Faculty Bibliography

Myocardial tagging is a non-invasive MR imaging technique; it generates a periodic tag pattern in the magnetization that deforms with the tissue during the cardiac cycle. It can be used to assess regional myocardial function, including tissue displacement and strain. Most image analysis methods require labor-intensive tag detection and tracking. We have developed an accurate and automated method for tag detection in order to calculate strain from tagged magnetic resonance images of the heart. It detects the local spatial frequency and phase of the tags using a bank of Gabor filters with varying frequency and phase. This variation in tag frequency is then used to calculate the local myocardial strain. The method is validated using computer simulations

Behavioral studies suggest that making a decision involves representing the overall desirability of all available actions and then selecting that action that is most desirable. Physiological studies have proposed that neurons in the parietal cortex play a role in selecting movements for execution. To test the hypothesis that these parietal neurons encode the subjective desirability of making particular movements, we exploited Nash's game theoretic equilibrium, during which the subjective desirability of multiple actions should be equal for human players. Behavior measured during a strategic game suggests that monkeys' choices, like those of humans, are guided by subjective desirability. Under these conditions, activity in the parietal cortex was correlated with the relative subjective desirability of actions irrespective of the specific combination of reward magnitude, reward probability, and response probability associated with each action. These observations may help place many recent findings regarding the posterior parietal cortex into a common conceptual framework.

Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta). In view of increased neuronal expression of RAGE in Alzheimer's disease, a murine model was developed to assess the impact of RAGE in an Abeta-rich environment, employing transgenics (Tgs) with targeted neuronal overexpression of RAGE and mutant amyloid precursor protein (APP). Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice. In contrast, Tg mice bearing a dominant-negative RAGE construct targeted to neurons crossed with mAPP animals displayed preservation of spatial learning/memory and diminished neuropathologic changes. These data indicate that RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology, and suggest its potential as a therapeutic target to ameliorate cellular dysfunction

In Alzheimer's disease (AD), selective expression of tau isoforms might underlie the susceptibility of different brain areas to develop neurofibrillary tangles and this pattern might change in the disease. In this study, we have analyzed in control subjects and in sporadic AD patients the pattern of expression of tau mRNA and tau proteins in areas unaffected (cerebellar cortex, white matter), moderately affected (occipital striate cortex, thalamus, caudate nucleus, and putamen) or strongly affected by neurofibrillary tangles (temporal and frontal associative cortex). After RT-PCR amplification, five products corresponding to the tau mRNAs containing exons 2 and 3, exon 2, without exons 2 or 3, with exon 10 and without exon 10 were identified. In control subjects, these five PCR products were present in all areas except in white matter, where transcripts with exons 2 or exons 2 and 3 were not identified. In AD patients, the same pattern of transcripts was observed in different areas, regardless of the presence of neurofibrillary lesions. After dephosphorylation of soluble tau proteins, the six tau isoforms were identified in the same areas by immunoblotting, including in the white matter, suggesting that most tau isoforms with exons 2 and 3 are transported along axons. The relative expression of 0N3R isoforms was higher in the temporal cortex than in the cerebellar cortex, both in control and AD subjects. The qualitative pattern of expression was identical in subjects with or without an APOE4 allele. Our results suggest that splicing regulation of the tau gene and the relative expression of tau isoforms are not significantly changed in sporadic cases of the disease, although differential expression of tau isoforms in temporal cortex might underlie this brain area susceptibility to neurofibrillary tangles formation

Interaction between an electronic and a biological circuit has been investigated for a pair of electrically connected nonlinear oscillators, with a spontaneously oscillating olivary neuron as the single-cell biological element. By varying the coupling strength between the oscillators, we observe a range of behaviors predicted by model calculations, including a reversible low-energy dissipation "amplitude death" where the oscillations in the coupled system cease entirely.

PURPOSE: Although an important risk factor for oral cancer is the presence of epithelial dysplasia, many lesions will not progress to malignancy. Matrix metalloproteinases (MMPs) are zinc-dependent proteinases capable of digesting various structural components of the extracellular matrix. Because MMPs are frequently overexpressed in oral squamous cell carcinoma (SCC), we hypothesized that they are also overexpressed in oral dysplasias; we also hypothesized that those dysplasias that progress to oral cancer express higher levels of MMPs than those lesions that do not progress. EXPERIMENTAL DESIGN: In this retrospective study, we examined changes in MMP-1, -2, and -9 mRNA expression using quantitative TaqMan reverse transcription-polymerase chain reaction in 34 routinely processed oral dysplasias and 15 SCCs obtained from 34 patients. After several years of close follow-up, 19 dysplasias progressed to oral SCC and 15 did not. RESULTS: Overall, MMP-1 mRNA was overexpressed (>2-fold) in 24 of 34 (71%) dysplasias and 13 of 15 (87%) oral SCCs. MMP-2 overexpression was seen in 11 of 34 (32%) dysplasias and 7 of 15 (47%) cancers; for MMP-9, overexpression was identified in 29 of 34 (85%) dysplasias and 15 of 15 (100%) cancers. MMP-1 and -9 levels were significantly higher in the SCCs compared with all oral dysplasias (P = 0.004 and P = 0.01, respectively). MMP-1 and -9 mRNA levels were significantly higher in the oral dysplasias that progressed to oral cancer compared with those that did not (P = 0.04 and P = 0.002, respectively). CONCLUSIONS: Levels of MMP-1 and -9 mRNA may be markers of malignant transformation of oral dysplasia to oral cancer

PURPOSE: The study goal was to evaluate neurosensory changes after liquid nitrogen cryotherapy in the management of mandibular lesions in close proximity to the inferior alveolar nerve. PATIENTS AND METHODS: The design of the study was a retrospective review. Sixteen patients with posterior mandibular lesions (15 odontogenic keratocysts and 1 fibromyxoma) in close proximity to the inferior alveolar nerve were treated with a standardized enucleation and cryotherapy technique. Postoperative evaluation included patients report of symptoms and formal neurosensory testing. RESULTS: All patients had altered sensation in the distribution of the inferior alveolar nerve immediately after cryotherapy. Two patients experienced anesthesia, and the remaining 14 patients showed paresthesia. The average time for return or improvement in sensation was 91 days (range, 6 to 235 days). The average time of follow-up was 2.6 years (range, 0.5 to 7.3 years). At the time of last follow-up, no patients had anesthesia or dysesthesia. Four patients had full return of sensation and 12 patients had paresthesia. No patients reported significant difficulty from abnormal nerve function. All 16 patients experienced some return of sensation; 9 patients had full or near full return of sensation. CONCLUSIONS: Based on these results, the combination of enucleation and liquid nitrogen cryotherapy produces minimal alteration of inferior alveolar nerve function

Across the animal kingdom, color discrimination is achieved by comparing the outputs of photoreceptor cells (PRs) that have different spectral sensitivities. Much remains to be understood about how the pattern of these different PRs is generated and maintained. The Drosophila eye has long provided a beautiful system for understanding various aspects of retinal-cell differentiation. Recent progress in this field is revealing that a highly ordered series of events, involving cell-cell communication, localized signaling and stochastic choices, creates a complex mosaic of PRs that is reminiscent of the human retina. Notably, several of the factors used in generating the retinal mosaic of the fruitfly have corresponding functions in vertebrates that are likely to have similar roles.

Evolution perfected brain design by maximizing its functionality while minimizing costs associated with building and maintaining it. Assumption that brain functionality is specified by neuronal connectivity, implemented by costly biological wiring, leads to the following optimal design problem. For a given neuronal connectivity, find a spatial layout of neurons that minimizes the wiring cost. Unfortunately, this problem is difficult to solve because the number of possible layouts is often astronomically large. We argue that the wiring cost may scale as wire length squared, reducing the optimal layout problem to a constrained minimization of a quadratic form. For biologically plausible constraints, this problem has exact analytical solutions, which give reasonable approximations to actual layouts in the brain. These solutions make the inverse problem of inferring neuronal connectivity from neuronal layout more tractable.

Functional ATP-sensitive potassium (K(ATP)) channels can be reconstituted by expression of various combinations of different pore-forming subunits (Kir6.1 and Kir6.2) and sulfonylurea receptor (SUR) subunits. Using dominant negative and gene knockout approaches, Kir6.2 subunits have been identified as required pore-forming components of plasmalemmal K(ATP) channels in ventricular myocytes. Previous data obtained in heterologous expression systems suggest that Kir6.1 and Kir6.2 subunits are capable of forming a functional heteromultimeric channel complex. However, until now the existence of such heteromultimeric Kir6.1/Kir6.2 complexes has not been demonstrated for native K(ATP) channels. The primary aim of this study was to identify the molecular composition of native K(ATP) channels in primary human coronary artery endothelial cells (HCAEC) and smooth muscle cells (HCASMC) from human origin. We specifically investigated the potential that heteromultimeric Kir6.1/Kir6.2 channels exist in these cells. Using reverse transcriptase-polymerase chain reaction, we detected the expression of Kir6.1, Kir6.2, and SUR2B in both cell types. Western blotting and immunoprecipitation assays demonstrated the presence of Kir6.1 protein in both HCAEC and HCASMC; however, Kir6.2 protein was only expressed in HCAEC. Interaction between Kir6.1 and Kir6.2 subunits was demonstrated by reciprocal co-immunoprecipitation of these two subunits in HCAEC. Furthermore, Kir6.1 and Kir6.2 were detected in the immunoprecipitate when using an anti-SUR2 antibody. Confocal microscopy imaging demonstrated Kir6.1 and Kir6.2 subunits to co-localize at the cell surface membrane in HCAEC. In conclusion, our data characterize the molecular composition of primary human coronary smooth muscle and endothelial cells. We demonstrate that human coronary endothelial K(ATP) channels consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits