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Bhaswar Ghosh - One of the best experts on this subject based on the ideXlab platform.
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Design of a MAPK Signalling Cascade balances energetic cost versus accuracy of information transmission.
Nature Communications, 2020Co-Authors: Alexander Anders, Bhaswar Ghosh, Timo Glatter, Victor SourjikAbstract:Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped Signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) Signalling Cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the Signalling Cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular Signalling systems. Cellular Signalling networks provide information to the cell, but the trade-off between accuracy of information transfer and energetic cost of doing so has not been assessed. Here, the authors investigate a MAPK Signalling Cascade in budding yeast and find that information is maximised per unit energetic cost.
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design of a mapk Signalling Cascade balances energetic cost versus accuracy of information transmission
Nature Communications, 2020Co-Authors: Alexander Anders, Bhaswar Ghosh, Timo Glatter, Victor SourjikAbstract:Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped Signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) Signalling Cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the Signalling Cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular Signalling systems.
Victor Sourjik - One of the best experts on this subject based on the ideXlab platform.
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Design of a MAPK Signalling Cascade balances energetic cost versus accuracy of information transmission.
Nature Communications, 2020Co-Authors: Alexander Anders, Bhaswar Ghosh, Timo Glatter, Victor SourjikAbstract:Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped Signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) Signalling Cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the Signalling Cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular Signalling systems. Cellular Signalling networks provide information to the cell, but the trade-off between accuracy of information transfer and energetic cost of doing so has not been assessed. Here, the authors investigate a MAPK Signalling Cascade in budding yeast and find that information is maximised per unit energetic cost.
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design of a mapk Signalling Cascade balances energetic cost versus accuracy of information transmission
Nature Communications, 2020Co-Authors: Alexander Anders, Bhaswar Ghosh, Timo Glatter, Victor SourjikAbstract:Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped Signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) Signalling Cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the Signalling Cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular Signalling systems.
Oliver Ritter - One of the best experts on this subject based on the ideXlab platform.
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abstract 270 the eya4 six1 Signalling Cascade is activated in acquired heart disease
Circulation Research, 2015Co-Authors: Tatjana Williams, Daniel Oppelt, Peter Nordbeck, Sabine Voll, Jost Schoenberger, Oliver RitterAbstract:Rationale: We previously identified a mutation in the human transcriptional cofactor Eya4 as cause of familial dilated cardiomyopathy (DCM). We now provide evidence that the Eya4/Six1 Signalling Cascade also is crucial in acquired heart disease. Hypothesis: We hypothesize that the transcriptional complex Eya4/Six1 regulates targets relevant in normal cardiac function. We speculate it, amongst others, regulates expression of p27kip1, a known inhibitor of hypertrophy in adult cardiomyocytes, upon hypertrophic stimuli. Methods and results: We first examined the correlation of Eya4 and p27 in regards to phosphorylation and cellular distribution in failing and normal human hearts. Immunhistology revealed Eya4 is mainly distributed in the cytoplasm while p27 predominantly resides in the nucleus of healthy myocardial tissue. In sections of failing human hearts, Eya4 accumulated in the perinuclear and nuclear region; nuclear p27 levels were significantly diminished, phosphorylated p27 was evenly distributed in the cytoplasm. In a murine model of MI, IH showed Eya4 translocates in a time-dependent manner. WB analyses for p27 showed an age dependent decrease in p27 protein levels upon MI compared to control littermates. We generated transgenic mice with constitutive myocardial overexpression of Eya4 and E193. As judged by MRI, hemodynamic and morphometric analysis both transgenic mouse models developed cardiac phenotypes compared to age-matched wildtype littermates already under basal conditions in an age dependent manner. p27 expression and downstream factors were also altered in both transgenic lines as a result of Eya4, and accordingly, E193 overexpression. In summary, we provide evidence that the Eya4/Six1 Signalling Cascade is not only relevant in a rare version of heritable DCM but also in more common forms of acquired heart disease. Eya4/Six1 seems to regulate p27, which was shown to be an important regulator of cardiac physiology in postmitotic cardiomyocytes.
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abstract 12702 the eya4 six1 Signalling Cascade is crucial in the development of heart disease
Circulation, 2011Co-Authors: Tatjana Williams, Franziska Panther, Moritz Hundertmark, Daniela Kraemer, Jost Schonberger, Martin Czolbe, Vera Pekarek, Oliver RitterAbstract:Introduction: We identified a mutation in the human transcription cofactor Eya4 (E193) to cause terminal heart failure preceded by sensorineural hearing loss. Eya proteins lack DNA-binding and nuclear translocation sequences and therefore must interact with real transcription factors, including Six family members. The cyclin-dependent kinase inhibitor p27kip1 (p27), which inhibits hypertrophic growth in adult cardiomyocytes, is one of the few known Eya-Six targets expressed in the heart. We hypothesize that Eya4/Six1 regulates targets relevant to sustain normal cardiac function via p27. Methods and results: We examined the correlation of Eya4 and the mutant E193 overexpression upon p27 in permanent mammalian cell lines and primary cardiac myocytes. Westernblot analysis demonstrated that an overexpression of Eya4 led to a significant suppression of p27, whereas E193 had no effect on p27 levels; knockdown of Eya4 via siRNA exerted opposing effects. Promoter studies using a p27 promoter fragment including Six1 consensus sites revealed that the constitutive suppression of p27 by Eya4 was released after targeting one of the Six1 consensus sites; E193 had no effect on p27 promoter activity. We constructed a transgenic mouse model with a constitutive myocardial overexpression of HA-tagged E193 to study the effect of a disturbed Eya4/Six1 complex upon cardiac physiology. Magnetic resonance imaging to visualize cardiac structures in detail along with hemodynamic measurements showed that an overexpression of E193 in mice leads to an age related onset of cardiomyopathy similar to patients carrying the E193 mutation. HE-stainings show dilation of the LV associated with a thinning of the myocardial wall. PSR-stainings show interstitial fibrosis of the myocardial tissue which is characteristic for cardiac disease. Conclusion: In summary, we identified a mutation in Eya4 to cause DCM. Eya4/Six1 seems to suppress the expression of p27, an important inhibitor of the development of hypertrophy in postmitotic cardiomyocytes. Our transgenic mouse model with overexpression of the Eya4 mutant E193 supports our hypothesis whereas the dysfunctional E193 mutant could not suppress p27, finally leading to an age related onset of cardiomyopathy.
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inhibition of the calcineurin nfat Signalling Cascade in the treatment of heart failure
Recent Patents on Cardiovascular Drug Discovery, 2009Co-Authors: Franziska Panther, Tatjana Williams, Oliver RitterAbstract:Calcineurin (Cn), a serine/threonine phosphatase, plays a crucial role in the development of myocardial hypertrophy. Cn is a cytosolic phosphatase which dephosphorylates various target molecules, e.g. the transcriptional factor nuclear factor of activated T cells (NFAT), thereby enabling its nuclear translocation. Recently, it was demonstrated that not only NFAT, but also Cn is translocated into the nucleus. The nuclear coexistence of Cn and NFAT is important for the full transcriptional activity of the Cn-NFAT Signalling Cascade. Once Cn and NFAT have entered the nucleus of cardiomyocytes, the transcription of genes characteristic for myocardial hypertrophy (e.g. BNP, ANP) is initiated. The nuclear localization sequence (NLS), a region spanning amino acids 172-183 of calcineurin Aβ (CnAβ) is essential for recognition and shuttling of Cn into the nucleus by importinβ1. A synthetic import blocking peptide (IBP) that mimics the NLS of Cn was tested recently. The NLS analogon IBP saturates the Cn binding site of importinβ1 thereby preventing binding of Cn and importin. This inhibits the translocation of Cn into the nucleus. Inhibiting the Cn/importin interaction with competing synthetic peptides is one of several new approaches to prevent the development of myocardial hypertrophy. Several patents have also been filed on molecules related to inhibition of Cn-NFAT Signalling.
Alexander Anders - One of the best experts on this subject based on the ideXlab platform.
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Design of a MAPK Signalling Cascade balances energetic cost versus accuracy of information transmission.
Nature Communications, 2020Co-Authors: Alexander Anders, Bhaswar Ghosh, Timo Glatter, Victor SourjikAbstract:Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped Signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) Signalling Cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the Signalling Cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular Signalling systems. Cellular Signalling networks provide information to the cell, but the trade-off between accuracy of information transfer and energetic cost of doing so has not been assessed. Here, the authors investigate a MAPK Signalling Cascade in budding yeast and find that information is maximised per unit energetic cost.
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design of a mapk Signalling Cascade balances energetic cost versus accuracy of information transmission
Nature Communications, 2020Co-Authors: Alexander Anders, Bhaswar Ghosh, Timo Glatter, Victor SourjikAbstract:Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped Signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) Signalling Cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the Signalling Cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular Signalling systems.
Peter B. Crino - One of the best experts on this subject based on the ideXlab platform.
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The mTOR Signalling Cascade: paving new roads to cure neurological disease
Nature Reviews Neurology, 2016Co-Authors: Peter B. CrinoAbstract:Overactivation of the mechanistic target of rapamycin (mTOR) Signalling pathway contributes to neurological disorders, including neurodevelopmental disorders, tuberous sclerosis complex, epilepsy, and tumours of the CNS. In this Review, Peter Crino discusses the pathophysiological role of mTOR in neurological diseases and provides an overview of clinical trials that have assessed the efficacy of mTOR inhibitors in these diseases. The serine/threonine protein kinase mechanistic target of rapamycin (mTOR) is evolutionarily conserved and modulates protein synthesis, cell growth, and cellular autophagy in response to distinct intracellular and extracellular cues Altered mTOR Signalling has been shown to play pathogenic roles in a number of neurological disorders, including epilepsy, autism, intellectual disability, neurodegenerative disorders, CNS tumours, and hypoxic–ischaemic brain injury Causative germline and somatic mutations in a number of genes encoding proteins involved in the mTOR Signalling pathway have been identified in malformations of cortical development that cause epilepsy, intellectual disability, and autism Clinical trials with mTOR inhibitors, such as sirolimus and everolimus, have shown that suppression of aberrant mTOR activity is effective in neurodevelopmental disorders, such as tuberous sclerosis complex Future clinical trials of mTOR inhibitors are being considered in neurodegenerative disorders, such as Alzheimer disease and stroke Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) Signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR — regulation of cell growth and proliferation, as well as autophagy and cell death — have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic–ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell Signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR Signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered Signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.
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the mtor Signalling Cascade paving new roads to cure neurological disease
Nature Reviews Neurology, 2016Co-Authors: Peter B. CrinoAbstract:Overactivation of the mechanistic target of rapamycin (mTOR) Signalling pathway contributes to neurological disorders, including neurodevelopmental disorders, tuberous sclerosis complex, epilepsy, and tumours of the CNS. In this Review, Peter Crino discusses the pathophysiological role of mTOR in neurological diseases and provides an overview of clinical trials that have assessed the efficacy of mTOR inhibitors in these diseases.
