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PubMed2002

Fast and precise independent component analysis for high field fMRI time series tailored using prior information on spatiotemporal structure.

Independent component analysis (ICA) has been shown as a promising tool for the analysis of functional magnetic resonance imaging (fMRI) time series. Each of these studies, however, used a general-purpose algorithm for performing ICA and the computational efficiency and accuracy of elicited neuronal activations have not been discussed in much detail. We have previously proposed a direct search method for improving computational efficiency. The method, which is based on independent component-cross correlation-sequential epoch (ICS) analysis, utilizes a form of the fixed-point ICA algorithm and considerably reduces the time required for extracting desired components. At the same time, it is shown that the accuracy of detecting physiologically meaningful components is much improved by tailoring the contrast function used in the algorithm. In this study, further improvement was made to this direct search method by integrating an optimal contrast function. Functional resolution of activation maps could be controlled with a suitable selection of the contrast function derived from prior knowledge of the spatial patterns of physiologically desired components. A simple skewness-weighted contrast function was verified to extract sufficiently precise activation maps from the fMRI time series acquired using a 3.0 Tesla MRI system.

Adolescent↗
PubMed2004

Regional variations in normal brain shown by quantitative magnetization transfer imaging.

A quantitative magnetization transfer imaging (qMTI) study, based on a two-pool model of magnetization transfer, was performed on seven normal subjects to determine, on a regional basis, normal values for the pool sizes, exchange, and relaxation parameters that characterize the MT phenomenon. Regions were identified on high-resolution anatomical scans using a combination of manual and automatic methods. Only voxels identified as pure tissue at the resolution of the quantitative scans were considered for analysis. While no left/right differences were observed, significant differences were found among white-matter regions and gray-matter regions. These regional differences were compared with existing cytoarchitectural data. In addition, the pattern and magnitude of the regional differences observed in white matter was found to be different from that reported previously for an alternative putative MRI measure of myelination, the 10-50-ms T2 component described as myelin water.

Adult↗
PubMed2004

Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and T2 characteristics of human knee articular cartilage: topographical variation and relationships to mechanical properties.

The macromolecular structure and mechanical properties of articular cartilage are interrelated and known to vary topographically in the human knee joint. To investigate the potential of delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), T1, and T2 mapping to elucidate these differences, full-thickness cartilage disks were prepared from six anatomical locations in nonarthritic human knee joints (N = 13). Young's modulus and the dynamic modulus at 1 Hz were determined with the use of unconfined compression tests, followed by quantitative MRI measurements at 9.4 Tesla. Mechanical tests revealed reproducible, statistically significant differences in moduli between the patella and the medial/lateral femoral condyles. Typically, femoral cartilage showed higher Young's (>1.0 MPa) and dynamic (>8 MPa) moduli than tibial or patellar cartilage (Young's modulus < 0.9 MPa, dynamic modulus < 8 MPa). dGEMRIC moderately reproduced the topographical variation in moduli. Additionally, T1, T2, and dGEMRIC revealed topographical differences that were not registered mechanically. The different MRI and mechanical parameters showed poor to excellent linear correlations, up to r = 0.87, at individual test sites. After all specimens were pooled, dGEMRIC was the best predictor of compressive stiffness (r = 0.57, N = 77). The results suggest that quantitative MRI can indirectly provide information on the mechanical properties of human knee articular cartilage, as well as the site-dependent variations of these properties. Investigators should consider the topographical variation in MRI parameters when conducting quantitative MRI of cartilage in vivo.

Adult↗
PubMed1997

Scent-marking by coyotes, Canis latrans: the influence of social and ecological factors

We observed 49 coyotes, Canis latransfrom five resident packs for 2456 h and five transient coyotes for 51 h from January 1991 to June 1993 in the Lamar River Valley, Yellowstone National Park, Wyoming, U.S.A. During these observations we recorded 3042 urinations, 451 defecations, 446 ground scratches and 743 double-marks. The rate of scent-marking (via urination) was influenced by the social organization (resident versus transient) to which the coyote belonged, the social class (alpha, beta or pup) of the animal and the time of the year. Transient coyotes scent-marked at a lower rate than did members of a resident pack. Within the resident packs, alpha coyotes scent-marked at a higher rate than beta coyotes (adults and yearlings subordinant to alphas, but dominant over pups) and pups. Alpha coyotes increased their rate of marking during the breeding season; beta and pup coyotes performed scent-marks at a relatively constant rate throughout the year. There was no influence of social class or time of year on the rate of defecation. The rate of double-marking was highest among alpha coyotes with a peak during the breeding season. Alpha coyotes ground-scratched at a higher rate than did beta and pup coyotes. Alpha and beta coyotes scent-marked more than expected along the periphery of the territory compared to the interior; pups marked in the interior and edge in proportion to expected frequencies. Double-marking and ground-scratching were higher than expected along the periphery of the territory. The distribution of defecations was not different from expected along the edge versus the interior of the territory. Pack size did not influence the rate of scent-marking performed by individuals in the pack or by the alpha pair. We concluded that alpha coyotes were the primary members of the resident pack involved in scent-marking. The large coyote packs and the high rate of marking by the alpha pairs were parallel to the scent-marking behaviour displayed by wolves, C. lupusto a greater extent than previously reported. Scent-marks appear to provide internal information to the members of the resident pack (internal map of territory, breeding condition, reproductive synchrony) and enhance demarcation of territorial boundaries.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour

Journal Article↗
PubMed1999

Human ZHX1: cloning, chromosomal location, and interaction with transcription factor NF-Y.

NF-YA, B, and C comprise the heterotrimeric transcription factor known as nuclear factor Y (NF-Y) or CCAAT-binding protein (CBF). NF-Y binds many CCAAT and Y box (an inverted CCAAT box, ATTGG) elements. Mutations of these elements that disrupt the binding of NF-Y result in decreased transcription from various tissue-specific and inducible promoters. We employed a yeast two-hybrid system to screen a human liver cDNA library in an effort to isolate proteins that interact with NF-Y and that may play a role in tissue-specific or hormone-inducible promoter activity. Using a fragment of the NF-YA subunit as bait we isolated a cDNA that encodes most of the open reading frame of the human zinc fingers and homeobox 1 (ZHX1) protein. The complete open reading frame was subsequently isolated and found to encode a protein of 873 amino acids that contains two zinc fingers and five homeodomain motifs. Northern blot analysis of poly(A)(+) RNA isolated from various tissues revealed two major ZHX1 transcripts of about 4.5 and 5 kilobases. Both transcripts were expressed ubiquitously, although the 5-kilobase transcript is of greater abundance in most tissues examined. The human ZHX1 gene is located on chromosome 8q, between markers CHCL.GATA50B06 and CHLC. GATA7G07.

Amino Acid Sequence↗
PubMed2002

Dynamics of a developmental switch: recursive intracellular and intranuclear redistribution of Caenorhabditis elegans POP-1 parallels Wnt-inhibited transcriptional repression.

POP-1, a Tcf/Lef factor, functions throughout Caenorhabditis elegans development as a Wnt-dependent reiterative switch to generate nonequivalent sister cells that are born by anterior-posterior cell divisions. We have observed the interaction between POP-1 and a target gene that it represses as it responds to Wnt signaling. Dynamic observations in living embryos reveal that POP-1 undergoes Wnt-dependent nucleocytoplasmic redistribution immediately following cytokinesis, explaining the differential nuclear POP-1 levels in nonequivalent sister cells. In unsignaled (anterior) but not Wnt-signaled (posterior) sister cells, POP-1 progressively coalesces into subnuclear domains during interphase, coincident with its action as a repressor. While the asymmetric distribution of POP-1 in nonequivalent sisters apparently requires a 124-amino-acid internal domain, neither the HMG box nor beta-catenin interaction domains are required. We find that a transcriptional activator, MED-1, associates in vivo with the end-1 and end-3 target genes in the mesoderm (anterior sister) and in the endoderm (posterior sister) following the asymmetric cell division that subdivides the mesendoderm. However, in the anterior sister, binding of POP-1 to the end-1 and end-3 genes blocks their expression. In vivo, binding of POP-1 to the end-1 and end-3 targets (in the posterior sister) is blocked by Wnt/MAPK signaling. Thus, a Tcf/Lef factor represses transactivation of genes in an unsignaled daughter cell by abrogating the function of a bound activator.

Animals↗
PubMed1994

The human T-cell receptor TCRAC/TCRDC (C alpha/C delta) region: organization, sequence, and evolution of 97.6 kb of DNA.

We sequenced and analyzed 97.6 kb of new DNA sequence containing the human TCRAC (C alpha) and TCRDC (C delta) genes as well as the TCRDV3 (V delta 3) and 61 different TCRAJ (J alpha) gene segments and compared its organization and structure to the previously described mouse T-cell receptor TCRAC/TCRDC (C alpha/C delta) region. A comprehensive nomenclature, consistent with the IUIS nomenclature committee recommendations, for both human and mouse TCRAJ gene segments is presented. In the human sequence, we identified 20 new TCRAJ gene segments and obtained the germline sequence for 23 additional TCRAJ gene segments known from cDNA clones. Using the sequence data obtained from the human TCRAC/TCRDC region, we have extended a polymerase chain reaction-based assay to test for the expression of the individual TCRAJ gene segments. At least five TCRAJ pseudogene segments were identified by sequence criteria. Like the murine TCRAC/TCRDC sequence, this sequence contains a high level of coding sequence, with over 6.6% of the total sequence being transcribed. Comparison of the human sequence with the previously reported mouse DNA sequence reveals homologous counterparts for the variable and joining (J) gene segments and both constant genes. Eleven new J pseudogene segments have been identified in the mouse TCRAC/TCRDC sequence through the use of human and mouse sequence comparisons. In terms of structure and organization, this region of the human and mouse genome appears to be remarkably conserved.

Amino Acid Sequence↗
PubMed2000

Visualization of subthalamic nuclei with cortex attenuated inversion recovery MR imaging.

There is a significant amount of interest in studying the thalamus because of its central location in the brain and its role as a gatekeeper to higher centers of cognition. Imaging and measuring of the individual subnuclei of the thalamus has proven extremely difficult in MR because of the contrast-to-noise (CNR) of the MR sequences used. This report describes a novel MR pulse sequence known as cortex attenuated inversion recovery (CAIR), which increases the CNR in images and allows the individual subnuclei of the thalamus to be visualized by selectively nulling the gray matter in the brain using an inversion recovery sequence with an inversion time of 700 ms at 1.5 T.

Adult↗
PubMed1995

Assessment of myocardial perfusion using contrast-enhanced MR imaging: current status and future developments.

Excellent inherent tissue contrast is one of the great promises of clinical magnetic resonance (MR) imaging, but functional information is relatively limited. However, MR imaging complemented by the administration of contrast agents can provide such functional assessment. The perfusion status of the myocardium is one of the most important functional information in cardiovascular imaging. Because the clinical acceptance of a contrast agent is measured by its ability to improve patient outcome and to guide therapy, it is unlikely that detection of myocardial infarction, the final stage of ischemic heart disease, should be the target for contrast media development. It would obviously be better if occult regional myocardial perfusion deficits could be reliably detected. The current article was prepared to help the clinical radiologist to keep pace with new strategies for myocardial enhancement and their potential clinical applicability for detection of early perfusion deficits. Several techniques for noninvasive measurement of myocardial perfusion are currently evolving which have the potential to be introduced into routine MR imaging. Most investigators favor a first-pass analysis of the contrast agent bolus through the myocardium using ultrafast sequences. However, such a technique may require clinical introduction of a blood pool agent. There are good reasons to favor T1-weighted sequences over susceptibility imaging in such first-pass studies. In the future, assessment of myocardial perfusion status using contrast-enhanced MR imaging may be done producing perfusion maps with high spatial resolution (e.g., 256 x 128), with sequences available on most scanners without special hardware requirements (e.g., IR-Turboflash, keyhole imaging), and requiring only a short period of time for examination (approximately 3 min).

Animals↗
PubMed1997

Generation of large insert yeast artificial chromosome libraries.

The development of YAC cloning technology has directly enhanced the relationship among genetic, physical, and functional mapping of genomes. Because of their large size, YACs have enabled the rapid construction of physical maps by ordered clone mapping and contig building, and they complement other molecular approaches for mapping complex genomes. Large insert libraries are constructed by size fractionating large DNA embedded in agarose and protecting DNA from degradation with polyamines.

Chromosomes, Artificial, Yeast↗
PubMed2005

Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery.

RATIONALE: In nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation. Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown. OBJECTIVES: This study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving. METHODS: Ten healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated. Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI). Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerström Test of Nicotine Dependence (FTND) and with cue-induced craving. RESULTS: Significant positive correlations between the BOLD activity and FTND scores were found in brain areas related to visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus) and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area). Intensity of cue-induced craving was significantly associated with greater BOLD activation in mesocorticolimbic areas engaged in incentive motivation and in brain regions related to episodic memory. CONCLUSIONS: Our study suggests that severity of nicotine dependence and intensity of craving are independently associated with cue-induced brain activation in separate neuronal networks. The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse.

Adult↗
PubMed1988

Identification of sequences in the long terminal repeat of avian sarcoma virus required for efficient transcription.

Two different vectors, LTR-NEO-LTR and LTR-CAT-LTR, were constructed and deletions were introduced in the upstream LTR at -299 and at -140. These deletion mutants were introduced into QT6 cells under transient expression conditions, and the levels of transcription were monitored by dot blot hybridization or by CAT assays. The results indicate that the nucleotides between -208 and -201 and between -141 and -119 in the U3 region of RSV LTR are required for efficient transcription.

Avian Sarcoma Viruses↗
PubMed1992

Isolation, characterization and chromosomal localization of the human GADD153 gene.

We report the isolation and characterization of the growth arrest and DNA-damage-inducible gene, GADD153, from human cells and show that it is localized in the region 12q13.1-q13.2 on chromosome 12. Comparison of the human gene with the previously described hamster gene revealed a high level of conservation in both the structural and regulatory regions of the genes. Each is composed of four exons with intron/exon junctions maintained at the identical positions. The human Gadd153 protein shares 91% identity with the hamster protein in amino acid sequence, and 78% identity in nucleotide sequence. A 900-bp fragment of 5' flanking sequence from the human gene, when linked to the bacterial cat reporter gene, was found to exhibit promoter activity in HeLa cells which could be further activated by treatment with the DNA alkylating agent, methyl methanesulfonate. Sequence analysis indicated that the human promoter region is relatively G+C-rich and contains putative binding sites for multiple transcription factors, including recognition sites for TATA- and CAAT-binding proteins, six Sp1-binding sites, an activator protein-1 binding site, an E-26-specific sequence-binding protein-1 DNA-binding site, and four interleukin-6 response elements. Many of these sites are also present in an identical position in the hamster gene suggesting they may play an important role in regulating GADD153 expression.

Amino Acid Sequence↗
PubMed1992

Interleukin-6 and its receptor in autoimmunity.

Interleukin-6 (IL-6) is a multifunctional cytokine which acts on a wide variety of cells, regulating immune response, acute phase reaction and hematopoiesis. In accordance with its pleiotropic functions, IL-6 is indicated to be involved in the pathogenesis of several diseases including autoimmunities, lymphoid malignancies and inflammations. An elevated level of IL-6 is demonstrated in patients with rheumatoid arthritis and cardiac myxoma, which can explain symptoms of these diseases, such as autoantibody production and increase in acute phase proteins. Therefore, inhibitors of IL-6 production or IL-6 receptor-mediated signal transduction may be used for treatment of IL-6-related diseases. The IL-6 receptor system consists of two membrane proteins, a ligand-binding chain (IL-6R) and a non-ligand-binding signal transducer, gp130, both of which belong to the cytokine receptor family. Binding of IL-6 to IL-6R triggers the association of IL-6R and gp130, and gp130 in turn transduces the signal. A nuclear factor for controlling IL-6 gene expression (NF-IL6) is also involved in the transcriptional regulation of various acute-phase protein genes. IL-6-stimulation of hepatocytes, through modification of pre-existing NF-IL6 protein, leads to binding of NF-IL6 to IL-6-responsive elements and activation of acute-phase protein genes. NF-IL6 is shown to recognize the enhancer core sequence of several viruses, suggesting a possible relationship of virus infection and IL-6 expression.

Acute-Phase Proteins↗
PubMed2004

Evolution of 8p loss in transformed human prostate epithelial cells.

Deletion or rearrangement of sequences that map to the short arm of chromosome 8 (8p) are frequently associated with human prostate tumorigenesis. These losses often involve the entire short arm of chromosome 8 or very large regions of distal or proximal 8p, and several putative tumor suppressor genes mapping to 8p have been described. However, the mechanism responsible for 8p loss during prostate tumorigenesis has not been elucidated. In this study, we report data obtained using array comparative genomic hybridization and spectral karyotyping, which demonstrate successive translocation and deletion events responsible for loss of one copy of 8p in transformed human prostate epithelial cells. Moreover, this loss was accompanied by a pronounced transcriptional downregulation of genes mapping to the remaining copy of 8p and enhanced expression of traits associated with neoplastic transformation. Taken together, these studies illustrate a potential mechanism and functional role for 8p loss in human prostate tumorigenesis.

Cell Line, Tumor↗
PubMed2003

Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways.

OBJECTIVE: Augmented atrial apoptosis, angiotensin II expression, and related signalling pathway activation have been shown in clinical atrial fibrillation (AF), but their significance is poorly understood. This study evaluated temporal relationships between changes in atrial histopathology, selected signalling mediators, and AF promotion, as well as effects of angiotensin-converting enzyme (ACE) inhibition, in a canine model of congestive heart failure (CHF). METHODS: Dogs were subjected to ventricular tachypacing (VTP) for varying periods up to 5 weeks. Apoptosis was assessed by terminal dUTP nick-end labelling (TUNEL) and DNA fragmentation. Protein expression was determined by Western blot, angiotensin II concentration by ELISA (tissue) and radioimmunoassay (plasma), and caspase-3 activity by enzymatic assay. Histopathological analyses were used to quantify fibrosis, inflammation, and cell death. RESULTS: Significant apoptosis developed 24 h after VTP onset and persisted for 1 week, returning to baseline thereafter. Apoptosis was preceded by increases in tissue (but not plasma) angiotensin II concentration; enhanced expression of phosphorylated mitogen-activated protein (MAP) kinases p38, JNK, and ERK; and augmented ratios of the proapoptotic protein Bax to the antiapoptotic protein Bcl-2. Increased cell death, leukocyte infiltration, and caspase-3 activity occurred at the time of peak apoptosis. Apoptosis was followed by interstitial fibrosis, which peaked at 5 weeks. ACE inhibition (enalapril) prevented increases in tissue angiotensin II concentration, phosphorylated ERK expression, Bax/Bcl-2 ratio, and cellular apoptosis, but did not affect total cell death, leukocyte infiltration, JNK or p38 activation, and reduced but did not eliminate tissue fibrosis. CONCLUSIONS: AF-promoting atrial structural remodeling in experimental CHF involves angiotensin II-dependent and angiotensin II-independent pathways. Significant apoptosis occurs, but prevention of apoptosis by ACE inhibition only partially prevents atrial structural remodeling.

Angiotensin II↗
PubMed2005

Butyrate, a gut-derived environmental signal, regulates tyrosine hydroxylase gene expression via a novel promoter element.

Butyrate is a diet-derived, gut fermentation product with an array of effects on cultured mammalian cells including inhibition of proliferation, induction of differentiation and regulation of gene expression. We showed that physiological concentrations of butyrate can regulate transcription of tyrosine hydroxylase (TH) and preproenkephalin (ppEnk) gene in PC12 cells. In promoter deletion studies, electrophoretic mobility shift assays and by site-directed mutagenesis, we identified a novel butyrate response element (BRE) in the 5' upstream region of the rat TH gene, homologous to the previously mapped motif in the ppEnk promoter. No such enhancers were found in DBH or PNMT promoters, and both catecholamine system-related gene promoters were unaffected by butyrate. The BRE motif interacts with nuclear proteins in a sequence-specific manner, shows binding potentiation in butyrate-differentiated PC12 cells and bound protein(s) are competed away with TH-CRE oligonucleotides or by the addition of CREB-specific antibodies, suggesting involvement of CREB or CREB-related transcription factors. Moreover, single point mutation in the distal BRE abolished binding of transcription factors and reduced the response to butyrate in transient transfection studies. The canonical CRE motif of the TH promoter was also found necessary for transcriptional activation of the TH gene by butyrate. Our data identified a novel functional element in the promoter of both the TH and ppEnk genes mediating transcriptional responses to butyrate. Dietary butyrate may have an extended role in the control of catecholamine and endogenous opioid production at the level of TH and ppEnk gene transcription neuronal plasticity, cardiovascular functions, stress adaptation and behavior.

Adrenal Medulla↗