The molecular mechanism by which virus induces expression of the early inflammatory genes has not yet been completely elucidated. Previous studies indicated that the virus-mediated transcription of type I interferon (IFN) genes required activation of two members of IFN regulatory factor (IRF) family, IRF-3 and IRF-7, where the expression of IRF-7 was found to be indispensable for the induction of IFNA genes. To determine the factors that regulate expression of IRF-7 gene, as well as its inducibility by type I IFNs, we have isolated and characterized the promoter and first intron of the human IRF-7 gene. This region shows a presence of two potential interferon-sensitive response elements (ISRE/ IRF-E). However, only the ISRE present in the first intron was functional and conferred interferon inducibility in a transient transfection assay. Using a pull-down assay with an oligodeoxynucleotide corresponding to this ISRE immobilized to magnetic beads, we have demonstrated that this ISRE binds ISGF3 complex and IRF-1 from the extract of IFN-treated cells but not from the untreated cells. We have further shown that the previously observed lack of expression of IRF-7 in 2fTGH fibrosarcoma cell line, correlated with hypermethylation of the CpG island in the human IRF-7 promoter. The repression of the promoter activity was relieved by treatment with DNA methyltransferase inhibitor 5-azadeoxycytidine. In vitro methylation of IRF-7 promoter silenced IRF-7 directed expression of luciferase gene in HeLa cells that express endogenous IRF-7 gene. Whether silencing of IRF-7 by methylation is instrumental for the process of tumorigenesis remains to be determined.Expression of eukaryotic genes is regulated at multiple levels including the accessibility of promoter DNA for binding of basic transcriptional machinery or the specific transcription factors and chromatin structure around the potential promoters. The molecular mechanism by which virus activates expression of the early inflammatory genes has not yet been completely elucidated. It was shown, however, that activation of the NFB family of transcription factors in infected cells plays a critical role in the transcriptional activation of many cytokine and chemokine genes, since large number of these genes contains NFB-binding sites in their promoters. Recently the importance of another family of transcription factors as the mediators of virus induced signaling has emerged. These factors designated interferon (IFN)

Cortical neurons with similar properties are grouped in columnar structures and supplied by matching vascular networks. The hemodynamic response to neuronal activation, however, is not well described on a fine spatial scale. We investigated the spatiotemporal characteristics of microvascular responses to neuronal activation in rat barrel cortex using optical intrinsic signal imaging and spectroscopy. Imaging was performed at 570 nm to provide functional maps of cerebral blood volume (CBV) changes and at 610 nm to estimate oxygenation changes. To emphasize parenchymal rather than large vessel contributions to the functional hemodynamic responses, we developed an ANOVA-based statistical analysis technique. Perfusion-based maps were compared with underlying neuroanatomy with cytochrome oxidase staining. Statistically determined CBV responses localized accurately to individually stimulated barrel columns and could resolve neighboring columns with a resolution better than 400 m. Both CBV and early oxygenation responses extended beyond anatomical boundaries of single columns, but this vascular point spread did not preclude spatial specificity. These results indicate that microvascular flow control structures providing targeted flow increases to metabolically active neuronal columns also produce finely localized changes in CBV. This spatial specificity, along with the high contrast/noise ratio, makes the CBV response an attractive mapping signal. We also found that functional oxygenation changes can achieve submillimeter specificity not only during the transient deoxygenation ("initial dip") but also during the early part of the hyperoxygenation. We, therefore, suggest that to optimize hemodynamic spatial specificity, appropriate response timing (using Յ2-3 sec changes) is more important than etiology (oxygenation or volume).

The goals of this study were to first determine whether the fractional anisotropy (FA) and mean diffusivity (MD) of major white matter pathways associate with schizophrenia, and secondly to characterize the extent to which differences in these metrics might reflect a genetic predisposition to schizophrenia. Differences in FA and MD were identified using a comprehensive atlas-based tract mapping approach using diffusion tensor imaging and high resolution structural data from 35 patients, 28 unaffected first-degree relatives of patients, 29 community controls, and 14 firstdegree relatives of controls. Schizophrenia patients had significantly higher MD in the following tracts compared to controls: the right anterior thalamic radiations, the forceps minor, the bilateral inferior fronto-occipital fasciculus (IFO), the temporal component of the left superior longitudinal fasciculus (tSLF), and the bilateral uncinate. FA showed schizophrenia effects and a linear relationship to genetic liability (represented by schizophrenia patients, first-degree relatives, and controls) for the bilateral IFO, the left inferior longitudinal fasciculus (ILF), and the left tSLF. Diffusion tensor imaging studies have previously identified white matter abnormalities in all three of these tracts in schizophrenia; however, this study is the first to identify a significant genetic liability. Thus, FA of these three tracts may serve as biomarkers for studies seeking to identify how genes influence brain structure predisposing to schizophrenia. However, differences in FA and MD in frontal and temporal white matter pathways may be additionally driven by state variables that involve processes associated with the disease.

Diffusion tensor imaging (DTI) studies have demonstrated abnormal anisotropic diffusion in schizophrenia. However, examining data with low spatial resolution and/or a low number of gradient directions and limitations associated with analysis approaches sensitive to registration confounds may have contributed to mixed findings concerning the regional specificity and direction of results. This study examined three major white matter tracts connecting lateral and medial temporal lobe regions with neocortical association regions widely implicated in systems-level functional and structural disturbances in schizophrenia. Using DTIstudio, a previously validated regions of interest tractography method was applied to 30 direction diffusion weighted imaging data collected from demographically similar schizophrenia (n=23) and healthy control subjects (n=22). The diffusion tensor was computed at each voxel after intra-subject registration of diffusion-weighted images. Three-dimensional tract reconstruction was performed using the Fiber Assignment by Continuous Tracking (FACT) algorithm. Tractography results showed reduced fractional anisotropy (FA) of the arcuate fasciculi (AF) and inferior longitudinal fasciculi (ILF) in patients compared to controls. FA changes within the right ILF were negatively correlated with measures of thought disturbance. Reduced volume of the left AF was also observed in patients. These results, which avoid registration issues associated with voxel-based analyses of DTI data, support that fiber pathways connecting lateral and medial temporal lobe regions with neocortical regions are compromised in schizophrenia. Disruptions of connectivity within these pathways may potentially contribute to the disturbances of memory, language, and social cognitive processing that characterize the disorder.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is caused by mutations in the ROBO3 gene, critical for the crossing of long ascending medial lemniscal and descending corticospinal tracts in the medulla. Diffusion tensor imaging in a patient with HGGPS revealed the absence of major pontine crossing fiber tracts and no decussation of the superior cerebellar peduncles. Mutations in the ROBO3 gene lead to a widespread lack of crossing fibers throughout the brainstem.