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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 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 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 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 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 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 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 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 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 detailBee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model.
Alvarez-Fischer, Daniel; Noelker, Carmen; Vulinovic, Franca et al

in PloS one (2013), 8(4), 61700

Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs ... [more ▼]

Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i) establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii) demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide. [less ▲]

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See detailThe central role of AMP-kinase and energy homeostasis impairment in Alzheimer’s disease: a multifactor network analysis
Caberlotto, Laura; Lauria, Mario; Nguyen, Thanh-Phuong UL et al

in PLoS ONE (2013)

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See detailA novel color change mechanism for breast cancer biomarker detection: naphthoquinones as specific ligands of human arylamine N-acetyltransferase 1.
Laurieri, Nicola; Egleton, James E.; Varney, Amy et al

in PloS one (2013), 8(8), 70600

Human arylamine N-acetyltransferase 1 (hNAT1) has become an attractive potential biomarker for estrogen-receptor-positive breast cancers. We describe here the mechanism of action of a selective non ... [more ▼]

Human arylamine N-acetyltransferase 1 (hNAT1) has become an attractive potential biomarker for estrogen-receptor-positive breast cancers. We describe here the mechanism of action of a selective non-covalent colorimetric biosensor for the recognition of hNAT1 and its murine homologue, mNat2, over their respective isoenzymes, leading to new opportunities in diagnosis. On interaction with the enzyme, the naphthoquinone probe undergoes an instantaneous and striking visible color change from red to blue. Spectroscopic, chemical, molecular modelling and biochemical studies reported here show that the color change is mediated by selective recognition between the conjugate base of the sulfonamide group within the probe and the conjugate acid of the arginine residue within the active site of both hNAT1 and mNat2. This represents a new mechanism for selective biomarker sensing and may be exploited as a general approach to the specific detection of biomarkers in disease. [less ▲]

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See detailMitochondrial phylogenomics of modern and ancient equids.
Vilstrup, Julia T.; Seguin-Orlando, Andaine; Stiller, Mathias et al

in PloS one (2013), 8(2), 55950

The genus Equus is richly represented in the fossil record, yet our understanding of taxonomic relationships within this genus remains limited. To estimate the phylogenetic relationships among modern ... [more ▼]

The genus Equus is richly represented in the fossil record, yet our understanding of taxonomic relationships within this genus remains limited. To estimate the phylogenetic relationships among modern horses, zebras, asses and donkeys, we generated the first data set including complete mitochondrial sequences from all seven extant lineages within the genus Equus. Bayesian and Maximum Likelihood phylogenetic inference confirms that zebras are monophyletic within the genus, and the Plains and Grevy's zebras form a well-supported monophyletic group. Using ancient DNA techniques, we further characterize the complete mitochondrial genomes of three extinct equid lineages (the New World stilt-legged horses, NWSLH; the subgenus Sussemionus; and the Quagga, Equus quagga quagga). Comparisons with extant taxa confirm the NWSLH as being part of the caballines, and the Quagga and Plains zebras as being conspecific. However, the evolutionary relationships among the non-caballine lineages, including the now-extinct subgenus Sussemionus, remain unresolved, most likely due to extremely rapid radiation within this group. The closest living outgroups (rhinos and tapirs) were found to be too phylogenetically distant to calibrate reliable molecular clocks. Additional mitochondrial genome sequence data, including radiocarbon dated ancient equids, will be required before revisiting the exact timing of the lineage radiation leading up to modern equids, which for now were found to have possibly shared a common ancestor as far as up to 4 Million years ago (Mya). [less ▲]

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See detailRisk for eating disorders modulates startle-responses to body words
Herbert, Cornelia; Kübler, Andrea; Vögele, Claus UL

in PLoS ONE (2013), 8(1), 53667

Body image disturbances are core symptoms of eating disorders (EDs). Recent evidence suggests that changes in body image may occur prior to ED onset and are not restricted to in-vivo exposure (e.g. mirror ... [more ▼]

Body image disturbances are core symptoms of eating disorders (EDs). Recent evidence suggests that changes in body image may occur prior to ED onset and are not restricted to in-vivo exposure (e.g. mirror image), but also evident during presentation of abstract cues such as body shape and weight related words. In the present study startle modulation, heart rate and subjective evaluations were examined during reading of body words and neutral words in 41 student female volunteers screened for risk of EDs. The aim was to determine if responses to body words are attributable to a general negativity bias regardless of ED risk or if activated, ED relevant negative body schemas facilitate priming of defensive responses. Heart rate and word ratings differed between body words and neutral words in the whole female sample, supporting a general processing bias for body weight and shape related concepts in young women regardless of ED risk. Startle modulation was specifically related to eating disorder symptoms as was indicated by significant positive correlations with self-reported body dissatisfaction. These results emphasize the relevance of examining body schema representations as a function of ED risk across different levels of responding. Peripheral-physiological measures such as the startle reflex could possibly be used as predictors of females’ risk for developing EDs in the future. [less ▲]

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See detailSwitch of Sensitivity Dynamics Revealed with DyGloSA Toolbox for Dynamical Global Sensitivity Analysis as an Early Warning for System's Critical Transition.
Baumuratova, Tatiana UL; Dobre, Simona; Bastogne, Thierry et al

in PloS one (2013), 8(12), 82973

Systems with bifurcations may experience abrupt irreversible and often unwanted shifts in their performance, called critical transitions. For many systems like climate, economy, ecosystems it is highly ... [more ▼]

Systems with bifurcations may experience abrupt irreversible and often unwanted shifts in their performance, called critical transitions. For many systems like climate, economy, ecosystems it is highly desirable to identify indicators serving as early warnings of such regime shifts. Several statistical measures were recently proposed as early warnings of critical transitions including increased variance, autocorrelation and skewness of experimental or model-generated data. The lack of automatized tool for model-based prediction of critical transitions led to designing DyGloSA - a MATLAB toolbox for dynamical global parameter sensitivity analysis (GPSA) of ordinary differential equations models. We suggest that the switch in dynamics of parameter sensitivities revealed by our toolbox is an early warning that a system is approaching a critical transition. We illustrate the efficiency of our toolbox by analyzing several models with bifurcations and predicting the time periods when systems can still avoid going to a critical transition by manipulating certain parameter values, which is not detectable with the existing SA techniques. DyGloSA is based on the SBToolbox2 and contains functions, which compute dynamically the global sensitivity indices of the system by applying four main GPSA methods: eFAST, Sobol's ANOVA, PRCC and WALS. It includes parallelized versions of the functions enabling significant reduction of the computational time (up to 12 times). DyGloSA is freely available as a set of MATLAB scripts at http://bio.uni.lu/systems_biology/software/dyglosa. It requires installation of MATLAB (versions R2008b or later) and the Systems Biology Toolbox2 available at www.sbtoolbox2.org. DyGloSA can be run on Windows and Linux systems, -32 and -64 bits. [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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See detailDerivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling.
Reinhardt, Peter; Glatza, Michael; Hemmer, Kathrin et al

in PLoS ONE (2013), 8(3), 59252

Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even ... [more ▼]

Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even small variability within the cell populations for screening could easily invalidate an entire campaign. Neurodegenerative assays are particularly challenging because neurons are post-mitotic and cannot be expanded for implementation in HTS. Therefore, HTS for neuroprotective compounds requires a cell type that is robustly expandable and able to differentiate into all of the neuronal subtypes involved in disease pathogenesis. Here, we report the derivation and propagation using only small molecules of human neural progenitor cells (small molecule neural precursor cells; smNPCs). smNPCs are robust, exhibit immortal expansion, and do not require cumbersome manual culture and selection steps. We demonstrate that smNPCs have the potential to clonally and efficiently differentiate into neural tube lineages, including motor neurons (MNs) and midbrain dopaminergic neurons (mDANs) as well as neural crest lineages, including peripheral neurons and mesenchymal cells. These properties are so far only matched by pluripotent stem cells. Finally, to demonstrate the usefulness of smNPCs we show that mDANs differentiated from smNPCs with LRRK2 G2019S are more susceptible to apoptosis in the presence of oxidative stress compared to wild-type. Therefore, smNPCs are a powerful biological tool with properties that are optimal for large-scale disease modeling, phenotypic screening, and studies of early human development. [less ▲]

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See detailKnockdown of Hsc70-5/mortalin induces loss of synaptic mitochondria in a Drosophila Parkinson's disease model.
Zhu, Jun-Yi; Vereshchagina, Natalia; Sreekumar, Vrinda et al

in PloS one (2013), 8(12), 83714

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of ... [more ▼]

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism. [less ▲]

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