Automaticity is a hallmark feature of walking in adults who are healthy and well-functioning. In the context of walking, "automaticity" refers to the ability of the nervous system to successfully ...control typical steady state walking with minimal use of attention-demanding executive control resources. Converging lines of evidence indicate that walking deficits and disorders are characterized in part by a shift in the locomotor control strategy from healthy automaticity to compensatory executive control. This is potentially detrimental to walking performance, as an executive control strategy is not optimized for locomotor control. Furthermore, it places excessive demands on a limited pool of executive reserves. The result is compromised ability to perform basic and complex walking tasks and heightened risk for adverse mobility outcomes including falls. Strategies for rehabilitation of automaticity are not well defined, which is due to both a lack of systematic research into the causes of impaired automaticity and to a lack of robust neurophysiological assessments by which to gauge automaticity. These gaps in knowledge are concerning given the serious functional implications of compromised automaticity. Therefore, the objective of this article is to advance the science of automaticity of walking by consolidating evidence and identifying gaps in knowledge regarding: (a) functional significance of automaticity; (b) neurophysiology of automaticity;
Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with ...sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Na
1.1, Na
1.6, Na
1.7, Na
1.8, and Na
1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Na
1.7, Na
1.8, and Na
1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.
Phytochrome evolution in 3D Rockwell, Nathan C.; Lagarias, J. Clark
The New phytologist,
March 2020, Letnik:
225, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Canonical plant phytochromes are master regulators of photomorphogenesis and the shade avoidance response. They are also part of a widespread superfamily of photoreceptors with diverse spectral and ...biochemical properties. Plant phytochromes belong to a clade including other phytochromes from glaucophyte, prasinophyte, and streptophyte algae (all members of the Archaeplastida) and those from cryptophyte algae. This is consistent with recent analyses supporting the existence of an AC (Archaeplastida + Cryptista) clade. AC phytochromes have been proposed to arise from ancestral cyanobacterial genes via endosymbiotic gene transfer (EGT), but most recent studies instead support multiple horizontal gene transfer (HGT) events to generate extant eukaryotic phytochromes. In principle, this scenario would be compared to the emerging understanding of early events in eukaryotic evolution to generate a coherent picture. Unfortunately, there is currently a major discrepancy between the evolution of phytochromes and the evolution of eukaryotes; phytochrome evolution is thus not a solved problem. We therefore examine phytochrome evolution in a broader context. Within this context, we can identify three important themes in phytochrome evolution: deletion, duplication, and diversification. These themes drive phytochrome evolution as organisms evolve in response to environmental challenges.
Atom transfer radical cyclization (ATRC) is a powerful technique to prepare functionalized 4–10 membered ring systems using transition metal catalysts. In this review recent advances in the use of ...copper complexes are described. In particular the effect of different ligands on reactivity, selectivity and product outcome are illustrated with application to heterocycle and natural product synthesis. New approaches that increase catalyst efficiency with supplemental reducing agents are reviewed and examples using green solvents, benign reducing agents (e.g. ascorbic acid) and with catalyst loadings as low as 0.05 mol‐% are highlighted. Radical addition to aromatic rings and rearrangement reactions under ATRC conditions as well as application to radical‐polar crossover reactions are also described.
Atom transfer radical cyclization (ATRC) is a powerful technique to prepare functionalized 4–10 membered ring systems using copper catalysts. The effect of different ligands on reactivity, selectivity and product outcome are illustrated with application to heterocycle and natural product synthesis. Approaches that increase catalyst efficiency with supplemental reducing agents are reviewed and examples using green solvents, benign reducing agents and with catalyst loadings as low as 0.05 mol‐% are highlighted.
Topological defects can markedly alter nanomaterial properties. This presents opportunities for "defect engineering," where desired functionalities are generated through defect manipulation. However, ...imaging defects in working devices with nanoscale resolution remains elusive. We report three-dimensional imaging of dislocation dynamics in individual battery cathode nanoparticles under operando conditions using Bragg coherent diffractive imaging. Dislocations are static at room temperature and mobile during charge transport. During the structural phase transformation, the lithium-rich phase nucleates near the dislocation and spreads inhomogeneously. The dislocation field is a local probe of elastic properties, and we find that a region of the material exhibits a negative Poisson's ratio at high voltage. Operando dislocation imaging thus opens a powerful avenue for facilitating improvement and rational design of nanostructured materials.
By coupling a macroscopic mechanical oscillator to two microwave cavities, we simultaneously prepare and monitor a nonclassical steady state of mechanical motion. In each cavity, correlated radiation ...pressure forces induced by two coherent drives engineer the coupling between the quadratures of light and motion. We, first, demonstrate the ability to perform a continuous quantum nondemolition measurement of a single mechanical quadrature at a rate that exceeds the mechanical decoherence rate, while avoiding measurement backaction by more than 13 dB. Second, we apply this measurement technique to independently verify the preparation of a squeezed state in the mechanical oscillator, resolving quadrature fluctuations 20% below the quantum noise.
Hibernation is characterized by prolonged periods of inactivity with concomitantly low nutrient intake, conditions that would typically result in muscle atrophy combined with a loss of oxidative ...fibers. Yet, hibernators consistently emerge from winter with very little atrophy, frequently accompanied by a slight shift in fiber ratios to more oxidative fiber types. Preservation of muscle morphology is combined with down-regulation of glycolytic pathways and increased reliance on lipid metabolism instead. Furthermore, while rates of protein synthesis are reduced during hibernation, balance is maintained by correspondingly low rates of protein degradation. Proposed mechanisms include a number of signaling pathways and transcription factors that lead to increased oxidative fiber expression, enhanced protein synthesis and reduced protein degradation, ultimately resulting in minimal loss of skeletal muscle protein and oxidative capacity. The functional significance of these outcomes is maintenance of skeletal muscle strength and fatigue resistance, which enables hibernating animals to resume active behaviors such as predator avoidance, foraging and mating immediately following terminal arousal in the spring.
Most therapeutic agents are excluded from entering the central nervous system by the blood–brain barrier (BBB). Receptor mediated transcytosis (RMT) is a common mechanism used by proteins, including ...transferrin (Tf), to traverse the BBB. Here, we prepared Tf-containing, 80-nm gold nanoparticles with an acid-cleavable linkage between the Tf and the nanoparticle core to facilitate nanoparticle RMT across the BBB. These nanoparticles are designed to bind to Tf receptors (TfRs) with high avidity on the blood side of the BBB, but separate from their multidentate Tf–TfR interactions upon acidification during the transcytosis process to allow release of the nanoparticle into the brain. These targeted nanoparticles show increased ability to cross an in vitro model of the BBB and, most important, enter the brain parenchyma of mice in greater amounts in vivo after systemic administration compared with similar high-avidity nanoparticles containing noncleavable Tf. In addition, we investigated this design with nanoparticles containing high-affinity antibodies (Abs) to TfR. With the Abs, the addition of the acid-cleavable linkage provided no improvement to in vivo brain uptake for Ab-containing nanoparticles, and overall brain uptake was decreased for all Ab-containing nanoparticles compared with Tf-containing ones. These results are consistent with recent reports of high-affinity anti-TfR Abs trafficking to the lysosome within BBB endothelium. In contrast, high-avidity, Tf-containing nanoparticles with the acid-cleavable linkage avoid major endothelium retention by shedding surface Tf during their transcytosis.
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