Faculty Bibliography

RATIONALE AND OBJECTIVES: The aim of the study is to develop a theory-based signal calibration approach to be used for the conversion of signal-time curves to absolute contrast concentration-time curves for first-pass contrast-enhanced quantitative myocardial perfusion studies. MATERIALS AND METHODS: A normalization procedure was used to obtain a theoretical relationship between image signal and T1 and perform rapid single-point T1 measurements. T1 measurements were compared with reference T1 measurements. The method also was used in preliminary in vivo contrast-enhanced first-pass perfusion studies, and its applicability for dual-delay-time acquisitions was shown. A theory-based error sensitivity analysis was used to characterize the robustness of the method. RESULTS: The normalization procedure was implemented with minimal noise enhancement and insensitivity to small misregistrations through postprocessing techniques. The rapid T1 measurements are in excellent agreement with the reference measurements (R = 0.99, slope = 1.05, bias = -5.96 milliseconds). For in vivo studies, it is possible to simultaneously calibrate the arterial input function and myocardial enhancement curves acquired with different effective trigger delays through appropriate use of the theory-based signal calibration model. With this method, errors of in vivo baseline T1 estimates are large, but the effect of these large errors on the accuracy of contrast agent concentration estimates is limited. CONCLUSION: This theory-based signal calibration approach can be used to perform rapid T1 mapping and provides flexibility for in vivo calibration of signal-time curves resulting from dual-delay-time first-pass contrast-enhanced acquisitions

The point spread function (PSF) of Hadamard encoding deviates from its ideal profile due to practical (as opposed to intrinsic) reasons. Finite radiofrequency (RF) pulse length and gradient strength cause slice profile imperfections that lead to cross-talk ('voxel bleed') as large as 17% for a 1-KHz bandwidth, 5.12-ms RF pulse under 3 mT/m. This could adversely affect localization and quantification, and consequently clinical usefulness. A simple modification of the Hadamard RF pulse synthesis that exploits its unique ability to encode noncontiguous slices is proposed and shown to markedly improve the PSF. Computer simulation, in vitro and in vivo experiments confirm the theoretical derivation of voxel bleed reduction from approximately 17% to below 5% per Hadamard-encoded direction

This article addresses the functional significance of the electrophysiological properties of thalamic neurons. We propose that thalamocortical activity, is the product of the intrinsic electrical properties of the thalamocortical (TC) neurons and the connectivity their axons weave. We begin with an overview of the electrophysiological properties of single neurons in different functional states, followed by a review of the phylogeny of the electrical properties of thalamic neurons, in several vertebrate species. The similarity in electrophysiological properties unambiguously indicates that the thalamocortical system must be as ancient as the vertebrate branch itself. We address the view that rather than simply relays, thalamic neurons have sui generis intrinsic electrical properties that govern their specific functional dynamics and regulate natural functional states such as sleep and vigilance. In addition, thalamocortical activity has been shown to be involved in the genesis of several neuropsychiatric conditions collectively described as thalamocortical dysrhythmia syndrome

Neurotransmitters and hormones are released from neurosecretory cells by exocytosis (fusion) of synaptic vesicles, large dense-core vesicles and other types of vesicles or granules. The exocytosis is terminated and followed by endocytosis (retrieval). More than fifty years of research have established full-collapse fusion and clathrin-mediated endocytosis as essential modes of exo-endocytosis. Kiss-and-run and vesicle reuse represent alternative modes, but their prevalence and importance have yet to be elucidated, especially in neurons of the mammalian CNS. Here we examine various modes of exo-endocytosis across a wide range of neurosecretory systems. Full-collapse fusion and kiss-and-run coexist in many systems and play active roles in exocytotic events. In small nerve terminals of CNS, kiss-and-run has an additional role of enabling nerve terminals to conserve scarce vesicular resources and respond to high-frequency inputs. Full-collapse fusion and kiss-and-run will each contribute to maintaining cellular communication over a wide range of frequencies

BACKGROUND INFORMATION: Ku is an abundant nuclear heterodimeric protein composed of 70 and 86 kDa subunits. As an activator of the catalytic subunit of DNA-PK (DNA-dependent protein kinase), Ku plays an important role in DNA repair and recombination. Ku is also involved in actions independent of DNA-PK, such as transcription regulation and telomere maintenance. Although Ku is localized in the cytoplasm under specific cellular conditions, no functions for Ku outside of the nucleus have as yet been reported. In addition to DNA binding, Ku binds specific RNA sequences with high affinity. However, no specific cellular mRNA targets for Ku have been identified. RESULTS: In a yeast three-hybrid system, Ku70 bound to an RNA bait that contained an IRES (internal ribosomal entry site) element. A single band with migration properties similar to those of Ku70 was immunoprecipitated with anti-Ku antibody, using UV cross-linked complexes formed by HeLa cell nuclear extracts and an IRES-containing RNA probe. IRES activity was reduced in Ku80(-/-) cells. Overexpression of Ku proteins stimulated IRES-dependent translation. CONCLUSIONS: The present study suggests that Ku binds IRES elements within RNA molecules, and that Ku plays a role in the modulation of IRES-mediated mRNA translation.

BACKGROUND AND PURPOSE: Evaluation of the spinal cord is important in the diagnosis and follow-up of patients with multiple sclerosis. Our purpose was to investigate diffusion tensor imaging (DTI) changes in different regions of normal-appearing spinal cord (NASC) in relapsing-remitting multiple sclerosis (RRMS). METHODS: Axial DTI of the cervical spinal cord was performed in 24 patients with RRMS and 24 age- and sex-matched control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated in separate regions of interest (ROIs) in the anterior, lateral, and posterior spinal cord, bilaterally, and the central spinal cord, at the C2-C3 level. Patients and control subjects were compared with respect to FA and MD with the use of an exact Mann-Whitney test. Logistic regression and receiver operating characteristic (ROC) curve analysis assessed the utility of each measure for the diagnosis of RRMS. RESULTS: DTI metrics in areas of NASC in MS were significantly different in patients compared with control subjects; FA was lower in the lateral (mean +/- SD of 0.56 +/- 0.10 versus 0.69 +/- 0.09 in control subjects, P < .0001), posterior (0.52 +/- 0.11 versus 0.63 +/- 0.10, P < .0001), and central (0.53 +/- 0.10 versus 0.58 +/- 0.10, P = .049) NASC ROIs. Assessing DTI metrics in the diagnosis of MS, a sensitivity of 87.0% (95% confidence interval [CI], 66.4 to 97.1) and a specificity of 91.7% (95% CI, 73.0 to 98.7) were demonstrated. CONCLUSION: The NASC in RRMS demonstrates DTI changes. This may prove useful in detecting occult spinal cord pathology, predicting clinical course, and monitoring disease progression and therapeutic effect in MS

Fibroblast growth factors (FGFs) are important regulators of hematopoiesis and have been implicated in the tumorigenesis of solid tumors. Recent evidence suggests that FGF signaling through FGF receptors (FGFRs) may play a role in the proliferation of subsets of acute myeloid leukemias (AMLs). However, the precise mechanism and specific FGF receptors that support leukemic cell growth are not known. We show that FGF-2, through activation of FGFR1beta signaling, promotes survival, proliferation and migration of AML cells. Stimulation of FGFR1beta results in phosphoinositide 3-kinase (PI3-K)/Akt activation and inhibits chemotherapy-induced apoptosis of leukemic cells. Neutralizing FGFR1-specific antibody abrogates the physiologic and chemoprotective effects of FGF-2/FGFR1beta signaling and inhibits tumor growth in mice xenotransplanted with human AML. These data suggest that activation of FGF-2/FGFR1beta supports progression and chemoresistance in subsets of AML. Therefore, FGFR1 targeting may be of therapeutic benefit in subsets of AML

ABSTRACT: BACKGROUND: Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. Methods: We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). Results: SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats. CONCLUSION: The present results suggest a potential alteration in D1R neurotransmission within the frontal-striatal circuitry of SHR involved in motor control. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD

Specificity of neurotrophin factor signaling is dictated through the action of Trk receptor tyrosine kinases. Once activated, Trk receptors are internalized and targeted for degradation. However, the mechanisms implicated in this process are incompletely understood. Here we report that the Trk receptors are multimonoubiquitinated in response to neurotrophins. We have identified an E3 ubiquitin ligase, Nedd4-2, that associates with the TrkA receptor and is phosphorylated upon NGF binding. The binding of Nedd4-2 to TrkA through a PPXY motif leads to the ubiquitination and downregulation of TrkA. Activated TrkA receptor levels and the survival of NGF-dependent sensory neurons, but not BDNF-dependent sensory neurons, are directly influenced by Nedd4-2 expression. Unexpectedly, Nedd4-2 does not bind or ubiquitinate related TrkB receptors, due to the lack of a consensus PPXY motif. Our results indicate that Trk neurotrophin receptors are differentially regulated by ubiquitination to modulate the survival of neurons