1,255 research outputs found

    Fast Sensing and Adaptive Actuation for Robust Legged Locomotion

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    Robust legged locomotion in complex terrain demands fast perturbation detection and reaction. In animals, due to the neural transmission delays, the high-level control loop involving the brain is absent from mitigating the initial disturbance. Instead, the low-level compliant behavior embedded in mechanics and the mid-level controllers in the spinal cord are believed to provide quick response during fast locomotion. Still, it remains unclear how these low- and mid-level components facilitate robust locomotion. This thesis aims to identify and characterize the underlining elements responsible for fast sensing and actuation. To test individual elements and their interplay, several robotic systems were implemented. The implementations include active and passive mechanisms as a combination of elasticities and dampers in multi-segment robot legs, central pattern generators inspired by intraspinal controllers, and a synthetic robotic version of an intraspinal sensor. The first contribution establishes the notion of effective damping. Effective damping is defined as the total energy dissipation during one step, which allows quantifying how much ground perturbation is mitigated. Using this framework, the optimal damper is identified as viscous and tunable. This study paves the way for integrating effective dampers to legged designs for robust locomotion. The second contribution introduces a novel series elastic actuation system. The proposed system tackles the issue of power transmission over multiple joints, while featuring intrinsic series elasticity. The design is tested on a hopper with two more elastic elements, demonstrating energy recuperation and enhanced dynamic performance. The third contribution proposes a novel tunable damper and reveals its influence on legged hopping. A bio-inspired slack tendon mechanism is implemented in parallel with a spring. The tunable damping is rigorously quantified on a central-pattern-generator-driven hopping robot, which reveals the trade-off between locomotion robustness and efficiency. The last contribution explores the intraspinal sensing hypothesis of birds. We speculate that the observed intraspinal structure functions as an accelerometer. This accelerometer could provide fast state feedback directly to the adjacent central pattern generator circuits, contributing to birds’ running robustness. A biophysical simulation framework is established, which provides new perspectives on the sensing mechanics of the system, including the influence of morphologies and material properties. Giving an overview of the hierarchical control architecture, this thesis investigates the fast sensing and actuation mechanisms in several control layers, including the low-level mechanical response and the mid-level intraspinal controllers. The contributions of this work provide new insight into animal loco-motion robustness and lays the foundation for future legged robot design

    2017 GREAT Day Program

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    SUNY Geneseo’s Eleventh Annual GREAT Day.https://knightscholar.geneseo.edu/program-2007/1011/thumbnail.jp

    Química dinámica combinatoria : optimización de la química reversible y aplicación en el descubrimiento de fármacos

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    Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 26-01-2023Dynamic combinatorial chemistry is defined as “the chemistry under thermodynamic control”. It is based on the combination of building blocks that react with each other through reversible chemical bonds to form the final products, reaching the thermodynamic equilibrium (dynamic combinatorial library, DCL). This chemistry is able to respond to external stimuli such as pH, temperature, or the addition of a biomolecule acting as a template. For instance, adding a template will shift the equilibrium towards the formation of the compounds with higher affinity to the template.Templated-DCLs developed under physiological conditions require an effective design of the dynamic chemical system composed of a biomolecule as a template, reversible chemistry that works effectively under physiological conditions, structurally diverse building blocks compatible with the target, and an analysis method. Protein-directed dynamic combinatorial chemistry (P-D DCC) is currently a powerful and efficient tool for discovering ligands with high affinity to a protein target. In this thesis, adding two different protein targets, NCS1 and glucose oxidase, shifted the DCL equilibrium to forming the best ligands in a pool of compounds...La química dinámica combinatoria se define como la química bajo control termodinámico. Se basa en la combinación de monómeros (en inglés, building blocks), que reaccionan entre sí a través de enlaces químicos reversibles formando compuestos, hasta alcanzar el equilibrio termodinámico (librería dinámica combinatoria, DCL, del inglés dynamic combinatorial library). Esta química reversible, en unas condiciones concretas, tiene la capacidad de responder a estímulos externos como el pH, la temperatura o la adición de una biomolécula que actúe como plantilla. En este último caso, el equilibrio se desplazará hacia la formación de complejos más estables y afines por la plantilla. En condiciones fisiológicas y en presencia de una plantilla, las DCLs requieren de un sistema químico-dinámico eficiente compuesto, además de la biomolécula que actúa como plantilla, de una química reversible adecuada y de unos monómeros estructuralmente distintos compatibles con la biomolécula y del método de análisis. La química dinámica combinatoria dirigida por proteínas (en inglés, protein-directed DCC, P-D DCC) se considera actualmente una herramienta eficaz y potente para encontrar ligandos que poseen una afinidad alta por la proteína que actúa como plantilla. En esta tesis, la adición de dos proteínas diferentes como dianas, NCS1 y glucosa oxidasa, desplaza el equilibrio de la dcl hacia la formación de los ligandos más prometedores del conjunto de compuestos formados en el equilibrio..Fac. de Ciencias QuímicasTRUEunpu

    Water and Brain Function: Effects of Hydration Status on Neurostimulation and Neurorecording

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    Introduction: TMS and EEG are used to study normal neurophysiology, diagnose, and treat clinical neuropsychiatric conditions, but can produce variable results or fail. Both techniques depend on electrical volume conduction, and thus brain volumes. Hydration status can affect brain volumes and functions (including cognition), but effects on these techniques are unknown. We aimed to characterize the effects of hydration on TMS, EEG, and cognitive tasks. Methods: EEG and EMG were recorded during single-pulse TMS, paired-pulse TMS, and cognitive tasks from 32 human participants on dehydrated (12-hour fast/thirst) and rehydrated (1 Liter oral water ingestion in 1 hour) testing days. Hydration status was confirmed with urinalysis. MEP, ERP, and network analyses were performed to examine responses at the muscle, brain, and higher-order functioning. Results: Rehydration decreased motor threshold (increased excitability) and shifted the motor hotspot. Significant effects on TMS measures occurred despite being re-localized and re-dosed to these new parameters. Rehydration increased SICF of the MEP, magnitudes of specific TEP peaks in inhibitory protocols, specific ERP peak magnitudes and reaction time during the cognitive task. Rehydration amplified nodal inhibition around the stimulation site in inhibitory paired-pulse networks and strengthened nodes outside the stimulation site in excitatory and CSP networks. Cognitive performance was not improved by rehydration, although similar performance was achieved with generally weaker network activity. Discussion: Results highlight differences between mild dehydration and rehydration. The rehydrated brain was easier to stimulate with TMS and produced larger responses to external and internal stimuli. This is explainable by the known physiology of body water dynamics, which encompass macroscopic and microscopic volume changes. Rehydration can shift 3D cortical positioning, decrease scalp cortex distance (bringing cortex closer to stimulator/recording electrodes), and cause astrocyte swelling-induced glutamate release. Conclusions: Previously unaccounted variables like osmolarity, astrocyte and brain volumes likely affect neurostimulation/neurorecording. Controlling for and carefully manipulating hydration may reduce variability and improve therapeutic outcomes of neurostimulation. Dehydration is common and produces less excitable circuits. Rehydration should offer a mechanism to macroscopically bring target cortical areas closer to an externally applied neurostimulation device to recruit greater volumes of tissue and microscopically favor excitability in the stimulated circuits

    Age-Related Differences in Motor Performance

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    The purpose of this work was to study the age effects on average performance and variability of movement responses in children, young adults, and older adults across multiple motor tasks. Optimal motor performance is observed in healthy young adults with declines observed at either end of the lifespan. This pattern has been represented as a U-shaped/inverted U-shaped curve. Little is known about if this pattern persists in chewing dynamics. While chewing has been found to improve aspects of attention, a cognitive function, research is limited on the relationship between chewing and other motor tasks. The first aim of this research was to conduct a scoping systematic review to identify what measures of variability are reported for preferred performance of chewing and walking in children, young adults, and older adults and the age-related differences across these age groups. The available research was insufficient across these groups and does not support the perspective that children and older adults are more variable than young adults. The second aim was to examine age-related differences in averages and variability of chewing, reaction time, balance, and walking responses across children, young adults, and older adults. A U-shaped curve was revealed for reaction time and postural sway with the young adults producing faster reaction times and decreased postural sway than the children and older adults. Chewing rates followed a similar curve but with children chewing at faster rates than young and older adults. No age-related differences were observed for normalized gait speed. The final aim was to examine dual task relationships between chewing and secondary motor tasks in children. Sixteen healthy children completed finger tapping, reaction time, and walking while chewing at different speeds. Chewing rates varied when produced with a secondary motor task and the secondary motor tasks were differentially influenced by chewing. Reaction times slowed during chewing while walking rates increased/decreased with changes in chewing rates. This relationship was not as strong as previous reports in adults. Overall, the anticipated patterns across the age groups were only partially revealed within this work. Understanding normal movement patterns is the foundation to identifying variations in atypical populations

    Plasticity of morphological and mechanical properties of muscles and tendons: Effects of maturation and athletic training

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    In den letzten Jahrzehnten ist die Zahl der Erwachsenen und Jugendlichen, die an nicht organisierten oder wettbewerbsorientierten Sportarten teilnehmen, gestiegen. In der Pubertät beeinflussen sowohl hormonelle Veränderungen als auch mechanische Belastungen die Entwicklung von Muskeln und Sehnen. Derzeit gibt es keine Informationen über die Interaktion dieser beiden Stimuli, aber es besteht die Vermutung, dass im Zuge der Pubertät bei Athleten und Nicht-Athleten im Vergleich zu Muskelkraft und Sehnensteifigkeit ungleiche Verhältnisse auftreten können. Die Folge dieses Ungleichgewichts könnte eine höhere mechanische Belastung für die Sehnen sein, was weiter zu Verletzungen führen kann. Angesichts der unzureichenden Beweise für die Entwicklung des muskulotendinösen Gewebes während der Pubertät und des Mangels an Kenntnissen darüber, wie die Reifung die Muskel-Sehnen-Einheit, insbesondere die Interaktion mit überlagerten mechanischen Belastungen, beeinflusst, untersucht diese Arbeit die morphologische und mechanische Entwicklung von Knieextensoren und Patellasehne, indem Nicht-Athleten und Athleten aus drei Altersgruppen verglichen werden (frühe Pubertät: 12–14 Jahre, engl.:EA; späte Pubertät: 16–18 Jahre, engl.: LA; Erwachsene: 20–35 Jahre, engl.: YA). Athleten erreichten häufiger Dehnungsgrößen von mehr als 9% Dehnung im Vergleich zu Nicht-Athleten, was auf einen erhöhten mechanischen Bedarf an der Sehne hinweist. Obwohl das Training die Eigenschaften der M. quadriceps femoris-Sehnen-Einheit verbessert, bleibt ihre Entwicklung von früher Pubertät bis zum Erwachsenenalter bei Athleten und Nicht-Athleten ähnlich, mit dem Hauptunterschied zwischen früher Pubertät und später Pubertät. Alter und sportliches Training waren jedoch mit einer höheren Prävalenz von Ungleichgewichten innerhalb der Muskel-Sehnen-Einheit und einer damit einhergehenden erhöhten mechanischen Belastung oder Beanspruchung für die Patellasehne verbunden.In recent decades, the number of adults and especially adolescents who participate in some kind of non-organized or competitive sports has been increasing. During adolescence, the development of muscle and tendons is affected both by maturation, due to hormonal changes, and by mechanical loading. However, there is no information currently on the interaction of this double fold stimulus although there is reason to believe that during adolescence in athletes and non-athletes there may be imbalances developing between muscle strength capacity and tendon stiffness. The result of this imbalance could be the tendon exposure to high mechanical demand by the associated working muscles, which might further lead to tendon injury. Considering the not satisfactory evidence of the musculotendinous tissue development during adolescence, and the lack of knowledge about how maturation affects the muscle-tendon unity, especially in interaction with superimposed mechanical loading, this thesis investigates the morphological and mechanical development of the knee extensors and patellar tendon, by comparing non-athletes and athletes in three different age groups (i.e., early adolescents: EA 12–14 years; late adolescents: LA 16–18 years, and young adults: YA 20–35 years). Athletes were more likely to reach strain magnitudes higher than 9% strain compared to non-athlete controls indicating an increased mechanical demand for the tendon. Although athletic training enhances the properties of the quadriceps femoris muscle-tendon unit, their development from early-adolescence to adulthood remains similar in athletes and non-athletes with the major alterations between early and LA. However, both age and athletic training were associated with a higher prevalence of imbalances within the muscle-tendon unit and a resultant increased mechanical demand for the patellar tendon

    Investigating the influence of inflammatory mediators on non-inflammatory features of sporadic inclusion body myositis in vitro

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    Sporadic inclusion body myositis (sIBM) is a progressive muscle disease causing weakness and ambulation difficulty. Muscle of sIBM patients presents with inflammation and degeneration. CD8+ T cells infiltrate affected muscles and inflammatory cytokines are upregulated. Degenerative/non-inflammatory features are observed including sarcoplasmic accumulation of proteins such as TDP-43 and p62, and TDP-43 sarcoplasmic mislocalisation. The cause of sIBM symptoms is poorly understood and there are no effective treatments. Further understanding of the interaction between inflammatory and non inflammatory features of sIBM may elucidate potential treatment targets. This thesis aimed to explore the effect of inflammation on non-inflammatory features of sIBM in healthy human myotubes. The effects of IL-1β and IFNγ, conditioned medium or coculture with a cytotoxic immune cell line TALL-104 on p62 and TDP-43 sarcoplasmic aggregation, protein expression, and TDP-43 subcellular localisation was investigated. Using 3D myotube cultures termed myobundles, the effect of inflammatory conditions on force generation was examined. No treatment caused aggregation of TDP-43, suggesting these inflammatory factors do not trigger TDP-43 sarcoplasmic aggregation in these cells. IL-1β+IFNγ combined but not these cytokines separately caused increased size of p62 puncta, but this may represent increased autophagic flux instead of dysfunctional p62 aggregation. Active force from myobundles representing muscle strength was not affected by IL-1β+IFNγ or TALL-104 coculture after 48 hours incubation. IL-1β+IFNγ increased half relaxation time and time to peak force, suggesting fatigue induction. This indicates acute exposure to inflammatory cytokines or cytotoxic immune cells may not trigger muscle weakness. Overall, these results highlight TDP-43 aggregation may not be influenced by inflammatory factors, but alterations in p62 can occur with simultaneous multiple inflammatory insults in cultured muscle cells. This work suggests further investigations of myobundle cultures with sIBM-like inflammatory mediators may be warranted to investigate muscle weakness

    Identification and Functional Assessment of Novel Neuromuscular Disease-Causing Genes

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    Inherited neuromuscular diseases comprise a highly heterogeneous group of disorders characterized by the impairment of the neural structures or motor unit components responsible for the generation of movement. While as single gene-associated disorder the majority of them are rare, taken together their estimated prevalence reaches 1 – 3 cases / 1000 individuals. Due to their elevated morbidity and mortality, they represent a significant health burden for the affected individuals, their families, and the healthcare systems. Moreover, their clinical and genetic heterogeneity makes their diagnosis a long and complex process, which often requires specialized diagnostic procedures and poses a challenge in about half of the cases. However, thanks to decreasing costs and increased availability of next-generation sequencing technologies, the last years had witnessed a rise in the number of novel genes associated to neuromuscular disorders. In this study, we identified three novel neuromuscular disease-causing genes: PIEZO2, whose biallelic loss-of-function mutations cause distal arthrogryposis with impaired proprioception and touch; VAMP1, whose biallelic loss-of-function mutations cause a novel presynaptic congenital myasthenic syndrome; CAPRIN1, whose specific p.Pro512Leu mutation causes a neurodegenerative disorder characterized by ataxia and muscle weakness. For PIEZO2, we identified biallelic loss-of-function mutations using exome sequencing, SNPchip-based linkage analysis, DNA microarray, and Sanger sequencing in ten affected individuals of four independent families showing arthrogryposis, hypotonia, respiratory insufficiency at birth, scoliosis, and delayed motor development. This phenotype is clearly distinct from distal arthrogryposis with ocular anomalies which characterize the autosomal dominant distal arthrogryposis 3 (DA3), distal arthrogryposis 5 (DA5), and Marden-Walker syndrome (MWKS). While these disorders are caused by heterozygous gain-of-function mutations in PIEZO2, the novel reported mutations result in the loss of PIEZO2, since they lead to nonsense-mediated mRNA decay in patient-derived fibroblast cell lines. PIEZO2 is a mechanosensitive ion channel playing a major role in light-touch sensation and proprioception. Mice ubiquitously depleted of PIEZO2 die postnatally because of respiratory distress, while individuals lacking PIEZO2 develop a neuromuscular disorder, likely due to the loss of proprioception inputs in muscles. For VAMP1, we identified biallelic loss-of-function mutations using exome or genome sequencing in two pairs of siblings from two independent families affected by a novel congenital myasthenic syndrome. Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. The two described homozygous mutations are a frameshift and a missense mutation of a highly conserved residue, therefore are likely to result in the loss of VAMP1 function. Indeed, the phenotype is resembled by VAMP1lew/lew mice, which carry a homozygous VAMP1 truncating mutation and show neurophysiological features of presynaptic impairment. For CAPRIN1, we identified the identical de novo c.1535C>T (p.Pro512Leu) missense variant using trio exome sequencing in two unrelated individuals displaying early-onset ataxia, dysarthria, cognitive decline and muscle weakness. This mutation causes the substitution of a highly conserved residue and in silico tools predict an increase in the protein aggregation propensity. Overexpression of CAPRIN1-P512L caused the formation of insoluble ubiquitinated aggregates, sequestrating proteins associated with neurodegenerative disorders, such as ATXN2, GEMIN5, SNRNP200, and SNCA. Upon differentiation in cortical neurons of induced pluripotent stem cell (iPSC) lines where the CAPRIN1-P512L was introduced via CRISPR/Cas9, reduced neuronal activity and altered stress granules dynamics were observed in the lines harboring the mutation. Moreover, nano-differential scanning fluorimetry revealed that CAPRIN1-P512L adopts an extended conformation, and fluorescence microscopy demonstrated that RNA greatly enhances its aggregation in vitro. Taken together, this study associates: (1) biallelic loss-of-function mutations in PIEZO2 with the autosomal recessive distal arthrogryposis with impaired proprioception and touch; (2) biallelic loss-of-function mutations in VAMP1 with an autosomal recessive presynaptic congenital myasthenic syndrome; (3) a recurrent de novo p.Pro512Leu mutation of CAPRIN1 with a neurodegenerative disorder characterized by ataxia and muscle weakness

    The role of intramyocellular lipid content in the physiological changes observed in inactivity, exercise, and non-alcoholic fatty liver disease

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    Lipid stored within droplets in skeletal muscle, referred to as intramyocellular lipid (IMCL), has established and emerging roles in health and disease. Lipid droplets (LDs) act as the first destination for activated fatty acids (FAs) following their esterification to triacylglycerol (TAG). Under normal physiological conditions these FAs are then released from LDs to supply adjacent mitochondria with substrate for ATP production during fasting and exercise. It has been proposed that dysregulation of adipose tissue storage, in the context of chronic overfeeding, and basal and insulin-mediated impairments in muscle lipid oxidation in response to inactivity are responsible for the ectopic accumulation of lipid in the skeletal muscles. This accumulation can result in increased sarcoplasmic and sarcolemmal expression of intermediates of TAG synthesis and lipolysis, which attenuate the insulin signalling pathway, resulting in skeletal muscle and whole-body insulin resistance, and potentially contributing to the aetiology of non-alcoholic fatty liver disease (NAFLD). However, the associations between IMCL accumulation and insulin resistance in inactivity and NAFLD are equivocal, and the adaptations in IMCL to resistance exercise training are poorly defined. Therefore, primarily using the hyperinsulinaemic-euglycaemic clamp technique, the gold standard method in the assessment of insulin action in humans in vivo, and histochemical quantification of total and fibre-type specific IMCL content, the results of the work in this thesis contribute to our understanding of the role of IMCL in inactivity, resistance exercise training, and NAFLD. This thesis comprises primarily of retrospective analyses of four comprehensive human volunteer studies. The studies described in Chapter 3 explored the role of IMCL in the development of whole-body insulin resistance during acute (3 days) and chronic (56 days) bed rest in healthy, male participants maintained in energy balance throughout. Glucose disposal was decreased by a similar magnitude after 3 and 56 days of bed rest, and these observations could not be explained by IMCL accumulation. This suggests that inactivity per se is the primary driver of whole-body insulin resistance during bed rest and that IMCL accumulation is likely to be a confounding response that occurs when participants are in positive energy balance. It has been proposed that overfeeding, which contributes to the pathogenesis of obese NAFLD by increasing plasma FA concentration and hepatic lipid content, also leads to the ectopic accumulation of IMCL. Given that the skeletal muscles are the main sites for the disposal of glucose and that IMCL accumulation is associated with muscle insulin resistance, increased muscle lipid content may contribute to the development of whole-body insulin resistance in those with NAFLD. The study described in Chapter 4 investigated differences in IMCL content, skeletal muscle glucose disposal, and whole-body glucose disposal between individuals with NAFLD and healthy controls to determine if muscle lipid content does in fact contribute to insulin resistance in those with NAFLD. It was observed that IMCL content was not different between healthy males and males with NAFLD, even though skeletal muscle and whole-body glucose disposal were significantly reduced in those with NAFLD. These findings suggest that IMCL accumulation is not a contributor to the development of insulin resistance in NAFLD. The study described in Chapter 5 explored changes in IMCL and perilipin 5 (PLIN5) content in response to a 12-week resistance training intervention, which has not been investigated in detail to date. A secondary aim was to determine the impact of the non-steroidal anti-inflammatory drug (NSAID), diclofenac, on the mRNA expression of genes involved in FA metabolism and oxidation. It was hypothesised that diclofenac would have a role in these processes based on evidence of its affinity for Peroxisome proliferator-activated receptor gamma (PPAR-γ) in vitro. This study comprised a randomised, placebo controlled, double-blind protocol in which one group of exercise-trained participants ingested diclofenac, 75 mg/daily, concurrent with the exercise protocol. IMCL content and muscle PLIN5 content did not change in response to the resistance exercise intervention, though diclofenac administration robustly altered the mRNA expression of genes involved in lipid metabolism. This thesis presents novel insights into the role of IMCL content in the development of insulin resistance in the context of bed rest-induced immobilisation and NAFLD. It also identifies a new trajectory for future research into diclofenac, an NSAID which may alter muscle FA oxidation via a previously underexplored mechanism
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