Scientometric mapping as a strategic intelligence tool for the governance of emerging technologies

How can scientometric mapping function as a tool of ’strategic intelligence’ to aid the governance of emerging technologies? The present paper aims to address this question by focusing on a set of recently developed scientometric techniques, namely overlay mapping. We examine the potential these techniques have to inform, in a timely manner, analysts and decision-makers about relevant dynamics of technical emergence. We investigate the capability of overlay mapping in generating informed perspectives about emergence across three spaces: geographical, social, and cognitive. Our analysis relies on three empirical studies of emerging technologies in the biomedical domain: RNA interference (RNAi), Human Papilloma Virus (HPV) testing technologies for cervical cancer, and Thiopurine Methyltransferase (TPMT) genetic testing. The case-studies are analysed and mapped longitudinally by using publication and patent data. Results show the variety of ’intelligence’ inputs overlay mapping can produce for the governance of emerging technologies. Overlay mapping also confers to the investigation of emergence flexibility and granularity in terms of adaptability to different sources of data and selection of the levels of the analysis, respectively. These features make possible the integration and comparison of results from different contexts and cases, thus providing possibilities for a potentially more ’distributed’ strategic intelligence. The generated perspectives allow triangulation of findings, which is important given the complexity featuring in technical emergence and the limitations associated with the use of single scientometric approaches

Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice

Rationale: Dopamine D1 receptor (D1R) signaling has been associated to ethanol consumption and reward in laboratory animals.Objectives: Here, we hypothesize that this receptor, which is located within the nucleus accumbens (NAc) neurons, modulates alcohol reward mechanisms.Methods: To test this hypothesis, we measured alcohol consumption and ethanol-induced psychomotor sensitization and conditioned place preference (CPP) in mice that received bilateral microinjections of small interference RNA (siRNA)-expressing lentiviral vectors (LV-siD1R) producing D1R knock-down. The other group received control (LV-Mock) viral vectors into the NAc.Results: There were no differences in the total fluid consumed and also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the LV-siD1R group consumed less ethanol than the control group. This difference was not associated to taste neophobia. In addition, results have shown that down-regulation of endogenous D1R using viral-mediated siRNA in the NAc significantly decreased ethanol-induced behavioral sensitization as well as acquisition, but not expression, of ethanol-induced place preference.Conclusions: We conclude that decreased D1R expression into the NAc led to reduced ethanol rewarding properties, thereby leading to lower voluntary ethanol consumption. Together, these findings demonstrate that the D1 receptor pathway within the NAc controls ethanol reward and intake

Importin-beta and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function

Protein conjugation with small ubiquitin-related modifier (SUMO) is a post-translational modification that modulates protein interactions and localisation. RANBP2 is a large nucleoporin endowed with SUMO E3 ligase and SUMO-stabilising activity, and is implicated in some cancer types. RANBP2 is part of a larger complex, consisting of SUMO-modified RANGAP1, the GTP-hydrolysis activating factor for the GTPase RAN. During mitosis, the RANBP2–SUMO-RANGAP1 complex localises to the mitotic spindle and to kinetochores after microtubule attachment. Here, we address the mechanisms that regulate this localisation and how they affect kinetochore functions. Using proximity ligation assays, we find that nuclear transport receptors importin-β and CRM1 play essential roles in localising the RANBP2–SUMO-RANGAP1 complex away from, or at kinetochores, respectively. Using newly generated inducible cell lines, we show that overexpression of nuclear transport receptors affects the timing of RANBP2 localisation in opposite ways. Concomitantly, kinetochore functions are also affected, including the accumulation of SUMO- conjugated topoisomerase-IIα and stability of kinetochore fibres. These results delineate a novel mechanism through which nuclear transport receptors govern the functional state of kinetochores by regulating the timely deposition of RANBP2

siRNA carrying an (E)-vinylphosphonate moiety at the 5' end of the guide strand augments gene silencing by enhanced binding to human Argonaute-2

Efficient gene silencing by RNA interference (RNAi) in vivo requires the recognition and binding of the 5'- phosphate of the guide strand of an siRNA by the Argonaute protein. However, for exogenous siRNAs it is limited by the rapid removal of the 5'- phosphate of the guide strand by metabolic enzymes. Here, we have determined the crystal structure of human Argonaute-2 in complex with the metabolically stable 5'-(E)-vinylphosphonate (5'-E-VP) guide RNA at 2.5-A resolution. The structure demonstrates how the 5' binding site in the Mid domain of human Argonaute-2 is able to adjust the key residues in the 5'-nucleotide binding pocket to compensate for the change introduced by the modified nucleotide. This observation also explains improved binding affinity of the 5'-E-VP -modified siRNA to human Argonaute-2 in-vitro, as well as the enhanced silencing in the context of the trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNA in mice relative to the un-modified siRNA

ATP-P2X7 Receptor Modulates Axon Initial Segment Composition and Function in Physiological Conditions and Brain Injury

© 2014 The Author. All rights reserved. Axon properties, including action potential initiation and modulation, depend on both AIS integrity and the regulation of ion channel expression in the AIS. Alteration of the axon initial segment (AIS) has been implicated in neurodegenerative, psychiatric, and brain trauma diseases, thus identification of the physiological mechanisms that regulate the AIS is required to understand and circumvent AIS alterations in pathological conditions. Here, we show that the purinergic P2X7 receptor and its agonist, adenosine triphosphate (ATP), modulate both structural proteins and ion channel density at the AIS in cultured neurons and brain slices. In cultured hippocampal neurons, an increment of extracellular ATP concentration or P2X7-green fluorescent protein (GFP) expression reduced the density of ankyrin G and voltage-gated sodium channels at the AIS. This effect is mediated by P2X7-regulated calcium influx and calpain activation, and impaired by P2X7 inhibition with Brilliant Blue G (BBG), or P2X7 suppression. Electrophysiological studies in brain slices showed that P2X7-GFP transfection decreased both sodium current amplitude and intrinsic neuronal excitability, while P2X7 inhibition had the opposite effect. Finally, inhibition of P2X7 with BBG prevented AIS disruption after ischemia/reperfusion in rats. In conclusion, our study demonstrates an involvement of P2X7 receptors in the regulation of AIS mediated neuronal excitability in physiological and pathological conditions.Plan Nacional I+D+i (Spain), INSERM and Agence National de la Recherche (EXCION, EPISOM)Peer Reviewe

The Role of RNAi in Downregulation of Physcomitrella Patens Defense Genes and the Preliminary Steps of PEG Mediated Transformation of Mosses

When attacked by a pathogen, the moss Physcomitrella patens will undergo both a hypersensitive response (HR) as well as a systematic acquired resistance (SAR) response. The SAR response turns on genes that ready the plant for future pathogen attacks. The hormone jasmonic acid (JA) is one of the products of SAR response in P. patens. In this study interference RNA (RNAi) was used to decrease gene expression of the allene oxide cyclase (ACe) gene, a key gene in the production pathway of JA. Using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), RNAi was found to significantly lower ACC gene levels in mosses, both before and after infection with the fungal pathogen Pythium irregulare. Furthermore RNAi was tested to see if it created a phenotypic difference when infecting P. patens. Lastly, the preliminary steps in a polyethylene glycol (PEG) mediated transformation were started by attempting to isolate single celled protoplasts in the mosses Mnium cuspidatum and Ceratadon purpureus. This transformation would cause a permanent knockout of a gene, as opposed to the short term decrease in expression achieved by RNAi

Endoglin Regulates Cyclooxygenase-2 Expression and Activity

Jerkic, Mirjana[et alt.] 9 p.-8 fig.The endoglin heterozygous (Eng+/−) mouse, which serves as a model of hereditary hemorrhagic telangiectasia (HHT), was shown to express reduced levels of endothelial NO synthase (eNOS) with impaired activity. Because of intricate changes in vasomotor function in the Eng+/− mice and the potential interactions between the NO- and prostaglandin-producing pathways, we assessed the expression and function of cyclooxygenase (COX) isoforms. A specific upregulation of COX-2 in the vascular endothelium and increased urinary excretion of prostaglandin E2 were observed in the Eng+/− mice. Specific COX-2 inhibition with parecoxib transiently increased arterial pressure in Eng+/− but not in Eng+/+ mice. Transfection of endoglin in L6E9 myoblasts, shown previously to stimulate eNOS expression, led to downregulation of COX-2 with no change in COX-1. In addition, COX-2 promoter activity and protein levels were inversely correlated with endoglin levels, in doxycyclin-inducible endothelial cells. Chronic NO synthesis inhibition with Nω-nitro-l-arginine methyl ester induced a marked increase in COX-2 only in the normal Eng+/+ mice. Nω-nitro-l-arginine methyl ester also increased COX-2 expression and promoter activity in doxycyclin-inducible endoglin expressing endothelial cells, but not in control cells. The level of COX-2 expression following transforming growth factor-β1 treatment was less in endoglin than in mock transfected L6E9 myoblasts and was higher in human endothelial cells silenced for endoglin expression. Our results indicate that endoglin is involved in the regulation of COX-2 activity. Furthermore, reduced endoglin levels and associated impaired NO production may be responsible, at least in part, for augmented COX-2 expression and activity in the Eng+/− miceThis work was supported by grants from Ministerio de Educacion y Ciencia (SAF2001/1701 to J.M.L.-N. and SAF2004–01390 to C.B.), Fondo de Investigación Sanitaria (PI020200 to C.B.), HHT Foundation International to C.B., and by the Heart and Stroke Foundation of Canada (T5016) to M.L. M.J. was supported by a Fellowship from Instituto Reina Sofía de Investigación Nefrológica. C.P.H.V. was supported by NIH grant #P2015555 from the National Center for Research ResourcesPeer reviewe

Natural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers.

Natural antisense transcripts are RNA sequences that can be transcribed from both DNA strands at the same locus but in the opposite direction from the gene transcript. Because strand-specific high-throughput sequencing of the antisense transcriptome has only been available for less than a decade, many natural antisense transcripts were first described as long non-coding RNAs. Although the precise biological roles of natural antisense transcripts are not known yet, an increasing number of studies report their implication in gene expression regulation. Their expression levels are altered in many physiological and pathological conditions, including breast cancers. Among the potential clinical utilities of the natural antisense transcripts, the non-coding|coding transcript pairs are of high interest for treatment. Indeed, these pairs can be targeted by antisense oligonucleotides to specifically tune the expression of the coding-gene. Here, we describe the current knowledge about natural antisense transcripts, their varying molecular mechanisms as gene expression regulators, and their potential as prognostic or predictive biomarkers in breast cancers

Epigenetic silencing of tumor suppressor <i>miR-3151</i> contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways

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