCR-ABL, which has a long protein half-life that is difficult to overcome using siRNA, we also developed a nontoxic transfection vector: poly(lactic-coglycolic acid) nanoparticles that release siRNA over many days. We show that this system can achieve effective killing of leukemic cells. These findings provide insights into the implications of siRNA sequence for potency and suggest strategies for the design of more effective therapeutic siRNA molecules. Furthermore, this work points to the importance of integrating studies of siRNA design and delivery, while heeding and addressing potential limitations such as restricted targetable mRNA regions, long protein half-lives, and nonspecific toxicities.

Resources and Transaction Costs

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai Juul

2004-01-01

resources depends on the propertyrights that she holds to those resources and on the transaction costs of exchanging,defining and protecting the relevant property rights. While transaction costs aremajor sources of value dissipation, value may be created by reducing suchdissipation. Implications for the RBV...

Lipid-Based Liquid Crystalline Nanoparticles Facilitate Cytosolic Delivery of siRNA via Structural Transformation.

Science.gov (United States)

He, Shufang; Fan, Weiwei; Wu, Na; Zhu, Jingjing; Miao, Yunqiu; Miao, Xiaran; Li, Feifei; Zhang, Xinxin; Gan, Yong

2018-04-11

RNA interference (RNAi) technology has shown great promise for the treatment of cancer and other genetic disorders. Despite the efforts to increase the target tissue distribution, the safe and effective delivery of siRNA to the diseased cells with sufficient cytosolic transport is another critical factor for successful RNAi clinical application. Here, the constructed lipid-based liquid crystalline nanoparticles, called nano-Transformers, can transform thestructure in the intracellular acidic environment and perform high-efficient siRNA delivery for cancer treatment. The developed nano-Transformers have satisfactory siRNA loading efficiency and low cytotoxicity. Different from the traditional cationic nanocarriers, the endosomal membrane fusion induced by the conformational transition of lipids contributes to the easy dissociation of siRNA from nanocarriers and direct release of free siRNA into cytoplasm. We show that transfection with cyclin-dependent kinase 1 (CDK1)-siRNA-loaded nano-Transformers causes up to 95% reduction of relevant mRNA in vitro and greatly inhibits the tumor growth without causing any immunogenic response in vivo. This work highlights that the lipid-based nano-Transformers may become the next generation of siRNA delivery system with higher efficacy and improved safety profiles.

Transaction cost of micro and small enterprises financing

Directory of Open Access Journals (Sweden)

Ghana Atma Sulistya

2016-10-01

Full Text Available High transaction costs become one of the obstacles for the micro and small enterprises (MSEs to access financial loans to the bank. In order to minimize the transaction costs, group lending scheme become  alternative, so that both sides are pay lower transaction costs, and MSEs are able to improve their welfare. This study aims to analyze the credit process and transaction costs incurred on the model of individuals and groups lending and to compare the magnitude of transaction costs on both models. Mixed Method Analysis is used to analyze the component of transaction costs and the magnitude of the transaction cost on both models.These results indicate there are differences in transaction costs incurred on both schemes. In the amount of the transaction costs, the overall group scheme still allows for greater compared to individual schemes and dominated by the cost of the disbursement. Even so, the transaction cost per member group is much smaller than the individual schemes.

Dual-functionalized graphene oxide for enhanced siRNA delivery to breast cancer cells.

Science.gov (United States)

Imani, Rana; Shao, Wei; Taherkhani, Samira; Emami, Shahriar Hojjati; Prakash, Satya; Faghihi, Shahab

2016-11-01

The aim of this study is to improve hydrocolloid stability and siRNA transfection ability of a reduced graphene oxide (rGO) based nano-carrier using a phospholipid-based amphiphilic polymer (PL-PEG) and cell penetrating peptide (CPPs). The dual functionalized nano-carrier is comprehensively characterized for its chemical structure, size, surface charge and morphology as well as thermal stability. The nano-carrier cytocompatibility, siRNA condensation ability both in the presence and absence of enzyme, endosomal buffering capacity, cellular uptake and intracellular localization are also assessed. The siRNA loaded nano-carrier is used for internalization to MCF-7 cells and its gene silencing ability is compared with AllStars Hs Cell Death siRNA as a model gene. The nano-carrier remains stable in biological solution, exhibits excellent cytocompatibility, retards the siRNA migration and protects it against enzyme degradation. The buffering capacity analysis shows that incorporation of the peptide in nano-carrier structure would increase the resistance to endo/lysosomal like acidic condition (pH 6-4) The functionalized nano-carrier which is loaded with siRNA in an optimal N:P ratio presents superior internalization efficiency (82±5.1% compared to HiPerFect(®)), endosomal escape quality and capable of inducing cell death in MCF-7 cancer cells (51±3.1% compared to non-treated cells). The success of siRNA-based therapy is largely dependent on the safe and efficient delivery system, therefore; the dual functionalized rGO introduced here could have a great potential to be used as a carrier for siRNA delivery with relevancy in therapeutics and clinical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Resources and transaction costs

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai Juul

2005-01-01

from resources depends on the property rights that he or she holds and on the transaction costs of exchanging, defining, and protecting them. While transaction costs are a major source of value dissipation, reducing such dissipation may create value. Implications for the RBV analysis of sustained...

Combining Tasking and Transactions

OpenAIRE

Kienzle, Jörg

1999-01-01

This position paper discusses the issues in design and development of a transaction support for Ada 95. Transactions and other fault tolerance mechanisms are reviewed, and their applicability in a concurrent programming language is analyzed. Possible ways of integration are presented and implementation problems are discussed.

31 CFR 541.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 541.406 Section 541.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... § 541.406 Offshore transactions. The prohibitions in § 541.201 on transactions involving blocked...

31 CFR 537.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 537.406 Section 537.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... § 537.406 Offshore transactions. The prohibitions in § 537.201 on transactions involving blocked...

31 CFR 542.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 542.406 Section 542.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... § 542.406 Offshore transactions. The prohibitions in § 542.201 on transactions involving blocked...

Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer.

Directory of Open Access Journals (Sweden)

Giorgia Urbinati

Full Text Available TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV, most frequently identified in patients' biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67. In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene.

Therapeutic Effects of Myeloid Cell Leukemia-1 siRNA on Human Acute Myeloid Leukemia Cells

Directory of Open Access Journals (Sweden)

Hadi Karami

2014-05-01

Full Text Available Purpose: Up-regulation of Mcl-1, a known anti-apoptotic protein, is associated with the survival and progression of various malignancies including leukemia. The aim of this study was to explore the effect of Mcl-1 small interference RNA (siRNA on the proliferation and apoptosis of HL-60 acute myeloid leukemia (AML cells. Methods: siRNA transfection was performed using Lipofectamine™2000 reagent. Relative mRNA and protein expressions were quantified by quantitative real-time PCR and Western blotting, respectively. Trypan blue assay was performed to assess tumor cell proliferation after siRNA transfection. The cytotoxic effect of Mcl-1 siRNA on leukemic cells was measured using MTT assay. Apoptosis was detected using ELISA cell death assay. Results: Mcl-1 siRNA clearly lowered both Mcl-1 mRNA and protein levels in a time-dependent manner, leading to marked inhibition of cell survival and proliferation. Furthermore, Mcl-1 down-regulation significantly enhanced the extent of HL-60 apoptotic cells. Conclusion: Our results suggest that the down-regulation of Mcl-1 by siRNA can effectively trigger apoptosis and inhibit the proliferation of leukemic cells. Therefore, Mcl-1 siRNA may be a potent adjuvant in AML therapy.

Transaction Costs in Housing Markets

OpenAIRE

Ommeren, van, Jos

2008-01-01

According to economic theory, there are no strong reasons to tax (or to subsidise) residential moves, although low levels of taxation may be potentially justified to deal with the presence of externalities and economic stability. This is in contrast to practise in most countries where governments have created strong barriers to moving (transaction taxes, rent control) which induces substantial transaction costs. Likely, the welfare losses due to these government-induced transaction costs are ...

Impact of target mRNA structure on siRNA silencing efficiency: A large-scale study.

Science.gov (United States)

Gredell, Joseph A; Berger, Angela K; Walton, S Patrick

2008-07-01

The selection of active siRNAs is generally based on identifying siRNAs with certain sequence and structural properties. However, the efficiency of RNA interference has also been shown to depend on the structure of the target mRNA, primarily through studies using exogenous transcripts with well-defined secondary structures in the vicinity of the target sequence. While these studies provide a means for examining the impact of target sequence and structure independently, the predicted secondary structures for these transcripts are often not reflective of structures that form in full-length, native mRNAs where interactions can occur between relatively remote segments of the mRNAs. Here, using a combination of experimental results and analysis of a large dataset, we demonstrate that the accessibility of certain local target structures on the mRNA is an important determinant in the gene silencing ability of siRNAs. siRNAs targeting the enhanced green fluorescent protein were chosen using a minimal siRNA selection algorithm followed by classification based on the predicted minimum free energy structures of the target transcripts. Transfection into HeLa and HepG2 cells revealed that siRNAs targeting regions of the mRNA predicted to have unpaired 5'- and 3'-ends resulted in greater gene silencing than regions predicted to have other types of secondary structure. These results were confirmed by analysis of gene silencing data from previously published siRNAs, which showed that mRNA target regions unpaired at either the 5'-end or 3'-end were silenced, on average, approximately 10% more strongly than target regions unpaired in the center or primarily paired throughout. We found this effect to be independent of the structure of the siRNA guide strand. Taken together, these results suggest minimal requirements for nucleation of hybridization between the siRNA guide strand and mRNA and that both mRNA and guide strand structure should be considered when choosing candidate siRNAs

31 CFR 543.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 543.406 Section 543.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... Interpretations § 543.406 Offshore transactions. The prohibitions in § 543.201 on transactions or dealings...

31 CFR 547.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 547.406 Section 547.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... REGULATIONS Interpretations § 547.406 Offshore transactions. The prohibitions in § 547.201 on transactions or...

31 CFR 548.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 548.406 Section 548.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... § 548.406 Offshore transactions. The prohibitions in § 548.201 on transactions or dealings involving...

31 CFR 546.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 546.406 Section 546.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... § 546.406 Offshore transactions. The prohibitions in § 546.201 on transactions or dealings involving...

31 CFR 588.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 588.406 Section 588.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... Interpretations § 588.406 Offshore transactions. The prohibitions in § 588.201 on transactions involving blocked...

Ring Confidential Transactions

Directory of Open Access Journals (Sweden)

Shen Noether

2016-12-01

Full Text Available This article introduces a method of hiding transaction amounts in the strongly decentralized anonymous cryptocurrency Monero. Similar to Bitcoin, Monero is a cryptocurrency which is distributed through a proof-of-work “mining” process having no central party or trusted setup. The original Monero protocol was based on CryptoNote, which uses ring signatures and one-time keys to hide the destination and origin of transactions. Recently the technique of using a commitment scheme to hide the amount of a transaction has been discussed and implemented by Bitcoin Core developer Gregory Maxwell. In this article, a new type of ring signature, A Multilayered Linkable Spontaneous Anonymous Group signature is described which allows one to include a Pedersen Commitment in a ring signature. This construction results in a digital currency with hidden amounts, origins and destinations of transactions with reasonable efficiency and verifiable, trustless coin generation. The author would like to note that early drafts of this were publicized in the Monero Community and on the #bitcoin-wizards IRC channel. Blockchain hashed drafts are available showing that this work was started in Summer 2015, and completed in early October 2015. An eprint is also available at http://eprint.iacr.org/2015/1098.

Intracellular Delivery of siRNA by Polycationic Superparamagnetic Nanoparticles

Directory of Open Access Journals (Sweden)

Betzaida Castillo

2012-01-01

Full Text Available The siRNA transfection efficiency of nanoparticles (NPs, composed of a superparamagnetic iron oxide core modified with polycationic polymers (poly(hexamethylene biguanide or branched polyethyleneimine, were studied in CHO-K1 and HeLa cell lines. Both NPs demonstrated to be good siRNA transfection vehicles, but unmodified branched polyethyleneimine (25 kD was superior on both cell lines. However, application of an external magnetic field during transfection (magnetofection increased the efficiency of the superparamagnetic NPs. Furthermore, our results reveal that these NPs are less toxic towards CHO-K1 cell lines than the unmodified polycationic-branched polyethyleneimine (PEI. In general, the external magnetic field did not alter the cell’s viability nor it disrupted the cell membranes, except for the poly(hexamethylene biguanide-modified NP, where it was observed that in CHO-K1 cells application of the external magnetic field promoted membrane damage. This paper presents new polycationic superparamagnetic NPs as promising transfection vehicles for siRNA and demonstrates the advantages of magnetofection.

Elucidating the role of free polycations in gene knockdown by siRNA polyplexes

DEFF Research Database (Denmark)

Klauber, Thomas Christopher Bogh; Søndergaard, Rikke Vicki; Sawant, Rupa R.

2016-01-01

capability, but are very different regarding siRNA decondensation, cellular internalization and induction of reporter gene knockdown. Lipid conjugation of bPEI 1.8. kDa improves the siRNA delivery properties, but with markedly different formulation requirements and mechanisms of action compared...... today.A major reason for the lack of progress is insufficient understanding of cell-polyplex interaction. We investigate siRNA delivery using polyethyleneimine (PEI) based vectors and examine how crucial formulation parameters determine the challenges associated with PEI as a delivery vector. We further...

Exosomes as nanocarriers for siRNA delivery: paradigms and challenges.

Science.gov (United States)

Shahabipour, Fahimeh; Banach, Maciej; Sahebkar, Amirhossein

2016-12-01

Exosomes are nano-sized vesicles that facilitate intercellular communications through carrying genetic materials and functional biomolecules. Owing to their unique size and structure, exosomes have emerged as a useful tool to overcome the limitations of siRNA delivery. The use of exosomes as siRNA delivery vehicles lacks certain disadvantages of the existing foreign delivery systems such as viruses, polycationic polymers and liposomes, and introduces several advantages including inherent capacity to pass through biological barriers and escape from phagocytosis by the reticuloendothelial system, as well as being biocompatible, non-toxic, and immunologically inert. Different strategies have been employed to harness exosome-based delivery systems, including surface modification with targeting ligands, and using exosome-display technology, virus-modified exosomes, and exosome-mimetic vesicles. The present review provides a capsule summary of the recent advances and current challenges in the field of exosome-mediated siRNA delivery.

Security of M-Commerce transactions

OpenAIRE

Ion IVAN; Daniel MILODIN; Alin ZAMFIROIU

2013-01-01

In this material electronic market are defined. How they are structured. Security in E-Commerce applications is very important both at the administrative level and from the user perspective. The new trend in the field is the M-commerce that involves making purchases through mobile devices. And for M-commerce transactions the security is a very important thing. Here’s how to analyze the security of M-commerce transactions and ways to increase security for these transactions taki...

Disintermediation of Inter-Blockchain Transactions

OpenAIRE

English, S. Matthew; Orlandi, Fabrizio; Auer, Soeren

2016-01-01

Different versions of peer-to-peer electronic cash exist as data represented by separate blockchains. Payments between such systems cannot be sent directly from one party to another without going through a financial institution. Bitcoin provided part of the solution but its utility is limited to intra-blockchain transactions. The benefits are lost if a trusted third party is required to execute inter-blockchain transactions. We propose a solution to the inter-blockchain transaction problem us...

[siRNAs with high specificity to the target: a systematic design by CRM algorithm].

Science.gov (United States)

Alsheddi, T; Vasin, L; Meduri, R; Randhawa, M; Glazko, G; Baranova, A

2008-01-01

'Off-target' silencing effect hinders the development of siRNA-based therapeutic and research applications. Common solution to this problem is an employment of the BLAST that may miss significant alignments or an exhaustive Smith-Waterman algorithm that is very time-consuming. We have developed a Comprehensive Redundancy Minimizer (CRM) approach for mapping all unique sequences ("targets") 9-to-15 nt in size within large sets of sequences (e.g. transcriptomes). CRM outputs a list of potential siRNA candidates for every transcript of the particular species. These candidates could be further analyzed by traditional "set-of-rules" types of siRNA designing tools. For human, 91% of transcripts are covered by candidate siRNAs with kernel targets of N = 15. We tested our approach on the collection of previously described experimentally assessed siRNAs and found that the correlation between efficacy and presence in CRM-approved set is significant (r = 0.215, p-value = 0.0001). An interactive database that contains a precompiled set of all human siRNA candidates with minimized redundancy is available at http://129.174.194.243. Application of the CRM-based filtering minimizes potential "off-target" silencing effects and could improve routine siRNA applications.

siRNA Treatment: “A Sword-in-the-Stone” for Acute Brain Injuries

Directory of Open Access Journals (Sweden)

Jerome Badaut

2013-09-01

Full Text Available Ever since the discovery of small interfering ribonucleic acid (siRNA a little over a decade ago, it has been highly sought after for its potential as a therapeutic agent for many diseases. In this review, we discuss the promising possibility of siRNA to be used as a drug to treat acute brain injuries such as stroke and traumatic brain injury. First, we will give a brief and basic overview of the principle of RNA interference as an effective mechanism to decrease specific protein expression. Then, we will review recent in vivo studies describing siRNA research experiments/treatment options for acute brain diseases. Lastly, we will discuss the future of siRNA as a clinical therapeutic strategy against brain diseases and injuries, while addressing the current obstacles to effective brain delivery.

SiRNAs in vivo imaging: methodology of fluorine-18 radiolabelling and application for the optimization of the siRNAs biodistribution and pharmaceutical properties

International Nuclear Information System (INIS)

Viel, Th.

2008-01-01

As RNA interference is a natural process which enables eukaryote cells to regulate the gene expressions, to control transposons, and to struggle against some viruses, two imagery techniques have been used in this research, i.e. optical imagery and Positron Emission Tomography (PET) imagery, to study the various modifications of the small interferential RNAs (siRNA). Different chemically modified siRNAs have been prepared and their in vitro activity, their in vivo metabolism (by HPLC analysis), their bio-distribution and their pharmacokinetic properties (by PET imagery) after marking them with fluorine-18. Their in vivo activity has been assessed by optical imagery

Anonymous Transactions in Computer Networks

Science.gov (United States)

Dolev, Shlomi; Kopeetsky, Marina

We present schemes for providing anonymous transactions while privacy and anonymity are preserved, providing user anonymous authentication in distributed networks such as the Internet. We first present a practical scheme for anonymous transactions while the transaction resolution is assisted by a Trusted Authority. This practical scheme is extended to a theoretical scheme where a Trusted Authority is not involved in the transaction resolution. Given an authority that generates for each player hard to produce evidence EVID (e. g., problem instance with or without a solution) to each player, the identity of a user U is defined by the ability to prove possession of said evidence. We use Zero-Knowledge proof techniques to repeatedly identify U by providing a proof that U has evidence EVID, without revealing EVID, therefore avoiding identity theft.

Low molecular weight chitosan conjugated with folate for siRNA delivery in vitro: optimization studies

Science.gov (United States)

Fernandes, Julio C; Qiu, Xingping; Winnik, Francoise M; Benderdour, Mohamed; Zhang, Xiaoling; Dai, Kerong; Shi, Qin

2012-01-01

The low transfection efficiency of chitosan is one of its drawbacks as a gene delivery carrier. Low molecular weight chitosan may help to form small-sized polymer-DNA or small interfering RNA (siRNA) complexes. Folate conjugation may improve gene transfection efficiency because of the promoted uptake of folate receptor-bearing cells. In the present study, chitosan was conjugated with folate and investigated for its efficacy as a delivery vector for siRNA in vitro. We demonstrate that the molecular weight of chitosan has a major influence on its biological and physicochemical properties, and very low molecular weight chitosan (below 10 kDa) has difficulty in forming stable complexes with siRNA. In this study, chitosan 25 kDa and 50 kDa completely absorbed siRNA and formed nanoparticles (≤220 nm) at a chitosan to siRNA weight ratio of 50:1. The introduction of a folate ligand onto chitosan decreased nanoparticle toxicity. Compared with chitosan-siRNA, folate-chitosan-siRNA nanoparticles improved gene silencing transfection efficiency. Therefore, folate-chitosan shows potential as a viable candidate vector for safe and efficient siRNA delivery. PMID:23209368

2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.

Science.gov (United States)

Wu, Sherry Y; Yang, Xianbin; Gharpure, Kshipra M; Hatakeyama, Hiroto; Egli, Martin; McGuire, Michael H; Nagaraja, Archana S; Miyake, Takahito M; Rupaimoole, Rajesha; Pecot, Chad V; Taylor, Morgan; Pradeep, Sunila; Sierant, Malgorzata; Rodriguez-Aguayo, Cristian; Choi, Hyun J; Previs, Rebecca A; Armaiz-Pena, Guillermo N; Huang, Li; Martinez, Carlos; Hassell, Tom; Ivan, Cristina; Sehgal, Vasudha; Singhania, Richa; Han, Hee-Dong; Su, Chang; Kim, Ji Hoon; Dalton, Heather J; Kovvali, Chandra; Keyomarsi, Khandan; McMillan, Nigel A J; Overwijk, Willem W; Liu, Jinsong; Lee, Ju-Seog; Baggerly, Keith A; Lopez-Berestein, Gabriel; Ram, Prahlad T; Nawrot, Barbara; Sood, Anil K

2014-03-12

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2'-O-Methyl (2'-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2'-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

Delivery of kinesin spindle protein targeting siRNA in solid lipid nanoparticles to cellular models of tumor vasculature

International Nuclear Information System (INIS)

Ying, Bo; Campbell, Robert B.

2014-01-01

Highlights: • siRNA-lipid nanoparticles are solid particles not lipid bilayers with aqueous core. • High, but not low, PEG content can prevent nanoparticle encapsulation of siRNA. • PEG reduces cellular toxicity of cationic nanoparticles in vitro. • PEG reduces zeta potential while improving gene silencing of siRNA nanoparticles. • Kinesin spindle protein can be an effective target for tumor vascular targeting. - Abstract: The ideal siRNA delivery system should selectively deliver the construct to the target cell, avoid enzymatic degradation, and evade uptake by phagocytes. In the present study, we evaluated the importance of polyethylene glycol (PEG) on lipid-based carrier systems for encapsulating, and delivering, siRNA to tumor vessels using cellular models. Lipid nanoparticles containing different percentage of PEG were evaluated based on their physical chemical properties, density compared to water, siRNA encapsulation, toxicity, targeting efficiency and gene silencing in vitro. siRNA can be efficiently loaded into lipid nanoparticles (LNPs) when DOTAP is included in the formulation mixture. However, the total amount encapsulated decreased with increase in PEG content. In the presence of siRNA, the final formulations contained a mixed population of particles based on density. The major population which contains the majority of siRNA exhibited a density of 4% glucose, and the minor fraction associated with a decreased amount of siRNA had a density less than PBS. The inclusion of 10 mol% PEG resulted in a greater amount of siRNA associated with the minor fraction. Finally, when kinesin spindle protein (KSP) siRNA was encapsulated in lipid nanoparticles containing a modest amount of PEG, the proliferation of endothelial cells was inhibited due to the efficient knock down of KSP mRNA. The presence of siRNA resulted in the formation of solid lipid nanoparticles when prepared using the thin film and hydration method. LNPs with a relatively modest amount of

Nanosystems based on siRNA silencing HuR expression counteract diabetic retinopathy in rat.

Science.gov (United States)

Amadio, Marialaura; Pascale, Alessia; Cupri, Sarha; Pignatello, Rosario; Osera, Cecilia; D Agata, Velia; D Amico, Agata Grazia; Leggio, Gian Marco; Ruozi, Barbara; Govoni, Stefano; Drago, Filippo; Bucolo, Claudio

2016-09-01

We evaluated whether specifically and directly targeting human antigen R (HuR), a member of embryonic lethal abnormal vision (ELAV) proteins family, may represent a new potential therapeutic strategy to manage diabetic retinopathy. Nanosystems loaded with siRNA silencing HuR expression (lipoplexes), consisting of solid lipid nanoparticles (SLN) and liposomes (SUV) were prepared. Photon correlation spectroscopy analysis, Zeta potential measurement and atomic force microscopy (AFM) studies were carried out to characterize the complexation of siRNA with the lipid nanocarriers. Nanosystems were evaluated by using AFM and scanning electron microscopy. The lipoplexes were injected into the eye of streptozotocin (STZ)-induced diabetic rats. Retinal HuR and VEGF levels were detected by Western blot and ELISA, respectively. Retinal histology was also carried out. The results demonstrated that retinal HuR and VEGF are significantly increased in STZ-rats and are blunted by HuR siRNA treatment. Lipoplexes with a weak positive surface charge and with a 4:1 N/P (cationic lipid nitrogen to siRNA phosphate) ratio exert a better transfection efficiency, significantly dumping retinal HuR and VEGF levels. In conclusion, we demonstrated that siRNA can be efficiently delivered into the rat retina using lipid-based nanocarriers, and some of the lipoplexes loaded with siRNA silencing HuR expression are potential candidates to manage retinal diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemosensitization of cancer cells by siRNA using targeted nanogel delivery

International Nuclear Information System (INIS)

Dickerson, Erin B; Blackburn, William H; Smith, Michael H; Kapa, Laura B; Lyon, L Andrew; McDonald, John F

2010-01-01

Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy. However, delivery represents the main hurdle for the broad development of RNAi therapeutics. We report here the use of core/shell hydrogel nanoparticles (nanogels) functionalized with peptides that specially target the EphA2 receptor to deliver small interfering RNAs (siRNAs) targeting EGFR. Expression of EGFR was determined by immunoblotting, and the effect of decreased EGFR expression on chemosensitization of ovarian cancer cells after siRNA delivery was investigated. Treatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel (P < 0.05). Nanogel treatment of SK-OV-3 cells, which are negative for EphA2 expression, failed to reduce EGFR levels and did not increase docetaxel sensitivity (P > 0.05). This study suggests that targeted delivery of siRNAs by nanogels may be a promising strategy to increase the efficacy of chemotherapy drugs for the treatment of ovarian cancer. In addition, EphA2 is a viable target for therapeutic delivery, and the siRNAs are effectively protected by the nanogel carrier, overcoming the poor stability and uptake that has hindered clinical advancement of therapeutic siRNAs

PLK-1 Silencing in Bladder Cancer by siRNA Delivered With Exosomes.

Science.gov (United States)

Greco, Kristin A; Franzen, Carrie A; Foreman, Kimberly E; Flanigan, Robert C; Kuo, Paul C; Gupta, Gopal N

2016-05-01

To use exosomes as a vector to deliver small interfering ribonucleic acid (siRNA) to silence the polo-like kinase 1 (PLK-1) gene in bladder cancer cells. Exosomes were isolated from both human embryonic kidney 293 (HEK293) cell and mesenchymal stem cell (MSC) conditioned media. Fluorescently labeled exosomes were co-cultured with bladder cancer and normal epithelial cells and uptake was quantified by image cytometry. PLK-1 siRNA and negative control siRNA were loaded into HEK293 and MSC exosomes using electroporation. An invasive bladder cancer cell line (UMUC3) was co-cultured with the electroporated exosomes. Quantitative reverse transcriptase polymerase chain reaction was performed. Protein analysis was performed by Western blot. Annexin V staining and MTT assays were used to investigate effects on apoptosis and viability. Bladder cancer cell lines internalize an increased percentage of HEK293 exosomes when compared to normal bladder epithelial cells. Treatment of UMUC3 cells with exosomes electroporated with PLK-1 siRNA achieved successful knockdown of PLK-1 mRNA and protein when compared to cells treated with negative control exosomes. HEK293 and MSC exosomes were effectively used as a delivery vector to transport PLK-1 siRNA to bladder cancer cells in vitro, resulting in selective gene silencing of PLK-1. The use of exosomes as a delivery vector for potential intravesical therapy is attractive. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of erythropoietin siRNA on corneal neovascularization of rabbit

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Yu-Shun Xue

2017-03-01

Full Text Available AIM: To observe the expression of erythropoietin(EPOon the corneal of rabbit and evaluate the inhibition effect of EPO siRNA on corneal neovascularization(CNV. METHODS: Totally 22 healthy rabbits were randomly divided into 2 groups, which were experimental group and normal control group. Both eyes of rabbits in experimental group were chosen to establish corneal neovascularization model by alkali burn. The morphologic change of corneal was observed with slit lamp microscope and the area of CNV was calculated every day. After alkali burn, the right eye of the experimental group was accepted EPO siRNA injection under the conjunctiva, and the left eye was assigned to be experimental control group. The corneal with CNV was collected for immunohistochemistry at 3d, 7d, 14d, 21d after alkali burn, and the expression of EPO was measured. RESULTS: CNV began growing at the 3d after alkali burn in experimental group, and it was vigorous growing at 7d-14d period. The result of immunohistochemistry shows that the expression of EPO increased after the operation. Compared with experimental group, the rabbits who were treated by EPO siRNA was found with less neovascularization on their corneal, and the expression of EPO decreased. There were statistical significance between the two group at different time(PCONCLUSION: EPO is likely to play an important role on CNV growth, and EPO siRNA can inhibit the growth of CNV by restraining the expression of EPO.

The antifibrotic effects of TGF-β1 siRNA on hepatic fibrosis in rats

International Nuclear Information System (INIS)

Lang, Qing; Liu, Qi; Xu, Ning; Qian, Ke-Li; Qi, Jing-Hu; Sun, Yin-Chun; Xiao, Lang; Shi, Xiao-Feng

2011-01-01

Highlights: → We constructed CCL4 induced liver fibrosis model successfully. → We proofed that the TGF-β1 siRNA had a definite therapy effect to CCL4 induced liver fibrosis. → The therapy effect of TGF-β1 siRNA had dose-dependent. -- Abstract: Background/aims: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-β1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-β1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). Methods: A total of 40 healthy, male SD (Sprague-Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-β1 siRNA 0.125 mg/kg treatment group, TGF-β1 siRNA 0.25 mg/kg treatment group and TGF-β1 siRNA negative control group (0.25 mg/kg). CCL4 and a high-fat diet were used for 8 weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin-Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-β1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-β1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-β1 by quantitative real-time polymerase chain reaction. Results: Comparing the TGF-β1 siRNA 0.25 mg/kg treatment group to the model group, the TGF-β1 siRNA negative control group and the TGF-β1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the mRNA expression of TGF-β1, type I collagen and type III collagen (P < 0

The antifibrotic effects of TGF-{beta}1 siRNA on hepatic fibrosis in rats

Energy Technology Data Exchange (ETDEWEB)

Lang, Qing; Liu, Qi [Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Instituted for Virus Hepatitis and Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China); Xu, Ning [The Second Hospital of YuLin, Shanxi Province (China); Qian, Ke-Li; Qi, Jing-Hu; Sun, Yin-Chun; Xiao, Lang [Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Instituted for Virus Hepatitis and Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China); Shi, Xiao-Feng, E-mail: sxff2003@yahoo.com.cn [Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Instituted for Virus Hepatitis and Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China)

2011-06-10

Highlights: {yields} We constructed CCL4 induced liver fibrosis model successfully. {yields} We proofed that the TGF-{beta}1 siRNA had a definite therapy effect to CCL4 induced liver fibrosis. {yields} The therapy effect of TGF-{beta}1 siRNA had dose-dependent. -- Abstract: Background/aims: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-{beta}1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-{beta}1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). Methods: A total of 40 healthy, male SD (Sprague-Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-{beta}1 siRNA 0.125 mg/kg treatment group, TGF-{beta}1 siRNA 0.25 mg/kg treatment group and TGF-{beta}1 siRNA negative control group (0.25 mg/kg). CCL4 and a high-fat diet were used for 8 weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin-Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-{beta}1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-{beta}1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-{beta}1 by quantitative real-time polymerase chain reaction. Results: Comparing the TGF-{beta}1 siRNA 0.25 mg/kg treatment group to the model group, the TGF-{beta}1 siRNA negative control group and the TGF-{beta}1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the m

Hippocalcin Is Required for Astrocytic Differentiation through Activation of Stat3 in Hippocampal Neural Precursor Cells.

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Min-Jeong Kang

2016-10-01

Full Text Available Hippocalcin (Hpca is a neuronal calcium sensor protein expressed in the mammalian brain. However, its function in neural stem/precursor cells has not yet been studied. Here, we clarify the function of Hpca in astrocytic differentiation in hippocampal neural precursor cells (HNPCs. When we overexpressed Hpca in HNPCs in the presence or absence of bFGF, expression levels of nerve-growth factors such as neurotrophin-3 (NT-3, neurotrophin-4/5 (NT-4/5 and brain-derived neurotrophic factor (BDNF, together with the proneural basic helix loop helix (bHLH transcription factors neuroD and neurogenin 1 (ngn1, increased significantly. In addition, there was an increase in the number of cells expressing glial fibrillary acidic protein (GFAP, an astrocyte marker, and in dendrite outgrowth, indicating astrocytic differentiation of the HNPCs. Downregulation of Hpca by transfection with Hpca siRNA reduced expression of NT-3, NT-4/5, BDNF, neuroD and ngn1 as well as levels of GFAP protein. Furthermore, overexpression of Hpca increased the phosphorylation of STAT3 (Ser727, and this effect was abolished by treatment with a STAT3 inhibitor (S3I-201, suggesting that STAT3 (Ser727 activation is involved in Hpca-mediated astrocytic differentiation. As expected, treatment with Stat3 siRNA or STAT3 inhibitor caused a complete inhibition of astrogliogenesis induced by Hpca overexpression. Taken together, this is the first report to show that Hpca, acting through Stat3, has an important role in the expression of neurotrophins and proneural bHLH transcription factors, and that it is an essential regulator of astrocytic differentiation and dendrite outgrowth in HNPCs.

Value and Transaction Costs

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai Juul

2003-01-01

caused by transaction costs), andnew types of resources (i.e., capture and protection capabilities), clarifies the roleof contracting in the exercise of market power, and suggests that `strategizing'and `economizing' perspectives are related to a larger extent than is normallyrecognized. Refutable......AbstractWe forge linkages between the economics of property rights (Coase, Demsetz,Cheung, Barzel) and strategic management. Property rights to resources consistof the rights to consume, obtain income from, and alienate these resources.Transaction costs are the costs of exchanging, protecting...... and capturing propertyrights. We clarify the key role of transaction costs with respect to understandingvalue creation and the limitations and opportunities of strategizing relative tocompetitive forces. The economics of property rights identifies new sources ofvalue creation (i.e., reducing the dissipation...

Transactive System: Part II: Analysis of Two Pilot Transactive Systems using Foundational Theory and Metrics

Energy Technology Data Exchange (ETDEWEB)

Lian, Jianming [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Sun, Y. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kalsi, Karanjit [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Widergren, Steven E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Wu, Di [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Ren, Huiying [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2018-01-24

This document is the second of a two-part report. Part 1 reviewed several demonstrations of transactive control and compared them in terms of their payoff functions, control decisions, information privacy, and mathematical solution concepts. It was suggested in Part 1 that these four listed components should be adopted for meaningful comparison and design of future transactive systems. Part 2 proposes qualitative and quantitative metrics that will be needed to compare alternative transactive systems. It then uses the analysis and design principles from Part 1 while conducting more in-depth analysis of two transactive demonstrations: the American Electric Power (AEP) gridSMART Demonstration, which used a double –auction market mechanism, and a consensus method like that used in the Pacific Northwest Smart Grid Demonstration. Ultimately, metrics must be devised and used to meaningfully compare alternative transactive systems. One significant contribution of this report is an observation that the decision function used for thermostat control in the AEP gridSMART Demonstration has superior performance if its decision function is recast to more accurately reflect the power that will be used under for thermostatic control under alternative market outcomes.

FcepsilonRI-alpha siRNA inhibits the antigen-induced activation of mast cells.

Science.gov (United States)

Safaralizadeh, Reza; Soheili, Zahra-Soheila; Deezagi, Abdolkhaleg; Pourpak, Zahra; Samiei, Shahram; Moin, Mostafa

2009-12-01

FcepsilonRI, The high affinity receptor for IgE plays a critical role in triggering the allergic reactions. It is responsible for inducing mast cell degranulation and deliberation of allergy mediators when it is aggregated by allergen and IgE complexes. FcepsilonRI on the mast cells consists of three subunits; alpha chain directly binds IgE, beta chain and dimmer of gamma chains together mediate intracellular signaling. Cross-linking of IgE-bound FcepsilonRI on the surface of mast cells and basophils by the multivalent antigen induces release of chemical mediators. The present in vitro study was designed to investigate the effect of synthetic FcepsilonRI-alpha siRNA on the antigen-induced activation of MC/9 cells. MC/9 cells which are murine mast cells were transfected by FcepsilonRI-alpha siRNA and negative control siRNA. After 6 h, anti-DNP (Dinitrophenyl) IgE was used for the cells sensitization. Then the cells were challenged with Dinitrophenyl-Human Serum Albumin (DNP-HSA) for mast cell degranulation induction before collection of supernatants. The amount of mRNA and protein expression was measured by Real Time PCR and western blot analysis, respectively. Determination of the expression rate of FcepsilonRI-alpha on cell surface was achieved by flow cytometry. ELISA and spectrophotometry methods were used subsequently for measuring the effects of FcepsilonRI-alpha siRNA on antigen-induced histamine and beta-hexosaminidase release. FcepsilonRI-alpha siRNA treated cells showed significant decrease in FcepsilonRI-alpha mRNA and protein expression in comparison to control cells. FcepsilonRI-mediated mast cell release of beta-hexosaminidase and histamine were also inhibited. In this study it was shown that FcepsilonRI-alpha siRNA could suppress FcepsilonRI-alpha expression and inhibited degranulation and histamine release in antigen-stimulated MC/9 cells. In conclusion, knock-down of FcepsilonRI-alpha by siRNA could be a promising method for inhibition of the mast

Optimizations of siRNA design for the activation of gene transcription by targeting the TATA-box motif.

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Miaomiao Fan

Full Text Available Small interfering RNAs (siRNAs are widely used to repress gene expression by targeting mRNAs. Some reports reveal that siRNAs can also activate or inhibit gene expression through targeting the gene promoters. Our group has found that microRNAs (miRNAs could activate gene transcription via interaction with the TATA-box motif in gene promoters. To investigate whether siRNA targeting the same region could upregulate the promoter activity, we test the activating efficiency of siRNAs targeting the TATA-box motif of 16 genes and perform a systematic analysis to identify the common features of the functional siRNAs for effective activation of gene promoters. Further, we try various modifications to improve the activating efficiency of siRNAs and find that it is quite useful to design the promoter-targeting activating siRNA by following several rules such as (a complementary to the TATA-box-centered region; (b UA usage at the first two bases of the antisense strand; (c twenty-three nucleotides (nts in length; (d 2'-O-Methyl (2'-OMe modification at the 3' terminus of the antisense strand; (e avoiding mismatches at the 3' end of the antisense strand. The optimized activating siRNAs potently enhance the expression of interleukin-2 (IL-2 gene in human and mouse primary CD4+ T cells with a long-time effect. Taken together, our study provides a guideline for rational design the promoter-targeting siRNA to sequence-specifically enhance gene expression.

Multi-period fuzzy mean-semi variance portfolio selection problem with transaction cost and minimum transaction lots using genetic algorithm

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Mohammad Ali Barati

2016-04-01

Full Text Available Multi-period models of portfolio selection have been developed in the literature with respect to certain assumptions. In this study, for the first time, the portfolio selection problem has been modeled based on mean-semi variance with transaction cost and minimum transaction lots considering functional constraints and fuzzy parameters. Functional constraints such as transaction cost and minimum transaction lots were included. In addition, the returns on assets parameters were considered as trapezoidal fuzzy numbers. An efficient genetic algorithm (GA was designed, results were analyzed using numerical instances and sensitivity analysis were executed. In the numerical study, the problem was solved based on the presence or absence of each mode of constraints including transaction costs and minimum transaction lots. In addition, with the use of sensitivity analysis, the results of the model were presented with the variations of minimum expected rate of programming periods.

Targeted transfection increases siRNA uptake and gene silencing of primary endothelial cells in vitro--a quantitative study.

Science.gov (United States)

Asgeirsdóttir, Sigridur A; Talman, Eduard G; de Graaf, Inge A; Kamps, Jan A A M; Satchell, Simon C; Mathieson, Peter W; Ruiters, Marcel H J; Molema, Grietje

2010-01-25

Applications of small-interfering RNA (siRNA) call for specific and efficient delivery of siRNA into particular cell types. We developed a novel, non-viral targeting system to deliver siRNA specifically into inflammation-activated endothelial cells. This was achieved by conjugating the cationic amphiphilic lipid SAINT to antibodies recognizing the inflammatory cell adhesion molecule E-selectin. These anti-E-selectin-SAINT lipoplexes (SAINTarg) maintained antigen recognition capacity of the parental antibody in vitro, and ex vivo in human kidney tissue slices subjected to inflammatory conditions. Regular SAINT mediated transfection resulted in efficient gene silencing in human microvascular endothelial cells (HMEC-1) and conditionally immortalized glomerular endothelial cells (ciGEnC). However, primary human umbilical vein endothelial cells (HUVEC) transfected poorly, a phenomenon that we could quantitatively correlate with a cell-type specific capacity to facilitate siRNA uptake. Importantly, SAINTarg increased siRNA uptake and transfection specificity for activated endothelial cells. Transfection with SAINTarg delivered significantly more siRNA into activated HUVEC, compared to transfection with non-targeted SAINT. The enhanced uptake of siRNA was corroborated by improved silencing of both gene- and protein expression of VE-cadherin in activated HUVEC, indicating that SAINTarg delivered functionally active siRNA into endothelial cells. The obtained results demonstrate a successful design of a small nucleotide carrier system with improved and specific siRNA delivery into otherwise difficult-to-transfect primary endothelial cells, which in addition reduced considerably the amount of siRNA needed for gene silencing. Copyright 2009 Elsevier B.V. All rights reserved.

Targeted siRNA Delivery and mRNA Knockdown Mediated by Bispecific Digoxigenin-binding Antibodies

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Britta Schneider

2012-01-01

Full Text Available Bispecific antibodies (bsAbs that bind to cell surface antigens and to digoxigenin (Dig were used for targeted small interfering RNA (siRNA delivery. They are derivatives of immunoglobulins G (IgGs that bind tumor antigens, such as Her2, IGF1-R, CD22, and LeY, with stabilized Dig-binding variable domains fused to the C-terminal ends of the heavy chains. siRNA that was digoxigeninylated at its 3′end was bound in a 2:1 ratio to the bsAbs. These bsAb–siRNA complexes delivered siRNAs specifically to cells that express the corresponding antigen as demonstrated by flow cytometry and confocal microscopy. The complexes internalized into endosomes and Dig-siRNAs separated from bsAbs, but Dig-siRNA was not released into the cytoplasm; bsAb-targeting alone was thus not sufficient for effective mRNA knockdown. This limitation was overcome by formulating the Dig-siRNA into nanoparticles consisting of dynamic polyconjugates (DPCs or into lipid-based nanoparticles (LNPs. The resulting complexes enabled bsAb-targeted siRNA-specific messenger RNA (mRNA knockdown with IC50 siRNA values in the low nanomolar range for a variety of bsAbs, siRNAs, and target cells. Furthermore, pilot studies in mice bearing tumor xenografts indicated mRNA knockdown in endothelial cells following systemic co-administration of bsAbs and siRNA formulated in LNPs that were targeted to the tumor vasculature.

Mapping Optimal Charge Density and Length of ROMP-Based PTDMs for siRNA Internalization.

Science.gov (United States)

Caffrey, Leah M; deRonde, Brittany M; Minter, Lisa M; Tew, Gregory N

2016-10-10

A fundamental understanding of how polymer structure impacts internalization and delivery of biologically relevant cargoes, particularly small interfering ribonucleic acid (siRNA), is of critical importance to the successful design of improved delivery reagents. Herein we report the use of ring-opening metathesis polymerization (ROMP) methods to synthesize two series of guanidinium-rich protein transduction domain mimics (PTDMs): one based on an imide scaffold that contains one guanidinium moiety per repeat unit, and another based on a diester scaffold that contains two guanidinium moieties per repeat unit. By varying both the degree of polymerization and, in effect, the relative number of cationic charges in each PTDM, the performances of the two ROMP backbones for siRNA internalization were evaluated and compared. Internalization of fluorescently labeled siRNA into Jurkat T cells demonstrated that fluorescein isothiocyanate (FITC)-siRNA internalization had a charge content dependence, with PTDMs containing approximately 40 to 60 cationic charges facilitating the most internalization. Despite this charge content dependence, the imide scaffold yielded much lower viabilities in Jurkat T cells than the corresponding diester PTDMs with similar numbers of cationic charges, suggesting that the diester scaffold is preferred for siRNA internalization and delivery applications. These developments will not only improve our understanding of the structural factors necessary for optimal siRNA internalization, but will also guide the future development of optimized PTDMs for siRNA internalization and delivery.

Security of M-Commerce transactions

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Ion IVAN

2013-07-01

Full Text Available In this material electronic market are defined. How they are structured. Security in E-Commerce applications is very important both at the administrative level and from the user perspective. The new trend in the field is the M-commerce that involves making purchases through mobile devices. And for M-commerce transactions the security is a very important thing. Here's how to analyze the security of M-commerce transactions and ways to increase security for these transactions taking into account the organization of M-Commerce applications, software used, hardware used and other important issues in the development of these applications.

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

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Eileen M Redmond

Full Text Available To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown.These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.

Synthesis of Polymer-Lipid Nanoparticles by Microfluidic Focusing for siRNA Delivery

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Yujing Li

2016-10-01

Full Text Available Polyethylenimine (PEI as a cationic polymer is commonly used as a carrier for gene delivery. PEI-800 is less toxic than PEI-25K but it is also less efficient. A novel nanocarrier was developed by combining PEI-800 with a pH-sensitive lipid to form polymer-lipid hybrid nanoparticles (P/LNPs. They were synthesized by microfluidic focusing (MF. Two microfluidic devices were used to synthesize P/LNPs loaded with VEGF siRNA. A series of P/LNPs with different particle sizes and distributions were obtained by altering the flow rate and geometry of microfluidic chips, and introducing sonication. Furthermore, the P/LNPs can be loaded with VEGF siRNA efficiently and were stable in serum for 12 h. Finally, P/LNPs produced by the microfluidic chip showed greater cellular uptake as well as down-regulation of VEGF protein level in both A549 and MCF-7 with reduced cellular toxicity. All in all, the P/LNPs produced by MF method were shown to be a safe and efficient carrier for VEGF siRNA, with potential application for siRNA therapeutics.

Polo-like kinase 1 siRNA-607 induces mitotic arrest and apoptosis in ...

African Journals Online (AJOL)

Polo-like kinase (Plk) 1 is overexpressed in many human malignancies including nasopharyngeal carcinoma, indicating its potential as a therapeutic target. Recently, using a simple cellular morphologybased strategy, we have identified several novel effective siRNAs against Plk1 including Plk1 siRNA- 607. In this study, we ...

In vivo silencing of alpha-synuclein using naked siRNA

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Charisse Klaus

2008-11-01

Full Text Available Abstract Background Overexpression of α-synuclein (SNCA in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD, possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. Results We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked, murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. Conclusion We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.

In vivo silencing of alpha-synuclein using naked siRNA

Science.gov (United States)

Lewis, Jada; Melrose, Heather; Bumcrot, David; Hope, Andrew; Zehr, Cynthia; Lincoln, Sarah; Braithwaite, Adam; He, Zhen; Ogholikhan, Sina; Hinkle, Kelly; Kent, Caroline; Toudjarska, Ivanka; Charisse, Klaus; Braich, Ravi; Pandey, Rajendra K; Heckman, Michael; Maraganore, Demetrius M; Crook, Julia; Farrer, Matthew J

2008-01-01

Background Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. Results We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. Conclusion We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression. PMID:18976489

MicroRNA-directed siRNA biogenesis in Caenorhabditis elegans.

Science.gov (United States)

Corrêa, Régis L; Steiner, Florian A; Berezikov, Eugene; Ketting, René F

2010-04-08

RNA interference (RNAi) is a post-transcriptional silencing process, triggered by double-stranded RNA (dsRNA), leading to the destabilization of homologous mRNAs. A distinction has been made between endogenous RNAi-related pathways and the exogenous RNAi pathway, the latter being essential for the experimental use of RNAi. Previous studies have shown that, in Caenorhabditis elegans, a complex containing the enzymes Dicer and the Argonaute RDE-1 process dsRNA. Dicer is responsible for cleaving dsRNA into short interfering RNAs (siRNAs) while RDE-1 acts as the siRNA acceptor. RDE-1 then guides a multi-protein complex to homologous targets to trigger mRNA destabilization. However, endogenous role(s) for RDE-1, if any, have remained unexplored. We here show that RDE-1 functions as a scavenger protein, taking up small RNA molecules from many different sources, including the microRNA (miRNA) pathway. This is in striking contrast to Argonaute proteins functioning directly in the miRNA pathway, ALG-1 and ALG-2: these proteins exclusively bind miRNAs. While playing no significant role in the biogenesis of the main pool of miRNAs, RDE-1 binds endogenous miRNAs and triggers RdRP activity on at least one perfectly matching, endogenous miRNA target. The resulting secondary siRNAs are taken up by a set of Argonaute proteins known to act as siRNA acceptors in exogenous RNAi, resulting in strong mRNA destabilization. Our results show that RDE-1 in an endogenous setting is actively screening the transcriptome using many different small RNAs, including miRNAs, as a guide, with implications for the evolution of transcripts with a potential to be recognized by Dicer.

MicroRNA–Directed siRNA Biogenesis in Caenorhabditis elegans

Science.gov (United States)

Corrêa, Régis L.; Steiner, Florian A.; Berezikov, Eugene; Ketting, René F.

2010-01-01

RNA interference (RNAi) is a post-transcriptional silencing process, triggered by double-stranded RNA (dsRNA), leading to the destabilization of homologous mRNAs. A distinction has been made between endogenous RNAi–related pathways and the exogenous RNAi pathway, the latter being essential for the experimental use of RNAi. Previous studies have shown that, in Caenorhabditis elegans, a complex containing the enzymes Dicer and the Argonaute RDE-1 process dsRNA. Dicer is responsible for cleaving dsRNA into short interfering RNAs (siRNAs) while RDE-1 acts as the siRNA acceptor. RDE-1 then guides a multi-protein complex to homologous targets to trigger mRNA destabilization. However, endogenous role(s) for RDE-1, if any, have remained unexplored. We here show that RDE-1 functions as a scavenger protein, taking up small RNA molecules from many different sources, including the microRNA (miRNA) pathway. This is in striking contrast to Argonaute proteins functioning directly in the miRNA pathway, ALG-1 and ALG-2: these proteins exclusively bind miRNAs. While playing no significant role in the biogenesis of the main pool of miRNAs, RDE-1 binds endogenous miRNAs and triggers RdRP activity on at least one perfectly matching, endogenous miRNA target. The resulting secondary siRNAs are taken up by a set of Argonaute proteins known to act as siRNA acceptors in exogenous RNAi, resulting in strong mRNA destabilization. Our results show that RDE-1 in an endogenous setting is actively screening the transcriptome using many different small RNAs, including miRNAs, as a guide, with implications for the evolution of transcripts with a potential to be recognized by Dicer. PMID:20386745

The development by the German Transactional Analysis Association of a scientifically-based online evaluation system of transactional analysis training

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Norbert Nagel

2017-07-01

Full Text Available The authors present the development and statistical analysis, conducted under the auspices of the German Transactional Analysis Association (DGTA, of an online evaluation system of transactional analysis training.  The understanding of evaluation research is clarified, and the data-entry form and its grounding in the theory of transactional analysis are presented. Emphasis is placed on the development of the competence concept, the definition of competence categories, and the representation of the foundations of a transactional-analytic educational theory.  The scientific examination of the validity and reliability of the scales, the research process with pre-test and re-test, and the evaluation of the data in the system of online evaluation are extensively documented.  In conclusion, it is claimed that this online-based DGTA evaluation is one of the few result-oriented teaching evaluation instruments in the German-speaking countries which meets scientific control criteria and is published. Citation - APA format: Nagel, N., König, J., Ottmann, S., & Hahnle, A. (2017. The development by the German Transactional Analysis Association of a scientifically-based online evaluation system of transactional analysis training. International Journal of Transactional Analysis Research & Practice, 8(2, 3-23.

Low cytotoxicity fluorescent PAMAM dendrimer as gene carriers for monitoring the delivery of siRNA

Energy Technology Data Exchange (ETDEWEB)

Guan, Lingmei [Sichuan University, State Key Laboratory of Bio-resources and Eco-environment, The Ministry of Education, College of Life Sciences (China); Huang, Saipeng [Chinese Academy of Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Sciences, Institute of Chemistry (China); Chen, Zhao [Xi’an Jiaotong University, School of Science (China); Li, Yanchao [Chinese Academy of Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Sciences, Institute of Chemistry (China); Liu, Ke [Sichuan University, State Key Laboratory of Bio-resources and Eco-environment, The Ministry of Education, College of Life Sciences (China); Liu, Yang, E-mail: yliu@iccas.ac.cn; Du, Libo, E-mail: dulibo@iccas.ac.cn [Chinese Academy of Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Sciences, Institute of Chemistry (China)

2015-09-15

Visual detection of gene vectors has attracted a great deal of attention due to the application of these vectors in monitoring and evaluating the effect of gene carriers in living cells. A non-viral vector, the fluorescent PAMAM dendrimer (F-PAMAM), was synthesized through conjugation of PAMAM dendrimers and fluorescein. In vitro and ex vivo experiments show that F-PAMAM exhibits superphotostability, low cytotoxicity and facilitates endocytosis by A549 cells. The vector has a high siRNA binding affinity and it increases the efficiency of cy5-siRNA delivery in A549 cells, in comparison with a cy5-siRNA monomer. Our results provide a new method for simultaneously monitoring the delivery of siRNA and its non-viral carriers in living cells.

Optimizing Concurrent M3-Transactions: A Fuzzy Constraint Satisfaction Approach

Directory of Open Access Journals (Sweden)

Peng LI

2004-10-01

Full Text Available Due to the high connectivity and great convenience, many E-commerce application systems have a high transaction volume. Consequently, the system state changes rapidly and it is likely that customers issue transactions based on out-of-date state information. Thus, the potential of transaction abortion increases greatly. To address this problem, we proposed an M3-transaction model. An M3-transaction is a generalized transaction where users can issue their preferences in a request by specifying multiple criteria and optional data resources simultaneously within one transaction. In this paper, we introduce the transaction grouping and group evaluation techniques. We consider evaluating a group of M3-transactions arrived to the system within a short duration together. The system makes optimal decisions in allocating data to transactions to achieve better customer satisfaction and lower transaction failure rate. We apply the fuzzy constraint satisfaction approach for decision-making. We also conduct experimental studies to evaluate the performance of our approach. The results show that the M3-transaction with group evaluation is more resilient to failure and yields much better performance than the traditional transaction model.

Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis.

Science.gov (United States)

Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis.

Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine

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Chiranjib Chakraborty

2017-09-01

Full Text Available In the past few years, therapeutic microRNA (miRNA and small interfering RNA (siRNA are some of the most important biopharmaceuticals that are in commercial space as future medicines. This review summarizes the patents of miRNA- and siRNA-based new drugs, and also provides a snapshot about significant biopharmaceutical companies that are investing for the therapeutic development of miRNA and siRNA molecules. An insightful view about individual siRNA and miRNA drugs has been depicted with their present status, which is gaining attention in the therapeutic landscape. The efforts of the biopharmaceuticals are discussed with the status of their preclinical and/or clinical trials. Here, some of the setbacks have been highlighted during the biopharmaceutical development of miRNA and siRNA as individual therapeutics. Finally, a snapshot is illustrated about pharmacokinetics, pharmacodynamics with absorption, distribution, metabolism, and excretion (ADME, which is the fundamental development process of these therapeutics, as well as the delivery system for miRNA- and siRNA-based drugs. Keywords: miRNA, siRNA, drug development

Down-regulation of viral replication by adenoviral-mediated expression of siRNA against cellular cofactors for hepatitis C virus

International Nuclear Information System (INIS)

Zhang Jing; Yamada, Osamu; Sakamoto, Takashi; Yoshida, Hiroshi; Iwai, Takahiro; Matsushita, Yoshihisa; Shimamura, Hideo; Araki, Hiromasa; Shimotohno, Kunitada

2004-01-01

Small interfering RNA (siRNA) is currently being evaluated not only as a powerful tool for functional genomics, but also as a potentially promising therapeutic agent for cancer and infectious diseases. Inhibitory effect of siRNA on viral replication has been demonstrated in multiple pathogenic viruses. However, because of the high sequence specificity of siRNA-mediated RNA degradation, antiviral efficacy of siRNA directed to viral genome will be largely limited by emergence of escape variants resistant to siRNA due to high mutation rates of virus, especially RNA viruses such as poliovirus and hepatitis C virus (HCV). To investigate the therapeutic feasibility of siRNAs specific for the putative cellular cofactors for HCV, we constructed adenovirus vectors expressing siRNAs against La, polypyrimidine tract-binding protein (PTB), subunit gamma of human eukaryotic initiation factors 2B (eIF2Bγ), and human VAMP-associated protein of 33 kDa (hVAP-33). Adenoviral-mediated expression of siRNAs markedly diminished expression of the endogenous genes, and silencing of La, PTB, and hVAP-33 by siRNAs substantially blocked HCV replication in Huh-7 cells. Thus, our studies demonstrate the feasibility and potential of adenoviral-delivered siRNAs specific for cellular cofactors in combating HCV infection, which can be used either alone or in combination with siRNA against viral genome to prevent the escape of mutant variants and provide additive or synergistic anti-HCV effects

Remedial transactions curtailment via optimization

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Maksimović Viktor

2009-01-01

Full Text Available The new method developed in this paper is aiming at transmission congestion management (CM. The new, Optimal Transactions Management method (OTM, is based on linear programming (LP, DC load flow (DCLF and linear security constraints. The OTM method is embedded in Available Transfer Capabilities (ATCs and Power Transfer Distribution Factors (PTDFs definitions' environment. Well-suited for both preventive and corrective modes of operation, the OTM method aids transmission system operator in running a congested power system network, where congestions are due to transactions. Potential congestion threat is solved by finding the 'culprit' transaction and its optimal reduction. Besides the proposed downsizing of scheduled and/or committed transactions, controls of the OTM method also include redispatching of generation and load levels. The task is to establish a system state without constraint violations. To ensure the feasible network solution, both DC and AC power flows are used. The common 5 nodes/7 lines Ward&Hale sample power system is used to clarify the OTM method. Besides, six other power system networks including the real-life power system network of Serbia, Macedonia and Montenegro (part of the South East Europe - SEE grid are used to test remedial potentials and CPU-time performances of the method. The 24-hour daily demand diagram is used with all test networks to study the effects of transactions as they are being superimposed to the regional grid. The remedial, transactions-curtailing OTM method is found well suited for market-related analyses precluding the hour-ahead, the day-ahead dispatch, as well as the real-time generation dispatch. It could also suit for the novel, Day Ahead Congestion Forecast (DACF procedure used in power markets. .

A High Throughput In Vivo Model for Testing Delivery and Antiviral Effects of siRNAs in Vertebrates

DEFF Research Database (Denmark)

Schyth, Brian Dall; Lorenzen, Niels; Pedersen, Finn Skou

2007-01-01

composed of small juvenile rainbow trout and a fish pathogenic virus to analyze the delivery and antiviral effects of formulated siRNAs. Intraperitoneally (IP) injected siRNAs formulated in polycationic liposomes, and to a lesser degree naked siRNAs, primarily entered free IP cells, including macrophage......-like cells. Uptake in these cells correlated with antiviral activity, seen as reduced mortality of virus-challenged fish. However, protection at the disease level was not dependent upon which of three tested siRNAs was used, and protection correlated with up-regulation of an interferon (IFN)-related gene...

Distributed Management of Concurrent Web Service Transactions

DEFF Research Database (Denmark)

Alrifai, Mohammad; Dolog, Peter; Balke, Wolf-Tilo

2009-01-01

Business processes involve dynamic compositions of interleaved tasks. Therefore, ensuring reliable transactional processing of Web services is crucial for the success of Web service-based B2B and B2C applications. But the inherent autonomy and heterogeneity of Web services render the applicability...... of conventional ACID transaction models for Web services far from being straightforward. Current Web service transaction models relax the isolation property and rely on compensation mechanisms to ensure atomicity of business transactions in the presence of service failures. However, ensuring consistency...... in the open and dynamic environment of Web services, where interleaving business transactions enter and exit the system independently, remains an open issue. In this paper, we address this problem and propose an architecture that supports concurrency control on the Web services level. An extension...

Soft computing model for optimized siRNA design by identifying off target possibilities using artificial neural network model.

Science.gov (United States)

Murali, Reena; John, Philips George; Peter S, David

2015-05-15

The ability of small interfering RNA (siRNA) to do posttranscriptional gene regulation by knocking down targeted genes is an important research topic in functional genomics, biomedical research and in cancer therapeutics. Many tools had been developed to design exogenous siRNA with high experimental inhibition. Even though considerable amount of work has been done in designing exogenous siRNA, design of effective siRNA sequences is still a challenging work because the target mRNAs must be selected such that their corresponding siRNAs are likely to be efficient against that target and unlikely to accidentally silence other transcripts due to sequence similarity. In some cases, siRNAs may tolerate mismatches with the target mRNA, but knockdown of genes other than the intended target could make serious consequences. Hence to design siRNAs, two important concepts must be considered: the ability in knocking down target genes and the off target possibility on any nontarget genes. So before doing gene silencing by siRNAs, it is essential to analyze their off target effects in addition to their inhibition efficacy against a particular target. Only a few methods have been developed by considering both efficacy and off target possibility of siRNA against a gene. In this paper we present a new design of neural network model with whole stacking energy (ΔG) that enables to identify the efficacy and off target effect of siRNAs against target genes. The tool lists all siRNAs against a particular target with their inhibition efficacy and number of matches or sequence similarity with other genes in the database. We could achieve an excellent performance of Pearson Correlation Coefficient (R=0. 74) and Area Under Curve (AUC=0.906) when the threshold of whole stacking energy is ≥-34.6 kcal/mol. To the best of the author's knowledge, this is one of the best score while considering the "combined efficacy and off target possibility" of siRNA for silencing a gene. The proposed model

Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes

International Nuclear Information System (INIS)

Zhang, Min; Chai, Yang D; Brumbaugh, Jeffrey; Liu, Xiaojun; Rabii, Ramin; Feng, Sizhe; Misuno, Kaori; Messadi, Diana; Hu, Shen

2014-01-01

Cancer cells may undergo metabolic adaptations that support their growth as well as drug resistance properties. The purpose of this study is to test if oral cancer cells can overcome the metabolic defects introduced by using small interfering RNA (siRNA) to knock down their expression of important metabolic enzymes. UM1 and UM2 oral cancer cells were transfected with siRNA to transketolase (TKT) or siRNA to adenylate kinase (AK2), and Western blotting was used to confirm the knockdown. Cellular uptake of glucose and glutamine and production of lactate were compared between the cancer cells with either TKT or AK2 knockdown and those transfected with control siRNA. Statistical analysis was performed with student T-test. Despite the defect in the pentose phosphate pathway caused by siRNA knockdown of TKT, the survived UM1 or UM2 cells utilized more glucose and glutamine and secreted a significantly higher amount of lactate than the cells transferred with control siRNA. We also demonstrated that siRNA knockdown of AK2 constrained the proliferation of UM1 and UM2 cells but similarly led to an increased uptake of glucose/glutamine and production of lactate by the UM1 or UM2 cells survived from siRNA silencing of AK2. Our results indicate that the metabolic defects introduced by siRNA silencing of metabolic enzymes TKT or AK2 may be compensated by alternative feedback metabolic mechanisms, suggesting that cancer cells may overcome single defective pathways through secondary metabolic network adaptations. The highly robust nature of oral cancer cell metabolism implies that a systematic medical approach targeting multiple metabolic pathways may be needed to accomplish the continued improvement of cancer treatment

Screening of siRNA nanoparticles for delivery to airway epithelial cells using high-content analysis

LENUS (Irish Health Repository)

Hibbitts, Alan

2011-08-01

Aims: Delivery of siRNA to the lungs via inhalation offers a unique opportunity to develop a new treatment paradigm for a range of respiratory conditions. However, progress has been greatly hindered by safety and delivery issues. This study developed a high-throughput method for screening novel nanotechnologies for pulmonary siRNA delivery. Methodology: Following physicochemical analysis, the ability of PEI–PEG–siRNA nanoparticles to facilitate siRNA delivery was determined using high-content analysis (HCA) in Calu-3 cells. Results obtained from HCA were validated using confocal microscopy. Finally, cytotoxicity of the PEI–PEG–siRNA particles was analyzed by HCA using the Cellomics® multiparameter cytotoxicity assay. Conclusion: PEI–PEG–siRNA nanoparticles facilitated increased siRNA uptake and luciferase knockdown in Calu-3 cells compared with PEI–siRNA.

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice.

Science.gov (United States)

Pardo, Marta; Cheng, Yuyan; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Martinez, Ana; Faghihi, Mohammad A; Jope, Richard S; Beurel, Eleonore

2017-03-23

Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA- or HDAC4 siRNA-induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1 -/- mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets.

Combination siRNA therapy against feline coronavirus can delay the emergence of antiviral resistance in vitro.

Science.gov (United States)

McDonagh, Phillip; Sheehy, Paul A; Norris, Jacqueline M

2015-03-23

Virulent biotypes of feline coronavirus (FCoV), commonly referred to as feline infectious peritonitis virus (FIPV), can result in the development of feline infectious peritonitis (FIP), a typically fatal immune mediated disease for which there is currently no effective antiviral treatment. We previously reported the successful in vitro inhibition of FIPV replication by synthetic siRNA mediated RNA interference (RNAi) in an immortalised cell line (McDonagh et al., 2011). A major challenge facing the development of any antiviral strategy is that of resistance, a problem which is particularly acute for RNAi based therapeutics due to the exquisite sequence specificity of the targeting mechanism. The development of resistance during treatment can be minimised using combination therapy to raise the genetic barrier or using highly potent compounds which result in a more rapid and pronounced reduction in the viral replication rate, thereby reducing the formation of mutant, and potentially resistant viruses. This study investigated the efficacy of combination siRNA therapy and its ability to delay or prevent viral escape. Virus serially passaged through cells treated with a single or dual siRNAs rapidly acquired resistance, with mutations identified in the siRNA target sites. Combination therapy with three siRNA prevented viral escape over the course of five passages. To identify more potent silencing molecules we also compared the efficacy, in terms of potency and duration of action, of canonical versus Dicer-substrate siRNAs for two previously identified effective viral motifs. Dicer-substrate siRNAs showed equivalent or better potency than canonical siRNAs for the target sites investigated, and may be a more appropriate molecule for in vivo use. Combined, these data inform the potential therapeutic application of antiviral RNAi against FIPV. Copyright © 2014 Elsevier B.V. All rights reserved.

Novel siRNA formulation to effectively knockdown mutant p53 in osteosarcoma.

Science.gov (United States)

Kundu, Anup K; Iyer, Swathi V; Chandra, Sruti; Adhikari, Amit S; Iwakuma, Tomoo; Mandal, Tarun K

2017-01-01

The tumor suppressor p53 plays a crucial role in the development of osteosarcoma. The primary objective of this study is to develop and optimize lipid based nanoparticle formulations that can carry siRNA and effectively silence mutant p53 in 318-1, a murine osteosarcoma cell line. The nanoparticles were composed of a mixture of two lipids (cholesterol and DOTAP) and either PLGA or PLGA-PEG and prepared by using an EmulsiFlex-B3 high pressure homogenizer. A series of studies that include using different nanoparticles, different amount of siRNAs, cell numbers, incubation time, transfection media volume, and storage temperature was performed to optimize the gene silencing efficiency. Replacement of lipids by PLGA or PLGA-PEG decreased the particle size and overall cytotoxicity. Among all lipid-polymer nanoformulations, nanoparticles with 10% PLGA showed highest mutant p53 knockdown efficiency while maintaining higher cell viability when a nanoparticle to siRNA ratio equal to 6.8:0.66 and 75 nM siRNA was used. With long term storage the mutant p53 knockdown efficiency decreased to a greater extent. This study warrants a future evaluation of this formulation for gene silencing efficiency of mutant p53 in tissue culture and animal models for the treatment of osteosarcoma.

Novel siRNA formulation to effectively knockdown mutant p53 in osteosarcoma.

Directory of Open Access Journals (Sweden)

Anup K Kundu

Full Text Available The tumor suppressor p53 plays a crucial role in the development of osteosarcoma. The primary objective of this study is to develop and optimize lipid based nanoparticle formulations that can carry siRNA and effectively silence mutant p53 in 318-1, a murine osteosarcoma cell line.The nanoparticles were composed of a mixture of two lipids (cholesterol and DOTAP and either PLGA or PLGA-PEG and prepared by using an EmulsiFlex-B3 high pressure homogenizer. A series of studies that include using different nanoparticles, different amount of siRNAs, cell numbers, incubation time, transfection media volume, and storage temperature was performed to optimize the gene silencing efficiency.Replacement of lipids by PLGA or PLGA-PEG decreased the particle size and overall cytotoxicity. Among all lipid-polymer nanoformulations, nanoparticles with 10% PLGA showed highest mutant p53 knockdown efficiency while maintaining higher cell viability when a nanoparticle to siRNA ratio equal to 6.8:0.66 and 75 nM siRNA was used. With long term storage the mutant p53 knockdown efficiency decreased to a greater extent.This study warrants a future evaluation of this formulation for gene silencing efficiency of mutant p53 in tissue culture and animal models for the treatment of osteosarcoma.

Synthesis and Gene Silencing Properties of siRNAs Containing Terminal Amide Linkages

Directory of Open Access Journals (Sweden)

Maria Gaglione

2014-01-01

Full Text Available The active components of the RNAi are 21 nucleotides long dsRNAs containing a 2 nucleotide overhang at the 3′ end, carrying 5′-phosphate and 3′-hydroxyl groups (siRNAs. Structural analysis revealed that the siRNA is functionally bound at both ends to RISC. Terminal modifications are considered with interest as the introduction of chemical moieties interferes with the 3′ overhang recognition by the PAZ domain and the 5′-phosphate recognition by the MID and PIWI domains of RISC. Herein, we report the synthesis of modified siRNAs containing terminal amide linkages by introducing hydroxyethylglycine PNA (hegPNA moieties at 5′, and at 3′ positions and on both terminals. Results of gene silencing studies highlight that some of these modifications are compatible with the RNAi machinery and markedly increase the resistance to serum-derived nucleases even after 24 h of incubation. Molecular docking simulations were attained to give at atomistic level a clearer picture of the effect of the most performing modifications on the interactions with the human Argonaute 2 PAZ, MID, and PIWI domains. This study adds another piece to the puzzle of the heterogeneous chemical modifications that can be attained to enhance the silencing efficiency of siRNAs.

Identification and characterization of microRNAs and endogenous siRNAs in Schistosoma japonicum

Directory of Open Access Journals (Sweden)

Wang Heng

2010-01-01

Full Text Available Abstract Background Small endogenous non-coding RNAs (sncRNAs such as small interfering RNA (siRNA, microRNA and other small RNA transcripts are derived from distinct loci in the genome and play critical roles in RNA-mediated gene silencing mechanisms in plants and metazoa. They are approximately 22 nucleotides long; regulate mRNA stability through perfect or imperfect match to the targets. The biological activities of sncRNAs have been related to many biological events, from resistance to microbe infections to cellular differentiation. The development of the zoonotic parasite Schistosoma japonicum parasite includes multiple steps of morphological alterations and biological differentiations, which provide a unique model for studies on the functions of small RNAs. Characterization of the genome-wide transcription of the sncRNAs will be a major step in understanding of the parasite biology. The objective of this study is to investigate the transcriptional profile and potential function of the small non-coding RNAs in the development of S. japanicum. Results The endogenous siRNAs were found mainly derived from transposable elements (TE or transposons and the natural antisense transcripts (NAT. In contrast to other organisms, the TE-derived siRNAs in S. japonicum were more predominant than other sncRNAs including microRNAs (miRNAs. Further, there were distinct length and 3'end variations in the sncRNAs, which were associated with the developmental differentiation of the parasite. Among the identified miRNA transcripts, there were 38 unique to S. japonicum and 16 that belonged to 13 miRNA families are common to other metazoan lineages. These miRNAs were either ubiquitously expressed, or they exhibited specific expression patterns related to the developmental stages or sex. Genes that encoded miRNAs are mainly located in clusters within the genome of S. japonicum. However, genes within one cluster could be differentially transcribed, which suggested

Targeted transfection increases siRNA uptake and gene silencing of primary endothelial cells in vitro - A quantitative study

NARCIS (Netherlands)

Asgeirsdottir, Sigridur A.; Talman, Eduard G.; de Graaf, Inge A.; Kamps, Jan A. A. M.; Satchell, Simon C.; Mathieson, Peter W.; Ruiters, Marcel H. J.; Molema, Grietje

2010-01-01

Applications of small-interfering RNA (siRNA) call for specific and efficient delivery of siRNA into particular cell types. We developed a novel, non-viral targeting system to deliver siRNA specifically into inflammation-activated endothelial cells. This was achieved by conjugating the cationic

Gold nanoclusters-assisted delivery of NGF siRNA for effective treatment of pancreatic cancer

Science.gov (United States)

Lei, Yifeng; Tang, Lixue; Xie, Yangzhouyun; Xianyu, Yunlei; Zhang, Lingmin; Wang, Peng; Hamada, Yoh; Jiang, Kai; Zheng, Wenfu; Jiang, Xingyu

2017-01-01

Pancreatic cancer is one of the deadliest human cancers, whose progression is highly dependent on the nervous microenvironment. The suppression of gene expression of nerve growth factor (NGF) may have great potential in pancreatic cancer treatment. Here we show that gold nanocluster-assisted delivery of siRNA of NGF (GNC–siRNA) allows efficient NGF gene silencing and pancreatic cancer treatment. The GNC–siRNA complex increases the stability of siRNA in serum, prolongs the circulation lifetime of siRNA in blood and enhances the cellular uptake and tumour accumulation of siRNA. The GNC–siRNA complex potently downregulates the NGF expression in Panc-1 cells and in pancreatic tumours, and effectively inhibits the tumour progression in three pancreatic tumour models (subcutaneous model, orthotopic model and patient-derived xenograft model) without adverse effects. Our study constitutes a straightforward but effective approach to inhibit pancreatic cancer via NGF knockdown, suggesting a promising therapeutic direction for pancreatic cancer. PMID:28440296

Management Control of Market Transactions: The Relation Between Transaction Characteristics, Incomplete Contract Design and Subsequent Performance

NARCIS (Netherlands)

Anderson, S.W.; Dekker, H.C.

2005-01-01

Using an unusually comprehensive database on 858 transactions for information technology products and accompanying services, we study how close partners who are exposed to opportunistic hazards structure and control a significant transaction. We analyze data on the terms of contracting to determine

45 CFR 162.1901 - Medicaid pharmacy subrogation transaction.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Medicaid pharmacy subrogation transaction. 162... STANDARDS AND RELATED REQUIREMENTS ADMINISTRATIVE REQUIREMENTS Medicaid Pharmacy Subrogation § 162.1901 Medicaid pharmacy subrogation transaction. The Medicaid pharmacy subrogation transaction is the...

siRNA inhibition of telomerase enhances the anti-cancer effect of doxorubicin in breast cancer cells

International Nuclear Information System (INIS)

Dong, Xuejun; Liu, Anding; Zer, Cindy; Feng, Jianguo; Zhen, Zhuan; Yang, Mingfeng; Zhong, Li

2009-01-01

Doxorubicin is an effective breast cancer drug but is hampered by a severe, dose-dependent toxicity. Concomitant administration of doxorubicin and another cancer drug may be able to sensitize tumor cells to the cytotoxicity of doxorubicin and lowers the therapeutic dosage. In this study, we examined the combined effect of low-dose doxorubicin and siRNA inhibition of telomerase on breast cancer cells. We found that when used individually, both treatments were rapid and potent apoptosis inducers; and when the two treatments were combined, we observed an enhanced and sustained apoptosis induction in breast cancer cells. siRNA targeting the mRNA of the protein component of telomerase, the telomerase reverse transcriptase (hTERT), was transfected into two breast cancer cell lines. The siRNA inhibition was confirmed by RT-PCR and western blot on hTERT mRNA and protein levels, respectively, and by measuring the activity level of telomerase using the TRAP assay. The effect of the hTERT siRNA on the tumorigenicity of the breast cancer cells was also studied in vivo by injection of the siRNA-transfected breast cancer cells into nude mice. The effects on cell viability, apoptosis and senescence of cells treated with hTERT siRNA, doxorubicin, and the combined treatment of doxorubicin and hTERT siRNA, were examined in vitro by MTT assay, FACS and SA-β-galactosidase staining. The hTERT siRNA effectively knocked down the mRNA and protein levels of hTERT, and reduced the telomerase activity to 30% of the untreated control. In vivo, the tumors induced by the hTERT siRNA-transfected cells were of reduced sizes, indicating that the hTERT siRNA also reduced the tumorigenic potential of the breast cancer cells. The siRNA treatment reduced cell viability by 50% in breast cancer cells within two days after transfection, while 0.5 μM doxorubicin treatment had a comparable effect but with a slower kinetics. The combination of hTERT siRNA and 0.5 μM doxorubicin killed twice as many

Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo

Directory of Open Access Journals (Sweden)

Hu Jim

2006-02-01

Full Text Available Abstract Background The cationic lipid Genzyme lipid (GL 67 is the current "gold-standard" for in vivo lung gene transfer. Here, we assessed, if GL67 mediated uptake of siRNAs and asODNs into airway epithelium in vivo. Methods Anti-lacZ and ENaC (epithelial sodium channel siRNA and asODN were complexed to GL67 and administered to the mouse airway epithelium in vivo Transfection efficiency and efficacy were assessed using real-time RT-PCR as well as through protein expression and functional studies. In parallel in vitro experiments were carried out to select the most efficient oligonucleotides. Results In vitro, GL67 efficiently complexed asODNs and siRNAs, and both were stable in exhaled breath condensate. Importantly, during in vitro selection of functional siRNA and asODN we noted that asODNs accumulated rapidly in the nuclei of transfected cells, whereas siRNAs remained in the cytoplasm, a pattern consistent with their presumed site of action. Following in vivo lung transfection siRNAs were only visible in alveolar macrophages, whereas asODN also transfected alveolar epithelial cells, but no significant uptake into conducting airway epithelial cells was seen. SiRNAs and asODNs targeted to β-galactosidase reduced βgal mRNA levels in the airway epithelium of K18-lacZ mice by 30% and 60%, respectively. However, this was insufficient to reduce protein expression. In an attempt to increase transfection efficiency of the airway epithelium, we increased contact time of siRNA and asODN using the in vivo mouse nose model. Although highly variable and inefficient, transfection of airway epithelium with asODN, but not siRNA, was now seen. As asODNs more effectively transfected nasal airway epithelial cells, we assessed the effect of asODN against ENaC, a potential therapeutic target in cystic fibrosis; no decrease in ENaC mRNA levels or function was detected. Conclusion This study suggests that although siRNAs and asODNs can be developed to inhibit

Reductively Responsive Hydrogel Nanoparticles with Uniform Size, Shape, and Tunable Composition for Systemic siRNA Delivery in Vivo.

Science.gov (United States)

Ma, Da; Tian, Shaomin; Baryza, Jeremy; Luft, J Christopher; DeSimone, Joseph M

2015-10-05

To achieve the great potential of siRNA based gene therapy, safe and efficient systemic delivery in vivo is essential. Here we report reductively responsive hydrogel nanoparticles with highly uniform size and shape for systemic siRNA delivery in vivo. "Blank" hydrogel nanoparticles with high aspect ratio were prepared using continuous particle fabrication based on PRINT (particle replication in nonwetting templates). Subsequently, siRNA was conjugated to "blank" nanoparticles via a disulfide linker with a high loading ratio of up to 18 wt %, followed by surface modification to enhance transfection. This fabrication process could be easily scaled up to prepare large quantity of hydrogel nanoparticles. By controlling hydrogel composition, surface modification, and siRNA loading ratio, siRNA conjugated nanoparticles were highly tunable to achieve high transfection efficiency in vitro. FVII-siRNA conjugated nanoparticles were further stabilized with surface coating for in vivo siRNA delivery to liver hepatocytes, and successful gene silencing was demonstrated at both mRNA and protein levels.

Site-Specific Modification Using the 2′-Methoxyethyl Group Improves the Specificity and Activity of siRNAs

Directory of Open Access Journals (Sweden)

Xinyun Song

2017-12-01

Full Text Available Rapid progress has been made toward small interfering RNA (siRNA-based therapy for human disorders, but rationally optimizing siRNAs for high specificity and potent silencing remains a challenge. In this study, we explored the effect of chemical modification at the cleavage site of siRNAs. We found that modifications at positions 9 and 10 markedly reduced the silencing potency of the unmodified strand of siRNAs but were well tolerated by the modified strand. Intriguingly, addition of the 2′-methoxyethyl (MOE group at the cleavage site improved both the specificity and silencing activity of siRNAs by facilitating the oriented RNA-induced silencing complex (RISC loading of the modified strand. Furthermore, we combined MOE modifications at positions 9 and 10 of one strand together with 2′-O-methylation (OMe at position 14 of the other strand and found a synergistic effect that improved the specificity of siRNAs. The surprisingly beneficial effect of the combined modification was validated using siRNA-targeting endogenous gene intercellular adhesion molecule 1 (ICAM1. We found that the combined modifications eliminated its off-target effects. In conclusion, we established effective strategies to optimize siRNAs using site-specific MOE modifications. The findings may allow the creation of superior siRNAs for therapy in terms of activity and specificity.

An albumin-mediated cholesterol design-based strategy for tuning siRNA pharmacokinetics and gene silencing.

Science.gov (United States)

Bienk, Konrad; Hvam, Michael Lykke; Pakula, Malgorzata Maria; Dagnæs-Hansen, Frederik; Wengel, Jesper; Malle, Birgitte Mølholm; Kragh-Hansen, Ulrich; Cameron, Jason; Bukrinski, Jens Thostrup; Howard, Kenneth A

2016-06-28

Major challenges for the clinical translation of small interfering RNA (siRNA) include overcoming the poor plasma half-life, site-specific delivery and modulation of gene silencing. In this work, we exploit the intrinsic transport properties of human serum albumin to tune the blood circulatory half-life, hepatic accumulation and gene silencing; based on the number of siRNA cholesteryl modifications. We demonstrate by a gel shift assay a strong and specific affinity of recombinant human serum albumin (rHSA) towards cholesteryl-modified siRNA (Kd>1×10(-7)M) dependent on number of modifications. The rHSA/siRNA complex exhibited reduced nuclease degradation and reduced induction of TNF-α production by human peripheral blood mononuclear cells. The increased solubility of heavily cholesteryl modified siRNA in the presence of rHSA facilitated duplex annealing and consequent interaction that allowed in vivo studies using multiple cholesteryl modifications. A structural-activity-based screen of in vitro EGFP-silencing was used to select optimal siRNA designs containing cholesteryl modifications within the sense strand that were used for in vivo studies. We demonstrate plasma half-life extension in NMRI mice from t1/2 12min (naked) to t1/2 45min (single cholesteryl) and t1/2 71min (double cholesteryl) using fluorescent live bioimaging. The biodistribution showed increased accumulation in the liver for the double cholesteryl modified siRNA that correlated with an increase in hepatic Factor VII gene silencing of 28% (rHSA/siRNA) compared to 4% (naked siRNA) 6days post-injection. This work presents a novel albumin-mediated cholesteryl design-based strategy for tuning pharmacokinetics and systemic gene silencing. Copyright © 2016 Elsevier B.V. All rights reserved.

21 CFR 1404.200 - What is a covered transaction?

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false What is a covered transaction? 1404.200 Section 1404.200 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Covered Transactions § 1404.200 What is a covered transaction? A covered transaction is a...

Multifunctional Cationic Lipid-Based Nanoparticles Facilitate Endosomal Escape and Reduction-Triggered Cytosolic siRNA Release

Science.gov (United States)

Gujrati, Maneesh; Malamas, Anthony; Shin, Tesia; Jin, Erlei; Sun, Lulu; Lu, Zheng-Rong

2015-01-01

Small interfering RNA (siRNA) has garnered much attention in recent years as a promising avenue for cancer gene therapy due to its ability to silence disease-related genes. Effective gene silencing is contingent upon the delivery of siRNA into the cytosol of target cells and requires the implementation of delivery systems possessing multiple functionalities to overcome delivery barriers. The present work explores the multifunctional properties and biological activity of a recently developed cationic lipid carrier, (1-aminoethyl)iminobis[N-(oleicylcysteinyl-1-amino-ethyl)propionamide]) (ECO). The physicochemical properties and biological activity of ECO/siRNA nanoparticles were assessed over a range of N/P ratios to optimize the formulation. Potent and sustained luciferase silencing in a U87 glioblastoma cell line was observed, even in the presence of serum proteins. ECO/siRNA nanoparticles exhibited pH-dependent membrane disruption at pH levels corresponding to various stages of the intracellular trafficking pathway. It was found that disulfide linkages created during nanoparticle formation enhanced the protection of siRNA from degradation and facilitated site-specific siRNA release in the cytosol by glutathione-mediated reduction. Confocal microscopy confirmed that ECO/siRNA nanoparticles readily escaped from late endosomes prior to cytosolic release of the siRNA cargo. These results demonstrate that the rationally designed multifunctionality of ECO/siRNA nanoparticles is critical for intracellular siRNA delivery and the continuing development of safe and effective delivery systems. PMID:25020033

2’f-OMe-phosphorodithioate modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Science.gov (United States)

Wu, Sherry Y.; Yang, Xianbin; Gharpure, Kshipra M.; Hatakeyama, Hiroto; Egli, Martin; McGuire, Michael H.; Nagaraja, Archana S.; Miyake, Takahito M.; Rupaimoole, Rajesha; Pecot, Chad V.; Taylor, Morgan; Pradeep, Sunila; Sierant, Malgorzata; Rodriguez-Aguayo, Cristian; Choi, Hyun J.; Previs, Rebecca A.; Armaiz-Pena, Guillermo N.; Huang, Li; Martinez, Carlos; Hassell, Tom; Ivan, Cristina; Sehgal, Vasudha; Singhania, Richa; Han, Hee-Dong; Su, Chang; Kim, Ji Hoon; Dalton, Heather J.; Kowali, Chandra; Keyomarsi, Khandan; McMillan, Nigel A.J.; Overwijk, Willem W.; Liu, Jinsong; Lee, Ju-Seog; Baggerly, Keith A.; Lopez-Berestein, Gabriel; Ram, Prahlad T.; Nawrot, Barbara; Sood, Anil K.

2014-01-01

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’-O-Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2’-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM Domain Containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumors following MePS2-modified siRNA treatment, leading to a synergistic anti-tumor effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types. PMID:24619206

17 CFR 155.6 - Trading standards for the transaction of business on registered derivatives transaction execution...

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Trading standards for the transaction of business on registered derivatives transaction execution facilities. 155.6 Section 155.6 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION TRADING STANDARDS § 155.6 Trading...

An effective tumor-targeting strategy utilizing hypoxia-sensitive siRNA delivery system for improved anti-tumor outcome.

Science.gov (United States)

Kang, Lin; Fan, Bo; Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Gao, Zhonggao

2016-10-15

Hypoxia is a feature of most solid tumors, targeting hypoxia is considered as the best validated yet not extensively exploited strategy in cancer therapy. Here, we reported a novel tumor-targeting strategy using a hypoxia-sensitive siRNA delivery system. In the study, 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazole (AI) through bioreduction under hypoxic conditions, was conjugated to the alkylated polyethyleneimine (bPEI1.8k-C6) to form amphiphilic bPEI1.8k-C6-NI polycations. bPEI1.8k-C6-NI could self-assemble into micelle-like aggregations in aqueous, which contributed to the improved stability of the bPEI1.8k-C6-NI/siRNA polyplexes, resulted in increased cellular uptake. After being transported into the hypoxic tumor cells, the selective nitro-to-amino reduction would cause structural change and elicit a relatively loose structure to facilitate the siRNA dissociation in the cytoplasm, for enhanced gene silencing efficiency ultimately. Therefore, the conflict between the extracellular stability and the intracellular siRNA release ability of the polyplexes was solved by introducing the hypoxia-responsive unit. Consequently, the survivin-targeted siRNA loaded polyplexes shown remarkable anti-tumor effect not only in hypoxic cells, but also in tumor spheroids and tumor-bearing mice, indicating that the hypoxia-sensitive siRNA delivery system had great potential for tumor-targeted therapy. Hypoxia is one of the most remarkable features of most solid tumors, and targeting hypoxia is considered as the best validated strategy in cancer therapy. However, in the past decades, there were few reports about using this strategy in the drug delivery system, especially in siRNA delivery system. Therefore, we constructed a hypoxia-sensitive siRNA delivery system utilizing a hypoxia-responsive unit, 2-nitroimidazole, by which the unavoidable conflict between improved extracellular stability and promoted intracellular siRNA

How to deal with malleability of BitCoin transactions

OpenAIRE

Andrychowicz, Marcin; Dziembowski, Stefan; Malinowski, Daniel; Mazurek, Łukasz

2013-01-01

BitCoin transactions are malleable in a sense that given a transaction an adversary can easily construct an equivalent transaction which has a different hash. This can pose a serious problem in some BitCoin distributed contracts in which changing a transaction's hash may result in the protocol disruption and a financial loss. The problem mostly concerns protocols, which use a "refund" transaction to withdraw a deposit in a case of the protocol interruption. In this short note, we show a gener...

Foreign exchange transaction exposure of enterprises in Serbia

Directory of Open Access Journals (Sweden)

Bogićević Jasmina

2016-01-01

Full Text Available Enterprises involved in international business face transaction exposure to foreign exchange risk. This type of exposure occurs when an enterprise trades, borrows, or lеnds in foreign currency. Transaction exposure has a direct effect on an enterprise’s financial position and profitability. It is one of the three forms of exposure to exchange rate fluctuations, the other two being translation exposure and operating exposure. The aim of this paper is to assess the transaction exposure of enterprises in Serbia operating internationally. In addition to identifying and measuring transaction exposure, this paper explores the practical importance that enterprises in Serbia attach to management of this type of foreign exchange risk. We do not find significant differences between domestic and foreign enterprises in their choice of the type of foreign exchange risk exposure to manage. Although transaction exposure is the most managed type of foreign exchange risk, research has shown that, compared to foreign businesses, Serbian enterprises do not use sufficient protective measures to minimize the negative impact of this type of exposure on their cash flows and profitability. We expected that there would be a statistically significant dependence between the volume of enterprises’ foreign currency transactions and the level of applied transaction exposure management practices. However, the results of our research, based on a sample of enterprises in Serbia operating internationally, show that transaction exposure management practices can be influenced by factors other than the level of an enterprise’s foreign currency transactions, such as the enterprise’s country of origin.

Entrepreneurship, transaction costs, and resource attributes

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai Juul

2006-01-01

transaction costs shape the process of entrepreneurial discovery. We provide a sketch of the mechanisms that link entrepreneurship, property rights, and transaction costs in a resource-based setting, contributing further to the attempt to take the RBV in a more dynamic direction.......This paper responds to Kim and Mahoney's "How Property Rights Economics Furthers the Resource-Based View: Resources, Transaction Costs and Entrepreneurial Discovery" (a comment on Foss and Foss, 2005). While we agree with many of their arguments, we argue that they fail to recognise how exactly...

Entrepreneurship, transaction costs, and resource attributes

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai Juul

2006-01-01

This paper responds to Kim and Mahoney's "How Property Rights Economics Furthers the Resource-Based View: Resources, Transaction Costs and Entrepreneurial Discovery" (a comment on Foss and Foss, 2005). While we agree with many of their arguments, we argue that they fail to recognise how exactly t...... transaction costs shape the process of entrepreneurial discovery. We provide a sketch of the mechanisms that link entrepreneurship, property rights, and transaction costs in a resource-based setting, contributing further to the attempt to take the RBV in a more dynamic direction....

Transactive Systems Simulation and Valuation Platform Trial Analysis

Energy Technology Data Exchange (ETDEWEB)

Widergren, Steven E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hammerstrom, Donald J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Huang, Qiuhua [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kalsi, Karanjit [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lian, Jianming [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Makhmalbaf, Atefe [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); McDermott, Thomas E. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Sivaraman, Deepak [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Tang, Yingying [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Veeramany, Arun [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Woodward, James C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2017-04-01

Transactive energy systems use principles of value to coordinate responsive supply and demand in energy systems. Work continues within the Transactive Systems Program, which is funded by the U.S. Department of Energy at Pacific Northwest National Laboratory, to understand the value of, understand the theory behind, and simulate the behaviors of transactive energy systems. This report summarizes recent advances made by this program. The main capability advances include a more comprehensive valuation model, including recommended documentation that should make valuation studies of all sorts more transparent, definition of economic metrics with which transactive mechanisms can be evaluated, and multiple improvements to the time-simulation environment that is being used to evaluate transactive scenarios.

Transactive Systems Simulation and Valuation Platform Trial Analysis

International Nuclear Information System (INIS)

Widergren, Steven E.; Hammerstrom, Donald J.; Huang, Qiuhua; Kalsi, Karanjit; Lian, Jianming; Makhmalbaf, Atefe; McDermott, Thomas E.; Sivaraman, Deepak; Tang, Yingying; Veeramany, Arun; Woodward, James C.

2017-01-01

Transactive energy systems use principles of value to coordinate responsive supply and demand in energy systems. Work continues within the Transactive Systems Program, which is funded by the U.S. Department of Energy at Pacific Northwest National Laboratory, to understand the value of, understand the theory behind, and simulate the behaviors of transactive energy systems. This report summarizes recent advances made by this program. The main capability advances include a more comprehensive valuation model, including recommended documentation that should make valuation studies of all sorts more transparent, definition of economic metrics with which transactive mechanisms can be evaluated, and multiple improvements to the time-simulation environment that is being used to evaluate transactive scenarios.

Data on cell growth inhibition induced by anti-VEGF siRNA delivered by Stealth liposomes incorporating G2 PAMAM-cholesterol versus Metafectene® as a function of exposure time and siRNA concentration

Directory of Open Access Journals (Sweden)

Nasim Golkar

2016-09-01

Full Text Available In this data article, carboxyfluorescein-loaded liposomes were prepared and purified from free carboxyfluorescein using gel filtration chromatography in the first part. In the next part, following preparation of anti-VEGF siRNA loaded liposomes incorporating hydrophobically modified G2 PAMAM dendrimer (G2-Chol40% (Golkar et al., 2016 [1], the cell growth inhibition induced by the formulations (siRNA/Metafectene complexes and siRNA loaded liposomes incorporating hydrophobic G2 was evaluated at two exposure times through MTT assay in a breast cancer cell (SKBR-3 and compared by two-way ANOVA. Keywords: Anti-VEGF siRNA, Cell growth inhibition, Polyamidoaminedendrimer, Liposome

Rational design of micro-RNA-like bifunctional siRNAs targeting HIV and the HIV coreceptor CCR5.

Science.gov (United States)

Ehsani, Ali; Saetrom, Pål; Zhang, Jane; Alluin, Jessica; Li, Haitang; Snøve, Ola; Aagaard, Lars; Rossi, John J

2010-04-01

Small-interfering RNAs (siRNAs) and micro-RNAs (miRNAs) are distinguished by their modes of action. SiRNAs serve as guides for sequence-specific cleavage of complementary mRNAs and the targets can be in coding or noncoding regions of the target transcripts. MiRNAs inhibit translation via partially complementary base-pairing to 3' untranslated regions (UTRs) and are generally ineffective when targeting coding regions of a transcript. In this study, we deliberately designed siRNAs that simultaneously direct cleavage and translational suppression of HIV RNAs, or cleavage of the mRNA encoding the HIV coreceptor CCR5 and suppression of translation of HIV. These bifunctional siRNAs trigger inhibition of HIV infection and replication in cell culture. The design principles have wide applications throughout the genome, as about 90% of genes harbor sites that make the design of bifunctional siRNAs possible.

Platinum Interference with siRNA Non-seed Regions Fine-Tunes Silencing Capacity

DEFF Research Database (Denmark)

Hedman, Hanna K; Kirpekar, Finn; Elmroth, Sofi K C

2011-01-01

expression, and the other one focused on the function of endogenous miRNAs. In both cases, the active molecule consists of a ∼20-nucleotide-long RNA duplex. In the siRNA case, improved systemic stability is of central interest for its further development toward clinical applications. With respect to mi......RNA processing and function, understanding its influence on mRNA targeting and the silencing ability of individual miRNAs, e.g., under pathological conditions, remains a scientific challenge. In the present study, a model system is presented where the influence of the two clinically used anticancer drugs......, cisplatin and oxaliplatin, on siRNA's silencing capacity has been evaluated. More specifically, siRNAs targeting the 3' UTR region of Wnt-5a mRNA (NM_003352) were constructed, and the biologically active antisense RNA strand was pre-platinated. Platinum adducts were detected and characterized...

The Influence of an External Transaction on a BPEL Scope

Science.gov (United States)

Kopp, Oliver; Mietzner, Ralph; Leymann, Frank

Business processes constitute an integral part of today's IT applications. They contain transactions as essential building blocks to ensure integrity and all-or-nothing behavior. The Business Process Execution Language is the dominant standard for modeling and execution of business processes in a Web service environment. BPEL itself contains a transaction model based on compensation, that describes the (local) transactions in a business process. The WS-Coordination framework deals with (external) transactions between Web services and is used to define the transaction behavior between a BPEL process and its partners. In this paper, we investigate how external transactions between Web services interrelate with local transactions of BPEL.

Dynamic Self-Healing Mechanism for Transactional Business Process

Directory of Open Access Journals (Sweden)

Yuhai Zhao

2015-01-01

Full Text Available It is clear that transactional behavior consistency is a prerequisite and basis for construction of a reliable services-based business application. However, in previous works, maintaining transactional consistency during exception handling was ignored. Maintaining transactional consistency requires functionality for rolling back some operations and revoking uploaded data. Replacing only the failed service will eventually lead to overall business application failure. In this study, we take fully into account the behavioral consistency of transactional services and propose two effective self-healing mechanisms for service-based applications. If a service enters into potential failure condition, a rescheduling mechanism is triggered to maintain consistent transactional behavior and to ensure reliable execution; if a service fails during execution, the compensation operation is triggered and the system will take action to ensure transactional behavior consistency. Meanwhile, cost-benefit analysis with compensation support is proposed to minimize the dynamic reselection cost. Finally, the experimental analysis shows that the proposed strategies can effectively guarantee the reliability of Web-based applications system.

In Silico Design and Experimental Validation of siRNAs Targeting Conserved Regions of Multiple Hepatitis C Virus Genotypes.

Directory of Open Access Journals (Sweden)

Mahmoud ElHefnawi

Full Text Available RNA interference (RNAi is a post-transcriptional gene silencing mechanism that mediates the sequence-specific degradation of targeted RNA and thus provides a tremendous opportunity for development of oligonucleotide-based drugs. Here, we report on the design and validation of small interfering RNAs (siRNAs targeting highly conserved regions of the hepatitis C virus (HCV genome. To aim for therapeutic applications by optimizing the RNAi efficacy and reducing potential side effects, we considered different factors such as target RNA variations, thermodynamics and accessibility of the siRNA and target RNA, and off-target effects. This aim was achieved using an in silico design and selection protocol complemented by an automated MysiRNA-Designer pipeline. The protocol included the design and filtration of siRNAs targeting highly conserved and accessible regions within the HCV internal ribosome entry site, and adjacent core sequences of the viral genome with high-ranking efficacy scores. Off-target analysis excluded siRNAs with potential binding to human mRNAs. Under this strict selection process, two siRNAs (HCV353 and HCV258 were selected based on their predicted high specificity and potency. These siRNAs were tested for antiviral efficacy in HCV genotype 1 and 2 replicon cell lines. Both in silico-designed siRNAs efficiently inhibited HCV RNA replication, even at low concentrations and for short exposure times (24h; they also exceeded the antiviral potencies of reference siRNAs targeting HCV. Furthermore, HCV353 and HCV258 siRNAs also inhibited replication of patient-derived HCV genotype 4 isolates in infected Huh-7 cells. Prolonged treatment of HCV replicon cells with HCV353 did not result in the appearance of escape mutant viruses. Taken together, these results reveal the accuracy and strength of our integrated siRNA design and selection protocols. These protocols could be used to design highly potent and specific RNAi-based therapeutic

A transaction assessment method for allocation of transmission services

Science.gov (United States)

Banunarayanan, Venkatasubramaniam

The purpose of this research is to develop transaction assessment methods for allocating transmission services that are provided by an area/utility to power transactions. Transmission services are the services needed to deliver, or provide the capacity to deliver, real and reactive power from one or more supply points to one or more delivery points. As the number of transactions increase rapidly in the emerging deregulated environment, accurate quantification of the transmission services an area/utility provides to accommodate a transaction is becoming important, because then appropriate pricing schemes can be developed to compensate for the parties that provide these services. The Allocation methods developed are based on the "Fair Resource Allocation Principle" and they determine for each transaction the following: the flowpath of the transaction (both real and reactive power components), generator reactive power support from each area/utility, real power loss support from each area/utility. Further, allocation methods for distributing the cost of relieving congestion on transmission lines caused by transactions are also developed. The main feature of the proposed methods is representation of actual usage of the transmission services by the transactions. The proposed method is tested extensively on a variety of systems. The allocation methods developed in this thesis for allocation of transmission services to transactions is not only useful in studying the impact of transactions on a transmission system in a multi-transaction case, but they are indeed necessary to meet the criteria set forth by FERC with regard to pricing based on actual usage. The "consistency" of the proposed allocation methods has also been investigated and tested.

siRNAs targeted to certain polyadenylation sites promote specific, RISC-independent degradation of messenger RNAs.

Science.gov (United States)

Vickers, Timothy A; Crooke, Stanley T

2012-07-01

While most siRNAs induce sequence-specific target mRNA cleavage and degradation in a process mediated by Ago2/RNA-induced silencing complex (RISC), certain siRNAs have also been demonstrated to direct target RNA reduction through deadenylation and subsequent degradation of target transcripts in a process which involves Ago1/RISC and P-bodies. In the current study, we present data suggesting that a third class of siRNA exist, which are capable of promoting target RNA reduction that is independent of both Ago and RISC. These siRNAs bind the target messenger RNA at the polyA signal and are capable of redirecting a small amount of polyadenylation to downstream polyA sites when present, however, the majority of the activity appears to be due to inhibition of polyadenylation or deadenylation of the transcript, followed by exosomal degradation of the immature mRNA.

Development of Gold Nanoparticle towards Radioenhancement Therapy, Renal Clearance, siRNA Delivery and Light-Controlled Gene Silencing

Science.gov (United States)

Wang, Jianxin

Gold nanoparticles (GNPs) have been widely studied and used in research for diagnostic, prophylactic or therapeutic purposes. However, they still face many technical challenges before they can be used to effectively address unmet biomedical needs. The theme of this dissertation is focused on addressing challenges of GNPs in clinical translation, and to improve their potential for application in radioenhancement therapy and siRNA delivery. We demonstrate the facile self-assembly of micellar gold nanocapsules using zwitterionic surfactants, with hydrodynamic diameters below 10 nm, which holds promise for good renal clearance to promote the excretion of GNPs in human body. We also prepared PEI- and PEG-coated GNPs and demonstrated their uptake into HeLa cells with exposure to soft X-rays (120 kVp), based on the consideration that the proximity of GNPs to nuclear DNA may be beneficial for enhancing low-energy ionizing radiotherapy. GNP-mediated siRNA delivery may be challenged by nonspecific siRNA desorption during circulation, which can cause off-target effects and immunogenicity. The use of gold nanorods (GNRs) for siRNA delivery also faces challenges like reduced dispersion stability during siRNA functionalization. We developed an effective way to load siRNA onto GNRs at high density, using oleylsulfobetaine (OSB) as an intermediate surfactant and dithiocarbamates (DTCs) as desorption-resistant anchors for siRNA. The GNR?siRNA complexes provided excellent control for laser-triggered gene silencing.

Screening nylon-3 polymers, a new class of cationic amphiphiles, for siRNA delivery.

Science.gov (United States)

Nadithe, Venkatareddy; Liu, Runhui; Killinger, Bryan A; Movassaghian, Sara; Kim, Na Hyung; Moszczynska, Anna B; Masters, Kristyn S; Gellman, Samuel H; Merkel, Olivia M

2015-02-02

Amphiphilic nucleic acid carriers have attracted strong interest. Three groups of nylon-3 copolymers (poly-β-peptides) possessing different cationic/hydrophobic content were evaluated as siRNA delivery agents in this study. Their ability to condense siRNA was determined in SYBR Gold assays. Their cytotoxicity was tested by MTT assays, their efficiency of delivering Alexa Fluor-488-labeled siRNA intracellularly in the presence and absence of uptake inhibitors was assessed by flow cytometry, and their transfection efficacies were studied by luciferase knockdown in a cell line stably expressing luciferase (H1299/Luc). Endosomal release was determined by confocal laser scanning microscopy and colocalization with lysotracker. All polymers efficiently condensed siRNA at nitrogen-to-phosphate (N/P) ratios of 5 or lower, as reflected in hydrodynamic diameters smaller than that at N/P 1. Although several formulations had negative zeta potentials at N/P 1, G2C and G2D polyplexes yielded >80% uptake in H1299/Luc cells, as determined by flow cytometry. Luciferase knockdown (20-65%) was observed after transfection with polyplexes made of the high molecular weight polymers that were the most hydrophobic. The ability of nylon-3 polymers to deliver siRNA intracellularly even at negative zeta potential implies that they mediate transport across cell membranes based on their amphiphilicity. The cellular uptake route was determined to strongly depend on the presence of cholesterol in the cell membrane. These polymers are, therefore, very promising for siRNA delivery at reduced surface charge and toxicity. Our study identified nylon-3 formulations at low N/P ratios for effective gene knockdown, indicating that nylon-3 polymers are a new, promising type of gene delivery agent.

Screening Nylon-3 Polymers, a New Class of Cationic Amphiphiles, for siRNA Delivery

Science.gov (United States)

2015-01-01

Amphiphilic nucleic acid carriers have attracted strong interest. Three groups of nylon-3 copolymers (poly-β-peptides) possessing different cationic/hydrophobic content were evaluated as siRNA delivery agents in this study. Their ability to condense siRNA was determined in SYBR Gold assays. Their cytotoxicity was tested by MTT assays, their efficiency of delivering Alexa Fluor-488-labeled siRNA intracellularly in the presence and absence of uptake inhibitors was assessed by flow cytometry, and their transfection efficacies were studied by luciferase knockdown in a cell line stably expressing luciferase (H1299/Luc). Endosomal release was determined by confocal laser scanning microscopy and colocalization with lysotracker. All polymers efficiently condensed siRNA at nitrogen-to-phosphate (N/P) ratios of 5 or lower, as reflected in hydrodynamic diameters smaller than that at N/P 1. Although several formulations had negative zeta potentials at N/P 1, G2C and G2D polyplexes yielded >80% uptake in H1299/Luc cells, as determined by flow cytometry. Luciferase knockdown (20–65%) was observed after transfection with polyplexes made of the high molecular weight polymers that were the most hydrophobic. The ability of nylon-3 polymers to deliver siRNA intracellularly even at negative zeta potential implies that they mediate transport across cell membranes based on their amphiphilicity. The cellular uptake route was determined to strongly depend on the presence of cholesterol in the cell membrane. These polymers are, therefore, very promising for siRNA delivery at reduced surface charge and toxicity. Our study identified nylon-3 formulations at low N/P ratios for effective gene knockdown, indicating that nylon-3 polymers are a new, promising type of gene delivery agent. PMID:25437915

Disincentives to voluntary transactions

International Nuclear Information System (INIS)

Anon.

1991-01-01

Current legal, regulatory and institutional standards and practices provide several disincentives for a utility wishing to engage in voluntary wheeling transactions, and are discussed here. These disincentives largely arise from the fact that regulation, like the transmission system itself, is based on the notion of integrated utilities engaging in transactions largely for reliability reasons. Factors which fall into this category are: a pricing regime based on embedded costs, the ratemaking treatment of revenues derived from coordination and transmission services, and several provisions in legislation and FERC regulations

Transaction Costs for Design-Build-Finance-Maintain Contracts

NARCIS (Netherlands)

Favie, R.; Beelen, W.A.; Maas, G.J.; Ceric, A.; Radujkovic, M.

2009-01-01

This paper gives insight in how transaction costs arise and how in theory transaction costs can be reduced. A comparison between theory and practice has been made. A study of a case in the Netherlands, the Second Coentunnel showed how transaction costs in practice appear, in which stage of the

31 CFR 587.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 587.406 Section 587.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... MONTENEGRO) MILOSEVIC SANCTIONS REGULATIONS Interpretations § 587.406 Offshore transactions. The prohibitions...

Entrepreneurship, Transaction Costs, and Resource Attributes

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai Juul

transaction costs and property rights shape the process of entrepreneurial discovery. We provide a sketch of the mechanisms that link entrepreneurship, property rights, and transaction costs in a resource-based setting, contributing further to the attempt to take the RBV in a more dynamic direction....

IN VIVO SCREENING OF CHEMICAL MODIFICATIONS OF siRNAs FOR EFFECT ON THE INNATE IMMUNE RESPONSE IN FISH

DEFF Research Database (Denmark)

Lorenzen, Niels; Schyth, Brian Dall; Bramsen, J. B.

Abstract Due to their sequence specific gene silencing activity siRNAs are regarded as promising new active compounds in gene medicine and functional studies. But one serious problem with delivering siRNAs as treatment is the now well-established non-specific activities of some RNAs duplexes. Cel...... of siRNAs into RISC for specific gene silencing....

On Transaction-Cost Models in Continuous-Time Markets

Directory of Open Access Journals (Sweden)

Thomas Poufinas

2015-04-01

Full Text Available Transaction-cost models in continuous-time markets are considered. Given that investors decide to buy or sell at certain time instants, we study the existence of trading strategies that reach a certain final wealth level in continuous-time markets, under the assumption that transaction costs, built in certain recommended ways, have to be paid. Markets prove to behave in manners that resemble those of complete ones for a wide variety of transaction-cost types. The results are important, but not exclusively, for the pricing of options with transaction costs.

Financial and Cost Aspects of Other Transactions

National Research Council Canada - National Science Library

1998-01-01

...." This report discusses the DoD administration of "other transactions." The second audit report will discuss the review of costs charged to the agreements by the "other transaction" participant...

Utility of MicroRNAs and siRNAs in Cervical Carcinogenesis

Directory of Open Access Journals (Sweden)

Sacnite del Mar Díaz-González

2015-01-01

Full Text Available MicroRNAs and siRNAs belong to a family of small noncoding RNAs which bind through partial sequence complementarity to 3′-UTR regions of mRNA from target genes, resulting in the regulation of gene expression. MicroRNAs have become an attractive target for genetic and pharmacological modulation due to the critical function of their target proteins in several signaling pathways, and their expression profiles have been found to be altered in various cancers. A promising technology platform for selective silencing of cell and/or viral gene expression using siRNAs is currently in development. Cervical cancer is the most common cancer in women in the developing world and sexually transmitted infection with HPV is the cause of this malignancy. Therefore, a cascade of abnormal events is induced during cervical carcinogenesis, including the induction of genomic instability, reprogramming of cellular metabolic pathways, deregulation of cell proliferation, inhibition of apoptotic mechanisms, disruption of cell cycle control mechanisms, and alteration of gene expression. Thus, in the present review article, we highlight new research on microRNA expression profiles which may be utilized as biomarkers for cervical cancer. Furthermore, we discuss selective silencing of HPV E6 and E7 with siRNAs which represents a potential gene therapy strategy against cervical cancer.

31 CFR 357.28 - Transaction requests.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Transaction requests. 357.28 Section 357.28 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... System (Legacy Treasury Direct) § 357.28 Transaction requests. (a) General. Unless otherwise authorized...

31 CFR 544.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 544.406 Section 544.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... SANCTIONS REGULATIONS Interpretations § 544.406 Offshore transactions. The prohibitions in § 544.201 on...

31 CFR 593.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 593.406 Section 593.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... SANCTIONS REGULATIONS Interpretations § 593.406 Offshore transactions. The prohibitions in § 593.201 on...

31 CFR 103.63 - Structured transactions.

Science.gov (United States)

2010-07-01

... Section 103.63 Money and Finance: Treasury Regulations Relating to Money and Finance FINANCIAL RECORDKEEPING AND REPORTING OF CURRENCY AND FOREIGN TRANSACTIONS General Provisions § 103.63 Structured transactions. No person shall for the purpose of evading the reporting requirements of § 103.22 with respect to...

Reactions to Corporate Insider’s Transactions

DEFF Research Database (Denmark)

Rose, Caspar; Søpstad, Nicolai

2015-01-01

We test the impact on security prices of top manager’s requirement’s to disclose their own share transactions in the firm. Specifically we study whether buy or sales transactions convey relevant information for market participants thereby studying the effects of legal stock market disclosure rules...

Transaction-Based Building Controls Framework, Volume 1: Reference Guide

Energy Technology Data Exchange (ETDEWEB)

Somasundaram, Sriram [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Pratt, Robert G. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Akyol, Bora A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Fernandez, Nicholas [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Foster, Nikolas AF [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Katipamula, Srinivas [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Mayhorn, Ebony T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Somani, Abhishek [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Steckley, Andrew C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Taylor, Zachary T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2014-12-01

This document proposes a framework concept to achieve the objectives of raising buildings’ efficiency and energy savings potential benefitting building owners and operators. We call it a transaction-based framework, wherein mutually-beneficial and cost-effective market-based transactions can be enabled between multiple players across different domains. Transaction-based building controls are one part of the transactional energy framework. While these controls realize benefits by enabling automatic, market-based intra-building efficiency optimizations, the transactional energy framework provides similar benefits using the same market -based structure, yet on a larger scale and beyond just buildings, to the society at large.

Transaction costs and social networks in productivity measurement

DEFF Research Database (Denmark)

Henningsen, Geraldine; Henningsen, Arne; Henning, Christian H. C. A.

2015-01-01

and support. Hence, we use measures of a firm’s access to social networks as a proxy for the transaction costs the firm faces. We develop a microeconomic production model that takes into account transaction costs and networks. Using a data set of 384 Polish farms, we empirically estimate this model......We argue that in the presence of transaction costs, observed productivity measures may in many cases understate the true productivity, as production data seldom distinguish between resources entering the production process and resources of a similar type that are sacrificed for transaction costs....... Hence, both the absolute productivity measures and, more importantly, the productivity ranking will be distorted. A major driver of transaction costs is poor access to information and contract enforcement assistance. Social networks often catalyse information exchange as well as generate trust...

The transactional interpretation of quantum mechanics

Science.gov (United States)

Cramer, John G.

2001-06-01

The transactional interpretation of quantum mechanics [1] was originally published in 1986 and is now about 14 years old. It is an explicitly nonlocal and Lorentz invariant alternative to the Copenhagen interpretation. It interprets the formalism for a quantum interaction as describing a "handshake" between retarded waves (ψ) and advanced waves (ψ*) for each quantum event or "transaction" in which energy, momentum, angular momentum, and other conserved quantities are transferred. The transactional interpretation offers the advantages that (1) it is actually "visible" in the formalism of quantum mechanics, (2) it is economical, involving fewer independent assumptions than its rivals, (3) it is paradox-free, resolving all of the paradoxes of standard quantum theory including nonlocality and wave function collapse, (4) it does not give a privileged role to observers or measurements, and (5) it permits the visualization of quantum events. We will review the transactional interpretation and some of its applications to "quantum paradoxes."

Optimal Hydrophobicity in Ring-Opening Metathesis Polymerization-Based Protein Mimics Required for siRNA Internalization.

Science.gov (United States)

deRonde, Brittany M; Posey, Nicholas D; Otter, Ronja; Caffrey, Leah M; Minter, Lisa M; Tew, Gregory N

2016-06-13

Exploring the role of polymer structure for the internalization of biologically relevant cargo, specifically siRNA, is of critical importance to the development of improved delivery reagents. Herein, we report guanidinium-rich protein transduction domain mimics (PTDMs) based on a ring-opening metathesis polymerization scaffold containing tunable hydrophobic moieties that promote siRNA internalization. Structure-activity relationships using Jurkat T cells and HeLa cells were explored to determine how the length of the hydrophobic block and the hydrophobic side chain compositions of these PTDMs impacted siRNA internalization. To explore the hydrophobic block length, two different series of diblock copolymers were synthesized: one series with symmetric block lengths and one with asymmetric block lengths. At similar cationic block lengths, asymmetric and symmetric PTDMs promoted siRNA internalization in the same percentages of the cell population regardless of the hydrophobic block length; however, with 20 repeat units of cationic charge, the asymmetric block length had greater siRNA internalization, highlighting the nontrivial relationships between hydrophobicity and overall cationic charge. To further probe how the hydrophobic side chains impacted siRNA internalization, an additional series of asymmetric PTDMs was synthesized that featured a fixed hydrophobic block length of five repeat units that contained either dimethyl (dMe), methyl phenyl (MePh), or diphenyl (dPh) side chains and varied cationic block lengths. This series was further expanded to incorporate hydrophobic blocks consisting of diethyl (dEt), diisobutyl (diBu), and dicyclohexyl (dCy) based repeat units to better define the hydrophobic window for which our PTDMs had optimal activity. High-performance liquid chromatography retention times quantified the relative hydrophobicities of the noncationic building blocks. PTDMs containing the MePh, diBu, and dPh hydrophobic blocks were shown to have superior

Absorbers in the Transactional Interpretation of Quantum Mechanics

Science.gov (United States)

Boisvert, Jean-Sébastien; Marchildon, Louis

2013-03-01

The transactional interpretation of quantum mechanics, following the time-symmetric formulation of electrodynamics, uses retarded and advanced solutions of the Schrödinger equation and its complex conjugate to understand quantum phenomena by means of transactions. A transaction occurs between an emitter and a specific absorber when the emitter has received advanced waves from all possible absorbers. Advanced causation always raises the specter of paradoxes, and it must be addressed carefully. In particular, different devices involving contingent absorbers or various types of interaction-free measurements have been proposed as threatening the original version of the transactional interpretation. These proposals will be analyzed by examining in each case the configuration of absorbers and, in the special case of the so-called quantum liar experiment, by carefully following the development of retarded and advanced waves through the Mach-Zehnder interferometer. We will show that there is no need to resort to the hierarchy of transactions that some have proposed, and will argue that the transactional interpretation is consistent with the block-universe picture of time.

76 FR 40779 - Retail Foreign Exchange Transactions

Science.gov (United States)

2011-07-12

... transaction are offset when: (i) The customer maintains separate accounts managed by different advisors; (ii... could nominate a deposit account as containing margin for its retail forex transactions. Nothing in this...

Targeted delivery of siRNA to activated T cells via transferrin-polyethylenimine (Tf-PEI) as a potential therapy of asthma.

Science.gov (United States)

Xie, Yuran; Kim, Na Hyung; Nadithe, Venkatareddy; Schalk, Dana; Thakur, Archana; Kılıç, Ayşe; Lum, Lawrence G; Bassett, David J P; Merkel, Olivia M

2016-05-10

Asthma is a worldwide health problem. Activated T cells (ATCs) in the lung, particularly T helper 2 cells (Th2), are strongly associated with inducing airway inflammatory responses and chemoattraction of inflammatory cells in asthma. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence inflammation related genes in ATCs, however, lack of safe and efficient siRNA delivery systems limits the application of siRNA as a therapeutic molecule in asthma. Here, we designed a novel pulmonary delivery system of siRNA, transferrin-polyethylenimine (Tf-PEI), to selectively deliver siRNA to ATCs in the lung. Tf-PEI polyplexes demonstrated optimal physicochemical properties such as size, distribution, zeta-potential, and siRNA condensation efficiency. Moreover, in vitro studies showed significantly enhanced cellular uptake and gene knockdown mediated by Tf-PEI polyplexes in human primary ATCs. Biodistribution of polyplexes in a murine asthmatic model confirmed that Tf-PEI polyplexes can efficiently and selectively deliver siRNA to ATCs. In conclusion, the present work proves the feasibility to target ATCs in asthma via Tf receptor. This strategy could potentially be used to design an efficient siRNA delivery system for asthma therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

31 CFR 597.406 - Offshore transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Offshore transactions. 597.406 Section 597.406 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... REGULATIONS Interpretations § 597.406 Offshore transactions. The prohibitions contained in § 597.201 apply to...

31 CFR 596.304 - Financial transaction.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Financial transaction. 596.304 Section 596.304 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... term includes: (a) A transaction which in any way or degree affects interstate or foreign commerce; (1...

siRNA as a tool to improve the treatment of brain diseases: Mechanism, targets and delivery.

Science.gov (United States)

Gomes, Maria João; Martins, Susana; Sarmento, Bruno

2015-05-01

As the population ages, brain pathologies such as neurodegenerative diseases and brain cancer increase their incidence, being the need to find successful treatments of upmost importance. Drug delivery to the central nervous system (CNS) is required in order to reach diseases causes and treat them. However, biological barriers, mainly blood-brain barrier (BBB), are the key obstacles that prevent the effectiveness of possible treatments due to their ability to strongly limit the perfusion of compounds into the brain. Over the past decades, new approaches towards overcoming BBB and its efflux transporters had been proposed. One of these approaches here reviewed is through small interfering RNA (siRNA), which is capable to specifically target one gene and silence it in a post-transcriptional way. There are different possible functional proteins at the BBB, as the ones responsible for transport or just for its tightness, which could be a siRNA target. As important as the effective silence is the way to delivery siRNA to its anatomical site of action. This is where nanotechnology-based systems may help, by protecting siRNA circulation and providing cell/tissue-targeting and intracellular siRNA delivery. After an initial overview on incidence of brain diseases and basic features of the CNS, BBB and its efflux pumps, this review focuses on recent strategies to reach brain based on siRNA, and how to specifically target these approaches in order to treat brain diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization and vectorization of siRNA targeting RET/PTC1 in human papillary thyroid carcinoma cells

Directory of Open Access Journals (Sweden)

Massade L.

2011-10-01

Full Text Available RET/PTC1 fusion oncogene is the most common genetic alteration identified to date in thyroid papillary carcinomas (PTC and represents a good target for small interfering RNA (siRNA. Our aim was: i to target the RET/PTC1 oncogene by siRNAs, ii to assess the knockdown effects on cell growth and cell cycle regulation and iii to vectorize it in order to protect it from degradation. Methods. Human cell lines expressing RET/PTC1 were transfected by siRNA RET/PTC1, inhibition of the oncogene expression was assessed by qRT-PCR and by Western blot. Conjugation of siRNA RET/PTC1 to squalene was performed by coupling it to squalene. In vivo studies are performed in nude mice. Conclusion. In this short communication, we report the main published results obtained during last years.

Novel targets for sensitizing breast cancer cells to TRAIL-induced apoptosis with siRNA delivery.

Science.gov (United States)

Thapa, Bindu; Bahadur Kc, Remant; Uludağ, Hasan

2018-02-01

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in variety of cancer cells without affecting most normal cells, which makes it a promising agent for cancer therapy. However, TRAIL therapy is clinically not effective due to resistance induction. To identify novel regulators of TRAIL that can aid in therapy, protein targets whose silencing sensitized breast cancer cells against TRAIL were screened with an siRNA library against 446 human apoptosis-related proteins in MDA-231 cells. Using a cationic lipopolymer (PEI-αLA) for delivery of library members, 16 siRNAs were identified that sensitized the TRAIL-induced death in MDA-231 cells. The siRNAs targeting BCL2L12 and SOD1 were further evaluated based on the novelty and their ability to sensitize TRAIL induced cell death. Silencing both targets sensitized TRAIL-mediated cell death in MDA-231 cells as well as TRAIL resistant breast cancer cells, MCF-7. Combination of TRAIL and siRNA silencing BCL2L12 had no effect in normal human umbilical vein cells and human bone marrow stromal cell. The silencing of BCL2L12 and SOD1 enhanced TRAIL-mediated apoptosis in MDA-231 cells via synergistically activating capsase-3 activity. Hence, here we report siRNAs targeting BCL2L12 and SOD1 as a novel regulator of TRAIL-induced cell death in breast cancer cells, providing a new approach for enhancing TRAIL therapy for breast cancer. The combination of siRNA targeting BCL2L12 and TRAIL can be a highly effective synergistic pair in breast cancer cells with minimal effect on the non-transformed cells. © 2017 UICC.

The transactional approach in company boundaries

Directory of Open Access Journals (Sweden)

Bruno Chaihuaque Dueñas

2009-12-01

Full Text Available This article shows the relationship between market and firms through the theory of transactional cost and the relationsthat determine the structure and boundaries of the firm. Using the assumptions from the transactional cost approach,this article proposes some variables that determine optimal organizational structures and their boundaries.

31 CFR 515.206 - Exempt transactions.

Science.gov (United States)

2010-07-01

... credit issued by a Cuban bank and confirmed by an American bank. These are permissible transactions under... enhancements. (b) Donation of food. The prohibitions contained in this part do not apply to transactions incident to the donation of food to nongovernmental organizations or individuals in Cuba. [54 FR 5233, Feb...

In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery

Directory of Open Access Journals (Sweden)

Taejin Kim

2013-01-01

Full Text Available Specific small interfering RNAs (siRNAs designed to silence different oncogenic pathways can be used for cancer therapy. However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biological membranes due to their negative charge. These obstacles can be overcome by using siRNAs complexed with bolaamphiphiles, consisting of two positively charged head groups that flank an internal hydrophobic chain. Bolaamphiphiles have relatively low toxicities, long persistence in the blood stream, and most importantly, in aqueous conditions can form poly-cationic micelles thus, becoming amenable to association with siRNAs. Herein, two different bolaamphiphiles with acetylcholine head groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAs and deliver them into cells inducing gene silencing. Our explicit solvent molecular dynamics (MD simulations showed that bolaamphiphiles associate with siRNAs due to electrostatic, hydrogen bonding, and hydrophobic interactions. These in silico studies are supported by various in vitro and in cell culture experimental techniques as well as by some in vivo studies. Results demonstrate that depending on the application, the extent of siRNA chemical protection, delivery efficiency, and further intracellular release can be varied by simply changing the type of bolaamphiphile used.

Hydrogel doped with nanoparticles for local sustained release of siRNA in breast cancer.

Science.gov (United States)

Segovia, Nathaly; Pont, Maria; Oliva, Nuria; Ramos, Victor; Borrós, Salvador; Artzi, Natalie

2015-01-28

Of all the much hyped and pricy cancer drugs, the benefits from the promising siRNA small molecule drugs are limited. Lack of efficient delivery vehicles that would release the drug locally, protect it from degradation, and ensure high transfection efficiency, precludes it from fulfilling its full potential. This work presents a novel platform for local and sustained delivery of siRNA with high transfection efficiencies both in vitro and in vivo in a breast cancer mice model. siRNA protection and high transfection efficiency are enabled by their encapsulation in oligopeptide-terminated poly(β-aminoester) (pBAE) nanoparticles. Sustained delivery of the siRNA is achieved by the enhanced stability of the nanoparticles when embedded in a hydrogel scaffold based on polyamidoamine (PAMAM) dendrimer cross-linked with dextran aldehyde. The combination of oligopeptide-terminated pBAE polymers and biodegradable hydrogels shows improved transfection efficiency in vivo even when compared with the most potent commercially available transfection reagents. These results highlight the advantage of using composite materials for successful delivery of these highly promising small molecules to combat cancer. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

How to Use EMTS to Report Transactions for Fuel Programs

Science.gov (United States)

Reporting instructions for parties who transact Renewable Identification Numbers (RINs) and must enter transaction information in the EPA Moderated Transaction System (EMTS) within five (5) business days.

Dual peptide-mediated targeted delivery of bioactive siRNAs to oral cancer cells in vivo.

Science.gov (United States)

Alexander-Bryant, Angela A; Zhang, Haiwen; Attaway, Christopher C; Pugh, William; Eggart, Laurence; Sansevere, Robert M; Andino, Lourdes M; Dinh, Lu; Cantini, Liliana P; Jakymiw, Andrew

2017-09-01

Despite significant advances in cancer treatment, the prognosis for oral cancer remains poor in comparison to other cancer types, including breast, skin, and prostate. As a result, more effective therapeutic modalities are needed for the treatment of oral cancer. Consequently, in the present study, we examined the feasibility of using a dual peptide carrier approach, combining an epidermal growth factor receptor (EGFR)-targeting peptide with an endosome-disruptive peptide, to mediate targeted delivery of small interfering RNAs (siRNAs) into EGFR-overexpressing oral cancer cells and induce silencing of the targeted oncogene, cancerous inhibitor of protein phosphatase 2A (CIP2A). Fluorescence microscopy, real-time PCR, Western blot analysis, and in vivo bioimaging of mice containing orthotopic xenograft tumors were used to examine the ability of the dual peptide carrier to mediate specific delivery of bioactive siRNAs into EGFR-overexpressing oral cancer cells/tissues. Co-complexation of the EGFR-targeting peptide, GE11R9, with the endosome-disruptive 599 peptide facilitated the specific uptake of siRNAs into oral cancer cells overexpressing EGFR in vitro with optimal gene silencing observed at a 60:30:1 (GE11R9:599:siRNA) molar ratio. Furthermore, when administered systemically to mice bearing xenograft oral tumors, this dual peptide complex mediated increased targeted delivery of siRNAs into tumor tissues in comparison to the 599 peptide alone and significantly enhanced CIP2A silencing. Herein we provide the first report demonstrating the clinical potential of a dual peptide strategy for siRNA-based therapeutics by synergistically mediating the effective targeting and delivery of bioactive siRNAs into EGFR-overexpressing oral cancer cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

ACCOUNTING TREATMENTS SPECIFIC TO COUNTERPART COMMERCIAL TRANSACTIONS

Directory of Open Access Journals (Sweden)

Lucia PALIU - POPA

2010-12-01

Full Text Available Given the lack of availability of funds in foreign currency, felt in many countries, especially in the developing and developed countries and the economic or financial crisis in the global foreign exchange, counterpart commercial transactions were imposed as a “disarming” condition of the international trade. In the counterpart a purchase transaction is combined with a sale transaction, an import with an export in order to ensure balanced trade between the partners, trade that involves eliminating or reducing the currency as a payment source and its replacement with trade of goods and services. Thus, in the context of an acute need to export of greatly industrialized countries, where the overproduction phenomenon tends to have a chronic character, the counterpart has become a highly complex and sustainable phenomenon, which has seen a steady increase in the volume of amounts, with a geographical area and large variety of forms and mechanisms of implementation. Based on the characteristics and structure of counterpart transactions, we shall describe in this paper the accounting models specific to international trade, as part of the combined foreign trade transactions without neglecting the tax treatments that influence the entry in the accounts

Efficient Inhibition of wear debris-induced inflammation by locally delivered siRNA

International Nuclear Information System (INIS)

Peng Xiaochun; Tao Kun; Cheng Tao; Zhu Junfeng; Zhang Xianlong

2008-01-01

Aseptic loosening is the most common long-term complication of total joint replacement, which is associated with the generation of wear debris. The purpose of this study was to investigate the inhibitory effect of small interfering RNA (siRNA) targeting tumor necrosis factor-α (TNF-α) on wear debris-induced inflammation. A local delivery of lentivirus-mediated TNF-α siRNA into the modified murine air pouch, which was stimulated by polymethylmethacrylate (PMMA) particles, resulted in significant blockage of TNF-α both in mRNA and protein levels for up to 4 weeks. In addition, significant down-regulation of interleukin-1 (IL-1) and interleukin-6 (IL-6) was observed in TNF-α siRNA-treated pouches. The safety profile of gene therapy was proven by Bioluminescent assay and quantitative fluorescent flux. Histological analysis revealed less inflammatory responses (thinner pouch membrane and decreased cellular infiltration) in TNF-α siRNA-treated pouches. These findings suggest that local delivery of TNF-α siRNA might be an excellent therapeutic candidate to inhibit particle-induced inflammation.

Novel targeted therapy for neuroblastoma: silencing the MXD3 gene using siRNA.

Science.gov (United States)

Duong, Connie; Yoshida, Sakiko; Chen, Cathy; Barisone, Gustavo; Diaz, Elva; Li, Yueju; Beckett, Laurel; Chung, Jong; Antony, Reuben; Nolta, Jan; Nitin, Nitin; Satake, Noriko

2017-09-01

BackgroundNeuroblastoma is the second most common extracranial cancer in children. Current therapies for neuroblastoma, which use a combination of chemotherapy drugs, have limitations for high-risk subtypes and can cause significant long-term adverse effects in young patients. Therefore, a new therapy is needed. In this study, we investigated the transcription factor MXD3 as a potential therapeutic target in neuroblastoma.MethodsMXD3 expression was analyzed in five neuroblastoma cell lines by immunocytochemistry and quantitative real-time reverse transcription PCR, and in 18 primary patient tumor samples by immunohistochemistry. We developed nanocomplexes using siRNA and superparamagnetic iron oxide nanoparticles to target MXD3 in neuroblastoma cell lines in vitro as a single-agent therapeutic and in combination with doxorubicin, vincristine, cisplatin, or maphosphamide-common drugs used in current neuroblastoma treatment.ResultsMXD3 was highly expressed in neuroblastoma cell lines and in patient tumors that had high-risk features. Neuroblastoma cells treated in vitro with the MXD3 siRNA nanocomplexes showed MXD3 protein knockdown and resulted in cell apoptosis. Furthermore, on combining MXD3 siRNA nanocomplexes with each of the four drugs, all showed additive efficacy.ConclusionThese results indicate that MXD3 is a potential new target and that the use of MXD3 siRNA nanocomplexes is a novel therapeutic approach for neuroblastoma.

Transaction management with integrity checking

DEFF Research Database (Denmark)

Martinenghi, Davide; Christiansen, Henning

2005-01-01

Database integrity constraints, understood as logical conditions that must hold for any database state, are not fully supported by current database technology. It is typically up to the database designer and application programmer to enforce integrity via triggers or tests at the application level....... 2.~In concurrent database systems, besides the traditional correctness criterion, the execution schedule must ensure that the different transactions can overlap in time without destroying the consistency requirements tested by other, concurrent transactions....

Supply Chain-Wide Consequences of Transaction Risks and Their Contractual Solutions: Towards an Extended Transaction Cost Economics Framework

NARCIS (Netherlands)

Wever, M.; Wognum, P.M.; Trienekens, J.H.; Omta, S.W.F.

2012-01-01

How supply chain actors manage their exposure to both supply- and demand-side risks is a topic that has been insufficiently examined within the transaction cost economics (TCE) literature. TCE studies often only examine transaction risks in the context of bilateral exchanges. This study aims to

A Case for Including Transactions in OpenMP

Energy Technology Data Exchange (ETDEWEB)

Wong, M; Bihari, B L; de Supinski, B R; Wu, P; Michael, M; Liu, Y; Chen, W

2010-01-25

Transactional Memory (TM) has received significant attention recently as a mechanism to reduce the complexity of shared memory programming. We explore the potential of TM to improve OpenMP applications. We combine a software TM (STM) system to support transactions with an OpenMP implementation to start thread teams and provide task and loop-level parallelization. We apply this system to two application scenarios that reflect realistic TM use cases. Our results with this system demonstrate that even with the relatively high overheads of STM, transactions can outperform OpenMP critical sections by 10%. Overall, our study demonstrates that extending OpenMP to include transactions would ease programming effort while allowing improved performance.

Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA.

Science.gov (United States)

Jensen, Ditte Krohn; Jensen, Linda Boye; Koocheki, Saeid; Bengtson, Lasse; Cun, Dongmei; Nielsen, Hanne Mørck; Foged, Camilla

2012-01-10

Matrix systems based on biocompatible and biodegradable polymers like the United States Food and Drug Administration (FDA)-approved polymer poly(DL-lactide-co-glycolide acid) (PLGA) are promising for the delivery of small interfering RNA (siRNA) due to favorable safety profiles, sustained release properties and improved colloidal stability, as compared to polyplexes. The purpose of this study was to design a dry powder formulation based on cationic lipid-modified PLGA nanoparticles intended for treatment of severe lung diseases by pulmonary delivery of siRNA. The cationic lipid dioleoyltrimethylammoniumpropane (DOTAP) was incorporated into the PLGA matrix to potentiate the gene silencing efficiency. The gene knock-down level in vitro was positively correlated to the weight ratio of DOTAP in the particles, and 73% silencing was achieved in the presence of 10% (v/v) serum at 25% (w/w) DOTAP. Optimal properties were found for nanoparticles modified with 15% (w/w) DOTAP, which reduced the gene expression with 54%. This formulation was spray-dried with mannitol into nanocomposite microparticles of an aerodynamic size appropriate for lung deposition. The spray-drying process did not affect the physicochemical properties of the readily re-dispersible nanoparticles, and most importantly, the in vitro gene silencing activity was preserved during spray-drying. The siRNA content in the powder was similar to the theoretical loading and the siRNA was intact, suggesting that the siRNA is preserved during the spray-drying process. Finally, X-ray powder diffraction analysis demonstrated that mannitol remained in a crystalline state upon spray-drying with PLGA nanoparticles suggesting that the sugar excipient might exert its stabilizing effect by sterical inhibition of the interactions between adjacent nanoparticles. This study demonstrates that spray-drying is an excellent technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local

PEGylated carboxymethyl chitosan/calcium phosphate hybrid anionic nanoparticles mediated hTERT siRNA delivery for anticancer therapy.

Science.gov (United States)

Xie, Ying; Qiao, Hongzhi; Su, Zhigui; Chen, Minglei; Ping, Qineng; Sun, Minjie

2014-09-01

Lack of safe and effective delivery vehicle is the main obstacle for siRNA mediated cancer therapy. In this study, we synthesized a pH-sensitive polymer of PEG grafted carboxymethyl chitosan (PEG-CMCS) and developed anionic-charged hybrid nanoparticles of PEG-CMCS and calcium phosphate (CaP) for siRNA delivery through a single-step self-assembly method in aqueous condition. The formed nanoparticles with charge of around -8.25 mv and average diameter of 102.1 nm exhibited efficient siRNA encapsulation and enhanced colloidal and serum stability. The test in vitro indicated that the nanoparticles entered into HepG2 cells by endocytosis, and achieved endosomal escape of siRNA effectively due to the pH-responsive disassembly of nanoparticles and dissolution of CaP in the endosome. Reporter gene silencing assay showed that luciferase siRNA delivered by the anionic nanoparticles could achieve gene silencing efficacy comparable to that of conventional Lipofectamine 2000. Additionally, dramatic hTERT knockdown mediated by the anionic nanoparticles transfection induced significant apoptosis of HepG2 cells in vitro. After intravenous injection in tumor-bearing BALB/c nude mice, the nanoparticles specifically accumulated into tumor regions by EPR effect, leading to efficient and specific gene silencing sequentially. Most importantly, the nanoparticles carrying hTERT siRNA inhibited tumor growth significantly via silencing hTERT expression and inducing cells apoptosis in HepG2 tumor xenograft. Moreover, comprehensive safety studies of the nanoparticles confirmed their superior safety both in vitro and in vivo. We concluded that the PEG-CMCS/CaP hybrid anionic nanoparticles possessed potential as a safe and effective siRNA delivery system for anticancer therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Topical treatment of herpes simplex virus infection with enzymatically created siRNA swarm.

Science.gov (United States)

Paavilainen, Henrik; Lehtinen, Jenni; Romanovskaya, Alesia; Nygårdas, Michaela; Bamford, Dennis H; Poranen, Minna M; Hukkanen, Veijo

2017-01-01

Herpes simplex virus (HSV) is a common human pathogen. Despite current antivirals, it causes a significant medical burden. Drug resistant strains exist and they are especially prevalent in immunocompromised patients and in HSV eye infections. New treatment modalities are needed. BALB/c mice were corneally infected with HSV and subsequently treated with a swarm of enzymatically created, Dicer-substrate small interfering RNA (siRNA) molecules that targeted the HSV gene UL29. Two infection models were used, one in which the infection was predominantly peripheral and another in which it spread to the central nervous system. Mouse survival, as well as viral spread, load, latency and peripheral shedding, was studied. The anti-HSV-UL29 siRNA swarm alleviated HSV infection symptoms, inhibited viral shedding and replication and had a favourable effect on mouse survival. Treatment with anti-HSV-UL29 siRNA swarm reduced symptoms and viral spread in HSV infection of mice and also inhibited local viral replication in mouse corneas.

31 CFR 575.533 - Certain new transactions.

Science.gov (United States)

2010-07-01

..., Authorizations, and Statements of Licensing Policy § 575.533 Certain new transactions. (a) New transactions..., including any aviation, financial, or trade requirements of agencies other than the Department of the... subsequent permanent Iraqi government: Agricultural Cooperative Bank Al-Rafidain Shipping Company Industrial...

Inhibition of Hepatitis B virus cccDNA replication by siRNA

International Nuclear Information System (INIS)

Li Guiqiu; Gu Hongxi; Li Di; Xu Weizhen

2007-01-01

The development of an effective therapy for Hepatitis B virus (HBV) infection is still a challenge. Progress in RNA interference (RNAi) has shed slight on developing a new anti-HBV strategy. Here, we present a series of experiments showing a significant reduction in HBV transcripts and replication intermediates in HepG2.2.15 cells by vector-based siRNA targeted nuclear localization signal (NLS) region. More importantly, we showed that siRNA1 markedly inhibited HBV covalently closed circular DNA (cccDNA) replication. Our results indicated that HBV NLS may serve as a novel RNAi target to combat HBV infection, which can enhance anti-HBV efficacy and overcome the drawbacks of current therapies

A selective logging mechanism for hardware transactional memory systems

OpenAIRE

Lupon Navazo, Marc; Magklis, Grigorios; González Colás, Antonio María

2011-01-01

Log-based Hardware Transactional Memory (HTM) systems offer an elegant solution to handle speculative data that overflow transactional L1 caches. By keeping the pre-transactional values on a software-resident log, speculative values can be safely moved across the memory hierarchy, without requiring expensive searches on L1 misses or commits.

Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

Science.gov (United States)

Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

2016-07-05

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

Deep Sequencing Insights in Therapeutic shRNA Processing and siRNA Target Cleavage Precision.

Science.gov (United States)

Denise, Hubert; Moschos, Sterghios A; Sidders, Benjamin; Burden, Frances; Perkins, Hannah; Carter, Nikki; Stroud, Tim; Kennedy, Michael; Fancy, Sally-Ann; Lapthorn, Cris; Lavender, Helen; Kinloch, Ross; Suhy, David; Corbau, Romu

2014-02-04

TT-034 (PF-05095808) is a recombinant adeno-associated virus serotype 8 (AAV8) agent expressing three short hairpin RNA (shRNA) pro-drugs that target the hepatitis C virus (HCV) RNA genome. The cytosolic enzyme Dicer cleaves each shRNA into multiple, potentially active small interfering RNA (siRNA) drugs. Using next-generation sequencing (NGS) to identify and characterize active shRNAs maturation products, we observed that each TT-034-encoded shRNA could be processed into as many as 95 separate siRNA strands. Few of these appeared active as determined by Sanger 5' RNA Ligase-Mediated Rapid Amplification of cDNA Ends (5-RACE) and through synthetic shRNA and siRNA analogue studies. Moreover, NGS scrutiny applied on 5-RACE products (RACE-seq) suggested that synthetic siRNAs could direct cleavage in not one, but up to five separate positions on targeted RNA, in a sequence-dependent manner. These data support an on-target mechanism of action for TT-034 without cytotoxicity and question the accepted precision of substrate processing by the key RNA interference (RNAi) enzymes Dicer and siRNA-induced silencing complex (siRISC).Molecular Therapy-Nucleic Acids (2014) 3, e145; doi:10.1038/mtna.2013.73; published online 4 February 2014.

Intraventricular Delivery of siRNA Nanoparticles to the Central Nervous System

Directory of Open Access Journals (Sweden)

Rishab Shyam

2015-01-01

Full Text Available Alzheimer's disease (AD is a progressive neurodegenerative disease currently lacking effective treatment. Efficient delivery of siRNA via nanoparticles may emerge as a viable therapeutic approach to treat AD and other central nervous system disorders. We report here the use of a linear polyethyleneimine (LPEI-g-polyethylene glycol (PEG copolymer-based micellar nanoparticle system to deliver siRNA targeting BACE1 and APP, two therapeutic targets of AD. Using LPEI-siRNA nanoparticles against either BACE1 or APP in cultured mouse neuroblastoma (N2a cells, we observe selective knockdown, respectively, of BACE1 or APP. The encapsulation of siRNA by LPEI-g-PEG carriers, with different grafting degrees of PEG, leads to the formation of micellar nanoparticles with distinct morphologies, including worm-like, rod-like, or spherical nanoparticles. By infusing these shaped nanoparticles into mouse lateral ventricles, we show that rod-shaped nanoparticles achieved the most efficient knockdown of BACE1 in the brain. Furthermore, such knockdown is evident in spinal cords of these treated mice. Taken together, our findings indicate that the shape of siRNA-encapsulated nanoparticles is an important determinant for their delivery and gene knockdown efficiency in the central nervous system.

Chimeric peptide-mediated siRNA transduction to inhibit HIV-1 infection.

Science.gov (United States)

Bivalkar-Mehla, Shalmali; Mehla, Rajeev; Chauhan, Ashok

2017-04-01

Persistent human immunodeficiency virus 1 (HIV-1) infection provokes immune activation and depletes CD4 +  lymphocytes, leading to acquired immunodeficiency syndrome. Uninterrupted administration of combination antiretroviral therapy (cART) in HIV-infected patients suppresses viral replication to below the detectable level and partially restores the immune system. However, cART-unresponsive residual HIV-1 infection and elusive transcriptionally silent but reactivatable viral reservoirs maintain a permanent viral DNA blue print. The virus rebounds within a few weeks after interruption of suppressive therapy. Adjunct gene therapy to control viral replication by ribonucleic acid interference (RNAi) is a post-transcriptional gene silencing strategy that could suppress residual HIV-1 burden and overcome viral resistance. Small interfering ribonucleic acids (siRNAs) are efficient transcriptional inhibitors, but need delivery systems to reach inside target cells. We investigated the potential of chimeric peptide (FP-PTD) to deliver specific siRNAs to HIV-1-susceptible and permissive cells. Chimeric FP-PTD peptide was designed with an RNA binding domain (PTD) to bind siRNA and a cell fusion peptide domain (FP) to enter cells. FP-PTD-siRNA complex entered and inhibited HIV-1 replication in susceptible cells, and could be a candidate for in vivo testing.

Visualizing Dynamic Bitcoin Transaction Patterns.

Science.gov (United States)

McGinn, Dan; Birch, David; Akroyd, David; Molina-Solana, Miguel; Guo, Yike; Knottenbelt, William J

2016-06-01

This work presents a systemic top-down visualization of Bitcoin transaction activity to explore dynamically generated patterns of algorithmic behavior. Bitcoin dominates the cryptocurrency markets and presents researchers with a rich source of real-time transactional data. The pseudonymous yet public nature of the data presents opportunities for the discovery of human and algorithmic behavioral patterns of interest to many parties such as financial regulators, protocol designers, and security analysts. However, retaining visual fidelity to the underlying data to retain a fuller understanding of activity within the network remains challenging, particularly in real time. We expose an effective force-directed graph visualization employed in our large-scale data observation facility to accelerate this data exploration and derive useful insight among domain experts and the general public alike. The high-fidelity visualizations demonstrated in this article allowed for collaborative discovery of unexpected high frequency transaction patterns, including automated laundering operations, and the evolution of multiple distinct algorithmic denial of service attacks on the Bitcoin network.

Visualizing Dynamic Bitcoin Transaction Patterns

Science.gov (United States)

McGinn, Dan; Birch, David; Akroyd, David; Molina-Solana, Miguel; Guo, Yike; Knottenbelt, William J.

2016-01-01

Abstract This work presents a systemic top-down visualization of Bitcoin transaction activity to explore dynamically generated patterns of algorithmic behavior. Bitcoin dominates the cryptocurrency markets and presents researchers with a rich source of real-time transactional data. The pseudonymous yet public nature of the data presents opportunities for the discovery of human and algorithmic behavioral patterns of interest to many parties such as financial regulators, protocol designers, and security analysts. However, retaining visual fidelity to the underlying data to retain a fuller understanding of activity within the network remains challenging, particularly in real time. We expose an effective force-directed graph visualization employed in our large-scale data observation facility to accelerate this data exploration and derive useful insight among domain experts and the general public alike. The high-fidelity visualizations demonstrated in this article allowed for collaborative discovery of unexpected high frequency transaction patterns, including automated laundering operations, and the evolution of multiple distinct algorithmic denial of service attacks on the Bitcoin network. PMID:27441715

MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer

Science.gov (United States)

Yang, Xiaoqian; Lyer, Arun K.; Singh, Amit; Choy, Edwin; Hornicek, Francis J.; Amiji, Mansoor M.; Duan, Zhenfeng

2015-02-01

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer.

31 CFR 800.302 - Transactions that are not covered transactions.

Science.gov (United States)

2010-07-01

... A also negotiates contractual rights that give it the power to control important matters of... Example 2, except that Corporation X, a U.S. business, has developed important technology in connection... Corporation X, including production facilities, customer lists, technology, and staff. This transaction is a...

26 CFR 1.1221-2 - Hedging transactions.

Science.gov (United States)

2010-04-01

... serves a hedging function, or that the transaction serves a similar function or purpose. (4) Coordination... business units. A separate set of books and records is maintained with respect to the activities, assets... under the marking member's method of accounting. (iii) Treatment of intercompany hedging transactions...

Transactive Campus Energy Systems: Final Report

Energy Technology Data Exchange (ETDEWEB)

Katipamula, Srinivas [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Corbin, Charles D. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Haack, Jereme N. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hao, He [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kim, Woohyun [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hostick, Donna J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Akyol, Bora A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Allwardt, Craig H. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Carpenter, Brandon J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Huang, Sen [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Liu, Guopeng [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lutes, Robert G. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Makhmalbaf, Atefe [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Mendon, Vrushali V. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Ngo, Hung [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Somasundaram, Sriram [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Underhill, Ronald M. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Zhao, Mingjie [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2017-09-26

Transactive energy refers to the combination of economic and control techniques to improve grid reliability and efficiency. The fundamental purpose of transactive energy management is to seamlessly coordinate the operation of large numbers of new intelligent assets—such as distributed solar, energy storage and responsive building loads—to provide the flexibility needed to operate the power grid reliably and at minimum cost, particularly one filled with intermittent renewable generation such as the Pacific Northwest. It addresses the key challenge of providing smooth, stable, and predictable “control” of these assets, despite the fact that most are neither owned nor directly controlled by the power grid. The Clean Energy and Transactive Campus (CETC) work described in this report was done as part of a Cooperative Research and Development Agreement (CRADA) between the U.S. Department of Energy’s Pacific Northwest National Laboratory (PNNL) and the Washington State Department of Commerce (Commerce) through the Clean Energy Fund (CEF). The project team consisted of PNNL, the University of Washington (UW) and Washington State University (WSU), to connect the PNNL, UW, and WSU campuses to form a multi-campus testbed for transaction-based energy management—transactive—solutions. Building on the foundational transactive system established by the Pacific Northwest Smart Grid Demonstration (PNWSGD), the purpose of the project was to construct the testbed as both a regional flexibility resource and as a platform for research and development (R&D) on buildings/grid integration and information-based energy efficiency. This report provides a summary of the various tasks performed under the CRADA.

Mechanistic profiling of the siRNA delivery dynamics of lipid-polymer hybrid nanoparticles.

Science.gov (United States)

Colombo, Stefano; Cun, Dongmei; Remaut, Katrien; Bunker, Matt; Zhang, Jianxin; Martin-Bertelsen, Birte; Yaghmur, Anan; Braeckmans, Kevin; Nielsen, Hanne M; Foged, Camilla

2015-03-10

Understanding the delivery dynamics of nucleic acid nanocarriers is fundamental to improve their design for therapeutic applications. We investigated the carrier structure-function relationship of lipid-polymer hybrid nanoparticles (LPNs) consisting of poly(DL-lactic-co-glycolic acid) (PLGA) nanocarriers modified with the cationic lipid dioleoyltrimethyl-ammoniumpropane (DOTAP). A library of siRNA-loaded LPNs was prepared by systematically varying the nitrogen-to-phosphate (N/P) ratio. Atomic force microscopy (AFM) and cryo-transmission electron microscopy (cryo-TEM) combined with small angle X-ray scattering (SAXS) and confocal laser scanning microscopy (CLSM) studies suggested that the siRNA-loaded LPNs are characterized by a core-shell structure consisting of a PLGA matrix core coated with lamellar DOTAP structures with siRNA localized both in the core and in the shell. Release studies in buffer and serum-containing medium combined with in vitro gene silencing and quantification of intracellular siRNA suggested that this self-assembling core-shell structure influences the siRNA release kinetics and the delivery dynamics. A main delivery mechanism appears to be mediated via the release of transfection-competent siRNA-DOTAP lipoplexes from the LPNs. Based on these results, we suggest a model for the nanostructural characteristics of the LPNs, in which the siRNA is organized in lamellar superficial assemblies and/or as complexes entrapped in the polymeric matrix. Copyright © 2015 Elsevier B.V. All rights reserved.

Stress Testing of Transactional Database Systems

OpenAIRE

Meira , Jorge Augusto; Cunha De Almeida , Eduardo; Sunyé , Gerson; Le Traon , Yves; Valduriez , Patrick

2013-01-01

International audience; Transactional database management systems (DBMS) have been successful at supporting traditional transaction processing workloads. However, web-based applications that tend to generate huge numbers of concurrent business operations are pushing DBMS performance over their limits, thus threatening overall system availability. Then, a crucial question is how to test DBMS performance under heavy workload conditions. Answering this question requires a testing methodology to ...

The TCA cycle as a bridge between oncometabolism and DNA transactions in cancer.

Science.gov (United States)

Ciccarone, Fabio; Vegliante, Rolando; Di Leo, Luca; Ciriolo, Maria Rosa

2017-12-01

Cancer cells exploit metabolic rearrangements for sustaining their high proliferation rate and energy demand. The TCA cycle is a central metabolic hub necessary for ATP production and for providing precursors used in many biosynthetic pathways. Thus, dysregulation of the TCA cycle flux is frequently observed in cancer. The identification of mutations in several enzymes of the TCA cycle in human tumours demonstrated a direct connection between this metabolic pathway and cancer occurrence. Moreover, changes in the expression/activity of these enzymes were also shown to promote metabolic adaptation of cancer cells. In this review, the main genetic and non-genetic alterations of TCA cycle in cancer will be described. Particular attention will be given to extrametabolic roles of TCA cycle enzymes and metabolites underlying the regulation of nuclear and mitochondrial DNA transactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Value Added Tax Implications of Illegal Transactions

Directory of Open Access Journals (Sweden)

SP van Zyl

2011-01-01

Full Text Available In the case of MP Finance Group CC (In Liquidation v CSARS the High Court of Appeal ruled that income "received by" a taxpayer from illegal gains will be taxable in the hands of the taxpayer. This article explores whether or not the decision in the MP Finance-case (and preceding cases on the taxation of illegal receipts can be applied to determine if illegal transactions are subject to VAT and moreover if a trader in illegal goods and services should register as a VAT vendor. Although strictly speaking no analogy can be drawn between the charging provisions for income tax and VAT, it is clear that in the determination of the taxability of illegal income, the courts applied the principle of tax neutrality. In terms of the principle of tax neutrality, taxes are not concerned with the legality or illegality of a transaction, but rather with whether the transaction complies with the requirements for it to be taxed or not. That said, the European Court of Justice has a different approach in applying this principle. According to the European Court of Justice where the intrinsic nature of the goods excludes it from the commercial arena (like narcotic drugs it should not be subject to VAT, but where the goods compete with a legal market it must be subject to VAT. Charging VAT on illegal transactions might give the impression that government benefits from criminal activities. However, if illegal transactions are not subject to VAT the trader in illegal goods will benefit as his products will be 14% cheaper than his rival’s. Is this necessarily a moral dilemma? In conclusion three arguments can be deduced on the question if illegal transactions should be subject to VAT:1. Illegal transactions should not be taxed at all. Illegal goods or services fall outside the sphere of the application of the charging provision in section 7(1 of the VAT Act. Moreover, taxing illegal transactions lends a quasi-validity to the contract and gives the impression that

Related Party Transactions and Firms Financial Performance

African Journals Online (AJOL)

Prof

Chien and Hsu (2010) found a positive moderating effect of corporate governance on the related transactions-firm performance relationship and deduce that presence of corporate governance could 'transfer' related party transactions 'conflict- of-interest' to be efficient. Past studies on the impact of RPT on financial reporting ...

Biocompatible and colloidally stabilized mPEG-PE/calcium phosphate hybrid nanoparticles loaded with siRNAs targeting tumors.

Science.gov (United States)

Gao, Pei; Zhang, Xiangyu; Wang, Hongzhi; Zhang, Qinghong; Li, He; Li, Yaogang; Duan, Yourong

2016-01-19

Calcium phosphate nanoparticles are safe and effective delivery vehicles for small interfering RNA (siRNA), as a result of their excellent biocompatibility. In this work, mPEG-PE (polyethylene glycol-L-α-phosphatidylethanolamine) was synthesized and used to prepare nanoparticles composed of mPEG-PE and calcium phosphate for siRNA delivery. Calcium phosphate and mPEG-PE formed the stable hybrid nanoparticles through self-assembly resulting from electrostatic interaction in water. The average size of the hybrid nanoparticles was approximately 53.2 nm with a negative charge of approximately -16.7 mV, which was confirmed by dynamic light scattering (DLS) measurements. The nanoparticles exhibited excellent stability in serum and could protect siRNA from ribonuclease (RNase) degradation. The cellular internalization of siRNA-loaded nanoparticles was evaluated in SMMC-7721 cells using a laser scanning confocal microscope (CLSM) and flow cytometry. The hybrid nanoparticles could efficiently deliver siRNA to cells compared with free siRNA. Moreover, the in vivo distribution of Cy5-siRNA-loaded hybrid nanoparticles was observed after being injected into tumor-bearing nude mice. The nanoparticles concentrated in the tumor regions through an enhanced permeability and retention (EPR) effect based on the fluorescence intensities of tissue distribution. A safety evaluation of the nanoparticles was performed both in vitro and in vivo demonstrating that the hybrid nanoparticle delivery system had almost no toxicity. These results indicated that the mPEG-PE/CaP hybrid nanoparticles could be a stable, safe and promising siRNA nanocarrier for anticancer therapy.

A genome-wide siRNA screen to identify modulators of insulin sensitivity and gluconeogenesis.

Directory of Open Access Journals (Sweden)

Ruojing Yang

Full Text Available BACKGROUND: Hepatic insulin resistance impairs insulin's ability to suppress hepatic glucose production (HGP and contributes to the development of type 2 diabetes (T2D. Although the interests to discover novel genes that modulate insulin sensitivity and HGP are high, it remains challenging to have a human cell based system to identify novel genes. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that modulate hepatic insulin signaling and HGP, we generated a human cell line stably expressing beta-lactamase under the control of the human glucose-6-phosphatase (G6PC promoter (AH-G6PC cells. Both beta-lactamase activity and endogenous G6PC mRNA were increased in AH-G6PC cells by a combination of dexamethasone and pCPT-cAMP, and reduced by insulin. A 4-gene High-Throughput-Genomics assay was developed to concomitantly measure G6PC and pyruvate-dehydrogenase-kinase-4 (PDK4 mRNA levels. Using this assay, we screened an siRNA library containing pooled siRNA targeting 6650 druggable genes and identified 614 hits that lowered G6PC expression without increasing PDK4 mRNA levels. Pathway analysis indicated that siRNA-mediated knockdown (KD of genes known to positively or negatively affect insulin signaling increased or decreased G6PC mRNA expression, respectively, thus validating our screening platform. A subset of 270 primary screen hits was selected and 149 hits were confirmed by target gene KD by pooled siRNA and 7 single siRNA for each gene to reduce G6PC expression in 4-gene HTG assay. Subsequently, pooled siRNA KD of 113 genes decreased PEPCK and/or PGC1alpha mRNA expression thereby demonstrating their role in regulating key gluconeogenic genes in addition to G6PC. Last, KD of 61 of the above 113 genes potentiated insulin-stimulated Akt phosphorylation, suggesting that they suppress gluconeogenic gene by enhancing insulin signaling. CONCLUSIONS/SIGNIFICANCE: These results support the proposition that the proteins encoded by the genes identified in

Precise engineering of siRNA delivery vehicles to tumors using polyion complexes and gold nanoparticles.

Science.gov (United States)

Kim, Hyun Jin; Takemoto, Hiroyasu; Yi, Yu; Zheng, Meng; Maeda, Yoshinori; Chaya, Hiroyuki; Hayashi, Kotaro; Mi, Peng; Pittella, Frederico; Christie, R James; Toh, Kazuko; Matsumoto, Yu; Nishiyama, Nobuhiro; Miyata, Kanjiro; Kataoka, Kazunori

2014-09-23

For systemic delivery of siRNA to solid tumors, a size-regulated and reversibly stabilized nanoarchitecture was constructed by using a 20 kDa siRNA-loaded unimer polyion complex (uPIC) and 20 nm gold nanoparticle (AuNP). The uPIC was selectively prepared by charge-matched polyionic complexation of a poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) copolymer bearing ∼40 positive charges (and thiol group at the ω-end) with a single siRNA bearing 40 negative charges. The thiol group at the ω-end of PEG-PLL further enabled successful conjugation of the uPICs onto the single AuNP through coordinate bonding, generating a nanoarchitecture (uPIC-AuNP) with a size of 38 nm and a narrow size distribution. In contrast, mixing thiolated PEG-PLLs and AuNPs produced a large aggregate in the absence of siRNA, suggesting the essential role of the preformed uPIC in the formation of nanoarchitecture. The smart uPIC-AuNPs were stable in serum-containing media and more resistant against heparin-induced counter polyanion exchange, compared to uPICs alone. On the other hand, the treatment of uPIC-AuNPs with an intracellular concentration of glutathione substantially compromised their stability and triggered the release of siRNA, demonstrating the reversible stability of these nanoarchitectures relative to thiol exchange and negatively charged AuNP surface. The uPIC-AuNPs efficiently delivered siRNA into cultured cancer cells, facilitating significant sequence-specific gene silencing without cytotoxicity. Systemically administered uPIC-AuNPs showed appreciably longer blood circulation time compared to controls, i.e., bare AuNPs and uPICs, indicating that the conjugation of uPICs onto AuNP was crucial for enhancing blood circulation time. Finally, the uPIC-AuNPs efficiently accumulated in a subcutaneously inoculated luciferase-expressing cervical cancer (HeLa-Luc) model and achieved significant luciferase gene silencing in the tumor tissue. These results demonstrate the strong

Layer-by-layer nanoparticles as an efficient siRNA delivery vehicle for SPARC silencing.

Science.gov (United States)

Tan, Yang Fei; Mundargi, Raghavendra C; Chen, Min Hui Averil; Lessig, Jacqueline; Neu, Björn; Venkatraman, Subbu S; Wong, Tina T

2014-05-14

Efficient and safe delivery systems for siRNA therapeutics remain a challenge. Elevated secreted protein, acidic, and rich in cysteine (SPARC) protein expression is associated with tissue scarring and fibrosis. Here we investigate the feasibility of encapsulating SPARC-siRNA in the bilayers of layer-by-layer (LbL) nanoparticles (NPs) with poly(L-arginine) (ARG) and dextran (DXS) as polyelectrolytes. Cellular binding and uptake of LbL NPs as well as siRNA delivery were studied in FibroGRO cells. siGLO-siRNA and SPARC-siRNA were efficiently coated onto hydroxyapatite nanoparticles. The multilayered NPs were characterized with regard to particle size, zeta potential and surface morphology using dynamic light scattering and transmission electron microscopy. The SPARC-gene silencing and mRNA levels were analyzed using ChemiDOC western blot technique and RT-PCR. The multilayer SPARC-siRNA incorporated nanoparticles are about 200 nm in diameter and are efficiently internalized into FibroGRO cells. Their intracellular fate was also followed by tagging with suitable reporter siRNA as well as with lysotracker dye; confocal microscopy clearly indicates endosomal escape of the particles. Significant (60%) SPARC-gene knock down was achieved by using 0.4 pmole siRNA/μg of LbL NPs in FibroGRO cells and the relative expression of SPARC mRNA reduced significantly (60%) against untreated cells. The cytotoxicity as evaluated by xCelligence real-time cell proliferation and MTT cell assay, indicated that the SPARC-siRNA-loaded LbL NPs are non-toxic. In conclusion, the LbL NP system described provides a promising, safe and efficient delivery platform as a non-viral vector for siRNA delivery that uses biopolymers to enhance the gene knock down efficiency for the development of siRNA therapeutics. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Accounting costs of transactions in real estate

DEFF Research Database (Denmark)

Stubkjær, Erik

2005-01-01

in relating theoretical conceptualizations of transaction costs to national accounting and further to the identification and quantification of actions on units of real estate. The notion of satellite accounting of the System of National Accounts is applied to the segment of society concerned with changes......The costs of transactions in real estate is of importance for households, for investors, for statistical services, for governmental and international bodies concerned with the efficient delivery of basic state functions, as well as for research. The paper takes a multi-disciplinary approach...... in real estate. The paper ends up with an estimate of the cost of a major real property transaction in Denmark....

Enhancement of allele discrimination by introduction of nucleotide mismatches into siRNA in allele-specific gene silencing by RNAi.

Directory of Open Access Journals (Sweden)

Yusuke Ohnishi

Full Text Available Allele-specific gene silencing by RNA interference (RNAi is therapeutically useful for specifically inhibiting the expression of disease-associated alleles without suppressing the expression of corresponding wild-type alleles. To realize such allele-specific RNAi (ASP-RNAi, the design and assessment of small interfering RNA (siRNA duplexes conferring ASP-RNAi is vital; however, it is also difficult. In a previous study, we developed an assay system to assess ASP-RNAi with mutant and wild-type reporter alleles encoding the Photinus and Renilla luciferase genes. In line with experiments using the system, we realized that it is necessary and important to enhance allele discrimination between mutant and corresponding wild-type alleles. Here, we describe the improvement of ASP-RNAi against mutant alleles carrying single nucleotide variations by introducing base substitutions into siRNA sequences, where original variations are present in the central position. Artificially mismatched siRNAs or short-hairpin RNAs (shRNAs against mutant alleles of the human Prion Protein (PRNP gene, which appear to be associated with susceptibility to prion diseases, were examined using this assessment system. The data indicates that introduction of a one-base mismatch into the siRNAs and shRNAs was able to enhance discrimination between the mutant and wild-type alleles. Interestingly, the introduced mismatches that conferred marked improvement in ASP-RNAi, appeared to be largely present in the guide siRNA elements, corresponding to the 'seed region' of microRNAs. Due to the essential role of the 'seed region' of microRNAs in their association with target RNAs, it is conceivable that disruption of the base-pairing interactions in the corresponding seed region, as well as the central position (involved in cleavage of target RNAs, of guide siRNA elements could influence allele discrimination. In addition, we also suggest that nucleotide mismatches at the 3'-ends of sense

VOLTTRON Lite: Integration Platform for the Transactional Network

Energy Technology Data Exchange (ETDEWEB)

Haack, Jereme N.; Katipamula, Srinivas; Akyol, Bora A.; Lutes, Robert G.

2013-10-31

In FY13, Pacific Northwest National Laboratory (PNNL) with funding from the Department of Energy’s (DOE’s) Building Technologies Office (BTO) designed, prototyped and tested a transactional network platform. The platform is intended to support energy, operational and financial transactions between any networked entities (equipment, organizations, buildings, grid, etc.). Initially, in FY13, the concept demonstrated transactions between packaged rooftop units (RTUs) and the electric grid using applications or “agents” that reside on the platform, on the equipment, on local building controller or in the Cloud. This document describes the core of the transactional network platform, the Volttron Lite™ software and associated services hosted on the platform. Future enhancements are also discussed. The appendix of the document provides examples of how to use the various services hosted on the platform.

Transaction-Based Controls for Building-Grid Integration: VOLTTRON™

Energy Technology Data Exchange (ETDEWEB)

Akyol, Bora A.; Haack, Jereme N.; Hernandez, George; Katipamula, Srinivas; Widergren, Steven E.

2015-07-01

The U.S. Department of Energy’s (DOE’s) Building Technologies Office (BTO) is supporting the development of a “transactional network” concept that supports energy, operational, and financial transactions between building systems (e.g., rooftop units -- RTUs), and the electric power grid using applications, or 'agents', that reside either on the equipment, on local building controllers, or in the Cloud. The transactional network vision is delivered using a real-time, scalable reference platform called VOLTTRON that supports the needs of the changing energy system. VOLTTRON is an agent execution and an innovative distributed control and sensing software platform that supports modern control strategies, including agent-based and transaction-based controls. It enables mobile and stationary software agents to perform information gathering, processing, and control actions.

Transaction costs and social networks in productivity measurement

DEFF Research Database (Denmark)

Henningsen, Geraldine; Henningsen, Arne; Henning, Christian H. C. A.

2015-01-01

. Hence, both the absolute productivity measures and, more importantly, the productivity ranking will be distorted. A major driver of transaction costs is poor access to information and contract enforcement assistance. Social networks often catalyse information exchange as well as generate trust...... and support. Hence, we use measures of a firm’s access to social networks as a proxy for the transaction costs the firm faces. We develop a microeconomic production model that takes into account transaction costs and networks. Using a data set of 384 Polish farms, we empirically estimate this model...... and compare different parametric, semiparametric, and nonparametric model specifications. Our results generally support our hypothesis. Especially, large trading networks and dense household networks have a positive influence on a farm’s productivity. Furthermore, our results indicate that transaction costs...

Combating Corruption in International Business Transactions

OpenAIRE

Celentani, Marco; Ganuza, Juan-José; Peydró, José-Luis

2004-01-01

International business transactions pose the problem of deterring bribing of public officials by foreign firms. We first analyse a convention styled after the OECD's 'Convention on Combating Bribery of Foreign Public Officials in International Business Transactions', which requires signatory countries to proceed against firms that have bribed public officials of any foreign country. We then study the case in which the convention requires signatory countries to proceed against firms that have ...

Enrichment of intersubtype HIV-1 recombinants in a dual infection system using HIV-1 strain-specific siRNAs

Science.gov (United States)

2011-01-01

Background Intersubtype HIV-1 recombinants in the form of unique or stable circulating recombinants forms (CRFs) are responsible for over 20% of infections in the worldwide epidemic. Mechanisms controlling the generation, selection, and transmission of these intersubtype HIV-1 recombinants still require further investigation. All intersubtype HIV-1 recombinants are generated and evolve from initial dual infections, but are difficult to identify in the human population. In vitro studies provide the most practical system to study mechanisms, but the recombination rates are usually very low in dual infections with primary HIV-1 isolates. This study describes the use of HIV-1 isolate-specific siRNAs to enrich intersubtype HIV-1 recombinants and inhibit the parental HIV-1 isolates from a dual infection. Results Following a dual infection with subtype A and D primary HIV-1 isolates and two rounds of siRNA treatment, nearly 100% of replicative virus was resistant to a siRNA specific for an upstream target sequence in the subtype A envelope (env) gene as well as a siRNA specific for a downstream target sequence in the subtype D env gene. Only 20% (10/50) of the replicating virus had nucleotide substitutions in the siRNA-target sequence whereas the remaining 78% (39/50) harbored a recombination breakpoint that removed both siRNA target sequences, and rendered the intersubtype D/A recombinant virus resistant to the dual siRNA treatment. Since siRNAs target the newly transcribed HIV-1 mRNA, the siRNAs only enrich intersubtype env recombinants and do not influence the recombination process during reverse transcription. Using this system, a strong bias is selected for recombination breakpoints in the C2 region, whereas other HIV-1 env regions, most notably the hypervariable regions, were nearly devoid of intersubtype recombination breakpoints. Sequence conservation plays an important role in selecting for recombination breakpoints, but the lack of breakpoints in many conserved

Transaction costs and community-based natural resource management in Nepal.

Science.gov (United States)

Adhikari, Bhim; Lovett, Jon C

2006-01-01

Transaction costs in community-based resource management are incurred by households attempting to enforce property right rules over common resources similar to those inherent in private property rights. Despite their importance, transaction costs of community-based management of common pool resources (CPRs) are often not incorporated into the economic analysis of participatory resource management. This paper examines the transaction costs incurred by forest users in community forestry (CF) based on a survey of 309 households belonging to eight different forest user groups (FUGs) in the mid hills of Nepal. The analysis reveals that the average 'poor' household incurred Nepalese rupees (NRS) 1265 in transaction costs annually, while wealthier 'rich' households incurred an average of NRS 2312 per year. Although richer households bear higher proportions of such costs, transaction costs for CF management as a percentage of resource appropriation costs are higher for poorer households (26%) than those of middle-wealth (24%) or rich households (14%). There are also village differences in the level of transaction costs. The results show that transaction costs are a major component of resource management costs and vary according to socio-economic status of resource users and characteristics of the community.

Uncovering the Hidden Transaction Costs of Market Power

DEFF Research Database (Denmark)

Foss, Kirsten; Foss, Nicolai J.; Klein, Peter G.

2018-01-01

A central construct in competitive strategy research is market power, the ability to raise price above marginal cost. Positioning research focuses on attempts to build, protect, and exercise market power. However, this approach contains hidden assumptions about transaction costs. Parties made worse...... off by the exercise of market power can negotiate, bargain, form coalitions, and otherwise contract around the focal firm's attempts to appropriate monopoly profits—depending on transaction costs. We build on property rights economics to explain how transaction costs affect positioning and offer...

49 CFR 1180.2 - Types of transactions.

Science.gov (United States)

2010-10-01

.... Transactions proposed under 49 U.S.C. 11323 involving more than one common carrier by railroad are of four... review and approval of these transactions is not necessary to carry out the rail transportation policy of... renewal of trackage rights by a rail carrier over lines owned or operated by any other rail carrier or...

Electronic Business Transaction Infrastructure Analysis Using Petri Nets and Simulation

Science.gov (United States)

Feller, Andrew Lee

2010-01-01

Rapid growth in eBusiness has made industry and commerce increasingly dependent on the hardware and software infrastructure that enables high-volume transaction processing across the Internet. Large transaction volumes at major industrial-firm data centers rely on robust transaction protocols and adequately provisioned hardware capacity to ensure…

15 CFR 908.14 - Business to be transacted in writing.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Business to be transacted in writing... MAINTAINING RECORDS AND SUBMITTING REPORTS ON WEATHER MODIFICATION ACTIVITIES § 908.14 Business to be transacted in writing. All business transacted with the National Oceanic and Atmospheric Administration with...

Strategic R&D transactions in personalized drug development.

Science.gov (United States)

Makino, Tomohiro; Lim, Yeongjoo; Kodama, Kota

2018-03-21

Although external collaboration capability influences the development of personalized medicine, key transactions in the pharmaceutical industry have not been addressed. To explore specific trends in interorganizational transactions and key players, we longitudinally surveyed strategic transactions, comparing them with other advanced medical developments, such as antibody therapy, as controls. We found that the financing deals of start-ups have surged over the past decade, accelerating intellectual property (IP) creation. Our correlation and regression analyses identified determinants of financing deals among alliance deals, acquisition deals, patents, research and development (R&D) licenses, market licenses, and scientific papers. They showed that patents positively correlated with transactions, and that the number of R&D licenses significantly predicted financing deals. This indicates, for the first time, that start-ups and investors lead progress in personalized medicine. Copyright © 2018 Elsevier Ltd. All rights reserved.

Structure and Anonymity of the Bitcoin Transaction Graph

Directory of Open Access Journals (Sweden)

Kay Hamacher

2013-05-01

Full Text Available The Bitcoin network of decentralized payment transactions has attracted a lot of attention from both Internet users and researchers in recent years. Bitcoin utilizes a peer-to-peer network to issue anonymous payment transactions between different users. In the currently used Bitcoin clients, the full transaction history is available at each node of the network to prevent double spending without the need for a central authority, forming a valuable source for empirical research on network structure, network dynamics, and the implied anonymity challenges, as well as guidance on the future evolution of complex payment systems. We found dynamical effects of which some increase anonymity while others decrease it. Most importantly, several parameters of the Bitcoin transaction graph seem to have become stationary over the last 12–18 months. We discuss the implications.

Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery.

Science.gov (United States)

Wada, Shun-Ichi; Takesada, Anna; Nagamura, Yurie; Sogabe, Eri; Ohki, Rieko; Hayashi, Junsuke; Urata, Hidehito

2017-12-15

The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure-activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

NIR-to-visible upconversion nanoparticles for fluorescent labeling and targeted delivery of siRNA

International Nuclear Information System (INIS)

Jiang Shan; Zhang Yong; Lim, Kian Meng; Sim, Eugene K W; Ye Lei

2009-01-01

Near-infrared (NIR)-to-visible upconversion fluorescent nanoparticles were synthesized and used for imaging and targeted delivery of small interfering RNA (siRNA) to cancer cells. Silica-coated NaYF 4 upconversion nanoparticles (UCNs) co-doped with lanthanide ions (Yb/Er) were synthesized. Folic acid and anti-Her2 antibody conjugated UCNs were used to fluorescently label the folate receptors of HT-29 cells and Her2 receptors of SK-BR-3 cells, respectively. The intracellular uptake of the folic acid and antibody conjugated UCNs was visualized using a confocal fluorescence microscope equipped with an NIR laser. siRNA was attached to anti-Her2 antibody conjugated UCNs and the delivery of these nanoparticles to SK-BR-3 cells was studied. Meanwhile, a luciferase assay was established to confirm the gene silencing effect of siRNA. Upconversion nanoparticles can serve as a fluorescent probe and delivery system for simultaneous imaging and delivery of biological molecules.

NIR-to-visible upconversion nanoparticles for fluorescent labeling and targeted delivery of siRNA

Science.gov (United States)

Jiang, Shan; Zhang, Yong; Lim, Kian Meng; Sim, Eugene K. W.; Ye, Lei

2009-04-01

Near-infrared (NIR)-to-visible upconversion fluorescent nanoparticles were synthesized and used for imaging and targeted delivery of small interfering RNA (siRNA) to cancer cells. Silica-coated NaYF4 upconversion nanoparticles (UCNs) co-doped with lanthanide ions (Yb/Er) were synthesized. Folic acid and anti-Her2 antibody conjugated UCNs were used to fluorescently label the folate receptors of HT-29 cells and Her2 receptors of SK-BR-3 cells, respectively. The intracellular uptake of the folic acid and antibody conjugated UCNs was visualized using a confocal fluorescence microscope equipped with an NIR laser. siRNA was attached to anti-Her2 antibody conjugated UCNs and the delivery of these nanoparticles to SK-BR-3 cells was studied. Meanwhile, a luciferase assay was established to confirm the gene silencing effect of siRNA. Upconversion nanoparticles can serve as a fluorescent probe and delivery system for simultaneous imaging and delivery of biological molecules.

Real-Time Wait-Free Queues using Micro-Transactions

DEFF Research Database (Denmark)

Meawad, Fadi; Iyer, Karthik; Schoeberl, Martin

2011-01-01

This paper evaluates the applicability of transactional mem- ory to the implementation of dierent non-blocking data structures in the context of the Real-time Specication for Java. In particular, we argue that hardware support for micro-transaction allows us to implement eciently data structures...... that are often dicult to realize with the atomic operations provided by stock hardware. Our main imple- mentation platform is the Java Optimized Processor sys- tem. We report on the performance of data structures imple- mented with locks, compare and swap and micro-transactions. Our results conrm...

Construction and Biological Evaluation of a Novel Integrin ανβ3-Specific Carrier for Targeted siRNA Delivery In Vitro

Directory of Open Access Journals (Sweden)

Xueqi Chen

2017-02-01

Full Text Available (1 Background: The great potential of RNA interference (RNAi-based gene therapy is premised on the effective delivery of small interfering RNAs (siRNAs to target tissues and cells. Hence, we aimed at developing and examining a novel integrin αvβ3-specific delivery carrier for targeted transfection of siRNA to malignant tumor cells; (2 Methods: Arginine-glycine-aspartate motif (RGD was adopted as a tissue target for specific recognition of integrin αvβ3. To enable siRNA binding, a chimeric peptide was synthesized by adding nonamer arginine residues (9R at the carboxy terminus of cyclic-RGD dimer, designated as c(RGD2-9R. The efficiency of 9R peptide transferring siRNA was biologically evaluated in vitro by flow cytometry, confocal microscopy, and Western blot; (3 Results: An optimal 10:1 molar ratio of c(RGD2-9R to siRNA was confirmed by the electrophoresis on agarose gels. Both the flow cytometry and confocal microscopy results testified that transfection of c(RGD2-9R as an siRNA delivery carrier was obviously higher than the naked-siRNA group. The results of Western blot demonstrated that these 9R peptides were able to transduce siRNA to HepG2 cells in vitro, resulting in efficient gene silencing; and (4 Conclusion: The chimeric peptide of c(RGD2-9R can be developed as an effective siRNA delivery carrier and shows potential as a new strategy for RNAi-based gene therapy.

Transaction costs, externalities and information technology in health care.

Science.gov (United States)

Ferguson, B; Keen, J

1996-01-01

This paper discusses some of the economic issues which underpin the rationale for investment in information and communications technologies (ICTs). Information imperfections lead to significant transaction costs (search, negotiating and monitoring) which in turn confer a negative externality on parties involved in exchange. This divergence in private and social costs leads to a degree of resource misallocation (efficiency loss) which, uncorrected, results in a sub-optimal outcome. Traditional solutions to this problem are to rely upon direct government action to reduce the costs of transacting between market agents, or to employ tax/subsidy measures and other legislative action to achieve the desired market outcome. Three key policy questions are raised in the context of the NHS purchaser/provider relationship. Firstly, what is the optimum level of transaction costs; secondly, can ICTs assist in lowering the level of transaction costs to the optimum level; thirdly, who should bear the investment cost in reducing the level of transaction costs? The issue of property rights in different information systems is discussed and raises interesting policy questions about how much investment should be undertaken centrally rather than devolved to a more local level. In some ways this economic framework offers a post hoc justification of why different ICT systems have been introduced at various levels of the NHS. Essentially this reduces to the problem of externalities: providing good information confers a positive externality: not providing relevant, timely and accurate information confers a negative externality, by increasing further the level of transaction costs. The crucial role which ICT systems can play lies in attempting to reduce the level of transaction costs and driving the market towards what Dahlman has described as the transaction-cost-constrained equilibrium.

Aid Effectiveness, Transaction Costs and Conditionality in the Education Sector

Science.gov (United States)

Ashford, Richard; Biswas, Shampa

2010-01-01

The reduction of transaction costs is a commonly mentioned yet rarely elaborated goal for aid effectiveness in educational development. The casual use of the concept of transaction costs conceals which costs may be reduced, which costs are required and, indeed, what transaction costs actually are. Examining issues related to harmonizing the…

Two-Layer Transaction Management for Workflow Management Applications

NARCIS (Netherlands)

Grefen, P.W.P.J.; Vonk, J.; Boertjes, E.M.; Apers, Peter M.G.

Workflow management applications require advanced transaction management that is not offered by traditional database systems. For this reason, a number of extended transaction models has been proposed in the past. None of these models seems completely adequate, though, because workflow management

HIV-1 resistance conferred by siRNA cosuppression of CXCR4 and CCR5 coreceptors by a bispecific lentiviral vector

Directory of Open Access Journals (Sweden)

Akkina Ramesh

2005-01-01

Full Text Available Abstract Background RNA interference (RNAi mediated by small interfering RNAs (siRNAs has proved to be a highly effective gene silencing mechanism with great potential for HIV/AIDS gene therapy. Previous work with siRNAs against cellular coreceptors CXCR4 and CCR5 had shown that down regulation of these surface molecules could prevent HIV-1 entry and confer viral resistance. Since monospecific siRNAs targeting individual coreceptors are inadequate in protecting against both T cell tropic (X4 and monocyte tropic (R5 viral strains simultaneously, bispecific constructs with dual specificity are required. For effective long range therapy, the bispecific constructs need to be stably transduced into HIV-1 target cells via integrating viral vectors. Results To achieve this goal, lentiviral vectors incorporating both CXCR4 and CCR5 siRNAs of short hairpin design were constructed. The CXCR4 siRNA was driven by a U6 promoter whereas the CCR5 siRNA was driven by an H1 promoter. A CMV promoter driven EGFP reporter gene is also incorporated in the bispecific construct. High efficiency transduction into coreceptor expressing Magi and Ghost cell lines with a concomitant down regulation of respective coreceptors was achieved with lentiviral vectors. When the siRNA expressing transduced cells were challenged with X4 and R5 tropic HIV-1, they demonstrated marked viral resistance. HIV-1 resistance was also observed in bispecific lentiviral vector transduced primary PBMCs. Conclusions Both CXCR4 and CCR5 coreceptors could be simultaneously targeted for down regulation by a single combinatorial lentiviral vector incorporating respective anti-coreceptor siRNAs. Stable down regulation of both the coreceptors protects cells against infection by both X4 and R5 tropic HIV-1. Stable down regulation of cellular molecules that aid in HIV-1 infection will be an effective strategy for long range HIV gene therapy.

Pokemon siRNA Delivery Mediated by RGD-Modified HBV Core Protein Suppressed the Growth of Hepatocellular Carcinoma.

Science.gov (United States)

Kong, Jing; Liu, Xiaoping; Jia, Jianbo; Wu, Jinsheng; Wu, Ning; Chen, Jun; Fang, Fang

2015-10-01

Hepatocellular carcinoma (HCC) is a deadly human malignant tumor that is among the most common cancers in the world, especially in Asia. Hepatitis B virus (HBV) infection has been well established as a high risk factor for hepatic malignance. Studies have shown that Pokemon is a master oncogene for HCC growth, suggesting it as an ideal therapeutic target. However, efficient delivery system is still lacking for Pokemon targeting treatment. In this study, we used core proteins of HBV, which is modified with RGD peptides, to construct a biomimetic vector for the delivery of Pokemon siRNAs (namely, RGD-HBc-Pokemon siRNA). Quantitative PCR and Western blot assays revealed that RGD-HBc-Pokemon siRNA possessed the highest efficiency of Pokemon suppression in HCC cells. In vitro experiments further indicated that RGD-HBc-Pokemon-siRNA exerted a higher tumor suppressor activity on HCC cell lines, evidenced by reduced proliferation and attenuated invasiveness, than Pokemon-siRNA or RGD-HBc alone. Finally, animal studies demonstrated that RGD-HBc-Pokemon siRNA suppressed the growth of HCC xenografts in mice by a greater extent than Pokemon-siRNA or RGD-HBc alone. Based on the above results, Pokemon siRNA delivery mediated by RGD-modified HBV core protein was shown to be an effective strategy of HCC gene therapy.

Gene silencing of HPV16 E6/E7 induced by promoter-targeting siRNA in SiHa cells

OpenAIRE

Hong, D; Lu, W; Ye, F; Hu, Y; Xie, X

2009-01-01

Background: Recently, transcriptional gene silencing induced by small interfering RNA (siRNA) was found in mammalian and human cells. However, previous studies focused on endogenous genes. Methods: In this study, we designed siRNA targeting the promoter of human papillomavirus 16 E6/E7 and transfected it into the cervical cancer cell line, SiHa. E6 and E7 mRNA and protein expression were detected in cells treated by promoter-targeting siRNA. Futhermore, cellular growth, proliferation, apoptos...

Transaction based approach

Science.gov (United States)

Hunka, Frantisek; Matula, Jiri

2017-07-01

Transaction based approach is utilized in some methodologies in business process modeling. Essential parts of these transactions are human beings. The notion of agent or actor role is usually used for them. The paper on a particular example describes possibilities of Design Engineering Methodology for Organizations (DEMO) and Resource-Event-Agent (REA) methodology. Whereas the DEMO methodology can be regarded as a generic methodology having its foundation in the theory of Enterprise Ontology the REA methodology is regarded as the domain specific methodology and has its origin in accountancy systems. The results of these approaches is that the DEMO methodology captures everything that happens in the reality with a good empirical evidence whereas the REA methodology captures only changes connected with economic events. Economic events represent either change of the property rights to economic resource or consumption or production of economic resources. This results from the essence of economic events and their connection to economic resources.

Distributed Global Transaction Support for Workflow Management Applications

NARCIS (Netherlands)

Vonk, J.; Grefen, P.W.P.J.; Boertjes, E.M.; Apers, Peter M.G.

Workflow management systems require advanced transaction support to cope with their inherently long-running processes. The recent trend to distribute workflow executions requires an even more advanced transaction support system that is able to handle distribution. This paper presents a model as well

Commercial agencies and surrogate motherhood: a transaction cost approach.

Science.gov (United States)

Galbraith, Mhairi; McLachlan, Hugh V; Swales, J Kim

2005-03-01

In this paper we investigate the legal arrangements involved in UK surrogate motherhood from a transaction-cost perspective. We outline the specific forms the transaction costs take and critically comment on the way in which the UK institutional and organisational arrangements at present adversely influence transaction costs. We then focus specifically on the potential role of surrogacy agencies and look at UK and US evidence on commercial and voluntary agencies. Policy implications follow.

Transactive Control of Commercial Buildings for Demand Response

Energy Technology Data Exchange (ETDEWEB)

Hao, He; Corbin, Charles D.; Kalsi, Karanjit; Pratt, Robert G.

2017-01-01

Transactive control is a type of distributed control strategy that uses market mechanism to engage self-interested responsive loads to achieve power balance in the electrical power grid. In this paper, we propose a transactive control approach of commercial building Heating, Ventilation, and Air- Conditioning (HVAC) systems for demand response. We first describe the system models, and identify their model parameters using data collected from Systems Engineering Building (SEB) located on our Pacific Northwest National Laboratory (PNNL) campus. We next present a transactive control market structure for commercial building HVAC system, and describe its agent bidding and market clearing strategies. Several case studies are performed in a simulation environment using Building Control Virtual Test Bed (BCVTB) and calibrated SEB EnergyPlus model. We show that the proposed transactive control approach is very effective at peak clipping, load shifting, and strategic conservation for commercial building HVAC systems.

Ionospheric earthquake precursors

International Nuclear Information System (INIS)

Bulachenko, A.L.; Oraevskij, V.N.; Pokhotelov, O.A.; Sorokin, V.N.; Strakhov, V.N.; Chmyrev, V.M.

1996-01-01

Results of experimental study on ionospheric earthquake precursors, program development on processes in the earthquake focus and physical mechanisms of formation of various type precursors are considered. Composition of experimental cosmic system for earthquake precursors monitoring is determined. 36 refs., 5 figs

Third sector organizations in rural development: a transaction cost perspective

Directory of Open Access Journals (Sweden)

V. VALENTINOV

2008-12-01

Full Text Available In many parts of the world, rural development is supported by third sector organizations, such as nongovernmental organizations, farmer associations, and cooperatives. This essay develops a transaction cost explanation of these organizations’ role in rural areas. Since the traditional transaction cost theory is concerned with the choice of governance mechanisms within the for-profit sector, this essay adopts an alternative conceptualization of the notion of transaction cost by building on the theory of the division of labor. This theory regards transaction cost as a constraint on the division of labor causing the replacement of exchange with self-sufficiency. The proposed transaction cost explanation of rural third sector organizations consists of two arguments: 1 third sector organizations embody partial reliance on self-sufficiency; and 2 rural areas exhibit rurality-specific transaction cost acting as a constraint on the division of labor and thus creating a niche for third sector organizations. The essay concludes with suggesting a research program on developing an economic theory of the rural third sector.;

Decreases in Casz1 mRNA by an siRNA Complex Do not Alter Blood Pressure in Mice.

Science.gov (United States)

Ji, Su-Min; Shin, Young-Bin; Park, So-Yon; Lee, Hyeon-Ju; Oh, Bermseok

2012-03-01

Recent genomewide association studies of large samples have identified genes that are associated with blood pressure. The Global Blood Pressure Genetics (Global BPgen) and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortiums identified 14 loci that govern blood pressure on a genomewide significance level, one of which is CASZ1 confirmed in both Europeans and Asians. CASZ1 is a zinc finger transcription factor that controls apoptosis and cell fate and suppresses neuroblastoma tumor growth by reprogramming gene expression, like a tumor suppressor. To validate the function of CASZ1 in blood pressure, we decreased Casz1 mRNA levels in mice by siRNA. Casz1 siRNA reduced mRNA levels by 59% in a mouse cell line. A polyethylenimine-mixed siRNA complex was injected into mouse tail veins, reducing Casz1 mRNA expression to 45% in the kidney. However, blood pressure in the treated mice was unaffected, despite a 55% reduction in Casz1 mRNA levels in the kidney on multiple siRNA injections daily. Even though Casz1 siRNA-treated mice did not experience any significant change in blood pressure, our study demonstrates the value of in vivo siRNA injection in analyzing the function of candidate genes identified by genomewide association studies.

A framework for multiple kernel support vector regression and its applications to siRNA efficacy prediction.

Science.gov (United States)

Qiu, Shibin; Lane, Terran

2009-01-01

The cell defense mechanism of RNA interference has applications in gene function analysis and promising potentials in human disease therapy. To effectively silence a target gene, it is desirable to select appropriate initiator siRNA molecules having satisfactory silencing capabilities. Computational prediction for silencing efficacy of siRNAs can assist this screening process before using them in biological experiments. String kernel functions, which operate directly on the string objects representing siRNAs and target mRNAs, have been applied to support vector regression for the prediction and improved accuracy over numerical kernels in multidimensional vector spaces constructed from descriptors of siRNA design rules. To fully utilize information provided by string and numerical data, we propose to unify the two in a kernel feature space by devising a multiple kernel regression framework where a linear combination of the kernels is used. We formulate the multiple kernel learning into a quadratically constrained quadratic programming (QCQP) problem, which although yields global optimal solution, is computationally demanding and requires a commercial solver package. We further propose three heuristics based on the principle of kernel-target alignment and predictive accuracy. Empirical results demonstrate that multiple kernel regression can improve accuracy, decrease model complexity by reducing the number of support vectors, and speed up computational performance dramatically. In addition, multiple kernel regression evaluates the importance of constituent kernels, which for the siRNA efficacy prediction problem, compares the relative significance of the design rules. Finally, we give insights into the multiple kernel regression mechanism and point out possible extensions.

16 CFR 802.53 - Certain foreign banking transactions.

Science.gov (United States)

2010-01-01

... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Certain foreign banking transactions. 802.53 Section 802.53 Commercial Practices FEDERAL TRADE COMMISSION RULES, REGULATIONS, STATEMENTS AND... foreign banking transactions. An acquisition which requires the consent or approval of the Board of...

Inhibition of ABCB1 (MDR1 expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma.

Directory of Open Access Journals (Sweden)

Michiro Susa

2010-05-01

Full Text Available The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients' average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR after prolonged therapy.In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOS(R2 and U-2OS(R2 were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines.Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma.

Effects of traditional land transactions on soil erosion and land degradation

OpenAIRE

Leduka, R.C.

1998-01-01

A research report on the effects of traditional land transactions on soil erosion and land degradation in Lesotho. This report focuses on the land transactions in Lesotho and how these transaction affect the growing erosion rates of the soil.

Dicer-like 3 produces transposable element-associated 24-nt siRNAs that control agricultural traits in rice

Science.gov (United States)

Wei, Liya; Gu, Lianfeng; Song, Xianwei; Cui, Xiekui; Lu, Zhike; Zhou, Ming; Wang, Lulu; Hu, Fengyi; Zhai, Jixian; Meyers, Blake C.; Cao, Xiaofeng

2014-01-01

Transposable elements (TEs) and repetitive sequences make up over 35% of the rice (Oryza sativa) genome. The host regulates the activity of different TEs by different epigenetic mechanisms, including DNA methylation, histone H3K9 methylation, and histone H3K4 demethylation. TEs can also affect the expression of host genes. For example, miniature inverted repeat TEs (MITEs), dispersed high copy-number DNA TEs, can influence the expression of nearby genes. In plants, 24-nt small interfering RNAs (siRNAs) are mainly derived from repeats and TEs. However, the extent to which TEs, particularly MITEs associated with 24-nt siRNAs, affect gene expression remains elusive. Here, we show that the rice Dicer-like 3 homolog OsDCL3a is primarily responsible for 24-nt siRNA processing. Impairing OsDCL3a expression by RNA interference caused phenotypes affecting important agricultural traits; these phenotypes include dwarfism, larger flag leaf angle, and fewer secondary branches. We used small RNA deep sequencing to identify 535,054 24-nt siRNA clusters. Of these clusters, ∼82% were OsDCL3a-dependent and showed significant enrichment of MITEs. Reduction of OsDCL3a function reduced the 24-nt siRNAs predominantly from MITEs and elevated expression of nearby genes. OsDCL3a directly targets genes involved in gibberellin and brassinosteroid homeostasis; OsDCL3a deficiency may affect these genes, thus causing the phenotypes of dwarfism and enlarged flag leaf angle. Our work identifies OsDCL3a-dependent 24-nt siRNAs derived from MITEs as broadly functioning regulators for fine-tuning gene expression, which may reflect a conserved epigenetic mechanism in higher plants with genomes rich in dispersed repeats or TEs. PMID:24554078

Efficient delivery of Notch1 siRNA to SKOV3 cells by cationic cholesterol derivative-based liposome

Directory of Open Access Journals (Sweden)

Zhao Y

2016-10-01

Full Text Available Yun-Chun Zhao,1 Li Zhang,2 Shi-Sen Feng,3 Lu Hong,3 Hai-Li Zheng,3 Li-Li Chen,4 Xiao-Ling Zheng,1 Yi-Qing Ye,1 Meng-Dan Zhao,1 Wen-Xi Wang,3 Cai-Hong Zheng1 1Pharmacy Department, Women’s Hospital, 2Pharmacy Department, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Pharmaceutic Preparation, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 4Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China Abstract: A novel cationic cholesterol derivative-based small interfering RNA (siRNA interference strategy was suggested to inhibit Notch1 activation in SKOV3 cells for the gene therapy of ovarian cancer. The cationic cholesterol derivative, N-(cholesterylhemisuccinoyl-amino-3-propyl-N, N-dimethylamine (DMAPA-chems liposome, was incubated with siRNA at different nitrogen-to-phosphate ratios to form stabilized, near-spherical siRNA/DMAPA-chems nanoparticles with sizes of 100–200 nm and zeta potentials of 40–50 mV. The siRNA/DMAPA-chems nanoparticles protected siRNA from nuclease degradation in 25% fetal bovine serum. The nanoparticles exhibited high cell uptake and Notch1 gene knockdown efficiency in SKOV3 cells at an nitrogen-to-phosphate ratio of 100 and an siRNA concentration of 50 nM. They also inhibited the growth and promoted the apoptosis of SKOV3 cells. These results may provide the potential for using cationic cholesterol derivatives as efficient nonviral siRNA carriers for the suppression of Notch1 activation in ovarian cancer cells. Keywords: siRNA, cationic cholesterol derivative, Notch1, ovarian cancer cells

Repression of multiple CYP2D genes in mouse primary hepatocytes with a single siRNA construct.

Science.gov (United States)

Elraghy, Omaima; Baldwin, William S

2015-01-01

The Cyp2d subfamily is the second most abun-dant subfamily of hepatic drug-metabolizing CYPs. In mice, there are nine Cyp2d members that are believed to have redundant catalytic activity. We are testing and optimizing the ability of one short interfering RNA (siRNA) construct to knockdown the expression of multiple mouse Cyp2ds in primary hepatocytes. Expression of Cyp2d10, Cyp2d11, Cyp2d22, and Cyp2d26 was observed in the primary male mouse hepatocytes. Cyp2d9, which is male-specific and growth hormone-dependent, was not expressed in male primary hepatocytes, potentially because of its dependence on pulsatile growth hormone release from the anterior pituitary. Several different siRNAs at different concentrations and with different reagents were used to knockdown Cyp2d expression. siRNA constructs designed to repress only one construct often mildly repressed several Cyp2d isoforms. A construct designed to knockdown every Cyp2d isoform provided the best results, especially when incubated with transfection reagents designed specifically for primary cell culture. Interestingly, a construct designed to knockdown all Cyp2d isoforms, except Cyp2d10, caused a 2.5× increase in Cyp2d10 expression, presumably because of a compensatory response. However, while RNA expression is repressed 24 h after siRNA treatment, associated changes in Cyp2d-mediated metabolism are tenuous. Overall, this study provides data on the expression of murine Cyp2ds in primary cell lines, valuable information on designing siRNAs for silencing multiple murine CYPs, and potential pros and cons of using siRNA as a tool for repressing Cyp2d and estimating Cyp2d's role in murine xenobiotic metabolism.

Utilization of unlocked nucleic acid (UNA) to enhance siRNA performance in vitro and in vivo

DEFF Research Database (Denmark)

Laursen, Maria B; Pakula, Malgorzata M; Gao, Shan

2010-01-01

Small interfering RNAs (siRNAs) are now established as a favourite tool to reduce gene expression by RNA interference (RNAi) in mammalian cell culture. However, limitations in potency, duration, delivery and specificity of the gene knockdown (KD) are still major obstacles that need further addres...... in a xenograft model of human pancreas cancer. Hereby UNA constitutes an important type of chemical modification for future siRNA designs....

The Abstract Machine Model for Transaction-based System Control

Energy Technology Data Exchange (ETDEWEB)

Chassin, David P.

2003-01-31

Recent work applying statistical mechanics to economic modeling has demonstrated the effectiveness of using thermodynamic theory to address the complexities of large scale economic systems. Transaction-based control systems depend on the conjecture that when control of thermodynamic systems is based on price-mediated strategies (e.g., auctions, markets), the optimal allocation of resources in a market-based control system results in an emergent optimal control of the thermodynamic system. This paper proposes an abstract machine model as the necessary precursor for demonstrating this conjecture and establishes the dynamic laws as the basis for a special theory of emergence applied to the global behavior and control of complex adaptive systems. The abstract machine in a large system amounts to the analog of a particle in thermodynamic theory. The permit the establishment of a theory dynamic control of complex system behavior based on statistical mechanics. Thus we may be better able to engineer a few simple control laws for a very small number of devices types, which when deployed in very large numbers and operated as a system of many interacting markets yields the stable and optimal control of the thermodynamic system.

Medium-term load forecasting and wholesale transaction profitability

International Nuclear Information System (INIS)

Selker, F.K.; Wroblewski, W.R.

1996-01-01

The volume of wholesale transactions quoted at firm prices is increasing. The cost, and thus profitability, of serving these contracts strongly depends upon native load during the time of delivery. However, transactions extend beyond load forecasts based on weather information, and long-term resource planning forecasts of load peaks and energy provide inadequate detail. To address this need, Decision Focus Inc. (DFI) and Commonwealth Edison (ComEd) developed a probabilistic, medium-term load forecasting capability. In this paper the authors use a hypothetical utility to explore the impact of uncertain medium-term loads on transaction profitability

New Evidence of the Effect of Transaction Costs on Residential Mobility

NARCIS (Netherlands)

Ommeren, van Jos; Leuvensteijn, van Michiel

2002-01-01

Transaction costs have attracted considerably attention in the theoretical literature on residential mobility. In many European countries, these costs mainly consist of ad-valorem transaction costs. In the current paper, we demonstrate empirically for the Netherlands that the transaction costs have

Challenges facing transactional e-government systems

OpenAIRE

AI-Sebie, Madi M

2005-01-01

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University, 17/10/2005. A review of normative literature, in the field of e-government, indicates that the transactional stage of e-government is one of the most important to the implementation of an e-government system as it represents the highest level of interaction within organisations and between customers and government organisations. Due to the importance of the transactional stage of the e-govern...

Viral RNAi suppressor reversibly binds siRNA to outcompete Dicer and RISC via multiple turnover.

Science.gov (United States)

Rawlings, Renata A; Krishnan, Vishalakshi; Walter, Nils G

2011-04-29

RNA interference is a conserved gene regulatory mechanism employed by most eukaryotes as a key component of their innate immune response to viruses and retrotransposons. During viral infection, the RNase-III-type endonuclease Dicer cleaves viral double-stranded RNA into small interfering RNAs (siRNAs) 21-24 nucleotides in length and helps load them into the RNA-induced silencing complex (RISC) to guide the cleavage of complementary viral RNA. As a countermeasure, many viruses have evolved viral RNA silencing suppressors (RSS) that tightly, and presumably quantitatively, bind siRNAs to thwart RNA-interference-mediated degradation. Viral RSS proteins also act across kingdoms as potential immunosuppressors in gene therapeutic applications. Here we report fluorescence quenching and electrophoretic mobility shift assays that probe siRNA binding by the dimeric RSS p19 from Carnation Italian Ringspot Virus, as well as by human Dicer and RISC assembly complexes. We find that the siRNA:p19 interaction is readily reversible, characterized by rapid binding [(1.69 ± 0.07) × 10(8) M(-)(1) s(-1)] and marked dissociation (k(off)=0.062 ± 0.002 s(-1)). We also observe that p19 efficiently competes with recombinant Dicer and inhibits the formation of RISC-related assembly complexes found in human cell extract. Computational modeling based on these results provides evidence for the transient formation of a ternary complex between siRNA, human Dicer, and p19. An expanded model of RNA silencing indicates that multiple turnover by reversible binding of siRNAs potentiates the efficiency of the suppressor protein. Our predictive model is expected to be applicable to the dosing of p19 as a silencing suppressor in viral gene therapy. Copyright © 2011 Elsevier Ltd. All rights reserved.

Viral RNAi suppressor reversibly binds siRNA to outcompete Dicer and RISC via multiple-turnover

Science.gov (United States)

Rawlings, Renata A.; Krishnan, Vishalakshi; Walter, Nils G.

2011-01-01

RNA interference (RNAi) is a conserved gene regulatory mechanism employed by most eukaryotes as a key component of their innate immune response against viruses and retrotransposons. During viral infection, the RNase III-type endonuclease Dicer cleaves viral double-stranded RNA into small interfering RNAs (siRNAs), 21–24 nucleotides in length, and helps load them into the RNA-induced silencing complex (RISC) to guide cleavage of complementary viral RNA. As a countermeasure, many viruses have evolved viral RNA silencing suppressor (RSS) proteins that tightly, and presumably quantitatively, bind siRNAs to thwart RNAi-mediated degradation. Viral RSS proteins also act across kingdoms as potential immunosuppressors in gene therapeutic applications. Here we report fluorescence quenching and electrophoretic mobility shift assays that probe siRNA binding by the dimeric RSS p19 from Carnation Italian Ringspot Virus (CIRV), as well as by human Dicer and RISC assembly complexes. We find that the siRNA:p19 interaction is readily reversible, characterized by rapid binding ((1.69 ± 0.07)×108 M−1s−1) and marked dissociation (koff = 0.062 ± 0.002 s−1). We also observe that p19 efficiently competes with recombinant Dicer and inhibits formation of RISC-related assembly complexes found in human cell extract. Computational modeling based on these results provides evidence for the transient formation of a ternary complex between siRNA, human Dicer, and p19. An expanded model of RNA silencing indicates that multiple-turnover by reversible binding of siRNAs potentiates the efficiency of the suppressor protein. Our predictive model is expected to be applicable to the dosing of p19 as a silencing suppressor in viral gene therapy. PMID:21354178

Environmental taxes and transaction costs

Energy Technology Data Exchange (ETDEWEB)

Vollebergh, Herman R.J. [Centre for Economic Policy OCFEB, Erasmus University Rotterdam (Netherlands)

1994-06-01

A well-known tax policy principle in the case of environmental bads holds that optimality would apply to a special class of environmental taxes, the so called Pigovian or effluent taxes (or fees or charges). However, an interesting paradox arises here for effluent taxes are seldom chosen in practical policies by governments. An explanation for this discrepancy is that effluent taxes are generally supposed to bring about the highest amount of transaction costs in order to enforce this kind of tax. This would be caused by the fact that usually large numbers of agents are involved if effluents are taken as the principal tax base. Unfortunately this explanation seems to boomerang for it brings about an impossibility result: effluent taxes can never be first best taxes if transaction costs are allowed. Up till now theoretical economics has not paid much attention to this problem. In contrast this essay offers an explanation for the discrepancy and it shows why the impossibility theorem is a paradox. As soon as one allows for transaction costs in welfare analysis, one not only has to acknowledge that such costs are attached to the internalization device but also to the initial status quo. Moreover, the amount of transaction costs is not independent of the tax contracts themselves, neither are the benefits of regulation through taxation. Accordingly a more general welfare assessment of questions where it is optimal to levy environmental taxes shows that first best Pigovian taxes need not be effluent taxes (even if abatement is possible), although in some cases effluent taxes might still be the best policy option from an economic perspective. 31 refs.

Environmental taxes and transaction costs

International Nuclear Information System (INIS)

Vollebergh, Herman R.J.

1994-06-01

A well-known tax policy principle in the case of environmental bads holds that optimality would apply to a special class of environmental taxes, the so called Pigovian or effluent taxes (or fees or charges). However, an interesting paradox arises here for effluent taxes are seldom chosen in practical policies by governments. An explanation for this discrepancy is that effluent taxes are generally supposed to bring about the highest amount of transaction costs in order to enforce this kind of tax. This would be caused by the fact that usually large numbers of agents are involved if effluents are taken as the principal tax base. Unfortunately this explanation seems to boomerang for it brings about an impossibility result: effluent taxes can never be first best taxes if transaction costs are allowed. Up till now theoretical economics has not paid much attention to this problem. In contrast this essay offers an explanation for the discrepancy and it shows why the impossibility theorem is a paradox. As soon as one allows for transaction costs in welfare analysis, one not only has to acknowledge that such costs are attached to the internalization device but also to the initial status quo. Moreover, the amount of transaction costs is not independent of the tax contracts themselves, neither are the benefits of regulation through taxation. Accordingly a more general welfare assessment of questions where it is optimal to levy environmental taxes shows that first best Pigovian taxes need not be effluent taxes (even if abatement is possible), although in some cases effluent taxes might still be the best policy option from an economic perspective. 31 refs

17 CFR 33.3 - Unlawful commodity option transactions.

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Unlawful commodity option... REGULATION OF DOMESTIC EXCHANGE-TRADED COMMODITY OPTION TRANSACTIONS § 33.3 Unlawful commodity option... of, or maintain a position in, any commodity option transaction subject to the provisions of this...

Enhancing reliable online transaction with intelligent rule-based ...

African Journals Online (AJOL)

Enhancing reliable online transaction with intelligent rule-based fraud detection technique. ... These are with a bid to reducing amongst other things the cost of production and also dissuade the poor handling of Nigeria currency. The CBN pronouncement has necessitated the upsurge in transactions completed with credit ...

Allocation and management issues in multiple-transaction open access transmission networks

Science.gov (United States)

Tao, Shu

This thesis focuses on some key issues related to allocation and management by the independent grid operator (IGO) of unbundled services in multiple-transaction open access transmission networks. The three unbundled services addressed in the thesis are transmission real power losses, reactive power support requirements from generation sources, and transmission congestion management. We develop the general framework that explicitly represents multiple transactions undertaken simultaneously in the transmission grid. This framework serves as the basis for formulating various problems treated in the thesis. We use this comprehensive framework to develop a physical-flow-based mechanism to allocate the total transmission losses to each transaction using the system. An important property of the allocation scheme is its capability to effectively deal with counter flows that result in the presence of specific transactions. Using the loss allocation results as the basis, we construct the equivalent loss compensation concept and apply it to develop flexible and effective procedures for compensating losses in multiple-transaction networks. We present a new physical-flow-based mechanism for allocating the reactive power support requirements provided by generators in multiple-transaction networks. The allocatable reactive support requirements are formulated as the sum of two specific components---the voltage magnitude variation component and the voltage angle variation component. The formulation utilizes the multiple-transaction framework and makes use of certain simplifying approximations. The formulation leads to a natural allocation as a function of the amount of each transaction. The physical interpretation of each allocation as a sensitivity of the reactive output of a generator is discussed. We propose a congestion management allocation scheme for multiple-transaction networks. The proposed scheme determines the allocation of congestion among the transactions on a physical

The transaction management perspective on procurement in the era of globalization

NARCIS (Netherlands)

den Butter, F.A.G.

2012-01-01

Fragmentation of production into more and more complex supply chains is a prominent feature of globalisation. Transaction management purports to minimise the transaction costs associated with this fragmentation of production. In this era of globalisation, transaction costs carry a large weight in

31 CFR 103.25 - Reports of transactions with foreign financial agencies.

Science.gov (United States)

2010-07-01

... Finance FINANCIAL RECORDKEEPING AND REPORTING OF CURRENCY AND FOREIGN TRANSACTIONS Reports Required To Be Made § 103.25 Reports of transactions with foreign financial agencies. (a) Promulgation of reporting... financial institutions to file reports of certain transactions with designated foreign financial agencies...

Marketable pollution permits with uncertainty and transaction costs

International Nuclear Information System (INIS)

Montero, Juan-Pablo

1998-01-01

Increasing interest in the use of marketable permits for pollution control has become evident in recent years. Concern regarding their performance still remains because empirical evidence has shown transaction costs and uncertainty to be significant in past and existing marketable permits programs. In this paper we develop theoretical and numerical models that include transaction costs and uncertainty (in trade approval) to show their effects on market performance (i.e., equilibrium price of permits and trading volume) and aggregate control costs. We also show that in the presence of transaction costs and uncertainty the initial allocation of permits may not be neutral in terms of efficiency. Furthermore, using a numerical model for a hypothetical NO x trading program in which participants have discrete control technology choices, we find that aggregate control costs and the equilibrium price of permits are sensitive to the initial allocation of permits, even for constant marginal transaction costs and certainty

Proving Opacity of Transactional Memory with Early Release

Directory of Open Access Journals (Sweden)

Siek Konrad

2015-12-01

Full Text Available Transactional Memory (TM is an alternative way of synchronizing concurrent accesses to shared memory by adopting the abstraction of transactions in place of low-level mechanisms like locks and barriers. TMs usually apply optimistic concurrency control to provide a universal and easy-to-use method of maintaining correctness. However, this approach performs a high number of aborts in high contention workloads, which can adversely affect performance. Optimistic TMs can cause problems when transactions contain irrevocable operations. Hence, pessimistic TMs were proposed to solve some of these problems. However, an important way of achieving efficiency in pessimistic TMs is to use early release. On the other hand, early release is seemingly at odds with opacity, the gold standard of TM safety properties, which does not allow transactions to make their state visible until they commit. In this paper we propose a proof technique that makes it possible to demonstrate that a TM with early release can be opaque as long as it prevents inconsistent views.

Transactional Infrastructure of the Economy: the Evolution of Concepts and Synthesis of Definitions

Directory of Open Access Journals (Sweden)

Maruschak Irina Valeryevna

2017-03-01

Full Text Available The overview of evolution of market infrastructure concepts is provided, the first concepts of institutional infrastructure are revealed in the paper. Evolutionarily developed narrowing of essence of infrastructure in connection with the priority analysis of its physical (material and technological components is proved. It ignores the fact that transactional resources, being drivers (driving forces of economic systems evolution, in turn evolve, becoming harder and harder, combining increase in efficiency of the elements and strengthening of heterogeneity and discrepancy of their structure. Transactional evolution of economy in general and evolution of separate transactional resources of production are the perspective directions of the special analysis. Transactional infrastructure is considered as the integrated complex of institutional, organizational (relational and information infrastructures. The problems of the first concepts of transactional infrastructure connected with difficulties of differentiation of its subsystems always operating jointly are revealed. Prospect of transition from the isolated analysis of separate resources of transactional type (institutes, organizations, information, social capital, trust, etc. to studying corresponding specific software infrastructures and to the system analysis of integrated transactional infrastructure of economy are argued. The transactional sector (as set of the specialized industries and the appropriate collective and individual subjects providing with resources market transaction is offered to be considered as transactional structure of economy. Transactional infrastructure is treated as critically significant factor of economic evolution which in the conditions of post-industrial type of economy gradually purchases transactional nature.

Transactional Sex among Noninjecting Illicit Drug Users: Implications for HIV Transmission

Directory of Open Access Journals (Sweden)

Rafael Alves Guimarães

2016-01-01

Full Text Available Noninjecting illicit drug users (NIDUs present high risk for HIV infection, due especially to transactional sex. This study aimed to estimate the prevalence and risk factors for transactional sex among NIDUs in the Southwest region of Goiás State, Central Brazil. The prevalence of self-reported transactional sex was 22.8%. Prevalence in women and men was 52.7% and 16.8%, respectively, a significant difference (p<0.001. Crack use and history of sexually transmitted infections (STI were risk factors for transactional sex in men. Homelessness, crack use, sex under the influence of drugs, and history of sexual violence were risk factors for transactional sex in women. A high prevalence of transactional sex was observed among NIDUs. This risk behavior may contribute to the high rates of HIV among this population and their social networks and in the general population.

The eukaryotic translation elongation factor eEF1A2 induces neoplastic properties and mediates tumorigenic effects of ZNF217 in precursor cells of human ovarian carcinomas

Energy Technology Data Exchange (ETDEWEB)

Sun, Yu; Wong, Nicholas; Guan, Yinghui; Salamanca, Clara M.; Cheng, Jung Chien; Lee, Jonathan M.; Gray, Joe W.; Auersperg, Nelly

2008-04-25

Ovarian epithelial carcinomas (OEC) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In this study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities, and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression.

Measuring the Influence of Networks on Transaction Costs Using a Nonparametric Regression Technique

DEFF Research Database (Denmark)

Henningsen, Geraldine; Henningsen, Arne; Henning, Christian H.C.A.

All business transactions as well as achieving innovations take up resources, subsumed under the concept of transaction costs. One of the major factors in transaction costs theory is information. Firm networks can catalyse the interpersonal information exchange and hence, increase the access to non......-public information so that transaction costs are reduced.Many resources that are sacrificed for transaction costs are inputs that also enter the technical production process. As most production data do not distinguish between these two usages of inputs, high transaction costs result in reduced observed productivity...

Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers

Directory of Open Access Journals (Sweden)

Md. Emranul Karim

2018-05-01

Full Text Available RNA Interference (RNAi has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made to establish catalytic RNA as a new class of biologics for cancer management, a lot of extracellular and intracellular barriers still pose a long-lasting challenge on the way to clinical approval. A series of chemically suitable, safe and effective viral and non-viral carriers have emerged to overcome physiological barriers and ensure targeted delivery of RNAi. The newly invented carriers, delivery techniques and gene editing technology made current treatment protocols stronger to fight cancer. This review has provided a platform about the chronicle of siRNA development and challenges of RNAi therapeutics for laboratory to bedside translation focusing on recent advancement in siRNA delivery vehicles with their limitations. Furthermore, an overview of several animal model studies of siRNA- or shRNA-based cancer gene therapy over the past 15 years has been presented, highlighting the roles of genes in multiple cancers, pharmacokinetic parameters and critical evaluation. The review concludes with a future direction for the development of catalytic RNA vehicles and design strategies to make RNAi-based cancer gene therapy more promising to surmount cancer gene delivery challenges.

Comparing 2-nt 3' overhangs against blunt-ended siRNAs: a systems biology based study.

Science.gov (United States)

Ghosh, Preetam; Dullea, Robert; Fischer, James E; Turi, Tom G; Sarver, Ronald W; Zhang, Chaoyang; Basu, Kalyan; Das, Sajal K; Poland, Bradley W

2009-07-07

In this study, we formulate a computational reaction model following a chemical kinetic theory approach to predict the binding rate constant for the siRNA-RISC complex formation reaction. The model allowed us to study the potency difference between 2-nt 3' overhangs against blunt-ended siRNA molecules in an RNA interference (RNAi) system. The rate constant predicted by this model was fed into a stochastic simulation of the RNAi system (using the Gillespie stochastic simulator) to study the overall potency effect. We observed that the stochasticity in the transcription/translation machinery has no observable effects in the RNAi pathway. Sustained gene silencing using siRNAs can be achieved only if there is a way to replenish the dsRNA molecules in the cell. Initial findings show about 1.5 times more blunt-ended molecules will be required to keep the mRNA at the same reduced level compared to the 2-nt overhang siRNAs. However, the mRNA levels jump back to saturation after a longer time when blunt-ended siRNAs are used. We found that the siRNA-RISC complex formation reaction rate was 2 times slower when blunt-ended molecules were used pointing to the fact that the presence of the 2-nt overhangs has a greater effect on the reaction in which the bound RISC complex cleaves the mRNA.

A surface-mediated siRNA delivery system developed with chitosan/hyaluronic acid-siRNA multilayer films through layer-by-layer self-assembly

Energy Technology Data Exchange (ETDEWEB)

Wu, Lijuan [Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai 200062 (China); Suzhou Novovita Bio-products Co., Ltd., Suzhou 215300 (China); Wu, Changlin, E-mail: Ph.Dclwu1314@sina.cn [Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai 200062 (China); Suzhou Novovita Bio-products Co., Ltd., Suzhou 215300 (China); Liu, Guangwan [Suzhou Novovita Bio-products Co., Ltd., Suzhou 215300 (China); Liao, Nannan [Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai 200062 (China); Suzhou Novovita Bio-products Co., Ltd., Suzhou 215300 (China); Zhao, Fang; Yang, Xuxia; Qu, Hongyuan [Suzhou Novovita Bio-products Co., Ltd., Suzhou 215300 (China); Peng, Bo [Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai 200062 (China); Chen, Li [Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai 200062 (China); Suzhou Novovita Bio-products Co., Ltd., Suzhou 215300 (China); Yang, Guang [Shanghai Key Laboratory of Magnetic Resonance, East China Normal University, Shanghai 200062 (China)

2016-12-15

Highlights: • We prepared Chitosan/Hyaluronic acid-siRNA multilayer as carrier to effectively load and protect siRNAs. • The stability and integrity of the siRNA was verified in the siRNA-loaded films. • The siRNA-loaded films showed good cells adhesion and gene silencing effect in eGFP-HEK 293T cells. • This is a new type of surface-mediated non-viral multilayer films. - Abstract: siRNA delivery remains highly challenging because of its hydrophilic and anionic nature and its sensitivity to nuclease degradation. Effective siRNA loading and improved transfection efficiency into cells represents a key problem. In our study, we prepared Chitosan/Hyaluronic acid-siRNA multilayer films through layer-by-layer self-assembly, in which siRNAs can be effectively loaded and protected. The construction process was characterized by FTIR, {sup 13}C NMR (CP/MAS), UV–vis spectroscopy, and atomic force microscopy (AFM). We presented the controlled-release performance of the films during incubation in 1 M NaCl solution for several days through UV–vis spectroscopy and polyacrylamide gel electrophoresis (PAGE). Additionally, we verified the stability and integrity of the siRNA loaded on multilayer films. Finally, the biological efficacy of the siRNA delivery system was evaluated via cells adhesion and gene silencing analyses in eGFP-HEK 293T cells. This new type of surface-mediated non-viral multilayer films may have considerable potential in the localized and controlled-release delivery of siRNA in mucosal tissues, and tissue engineering application.

Transactional Sex among Noninjecting Illicit Drug Users: Implications for HIV Transmission.

Science.gov (United States)

Guimarães, Rafael Alves; Rodovalho, Aurélio Goulart; Fernandes, Inaina Lara; Silva, Graciele Cristina; de Felipe, Rodrigo Lopes; Vera, Ivânia; Gregório, Valéria Duarte; Lucchese, Roselma

2016-01-01

Noninjecting illicit drug users (NIDUs) present high risk for HIV infection, due especially to transactional sex. This study aimed to estimate the prevalence and risk factors for transactional sex among NIDUs in the Southwest region of Goiás State, Central Brazil. The prevalence of self-reported transactional sex was 22.8%. Prevalence in women and men was 52.7% and 16.8%, respectively, a significant difference (p drugs, and history of sexual violence were risk factors for transactional sex in women. A high prevalence of transactional sex was observed among NIDUs. This risk behavior may contribute to the high rates of HIV among this population and their social networks and in the general population.

Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA.

Science.gov (United States)

Zhang, Haiyang; Wang, Yi; Bai, Ming; Wang, Junyi; Zhu, Kegan; Liu, Rui; Ge, Shaohua; Li, JiaLu; Ning, Tao; Deng, Ting; Fan, Qian; Li, Hongli; Sun, Wu; Ying, Guoguang; Ba, Yi

2018-03-01

Exosomes derived from cells have been found to mediate signal transduction between cells and to act as efficient carriers to deliver drugs and small RNA. Hepatocyte growth factor (HGF) is known to promote the growth of both cancer cells and vascular cells, and the HGF-cMET pathway is a potential clinical target. Here, we characterized the inhibitory effect of HGF siRNA on tumor growth and angiogenesis in gastric cancer. In addition, we showed that HGF siRNA packed in exosomes can be transported into cancer cells, where it dramatically downregulates HGF expression. A cell co-culture model was used to show that exosomes loaded with HGF siRNA suppress proliferation and migration of both cancer cells and vascular cells. Moreover, exosomes were able to transfer HGF siRNA in vivo, decreasing the growth rates of tumors and blood vessels. The results of our study demonstrate that exosomes have potential for use in targeted cancer therapy by delivering siRNA. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

17 CFR 32.3 - Unlawful commodity option transactions.

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Unlawful commodity option... REGULATION OF COMMODITY OPTION TRANSACTIONS § 32.3 Unlawful commodity option transactions. (a) On and after... extend credit in lieu thereof) from an option customer as payment of the purchase price in connection...

12 CFR 370.4 - Transaction Account Guarantee Program.

Science.gov (United States)

2010-01-01

... GENERAL POLICY TEMPORARY LIQUIDITY GUARANTEE PROGRAM § 370.4 Transaction Account Guarantee Program. (a) In addition to the coverage afforded to depositors under 12 CFR Part 330, a depositor's funds in a noninterest... determining whether funds are in a noninterest-bearing transaction account for purposes of this section, the...

2008 Annual Report of SGCC on Electricity Market Transactions

Institute of Scientific and Technical Information of China (English)

无

2009-01-01

On April 14,2009,the State Grid Corporation of China (SGCC) held the press conference in Beijing on electricity market transactions and then released the "2008 Annual Report of SGCC on Electricity Market Transactions".

The Econometric Procedures of Specific Transaction Identification

Directory of Open Access Journals (Sweden)

Doszyń Mariusz

2017-06-01

Full Text Available The paper presents the econometric procedures of identifying specific transactions, in which atypical conditions or attributes may occur. These procedures are based on studentized and predictive residuals of the accordingly specified econometric models. The dependent variable is a unit transactional price, and explanatory variables are both the real properties’ attributes and accordingly defined artificial binary variables. The utility of the proposed method has been verified by means of a real market data base. The proposed procedures can be helpful during the property valuation process, making it possible to reject real properties that are specific (both from the point of view of the transaction conditions and the properties’ attributes and, consequently, to select an appropriate set of similar attributes that are essential for the valuation process.

General method for labeling siRNA by click chemistry with fluorine-18 for the purpose of PET imaging.

Science.gov (United States)

Mercier, Frédéric; Paris, Jérôme; Kaisin, Geoffroy; Thonon, David; Flagothier, Jessica; Teller, Nathalie; Lemaire, Christian; Luxen, André

2011-01-19

The alkyne-azide Cu(I)-catalyzed Huisgen cycloaddition, a click-type reaction, was used to label a double-stranded oligonucleotide (siRNA) with fluorine-18. An alkyne solid support CPG for the preparation of monostranded oligonucleotides functionalized with alkyne has been developed. Two complementary azide labeling agents (1-(azidomethyl)-4-[(18)F]fluorobenzene) and 1-azido-4-(3-[(18)F]fluoropropoxy)benzene have been produced with 41% and 35% radiochemical yields (decay-corrected), respectively. After annealing with the complementary strand, the siRNA was directly labeled by click chemistry with [(18)F]fluoroazide to produce the [(18)F]-radiolabeled siRNA with excellent radiochemical yield and purity.

Sampling returns for realized variance calculations: tick time or transaction time?

NARCIS (Netherlands)

Griffin, J.E.; Oomen, R.C.A.

2008-01-01

This article introduces a new model for transaction prices in the presence of market microstructure noise in order to study the properties of the price process on two different time scales, namely, transaction time where prices are sampled with every transaction and tick time where prices are

Leveraged Public to Private Transactions in the UK

NARCIS (Netherlands)

Renneboog, L.D.R.; Simons, T.; Wright, M.

2005-01-01

This paper examines the magnitude and the sources of the expected shareholder gains in UK public to private transactions (PTPs) in the second wave from 1997-2003.Pre-transaction shareholders on average receive a premium of 40% and the share price reaction to the PTP announcement is about 30%.The

The Caenorhabditis elegans RDE-10/RDE-11 complex regulates RNAi by promoting secondary siRNA amplification.

Science.gov (United States)

Zhang, Chi; Montgomery, Taiowa A; Fischer, Sylvia E J; Garcia, Susana M D A; Riedel, Christian G; Fahlgren, Noah; Sullivan, Christopher M; Carrington, James C; Ruvkun, Gary

2012-05-22

In nematodes, plants, and fungi, RNAi is remarkably potent and persistent due to the amplification of initial silencing signals by RNA-dependent RNA polymerases (RdRPs). In Caenorhabditis elegans (C. elegans), the interaction between the RNA-induced silencing complex (RISC) loaded with primary small interfering RNAs (siRNAs) and the target messenger RNA (mRNA) leads to the recruitment of RdRPs and synthesis of secondary siRNAs using the target mRNA as the template. The mechanism and genetic requirements for secondary siRNA accumulation are not well understood. From a forward genetic screen for C. elegans genes required for RNAi, we identified rde-10, and through proteomic analysis of RDE-10-interacting proteins, we identified a protein complex containing the new RNAi factor RDE-11, the known RNAi factors RSD-2 and ERGO-1, and other candidate RNAi factors. The RNAi defective genes rde-10 and rde-11 encode a novel protein and a RING-type zinc finger domain protein, respectively. Mutations in rde-10 and rde-11 genes cause dosage-sensitive RNAi deficiencies: these mutants are resistant to low dosage but sensitive to high dosage of double-stranded RNAs. We assessed the roles of rde-10, rde-11, and other dosage-sensitive RNAi-defective genes rsd-2, rsd-6, and haf-6 in both exogenous and endogenous small RNA pathways using high-throughput sequencing and qRT-PCR. These genes are required for the accumulation of secondary siRNAs in both exogenous and endogenous RNAi pathways. The RDE-10/RDE-11 complex is essential for the amplification of RNAi in C. elegans by promoting secondary siRNA accumulation. Copyright © 2012 Elsevier Ltd. All rights reserved.

TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations.

Science.gov (United States)

Bielski, Elizabeth; Zhong, Qian; Mirza, Hamad; Brown, Matthew; Molla, Ashura; Carvajal, Teresa; da Rocha, Sandro R P

2017-07-15

The regulation of genes utilizing the RNA interference (RNAi) mechanism via the delivery of synthetic siRNA has great potential in the treatment of a variety of lung diseases. However, the delivery of siRNA to the lungs is challenging due to the poor bioavailability of siRNA when delivered intraveneously, and difficulty in formulating and maintaining the activity of free siRNA when delivered directly to the lungs using inhalation devices. The use of non-viral vectors such as cationic dendrimers can help enhance the stability of siRNA and its delivery to the cell cytosol. Therefore, in this work, we investigate the ability of a triphenylphosphonium (TPP) modified generation 4 poly(amidoamine) (PAMAM) dendrimer (G4NH 2 -TPP) to enhance the in vitro transfection efficiency of siRNA in a model of the pulmonary epithelium and their aerosol formulations in pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Complexes of siRNA and G4NH 2 -TPP were prepared with varying TPP densities and increasing N/P ratios. The complexation efficiency was modulated by the presence of the TPP on the dendrimer surface, allowing for a looser complexation compared to unmodified dendrimer as determined by gel electrophoresis and polyanion competition assay. An increase in TPP density and N/P ratio led to an increase in the in vitro gene knockdown of stably green fluorescent protein (eGFP) expressing lung alveolar epithelial (A549) cells. G4NH 2 -12TPP dendriplexes (G4NH 2 PAMAM dendrimers containing 12 TPP molecules on the surface complexed with siRNA) at N/P ratio 30 showed the highest in vitro gene knockdown efficiency. To assess the potential of TPP-dendriplexes for pulmonary use, we also developed micron particle technologies for both pMDIs and DPIs and determined their aerosol characteristics utilizing an Andersen Cascade Impactor (ACI). Mannitol microparticles encapsulating 12TPP-dendriplexes were shown to be effective in producing aerosols suitable for deep lung

How vulnerable is the emissions market to transaction costs?: An ABMS Approach

International Nuclear Information System (INIS)

Lee, Kangil; Han, Taek-Whan

2016-01-01

The impact of transaction costs on the early emissions trading market is examined by applying an agent-based model and simulation (ABMS) approach. For a realistic model set up, bounded rationality, stochastic characteristics, and learning-by-doing are considered in our search processes. Marginal abatement cost parameters are obtained from Yoo et al. (2010), which is an experimental study on the emissions trading in the Korean power sector. Sensitivity analyses are performed on market performance indices with regard to transaction cost parameters, which represent scales and the learning elasticities of transaction costs. A total of 960 simulations were run in this sensitivity analysis. Sensitivity analysis results consistently show that higher transaction costs worsen market performance. The most remarkable finding in these results is that welfare performance of all the transactions decreases by up to 50% as the scale parameters of transaction costs increase, implying that welfare gain from introducing emissions trading disappears significantly. However, with learning curve effect, welfare performance could be regained by up to 26%. In sum, although transaction costs significantly encroach upon trade gains at the early stage, based on our simulation results, the welfare loss by way of transaction costs is lessened as the knowledge of market participants progresses. - Highlights: • Impact of transaction costs on small and early, primitive emissions trading market • Bounded Rationality (BR) and Zero Intelligence Plus (ZIP) agents concept • Marginal Abatement Cost (MAC) parameters delineate Korean power companies • With transaction costs, welfare gain from trade found to be shrunken • As learning proceeds, welfare loss is reduced

Understanding the application of OSC policy 9.1 during a takeover transaction

International Nuclear Information System (INIS)

Hayduk, M.F.; Rasmuson, M.A.

1998-01-01

Legal aspects of ownership of publicly traded companies in Canada are explored, with particular emphasis on transactions involving 'related parties'. In this context, Policy 9.1 of the Ontario Securities Commission is examined. The policy seeks to enhance minority shareholder protection by providing for independent valuation, majority of minority approval, enhanced disclosure and review of substantial transactions by independent directors. This paper focuses on four types of transactions governed by Policy 9.1, i.e. insider bids, issuer bids, going private transactions, related party transactions and the recent proposed rule reformulation proposed by the Ontario Securities Commission (OSC)

Providing hedging protection for the transaction

International Nuclear Information System (INIS)

Richardson, D.W.

1999-01-01

This presentation dealt with methods for assessing commodity price risk in an asset transaction; the setting of risk management objectives; building hedging into the financing; and internal reporting and accounting to mitigate trading risks. It also provided some recent examples of successful hedging in gas asset transactions. The objectives of risk management and the nature of hedging and speculation were explored. An approach to price risk management was proposed. The development of price risk management tools, and techniques for managing risks involving interest rates, foreign exchange, and commodities were examined. figs

A transactional framework for pediatric rehabilitation: shifting the focus to situated contexts, transactional processes, and adaptive developmental outcomes.

Science.gov (United States)

King, Gillian; Imms, Christine; Stewart, Debra; Freeman, Matt; Nguyen, Tram

2018-07-01

A paradigm shift is taking place in pediatric rehabilitation research, practice, and policy - a shift towards the real-life contexts of clients rather than requiring clients to navigate the world of pediatric rehabilitation. This article proposes a conceptual framework to bring about a broader awareness of clients' lives and transactional processes of change over the life course. The framework draws attention to transactional processes by which individuals, situated in life contexts, change and adapt over the life course and, in turn, influence their contextual settings and broader environments. This framework is based on (a) basic tenets derived from foundational theories taking a life course perspective to change, and (b) transactional processes identified from relevant pediatric rehabilitation models that bring these foundational theories into the pediatric rehabilitation sphere. The framework identifies three types of transactional processes relevant to pediatric rehabilitation: facilitative, resiliency, and socialization processes. These processes describe how contexts and people mutually influence each other via opportunities and situated experiences, thus facilitating capacity, adaptation to adversity, and socialization to new roles and life transitions. The utility of the framework is considered for research, practice, service organizations, and policy. Implications for Rehabilitation The framework supports practitioners going beyond person and environment as separate entities, to provide services to the "situated person" in real-life contexts The framework shifts the focus from "body structures/functions" and "person in activity" to "person in changing and challenging life contexts" Working from a transactional perspective, practitioner-client conversations will change; practitioners will view client situations through a lens of opportunities and experiences, assess client experiences in real-life contexts, and strive to create context-based therapy

In vivo siRNA delivery system for targeting to the liver by poly-l-glutamic acid-coated lipoplex

Directory of Open Access Journals (Sweden)

Yoshiyuki Hattori

2014-01-01

Full Text Available In this study, we developed anionic polymer-coated liposome/siRNA complexes (lipoplexes with chondroitin sulfate C (CS, poly-l-glutamic acid (PGA and poly-aspartic acid (PAA for siRNA delivery by intravenous injection, and evaluated the biodistribution and gene silencing effect in mice. The sizes of CS-, PGA- and PAA-coated lipoplexes were about 200 nm and their ζ-potentials were negative. CS-, PGA- and PAA-coated lipoplexes did not induce agglutination after mixing with erythrocytes. In terms of biodistribution, siRNAs after intravenous administration of cationic lipoplexes were largely observed in the lungs, but those of CS-, PGA- and PAA-coated lipoplexes were in both the liver and the kidneys, indicating that siRNA might be partially released from the anionic polymer-coated lipoplexes in the blood circulation and accumulate in the kidney, although the lipoplexes can prevent the agglutination with blood components. To increase the association between siRNA and cationic liposome, we used cholesterol-modified siRNA (siRNA-Chol for preparation of the lipoplexes. When CS-, PGA- and PAA-coated lipoplexes of siRNA-Chol were injected into mice, siRNA-Chol was mainly observed in the liver, not in the kidneys. In terms of the suppression of gene expression in vivo, apolipoprotein B (ApoB mRNA in the liver was significantly reduced 48 h after single intravenous injection of PGA-coated lipoplex of ApoB siRNA-Chol (2.5 mg siRNA/kg, but not cationic, CS- and PAA-coated lipoplexes. In terms of toxicity after intravenous injection, CS-, PGA- and PAA-coated lipoplexes did not increase GOT and GPT concentrations in blood. From these findings, PGA coatings for cationic lipoplex of siRNA-Chol might produce a systemic vector of siRNA to the liver.

Connexin43 Mediated Delivery of ADAMTS5 Targeting siRNAs from Mesenchymal Stem Cells to Synovial Fibroblasts.

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Shuo Liu

Full Text Available Osteoarthritis is a joint-destructive disease that has no effective cure. Human mesenchymal stem cells (hMSCs could offer therapeutic benefit in the treatment of arthritic diseases by suppressing inflammation and permitting tissue regeneration, but first these cells must overcome the catabolic environment of the diseased joint. Likewise, gene therapy also offers therapeutic promise given its ability to directly modulate key catabolic factors that mediate joint deterioration, although it too has limitations. In the current study, we explore an approach that combines hMSCs and gene therapy. Specifically, we test the use of hMSC as a vehicle to deliver ADAMTS5 (an aggrecanase with a key role in osteoarthritis-targeting siRNAs to SW982 synovial fibroblast-like cells via connexin43 containing gap junctions. Accordingly, we transduced hMSCs with ADAMTS5-targeting shRNA or non-targeted shRNA, and co-cultured them with synovial fibroblasts to allow delivery of siRNAs from hMSC to synovial fibroblasts. We found that co-culture of hMSCs-shRNA-ADAMTS5 and synovial fibroblasts reduced ADAMTS5 expression relative to co-culture of hMSCs-shRNA-control and synovial fibroblasts. Furthermore, ADAMTS5 was specifically reduced in the synovial fibroblasts populations as determined by fluorescence-activated cell sorting, suggesting transfer of the siRNA between cells. To test if Cx43-containing gap junctions are involved in the transfer of siRNA, we co-cultured hMSCs-shRNA-ADAMTS5 cells with synovial fibroblasts in which connexin43 was knocked down. Under these conditions, ADAMTS5 levels were not inhibited by co-culture, indicating that connexin43 mediates the delivery of siRNA from hMSCs to synovial fibroblasts. In total, our findings demonstrate that hMSCs can function as donor cells to host and deliver siRNAs to synovial fibroblasts via connexin43 gap junction in vitro. These data may have implications in the combination of hMSCs and gene therapy to treat diseases

Connexin43 Mediated Delivery of ADAMTS5 Targeting siRNAs from Mesenchymal Stem Cells to Synovial Fibroblasts.

Science.gov (United States)

Liu, Shuo; Niger, Corinne; Koh, Eugene Y; Stains, Joseph P

2015-01-01

Osteoarthritis is a joint-destructive disease that has no effective cure. Human mesenchymal stem cells (hMSCs) could offer therapeutic benefit in the treatment of arthritic diseases by suppressing inflammation and permitting tissue regeneration, but first these cells must overcome the catabolic environment of the diseased joint. Likewise, gene therapy also offers therapeutic promise given its ability to directly modulate key catabolic factors that mediate joint deterioration, although it too has limitations. In the current study, we explore an approach that combines hMSCs and gene therapy. Specifically, we test the use of hMSC as a vehicle to deliver ADAMTS5 (an aggrecanase with a key role in osteoarthritis)-targeting siRNAs to SW982 synovial fibroblast-like cells via connexin43 containing gap junctions. Accordingly, we transduced hMSCs with ADAMTS5-targeting shRNA or non-targeted shRNA, and co-cultured them with synovial fibroblasts to allow delivery of siRNAs from hMSC to synovial fibroblasts. We found that co-culture of hMSCs-shRNA-ADAMTS5 and synovial fibroblasts reduced ADAMTS5 expression relative to co-culture of hMSCs-shRNA-control and synovial fibroblasts. Furthermore, ADAMTS5 was specifically reduced in the synovial fibroblasts populations as determined by fluorescence-activated cell sorting, suggesting transfer of the siRNA between cells. To test if Cx43-containing gap junctions are involved in the transfer of siRNA, we co-cultured hMSCs-shRNA-ADAMTS5 cells with synovial fibroblasts in which connexin43 was knocked down. Under these conditions, ADAMTS5 levels were not inhibited by co-culture, indicating that connexin43 mediates the delivery of siRNA from hMSCs to synovial fibroblasts. In total, our findings demonstrate that hMSCs can function as donor cells to host and deliver siRNAs to synovial fibroblasts via connexin43 gap junction in vitro. These data may have implications in the combination of hMSCs and gene therapy to treat diseases like

DETERMINANTS OF RURAL FARMERS PREFERENCE FOR CASH-LESS TRANSACTIONS IN IMO STATE

Directory of Open Access Journals (Sweden)

Igwe Ikenna UKOHA

2017-04-01

Full Text Available The preference for cash-less transaction by Nigerians cannot be exaggerated, but despite its patronage, there exist limited access and utilization of the cash-less technologies among farmers in South-East Nigeria. The study analysed the determinants of rural farmers’ preference for cash-less transactions in Imo state, South-East Nigeria. Multi-stage sampling technique was employed in selection of 100 farmers for the study. The determinant of rural farmers’ preference for cash-less transactions in Imo State, was achieved using logit model. The result of the analysis showed that age (5%, gender (10% education levels of the farmers (1%, user friendliness of technologies (5%, transaction charge (5% and security of transactions (5% were found to be the major determinants of farmers preference for cash-less transactions based on their levels of significance. Centred on the findings, the study recommended the strengthening of the use of cash-less transaction by farmers by providing a favourable financial environment through better orientation programs, so as to enable a smooth transition from a cash-based economy to cash-less economy.

Corporate Governance and Related Parties Transactions - Evidence from Romanian Listed Companies

Directory of Open Access Journals (Sweden)

Iuliana Oana MIHAI

2017-06-01

Full Text Available The objective of this work is to offer contributions to improve the understanding of related party transactions. Our goal is to explore the role of related party transactions from the perspective of company�s corporate governance environment. Even though there is a growing interest in related party transactions, there is little academic literature to understand the nature of related party transactions and their economic consequences. Our study was conducted on a sample of 40 companies listed companies on Bucharest Stock Exchange activating in manuafacuring sector. Our objective was to analyse the way the companies follow the requirements of transparency of related party transaction. Based on our observations on companies� financial reports and companies web-sites, the level of transparency between these companies was reflected by an index estimated from producers� scores on Likert-type scales (one to five that showed to what extent they disclose or not disclose information such as relationship between parents and subsidiaries, key management personnel compensation, the value of transactions with related parties or separate disclosure for the group entities.

Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study)

DEFF Research Database (Denmark)

Nguyen, Quan Dong; Schachar, Ronald A; Nduaka, Chudy I

2012-01-01

To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation.......To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation....

Spatially Controlled Delivery of siRNAs to Stem Cells in Implants Generated by Multi-Component Additive Manufacturing

DEFF Research Database (Denmark)

Andersen, Morten Østergaard; Le, Dang Quang Svend; Chen, Muwan

2013-01-01

Additive manufacturing is a promising technique in tissue engineering, as it enables truly individualized implants to be made to fit a particular defect. As previously shown, a feasible strategy to produce complex multicellular tissues is to deposit different small interfering RNA (siRNA) in porous...... implants that are subsequently sutured together. In this study, an additive manufacturing strategy to deposit carbohydrate hydrogels containing different siRNAs is applied into an implant, in a spatially controlled manner. When the obtained structures are seeded with mesenchymal stem (stromal) cells......, the selected siRNAs are delivered to the cells and induces specific and localized gene silencing. Here, it is demonstrated how to replicate part of a patient's spinal cord from a computed tomography scan, using an additive manufacturing technique to produce an implant with compartmentalized si...

Evaluation of carrier-mediated siRNA delivery

DEFF Research Database (Denmark)

Colombo, Stefano; Nielsen, Hanne Mørck; Foged, Camilla

2013-01-01

RNA delivery. An in vitro cell culture model system expressing enhanced green fluorescent protein (EGFP) was used to develop the assay, which was based on the intracellular quantification of a full-length double-stranded Dicer substrate siRNA by stem-loop RT qPCR. The result is a well-documented protocol......RNA delivered by use of carriers remains an analytical challenge. The purpose of the present study was to optimize and validate an analytical protocol based on stem-loop reverse transcription quantitative polymerase chain reaction (RT qPCR) to quantitatively monitor the carrier-mediated intracellular si...

Peptidomimetics with beta-peptoid resudies as carriers for intracellular delivery of small interfering RNA (siRNA)

DEFF Research Database (Denmark)

Foged, Camilla

cytometry. We conclude that simple complex formation via electrostatic interactions between siRNA and the cationic peptidomimetics is not sufficient for the delivery of siRNA to the RNA interference (RNAi) pathway in the cytoplasm. We are currently testing chemical conjugates of si...... prepared by mixing and characterized with respect to size and surface charge. At ratios of peptide nitrogen to siRNA phosphate (N/P) of 1 and below, particles with narrow size distributions (poly dispersity indexes lower than 0.11) ranging from approximately 100 to 350 nm were formed, and they showed...... a negative zeta potential (-24 to -31 mV). At higher N/P ratios, larger aggregates with zeta potential close to neutral were formed. However, the complexes were not able to silence the expression of enhanced green fluorescent protein (EGFP) in HeLa-cells stably expressing EGFP, which was measured by flow...

A survey on the history of transaction management: from flat to grid transactions

NARCIS (Netherlands)

Wang, T.; Vonk, J.; Kratz, B.; Grefen, P.W.P.J.

2008-01-01

Transactions have been around since the Seventies to provide reliable information processing in automated information systems. Originally developed for simple ‘debit-credit’ style database operations in centralized systems, they have moved into much more complex application domains including aspects

24 CFR 100.110 - Discriminatory practices in residential real estate-related transactions.

Science.gov (United States)

2010-04-01

... residential real estate-related transactions. 100.110 Section 100.110 Housing and Urban Development... Discrimination in Residential Real Estate-Related Transactions § 100.110 Discriminatory practices in residential real estate-related transactions. (a) This subpart provides the Department's interpretation of the...

Influence of the internalization pathway on the efficacy of siRNA delivery by cationic fluorescent nanodiamonds in the Ewing sarcoma cell model.

Directory of Open Access Journals (Sweden)

Anna Alhaddad

Full Text Available Small interfering RNAs (siRNAs are powerful tools commonly used for the specific inhibition of gene expression. However, vectorization is required to facilitate cell penetration and to prevent siRNA degradation by nucleases. We have shown that diamond nanocrystals coated with cationic polymer can be used to carry siRNAs into Ewing sarcoma cells, in which they remain traceable over long periods, due to their intrinsic stable fluorescence. We tested two cationic polymers, polyallylamine and polyethylenimine. The release of siRNA, accompanied by Ewing sarcoma EWS-Fli1 oncogene silencing, was observed only with polyethylenimine. We investigated cell penetration and found that the underlying mechanisms accounted for these differences in behavior. Using drugs selectively inhibiting particular pathways and a combination of fluorescence and electronic microscopy, we showed that siRNA gene silencing occurred only if the siRNA:cationic nanodiamond complex followed the macropinocytosis route. These results have potential implications for the design of efficient drug-delivery vectors.

Influence of the Internalization Pathway on the Efficacy of siRNA Delivery by Cationic Fluorescent Nanodiamonds in the Ewing Sarcoma Cell Model

Science.gov (United States)

Alhaddad, Anna; Durieu, Catherine; Dantelle, Géraldine; Le Cam, Eric; Malvy, Claude; Treussart, François; Bertrand, Jean-Rémi

2012-01-01

Small interfering RNAs (siRNAs) are powerful tools commonly used for the specific inhibition of gene expression. However, vectorization is required to facilitate cell penetration and to prevent siRNA degradation by nucleases. We have shown that diamond nanocrystals coated with cationic polymer can be used to carry siRNAs into Ewing sarcoma cells, in which they remain traceable over long periods, due to their intrinsic stable fluorescence. We tested two cationic polymers, polyallylamine and polyethylenimine. The release of siRNA, accompanied by Ewing sarcoma EWS-Fli1 oncogene silencing, was observed only with polyethylenimine. We investigated cell penetration and found that the underlying mechanisms accounted for these differences in behavior. Using drugs selectively inhibiting particular pathways and a combination of fluorescence and electronic microscopy, we showed that siRNA gene silencing occurred only if the siRNA:cationic nanodiamond complex followed the macropinocytosis route. These results have potential implications for the design of efficient drug-delivery vectors. PMID:23284935

Influence of the internalization pathway on the efficacy of siRNA delivery by cationic fluorescent nanodiamonds in the Ewing sarcoma cell model.

Science.gov (United States)

Alhaddad, Anna; Durieu, Catherine; Dantelle, Géraldine; Le Cam, Eric; Malvy, Claude; Treussart, François; Bertrand, Jean-Rémi

2012-01-01

Small interfering RNAs (siRNAs) are powerful tools commonly used for the specific inhibition of gene expression. However, vectorization is required to facilitate cell penetration and to prevent siRNA degradation by nucleases. We have shown that diamond nanocrystals coated with cationic polymer can be used to carry siRNAs into Ewing sarcoma cells, in which they remain traceable over long periods, due to their intrinsic stable fluorescence. We tested two cationic polymers, polyallylamine and polyethylenimine. The release of siRNA, accompanied by Ewing sarcoma EWS-Fli1 oncogene silencing, was observed only with polyethylenimine. We investigated cell penetration and found that the underlying mechanisms accounted for these differences in behavior. Using drugs selectively inhibiting particular pathways and a combination of fluorescence and electronic microscopy, we showed that siRNA gene silencing occurred only if the siRNA:cationic nanodiamond complex followed the macropinocytosis route. These results have potential implications for the design of efficient drug-delivery vectors.

A TRANSACTION COST ANALYSIS OF MICROPAYMENTS IN MOBILE COMMERCE

Directory of Open Access Journals (Sweden)

Daniel Gille

2012-07-01

Full Text Available Personalised, location-related and differentiated services in the mobile digitaleconomy create a demand for suitable pricing models. In the case of disaggregated“microservices” (e.g., small digitalized information or service units, as well as for theacquisition of low-value physical goods, the deployment of micropayments seemsappropriate.This paper analyzes the economic efficiency of marginal transaction amounts in the mcommercearea by applying the theoretical approach of transaction cost economics. Forthis purpose, a separation of technical and cognitive transaction costs is applied. Theinfluence of selected determinants such as specifity, uncertainty and bounded rationality ontransaction costs in mobile commerce micropayments is analyzed. The result is a morelikely application of micropayments for physical goods such as beverages or parking ticketsthan for digital goods and services, given the theoretical assumptions of the model. Inaddition, indicators for a significant above-zero lower limit of transaction amounts inmobile commerce are presented.

Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Cengiz, Bagdat Burcu; Asik, Mehmet Dogan [Hacettepe University, Nanotechnology and Nanomedicine Division (Turkey); Kara, Goknur [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey); Turk, Mustafa [Kirikkale University, Bioengineering Department (Turkey); Denkbas, Emir Baki, E-mail: denkbas@hacettepe.edu.tr [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey)

2015-04-15

In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

SKI2 mediates degradation of RISC 5'-cleavage fragments and prevents secondary siRNA production from miRNA targets in Arabidopsis.

Science.gov (United States)

Branscheid, Anja; Marchais, Antonin; Schott, Gregory; Lange, Heike; Gagliardi, Dominique; Andersen, Stig Uggerhøj; Voinnet, Olivier; Brodersen, Peter

2015-12-15

Small regulatory RNAs are fundamental in eukaryotic and prokaryotic gene regulation. In plants, an important element of post-transcriptional control is effected by 20-24 nt microRNAs (miRNAs) and short interfering RNAs (siRNAs) bound to the ARGONAUTE1 (AGO1) protein in an RNA induced silencing complex (RISC). AGO1 may cleave target mRNAs with small RNA complementarity, but the fate of the resulting cleavage fragments remains incompletely understood. Here, we show that SKI2, SKI3 and SKI8, subunits of a cytoplasmic cofactor of the RNA exosome, are required for degradation of RISC 5', but not 3'-cleavage fragments in Arabidopsis. In the absence of SKI2 activity, many miRNA targets produce siRNAs via the RNA-dependent RNA polymerase 6 (RDR6) pathway. These siRNAs are low-abundant, and map close to the cleavage site. In most cases, siRNAs were produced 5' to the cleavage site, but several examples of 3'-spreading were also identified. These observations suggest that siRNAs do not simply derive from RDR6 action on stable 5'-cleavage fragments and hence that SKI2 has a direct role in limiting secondary siRNA production in addition to its function in mediating degradation of 5'-cleavage fragments. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Effects of a human plasma membrane-associated sialidase siRNA on prostate cancer invasion

Energy Technology Data Exchange (ETDEWEB)

Li, Xiaojie [Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune Medical School, Jilin University, Changchun (China); Taizhou Polytechnic College, Taizhou (China); Zhang, Ling; Shao, Yueting; Liang, Zuowen; Shao, Chen; Wang, Bo; Guo, Baofeng; Li, Na; Zhao, Xuejian [Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune Medical School, Jilin University, Changchun (China); Li, Yang, E-mail: lyang@jlu.edu.cn [Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune Medical School, Jilin University, Changchun (China); Xu, Deqi [Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States)

2011-12-16

Highlights: Black-Right-Pointing-Pointer Neu3 is as one of the sialidases and regulates cell surface functions. Black-Right-Pointing-Pointer A Neu3-specific siRNA inhibited prostrate cancer cell invasion and migration. Black-Right-Pointing-Pointer The Neu3-specific siRNA inhibited prostate cancer metastasis in mice. Black-Right-Pointing-Pointer Targeting Neu3 may have utility for gene-based therapy of human cancer metastasis. -- Abstract: Human plasma membrane-associated sialidase (Neu3) is one of several sialidases that hydrolyze sialic acids in the terminal position of the carbohydrate groups of glycolipids and glycoproteins. Neu3 is mainly localized in plasma membranes and plays crucial roles in the regulation of cell surface functions. In this study, we investigated the effects and molecular mechanisms of Neu3 on cell invasion and migration in vivo and in vitro. Initially, we found that the levels of Neu3 expression were higher in prostate cancer tissues and cell lines than in normal prostate tissues based on RT-PCR and Western blotting analyses. We then applied a Neu3 siRNA approach to block Neu3 signaling using PC-3M cells as model cells. Transwell invasion assays and wound assays showed significantly decreased invasion and migration potential in the Neu3 siRNA-transfected cells. RT-PCR and Western blotting analyses revealed that Neu3 knockdown decreased the expressions of the matrix metalloproteinases MMP-2 and MMP-9. In vivo, mice injected with PC-3M cell tumors were evaluated by SPECT/CT to determine the presence of bone metastases. Mice treated with attenuated Salmonella carrying the Neu3 siRNA developed fewer bone metastases than mice treated with attenuated Salmonella carrying a control Scramble siRNA, attenuated Salmonella alone or PBS. The results for bone metastasis detection by pathology were consistent with the data obtained by SPECT/CT. Tumor blocks were evaluated by histochemical, RT-PCR and Western blotting analyses. The results revealed

High loading efficiency and sustained release of siRNA encapsulated in PLGA nanoparticles: quality by design optimization and characterization.

Science.gov (United States)

Cun, Dongmei; Jensen, Ditte Krohn; Maltesen, Morten Jonas; Bunker, Matthew; Whiteside, Paul; Scurr, David; Foged, Camilla; Nielsen, Hanne Mørck

2011-01-01

Poly(DL-lactide-co-glycolide acid) (PLGA) is an attractive polymer for delivery of biopharmaceuticals owing to its biocompatibility, biodegradability and outstanding controlled release characteristics. The purpose of this study was to understand and define optimal parameters for preparation of small interfering RNA (siRNA)-loaded PLGA nanoparticles by the double emulsion solvent evaporation method and characterize their properties. The experiments were performed according to a 2(5-1) fractional factorial design based on five independent variables: The volume ratio between the inner water phase and the oil phase, the PLGA concentration, the sonication time, the siRNA load and the amount of acetylated bovine serum albumin (Ac-BSA) in the inner water phase added to stabilize the primary emulsion. The effects on the siRNA encapsulation efficiency and the particle size were investigated. The most important factors for obtaining an encapsulation efficiency as high as 70% were the PLGA concentration and the volume ratio whereas the size was mainly affected by the PLGA concentration. The viscosity of the oil phase was increased at high PLGA concentration, which explains the improved encapsulation by stabilization of the primary emulsion and reduction of siRNA leakage to the outer water phase. Addition of Ac-BSA increased the encapsulation efficiency at low PLGA concentrations. The PLGA matrix protected siRNA against nuclease degradation, provided a burst release of surface-localized siRNA followed by a triphasic sustained release for two months. These results enable careful understanding and definition of optimal process parameters for preparation of PLGA nanoparticles encapsulating high amounts of siRNA with immediate and long-term sustained release properties. Copyright © 2010 Elsevier B.V. All rights reserved.

Measuring the influence of networks on transaction costs using a non-parametric regression technique

DEFF Research Database (Denmark)

Henningsen, Géraldine; Henningsen, Arne; Henning, Christian H.C.A.

All business transactions as well as achieving innovations take up resources, subsumed under the concept of transaction costs. One of the major factors in transaction costs theory is information. Firm networks can catalyse the interpersonal information exchange and hence, increase the access to non......-public information so that transaction costs are reduced. Many resources that are sacrificed for transaction costs are inputs that also enter the technical production process. As most production data do not distinguish between these two usages of inputs, high transaction costs result in reduced observed productivity...

Detection of small interfering RNA (siRNA) by mass spectrometry procedures in doping controls.

Science.gov (United States)

Thomas, Andreas; Walpurgis, Katja; Delahaut, Philippe; Kohler, Maxie; Schänzer, Wilhelm; Thevis, Mario

2013-01-01

Uncovering manipulation of athletic performance via small interfering (si)RNA is an emerging field in sports drug testing. Due to the potential to principally knock down every target gene in the organism by means of the RNA interference pathway, this facet of gene doping has become a realistic scenario. In the present study, two distinct model siRNAs comprising 21 nucleotides were designed as double strands which were perfect counterparts to a sequence of the respective messenger RNA coding the muscle regulator myostatin of Rattus norvegicus. Several modified nucleotides were introduced in both the sense and the antisense strand comprising phosphothioates, 2'-O-methylation, 2'-fluoro-nucleotides, locked nucleic acids and a cholesterol tag at the 3'-end. The model siRNAs were applied to rats at 1 mg/kg (i.v.) and blood as well as urine samples were collected. After isolation of the RNA by means of a RNA purification kit, the target analytes were detected by liquid chromatography - high resolution/high accuracy mass spectrometry (LC-HRMS). Analytes were detected as modified nucleotides after alkaline hydrolysis, as intact oligonucleotide strands (top-down) and by means of denaturing SDS-PAGE analysis. The gel-separated siRNA was further subjected to in-gel hydrolysis with different RNases and subsequent identification of the fragments by untargeted LC-HRMS analysis (bottom-up, 'experimental RNomics'). Combining the results of all approaches, the identification of several 3'-truncated urinary metabolites was accomplished and target analytes were detected up to 24 h after a single administration. Simultaneously collected blood samples yielded no promising results. The methods were validated and found fit-for-purpose for doping controls. Copyright © 2013 John Wiley & Sons, Ltd.

siRNAs targeting PB2 and NP genes potentially inhibit replication

Indian Academy of Sciences (India)

% and has caused the death or culling of millions of poultry since 2003. In this study, we have designed three siRNAs (PB2-2235, PB2-479 and NP-865) targeting PB2 and NP genes of avian influenza virus and evaluated their potential, ...

31 CFR 585.513 - Transactions related to telecommunications authorized.

Science.gov (United States)

2010-07-01

... telecommunications authorized. 585.513 Section 585.513 Money and Finance: Treasury Regulations Relating to Money and... Transactions related to telecommunications authorized. (a) All transactions of U.S. common carriers with respect to the receipt and transmission of telecommunications involving the FRY (S&M) are authorized...

31 CFR 586.510 - Transactions related to telecommunications authorized.

Science.gov (United States)

2010-07-01

... telecommunications authorized. 586.510 Section 586.510 Money and Finance: Treasury Regulations Relating to Money and... Licensing Policy § 586.510 Transactions related to telecommunications authorized. All transactions with respect to the receipt and transmission of telecommunications involving the FRY (S&M) are authorized. This...

A Template Model for Multidimensional Inter-Transactional Association Rules

NARCIS (Netherlands)

Feng, L.; Yu, J.X.; Lu, H.J.; Han, J.W.

2002-01-01

Multidimensional inter-transactional association rules extend the traditional association rules to describe more general associations among items with multiple properties across transactions. “After McDonald and Burger King open branches, KFC will open a branch two months later and one mile away��?

31 CFR 515.404 - Transactions between principal and agent.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Transactions between principal and agent. 515.404 Section 515.404 Money and Finance: Treasury Regulations Relating to Money and Finance... transaction were in no way affiliated or associated with each other. ...

31 CFR 500.404 - Transactions between principal and agent.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Transactions between principal and agent. 500.404 Section 500.404 Money and Finance: Treasury Regulations Relating to Money and Finance... transaction were in no way affiliated or associated with each other. ...

Modeling an Application's Theoretical Minimum and Average Transactional Response Times

Energy Technology Data Exchange (ETDEWEB)

Paiz, Mary Rose [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

2015-04-01

The theoretical minimum transactional response time of an application serves as a ba- sis for the expected response time. The lower threshold for the minimum response time represents the minimum amount of time that the application should take to complete a transaction. Knowing the lower threshold is beneficial in detecting anomalies that are re- sults of unsuccessful transactions. On the converse, when an application's response time falls above an upper threshold, there is likely an anomaly in the application that is causing unusual performance issues in the transaction. This report explains how the non-stationary Generalized Extreme Value distribution is used to estimate the lower threshold of an ap- plication's daily minimum transactional response time. It also explains how the seasonal Autoregressive Integrated Moving Average time series model is used to estimate the upper threshold for an application's average transactional response time.

The consequences of hospital autonomization in Colombia: a transaction cost economics analysis.

Science.gov (United States)

Castano, Ramon; Mills, Anne

2013-03-01

Granting autonomy to public hospitals in developing countries has been common over recent decades, and implies a shift from hierarchical to contract-based relationships with health authorities. Theory on transactions costs in contractual relationships suggests they stem from relationship-specific investments and contract incompleteness. Transaction cost economics argues that the parties involved in exchanges seek to reduce transaction costs. The objective of this research was to analyse the relationships observed between purchasers and the 22 public hospitals of the city of Bogota, Colombia, in order to understand the role of relationship-specific investments and contract incompleteness as sources of transaction costs, through a largely qualitative study. We found that contract-based relationships showed relevant transaction costs associated mainly with contract incompleteness, not with relationship-specific investments. Regarding relationships between insurers and local hospitals for primary care services, compulsory contracting regulations locked-in the parties to the contracts. For high-complexity services (e.g. inpatient care), no restrictions applied and relationships suggested transaction-cost minimizing behaviour. Contract incompleteness was found to be a source of transaction costs on its own. We conclude that transaction costs seemed to play a key role in contract-based relationships, and contract incompleteness by itself appeared to be a source of transaction costs. The same findings are likely in other contexts because of difficulties in defining, observing and verifying the contracted products and the underlying information asymmetries. The role of compulsory contracting might be context-specific, although it is likely to emerge in other settings due to the safety-net role of public hospitals.

Reduction of bilirubin by targeting human heme oxygenase-1 through siRNA.

Science.gov (United States)

Xia, Zhen-Wei; Li, Chun-E; Jin, You-Xin; Shi, Yi; Xu, Li-Qing; Zhong, Wen-Wei; Li, Yun-Zhu; Yu, Shan-Chang; Zhang, Zi-Li

2007-04-01

Neonatal hyperbilirubinemia is a common clinical condition caused mainly by the increased production and decreased excretion of bilirubin. Current treatment is aimed at reducing the serum levels of bilirubin. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that generates bilirubin. In this study we intended to suppress HO-1 using the RNA interference technique. Small interfering RNA (siRNA)-A, -B, and -C were designed based on human HO-1 (hHO-1) mRNA sequences. siRNA was transfected into a human hepatic cell line (HL-7702). hHO-1 transcription and protein levels were then determined. In addition, the inhibitory effect of siRNA on hHO-1 was assessed in cells treated with hemin or transfected with an hHO-1 plasmid. siRNA-C showed the most potent suppressive effect on hHO-1. This inhibition is dose and time dependent. Compared with control, both hemin and hHO-1 plasmids up-regulated hHO-1 expression in HL-7702 cells. However, the up-regulation was significantly attenuated by siRNA-C. Furthermore, the decrease in hHO-1 activity was coincident with the suppression of its transcription. Finally, siRNA-C was shown to reduce hHO-1 enzymatic activity and bilirubin levels. Thus, this study provides a novel therapeutic rationale by blocking bilirubin formation via siRNA for preventing and treating neonatal hyperbilirubinemia and bilirubin encephalopathy at an early clinical stage.

COULD SOCIOECONOMIC METABOLISM BE MOLDED BY TRANSACTION COSTS?

Directory of Open Access Journals (Sweden)

RALUCA I. IORGULESCU

2017-06-01

Full Text Available Two key issues that shape the economic development and growth of a country are the independence and effectiveness of the judicial system and the level of bureaucracy. The theory of transaction costs, developed, among others, by Douglass C. North, explores both. Increasing the independence and effectiveness of the judicial system reduces corruption and protects private property and economic freedom while reducing bureaucracy is absolutely necessary to increase a country's competitiveness by lowering the cost and increasing the speed of transactions. This paper introduces the transaction costs approach, the concept of ‘socioeconomic/societal metabolism’ and takes advantage of the Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MuSIASEM to examine how the ‘socioeconomic/societal metabolism’ could be impacted.

26 CFR 157.5891-1 - Imposition of excise tax on structured settlement factoring transactions.

Science.gov (United States)

2010-04-01

... settlement factoring transactions. 157.5891-1 Section 157.5891-1 Internal Revenue INTERNAL REVENUE SERVICE... SETTLEMENT FACTORING TRANSACTIONS Tax on Structured Settlement Factoring Transactions § 157.5891-1 Imposition of excise tax on structured settlement factoring transactions. (a) In general. Section 5891 imposes...

Neuroprotection by biodegradable PAMAM ester (e-PAM-R)-mediated HMGB1 siRNA delivery in primary cortical cultures and in the postischemic brain.

Science.gov (United States)

Kim, Il-Doo; Lim, Chae-Moon; Kim, Jung-Bin; Nam, Hye Yeong; Nam, Kihoon; Kim, Seung-Woo; Park, Jong-Sang; Lee, Ja-Kyeong

2010-03-19

Although RNA interference (RNAi)-mediated gene silencing provides a powerful strategy for modulating specific gene functions, difficulties associated with siRNA delivery have impeded the development of efficient therapeutic applications. In particular, the efficacy of siRNA delivery into neurons has been limited by extremely low transfection efficiencies. e-PAM-R is a biodegradable arginine ester of PAMAM dendrimer, which is readily degradable under physiological conditions (pH 7.4, 37 degrees C). In the present study, we investigated the efficiency of siRNA delivery by e-PAM-R in primary cortical cultures and in rat brain. e-PAM-R/siRNA complexes showed high transfection efficiencies and low cytotoxicities in primary cortical cultures. Localization of fluorescence-tagged siRNA revealed that siRNA was delivered not only into the nucleus and cytoplasm, but also along the processes of the neuron. e-PAM-R/siRNA complex-mediated target gene reduction was observed in over 40% of cells and it was persistent for over 48 h. The potential use of e-PAM-R was demonstrated by gene knockdown after transfecting High mobility group box-1 (HMGB1, a novel cytokine-like molecule) siRNA into H(2)O(2)- or NMDA-treated primary cortical cultures. In these cells, HMGB1 siRNA delivery successfully reduced both basal and H(2)O(2)- or NMDA-induced HMGB1 levels, and as a result of that, neuronal cell death was significantly suppressed in both cases. Furthermore, we showed that e-PAM-R successfully delivered HMGB1 siRNA into the rat brain, wherein HMGB1 expression was depleted in over 40% of neurons and astrocytes of the normal brain. Moreover, e-PAM-R-mediated HMGB1 siRNA delivery notably reduced infarct volume in the postischemic rat brain, which is generated by occluding the middle cerebral artery for 60 min. These results indicate that e-PAM-R, a novel biodegradable nonviral gene carrier, offers an efficient means of transfecting siRNA into primary neuronal cells and in the brain and of

The transaction costs driving captive power generation: Evidence from India

International Nuclear Information System (INIS)

Ghosh, Ranjan; Kathuria, Vinish

2014-01-01

The 2003 Indian Electricity Act incentivizes captive power production through open access in an attempt to harness all sources of generation. Yet, we observe that only some firms self-generate while others do not. In this paper we give a transaction cost explanation for such divergent behavior. Using a primary survey of 107 firms from India, we construct a distinct variable to measure the transaction-specificity of electricity use. The ‘make or buy’ decision is then econometrically tested using probit model. Results are highly responsive to transaction-specificity and the likelihood of captive power generation is positively related to it. At the industrial level, this explains why food and chemical firms are more likely to make their own electricity. Since the burden of poor grid supply is highest on smaller sized and high transaction-specific firms, the grid access policies need to account for firm-level characteristics if government wants to incentivize captive power generation. - Highlights: • We analyze why some firms opt for captive power generation while others do not. • We examine the role of transaction costs in this decision making using probit model. • Unique data from a primary survey of manufacturing firms in Andhra Pradesh, India. • Transaction-specificity significantly determines who installs captive power plant (CPP). • Firm-level characteristics crucial in policies incentivizing captive generation

31 CFR 515.511 - Transactions by certain business enterprises.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Transactions by certain business enterprises. 515.511 Section 515.511 Money and Finance: Treasury Regulations Relating to Money and Finance... Licenses, Authorizations, and Statements of Licensing Policy § 515.511 Transactions by certain business...

31 CFR 500.511 - Transactions by certain business enterprises.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Transactions by certain business enterprises. 500.511 Section 500.511 Money and Finance: Treasury Regulations Relating to Money and Finance... Licenses, Authorizations and Statements of Licensing Policy § 500.511 Transactions by certain business...

The price impact of block transactions in the Netherlands

NARCIS (Netherlands)

de Jong, Abe; Marra, Teye; van Beusichem, Herman Clasinus

2016-01-01

In this paper, the authors analyse the stock price effects of block transactions and the disclosure thereof for Dutch firms. The authors measure a significant positive price effect for block purchases directly around the transaction date, but not for block sales. The authors do not measure a

Automated Measurement and Signaling Systems for the Transactional Network

Energy Technology Data Exchange (ETDEWEB)

Piette, Mary Ann; Brown, Richard; Price, Phillip; Page, Janie; Granderson, Jessica; Riess, David; Czarnecki, Stephen; Ghatikar, Girish; Lanzisera, Steven

2013-12-31

The Transactional Network Project is a multi-lab activity funded by the US Department of Energy?s Building Technologies Office. The project team included staff from Lawrence Berkeley National Laboratory, Pacific Northwest National Laboratory and Oak Ridge National Laboratory. The team designed, prototyped and tested a transactional network (TN) platform to support energy, operational and financial transactions between any networked entities (equipment, organizations, buildings, grid, etc.). PNNL was responsible for the development of the TN platform, with agents for this platform developed by each of the three labs. LBNL contributed applications to measure the whole-building electric load response to various changes in building operations, particularly energy efficiency improvements and demand response events. We also provide a demand response signaling agent and an agent for cost savings analysis. LBNL and PNNL demonstrated actual transactions between packaged rooftop units and the electric grid using the platform and selected agents. This document describes the agents and applications developed by the LBNL team, and associated tests of the applications.

R&D Cooperation Between Firms---A Perceived Transaction Cost Perspective

OpenAIRE

Klaus Brockhoff

1992-01-01

Transaction cost is considered as an explanatory variable for the choice between markets and various organizational arrangements for performing some predefined tasks, such as engaging in private R&D. With respect to R&D cooperation between firms, we show that the perception of high transaction cost is related to certain characteristics of the firm and to the type of R&D task. We also show a relationship between the perception of transaction cost and the perceived success of the cooperation. T...

Adaptive salinity management in the Murray-Darling Basin: a transaction cost study

Science.gov (United States)

Loch, A. J.

2017-12-01

Transaction costs hinder or promote effective management of common good resource intertemporal externalities. Appropriate policy choices may reduce externalities and improve social welfare, and transaction cost analysis can help to evaluate policy choices. However, without measurement of relevant transaction costs such policy evaluation remains challenging. This article uses a time series dataset of salinity management program to test theory aimed at transaction cost-based policy evaluation and adaptive resource management over a period of 30 years worth of data. We identify peaks and troughs in transaction costs over time, lag-effects in program expenditure, and calculate the decay in transaction cost impacts. We conclude that Australian salinity management programs are achieving flexible institutional outcomes and effective policy arrangements with long-term benefits. Proposed changes to the program moving forward add weight to our assertions of adaptive strategies, and illustrate the value of the novel data-driven tracnsaction cost analysis approach for other jurisdictions.

INTER-BANK CALL MONEY MARKET TRANSACTION IN INDONESIA

Directory of Open Access Journals (Sweden)

Aries Haryadi

2013-10-01

Full Text Available AbstractThis study analyzes the effect of Indonesian Bank loan, the amount of demand deposits, and the Indonesia economic crisis in 1997 on the interbank call money market transactions in Indonesia using a multiple linear regression method. This study finds that the variables influencing the interbank call money market transactions are the interest rate of interbank call money market and the check money. Both variables have positive effect on the interbank money market transactions in Indonesia.Keywords: Loans, Interest Rate, Check Money, Monetary Crisis, Interbank Money Market TransactionsJEL Classification Numbers: G21, G28AbstrakPenelitian ini menganalisis pengaruh pinjaman Bank Indonesia terhadap tingkat bunga pasar uang antar bank, jumlah uang giral, dan krisis ekonomi Indonesia tahun 1997 terhadap transaksi pasar uang antar bank di Indonesia menggunakan metode regresi linier berganda. Penelitian ini menemukan bahwa variabel yang berpengaruh terhadap transaksi pasar uang antar bank tersebut adalah tingkat bunga pasar uang antar bank dan jumlah uang giral. Dua variabel tersebut berpengaruh positif terhadap transaksi pasar uang antar bank di Indonesia.Keywords: Pinjaman, Tingkat Bunga, Uang Giral, Krisis Moneter, Transaksi Pasar Uang antar BankJEL Classification Numbers: G21, G28

Disclosure requirements for merger and acquisition transactions

International Nuclear Information System (INIS)

Holm, D.I.

1998-01-01

The legal disclosure requirements for merger and acquisition transactions involving Canadian public companies are described. The focus is on issues regarding merger and acquisition related disclosure, including the potential consequences of failing to provide proper information, Ontario Securities Commission Policy 9.1 considerations regarding valuation, review, and approval, cross border considerations and financing a merger and acquisition transaction. Legal and practical consequences for failing to provide proper disclosure, including the steps involved in establishing the due diligence defence, are also discussed

17 CFR 32.11 - Suspension of commodity option transactions.

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Suspension of commodity option... REGULATION OF COMMODITY OPTION TRANSACTIONS § 32.11 Suspension of commodity option transactions. (a... accept money, securities or property in connection with, the purchase or sale of any commodity option, or...

Biocompatible and colloidally stabilized mPEG-PE/calcium phosphate hybrid nanoparticles loaded with siRNAs targeting tumors

OpenAIRE

Gao, Pei; Zhang, Xiangyu; Wang, Hongzhi; Zhang, Qinghong; Li, He; Li, Yaogang; Duan, Yourong

2015-01-01

Calcium phosphate nanoparticles are safe and effective delivery vehicles for small interfering RNA (siRNA), as a result of their excellent biocompatibility. In this work, mPEG-PE (polyethylene glycol-L-?-phosphatidylethanolamine) was synthesized and used to prepare nanoparticles composed of mPEG-PE and calcium phosphate for siRNA delivery. Calcium phosphate and mPEG-PE formed the stable hybrid nanoparticles through self-assembly resulting from electrostatic interaction in water. The average s...

An albumin-mediated cholesterol design-based strategy for tuning siRNA pharmacokinetics and gene silencing

DEFF Research Database (Denmark)

Bienk, Konrad; Hvam, Michael Lykke; Pakula, Malgorzata Maria

2016-01-01

/2 12 min (naked) to t1/2 45 min (single cholesteryl) and t1/2 71 min (double cholesteryl) using fluorescent live bioimaging. The biodistribution showed increased accumulation in the liver for the double cholesteryl modified siRNA that correlated with an increase in hepatic Factor VII gene silencing......HSA/siRNA complex exhibited reduced nuclease degradation and reduced induction of TNF-α production by human peripheral blood mononuclear cells. The increased solubility of heavily cholesteryl modified siRNA in the presence of rHSA facilitated duplex annealing and consequent interaction that allowed in vivo studies...

Transaction Costs, the Phenomenon of the Trading House and Economic Organization

Directory of Open Access Journals (Sweden)

Kiryanov Igor, V.

2015-12-01

Full Text Available The present paper contains a study of the phenomenon of company’s specific internal divisions called “trading house”. The analysis of different approaches (based on results obtained by R. Coase and O. Williamson towards the problem of impact of transaction cost on company size leads to the following conclusion: the company size mostly depends on its institutional architecture which includes specific divisions that ensure outsourcing of intergroup transaction cost. I propose to call these divisions centers of transaction cost. I suppose that the wide popularity of trading houses among companies belonging to different branches can be explained by the fact that a trading house is mostly used not as selling and purchasing division, but as a center of transaction cost that concentrates the biggest transaction cost (by its share within company’s general expenses. This reasoning leads to possibility of existence of a set of methodological principles that allow to build up an a priori model of expanding company. The process of expansion represents a series of inclusion of centers of transactions cost by the company after institutional advantages of an earlier institutional architecture disappear. This methodology allows to set up a classification between a classical company as a structure with low level of integration and frozen institutional architecture and an economic organization that represents an explicitly constructed composition including centers of transaction cost that help to extend the transformational space of an expanding company.

siRNA associated with immunonanoparticles directed against cd99 antigen improves gene expression inhibition in vivo in Ewing's sarcoma.

Science.gov (United States)

Ramon, A L; Bertrand, J R; de Martimprey, H; Bernard, G; Ponchel, G; Malvy, C; Vauthier, C

2013-07-01

Ewing's sarcoma is a rare, mostly pediatric bone cancer that presents a chromosome abnormality called EWS/Fli-1, responsible for the development of the tumor. In vivo, tumor growth can be inhibited specifically by delivering small interfering RNA (siRNA) associated with nanoparticles. The aim of the work was to design targeted nanoparticles against the cell membrane glycoprotein cd99, which is overexpressed in Ewing's sarcoma cells to improve siRNA delivery to tumor cells. Biotinylated poly(isobutylcyanoacrylate) nanoparticles were conceived as a platform to design targeted nanoparticles with biotinylated ligands and using the biotin-streptavidin coupling method. The targeted nanoparticles were validated in vivo for the targeted delivery of siRNA after systemic administration to mice bearing a tumor model of the Ewing's sarcoma. The expression of the gene responsible of Ewing's sarcoma was inhibited at 78% ± 6% by associating the siRNA with the cd99-targeted nanoparticles compared with an inhibition of only 41% ± 9% achieved with the nontargeted nanoparticles. Copyright © 2013 John Wiley & Sons, Ltd.

Disregarded Effect of Biological Fluids in siRNA Delivery: Human Ascites Fluid Severely Restricts Cellular Uptake of Nanoparticles.

Science.gov (United States)

Dakwar, George R; Braeckmans, Kevin; Demeester, Joseph; Ceelen, Wim; De Smedt, Stefaan C; Remaut, Katrien

2015-11-04

Small interfering RNA (siRNA) offers a great potential for the treatment of various diseases and disorders. Nevertheless, inefficient in vivo siRNA delivery hampers its translation into the clinic. While numerous successful in vitro siRNA delivery stories exist in reduced-protein conditions, most studies so far overlook the influence of the biological fluids present in the in vivo environment. In this study, we compared the transfection efficiency of liposomal formulations in Opti-MEM (low protein content, routinely used for in vitro screening) and human undiluted ascites fluid obtained from a peritoneal carcinomatosis patient (high protein content, representing the in vivo situation). In Opti-MEM, all formulations are biologically active. In ascites fluid, however, the biological activity of all lipoplexes is lost except for lipofectamine RNAiMAX. The drop in transfection efficiency was not correlated to the physicochemical properties of the nanoparticles, such as premature siRNA release and aggregation of the nanoparticles in the human ascites fluid. Remarkably, however, all of the formulations except for lipofectamine RNAiMAX lost their ability to be taken up by cells following incubation in ascites fluid. To take into account the possible effects of a protein corona formed around the nanoparticles, we recommend always using undiluted biological fluids for the in vitro optimization of nanosized siRNA formulations next to conventional screening in low-protein content media. This should tighten the gap between in vitro and in vivo performance of nanoparticles and ensure the optimal selection of nanoparticles for further in vivo studies.

Modelling Real Property Transactions

DEFF Research Database (Denmark)

Stubkjær, Erik

2002-01-01

for more elaborated concept sets - for a theoretical basis - was among the motives for proposing a concerted research project: Modelling Real Property Transactions. Researchers from 11 European countries co-operate in the project that gained status as a COST action as of March 1st 2001. The majority...

Modelling Real Property Transactions

DEFF Research Database (Denmark)

Stubkjær, Erik

2003-01-01

Der er store forskelle i financieringsomkostningerne ved hussalg i forskellige lande. Er disse forskelle nødvendige? og kan udgifterne reduceres? Sådanne spørgsmål søger forskningsprojektet ?Modelling Real Property Transactions?, officielt sat i værk indenfor rammerne af COST (European Co...

Multifunctional triblock co-polymer mP3/4HB-b-PEG-b-lPEI for efficient intracellular siRNA delivery and gene silencing.

Science.gov (United States)

Zhou, Li; Chen, Zhifei; Wang, Feifei; Yang, Xiuqun; Zhang, Biliang

2013-04-01

A non-viral siRNA carrier composed of mono-methoxy-poly (3-hydroxybutyrate-co-4-hydroxybutyrate)-block-polyethylene glycol-block-linear polyethyleneimine (mP3/4HB-b-PEG-b-lPEI) was synthesized using 1800 Da linear polyethyleneimine and evaluated for siRNA delivery. Our study demonstrated that siRNA could be efficiently combined with mP3/4HB-b-PEG-b-lPEI (mAG) co-polymer and was protected from nuclease degradation. The combined siRNA were released from the complexes easily under heparin competition. The particle size of the mAG/siRNA complexes was 158 nm, with a ζ-potential of around 28 mV. Atomic force microscopy images displayed spherical and homogeneously distributed complexes. The mAG block co-polymer displayed low cytotoxicity and efficient cellular uptake of Cy3-siRNA in A549 cells by flow cytometry and confocal microscopy. In vitro transfection efficiency of the block co-polymer was assessed using siRNA against luciferase in cultured A549-Luc, HeLa-Luc, HLF-Luc, A375-Luc and MCF-7-Luc cells. A higher transfection efficiency and lower cytotoxicity was obtained by mAG block co-polymer in five cell lines. Furthermore, a remarkable improvement in luciferase gene silencing efficiency of the mAG complex (up to 90-95%) over that of Lipofectamine™ 2000 (70-82%) was observed in HLF-Luc and A375-Luc cells. Additionally, a mAG/p65-siRNA complex also showed a better capability than Lipofectamine™ 2000/p65-siRNA complex to drastically reduce the p65 mRNA level down to 10-16% in HeLa, U251 and HUVEC cells at an N/P ratio of 70. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Tax-driven Bunching of Housing Market Transactions: The Case of Hong Kong

OpenAIRE

Charles Ka Yui Leung; Tin Cheuk Leung; Kwok Ping Tsang

2015-01-01

We study the implications of a property market transaction tax. As property buyers are obligated to pay a transaction tax (¡§stamp duty¡¨ or SD) where the rate increases with the value of the transaction, there are incentives to trade at the cutoff points of the tax schedule or just below them. Thus, both ¡§bunching in transactions¡¨ and ¡§underpricing¡¨ should be observed near those cutoffs. Furthermore, the bunching points should change with the tax schedule. We confirm these conjectures wi...

Money laundering: correlation between risk assessment and suspicious transactions

Directory of Open Access Journals (Sweden)

Sonja Cindori

2013-06-01

Full Text Available The risk assessment system was introduced in the Republic of Croatia in 2009, as a result of harmonization with international standards, especially the Directive 2005/60/EC on the prevention of the use of the financial system for the purpose of money laundering and terrorist financing. Risk assessment is an extensive concept which requires not only a legislative framework, but also the application of numerous criteria for its effective implementation in practice. Among these criteria are suspicious transactions, closely related to the assessment of the customer, transaction, product or service.The undeniable contribution of suspicious transactions to the quality of the risk assessment system will be confirmed by a statistical analysis of a number of West and East European countries. A combination of strict, but sufficiently flexible legal provisions governing the system for prevention of money laundering and terrorist financing and a statistical analysis of reported suspicious transactions will lead to conclusions that either support or represent criticism of the efficiency of application of the risk assessment system in practice.The aforementioned statistical analysis will show whether suspicious transactions are a reliable criterion for the risk assessment analysis, and whether they can be considered the only such criterion. There is a possibility that the findings of the analysis will be contradictory to those of some international studies.

SKI2 mediates degradation of RISC 5′-cleavage fragments and prevents secondary siRNA production from miRNA targets in Arabidopsis

Science.gov (United States)

Branscheid, Anja; Marchais, Antonin; Schott, Gregory; Lange, Heike; Gagliardi, Dominique; Andersen, Stig Uggerhøj; Voinnet, Olivier; Brodersen, Peter

2015-01-01

Small regulatory RNAs are fundamental in eukaryotic and prokaryotic gene regulation. In plants, an important element of post-transcriptional control is effected by 20–24 nt microRNAs (miRNAs) and short interfering RNAs (siRNAs) bound to the ARGONAUTE1 (AGO1) protein in an RNA induced silencing complex (RISC). AGO1 may cleave target mRNAs with small RNA complementarity, but the fate of the resulting cleavage fragments remains incompletely understood. Here, we show that SKI2, SKI3 and SKI8, subunits of a cytoplasmic cofactor of the RNA exosome, are required for degradation of RISC 5′, but not 3′-cleavage fragments in Arabidopsis. In the absence of SKI2 activity, many miRNA targets produce siRNAs via the RNA-dependent RNA polymerase 6 (RDR6) pathway. These siRNAs are low-abundant, and map close to the cleavage site. In most cases, siRNAs were produced 5′ to the cleavage site, but several examples of 3′-spreading were also identified. These observations suggest that siRNAs do not simply derive from RDR6 action on stable 5′-cleavage fragments and hence that SKI2 has a direct role in limiting secondary siRNA production in addition to its function in mediating degradation of 5′-cleavage fragments. PMID:26464441

Development of a cell-defined siRNA microarray for analysis of gene function in human bone marrow stromal cells

Directory of Open Access Journals (Sweden)

Hi Chul Kim

2016-03-01

The efficiency of this CDSM was verified using three siRNAs (targeting p65, Slug, and N-cadherin, with persistent gene silencing for 5 days. We obtained the significant and reliable data with effective knock-down in our condition, and suggested our method as the qualitatively improved siRNA microarray screening method for hBMSCs.

Transactional Mechanism of Territorial Administration: Conceptualisation and Systematization of Elements

Directory of Open Access Journals (Sweden)

Elena Аleksandrovna Petrova

2016-12-01

Full Text Available The concept of transaction expenses developed by R. Coase allows to consider functioning of economy and its agents from the information viewpoint. This viewpoint implies that information exchange between agents and the urge to overcome information incompleteness start playing the crucial role. Transaction expenses are information exchange costs for the purpose of elimination (reduction of its incompleteness and the related uncertainty. R. Coase showed that creation and the size of firms are closely connected with the urge to minimize transaction expenses. Traditionally transaction expenses are associated with functioning of firms, however, the state actively participates in economy, for example, through formation of tax policy. Besides, financing of the public benefits takes place on the basis of collective decisions. But collective character of the decision causes interest, though smaller in comparison with the private choice, in the maximum efficiency of the decision. It is ensured by two factors: firstly, the position of an individual is not of great importance at collective decision-making; secondly, an individual is responsible for a small part of benefits and expenses which are formed in the course of decision implementation. The article deals with the concept of transaction costs, and systematically occurring types of transaction costs in the following groups: search information costы, the cost of negotiating, measuring costs, the costs of specification and protection of property rights, the costs of opportunistic behavior, the cost of “politicizing”, the costs of collective decisionmaking, influence costs. The authors propose a model of transaction mechanism of territorial administration, which includes the following elements: economic entities; a goal determined by system of indicators; methods; instruments; channels; forms of target use; landmark feedback on the system; subject to the experience stage of modernization; criteria

Emissions trading to combat climate change: The impact of scheme design on transaction costs

OpenAIRE

Betz, Regina

2006-01-01

This paper explores the likely impact of emissions trading design on transaction costs. Transaction costs include both the costs for the private sector to comply with the scheme rules and the costs of scheme administration. In economic theory transaction costs are often assumed to be zero. But transaction costs are real costs and there is no reason for treating them differently to other costs. Thus, in setting up an emissions trading scheme, transaction costs have to be taken into account in ...

25 CFR 117.23 - Transactions between guardian and ward.

Science.gov (United States)

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Transactions between guardian and ward. 117.23 Section... COMPETENCY § 117.23 Transactions between guardian and ward. Business dealings between the guardian and his ward involving the sale or purchase of any property, real or personal, by the guardian to or from the...

Impact of multilateral congestion management on the reliability of power transactions

International Nuclear Information System (INIS)

Rodrigues, A.B.; Da Silva, M.G.

2003-01-01

The restructuring of the electricity industry has caused an increase in the number of transactions in the energy market. These transactions are defined by market forces without considering operational constraints of the transmission system. Consequently, there are transactions that cause congestion in the transmission network. This paper has as objective to assess the impact of multilateral congestion management on the reliability of power transactions. This assessment is based on reliability indices such as expected power curtailments, curtailment probability, expected cost of congestion management and probability distributions of the total power curtailment. Tests results with IEEE RTS-1996 demonstrate that the multilateral management results in smaller curtailments and congestion costs than traditional bilateral management. (author)

Analysis of transaction costs for the supply and demand for wood fuels

International Nuclear Information System (INIS)

Roos, A.; Bohlin, F.; Hektor, B.; Hillring, B.; Parikka, M.

2001-12-01

The objective of the project was to analyse the importance of transaction costs for the supply and demand for woodfuels in Sweden. The project covered the period of great expansion of woodfuel use in the district heating sector, from 1980 until present. It uses literature studies, case studies and surveys. New institutional theory and transaction cost theory was applied. Several transaction costs have influenced both supply from the forest owners and demand from the main users, the district heating plants. Many of these transaction costs have been reduced by the market players, through learning, technical improvements and institutional innovations. Actions to reduce transaction costs have accompanied technical improvements of handling and transport. Strategies for woodfuel procurement have also been analysed. Important conclusions of the project for a change in the energy system are presented

Novel siRNA delivery system using a ternary polymer complex with strong silencing effect and no cytotoxicity.

Science.gov (United States)

Kodama, Yukinobu; Shiokawa, Yumi; Nakamura, Tadahiro; Kurosaki, Tomoaki; Aki, Keisei; Nakagawa, Hiroo; Muro, Takahiro; Kitahara, Takashi; Higuchi, Norihide; Sasaki, Hitoshi

2014-01-01

We developed a novel small interfering RNA (siRNA) delivery system using a ternary complex with polyethyleneimine (PEI) and γ-polyglutamic acid (γ-PGA), which showed silencing effect and no cytotoxicity. The binary complexes of siRNA with PEI were approximately 73-102 nm in particle size and 45-52 mV in ζ-potential. The silencing effect of siRNA/PEI complexes increased with an increase of PEI, and siRNA/PEI complexes with a charge ratio greater than 16 showed significant luciferase knockdown in a mouse colon carcinoma cell line regularly expressing luciferase (Colon26/Luc cells). However, strong cytotoxicity and blood agglutination were observed in the siRNA/Lipofectamine complex and siRNA/PEI16 complex. Recharging cationic complexes with an anionic compound was reported to be a promising method for overcoming these toxicities. We therefore prepared ternary complexes of siRNA with PEI (charge ratio 16) by the addition of γ-PGA to reduce cytotoxicity and deliver siRNA. As expected, the cytotoxicity of the ternary complexes decreased with an increase of γ-PGA content, which decreased the ζ-potential of the complexes. A strong silencing effect comparable to siRNA/Lipofectamine complex was discovered in ternary complexes including γ-PGA with an anionic surface charge. The high incorporation of ternary complexes into Colon26/Luc cells was confirmed with fluorescence microcopy. Having achieved knockdown of an exogenously transfected gene, the ability of the complex to mediate knockdown of an endogenous housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), was assessed in B16-F10 cells. The ternary complex (siRNA/PEI16/γ-PGA12 complex) exhibited a significant GAPDH knockdown effect. Thus, we developed a useful siRNA delivery system.

Realisation of functions of planning and organisation in the system of management of transaction expenses

Directory of Open Access Journals (Sweden)

Krush Peter V.

2014-01-01

Full Text Available The goal of the article lies in building a functional model of management of transaction expenses of an enterprise with specification of stages of realisation of planning functions in an organisation. In the result of the study the article marks out functions of management of transaction expenses, which ensure transformation of incoming (financial resources into outgoing ones (optimised transaction expenses. The article identifies stages of realisation of “Planning transaction expenses” and “Organisation of management of transaction expenses” functions. It characterises in detail responsibilities of enterprise subdivisions that deal with management of transaction expenses. It establishes that the original element of the planning function is the budget of transaction expenses for a planning period and organisation – job descriptions of employees with detailed description of their duties and authorities, rights and obligations. The prospect of further scientific developments is study of stages of realisation of such management functions as “Motivation of personnel on rational use of funds and management of transaction expenses”, “Control over the state of management of transaction expenses” and “Regulation of the process of management of transaction expenses” of enterprises.

Thermoresponsive pegylated bubble liposome nanovectors for efficient siRNA delivery via endosomal escape

KAUST Repository

Alamoudi, Kholod

2017-05-19

Improving the delivery of siRNA into cancer cells via bubble liposomes. Designing a thermoresponsive pegylated liposome through the introduction of ammonium bicarbonate salt into liposomes so as to control their endosomal escape for gene therapy.A sub-200 nm nanovector was fully characterized and examined for cellular uptake, cytotoxicity, endosomal escape and gene silencing.The siRNA-liposomes were internalized into cancer cells within 5 min and then released siRNAs in the cytosol prior to lysosomal degradation upon external temperature elevation. This was confirmed by confocal bioimaging and gene silencing reaching up to 90% and further demonstrated by the protein inhibition of both target genes.The thermoresponsiveness of ammonium bicarbonate containing liposomes enabled the rapid endosomal escape of the particles and resulted in an efficient gene silencing.

Thermoresponsive pegylated bubble liposome nanovectors for efficient siRNA delivery via endosomal escape

KAUST Repository

Alamoudi, Kholod; Martins, Patricia; Croissant, Jonas G.; Patil, Sachin; Omar, Haneen; Khashab, Niveen M.

2017-01-01

Improving the delivery of siRNA into cancer cells via bubble liposomes. Designing a thermoresponsive pegylated liposome through the introduction of ammonium bicarbonate salt into liposomes so as to control their endosomal escape for gene therapy.A sub-200 nm nanovector was fully characterized and examined for cellular uptake, cytotoxicity, endosomal escape and gene silencing.The siRNA-liposomes were internalized into cancer cells within 5 min and then released siRNAs in the cytosol prior to lysosomal degradation upon external temperature elevation. This was confirmed by confocal bioimaging and gene silencing reaching up to 90% and further demonstrated by the protein inhibition of both target genes.The thermoresponsiveness of ammonium bicarbonate containing liposomes enabled the rapid endosomal escape of the particles and resulted in an efficient gene silencing.

7 CFR 1927.53 - Costs of title clearance and closing of transactions.

Science.gov (United States)

2010-01-01

... 7 Agriculture 12 2010-01-01 2010-01-01 false Costs of title clearance and closing of transactions... and Loan Closing § 1927.53 Costs of title clearance and closing of transactions. The borrower or the... payment of all costs of title clearance and closing of the transaction and will arrange for payment before...

A Mechanically Proved and an Incremental Development of the Session Initiation Protocol INVITE Transaction

Directory of Open Access Journals (Sweden)

Rajaa Filali

2014-01-01

Full Text Available The Session Initiation Protocol (SIP is an application layer signaling protocol used to create, manage, and terminate sessions in an IP based network. SIP is considered as a transactional protocol. There are two main SIP transactions, the INVITE transaction and the non-INVITE transaction. The SIP INVITE transaction specification is described in an informal way in Request for Comments (RFC 3261 and modified in RFC 6026. In this paper we focus on the INVITE transaction of SIP, over reliable and unreliable transport mediums, which is used to initiate a session. In order to ensure the correctness of SIP, the INVITE transaction is modeled and verified using event-B method and its Rodin platform. The Event-B refinement concept allows an incremental development by defining the studied system at different levels of abstraction, and Rodin discharges almost all proof obligations at each level. This interaction between modeling and proving reduces the complexity and helps in assuring that the INVITE transaction SIP specification is correct, unambiguous, and easy to understand.

Implementation and Analysis of the use of the Blockchain Transactions on the Workings of the Bitcoin

Science.gov (United States)

Rizky Fauzi, Muhammad Reza; Michrandi Nasution, Surya; Paryasto, Marisa W.

2017-11-01

The present study discusses the workings of blockchain bitcoin in the transactions sector, on the development of today’s emerging computers in the financial sector of blockchain bitcoin traction. In this case the author analyzes how the transaction is running, as well as how blockchain bitcoin is doing work in transactions on the system to make transactions. Transaction is a data structure that encodes the transfer of values between users with in a bitcoin system. Every transaction is a public entry in this bitcoin blockchain. And become a large transaction bookkeeping global.

27 CFR 555.127 - Daily summary of magazine transactions.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 3 2010-04-01 2010-04-01 false Daily summary of magazine....127 Daily summary of magazine transactions. In taking the inventory required by §§ 555.122, 555.123... transactions to be kept at each magazine of an approved storage facility; however, these records may be kept at...

Plural Governance: A Modified Transaction Cost Model

DEFF Research Database (Denmark)

Mols, Niels Peter; Menard, Claude

2014-01-01

Plural governance is a form of governance where a firm both makes and buys similar goods or services. Despite a widespread use of plural governance there are no transaction cost models of how plural governance affects performance. This paper reviews the literature about plural forms and proposes...... a model relating transaction cost and resource-based variables to the cost of the plural form. The model is then used to analyze when the plural form is efficient compared to alternative governance structures. We also use the model to discuss the strength of three plural form synergies....

Determinants of Transactions Costs in the Brazilian Stock Market

Directory of Open Access Journals (Sweden)

Antonio Zoratto Sanvicente

2012-06-01

Full Text Available The Lesmond (2005 method for estimating transactions costs, based on a limited-dependent variable model, is used in order to test for the significance of plausible explanations for cross sectional cost differences. Variables such as liquidity, volatility, firm size, quality of corporate governance and participation in ADR programs are considered, in addition to the possible impact of the 2008 crisis. Daily data for 1999-2009 are used, covering at least 250 securities each year. The average total transaction cost declined from 2.95% in 1999 to 1.22% in 2009. Stock volatility and quality of corporate governance appear to be the most relevant factors associated with the measure of transactions cost.

Synthetic siRNAs effectively target cystein protease 12 and α-actinin transcripts in Trichomonas vaginalis.

Science.gov (United States)

Ravaee, Roya; Ebadi, Parimah; Hatam, Gholamreza; Vafafar, Arghavan; Ghahramani Seno, Mohammad Mahdi

2015-10-01

The flagellated protozoan Trichomonas vaginalis (T. vaginalis) causes trichomoniasis, a reproductive tract infection, in humans. Trichomoniasis is the most common non-viral sexually transmitted disease worldwide. In addition to direct consequences such as infertility and abortion, there are indications that trichomoniasis favours development of prostate cancer and it has also been associated with increased risk of spreading human immunodeficiency virus and papillomavirus infections. Reports from around the world show that the rate of drug resistance in T. vaginalis is increasing, and therefore new therapeutic approaches have to be developed. Studying molecular biology of T. vaginalis will be quite helpful in identifying new drugable targets. RNAi is a powerful technique which allows biologist to specifically target gene products (i.e. mRNA) helping them in unravelling gene functions and biology of systems. However, due to lack of some parts of the required intrinsic RNAi machinery, the RNAi system is not functional in all orders of life. Here, by using synthetic siRNAs targeting two genes, i.e. α-actinin and cystein protease 12 (cp12), we demonstrate T. vaginalis cells are amenable to RNAi experiments conducted by extrinsic siRNAs. Electroporation of siRNAs targeting α-actinin or cp12 into T. vaginalis cells resulted in, respectively, 48-67% and 33-72% downregulation of the cognate transcripts compared to the T. vaginalis cells received siRNAs targeting GL2 luciferase as a control. This finding is helpful in that it demonstrates the potential of using extrinsically induced RNAi in studies on molecular biology of T. vaginalis such as those aiming at identifying new drug targets. Copyright © 2015 Elsevier Inc. All rights reserved.

78 FR 56769 - Genesee & Wyoming Inc.-Corporate Family Transaction Exemption

Science.gov (United States)

2013-09-13

... unnecessary intermediate subsidiaries, which will save unnecessary accounting and corporate maintenance. This... Inc.--Corporate Family Transaction Exemption Genesee & Wyoming Inc. (GWI), a noncarrier holding company, filed a verified notice of exemption under 49 CFR 1180.2(d)(3) for a corporate family transaction...

Parallel transaction processing in functional languages, towards practical functional databases

NARCIS (Netherlands)

Wevers, L.; Huisman, Marieke; de Keijzer, Ander

2013-01-01

This paper shows how functional languages can be adapted for transaction processing, and discusses the implementation of a parallel runtime system for such functional transaction processing languages. We extend functional languages with current state variables and result state variables to allow the

Transaction aware tape-infrastructure monitoring

International Nuclear Information System (INIS)

Nikolaidis, Fotios; Kruse, Daniele Francesco

2014-01-01

Administrating a large scale, multi protocol, hierarchical tape infrastructure like the CERN Advanced STORage manager (CASTOR)[2], which stores now 100 PB (with an increasing step of 25 PB per year), requires an adequate monitoring system for quick spotting of malfunctions, easier debugging and on demand report generation. The main challenges for such system are: to cope with CASTOR's log format diversity and its information scattered among several log files, the need for long term information archival, the strict reliability requirements and the group based GUI visualization. For this purpose, we have designed, developed and deployed a centralized system consisting of four independent layers: the Log Transfer layer for collecting log lines from all tape servers to a single aggregation server, the Data Mining layer for combining log data into transaction context, the Storage layer for archiving the resulting transactions and finally the Web UI layer for accessing the information. Having flexibility, extensibility and maintainability in mind, each layer is designed to work as a message broker for the next layer, providing a clean and generic interface while ensuring consistency, redundancy and ultimately fault tolerance. This system unifies information previously dispersed over several monitoring tools into a single user interface, using Splunk, which also allows us to provide information visualization based on access control lists (ACL). Since its deployment, it has been successfully used by CASTOR tape operators for quick overview of transactions, performance evaluation, malfunction detection and from managers for report generation.

Parallel-Architecture Simulator Development Using Hardware Transactional Memory

OpenAIRE

Armejach Sanosa, Adrià

2009-01-01

To address the need for a simpler parallel programming model, Transactional Memory (TM) has been developed and promises good parallel performance with easy-to-write parallel code. Unlike lock-based approaches, with TM, programmers do not need to explicitly specify and manage the synchronization among threads. However, programmers simply mark code segments as transactions, and the TM system manages the concurrency control for them. TM can be implemented either in software (STM) or hardware (HT...

THE IMPACT OF MERGER AND ACQUISITION TRANSACTIONS AT THE COMPANY AND INDUSTRY LEVEL

Directory of Open Access Journals (Sweden)

Elif Akben Selçuk

2016-04-01

Full Text Available The objective of this study is to provide a literature review consisting of studies investigating the impact of mergers and acquisition (M&A transactions at the micro and macro levels. The review has three different parts. In the first part, the focus is on the macro effects of M&A transactions and the impact of these transactions at the industry and market levels as well as their determinants are investigated. The second part comprises studies analyzing the effects of M&A transactions on the financial performance of the acquirer and target companies. In the third and final section, the factors affecting the financial performance changes as a result of M&A transactions are discussed.

Provable Fair Document Exchange Protocol with Transaction Privacy for E-Commerce

Directory of Open Access Journals (Sweden)

Ren-Junn Hwang

2015-04-01

Full Text Available Transaction privacy has attracted a lot of attention in the e-commerce. This study proposes an efficient and provable fair document exchange protocol with transaction privacy. Using the proposed protocol, any untrusted parties can fairly exchange documents without the assistance of online, trusted third parties. Moreover, a notary only notarizes each document once. The authorized document owner can exchange a notarized document with different parties repeatedly without disclosing the origin of the document or the identities of transaction participants. Security and performance analyses indicate that the proposed protocol not only provides strong fairness, non-repudiation of origin, non-repudiation of receipt, and message confidentiality, but also enhances forward secrecy, transaction privacy, and authorized exchange. The proposed protocol is more efficient than other works.

Components of the costs of controlling quality: a transaction cost economics approach.

Science.gov (United States)

Stiles, R A; Mick, S S

1997-01-01

This article identifies the components that contribute to a healthcare organization's costs in controlling quality. A central tenet of our argument is that at its core, quality is the result of a series of transactions among members of a diverse network. Transaction cost economics is applied internally to analyze intraorganizational transactions that contribute to quality control, and questions for future research are posed.

17 CFR 210.3A-04 - Intercompany items and transactions.

Science.gov (United States)

2010-04-01

... Financial Statements § 210.3A-04 Intercompany items and transactions. In general, there shall be eliminated intercompany items and transactions between persons included in the (a) consolidated financial statements being... FORM AND CONTENT OF AND REQUIREMENTS FOR FINANCIAL STATEMENTS, SECURITIES ACT OF 1933, SECURITIES...

Transaction Costs, Property Rights, and Organizational Culture: An Exchange Perspective.

Science.gov (United States)

Jones, Gareth R.

1983-01-01

Applying the language of exchange theory, this paper analyses how organizational culture emerges out of the institutional arrangements developed to regulate the transactions between members. Transaction costs of social exchange, the characteristics and etiology of those institutional arrangements, and three ideal-typical cultural forms are…

Optimization-based sale transactions and hydrothermal scheduling

International Nuclear Information System (INIS)

Prasannan, B.; Luh, P.B.; Zhang, L.

1996-01-01

Selling and purchasing power are important activities for utilities because of potential savings. When a selling utility presents an offer including prices, power levels and durations, a purchasing utility selects power levels and durations within the offered range subject to relevant constraints. The decisionmaking process is complicated because transactions are coupled with system demand and reserve, therefore decisions have to be made in conjunction with the commitment and dispatching of units. Furthermore, transaction decisions have to be made in almost real time in view of the competitiveness of the power market caused by deregulation. In this paper, transactions are analyzed from a selling utility's viewpoint for a system consisting of thermal, hydro and pumped-storage units. To effectively solve the problem, linear sale revenues are approximated by nonlinear functions, and non-profitable options are identified and eliminated from consideration. The multipliers are then updated at the high level by using a modified subgradient method to obtain near optimal solutions quickly. Testing results show that the algorithm produces good sale offers efficiently

Transaction costs of raising energy efficiency

Energy Technology Data Exchange (ETDEWEB)

Ostertag, K.

2003-07-01

Part of the debate evolves around the existence and importance of energy saving potentials to reduce CO{sub 2} emissions that may be available at negative net costs, implying that the energy cost savings of one specific technology can actually more than offset the costs of investing into this technology and of using it. This so called ''no-regret'' potential would comprise measures that from a pure economic efficiency point of view would be ''worth undertaking whether or not there are climate-related reasons for doing so''. The existence of the no-regret potential is often denied by arguing, that the economic evaluation of the energy saving potentials did not take into account transaction costs. This paper will re-examine in more detail the concept of transaction costs as it is used in the current debate on no-regret potentials (section 1). Four practical examples are presented to illustrate how transaction costs and their determinants can be identified, measured and possibly influenced (section 2). In order to link the presented cases to modelling based evaluation approaches the implications for cost evaluations of energy saving measures, especially in the context of energy system modelling, will be shown (section 3). (author)

siRNA targeting PLK-1 induces apoptosis of synoviocytes in rheumatoid arthritis

International Nuclear Information System (INIS)

Wada, Makoto; Kawahito, Yutaka; Kimura, Shinya; Kohno, Masataka; Ishino, Hidetaka; Kimura, Mizuho; Omoto, Atsushi; Yamamoto, Aihiro; Hamaguchi, Masahide; Tsubouchi, Yasunori; Tokunaga, Daisaku; Hojo, Tatsuya; Ashihara, Eishi; Maekawa, Taira; Yoshikawa, Toshikazu

2007-01-01

Polo-like kinase-1 (PLK-1) is a member of the PLK family and participates in the control of cell mitosis. Here, we show that immunoreactive PLK-1 is strongly expressed in synoviocytes and some infiltrative mononuclear cells in synovial tissues from patients with rheumatoid arthritis (RA), while patients with osteoarthritis and injury show little or no expression of PLK-1 in synovial tissues. Western blot analysis shows that PLK is expressed and its expression is enhanced by IL-1β in RA synoviocytes. IL-1β also enhanced the cell growth of RA synoviocytes. Moreover, siRNA targeted against PLK-1 significantly decreases the expression of PLK-1 of RA synoviocytes stimulated by IL-1β and suppresses the proliferation of these synoviocytes through apoptosis. These findings suggest that PLK-1 plays a critical role in the proliferation of RA synoviocytes leading to bone destruction, and siRNA against PLK-1 is potentially useful for the treatment of RA

International business transactions

OpenAIRE

Buczkowski, Bogdan

2016-01-01

Running a business on an international scale requires not only a substantial body of knowledge but also the ability to apply it in practice. That is why our textbook, with a vast collection of practical examples, discusses a wide variety of pertinent issues connected with business operations in international markets, from international market analysis, drafting business plans, concluding business transactions and the insurance of goods through to customs clearance procedures and professional ...

Do transactive memory and participative teamwork improve nurses' quality of work life?

Science.gov (United States)

Brunault, Paul; Fouquereau, Evelyne; Colombat, Philippe; Gillet, Nicolas; El-Hage, Wissam; Camus, Vincent; Gaillard, Philippe

2014-03-01

Improvement in nurses' quality of work life (QWL) has become a major issue in health care organizations. We hypothesized that the level of transactive memory (defined as the way groups collectively encode, store, and retrieve knowledge) and participative teamwork (an organizational model of care based on vocational training, a specific service's care project, and regular interdisciplinary staffing) positively affect nurses' QWL. This cross-sectional study enrolled 84 ward-based psychiatric nurses. We assessed transactive memory, participative teamwork, perceived organizational justice, perceived organizational support, and QWL using psychometrically reliable and valid scales. Participative teamwork and transactive memory were positively associated with nurses' QWL. Perceived organizational support and organizational justice fully mediated the relationship between participative teamwork and QWL, but not between transactive memory and QWL. Improved transactive memory could directly improve nurses' QWL. Improved participative teamwork could improve nurses' QWL through better perceived organizational support and perceived organizational justice.

Real-Time Wait-Free Queues using Micro-Transactions

OpenAIRE

Meawad, Fadi; Iyer, Karthik; Schoeberl, Martin; Vitek, Jan

2011-01-01

This paper evaluates the applicability of transactional mem- ory to the implementation of dierent non-blocking data structures in the context of the Real-time Specication for Java. In particular, we argue that hardware support for micro-transaction allows us to implement eciently data structures that are often dicult to realize with the atomic operations provided by stock hardware. Our main imple- mentation platform is the Java Optimized Processor sys- tem. We report on the performance of dat...

Protecting Online Transactions with Unique Embedded Key Generators

DEFF Research Database (Denmark)

Boesgaard, Martin; Zenner, Erik

2007-01-01

We present a novel approach for protecting transactions over networks. While we use the example of a netbank application, the proposal is relevant for many security-critical transactions. The approach is based on two major changes compared to current solutions. The first one is the use...... difficult. In combination, these techniques allow to build a secure channel between the client program and the server, while current solutions only build such a channel between the client computer and the server....

17 CFR 31.13 - Financial reports of leverage transaction merchants.

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Financial reports of leverage... COMMISSION LEVERAGE TRANSACTIONS § 31.13 Financial reports of leverage transaction merchants. (a) Each... person must include with such financial report a statement describing the source of his current assets...

Transactive memory in organizational groups: the effects of content, consensus, specialization, and accuracy on group performance.

Science.gov (United States)

Austin, John R

2003-10-01

Previous research on transactive memory has found a positive relationship between transactive memory system development and group performance in single project laboratory and ad hoc groups. Closely related research on shared mental models and expertise recognition supports these findings. In this study, the author examined the relationship between transactive memory systems and performance in mature, continuing groups. A group's transactive memory system, measured as a combination of knowledge stock, knowledge specialization, transactive memory consensus, and transactive memory accuracy, is positively related to group goal performance, external group evaluations, and internal group evaluations. The positive relationship with group performance was found to hold for both task and external relationship transactive memory systems.

Transactional Sex among Noninjecting Illicit Drug Users: Implications for HIV Transmission

OpenAIRE

Guimar?es, Rafael Alves; Rodovalho, Aur?lio Goulart; Fernandes, Inaina Lara; Silva, Graciele Cristina; de Felipe, Rodrigo Lopes; Vera, Iv?nia; Greg?rio, Val?ria Duarte; Lucchese, Roselma

2016-01-01

Noninjecting illicit drug users (NIDUs) present high risk for HIV infection, due especially to transactional sex. This study aimed to estimate the prevalence and risk factors for transactional sex among NIDUs in the Southwest region of Goi?s State, Central Brazil. The prevalence of self-reported transactional sex was 22.8%. Prevalence in women and men was 52.7% and 16.8%, respectively, a significant difference (p < 0.001). Crack use and history of sexually transmitted infections (STI) were ri...

Precursors prior to type IIn supernova explosions are common: Precursor rates, properties, and correlations

Energy Technology Data Exchange (ETDEWEB)

Ofek, Eran O.; Steinbok, Aviram; Arcavi, Iair; Gal-Yam, Avishay; Tal, David; Ben-Ami, Sagi; Yaron, Ofer [Benoziyo Center for Astrophysics, Weizmann Institute of Science, 76100 Rehovot (Israel); Sullivan, Mark [School of Physics and Astronomy, University of Southampton, Southampton SO17 1BJ (United Kingdom); Shaviv, Nir J. [Racah Institute of Physics, The Hebrew University, 91904 Jerusalem (Israel); Kulkarni, Shrinivas R. [Cahill Center for Astronomy and Astrophysics, California Institute of Technology, Pasadena, CA 91125 (United States); Nugent, Peter E. [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States); Kasliwal, Mansi M. [Observatories of the Carnegie Institution for Science, 813 Santa Barbara Street, Pasadena, CA 91101 (United States); Cenko, S. Bradley [Astrophysics Science Division, NASA/Goddard Space Flight Center, Mail Code 661, Greenbelt, MD 20771 (United States); Laher, Russ; Surace, Jason [Spitzer Science Center, California Institute of Technology, M/S 314-6, Pasadena, CA 91125 (United States); Bloom, Joshua S.; Filippenko, Alexei V. [Department of Astronomy, University of California, Berkeley, CA 94720-3411 (United States); Silverman, Jeffrey M. [Department of Astronomy, University of Texas, Austin, TX 78712 (United States)

2014-07-10

There is a growing number of Type IIn supernovae (SNe) which present an outburst prior to their presumably final explosion. These precursors may affect the SN display, and are likely related to poorly charted phenomena in the final stages of stellar evolution. By coadding Palomar Transient Factory (PTF) images taken prior to the explosion, here we present a search for precursors in a sample of 16 Type IIn SNe. We find five SNe IIn that likely have at least one possible precursor event (PTF 10bjb, SN 2010mc, PTF 10weh, SN 2011ht, and PTF 12cxj), three of which are reported here for the first time. For each SN we calculate the control time. We find that precursor events among SNe IIn are common: at the one-sided 99% confidence level, >50% of SNe IIn have at least one pre-explosion outburst that is brighter than 3 × 10{sup 7} L{sub ☉} taking place up to 1/3 yr prior to the SN explosion. The average rate of such precursor events during the year prior to the SN explosion is likely ≳ 1 yr{sup –1}, and fainter precursors are possibly even more common. Ignoring the two weakest precursors in our sample, the precursors rate we find is still on the order of one per year. We also find possible correlations between the integrated luminosity of the precursor and the SN total radiated energy, peak luminosity, and rise time. These correlations are expected if the precursors are mass-ejection events, and the early-time light curve of these SNe is powered by interaction of the SN shock and ejecta with optically thick circumstellar material.

From Intra-transaction to Generalized Inter-transaction: Landscaping Multidimensional Contexts in Association Rule Mining

NARCIS (Netherlands)

Li, Q; Feng, L.; Wong, A.K.Y.

The problem of mining multidimensional inter-transactional association rules was recently introduced in [ACM Trans. Inform. Syst. 18(4) (2000) 423; Proc. of the ACM SIGMOD Workshop on Research Issues on Data Mining and Knowledge Discovery, Seattle, Washington, June 1998, p. 12:1]. It extends the

Trust and Control Dynamics in Agrifood Supply Networks: Communication Strategies for Electronic Transaction Environments

OpenAIRE

Fritz, Melanie; Hausen, Tobias

2006-01-01

Agrifood supply networks are dynamic structures where firms regularly face the need to search for new market partners. A decision for a transaction with a new partner requires the existence of appropriate control and safeguard mechanisms as well as trust to overcome perceived risk and uncertainties. Electronic transaction environments offer new potentials for the identification of new transaction partners. However, trust and control need to be communicated appropriately in electronic transact...

Stable Dispersions of Covalently Tethered Polymer Improved Graphene Oxide Nanoconjugates as an Effective Vector for siRNA Delivery.

Science.gov (United States)

Yadav, Nisha; Kumar, Naveen; Prasad, Peeyush; Shirbhate, Shivani; Sehrawat, Seema; Lochab, Bimlesh

2018-05-02

Conjugates of poly(amidoamine) (PAMAM) with modified graphene oxide (GO) are attractive nonviral vectors for gene-based cancer therapeutics. GO protects siRNA from enzymatic cleavage and showed reasonable transfection efficiency along with simultaneous benefits of low cost and large scale production. PAMAM is highly effective in siRNA delivery but suffers from high toxicity with poor in vivo efficacy. Co-reaction of GO and PAMAM led to aggregation and more importantly, have detrimental effect on stability of dispersion at physiological pH preventing their exploration at clinical level. In the current work, we have designed, synthesized, characterized and explored a new type of hybrid vector (GPD), using GO synthesized via improved method which was covalently tethered with poly(ethylene glycol) (PEG) and PAMAM. The existence of covalent linkage, relative structural changes and properties of GPD is well supported by Fourier transform infrared (FTIR), UV-visible (UV-vis), Raman, X-ray photoelectron (XPS), elemental analysis, powder X-ray diffraction (XRD), thermogravimetry analysis (TGA), dynamic light scattering (DLS), and zeta potential. Scanning electron microscopy (SEM), and transmission electron microscopy (TEM) of GPD showed longitudinally aligned columnar self-assembled ∼10 nm thick polymeric nanoarchitectures onto the GO surface accounting to an average size reduction to ∼20 nm. GPD revealed an outstanding stability in both phosphate buffer saline (PBS) and serum containing cell medium. The binding efficiency of EPAC1 siRNA to GPD was supported by gel retardation assay, DLS, zeta potential and photoluminescence (PL) studies. A lower cytotoxicity with enhanced cellular uptake and homogeneous intracellular distribution of GPD/siRNA complex is confirmed by imaging studies. GPD exhibited a higher transfection efficiency with remarkable inhibition of cell migration and lower invasion than PAMAM and Lipofectamine 2000 suggesting its role in prevention of breast

A Java Reference Model of Transacted Memory for Smart Cards

NARCIS (Netherlands)

Poll, Erik; Hartel, Pieter H.; de Jong, Eduard

Transacted Memory offers persistence, undoability and auditing. We present a Java/JML Reference Model of the Transacted Memory system on the basis of our earlier separate Z model and C implementation. We conclude that Java/JML combines the advantages of a high level specification in the JML part

A Java Reference Model of Transacted Memory for Smart Cards

NARCIS (Netherlands)

Poll, Erik; Hartel, Pieter H.; de Jong, Eduard

2002-01-01

Transacted Memory offers persistence, undoability and auditing. We present a Java/JML Reference Model of the Transacted Memory system on the basis of our earlier separate Z model and C implementation. We conclude that Java/JML combines the advantages of a high level specification in the JML part

Synthesis of two new alkyne-bearing linkers used for the preparation of siRNA for labeling by click chemistry with fluorine-18

International Nuclear Information System (INIS)

Flagothier, Jessica; Kaisin, Geoffroy; Mercier, Frederic; Thonon, David; Teller, Nathalie; Wouters, Johan; Luxen, André

2012-01-01

Oligonucleotides (ONs) and more particularly siRNAs are promising drugs but their pharmacokinetics and biodistribution are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to quantify these biological processes. Click chemistry (Huisgen cycloaddition) is the current method for labeling siRNA. In order to study the influence of a linker bearing by [ 18 F] labeled ONs, on the in vivo pharmacokinetic and metabolism, we have developed two modified ONs by two new linkers. Here we report the synthesis of two alkyne-bearing linkers, the incorporation onto a ONs and the conjugation by click chemistry with a [ 18 F] prosthetic group. - Highlights: ► Synthesis of two new alkyne linkers. ► Functionalization at the 3′-end siRNA by alkyne linker derived of proline. ► Click chemistry between alkyne modified siRNA and [ 18 F] prosthetic group.

Multiple Delivery of siRNA against Endoglin into Murine Mammary Adenocarcinoma Prevents Angiogenesis and Delays Tumor Growth

Science.gov (United States)

Dolinsek, Tanja; Markelc, Bostjan; Sersa, Gregor; Coer, Andrej; Stimac, Monika; Lavrencak, Jaka; Brozic, Andreja; Kranjc, Simona; Cemazar, Maja

2013-01-01

Endoglin is a transforming growth factor-β (TGF- β) co-receptor that participates in the activation of a signaling pathway that mediates endothelial cell proliferation and migration in angiogenic tumor vasculature. Therefore, silencing of endoglin expression is an attractive approach for antiangiogenic therapy of tumors. The aim of our study was to evaluate the therapeutic potential of small interfering RNA (siRNA) molecules against endoglin in vitro and in vivo. Therapeutic potential in vitro was assessed in human and murine endothelial cells (HMEC-1, 2H11) by determining endoglin expression level, cell proliferation and tube formation. In vivo, the therapeutic potential of siRNA molecules was evaluated in TS/A mammary adenocarcinoma growing in BALB/c mice. Results of our study showed that siRNA molecules against endoglin have a good antiangiogenic therapeutic potential in vitro, as expression of endoglin mRNA and protein levels in mouse and human microvascular endothelial cells after lipofection were efficiently reduced, which resulted in the inhibition of endothelial cell proliferation and tube formation. In vivo, silencing of endoglin with triple electrotransfer of siRNA molecules into TS/A mammary adenocarcinoma also significantly reduced the mRNA levels, number of tumor blood vessels and the growth of tumors. The obtained results demonstrate that silencing of endoglin is a promising antiangiogenic therapy of tumors that could not be used as single treatment, but as an adjunct to the established cytotoxic treatment approaches. PMID:23593103

Multiple delivery of siRNA against endoglin into murine mammary adenocarcinoma prevents angiogenesis and delays tumor growth.

Directory of Open Access Journals (Sweden)

Tanja Dolinsek

Full Text Available Endoglin is a transforming growth factor-β (TGF- β co-receptor that participates in the activation of a signaling pathway that mediates endothelial cell proliferation and migration in angiogenic tumor vasculature. Therefore, silencing of endoglin expression is an attractive approach for antiangiogenic therapy of tumors. The aim of our study was to evaluate the therapeutic potential of small interfering RNA (siRNA molecules against endoglin in vitro and in vivo. Therapeutic potential in vitro was assessed in human and murine endothelial cells (HMEC-1, 2H11 by determining endoglin expression level, cell proliferation and tube formation. In vivo, the therapeutic potential of siRNA molecules was evaluated in TS/A mammary adenocarcinoma growing in BALB/c mice. Results of our study showed that siRNA molecules against endoglin have a good antiangiogenic therapeutic potential in vitro, as expression of endoglin mRNA and protein levels in mouse and human microvascular endothelial cells after lipofection were efficiently reduced, which resulted in the inhibition of endothelial cell proliferation and tube formation. In vivo, silencing of endoglin with triple electrotransfer of siRNA molecules into TS/A mammary adenocarcinoma also significantly reduced the mRNA levels, number of tumor blood vessels and the growth of tumors. The obtained results demonstrate that silencing of endoglin is a promising antiangiogenic therapy of tumors that could not be used as single treatment, but as an adjunct to the established cytotoxic treatment approaches.

Transaction costs of unilateral CDM projects in India-results from an empirical survey

International Nuclear Information System (INIS)

Krey, Matthias

2005-01-01

Recently, transaction costs in the context of the Clean Development Mechanism (CDM) gained considerable attention as they were generally perceived to be significantly higher than for the other Kyoto Mechanisms. However, empirical evidence on the amount of transaction costs of CDM projects is very scarce. This paper presents the results from an empirical survey designed to quantify transaction costs of potential non-sink CDM projects in India. The definition of transaction costs of CDM projects was derived from recent literature and observations made in the current market for Certified Emission Reductions (CERs). During the survey, parts of transaction costs of 15 projects were quantified. An assessment of the results showed that specific transaction costs depend, to a large extent, on economies of scale in terms of total amount of CERs generated over the crediting period. Total transaction costs were quantified for seven projects. The costs range from 0.07 to 0.47 dollar/t CO 2 . As the projects have an emission reduction between 0.24 Mt CO 2 and 5.00 Mt CO 2 over the crediting period, the results support the assumption of Michaelowa et al. (Climate Policy 3 (2003) 273) that projects with emission reductions smaller than 0.20 Mt CO 2 are not economically viable at current CER prices

Analysis of e-commerce transaction system’s division of labor based on essential services quantity

Directory of Open Access Journals (Sweden)

Li Wang

2017-09-01

Full Text Available Purpose – The division of labor of e-commerce transaction system is an important research topic. However, there is a certain disparity between the current mainstream research model and the reality, which leads to a biased result. This paper aims to find the effects of transaction efficiency on the evolution of e-commerce transaction system’s division of labor and the relationships between the results and other parameters. Design/methodology/approach – This paper puts forward a definition of transaction efficiency based on transaction services and establishes a model of middleman’s specialized production decision of transaction services on this basis. Findings – The research results show that the transaction efficiency plays an important role on the change of middlemen’s division of labor level. The degree of economic specialization, price of commodities and transaction services and other associated factors also affect middlemen’s division of labor. Originality/value – This paper is of great significance for evaluating the development level and forecast the development direction of e-commerce.

The relationship between trading volumes, number of transactions, and stock volatility in GARCH models

Science.gov (United States)

Takaishi, Tetsuya; Chen, Ting Ting

2016-08-01

We examine the relationship between trading volumes, number of transactions, and volatility using daily stock data of the Tokyo Stock Exchange. Following the mixture of distributions hypothesis, we use trading volumes and the number of transactions as proxy for the rate of information arrivals affecting stock volatility. The impact of trading volumes or number of transactions on volatility is measured using the generalized autoregressive conditional heteroscedasticity (GARCH) model. We find that the GARCH effects, that is, persistence of volatility, is not always removed by adding trading volumes or number of transactions, indicating that trading volumes and number of transactions do not adequately represent the rate of information arrivals.

Personality-Relationship transaction in young adulthood.

Science.gov (United States)

Neyer, F J; Asendorpf, J B

2001-12-01

Personality and social relationships were assessed twice across a 4-year period in a general population sample of 489 German young adults. Two kinds of personality-relationship transaction were observed. First, mean-level change in personality toward maturity (e.g., increase in Conscientiousness and decrease in Neuroticism) was moderated by the transition to partnership but was independent of other developmental transitions. Second, individual differences in personality traits predicted social relationships much better than vice versa. Specifically, once initial correlations were controlled for, Extraversion, Shyness, Neuroticism, self-esteem, and Agreeableness predicted change in various qualities of relationships (especially with friends and colleagues), whereas only quality of relationships with preschool children predicted later Extraversion and Neuroticism. Consequences for the transactional view of personality in young adulthood are discussed.

Dynamic Portfolio Optimization with Transaction Costs and State-Dependent Drift

DEFF Research Database (Denmark)

Palczewski, Jan; Poulsen, Rolf; Schenk-Hoppe, Klaus Reiner

2015-01-01

The problem of dynamic portfolio choice with transaction costs is often addressed by constructing a Markov Chain approximation of the continuous time price processes. Using this approximation, we present an efficient numerical method to determine optimal portfolio strategies under time- and state......-dependent drift and proportional transaction costs. This scenario arises when investors have behavioral biases or the actual drift is unknown and needs to be estimated. Our numerical method solves dynamic optimal portfolio problems with an exponential utility function for time-horizons of up to 40 years....... It is applied to measure the value of information and the loss from transaction costs using the indifference principle....

Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates

Directory of Open Access Journals (Sweden)

Santiago Grijalvo

2018-02-01

Full Text Available Oligonucleotide-based therapy has become an alternative to classical approaches in the search of novel therapeutics involving gene-related diseases. Several mechanisms have been described in which demonstrate the pivotal role of oligonucleotide for modulating gene expression. Antisense oligonucleotides (ASOs and more recently siRNAs and miRNAs have made important contributions either in reducing aberrant protein levels by sequence-specific targeting messenger RNAs (mRNAs or restoring the anomalous levels of non-coding RNAs (ncRNAs that are involved in a good number of diseases including cancer. In addition to formulation approaches which have contributed to accelerate the presence of ASOs, siRNAs and miRNAs in clinical trials; the covalent linkage between non-viral vectors and nucleic acids has also added value and opened new perspectives to the development of promising nucleic acid-based therapeutics. This review article is mainly focused on the strategies carried out for covalently modifying siRNA and miRNA molecules. Examples involving cell-penetrating peptides (CPPs, carbohydrates, polymers, lipids and aptamers are discussed for the synthesis of siRNA conjugates whereas in the case of miRNA-based drugs, this review article makes special emphasis in using antagomiRs, locked nucleic acids (LNAs, peptide nucleic acids (PNAs as well as nanoparticles. The biomedical applications of siRNA and miRNA conjugates are also discussed.

17 CFR 229.1004 - (Item 1004) Terms of the transaction.

Science.gov (United States)

2010-04-01

... to the accounting treatment of the transaction, if material; and (xii) The federal income tax... security holders as a result of the transaction, if material; (vi) A brief statement as to the accounting... access to the corporate files of the filing person or to obtain counsel or appraisal services at the...

25 CFR 141.36 - Maximum finance charges on pawn transactions.

Science.gov (United States)

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Maximum finance charges on pawn transactions. 141.36... PRACTICES ON THE NAVAJO, HOPI AND ZUNI RESERVATIONS Pawnbroker Practices § 141.36 Maximum finance charges on pawn transactions. No pawnbroker may impose an annual finance charge greater than twenty-four percent...

26 CFR 1.356-5 - Transactions involving gift or compensation.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Transactions involving gift or compensation. 1... involving gift or compensation. With respect to transactions described in sections 354, 355, or 356, but which— (a) Result in a gift, see section 2501 and following, and the regulations pertaining thereto, or...

Zero tolerance for incorrect data: Best practices in SQL transaction programming

Science.gov (United States)

Laiho, M.; Skourlas, C.; Dervos, D. A.

2015-02-01

DBMS products differ in the way they support even the basic SQL transaction services. In this paper, a framework of best practices in SQL transaction programming is given and discussed. The SQL developers are advised to experiment with and verify the services supported by the DBMS product used. The framework has been developed by DBTechNet, a European network of teachers, trainers and ICT professionals. A course module on SQL transactions, offered by the LLP "DBTech VET Teachers" programme, is also presented and discussed. Aims and objectives of the programme include the introduction of the topics and content of SQL transactions and concurrency control to HE/VET curricula and addressing the need for initial and continuous training on these topics to in-company trainers, VET teachers, and Higher Education students. An overview of the course module, its learning outcomes, the education and training (E&T) content, virtual database labs with hands-on self-practicing exercises, plus instructions for the teacher/trainer on the pedagogy and the usage of the course modules' content are briefly described. The main principle adopted is to "Learn by verifying in practice" and the transactions course motto is: "Zero Tolerance for Incorrect Data".

[Pay for performance explained by transaction costs theory].

Science.gov (United States)

Gorbaneff, Yuri; Cortes, Ariel; Torres, Sergio; Yepes, Francisco

2011-01-01

To evaluate the ability of transaction costs theory to explain incentives in the health care chain. We performed a case study of CPS, a health insurance company in Bogota (Colombia), which preferred not to publish its name. CPS moves in the environment of high transaction costs and uses the hybrid form of governance at the outpatient level. Incentive intensity, administrative control and the contract all agree with the theory. At the hospital level, the market is used, despite greater uncertainty. Because of the discrete form (1.0) of the incentives and the absence of administrative control, it is difficult for CPS to relate payment to hospital performance. Transaction costs theory explains the configuration of incentives. Another contribution made by this theory to the literature is the criterion to differentiate between the market and the hybrid. We propose that the market uses discrete-type (1.0) incentives, while the hybrid uses continuous, commission-like incentives. Copyright © 2011 SESPAS. Published by Elsevier Espana. All rights reserved.

From Transactional to Transformational Accounting.

Science.gov (United States)

Cooper, Bruce S.; Randall, E. Vance

1998-01-01

Accurate transactional financial data are necessary for governmental compliance; transformational information is crucial for measuring and improving school performance. Some districts are shifting from a systems to a service, focus, from partial to full-cost accounting, from centralized to decentralized reporting procedures and facilities, and…

12 CFR 223.33 - What rules apply to derivative transactions?

Science.gov (United States)

2010-01-01

... Requirements Under Section 23A § 223.33 What rules apply to derivative transactions? (a) Market terms... with affiliates comply with the market terms requirement of § 223.51. (c) Credit derivatives. A credit... 12 Banks and Banking 3 2010-01-01 2010-01-01 false What rules apply to derivative transactions...

37 CFR 1.2 - Business to be transacted in writing.

Science.gov (United States)

2010-07-01

... Correspondence § 1.2 Business to be transacted in writing. All business with the Patent and Trademark Office... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Business to be transacted in writing. 1.2 Section 1.2 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE...

37 CFR 2.191 - Business to be transacted in writing.

Science.gov (United States)

2010-07-01

... Trademark Cases § 2.191 Business to be transacted in writing. All business with the Office should be... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Business to be transacted in writing. 2.191 Section 2.191 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE...

Continuous time Black-Scholes equation with transaction costs in subdiffusive fractional Brownian motion regime

Science.gov (United States)

Wang, Jun; Liang, Jin-Rong; Lv, Long-Jin; Qiu, Wei-Yuan; Ren, Fu-Yao

2012-02-01

In this paper, we study the problem of continuous time option pricing with transaction costs by using the homogeneous subdiffusive fractional Brownian motion (HFBM) Z(t)=X(Sα(t)), 0transaction costs of replicating strategies. We also give the total transaction costs.

Economic and Mathematical Modelling of Optimisation of Transaction Expenses of Engineering Enterprises

OpenAIRE

Makaliuk Iryna V.

2014-01-01

The article identifies stages of the process of optimisation of transaction expenses. It develops an economic and mathematical model of optimisation of transaction expenses of engineering enterprises by the criterion of maximisation of income from realisation of products and system of restrictions, which envisages exceeding income growth rate over the expenses growth rate. The article offers to use types of expenses by accounting accounts as indicators of transaction expenses. In the result o...

Transaction hubs: can tame energy market communications

Energy Technology Data Exchange (ETDEWEB)

Hamilos, C.

2002-07-01

The nature and function of transaction hubs is described in view of their growing usefulness as electric industry deregulation takes hold and with it the urgent requirement for trading partners to exchange information quickly and efficiently. The paper stresses the many difficulties involved in communications between trading partners since each partner operates under a different set of business rules, with the result that there are 'language differences' to overcome, not to mention the sheer volume of data that must be handled. To make it all work, companies turn increasingly to products like communication hubs. They are able to overcome the fact that different companies have different systems, different data formats and different business rules, and are able to help companies to package, transmit, receive and process information. The principal advantage of a hub is that no one has to learn anyone else's interface. Everyone can continue to use their own data format and transaction models. The hub supplies the protocols and processing rules needed to work with any of the partners connected to the hub. In order to achieve the level of efficiency and reliability required in a hub, certain design principles must be satisfied. These are : scalability, facilities for load balancing, availability of standard routine services, ability to recognize a process as consisting of various transactions, and a transaction as belonging to a specific process, ability to allow the user to configure expiration times around the business processes according to market rules, facility to easily configure validation rules, ability to handle exceptions, ability to interoperate with many middle-ware products, and to manage work flow in a manner that is transparent to operating personnel.

Trans-acting translational regulatory RNA binding proteins.

Science.gov (United States)

Harvey, Robert F; Smith, Tom S; Mulroney, Thomas; Queiroz, Rayner M L; Pizzinga, Mariavittoria; Dezi, Veronica; Villenueva, Eneko; Ramakrishna, Manasa; Lilley, Kathryn S; Willis, Anne E

2018-05-01

The canonical molecular machinery required for global mRNA translation and its control has been well defined, with distinct sets of proteins involved in the processes of translation initiation, elongation and termination. Additionally, noncanonical, trans-acting regulatory RNA-binding proteins (RBPs) are necessary to provide mRNA-specific translation, and these interact with 5' and 3' untranslated regions and coding regions of mRNA to regulate ribosome recruitment and transit. Recently it has also been demonstrated that trans-acting ribosomal proteins direct the translation of specific mRNAs. Importantly, it has been shown that subsets of RBPs often work in concert, forming distinct regulatory complexes upon different cellular perturbation, creating an RBP combinatorial code, which through the translation of specific subsets of mRNAs, dictate cell fate. With the development of new methodologies, a plethora of novel RNA binding proteins have recently been identified, although the function of many of these proteins within mRNA translation is unknown. In this review we will discuss these methodologies and their shortcomings when applied to the study of translation, which need to be addressed to enable a better understanding of trans-acting translational regulatory proteins. Moreover, we discuss the protein domains that are responsible for RNA binding as well as the RNA motifs to which they bind, and the role of trans-acting ribosomal proteins in directing the translation of specific mRNAs. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes Translation > Translation Regulation Translation > Translation Mechanisms. © 2018 Medical Research Council and University of Cambridge. WIREs RNA published by Wiley Periodicals, Inc.

DBR1 siRNA inhibition of HIV-1 replication

Directory of Open Access Journals (Sweden)

Naidu Yathi

2005-10-01

Full Text Available Abstract Background HIV-1 and all retroviruses are related to retroelements of simpler organisms such as the yeast Ty elements. Recent work has suggested that the yeast retroelement Ty1 replicates via an unexpected RNA lariat intermediate in cDNA synthesis. The putative genomic RNA lariat intermediate is formed by a 2'-5' phosphodiester bond, like that found in pre-mRNA intron lariats and it facilitates the minus-strand template switch during cDNA synthesis. We hypothesized that HIV-1 might also form a genomic RNA lariat and therefore that siRNA-mediated inhibition of expression of the human RNA lariat de-branching enzyme (DBR1 expression would specifically inhibit HIV-1 replication. Results We designed three short interfering RNA (siRNA molecules targeting DBR1, which were capable of reducing DBR1 mRNA expression by 80% and did not significantly affect cell viability. We assessed HIV-1 replication in the presence of DBR1 siRNA and found that DBR1 knockdown led to decreases in viral cDNA and protein production. These effects could be reversed by cotransfection of a DBR1 cDNA indicating that the inhibition of HIV-1 replication was a specific effect of DBR1 underexpression. Conclusion These data suggest that DBR1 function may be needed to debranch a putative HIV-1 genomic RNA lariat prior to completion of reverse transcription.

Lipofection of siRNA into bovine 8-16-cell stage embryos using zona removal and the well-of-the-well culture system.

Science.gov (United States)

Ikeda, Shuntaro; Sugimoto, Miki; Kume, Shinichi

2018-04-13

Bovine preimplantation embryos exhibit dramatic biological changes between before and after the 8-16-cell stage. Here we report a simple lipofection method to transfect siRNA into bovine 8-16-cell stage embryos using zona removal and the well-of-the-well (WOW) culture system. Bovine one-cell embryos produced in vitro were freed from the zona pellucida and cultured up to the 8-16-cell stage in WOW dishes. The 8-16-cell embryos were lipofected with siRNA and the transfection efficiency was assessed at 48 h of transfection. Lipofection with a red fluorescent non-targeting siRNA revealed the importance of zona removal for transfection of siRNA into embryos. Using this method, we knocked down the methionine adenosyltransferase 2A (MAT2A) gene, achieving a significant reduction in MAT2A expression (P lipofection', may be useful to analyze gene functions in bovine preimplantation embryos without expensive equipment and skill-intensive techniques.

Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.

Science.gov (United States)

Lin, Liteng; Cai, Mingyue; Deng, Shaohui; Huang, Wensou; Huang, Jingjun; Huang, Xinghua; Huang, Mingsheng; Wang, Yong; Shuai, Xintao; Zhu, Kangshun

2017-10-01

Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A 2 (TXA 2 ), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA 2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH. Copyright © 2017 Elsevier Inc. All rights reserved.

17 CFR 229.910 - (Item 910) Fairness of the transaction.

Science.gov (United States)

2010-04-01

... transaction is fair or unfair to investors and the reasons for such belief. Such discussion must address the fairness of the roll-up transaction to investors in each of the partnerships and as a whole. If the roll-up... the general partner that may affect materially the value of the consideration to be received by...

Tandemly arranged chalcone synthase A genes contribute to the spatially regulated expression of siRNA and the natural bicolor floral phenotype in Petunia hybrida.

Science.gov (United States)

Morita, Yasumasa; Saito, Ryoko; Ban, Yusuke; Tanikawa, Natsu; Kuchitsu, Kazuyuki; Ando, Toshio; Yoshikawa, Manabu; Habu, Yoshiki; Ozeki, Yoshihiro; Nakayama, Masayoshi

2012-06-01

The natural bicolor floral traits of the horticultural petunia (Petunia hybrida) cultivars Picotee and Star are caused by the spatial repression of the chalcone synthase A (CHS-A) gene, which encodes an anthocyanin biosynthetic enzyme. Here we show that Picotee and Star petunias carry the same short interfering RNA (siRNA)-producing locus, consisting of two intact CHS-A copies, PhCHS-A1 and PhCHS-A2, in a tandem head-to-tail orientation. The precursor CHS mRNAs are transcribed from the two CHS-A copies throughout the bicolored petals, but the mature CHS mRNAs are not found in the white tissues. An analysis of small RNAs revealed the accumulation of siRNAs of 21 nucleotides that originated from the exon 2 region of both CHS-A copies. This accumulation is closely correlated with the disappearance of the CHS mRNAs, indicating that the bicolor floral phenotype is caused by the spatially regulated post-transcriptional silencing of both CHS-A genes. Linkage between the tandemly arranged CHS-A allele and the bicolor floral trait indicates that the CHS-A allele is a necessary factor to confer the trait. We suppose that the spatially regulated production of siRNAs in Picotee and Star flowers is triggered by another putative regulatory locus, and that the silencing mechanism in this case may be different from other known mechanisms of post-transcriptional gene silencing in plants. A sequence analysis of wild Petunia species indicated that these tandem CHS-A genes originated from Petunia integrifolia and/or Petunia inflata, the parental species of P. hybrida, as a result of a chromosomal rearrangement rather than a gene duplication event. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

The Problematic Aspects of Accounting the Transaction Costs and Ways to Address Them

Directory of Open Access Journals (Sweden)

Khorunzhak Nadiya M.

2017-05-01

Full Text Available The article is aimed at a theoretical generalization of the nature and causes of appearance of transaction costs, development of proposals on formation of an effective model for their management, including the proposals on the basis of improved accounting for brewery enterprises. According to the carried out analysis of the authors’ positions on accounting, including the positions related to reflection of transaction costs in the accounting records, it has been concluded about expediency to account such costs by types, although only in regard to the activities, directed toward sales of production. A goal tree graph has been built to ensure the rationality of research on elaborating the classification (grouping of transaction costs and on substantiating the composition of working accounts for their accounting. In order to ensure the continuity and timeliness of including the transaction costs into the prime cost of the production sold, it has been proposed to use planning and reporting calculations. An approach has been developed to determine the planned inclusion of transaction costs in the prime cost of the production sold (exponential average. An appropriate model for recording the transaction costs has been built. Prospect for further research will be construction of the efficient policy decisions concerning the enterprise’s activities, based on the above conception of the system of management of transaction costs together with its information base.

A Novel Electricity Transaction Mode of Microgrids Based on Blockchain and Continuous Double Auction

Directory of Open Access Journals (Sweden)

Jian Wang

2017-11-01

Full Text Available The installed capacity of distributed generation (DG based on renewable energy sources has increased continuously in power systems, and its market-oriented transaction is imperative. However, traditional transaction management based on centralized organizations has many disadvantages, such as high operation cost, low transparency, and potential risk of transaction data modification. Therefore, a decentralized electricity transaction mode for microgrids is proposed in this study based on blockchain and continuous double auction (CDA mechanism. A buyer and seller initially complete the transaction matching in the CDA market. In view of the frequent price fluctuation in the CDA market, an adaptive aggressiveness strategy is used to adjust the quotation timely according to market changes. DG and consumer exchange digital certificate of power and expenditure on the blockchain system and the interests of consumers are then guaranteed by multi-signature when DG cannot generate power due to failure or other reasons. The digital certification of electricity assets is replaced by the sequence number with specific tags in the transaction script, and the size of digital certification can be adjusted according to transaction energy quantity. Finally, the feasibility of market mechanism through specific microgrid case and settlement process is also provided.

Emissions trading and transaction costs : analyzing the flaws in the discussion

NARCIS (Netherlands)

Woerdman, E.

Although emissions trading lowers the costs of climate change mitigation, transaction costs (e.g. to find a trading partner) may reduce its cost-effectiveness. Some economists claim that transaction costs for Joint Implementation (JI) and Clean Development Mechanism (CDM) projects will be higher

The highly conserved 5' untranslated region as an effective target towards the inhibition of Enterovirus 71 replication by unmodified and appropriate 2'-modified siRNAs

Directory of Open Access Journals (Sweden)

Deng Jun-Xia

2012-08-01

Full Text Available Abstract Background Enterovirus 71 (EV71 is a highly infectious agent that plays an etiological role in hand, foot, and mouth disease. It is associated with severe neurological complications and has caused significant mortalities in recent large-scale outbreaks. Currently, no effective vaccine or specific clinical therapy is available against EV71. Methods Unmodified 21 nucleotide small interfering RNAs (siRNAs and classic 2′-modified (2′-O-methylation or 2′-fluoro modification siRNAs were designed to target highly conserved 5′ untranslated region (UTR of the EV71 genome and employed as anti-EV71 agents. Real-time TaqMan RT-PCR, western blot analysis and plaque assays were carried out to evaluate specific viral inhibition by the siRNAs. Results Transfection of rhabdomyosarcoma (RD cells with siRNAs targeting the EV71 genomic 5′ UTR significantly delayed and alleviated the cytopathic effects of EV71 infection, increased cell viability in EV71-infected RD cells. The inhibitory effect on EV71 replication was sequence-specific and dosage-dependent, with significant corresponding decreases in viral RNA, VP1 protein and viral titer. Appropriate 2′-modified siRNAs exhibited similar RNA interference (RNAi activity with dramatically increased serum stability in comparison with unmodified counterparts. Conclusion Sequences were identified within the highly conserved 5′ UTR that can be targeted to effectively inhibit EV71 replication through RNAi strategies. Appropriate 2′-modified siRNAs provide a promising approach to optimizing siRNAs to overcome barriers on RNAi-based antiviral therapies for broader administration.

Division of Labor, Transaction Cost, Emergence of the Firm and Firm Size

OpenAIRE

Pak-Wai Liu; Xiaokai Yang

1999-01-01

In this paper a general equilibrium model is constructed to explain the emergence of firms and change in firm size by the tradeoff between economies of specialization and transaction cost. We show that firms emerge from the development of division of labor if the transaction efficiency for labor is smaller than that for intermediate goods. Given the emergence of firms, change in the average size of firms (average employment) will depend on the change in transaction efficiency for intermediate...

Academic Activities Transaction Extraction Based on Deep Belief Network

Directory of Open Access Journals (Sweden)

Xiangqian Wang

2017-01-01

Full Text Available Extracting information about academic activity transactions from unstructured documents is a key problem in the analysis of academic behaviors of researchers. The academic activities transaction includes five elements: person, activities, objects, attributes, and time phrases. The traditional method of information extraction is to extract shallow text features and then to recognize advanced features from text with supervision. Since the information processing of different levels is completed in steps, the error generated from various steps will be accumulated and affect the accuracy of final results. However, because Deep Belief Network (DBN model has the ability to automatically unsupervise learning of the advanced features from shallow text features, the model is employed to extract the academic activities transaction. In addition, we use character-based feature to describe the raw features of named entities of academic activity, so as to improve the accuracy of named entity recognition. In this paper, the accuracy of the academic activities extraction is compared by using character-based feature vector and word-based feature vector to express the text features, respectively, and with the traditional text information extraction based on Conditional Random Fields. The results show that DBN model is more effective for the extraction of academic activities transaction information.

Research on e-commerce transaction networks using multi-agent modelling and open application programming interface

Science.gov (United States)

Piao, Chunhui; Han, Xufang; Wu, Harris

2010-08-01

We provide a formal definition of an e-commerce transaction network. Agent-based modelling is used to simulate e-commerce transaction networks. For real-world analysis, we studied the open application programming interfaces (APIs) from eBay and Taobao e-commerce websites and captured real transaction data. Pajek is used to visualise the agent relationships in the transaction network. We derived one-mode networks from the transaction network and analysed them using degree and betweenness centrality. Integrating multi-agent modelling, open APIs and social network analysis, we propose a new way to study large-scale e-commerce systems.