References of "Krüger, Rejko 50002143"
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See detailMissing heritability in Parkinson’s disease: the emerging role of non‑coding genetic variation
Ohnmacht, Jochen UL; May, Patrick UL; Sinkkonen, Lasse UL et al

in Journal of Neural Transmission (2020)

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical ... [more ▼]

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease- and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future. [less ▲]

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See detailExcess of singleton loss-of-function variants in Parkinson's disease contributes to genetic risk.
Bobbili, Dheeraj Reddy; Banda, Peter UL; Krüger, Rejko UL et al

in Journal of Medical Genetics (2020)

Background Parkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple ... [more ▼]

Background Parkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple variants associated with sporadic PD were discovered via association studies. Methods We studied the whole-exome sequencing data of 340 PD cases and 146 ethnically matched controls from the Parkinson’s Progression Markers Initiative (PPMI) and performed burden analysis for different rare variant classes. Disease prediction models were built based on clinical, non-clinical and genetic features, including both common and rare variants, and two machine learning methods. Results We observed a significant exome-wide burden of singleton loss-of-function variants (corrected p=0.037). Overall, no exome-wide burden of rare amino acid changing variants was detected. Finally, we built a disease prediction model combining singleton loss-of-function variants, a polygenic risk score based on common variants, and family history of PD as features and reached an area under the curve of 0.703 (95% CI 0.698 to 0.708). By incorporating a rare variant feature, our model increased the performance of the state-of-the-art classification model for the PPMI dataset, which reached an area under the curve of 0.639 based on common variants alone. Conclusion The main finding of this study is to highlight the contribution of singleton loss-of-function variants to the complex genetics of PD and that disease risk prediction models combining singleton and common variants can improve models built solely on common variants. [less ▲]

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See detailMachine learning-assisted neurotoxicity prediction in human midbrain organoids
Monzel, Anna Sophia UL; Hemmer, K; Smits, Lisa UL et al

in Parkinsonism and Related Disorders (2020)

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See detailImpaired Mitochondrial-Endoplasmic Reticulum Interaction and Mitophagy in Miro1-Mutant Neurons in Parkinson’s Disease
Berenguer-Escuder, Clara; Grossmann, Dajana; Antony, Paul UL et al

in Human Molecular Genetics (2020)

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See detailVariants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients
Berenguer, Clara UL; Grossmann, Dajana; Massart, François UL et al

in Journal of Clinical Medicine (2019)

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD ... [more ▼]

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. [less ▲]

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See detailGene-environment interaction and Mendelian randomisation
Krüger, Rejko UL; Kolber, Pierre Luc UL

in Revue Neurologique (2019)

Genetic factors only account for up to a third of the cases of Parkinson's disease (PD), while the remaining cases are of unknown aetiology. Environmental exposures (such as pesticides or heavy metals ... [more ▼]

Genetic factors only account for up to a third of the cases of Parkinson's disease (PD), while the remaining cases are of unknown aetiology. Environmental exposures (such as pesticides or heavy metals) and the interaction with genetic susceptibility factors (summarized in the concept of impaired xenobiotic metabolism) are believed to play a major role in the mechanisms of neurodegeneration. Beside of the classical association studies (e.g. genome-wide association studies), a novel approach to investigate environmental risk factors are Mendelian randomisation studies. This review explores the gene-environment interaction and the gain of Mendelian randomisation studies in assessing causalities of modifiable risk factors for PD. [less ▲]

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See detailMultilingual Validation of the First French Version of Munich Dysphagia Test-Parkinson's Disease (MDT-PD) in the Luxembourg Parkinson's Study
Simons, Janine UL; Vaillant, Michel; Hipp Epouse D'amico, Géraldine UL et al

in Frontiers in Neurology (2019)

The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect ... [more ▼]

The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect early oropharyngeal symptoms and aspiration risk in patients with idiopathic Parkinson's disease (iPD). In order to make this tool accessible for prevention in the French speaking populations worldwide, we performed the first French translation and provide a linguistic and psychometric validation in the unique multilingual environment of the Luxembourg Parkinson's Study. [less ▲]

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See detailConnecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges
Schymanski, Emma UL; Baker, Nancy C.; Williams, Antony J et al

in Environmental Science. Processes and Impacts (2019)

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary ... [more ▼]

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary approach. Rapid developments in analytical and data technologies, such as non-target high resolution mass spectrometry (NT-HR-MS), have opened up new possibilities to accomplish this, inconceivable 20 years ago. While NT-HR-MS is being applied to increasingly complex research questions, there are still many unidentified chemicals and uncertainties in linking exposures to human health outcomes and environmental impacts. In this perspective, we explore the possibilities and challenges involved in using cheminformatics and NT-HR-MS to answer complex questions that cross many scientific disciplines, taking the identification of potential (small molecule) neurotoxicants in environmental or biological matrices as a case study. We explore capturing literature knowledge and patient exposure information in a form amenable to high-throughput data mining, and the related cheminformatic challenges. We then briefly cover which sample matrices are available, which method(s) could potentially be used to detect these chemicals in various matrices and what remains beyond the reach of NT-HR-MS. We touch on the potential for biological validation systems to contribute to mechanistic understanding of observations and explore which sampling and data archiving strategies may be required to form an accurate, sustained picture of small molecule signatures on extensive cohorts of patients with chronic neurodegenerative disorders. Finally, we reflect on how NT-HR-MS can support unravelling the contribution of the environment to complex diseases. [less ▲]

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See detailDeep Brain Stimulation for Freezing of Gait in Parkinson’s Disease With Early Motor Complications
Krüger, Rejko UL; EARLYSTIM study group; Barbe, Michael

in Movement Disorders (2019)

Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized ... [more ▼]

Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIMtrial). [less ▲]

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See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

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See detailAutomated high-throughput high-content autophagy and mitophagy analysis platform
Arias, Jonathan UL; Jarazo, Javier UL; Walter, Jonas UL et al

in Scientific Reports (2019)

Autophagic processes play a central role in cellular homeostasis. In pathological conditions, the flow of autophagy can be affected at multiple and distinct steps of the pathway. Current analyses tools do ... [more ▼]

Autophagic processes play a central role in cellular homeostasis. In pathological conditions, the flow of autophagy can be affected at multiple and distinct steps of the pathway. Current analyses tools do not deliver the required detail for dissecting pathway intermediates. The development of new tools to analyze autophagic processes qualitatively and quantitatively in a more straightforward manner is required. Defining all autophagy pathway intermediates in a high-throughput manner is technologically challenging and has not been addressed yet. Here, we overcome those requirements and limitations by the developed of stable autophagy and mitophagy reporter-iPSC and the establishment of a novel high-throughput phenotyping platform utilizing automated high-content image analysis to assess autophagy and mitophagy pathway intermediates. [less ▲]

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See detailα-Synuclein in Parkinson's disease: causal or bystander?
Krüger, Rejko UL; Riederer, Peter; Berg, Daniela et al

in Journal of Neural Transmission (2019)

Parkinson’s disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying ... [more ▼]

Parkinson’s disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration. [less ▲]

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See detailUsing global team science to identify genetic parkinson's disease worldwide
Krüger, Rejko UL; Vollstedt, Eva‐Juliane; Kasten, Meike et al

in Annals of Neurology (2019)

Large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.

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See detailSingle-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Smits, Lisa UL; Magni, Stefano UL; Grzyb, Kamil UL et al

E-print/Working paper (2019)

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an ... [more ▼]

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating these in vivo features makes hMOs an excellent tool for in vitro disease phenotyping and drug discovery. [less ▲]

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See detailFamily-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder
Krüger, Rejko UL; Gerlach, Manfred; Sharma, Manu et al

in ADHD Attention Deficit and Hyperactivity Disorders (2019)

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD). A genetic and phenotypic overlap ... [more ▼]

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, pnom = 1 padj = 1) and rs356219 (OR 1.28; pnom = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, pnom = 0.020), which survived Bonferroni correction (padj = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, padj = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation. [less ▲]

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See detailQuality of life predicts outcome of deep brain stimulation in early Parkinson disease
Krüger, Rejko UL; EARLYSTIM study group; Schuepbach, Michael et al

in Neurology (2019)

Objective Toinvestigatepredictorsforimprovementofdisease-specificqualityoflife(QOL)afterdeepbrainstimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications ... [more ▼]

Objective Toinvestigatepredictorsforimprovementofdisease-specificqualityoflife(QOL)afterdeepbrainstimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications. Methods We performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomizedtrialcomparingSTN-DBS(n= 124)tobestmedicaltreatment(n= 127)after2yearsfollow-up with disease-specific QOL (39-item Parkinson ’s Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson’s Disease Rating Scale(UPDRS)(UPDRS-III“off”and“on”medications,UPDRS-IV)wereconductedtodeterminepredictors of change in PDQ-39-SI. Results PDQ-39-SIatbaselinewascorrelatedtothechangeinPDQ-39-SIafter24monthsinbothtreatmentgroups (p<0.05).Thehigherthebaselinescore(worseQOL)thelargertheimprovementinQOLafter24months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group. Conclusion Impaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS. [less ▲]

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See detailIntegrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson’s Disease
Hertel, Johannes; Harms, Amy C.; Heinken, Almut et al

in Cell Reports (2019), 29(7), 1767-1777

Parkinson’s disease (PD) exhibits systemic effects on human metabolism with emerging roles for the gut microbiome. Here, we integrated longitudinal metabolome data from 30 drug-naïve, de-novo PD patients ... [more ▼]

Parkinson’s disease (PD) exhibits systemic effects on human metabolism with emerging roles for the gut microbiome. Here, we integrated longitudinal metabolome data from 30 drug-naïve, de-novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naïve PD cohort, and prospective data from a general population. Our key results are i) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls, ii) dopaminergic medication showed strong lipidomic signatures, iii) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with incident PD in the general population, and iv) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, consistent with the changed metabolome. In conclusion, the multi-omics integration revealed PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity. [less ▲]

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See detailAnodal tDCS modulates cortical activity and synchronization in Parkinson's disease depending on motor processing.
Schoellmann, Anna; Scholten, Marlieke; Wasserka, Barbara et al

in NeuroImage. Clinical (2019), 22

BACKGROUND: Transcranial direct current stimulation (tDCS) may alleviate motor symptoms in Parkinson's disease (PD). However, the neurophysiological effects of tDCS on cortical activation, synchronization ... [more ▼]

BACKGROUND: Transcranial direct current stimulation (tDCS) may alleviate motor symptoms in Parkinson's disease (PD). However, the neurophysiological effects of tDCS on cortical activation, synchronization, and the relation to clinical motor symptoms and motor integration need characterization. OBJECTIVE: We aimed to explore the effect of tDCS over the left sensorimotor area on clinical motor outcome, right hand fine motor performance as well as cortical activity and synchronization in the high beta range. METHODS: In this double-blind randomized sham-controlled clinico-neurophysiological study we investigated ten idiopathic PD patients and eleven matched healthy controls (HC) on two days during an isometric precision grip task and at rest before and after 'verum' and 'sham' anodal tDCS (20min; 1mA; anode [C3], cathode [Fp2]). We measured clinical outcome, fine motor performance, and analysed both cortical frequency domain activity and corticocortical imaginary coherence. RESULTS: tDCS improved PD motor symptoms. Neurophysiological features indicated a motor-task-specific modulation of activity and coherence from 22 to 27Hz after 'verum' stimulation in PD. Activity was significantly reduced over the left sensorimotor and right frontotemporal area. Before stimulation, PD patients showed reduced coherence over the left sensorimotor area during motor task compared to HC, and this increased after 'verum' stimulation in the motor task. The activity and synchronization modulation were neither observed at rest, after sham stimulation nor in healthy controls. CONCLUSION: Verum tDCS modulated the PD cortical network specifically during fine motor integration. Cortical oscillatory features were not in general deregulated in PD, but depended on motor processing. [less ▲]

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See detailLarge-scale validation of miRNAs by disease association, evolutionary conservation and pathway activity.
Keller, Andreas; Fehlmann, Tobias; Laufer, Thomas et al

in RNA biology (2018)

The validation of microRNAs (miRNAs) identified by next generation sequencing involves amplification-free and hybridization-based detection of transcripts as criteria for confirming valid miRNAs. Since ... [more ▼]

The validation of microRNAs (miRNAs) identified by next generation sequencing involves amplification-free and hybridization-based detection of transcripts as criteria for confirming valid miRNAs. Since respective validation is frequently not performed, miRNA repositories likely still contain a substantial fraction of false positive candidates while true miRNAs are not stored in the repositories yet. Especially if downstream analyses are performed with these candidates (e.g. target or pathway prediction), the results may be misleading. In the present study, we evaluated 558 mature miRNAs from miRBase and 1,709 miRNA candidates from next generation sequencing experiments by amplification-free hybridization and investigated their distributions in patients with various disease conditions. Notably, the most significant miRNAs in diseases are often not contained in the miRBase. However, these candidates are evolutionary highly conserved. From the expression patterns, target gene and pathway analyses and evolutionary conservation analyses, we were able to shed light on the complexity of miRNAs in humans. Our data also highlight that a more thorough validation of miRNAs identified by next generation sequencing is required. The results are available in miRCarta ( https://mircarta.cs.uni-saarland.de ). [less ▲]

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