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See detailThe European general practice research network presents the translations of its comprehensive definition of multimorbidity in family medicine in ten European languages.
Le Reste, Jean Yves; Nabbe, Patrice; Rivet, Charles et al

in PloS one (2015), 10(1), 0115796

BACKGROUND: Multimorbidity, according to the World Health Organization, exists when there are two or more chronic conditions in one patient. This definition seems inaccurate for the holistic approach to ... [more ▼]

BACKGROUND: Multimorbidity, according to the World Health Organization, exists when there are two or more chronic conditions in one patient. This definition seems inaccurate for the holistic approach to Family Medicine (FM) and long-term care. To avoid this pitfall the European General Practitioners Research Network (EGPRN) designed a comprehensive definition of multimorbidity using a systematic literature review. OBJECTIVE: To translate that English definition into European languages and to validate the semantic, conceptual and cultural homogeneity of the translations for further research. METHOD: Forward translation of the EGPRN's definition of multimorbidity followed by a Delphi consensus procedure assessment, a backward translation and a cultural check with all teams to ensure the homogeneity of the translations in their national context. Consensus was defined as 70% of the scores being higher than 6. Delphi rounds were repeated in each country until a consensus was reached. RESULTS: 229 European medical expert FPs participated in the study. Ten consensual translations of the EGPRN comprehensive definition of multimorbidity were achieved. CONCLUSION: A comprehensive definition of multimorbidity is now available in English and ten European languages for further collaborative research in FM and long-term care. [less ▲]

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See detailMediaDB: A Database of Microbial Growth Conditions in Defined Media
Richards, Matthew A.; Cassen, Victor; Heavner, Benjamin D. et al

in PLoS ONE (2014), 9(8), 103548

Isolating pure microbial cultures and cultivating them in the laboratory on defined media is used to more fully characterize the metabolism and physiology of organisms. However, identifying an appropriate ... [more ▼]

Isolating pure microbial cultures and cultivating them in the laboratory on defined media is used to more fully characterize the metabolism and physiology of organisms. However, identifying an appropriate growth medium for a novel isolate remains a challenging task. Even organisms with sequenced and annotated genomes can be difficult to grow, despite our ability to build genome-scale metabolic networks that connect genomic data with metabolic function. The scientific literature is scattered with information about defined growth media used successfully for cultivating a wide variety of organisms, but to date there exists no centralized repository to inform efforts to cultivate less characterized organisms by bridging the gap between genomic data and compound composition for growth media. Here we present MediaDB, a manually curated database of defined media that have been used for cultivating organisms with sequenced genomes, with an emphasis on organisms with metabolic network models. The database is accessible online, can be queried by keyword searches or downloaded in its entirety, and can generate exportable individual media formulation files. The data assembled in MediaDB facilitate comparative studies of organism growth media, serve as a starting point for formulating novel growth media, and contribute to formulating media for in silico investigation of metabolic networks. MediaDB is freely available for public use at https://mediadb.systemsbiology.net. [less ▲]

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See detailoptPBN: An Optimisation Toolbox for Probabilistic Boolean Networks
Trairatphisan, Panuwat UL; Mizera, Andrzej UL; Pang, Jun UL et al

in PLoS ONE (2014), 9(7), 980011-15

Background There exist several computational tools which allow for the optimisation and inference of biological networks using a Boolean formalism. Nevertheless, the results from such tools yield only ... [more ▼]

Background There exist several computational tools which allow for the optimisation and inference of biological networks using a Boolean formalism. Nevertheless, the results from such tools yield only limited quantitative insights into the complexity of biological systems because of the inherited qualitative nature of Boolean networks. Results We introduce optPBN, a Matlab-based toolbox for the optimisation of probabilistic Boolean networks (PBN) which operates under the framework of the BN/PBN toolbox. optPBN offers an easy generation of probabilistic Boolean networks from rule-based Boolean model specification and it allows for flexible measurement data integration from multiple experiments. Subsequently, optPBN generates integrated optimisation problems which can be solved by various optimisers. In term of functionalities, optPBN allows for the construction of a probabilistic Boolean network from a given set of potential constitutive Boolean networks by optimising the selection probabilities for these networks so that the resulting PBN fits experimental data. Furthermore, the optPBN pipeline can also be operated on large-scale computational platforms to solve complex optimisation problems. Apart from exemplary case studies which we correctly inferred the original network, we also successfully applied optPBN to study a large-scale Boolean model of apoptosis where it allows identifying the inverse correlation between UVB irradiation, NFκB and Caspase 3 activations, and apoptosis in primary hepatocytes quantitatively. Also, the results from optPBN help elucidating the relevancy of crosstalk interactions in the apoptotic network. Summary The optPBN toolbox provides a simple yet comprehensive pipeline for integrated optimisation problem generation in the PBN formalism that can readily be solved by various optimisers on local or grid-based computational platforms. optPBN can be further applied to various biological studies such as the inference of gene regulatory networks or the identification of the interaction's relevancy in signal transduction networks. [less ▲]

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See detailEffect of seated trunk posture on eye blink startle and subjective experience: Comparing flexion, neutral upright posture, and extension of spine
Ceunen, Erik UL; Zaman, Jonas; Vlaeyen, Johan et al

in PLoS ONE (2014), 9(2),

Postures are known to be able to affect emotion and motivation. Much less is known about whether (affective) modulation of eye blink startle occurs following specific postures. The objective of the ... [more ▼]

Postures are known to be able to affect emotion and motivation. Much less is known about whether (affective) modulation of eye blink startle occurs following specific postures. The objective of the current study was to explore this. Participants in the present study were requested to assume three different sitting postures: with the spine flexed (slouched), neutral upright, and extended. Each posture was assumed for four minutes, and was followed by the administration of brief self-report questionnaires before proceeding to the next posture. The same series of postures and measures were repeated prior to ending the experiment. Results indicate that, relative to the other postures, the extended sitting posture was associated with an increased startle, was more unpleasant, arousing, had smaller levels of dominance, induced more discomfort, and was perceived as more difficult. The upright and flexed sitting postures differed in the level of self-reported positive affect, but not in eye blink startle amplitudes. [less ▲]

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See detailThe Impact of Mathematical Proficiency on the Number-Space Association
Hoffmann, Danielle UL; Mussolin, Christophe; Martin, Romain UL et al

in PLoS ONE (2014)

A specific instance of the association between numerical and spatial representations is the SNARC (Spatial Numerical Association of Response Codes) effect. The SNARC effect describes the finding that ... [more ▼]

A specific instance of the association between numerical and spatial representations is the SNARC (Spatial Numerical Association of Response Codes) effect. The SNARC effect describes the finding that during binary classification of numbers participants are faster to respond to small/large numbers with the left/right hand respectively. Even though it has been frequently replicated, important inter-individual variability has also been reported. Mathematical proficiency is an obvious candidate source for inter-individual variability in numerical judgments, but studies investigating its influence on the SNARC effect remain scarce. The present experiment included a total of 95 University students, divided into three groups differing significantly in their mathematical proficiency levels. Using group analyses, it appeared that the three groups differed significantly in the strength of their number-space associations in a parity judgment task. This result was further confirmed on an individual level, with higher levels in arithmetic leading to relatively weaker SNARC effects. To explain this negative relationship we propose accounts based on differences in access to qualitatively different numerical representations and also consider more domain general factors, with a focus on inhibition capacities. [less ▲]

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See detailUnidirectional P-body transport during the yeast cell cycle.
Garmendia-Torres, Cecilia; Skupin, Alexander UL; Michael, Sean A. et al

in PloS one (2014), 9(6), 99428

P-bodies belong to a large family of RNA granules that are associated with post-transcriptional gene regulation, conserved from yeast to mammals, and influence biological processes ranging from germ cell ... [more ▼]

P-bodies belong to a large family of RNA granules that are associated with post-transcriptional gene regulation, conserved from yeast to mammals, and influence biological processes ranging from germ cell development to neuronal plasticity. RNA granules can also transport RNAs to specific locations. Germ granules transport maternal RNAs to the embryo, and neuronal granules transport RNAs long distances to the synaptic dendrites. Here we combine microfluidic-based fluorescent microscopy of single cells and automated image analysis to follow p-body dynamics during cell division in yeast. Our results demonstrate that these highly dynamic granules undergo a unidirectional transport from the mother to the daughter cell during mitosis as well as a constrained "hovering" near the bud site half an hour before the bud is observable. Both behaviors are dependent on the Myo4p/She2p RNA transport machinery. Furthermore, single cell analysis of cell size suggests that PBs play an important role in daughter cell growth under nutrient limiting conditions. [less ▲]

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See detailBasic Regulatory Principles of Escherichia coli's Electron Transport Chain for Varying Oxygen Conditions.
Henkel, Sebastian G.; Beek, Alexander Ter; Steinsiek, Sonja et al

in PloS one (2014), 9(9), 107640

For adaptation between anaerobic, micro-aerobic and aerobic conditions Escherichia coli's metabolism and in particular its electron transport chain (ETC) is highly regulated. Although it is known that the ... [more ▼]

For adaptation between anaerobic, micro-aerobic and aerobic conditions Escherichia coli's metabolism and in particular its electron transport chain (ETC) is highly regulated. Although it is known that the global transcriptional regulators FNR and ArcA are involved in oxygen response it is unclear how they interplay in the regulation of ETC enzymes under micro-aerobic chemostat conditions. Also, there are diverse results which and how quinones (oxidised/reduced, ubiquinone/other quinones) are controlling the ArcBA two-component system. In the following a mathematical model of the E. coli ETC linked to basic modules for substrate uptake, fermentation product excretion and biomass formation is introduced. The kinetic modelling focusses on regulatory principles of the ETC for varying oxygen conditions in glucose-limited continuous cultures. The model is based on the balance of electron donation (glucose) and acceptance (oxygen or other acceptors). Also, it is able to account for different chemostat conditions due to changed substrate concentrations and dilution rates. The parameter identification process is divided into an estimation and a validation step based on previously published and new experimental data. The model shows that experimentally observed, qualitatively different behaviour of the ubiquinone redox state and the ArcA activity profile in the micro-aerobic range for different experimental conditions can emerge from a single network structure. The network structure features a strong feed-forward effect from the FNR regulatory system to the ArcBA regulatory system via a common control of the dehydrogenases of the ETC. The model supports the hypothesis that ubiquinone but not ubiquinol plays a key role in determining the activity of ArcBA in a glucose-limited chemostat at micro-aerobic conditions. [less ▲]

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See detailDiscovering pair-wise genetic interactions: an information theory-based approach.
Ignac, Tomasz UL; Skupin, Alexander UL; Sakhanenko, Nikita A. et al

in PloS one (2014), 9(3), 92310

Phenotypic variation, including that which underlies health and disease in humans, results in part from multiple interactions among both genetic variation and environmental factors. While diseases or ... [more ▼]

Phenotypic variation, including that which underlies health and disease in humans, results in part from multiple interactions among both genetic variation and environmental factors. While diseases or phenotypes caused by single gene variants can be identified by established association methods and family-based approaches, complex phenotypic traits resulting from multi-gene interactions remain very difficult to characterize. Here we describe a new method based on information theory, and demonstrate how it improves on previous approaches to identifying genetic interactions, including both synthetic and modifier kinds of interactions. We apply our measure, called interaction distance, to previously analyzed data sets of yeast sporulation efficiency, lipid related mouse data and several human disease models to characterize the method. We show how the interaction distance can reveal novel gene interaction candidates in experimental and simulated data sets, and outperforms other measures in several circumstances. The method also allows us to optimize case/control sample composition for clinical studies. [less ▲]

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See detailGene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Escott-Price, Valentina; Bellenguez, Celine; Wang, Li-San et al

in PloS one (2014), 9(6), 94661

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study ... [more ▼]

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10-6) and 14 (IGHV1-67 p = 7.9x10-8) which indexed novel susceptibility loci. SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. [less ▲]

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See detailGlucocorticoid-Mediated Enhancement of Glutamatergic Transmission May Outweigh Anti-Inflammatory Effects under Conditions of Neuropathic Pain.
Le Coz, Glenn-Marie UL; Anton, Fernand UL; Hanesch, Ulrike UL

in PloS one (2014), 9(3), 91393

At the clinical level comorbidity between chronic pain and dysfunctional hypothalamus-pituitary-adrenal (HPA) axis is well established. We aimed to identify causal relationships in a model of neuropathic ... [more ▼]

At the clinical level comorbidity between chronic pain and dysfunctional hypothalamus-pituitary-adrenal (HPA) axis is well established. We aimed to identify causal relationships in a model of neuropathic pain (chronic constriction injury, CCI) by studying the effects of glucocorticoid receptor agonist (dexamethasone) and antagonist (RU-486) administration on pain behavior and spinal biochemical mediators. Daily injections were performed in Sprague Dawley rats. Weight, plasma corticosterone levels and mechanical pain thresholds were assessed before and during 21 days post-CCI. At days four and 21 we investigated the mRNA expression of spinal mediators. In the dexamethasone-injected group, we observed a diminution of body weight and plasma corticosterone levels during the 21 days post surgery period and a more pronounced pain sensitivity until day 7 post-CCI. This enhanced pain sensitivity in the early period following nerve injury was accompanied by a transient increase of the glutamate receptors mGluR5 and NMDA at day 4. However, at this time point we did not observe any effect of the agonist/antagonist injections on the mRNA expression of pro-inflammatory cytokines. The RU-486-injected rats showed a slight mechanical hypoalgesia until 7 days post-CCI, but without any significant correlation with the expression of the measured markers. Our results indicate that glucocorticoid-related modulations of neuropathic pain processing may rather depend on a modification of glutamatergic transmission than on a change in pro-inflammatory cytokine expression. [less ▲]

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See detailTrade integration and trade imbalances in the European Union: a network perspective
Carpantier, Jean-Francois UL; Delvenne, Jean-Charles; Kriegs, Gautier

in PLoS ONE (2014), 9(1), 83448

We study the ever more integrated and ever more unbalanced trade relationships between European countries. To better capture the complexity of economic networks, we propose two global measures that assess ... [more ▼]

We study the ever more integrated and ever more unbalanced trade relationships between European countries. To better capture the complexity of economic networks, we propose two global measures that assess the trade integration and the trade imbalances of the European countries. These measures are the network (or indirect) counterparts to traditional (or direct) measures such as the trade-to-GDP (Gross Domestic Product) and trade deficit-to-GDP ratios. Our indirect tools account for the European inter-country trade structure and follow (i) a decomposition of the global trade flow into elementary flows that highlight the long-range dependencies between exporting and importing economies and (ii) the commute-time distance for trade integration,which measures the impact of a perturbation in the economy of a country on another country, possibly through intermediate partners by domino effect. Our application addresses the impact of the launch of the Euro. We find that the indirect imbalance measures better identify the countries ultimately bearing deficits and surpluses, by neutralizing the impact of trade transit countries, such as the Netherlands. Among others, we find that ultimate surpluses of Germany are quite concentrated in only three partners. We also show that for some countries, the direct and indirect measures of trade integration diverge, thereby revealing that these countries (e.g. Greece and Portugal) trade to a smaller extent with countries considered as central in the European Union network. [less ▲]

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See detailOutcomes in patients with acute and stable coronary syndromes; insights from the prospective NOBORI-2 study
Fath-Ordoubadi, F. A; Spaepen, E. B; El-Omar, M. A et al

in PLoS ONE (2014), 9(2),

Background: Contemporary data remains limited regarding mortality and major adverse cardiac events (MACE) outcomes in patients undergoing PCI for different manifestations of coronary artery disease ... [more ▼]

Background: Contemporary data remains limited regarding mortality and major adverse cardiac events (MACE) outcomes in patients undergoing PCI for different manifestations of coronary artery disease. Objectives: We evaluated mortality and MACE outcomes in patients treated with PCI for STEMI (ST-elevation myocardial infarction), NSTEMI (non ST-elevation myocardial infarction) and stable angina through analysis of data derived from the Nobori-2 study. Methods: Clinical endpoints were cardiac mortality and MACE (a composite of cardiac death, myocardial infarction and target vessel revascularization). Results: 1909 patients who underwent PCI were studied; 1332 with stable angina, 248 with STEMI and 329 with NSTEMI. Age-adjusted Charlson co-morbidity index was greatest in the NSTEMI cohort (3.78±1.91) and lowest in the stable angina cohort (3.00±1.69); P<0.0001. Following Cox multivariate analysis cardiac mortality was independently worse in the NSTEMI vs the stable angina cohort (HR 2.31 (1.10-4.87), p = 0.028) but not significantly different for STEMI vs stable angina cohort (HR 0.72 (0.16-3.19), p = 0.67). Similar observations were recorded for MACE (<180 days) (NSTEMI vs stable angina: HR 2.34 (1.21-4.55), p = 0.012; STEMI vs stable angina: HR 2.19 (0.97-4.98), p = 0.061. Conclusions: The longer-term Cardiac mortality and MACE were significantly worse for patients following PCI for NSTEMI even after adjustment of clinical demographics and Charlson co-morbidity index whilst the longer-term prognosis of patients following PCI STEMI was favorable, with similar outcomes as those patients with stable angina following PCI. © 2014 Fath-Ordoubadi et al. [less ▲]

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See detailElevated social stress levels and depressive symptoms in primary hyperhidrosis
Gross, K. M.; Schote, A. B.; Schneider, K. K. et al

in PLoS ONE (2014), 9(3), 92412

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See detailBeep Tones Attenuate Pain following Pavlovian Conditioning of an Endogenous Pain Control Mechanism
Scheuren, Raymonde UL; Anton, Fernand UL; Erpelding, Nathalie et al

in PLoS ONE (2014), 9(2), 88710

Heterotopic noxious counter-stimulation (HNCS) is commonly used to study endogenous pain control systems. The resulting pain inhibition is primarily based on spinal cord-brainstem loops. Recently ... [more ▼]

Heterotopic noxious counter-stimulation (HNCS) is commonly used to study endogenous pain control systems. The resulting pain inhibition is primarily based on spinal cord-brainstem loops. Recently, functional imaging studies have shown that limbic structures like the anterior cingulate cortex and amygdala are also implicated. Since these structures are involved in learning processes, it is possible that the HNCS-induced pain inhibition may depend on specific cues from the environment that have been associated with pain reduction through associative learning. We investigated the influence of Pavlovian conditioning on HNCS-induced pain inhibition in 32 healthy subjects by using a differential conditioning paradigm in which two different acoustic stimuli were either repeatedly paired or unpaired with HNCS. Series of noxious electrical pulse trains delivered to the non-dominant foot served as test stimuli. Diffuse noxious inhibitory control (DNIC)-like effects were induced by concurrent application of tonic HNCS (immersion of the contralateral hand in ice water). Subjective pain intensity and pain unpleasantness ratings and electromyographic recordings of the facial corrugator muscle and the nocifensive RIII flexion reflex were used to measure changes in pain sensitivity. HNCS induced significant pain and reflex inhibitions. In the post-conditioning phase, only the paired auditory cue was able to significantly reduce pain perceptions and corrugator muscle activity. No conditioned effect could be observed in RIII reflex responses. Our results indicate that the functional state of endogenous pain control systems may depend on associative learning processes that, like in the present study, may lead to an attenuation of pain perception. Similar albeit opposite conditioning of pain control mechanisms may significantly be involved in the exacerbation and chronification of pain states. [less ▲]

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See detailSystematic Design of 18S rRNA Gene Primers for Determining Eukaryotic Diversity in Microbial Consortia
Hugerth, Luisa; Muller, Emilie UL; Hu, Yue et al

in PLoS ONE (2014)

High-throughput sequencing of ribosomal RNA gene (rDNA) amplicons has opened up the door to large-scale comparative studies of microbial community structures. The short reads currently produced by ... [more ▼]

High-throughput sequencing of ribosomal RNA gene (rDNA) amplicons has opened up the door to large-scale comparative studies of microbial community structures. The short reads currently produced by massively parallel sequencing technologies make the choice of sequencing region crucial for accurate phylogenetic assignments. While for 16S rDNA, relevant regions have been well described, no truly systematic design of 18S rDNA primers aimed at resolving eukaryotic diversity has yet been reported. Here we used 31,862 18S rDNA sequences to design a set of broad-taxonomic range degenerate PCR primers. We simulated the phylogenetic information that each candidate primer pair would retrieve using paired- or single-end reads of various lengths, representing different sequencing technologies. Primer pairs targeting the V4 region performed best, allowing discrimination with paired-end reads as short as 150 bp (with 75% accuracy at genus level). The conditions for PCR amplification were optimised for one of these primer pairs and this was used to amplify 18S rDNA sequences from isolates as well as from a range of environmental samples which were then Illumina sequenced and analysed, revealing good concordance between expected and observed results. In summary, the reported primer sets will allow minimally biased assessment of eukaryotic diversity in different microbial ecosystems. [less ▲]

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See detailStriking discrepancy of anomalous body experiences with normal interoceptive accuracy in depersonalization-derealization disorder
Michal, M.; Reuchlein, B.; Adler, J. et al

in PLoS ONE (2014), 9(2), 89823

BACKGROUND: Disembodiment is a core feature of depersonalization disorder (DPD). Given the narratives of DPD patients about their disembodiment and emotional numbing and neurobiological findings of an ... [more ▼]

BACKGROUND: Disembodiment is a core feature of depersonalization disorder (DPD). Given the narratives of DPD patients about their disembodiment and emotional numbing and neurobiological findings of an inhibition of insular activity, DPD may be considered as a mental disorder with specific impairments of interoceptive awareness and body perception. METHODS: We investigated cardioceptive accuracy (CA) of DPD patients (n = 24) as compared to healthy controls (n = 26) with two different heartbeat detection tasks ("Schandry heartbeat counting task" and "Whitehead heartbeat discrimination task"). Self-rated clearness of body perception was measured by questionnaire. RESULTS: Contrary to our hypothesis, DPD patients performed similarly to healthy controls on the two different heartbeat detection tasks, and they had equal scores regarding their self-rated clearness of body perception. There was no correlation of the severity of "anomalous body experiences" and depersonalization with measures of interoceptive accuracy. Only among healthy controls CA in the Schandry task was positively correlated with self-rated clearness of body perception. Depersonalization was unrelated to severity of depression or anxiety, while depression and anxiety were highly correlated. Anxiety and depression did not modify the associations of depersonalization with interoceptive accuracy. CONCLUSIONS: Our main findings highlight a striking discrepancy of normal interoception with overwhelming experiences of disembodiment in DPD. This may reflect difficulties of DPD patients to integrate their visceral and bodily perceptions into a sense of their selves. This problem may be considered an important target for psychotherapeutic treatment approaches. [less ▲]

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See detailNew Target Genes of MITF-Induced microRNA-211 Contribute to Melanoma Cell Invasion
Margue, Christiane UL; Philippidou, Demetra UL; Reinsbach, Susanne UL et al

in PLoS ONE (2013), 8(9),

The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential ... [more ▼]

The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential expression patterns of miRNAs are currently being exploited for identification of biomarkers for early disease diagnosis, prediction of progression for melanoma and other cancers and as promising drug targets, since they can easily be inhibited or replaced in a given cellular context. Before successfully manipulating miRNAs in clinical settings, their precise expression levels, endogenous functions and thus their target genes have to be determined. MiR-211, a melanocyte lineage-specific small non-coding miRNA, is located in an intron of TRPM1, a target gene of the microphtalmia-associated transcription factor (MITF). By transcriptionally up-regulating TRPM1, MITF, which is critical for both melanocyte differentiation and survival and for melanoma progression, indirectly drives the expression of miR-211. Expression of this miRNA is often reduced in melanoma samples. Here, we investigated functional roles of miR-211 by identifying and studying new target genes. We show that MITF-correlated miR-211 expression levels are mostly but not always reduced in a panel of 11 melanoma cell lines and in primary and metastatic melanoma compared to normal melanocytes and nevi, respectively. MiR-211 itself only marginally impacted on cell invasion and migration, while perturbation of some new miR-211 target genes, such as AP1S2, SOX11, IGFBP5, and SERINC3 significantly increased invasion. These results and the variable expression levels of miR-211 raise serious doubts on the value of miR-211 as a melanoma tumor-suppressing miRNA and/or as a biomarker for melanoma. [less ▲]

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See detailTripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP’s Distribution on Microtubules
Koffa, Maria UL; Giannis, Athanassios; Kesisova, Iliana A. et al

in PLoS ONE (2013), 8(3),

Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of ... [more ▼]

Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development. © 2013 Kesisova et al. [less ▲]

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See detailAbolition of peroxiredoxin-5 mitochondrial targeting during canid evolution.
Van der Eecken, Valerie; Clippe, Andre; Dekoninck, Sophie et al

in PloS one (2013), 8(9), 72844

In human, the subcellular targeting of peroxiredoxin-5 (PRDX5), a thioredoxin peroxidase, is dependent on the use of multiple alternative transcription start sites and two alternative in-frame translation ... [more ▼]

In human, the subcellular targeting of peroxiredoxin-5 (PRDX5), a thioredoxin peroxidase, is dependent on the use of multiple alternative transcription start sites and two alternative in-frame translation initiation sites, which determine whether or not the region encoding a mitochondrial targeting sequence (MTS) is translated. In the present study, the abolition of PRDX5 mitochondrial targeting in dog is highlighted and the molecular mechanism underlying the loss of mitochondrial PRDX5 during evolution is examined. Here, we show that the absence of mitochondrial PRDX5 is generalized among the extant canids and that the first events leading to PRDX5 MTS abolition in canids involve a mutation in the more 5' translation initiation codon as well as the appearance of a STOP codon. Furthermore, we found that PRDX5 MTS functionality is maintained in giant panda and northern elephant seal, which are phylogenetically closely related to canids. Also, the functional consequences of the restoration of mitochondrial PRDX5 in dog Madin-Darby canine kidney (MDCK) cells were investigated. The restoration of PRDX5 mitochondrial targeting in MDCK cells, instead of protecting, provokes deleterious effects following peroxide exposure independently of its peroxidase activity, indicating that mitochondrial PRDX5 gains cytotoxic properties under acute oxidative stress in MDCK cells. Altogether our results show that, although mitochondrial PRDX5 cytoprotective function against oxidative stress has been clearly demonstrated in human and rodents, PRDX5 targeting to mitochondria has been evolutionary lost in canids. Moreover, restoration of mitochondrial PRDX5 in dog MDCK cells, instead of conferring protection against peroxide exposure, makes them more vulnerable. [less ▲]

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