Faculty Bibliography

We have examined the effects of RNS60, a 0.9% saline containing charge-stabilized oxygen nanobubble-based structures. RNS60 is generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. This study, implemented in Xenopus laevis oocytes, addresses both the electrophysiological membrane properties and parallel biological processes in the cytoplasm. Intracellular recordings from defolliculated X. laevis oocytes were implemented in: (1) air oxygenated standard Ringer's solution, (2) RNS60-based Ringer's solution, (3) RNS10.3 (TCP-modified saline without excess oxygen)-based Ringer's, and (4) ONS60 (saline containing high pressure oxygen without TCP modification)-based Ringer's. RNS60-based Ringer's solution induced membrane hyperpolarization from the resting membrane potential. This effect was prevented by: (1) ouabain (a blocker of the sodium/potassium ATPase), (2) rotenone (a mitochondrial electron transfer chain inhibitor preventing usable ATP synthesis), and (3) oligomycin A (an inhibitor of ATP synthase) indicating that RNS60 effects intracellular ATP levels. Increased intracellular ATP levels following RNS60 treatment were directly demonstrated using luciferin/luciferase photon emission. These results indicate that RNS60 alters intrinsic the electrophysiological properties of the X. laevis oocyte membrane by increasing mitochondrial-based ATP synthesis. Ultrastructural analysis of the oocyte cytoplasm demonstrated increased mitochondrial length in the presence of RNS60-based Ringer's solution. It is concluded that the biological properties of RNS60 relate to its ability to optimize ATP synthesis.

The head-direction (HD) system functions as a compass, with member neurons robustly increasing their firing rates when the animal's head points in a specific direction. HD neurons may be driven by peripheral sensors or, as computational models postulate, internally generated (attractor) mechanisms. We addressed the contributions of stimulus-driven and internally generated activity by recording ensembles of HD neurons in the antero-dorsal thalamic nucleus and the post-subiculum of mice by comparing their activity in various brain states. The temporal correlation structure of HD neurons was preserved during sleep, characterized by a 60 degrees -wide correlated neuronal firing (activity packet), both within and across these two brain structures. During rapid eye movement sleep, the spontaneous drift of the activity packet was similar to that observed during waking and accelerated tenfold during slow-wave sleep. These findings demonstrate that peripheral inputs impinge on an internally organized network, which provides amplification and enhanced precision of the HD signal.

Diffusional kurtosis imaging (DKI) measures the diffusion and kurtosis tensors to quantify restricted, non-Gaussian diffusion that occurs in biological tissue. By estimating the kurtosis tensor, DKI accounts for higher order diffusion dynamics, when compared with diffusion tensor imaging (DTI), and consequently can describe more complex diffusion profiles. Here, we compare several measures of diffusional anisotropy which incorporate information from the kurtosis tensor, including kurtosis fractional anisotropy (KFA) and generalized fractional anisotropy (GFA), with the diffusion tensor-derived fractional anisotropy (FA). KFA and GFA demonstrate a net enhancement relative to FA when multiple white matter fiber bundle orientations are present in both simulated and human data. In addition, KFA shows net enhancement in deep brain structures, such as the thalamus and the lenticular nucleus, where FA indicates low anisotropy. Thus, KFA and GFA provide additional information relative to FA with regard to diffusional anisotropy, and may be particularly advantageous for the assessment of diffusion in complex tissue environments

Although undulatory swimming is observed in many organisms, the neuromuscular basis for undulatory movement patterns is not well understood. To better understand the basis for the generation of these movement patterns, we studied muscle activity in the nematode Caenorhabditis elegans. Caenorhabditis elegans exhibits a range of locomotion patterns: in low viscosity fluids the undulation has a wavelength longer than the body and propagates rapidly, while in high viscosity fluids or on agar media the undulatory waves are shorter and slower. Theoretical treatment of observed behaviour has suggested a large change in force-posture relationships at different viscosities, but analysis of bend propagation suggests that short-range proprioceptive feedback is used to control and generate body bends. How muscles could be activated in a way consistent with both these results is unclear. We therefore combined automated worm tracking with calcium imaging to determine muscle activation strategy in a variety of external substrates. Remarkably, we observed that across locomotion patterns spanning a threefold change in wavelength, peak muscle activation occurs approximately 45 degrees (1/8th of a cycle) ahead of peak midline curvature. Although the location of peak force is predicted to vary widely, the activation pattern is consistent with required force in a model incorporating putative length- and velocity-dependence of muscle strength. Furthermore, a linear combination of local curvature and velocity can match the pattern of activation. This suggests that proprioception can enable the worm to swim effectively while working within the limitations of muscle biomechanics and neural control.

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome.

The two major melanoma histologic subtypes, superficial spreading and nodular melanomas, differ in their speed of dermal invasion but converge biologically once they invade and metastasize. Herein, we tested the hypothesis that distinct molecular alterations arising in primary melanoma cells might persist as these tumors progress to invasion and metastasis. Ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) was significantly hyperactivated in human melanoma lines and metastatic tissues derived from nodular compared with superficial spreading melanoma. RSK1 was constitutively phosphorylated at Ser-380 in nodular but not superficial spreading melanoma and did not directly correlate with BRAF or MEK activation. Nodular melanoma cells were more sensitive to RSK1 inhibition using siRNA and the pharmacological inhibitor BI-D1870 compared with superficial spreading cells. Gene expression microarray analyses revealed that RSK1 orchestrated a program of gene expression that promoted cell motility and invasion. Differential overexpression of the prometastatic matrix metalloproteinase 8 and tissue inhibitor of metalloproteinases 1 in metastatic nodular compared with metastatic superficial spreading melanoma was observed. Finally, using an in vivo zebrafish model, constitutive RSK1 activation increased melanoma invasion. Together, these data reveal a novel role for activated RSK1 in the progression of nodular melanoma and suggest that melanoma originating from different histologic subtypes may be biologically distinct and that these differences are maintained as the tumors invade and metastasize.

What is the best way to help humans adapt to a distorted sensory input? Interest in this question is more than academic. The answer may help facilitate auditory learning by people who became deaf after learning language and later received a cochlear implant (a neural prosthesis that restores hearing through direct electrical stimulation of the auditory nerve). There is evidence that some cochlear implants (which provide information that is spectrally degraded to begin with) stimulate neurons with higher characteristic frequency than the acoustic frequency of the original stimulus. In other words, the stimulus is shifted in frequency with respect to what the listener expects to hear. This frequency misalignment may have a negative influence on speech perception by CI users. However, a perfect frequency-place alignment may result in the loss of important low frequency speech information. A trade-off may involve a gradual approach: start with correct frequency-place alignment to allow listeners to adapt to the spectrally degraded signal first, and then gradually increase the frequency shift to allow them to adapt to it over time. We used an acoustic model of a cochlear implant to measure adaptation to a frequency-shifted signal, using either the gradual approach or the "standard" approach (sudden imposition of the frequency shift). Listeners in both groups showed substantial auditory learning, as measured by increases in speech perception scores over the course of fifteen one-hour training sessions. However, the learning process was faster for listeners who were exposed to the gradual approach. These results suggest that gradual rather than sudden exposure may facilitate perceptual learning in the face of a spectrally degraded, frequency-shifted input. This article is part of a Special Issue entitled .

Neural oscillations have been measured and interpreted in multitudinous ways, with a variety of hypothesized functions in physiology, information processing and cognition. Much attention has been paid in recent years to gamma-band (30-100 Hz) oscillations and synchrony, with an increasing interest in 'high gamma' (>100 Hz) signals as mesoscopic measures of inter-regional communication. The biophysical origins of the measured variables are often difficult to precisely identify, however, making their interpretation fraught with pitfalls. Here we discuss how measurements of inter-regional gamma coherence can be prone to misinterpretation and suggest strategies for deciphering the roles that synchronized oscillations across brain networks may play in neural function.