Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy

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Design and estimator for the total sensitivity index Global sensitivity indices for nonlinear mathematical models and their Monte Carlo estimates Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropediatrics, 10117 Berlin, Germany Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Clinical Research Center, 10117 Berlin, Germany Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany Faculty of sildenafil citrate tables Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4366 Esch-sur-Alzette, Luxembourg Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), 57001 Thessaloniki, Greece Department of Physics, University of South Florida, Tampa, FL 33620, USA Stem Cells and Metabolism Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland Institute of Neurobiology, Heinrich Heine University, 40225 Düsseldorf, Germany Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany Faculty of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands Institute of Neurobiology, Heinrich Heine University, 40225 Düsseldorf, Germany Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Insti

Two-day LV pressure overload (TAC) did not affect RV pressure or function, but prolonged LV relaxation that was ameliorated by sildenafil

∙ Groschner, L.N...

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Molecularly distinct routes of mitochondrial Ca2+ uptake are activated depending on the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats Ca2+-activated K+ (KCa) channels are involved in the relaxations elicited by sildenafil in penile resistance arteries Checchetto, V. ∙ Leanza, L. ∙ De Stefani, D. .. Mitochondrial K+ channels and their implications for disease mechanisms Loss of the large conductance calcium-activated potassium channel causes an increase in mitochondrial reactive oxygen species in glioblastoma cells High-content analysis of neuronal morphology in human iPSC-derived neurons Local and long-range reciprocal regulation of cAMP and cGMP in axon/dendrite formation Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells Modulation of synaptic function by cGMP and cGMP-gated cation channels Schmidt, H.

∙ Werner, M. ∙ Heppenstall, P.A...

cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome Human iPSC-Derived Blood-Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development?

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A scale to monitor progression and treatment of mitochondrial disease in children Schaefer, A.M. ∙ Phoenix, C. ∙ Elson, J.L... Mitochondrial disease in adults: a scale to monitor progression and treatment Natural History of Leigh Syndrome: A Study of Disease Burden and Progression Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8 Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF Resurrection of sildenafil: potential for Huntington’s Disease, too? Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse Function of cGMP-dependent protein kinases in the nervous system Impairment of LTD and cerebellar learning by Purkinje cell-specific ablation of cGMP-dependent protein kinase I PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression The mitochondrial regulator PGC1alpha is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure cGMP-dependent protein kinase: linking foraging to energy homeostasis Paupardin-Tritsch, D.

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∙ Hammond, C. ∙ Gerschenfeld, H.M. .. cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurones Distinct functions of a cGMP-dependent protein kinase in nerve terminal growth and synaptic vesicle cycling Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial Turning the Oxygen Dial: Balancing the Highs and Lows Cunnane, S.C. ∙ Trushina, E. A scale to monitor progression and treatment of mitochondrial disease in children Schaefer, A.M. ∙ Phoenix, C. ∙ Elson, J.L...

Mitochondrial disease in adults: a scale to monitor progression and treatment Natural History of Leigh Syndrome: A Study of Disease Burden and Progression Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8 Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF Resurrection of sildenafil: potential for Huntington’s Disease, too? Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord Phosphodiesterase 5 inhibition as a therapeutic target for ischemic stroke: A systematic review of preclinical studies Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse Function of cGMP-dependent protein kinases in the nervous system Impairment of LTD and cerebellar learning by Purkinje cell-specific ablation of cGMP-dependent protein kinase I PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression The mitochondrial regulator PGC1alpha is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure cGMP-dependent protein kinase: linking foraging to energy homeostasis Paupardin-Tritsch, D. ∙ Hammond, C.

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∙ Gerschenfeld, H.M. .. cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurones Distinct functions of a cGMP-dependent protein kinase in nerve terminal growth and synaptic vesicle cycling Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial Turning the Oxygen Dial: Balancing the Highs and Lows Cunnane, S.C. ∙ Trushina, E.

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∙ Deak, A.T. ∙ Groschner, L.N... Molecularly distinct routes of mitochondrial Ca2+ uptake are activated depending on the activity of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats Ca2+-activated K+ (KCa) channels are involved in the relaxations elicited by sildenafil in penile resistance arteries Checchetto, V. ∙ Leanza, L. ∙ De Stefani, D.

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.. Mitochondrial K+ channels and their implications for disease mechanisms Loss of the large conductance calcium-activated potassium channel causes an increase in mitochondrial reactive oxygen species in glioblastoma cells High-content analysis of neuronal morphology in human iPSC-derived neurons Local and long-range reciprocal regulation of cAMP and cGMP in axon/dendrite formation Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells Modulation of synaptic function by cGMP and cGMP-gated cation channels Schmidt, H. ∙ Werner, M. ∙ Heppenstall, P.A... cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome Human iPSC-Derived Blood-Brain Barrier Models: Valuable Tools for Preclinical Drug Discovery and Development? ∙ Morland, C. .. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing Mitochondria at the crossroads of health and disease Mitochondria metabolism sets the species-specific tempo of neuronal development Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial Testing Higher Doses of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia: An Open-Label Dose-Finding Phase 1b Clinical Trial-Sildenafil Administration to Treat Neonatal Encephalopathy-Study 02 Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences A reference human induced pluripotent stem cell line for large-scale collaborative studies A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells Genome-wide analysis of PDX1 target genes in human pancreatic progenitors Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis Prime-Editing of human ACTB in induced pluripotent stem cells to model human ACTB Loss-of-Function diseases and compensatory mechanisms Induced pluripotent stem cell lines derived from human somatic cells Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling Individual brain organoids reproducibly form cell diversity of the human cerebral cortex Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells A new mathematical model for relative quantification in real-time RT-PCR Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Dictionary learning for integrative, multimodal and scalable single-cell analysis Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression Modelling viral encephalitis caused by herpes simplex virus 1 infection in cerebral organoids SCENIC: single-cell regulatory network inference and clustering The Molecular Signatures Database (MSigDB) hallmark gene set collection Protocol for the generation of cultured cortical brain organoid slices Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation Mitochondrial genomes gleaned from human whole-exome sequencing Rubino, F. ∙ Piredda, R. ∙ Calabrese, F.M... HmtDB, a genomic resource for mitochondrion-based human variability studies The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2 Stem Cell Rep. 2022; 17:307-320 Human isogenic cells of the neurovascular unit exert transcriptomic cell type-specific effects on a blood-brain barrier in vitro model of late-onset Alzheimer disease Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells Stem Cell Rep. 2017; 8:894-906 A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources Subtype-Directed Differentiation of Human iPSCs into Atrial and Ventricular Cardiomyocytes Deep phenotyping of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ Bertram, R.

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∙ Morland, C. .. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing Mitochondria at the crossroads of health and disease Mitochondria metabolism sets the species-specific tempo of neuronal development Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial Testing Higher Doses of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia: An Open-Label Dose-Finding Phase 1b Clinical Trial-Sildenafil Administration to Treat Neonatal Encephalopathy-Study 02 Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences A reference human induced pluripotent stem cell line for large-scale collaborative studies A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells Genome-wide analysis of PDX1 target genes in human pancreatic progenitors Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis Prime-Editing of human ACTB in induced pluripotent stem cells to model human ACTB Loss-of-Function diseases and compensatory mechanisms Induced pluripotent stem cell lines derived from human somatic cells Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling Individual brain organoids reproducibly form cell diversity of the human cerebral cortex Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells A new mathematical model for relative quantification in real-time RT-PCR Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Dictionary learning for integrative, multimodal and scalable single-cell analysis Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression Modelling viral encephalitis caused by herpes simplex virus 1 infection in cerebral organoids SCENIC: single-cell regulatory network inference and clustering The Molecular Signatures Database (MSigDB) hallmark gene set collection Protocol for the generation of cultured cortical brain organoid slices Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation Mitochondrial genomes gleaned from human whole-exome sequencing Rubino, F. ∙ Piredda, R. ∙ Calabrese, F.M...

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HmtDB, a genomic resource for mitochondrion-based human variability studies The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2 Stem Cell Rep. 2022; 17:307-320 Human isogenic cells of the neurovascular unit exert transcriptomic cell type-specific effects on a blood-brain barrier in vitro model of late-onset Alzheimer disease Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells Stem Cell Rep. 2017; 8:894-906 A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources Subtype-Directed Differentiation of Human iPSCs into Atrial and Ventricular Cardiomyocytes Deep phenotyping of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ Bertram, R. ∙ Gram Pedersen, M. ∙ Luciani, D.S... ∙ Luciani, D.S... A simplified model for mitochondrial ATP production Model of beta-cell mitochondrial calcium handling and electrical activity. Actin-based confinement of calcium responses during Shigella invasion Contreras, L. ∙ Gomez-Puertas, P. ∙ Iijima, M. ..

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Ca2+ Activation kinetics of the two aspartate-glutamate mitochondrial carriers, aralar and citrin: role in the heart malate-aspartate NADH shuttle Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps Estimating intracellular calcium concentrations and buffering without wavelength ratioing Csordás, G. ∙ Golenár, T.

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A simplified model for mitochondrial ATP production Model of beta-cell mitochondrial calcium handling and electrical activity. Actin-based confinement of calcium responses during Shigella invasion Contreras, L. ∙ Gomez-Puertas, P. ∙ Iijima, M. ..

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Ca2+ Activation kinetics of the two aspartate-glutamate mitochondrial carriers, aralar and citrin: role in the heart malate-aspartate NADH shuttle Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps Estimating intracellular calcium concentrations and buffering without wavelength ratioing Csordás, G. ∙ Golenár, T. ∙ Seifert, E.L. .. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter Analysis of variance designs for model output Variance based sensitivity analysis of model output. ∙ Seifert, E.L.

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MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter Analysis of variance designs for model output Variance based sensitivity analysis of model output. Design and estimator for the total sensitivity index Global sensitivity indices for nonlinear mathematical models and their Monte Carlo estimates Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropediatrics, 10117 Berlin, Germany Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Clinical Research Center, 10117 Berlin, Germany Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany Faculty of sildenafil citrate tables Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4366 Esch-sur-Alzette, Luxembourg Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), 57001 Thessaloniki, Greece Department of Physics, University of South Florida, Tampa, FL 33620, USA Stem Cells and Metabolism Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland Institute of Neurobiology, Heinrich Heine University, 40225 Düsseldorf, Germany Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany Faculty of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands Institute of Neurobiology, Heinrich Heine University, 40225 Düsseldorf, Germany Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany Fraunhofer Insti