The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Silvia Arber - One of the best experts on this subject based on the ideXlab platform.
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functional local proprioceptive Feedback Circuits initiate and maintain locomotor recovery after spinal cord injury
Cell Reports, 2019Co-Authors: Aya Takeoka, Silvia ArberAbstract:Somatosensory Feedback from proprioceptive afferents (PAs) is essential for locomotor recovery after spinal cord injury. To determine where or when proprioception is required for locomotor recovery after injury, we established an intersectional genetic model for PA ablation with spatial and temporal confinement. We found that complete or spatially restricted PA ablation in intact mice differentially affects locomotor performance. Following incomplete spinal cord injury, PA ablation below but not above the lesion severely restricts locomotor recovery and descending circuit reorganization. Furthermore, ablation of PAs after behavioral recovery permanently reverts functional improvements, demonstrating their essential role for maintaining regained locomotor function despite the presence of reorganized descending Circuits. In parallel to recovery, PAs undergo reorganization of activity-dependent synaptic connectivity to specific local spinal targets. Our study reveals that PAs interacting with local spinal Circuits serve as a continued driving force to initiate and maintain locomotor output after injury.
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Functional Local Proprioceptive Feedback Circuits Initiate and Maintain Locomotor Recovery after Spinal Cord Injury
Elsevier, 2019Co-Authors: Aya Takeoka, Silvia ArberAbstract:Summary: Somatosensory Feedback from proprioceptive afferents (PAs) is essential for locomotor recovery after spinal cord injury. To determine where or when proprioception is required for locomotor recovery after injury, we established an intersectional genetic model for PA ablation with spatial and temporal confinement. We found that complete or spatially restricted PA ablation in intact mice differentially affects locomotor performance. Following incomplete spinal cord injury, PA ablation below but not above the lesion severely restricts locomotor recovery and descending circuit reorganization. Furthermore, ablation of PAs after behavioral recovery permanently reverts functional improvements, demonstrating their essential role for maintaining regained locomotor function despite the presence of reorganized descending Circuits. In parallel to recovery, PAs undergo reorganization of activity-dependent synaptic connectivity to specific local spinal targets. Our study reveals that PAs interacting with local spinal Circuits serve as a continued driving force to initiate and maintain locomotor output after injury. : Takeoka and Arber examined the spatial and temporal requirements of proprioceptive Feedback in recovery after spinal cord injury. They reveal an indispensable role for proprioceptive afferents below the injury in the initiation and maintenance of locomotor recovery. The activity of proprioceptive afferents contributes to local and descending circuit rearrangements that parallel recovery. Keywords: spinal cord injury, proprioception, mouse genetics, neuronal circuit reorganization, somatosensory Feedback, viral tracing, locomotio
Silvestro Micera - One of the best experts on this subject based on the ideXlab platform.
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Closed-loop control of trunk posture improves locomotion through the regulation of leg proprioceptive Feedback after spinal cord injury
Scientific reports, 2018Co-Authors: Eduardo Martin Moraud, Joachim Von Zitzewitz, Jenifer Miehlbradt, Sophie Wurth, Emanuele Formento, Jack Digiovanna, Marco Capogrosso, Grégoire Courtine, Silvestro MiceraAbstract:After spinal cord injury (SCI), sensory Feedback Circuits critically contribute to leg motor execution. Compelled by the importance to engage these Circuits during gait rehabilitation, assistive robotics and training protocols have primarily focused on guiding leg movements to reinforce sensory Feedback. Despite the importance of trunk postural dynamics on gait and balance, trunk assistance has comparatively received little attention. Typically, trunk movements are either constrained within bodyweight support systems, or manually adjusted by therapists. Here, we show that real-time control of trunk posture re-established dynamic balance amongst bilateral proprioceptive Feedback Circuits, and thereby restored left-right symmetry, loading and stepping consistency in rats with severe SCI. We developed a robotic system that adjusts mediolateral trunk posture during locomotion. This system uncovered robust relationships between trunk orientation and the modulation of bilateral leg kinematics and muscle activity. Computer simulations suggested that these modulations emerged from corrections in the balance between flexor- and extensor-related proprioceptive Feedback. We leveraged this knowledge to engineer control policies that regulate trunk orientation and postural sway in real-time. This dynamical postural interface immediately improved stepping quality in all rats regardless of broad differences in deficits. These results emphasize the importance of trunk regulation to optimize performance during rehabilitation.
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mechanisms underlying the neuromodulation of spinal Circuits for correcting gait and balance deficits after spinal cord injury
Neuron, 2016Co-Authors: Eduardo Martin Moraud, Emanuele Formento, Jack Digiovanna, Marco Capogrosso, Grégoire Courtine, Silvestro Micera, Nikolaus WengerAbstract:Epidural electrical stimulation of lumbar segments facilitates standing and walking in animal models and humans with spinal cord injury. However, the mechanisms through which this neuromodulation therapy engages spinal Circuits remain enigmatic. Using computer simulations and behavioral experiments, we provide evidence that epidural electrical stimulation interacts with muscle spindle Feedback Circuits to modulate muscle activity during locomotion. Hypothesis-driven strategies emerging from simulations steered the design of stimulation protocols that adjust bilateral hindlimb kinematics throughout gait execution. These stimulation strategies corrected subject-specific gait and balance deficits in rats with incomplete and complete spinal cord injury. The conservation of muscle spindle Feedback Circuits across mammals suggests that the same mechanisms may facilitate motor control in humans. These results provide a conceptual framework to improve stimulation protocols for clinical applications.
Aya Takeoka - One of the best experts on this subject based on the ideXlab platform.
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functional local proprioceptive Feedback Circuits initiate and maintain locomotor recovery after spinal cord injury
Cell Reports, 2019Co-Authors: Aya Takeoka, Silvia ArberAbstract:Somatosensory Feedback from proprioceptive afferents (PAs) is essential for locomotor recovery after spinal cord injury. To determine where or when proprioception is required for locomotor recovery after injury, we established an intersectional genetic model for PA ablation with spatial and temporal confinement. We found that complete or spatially restricted PA ablation in intact mice differentially affects locomotor performance. Following incomplete spinal cord injury, PA ablation below but not above the lesion severely restricts locomotor recovery and descending circuit reorganization. Furthermore, ablation of PAs after behavioral recovery permanently reverts functional improvements, demonstrating their essential role for maintaining regained locomotor function despite the presence of reorganized descending Circuits. In parallel to recovery, PAs undergo reorganization of activity-dependent synaptic connectivity to specific local spinal targets. Our study reveals that PAs interacting with local spinal Circuits serve as a continued driving force to initiate and maintain locomotor output after injury.
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Functional Local Proprioceptive Feedback Circuits Initiate and Maintain Locomotor Recovery after Spinal Cord Injury
Elsevier, 2019Co-Authors: Aya Takeoka, Silvia ArberAbstract:Summary: Somatosensory Feedback from proprioceptive afferents (PAs) is essential for locomotor recovery after spinal cord injury. To determine where or when proprioception is required for locomotor recovery after injury, we established an intersectional genetic model for PA ablation with spatial and temporal confinement. We found that complete or spatially restricted PA ablation in intact mice differentially affects locomotor performance. Following incomplete spinal cord injury, PA ablation below but not above the lesion severely restricts locomotor recovery and descending circuit reorganization. Furthermore, ablation of PAs after behavioral recovery permanently reverts functional improvements, demonstrating their essential role for maintaining regained locomotor function despite the presence of reorganized descending Circuits. In parallel to recovery, PAs undergo reorganization of activity-dependent synaptic connectivity to specific local spinal targets. Our study reveals that PAs interacting with local spinal Circuits serve as a continued driving force to initiate and maintain locomotor output after injury. : Takeoka and Arber examined the spatial and temporal requirements of proprioceptive Feedback in recovery after spinal cord injury. They reveal an indispensable role for proprioceptive afferents below the injury in the initiation and maintenance of locomotor recovery. The activity of proprioceptive afferents contributes to local and descending circuit rearrangements that parallel recovery. Keywords: spinal cord injury, proprioception, mouse genetics, neuronal circuit reorganization, somatosensory Feedback, viral tracing, locomotio
Ciaran L Kelly - One of the best experts on this subject based on the ideXlab platform.
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synthetic negative Feedback Circuits using engineered small rnas
Nucleic Acids Research, 2018Co-Authors: Ciaran L Kelly, Andreas W K Harris, Harrison Steel, Edward J Hancock, John T Heap, Antonis PapachristodoulouAbstract:Negative Feedback is known to enable biological and man-made systems to perform reliably in the face of uncertainties and disturbances. To date, synthetic biological Feedback Circuits have primarily relied upon protein-based, transcriptional regulation to control circuit output. Small RNAs (sRNAs) are non-coding RNA molecules that can inhibit translation of target messenger RNAs (mRNAs). In this work, we modelled, built and validated two synthetic negative Feedback Circuits that use rationally-designed sRNAs for the first time. The first circuit builds upon the well characterised tet-based autorepressor, incorporating an externally-inducible sRNA to tune the effective Feedback strength. This allows more precise fine-tuning of the circuit output in contrast to the sigmoidal, steep input-output response of the autorepressor alone. In the second circuit, the output is a transcription factor that induces expression of an sRNA, which inhibits translation of the mRNA encoding the output, creating direct, closed-loop, negative Feedback. Analysis of the noise profiles of both Circuits showed that the use of sRNAs did not result in large increases in noise. Stochastic and deterministic modelling of both Circuits agreed well with experimental data. Finally, simulations using fitted parameters allowed dynamic attributes of each circuit such as response time and disturbance rejection to be investigated.
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synthetic negative Feedback Circuits using engineered small rnas
bioRxiv, 2017Co-Authors: Ciaran L Kelly, Andreas W K Harris, Harrison Steel, Edward J Hancock, John T Heap, Antonis PapachristodoulouAbstract:Negative Feedback control is known to endow natural biological and man-made technological systems with robust performance in the face of uncertainties. To date synthetic biological Feedback Circuits have predominantly relied upon transcription factors and suffer from limitations such as excessive burden and lack of flexible tunability. Small RNAs (sRNAs) are non-coding RNA molecules which can post-transcriptionally regulate gene expression through interaction with messenger RNA (mRNA). In this paper, we design, model and build two new negative Feedback architectures that use rationally-designed, translation-inhibiting sRNA modules for the first time. The first circuit builds upon the well characterised tet-based autorepressor, allowing fine tuning of the circuit output through the use of an external input molecule that modulates sRNA expression. The second circuit involves an sRNA in direct negative Feedback with the output protein of the circuit, regulating the mRNA encoding this protein in response to output protein concentration. Stochastic and deterministic modelling, taking implementation topology into account, guided the design and the experimental data obtained compared well with model predictions. The detailed and well-characterised Circuits presented in this work can be integrated into larger, more complex, synthetic biological Circuits, pathways and systems.
Kwanghyun Cho - One of the best experts on this subject based on the ideXlab platform.
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multiple roles of the nf b signaling pathway regulated by coupled negative Feedback Circuits
The FASEB Journal, 2009Co-Authors: Dongsan Kim, Walter Kolch, Kwanghyun ChoAbstract:The NF-kappaB signaling pathway can perform multiple functional roles depending on specific cellular environments and cell types. Even in the same cell clones, the pathway can show different kinetic and phenotypic properties. It is believed that the complex networks controlling the NF-kappaB signaling pathway can generate these diverse and sometimes ambiguous phenomena. We noted, however, that the dynamics of NF-kappaB signaling pathway is highly stochastic and that the NF-kappaB signaling pathway contains multiple negative Feedback Circuits formed by IkappaB isoform proteins, IkappaBalpha and IkappaBepsilon in particular. Considering the topological similarity, their functional roles seem to be redundant, raising the question why different types of IkappaB isoforms need to exist. From extensive stochastic simulations of the NF-kappaB signaling pathway, we found that each IkappaB isoform actually conducts a different regulatory role through its own negative Feedback. Specifically, our data suggest that IkappaBalpha controls the dynamic patterns of nuclear NF-kappaB, while IkappaBepsilon induces cellular heterogeneity of the NF-kappaB activities. These results may provide an answer to the question of how a single NF-kappaB signaling pathway can perform multiple biological functions even in the same clonal populations.
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coupled positive and negative Feedback Circuits form an essential building block of cellular signaling pathways
BioEssays, 2007Co-Authors: Dongsan Kim, Yungkeun Kwon, Kwanghyun ChoAbstract:Cellular Circuits have positive and negative Feedback loops that allow them to respond properly to noisy external stimuli. It is intriguing that such Feedback loops exist in many cases in a particular form of coupled positive and negative Feedback loops with different time delays. As a result of our mathematical simulations and investigations into various experimental evidences, we found that such coupled Feedback Circuits can rapidly turn on a reaction to a proper stimulus, robustly maintain its status, and immediately turn off the reaction when the stimulus disappears. In other words, coupled Feedback loops enable cellular systems to produce perfect responses to noisy stimuli with respect to signal duration and amplitude. This suggests that coupled positive and negative Feedback loops form essential signal transduction motifs in cellular signaling systems.
