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1.  Enhancement of neuromuscular dynamics and strength behavior using extremely low magnitude mechanical signals in mice 
Journal of biomechanics  2013;47(1):10.1016/j.jbiomech.2013.09.024.
Exercise in general, and mechanical signals in particular, help ameliorate the neuromuscular symptoms of aging and possibly other neurodegenerative disorders by enhancing muscle function. To better understand the salutary mechanisms of such physical stimuli, we evaluated the potential for low intensity mechanical signals to promote enhanced muscle dynamics. The effects of daily brief periods of low intensity vibration (LIV) on neuromuscular functions and behavioral correlates were assessed in mice. Physiological analysis revealed that LIV increased isometric force production in semitendinosus skeletal muscle. This effect was evident in both young and old mice. Isometric force recordings also showed that LIV reduced the fatiguing effects of intensive synaptic muscle stimulation. Furthermore, LIV increased evoked neurotransmitter release at neuromuscular synapses but had no effect on spontaneous end plate potential amplitude or frequency. In behavioral studies, LIV increased mouse grip strength and potentiated initial motor activity in a novel environment. These results provide evidence for the efficacy of LIV in producing changes in the neuromuscular system that translate into performance gains at a behavioral scale.
doi:10.1016/j.jbiomech.2013.09.024
PMCID: PMC3881264  PMID: 24157062
Whole body vibration; neuromuscular; quantal content; muscle strength; mechanical signals
2.  Preferential cell attachment to nitrogen-doped diamond-like carbon (DLC:N) for the measurement of quantal exocytosis 
Biomaterials  2009;30(8):1604-1612.
Electrochemical measurement of transmitter or hormone release from individual cells on microchips has applications both in basic science and drug screening. High-resolution measurement of quantal exocytosis requires the working electrode to be small (cell-sized) and located in immediate proximity to the cell. We examined the ability of candidate electrode materials to promote the attachment of two hormone-secreting cell types as a mechanism for targeting cells for to recording electrodes with high precision. We found that nitrogen-doped diamond-like carbon (DLC:N) promoted cell attachment relative to other materials tested in the rank order of DLC:N > In2O3/SnO2 (ITO), Pt > Au. In addition, we found that treating candidate electrode materials with polylysine did not increase attachment of chromaffin cells to DLC:N, but promoted cell attachment to the other tested materials. We found that hormone-secreting cells did not attach readily to Teflon AF as a potential insulating material, and demonstrated that patterning of Teflon AF leads to selective cell targeting to DLC:N “docking sites”. These results will guide the design of the next generation of biochips for automated and high-throughput measurement of quantal exocytosis.
doi:10.1016/j.biomaterials.2008.11.039
PMCID: PMC3748607  PMID: 19124153
INS-1 cells; Cell adhesion; Contact angle; Diamond-like carbon; BioMEMS; Chromaffin cells
3.  Confeito-like Assembly of Organosilicate-caged Fluorophores: Ultrabright Suprananoparticles for Fluorescence Imaging 
Nanotechnology  2012;23(17):175601.
We report ultrabright, photostable, sub-25 nm nanoparticle agglomerates (suprananoparticles) assembled from a few hundred 3.3 ± 0.9 nm units, each hosting on average a single rhodamine 6G (Rh6G) dye molecule encased in a thin organosilicate cage. These individual Rh6G-doped nanoparticle (DOSNP) units consist of a hydrophobic core containing the dye and an ultrathin, conformal silicate shell modified by CO2 plasma to confer a beneficial “cage effect” as well as surface hydrophilicity. The isolation of the dye within individual DOSNP units in the final 22 ± 5 nm agglomerate avoids dimerization and related spontaneous molecular interactions that otherwise lead to self-quenching in closely co-localized fluorophores. The resulting suprananoparticles are over 200 times brighter than the free Rh6G molecules in the same volume. There is no observable dye leaching, and the labels are 20-fold more resistant to photobleaching than free Rh6G in solution. We demonstrate the attractive features of DOSNPs as labels in bioimaging applications.
doi:10.1088/0957-4484/23/17/175601
PMCID: PMC3360483  PMID: 22481044
4.  Knockdown of embryonic myosin heavy chain reveals an essential role in the morphology and function of the developing heart 
Development (Cambridge, England)  2011;138(18):3955-3966.
The expression and function of embryonic myosin heavy chain (eMYH) has not been investigated within the early developing heart. This is despite the knowledge that other structural proteins, such as alpha and beta myosin heavy chains and cardiac alpha actin, play crucial roles in atrial septal development and cardiac function. Most cases of atrial septal defects and cardiomyopathy are not associated with a known causative gene, suggesting that further analysis into candidate genes is required. Expression studies localised eMYH in the developing chick heart. eMYH knockdown was achieved using morpholinos in a temporal manner and functional studies were carried out using electrical and calcium signalling methodologies. Knockdown in the early embryo led to abnormal atrial septal development and heart enlargement. Intriguingly, action potentials of the eMYH knockdown hearts were abnormal in comparison with the alpha and beta myosin heavy chain knockdowns and controls. Although myofibrillogenesis appeared normal, in knockdown hearts the tissue integrity was affected owing to apparent focal points of myocyte loss and an increase in cell death. An expression profile of human skeletal myosin heavy chain genes suggests that human myosin heavy chain 3 is the functional homologue of the chick eMYH gene. These data provide compelling evidence that eMYH plays a crucial role in important processes in the early developing heart and, hence, is a candidate causative gene for atrial septal defects and cardiomyopathy.
doi:10.1242/dev.059063
PMCID: PMC3160091  PMID: 21862559
Atrial septal development; Cardiomyopathy; Myosin; Chick
5.  Characterization of rhythmic Ca2+ transients in early embryonic chick motoneurons: Ca2+ sources and effects of altered activation of transmitter receptors 
In the nervous system, spontaneous Ca2+ transients play important roles in many developmental processes. We previously found that altering the frequency of rhythmic spontaneous bursting episodes in embryonic chick spinal cords differentially perturbed the two main pathfinding decisions made by motoneurons, dorsal-ventral and pool-specific, depending on the sign of the frequency alteration. Here, we characterized the Ca2+ transients associated with these bursts, showing that at early stages while motoneurons are still migrating and extending axons to the base of the limb bud, they display spontaneous, highly rhythmic, and synchronized Ca2+ transients, as did some precursor cells in the ependymal layer. T-type Ca2+ channels and a persistent Na+ current were essential to initiate spontaneous bursts and associated transients, but subsequent propagation of activity throughout the cord resulted from network driven chemical transmission mediated presynaptically by Ca2+ entry through N-type Ca2+ channels and postsynaptically by acetylcholine acting on nicotinic receptors. The increased [Ca2+]i during transients depended primarily on L-type and T-type channels with a modest contribution from TRP channels and ryanodine sensitive internal stores. Significantly, the drugs used previously to produce pathfinding errors altered transient frequency but not duration or amplitude. These observations imply that the different transient frequencies may differentially modulate motoneuron pathfinding. In addition, the duration of the Ca2+ transients differed significantly between pools, potentially enabling additional distinct pool-specific downstream signaling. Many early events in spinal motor circuit formation are thus potentially sensitive to the rhythmic Ca2+ transients we have characterized and to any drugs that perturb them.
doi:10.1523/JNEUROSCI.3809-09.2009
PMCID: PMC2956416  PMID: 19955376
Ca2+ channels; calcium induced calcium release; nicotinic receptors; GABAA receptors; persistent Na+ current; spontaneous activity
6.  Block of N-type Calcium Channels in Chick Sensory Neurons by External Sodium  
The Journal of General Physiology  1997;109(6):693-702.
L-type Ca2+ channels select for Ca2+ over sodium Na+ by an affinity-based mechanism. The prevailing model of Ca2+ channel permeation describes a multi-ion pore that requires pore occupancy by at least two Ca2+ ions to generate a Ca2+ current. At [Ca2+] < 1 μM, Ca2+ channels conduct Na+. Due to the high affinity of the intrapore binding sites for Ca2+ relative to Na+, addition of μM concentrations of Ca2+ block Na+ conductance through the channel. There is little information, however, about the potential for interaction between Na+ and Ca2+ for the second binding site in a Ca2+ channel already occupied by one Ca2+. The two simplest possibilities, (a) that Na+ and Ca2+ compete for the second binding site or (b) that full time occupancy by one Ca2+ excludes Na+ from the pore altogether, would imply considerably different mechanisms of channel permeation. We are studying permeation mechanisms in N-type Ca2+ channels. Similar to L-type Ca2+ channels, N-type channels conduct Na+ well in the absence of external Ca2+. Addition of 10 μM Ca2+ inhibited Na+ conductance by 95%, and addition of 1 mM Mg2+ inhibited Na+ conductance by 80%. At divalent ion concentrations of 2 mM, 120 mM Na+ blocked both Ca2+ and Ba2+ currents. With 2 mM Ba2+, the IC50 for block of Ba2+ currents by Na+ was 119 mM. External Li+ also blocked Ba2+ currents in a concentration-dependent manner, with an IC50 of 97 mM. Na+ block of Ba2+ currents was dependent on [Ba2+]; increasing [Ba2+] progressively reduced block with an IC50 of 2 mM. External Na+ had no effect on voltage-dependent activation or inactivation of the channel. These data suggest that at physiological concentrations, Na+ and Ca2+ compete for occupancy in a pore already occupied by a single Ca2+. Occupancy of the pore by Na+ reduced Ca2+ channel conductance, such that in physiological solutions, Ca2+ channel currents are between 50 and 70% of maximal.
PMCID: PMC2217043  PMID: 9222896
calcium channels; ion channel selectivity; sodium; permeation

Results 1-6 (6)