Faculty Bibliography

An imaging system composed of an array of adaptive optics subapertures referred to as a conformal imaging system is considered. A conformal image of an object viewed through atmospheric turbulence is obtained using the following sequential steps: adaptive compensation of phase distortions through optimization of image quality metrics at each subaperture, measurements of the phase and intensity distributions corresponding to the compensated subaperture images, digital combining and processing of the obtained data, computation of a conformal image using arbitrary phase shifts between subapertures, and correction of these phase shifts through conformal image quality optimization using the stochastic parallel gradient descent algorithm. Numerical simulation results of a dual-star conformal image through atmospheric turbulence are presented

PURPOSE: The heat shock protein 90 (Hsp90) chaperone plays an important role in transformation by regulating the conformational maturation and stability of oncogenic kinases and transcription factors. Ansamycins, such as 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), inhibit Hsp90 function; induce the degradation of Hsp90 client proteins such as HER2, and have shown activity in early clinical trials. However, the utility of these drugs has been limited by their hepatotoxicity, poor solubility, and poorly tolerated formulations. EXPERIMENTAL DESIGN: We determined the pharmacodynamic and antitumor properties of a novel, synthetic Hsp90 inhibitor, SNX-2112, in cell culture and xenograft models of HER kinase-dependent cancers. RESULTS: We show in a panel of tumor cell lines that SNX-2112 and its prodrug SNX-5542 are Hsp90 inhibitors with properties and potency similar to that of 17-AAG, including: degradation of HER2, mutant epidermal growth factor receptor, and other client proteins, inhibition of extracellular signal-regulated kinase and Akt activation, and induction of a Rb-dependent G(1) arrest with subsequent apoptosis. SNX-5542 can be administered to mice orally on a daily schedule. Following oral administration, SNX-5542 is rapidly converted to SNX-2112, which accumulates in tumors relative to normal tissues. A single dose of SNX-5542 causes HER2 degradation and inhibits its downstream signaling for up to 24 h, and daily dosing results in regression of HER2-dependent xenografts. SNX-5542 also shows greater activity than 17-AAG in a non-small cell lung cancer xenograft model expressing mutant EGFR. CONCLUSIONS: These results suggest that Hsp90 inhibition with SNX-2112 (delivered as a prodrug) may represent a promising therapeutic strategy for tumors whose growth and survival is dependent on Hsp90 clients.

We are pursuing a hybrid optical-electrophysiological-computational approach for studying and modeling neuronal input-output transformations in CNS neurons in vitro under increasingly realistic conditions. Our approach combines two-photon glutamate uncaging, which enables non-invasive stimulation of neurons with single synapse specificity, and rapid three-dimensional hopping between many different uncaging locations (termed "patterned uncaging"). The input sequences used are doubly stochastic Poisson point processes with predefined custom auto- and cross-correlation functions, generated using a new method we developed. Our experiments quantitatively analyze the role of the input correlation structure on dendritic integration in CNS neurons by experimentally mimicking natural synaptic activity while simultaneously electrically measuring the output soma potentials.

The main psychoactive component of marijuana, Delta9-tetrahydrocannabinol (THC), acts in the CNS via type 1 cannabinoid receptors (CB1Rs). The behavioral consequences of THC or synthetic CB1R agonists include suppression of motor activity. One explanation for movement suppression might be inhibition of striatal dopamine (DA) release by CB1Rs, which are densely localized in motor striatum; however, data from previous studies are inconclusive. Here we examined the effect of CB1R activation on locally evoked DA release monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices. Consistent with previous reports, DA release evoked by a single stimulus pulse was unaffected by WIN55,212-2, a cannabinoid receptor agonist. However, when DA release was evoked by a train of stimuli, WIN55,212-2 caused a significant decrease in evoked extracellular DA concentration ([DA]o), implicating the involvement of local striatal circuitry, with similar suppression seen in guinea pig, rat, and mouse striatum. Pulse-train evoked [DA]o was not altered by either AM251, an inverse CB1R agonist, or VCHSR1, a neutral antagonist, indicating the absence of DA release regulation by endogenous cannabinoids with the stimulation protocol used. However, both CB1R antagonists prevented and reversed suppression of evoked [DA]o by WIN55,212-2. The effect of WIN55,212-2 was also prevented by picrotoxin, a GABAA receptor antagonist, and by catalase, a metabolizing enzyme for hydrogen peroxide (H2O2). Furthermore, blockade of ATP-sensitive K+ (KATP) channels by tolbutamide or glybenclamide prevented the effect of WIN55,212-2 on DA release. Together, these data indicate that suppression of DA release by CB1R activation within striatum occurs via a novel nonsynaptic mechanism that involves GABA release inhibition, increased generation of the diffusible messenger H2O2, and activation of KATP channels to inhibit DA release. In addition, the findings suggest a possible physiological substrate for the motor effects of cannabinoid agonist administration

Cardiovascular magnetic resonance imaging (CVMRI) is of proven clinical value in the non-invasive imaging of cardiovascular diseases. CVMRI requires rapid image acquisition, but acquisition speed is fundamentally limited in conventional MRI. Parallel imaging provides a means for increasing acquisition speed and efficiency. However, signal-to-noise (SNR) limitations and the limited number of receiver channels available on most MR systems have in the past imposed practical constraints, which dictated the use of moderate accelerations in CVMRI. High levels of acceleration, which were unattainable previously, have become possible with many-receiver MR systems and many-element, cardiac-optimized RF-coil arrays. The resulting imaging speed improvements can be exploited in a number of ways, ranging from enhancement of spatial and temporal resolution to efficient whole heart coverage to streamlining of CVMRI work flow. In this review, examples of these strategies are provided, following an outline of the fundamentals of the highly accelerated imaging approaches employed in CVMRI. Topics discussed include basic principles of parallel imaging; key requirements for MR systems and RF-coil design; practical considerations of SNR management, supported by multi-dimensional accelerations, 3D noise averaging and high field imaging; highly accelerated clinical state-of-the art cardiovascular imaging applications spanning the range from SNR-rich to SNR-limited; and current trends and future directions

OBJECTIVE/HYPOTHESIS:: The role of fungal pathogens in the etiology of nasal polyposis remains unclear. The aim of this study was to determine whether there was a correlation between the presence of Alternaria-specific immunoglobulin (Ig)E antibodies, eosinophilic inflammation, and the development of nasal polyps. STUDY DESIGN:: Prospective study. METHODS:: Serum and nasal tissue homogenates from 21 patients with manifestations of chronic sinusitis with nasal polyps were compared with specimens from 13 chronic sinusitis patients without polyps and 8 healthy controls. The Phadia ImmunoCAP and enzyme-linked immunosorbent assay were used to quantify levels of total IgE and Alternaria-specific (IgE, IgG, and IgA) antibodies. Eosinophil cationic protein (ECP) and tryptase levels were measured in tissue homogenates, whereas the inflammatory response was evaluated using tissue eosinophil counts in tissue samples. RESULTS:: Serum analysis revealed no difference in the levels of total IgE and Alternaria-specific IgE, IgG, and IgA antibodies between the study groups. In contrast, the levels of Alternaria-specific IgE in tissue with polyps were significantly higher than in nonpolyp tissue. Increases in total tissue IgE paralleled increased levels of Alternaria-specific IgG and IgA antibodies in chronic sinusitis with nasal polyps as compared with control groups. A positive correlation was found between Alternaria-specific IgE and ECP in tissue. Increased mean levels of ECP corresponded to increased eosinophil counts in the group of patients with polyps. CONCLUSIONS:: Alternaria-specific IgE and eosinophilic inflammation in nasal tissue correlates with the incidence of nasal polyps irrespective of specific IgE antibodies in serum. Together, the correlation between the local immune responses and the eosinophilic inflammation in nasal polyps suggests a possible role of Alternaria in the pathogenesis of nasal polyposis

Time invariant description of synaptic connectivity in cortical circuits may be precluded by the ongoing growth and retraction of dendritic spines accompanied by the formation and elimination of synapses. On the other hand, the spatial arrangement of axonal and dendritic branches appears stable. This suggests that an invariant description of connectivity can be cast in terms of potential synapses, which are locations in the neuropil where an axon branch of one neuron is proximal to a dendritic branch of another neuron. In this paper, we attempt to reconstruct the potential connectivity in local cortical circuits of the cat primary visual cortex (V1). Based on multiple single-neuron reconstructions of axonal and dendritic arbors in 3 dimensions, we evaluate the expected number of potential synapses and the probability of potential connectivity among excitatory (pyramidal and spiny stellate) neurons and inhibitory basket cells. The results provide a quantitative description of structural organization of local cortical circuits. For excitatory neurons from different cortical layers, we compute local domains, which contain their potentially pre- and postsynaptic excitatory partners. These domains have columnar shapes with laminar specific radii and are roughly of the size of the ocular dominance column. Therefore, connections between most excitatory neurons in the ocular dominance column can be implemented by local synaptogenesis. Structural connectivity involving inhibitory basket cells is generally weaker than excitatory connectivity. Here, only nearby neurons are capable of establishing more than one potential synapse, implying that within the ocular dominance column these connections have more limited potential for circuit remodeling.

Cardiac MRI at 3T provides a means to increase the contrast-to-noise ratio (CNR) for first-pass perfusion MRI. However, both the static magnetic field (B(0)) and radio frequency (RF) field (B(1)) variations within the heart are comparatively higher at 3T than at 1.5T. The increased field variations can degrade the performance of a single rectangular saturation pulse that is conventionally used for magnetization preparation. The accuracy of T(1)-weighted signal measurement depends on the uniformity of the magnetization saturation. The purpose of this study was to assess the relative effectiveness of the rectangular, pulse train, and adiabatic composite (BIR-4) saturation pulses in the human heart at 3T. In volunteers, after nominal saturation, the mean residual magnetization within the left ventricle (LV) was different between all three pulses (0.13 +/- 0.06 vs. 0.03 +/- 0.02 vs. 0.03 +/- 0.01, respectively; P < 0.001). Within paired groups, the mean residual magnetization was significantly higher for the rectangular pulse than for either the pulse train and BIR-4 pulses (P < 0.001), but not different between the pulse train and BIR-4 pulses. The performances of all three saturation pulses were comparatively poorer in the right ventricle (RV) than in the LV, respectively. Magn Reson Med, 2007. (c) 2007 Wiley-Liss, Inc