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Results for “Enhancer mapping”

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At least 1,153 records · Page 64Linked to original sources

PubMed2005

Quantitative T(1rho) and adiabatic Carr-Purcell T2 magnetic resonance imaging of human occipital lobe at 4 T.

The feasibility of performing quantitative T(1rho) MRI in human brain at 4 T is shown. T(1rho) values obtained from five volunteers were compared with T2 and adiabatic Carr-Purcell (CP) T2 values. Measured relaxation time constants increased in order from T2, CP-T2, T(1rho) both in white and gray matter, demonstrating differential sensitivities of these methods to dipolar interactions and/or proton exchange and diffusion in local microscopic field gradients, which are so-called dynamic averaging (DA) processes. In occipital lobe, all relaxation time constants were found to be higher in white matter than in gray matter, demonstrating contrast denoted as an "inverse transverse relaxation contrast." This contrast persisted despite changing the delay between refocusing pulses or changing the magnitude of the spin-lock field strength, which suggests that it does not originate from DA, as might be induced by the presence of Fe, but rather is related to dipolar interactions in the brain tissue.

Adipose Tissue↗

PubMed2006

Gradient and stimulated echo (GRASTE) imaging.

As a modification of single-shot stimulated echo acquisition mode (STEAM) MRI, a gradient and stimulated echo (GRASTE) sequence is presented that acquires multiple gradient echoes in addition to each stimulated echo. While "contiguous" GRASTE exploits all stimulated echoes for the central part of k-space and the gradient echoes for outer lines, "interleaved" GRASTE assigns all echoes of a particular readout interval to directly neighboring lines. Phase distortions may be corrected by the reference signals of a single readout interval without phase encoding. Experimental results obtained for the human brain demonstrate that contiguous GRASTE yields up to 30% better SNR per acquisition time than conventional single-shot STEAM due to a better efficiency and maintains most of its robustness. Interleaved GRASTE can improve the SNR by a factor of 2 because of the possibility of using larger flip angles in the readout interval. However, its more pronounced sensitivity to off-resonance effects requires short echo trains.

Brain Mapping↗

PubMed2006

Fast-kz three-dimensional tailored radiofrequency pulse for reduced B1 inhomogeneity.

This article presents a small-flip-angle, three-dimensional tailored RF pulse that excites thin slices with an adjustable quadratic in-plane spatial variation. The quadratic spatial variation helps to compensate for the loss in image uniformity using a volume coil at 3 T due to the wavelike properties of the RF field. The pulse is based on a novel "fast-kz" design that uses a series of slice-select subpulses along kz and phase encoding "blips" along kx-ky. The method is demonstrated by acquiring a series of 5-mm-thick T2-weighted images of the human brain at 3 T using pulses 4.8 ms in length with a 45 degrees flip angle.

Brain Mapping↗

PubMed2006

Direct parallel image reconstructions for spiral trajectories using GRAPPA.

The use of spiral trajectories is an efficient way to cover a desired k-space partition in magnetic resonance imaging (MRI). Compared to conventional Cartesian k-space sampling, it allows faster acquisitions and results in a slight reduction of the high gradient demand in fast dynamic scans, such as in functional MRI (fMRI). However, spiral images are more susceptible to off-resonance effects that cause blurring artifacts and distortions of the point-spread function (PSF), and thereby degrade the image quality. Since off-resonance effects scale with the readout duration, the respective artifacts can be reduced by shortening the readout trajectory. Multishot experiments represent one approach to reduce these artifacts in spiral imaging, but result in longer scan times and potentially increased flow and motion artifacts. Parallel imaging methods are another promising approach to improve image quality through an increase in the acquisition speed. However, non-Cartesian parallel image reconstructions are known to be computationally time-consuming, which is prohibitive for clinical applications. In this study a new and fast approach for parallel image reconstructions for spiral imaging based on the generalized autocalibrating partially parallel acquisitions (GRAPPA) methodology is presented. With this approach the computational burden is reduced such that it becomes comparable to that needed in accelerated Cartesian procedures. The respective spiral images with two- to eightfold acceleration clearly benefit from the advantages of parallel imaging, such as enabling parallel MRI single-shot spiral imaging with the off-resonance behavior of multishot acquisitions.

Algorithms↗

PubMed2006

Optimal acquisition schemes for in vivo quantitative magnetization transfer MRI.

This paper uses the theory of Cramer-Rao lower bounds (CRLB) to obtain optimal acquisition schemes for in vivo quantitative magnetization transfer (MT) imaging, although the method is generally applicable to any multiparametric MRI technique. Quantitative MT fits a two-pool model to data collected at different sampling points or settings of amplitude and offset frequency in the MT saturation pulses. Here we use simple objective functions based on the CRLB to optimize sampling strategies for multiple parameters simultaneously, and use simulated annealing to minimize these objective functions with respect to the sampling configuration. Experiments compare optimal schemes derived for quantitative MT in the human white matter (WM) at 1.5T with previously published schemes using both synthetic and human-brain data. Results show large reductions in error of the fitted parameters with the new schemes, which greatly increases the clinical potential of in vivo quantitative MT. Since the sampling-scheme optimization requires specific settings of the MT parameters, we also show that the optimum schemes are robust to these settings within the range of MT parameters observed in the brain.

Adult↗

PubMed2006

Accelerated parallel imaging for functional imaging of the human brain.

Accelerated parallel imaging (PI) techniques have recently been applied to functional imaging experiments of the human brain in order to improve the performance of commonly used single-shot techniques like echo-planar imaging (EPI). Potential benefits of PI-fMRI include the reduction of geometrical distortions due to off-resonance signals, the reduction of signal-loss in areas with substantial signal inhomogeneity, increases of the spatial and temporal resolution of the fMRI experiment and reduction of gradient acoustic noise. Although PI generally leads to a substantial decrease in image signal-to-noise ratio (SNR), its effect on the temporal stability of the signal, which ultimately determines fMRI performance, is only partially determined by image SNR. Therefore, the penalty for using PI is generally not as severe as the SNR reduction. The majority of problems related to single-shot techniques become more severe at an increased magnetic field strength, making PI an important tool in achieving the full potential of fMRI at high field.

Algorithms↗

PubMed2000

Mercury distribution in the squirrel monkey retina after in Utero exposure to mercury vapor.

Pregnant squirrel monkeys were exposed to mercury vapor during approximately 2/3 of a pregnancy, at a concentration of 0.5 or 1 mg Hg/m(3) air for 4 or 7 h a day, 5 days a week. The offspring were sacrificed at different ages (gestational week 16 to 5 years). The eyes were enucleated and horizontal sections of the retina, comprising the optic disc and the fovea, were processed for autometallographic (AMG) silver enhancement. The AMG mercury distribution was mapped using light and epipolarization microscopy. In young offspring (16-week-old fetus to 3 days old), mercury was detected mainly in the optic nerve, retinal pigment epithelium, inner plexiform layer, vessel walls, and ganglion cells. Three and a half months later, the amount of visualized mercury had decreased in all areas except for the retinal pigment epithelium. In adult monkeys that had survived for 2 to 5 years, only a faint AMG staining was seen in the retinal pigment epithelium, the optic nerve, and in some vessel walls. In conclusion, in offspring sacrificed in utero or shortly after birth, the structures accumulating mercury were the same as those which accumulate mercury following direct exposure through the lungs, as reported previously (K. Warfvinge and A. Bruun, 1996, Toxicology 107, 189-200), although the amount of AMG staining was less in transplacental animals. This demonstrates that inorganic mercury penetrates the blood-retina barrier. In monkeys that had survived 3 to 5 years, only tiny amounts of mercury were detected, which is in contrast to findings from direct exposure, in which large amounts were still found 3 years after exposure. This may suggest that the elimination process in the retina is more efficient in young animals, but a possible adverse effect of mercury on retinal development cannot be ruled out.

Animals↗

PubMed1999

A direct comparison between whole-brain PET and BOLD fMRI measurements of single-subject activation response.

We present the results of a direct comparison of single-subject activation using identical tasks for both functional PET and fMRI whole-brain studies. We examined the most commonly employed methods for each modality. For fMRI this is the blood oxygenation level-dependent (BOLD) contrast method with echo-planar imaging. In PET single-subject activation studies are based on the development of high sensitivity 3D imaging of regional cerebral blood flow from multiple [15O]water injections. The identical activation paradigm of a visually cued sequential finger opposition was used for PET and fMRI. For both modalities the entire brain volume difference images were smoothed to the same final resolution and the peak t value within the primary sensory/motor (PSM) area was then identified. All contiguous voxels in the PSM above a predetermined threshold of statistical significance were determined. Finally, the difference-weighted centroid location was calculated for the PSM region for each modality. These studies showed a very similar pattern of activation, with the volume of activation greater in fMRI and higher levels of statistical significance. The centroids of activation, however, differed by 9 +/- 3 mm between the modalities, with the fMRI centroid location dorsal to that for PET. These results were stable across all processing options including differing levels of image smoothing and thresholds of statistical significance. These results are consistent with the hypothesis that draining veins contribute a substantial signal for fMRI activation studies and indicate caution for the interpretation of BOLD fMRI images with activation sites near draining veins.

Adult↗

PubMed2001

Spatial heterogeneity of the nonlinear dynamics in the FMRI BOLD response.

Recent studies of blood oxygenation level dependent (BOLD) signal responses averaged over a region of interest have demonstrated that the response is nonlinear with respect to stimulus duration. Specifically, shorter duration stimuli produce signal changes larger than expected from a linear system. The focus of this study is to characterize the spatial heterogeneity of this nonlinear effect. A series of MR images of the visual and motor cortexes were acquired during visual stimulation and finger tapping, respectively, at five different stimulus durations (SD). The nonlinearity was assessed by fitting ideal linear responses to the responses at each SD. This amplitude, which is constant for different SD in a linear system, was normalized by the amplitude of the response to a blocked design, thus describing the amount by which the stimulus is larger than predicted from a linear extrapolation of the response to the long duration stimulus. The amplitude of the BOLD response showed a nonlinear behavior that varied considerably and consistently over space, ranging from almost linear to 10 times larger than a linear prediction at short SD. In the motor cortex different nonlinear behavior was found in the primary and supplementary motor cortexes.

Adult↗

PubMed1998

Positive and negative roles of the tyrosine kinase Lyn in B cell function.

The function of Lyn in B cell activation has been studied recently by examining the properties of B cells from mice in which the lyn gene has been inactivated by gene targeting. These mice show evidence of B cell hyperreactivity in vivo, as the number of B lymphoblastoid cells greatly increase with age, IgM levels increase by 10-fold or more, and auto-antibodies to double-stranded DNA and other nuclear antigens become apparent. B cells from lyn -/- mice also exhibit enhanced BCR-induced activation of MAP kinases, intracellular calcium elevation and proliferative responses in vitro. These phenomena may relate to participation of Lyn in events that serve to decrease B cell responses to antigen. Among the leading candidates for these suppressive events are the inhibition of B cell antigen receptor function by Fc gamma RIIb1 and by CD22. Although Lyn also participates positively in the initial events of B cell antigen receptor signal transduction, this function can also be supplied by other tyrosine kinases, presumably other Src-family kinases. In contrast, some aspects of inhibition by CD22 appear to be almost completely dependent upon Lyn and Fc gamma RIIb1 inhibition is also diminished in the absence of Lyn. Thus, the net effect of Lyn action is negative rather than positive for B cell activation.

Animals↗

PubMed2005

Simultaneous registration and segmentation of anatomical structures from brain MRI.

In this paper, we present a novel variational formulation of the registration assisted image segmentation problem which leads to solving a coupled set of nonlinear PDEs that are solved using efficient numerical schemes. Our work is a departure from earlier methods in that we have a unified variational principle wherein non-rigid registration and segmentation are simultaneously achieved; unlike previous methods of solution for this problem, our algorithm can accommodate for image pairs having very distinct intensity distributions. We present examples of performance of our algorithm on synthetic and real data sets along with quantitative accuracy estimates of the registration.

Algorithms↗

PubMed1997

Alpha2-adrenoceptors in opossum kidney cells couple to stimulation of mitogen-activated protein kinase independently of adenylyl cyclase inhibition.

We have compared the effects of adrenaline on activation of mitogen-activated protein kinase (MAP kinase), cyclic AMP accumulation and [3H]thymidine uptake in OK cells, a cell line derived from proximal tubules of the opossum kidney. Effects of serotonin and the direct protein kinase C activator, phorbol-12-myristate-13-acetate (PMA), were also studied. Adrenaline transiently (peak at 5 min, return to baseline by 30 min) and concentration-dependently (EC50 between 10 and 100 nM) stimulated MAP kinase activity. Maximal stimulation was approximately 100% above basal and was similar to the effects of 1 microM serotonin or 1 microM PMA. MAP kinase activation by adrenaline was inhibited by 10 microM phentolamine or 1 microM yohimbine but not significantly affected by 100 nM prazosin or 200 nM pindolol. The selective alpha2-adrenoceptor agonist UK 14,304 (10 microM) also stimulated MAP kinase activity. Activation of the 42 and 44 kDa ERK forms of MAP kinase was demonstrated by immunoblot analysis. The effect of adrenaline and UK 14,304 on MAP kinase was inhibited by pertussis toxin pretreatment and by the MAP kinase kinase inhibitor, PD 98059 (100 microM). Stimulation of MAP kinase activity was independent of cellular cAMP levels and was not affected by protein kinase C downregulation. Adrenaline, UK 14,304, serotonin, and PMA stimulated [3H]thymidine uptake, an effect inhibited by PD 98059. We conclude that adrenaline stimulates MAP kinase activity in OK-cells via alpha2-adrenoceptors and pertussis sensitive G proteins. While this occurs independently of cellular cAMP levels and protein kinase C, it involves the MEKI form of MAP kinase kinase and the ERK forms of MAP kinase. This activation results in enhanced cellular proliferation as assessed by [3H]thymidine uptake.

Adenylate Cyclase Toxin↗

PubMed2005

[Methodological principles for optimising functional MR experiments].

Functional magnetic resonance imaging (fMRI) is one of the most common methods for localising neuronal activity in the brain. Even though the sensitivity of fMRI is comparatively low, the optimisation of certain experimental parameters allows obtaining reliable results. In this article, approaches for optimising the experimental design, imaging parameters and analytic strategies will be discussed. Clinical neuroscientists and interested physicians will receive practical rules of thumb for improving the efficiency of brain imaging experiments.

Algorithms↗

PubMed1999

Tetramethylpyradizine prevents inducible NO synthase expression and improves survival in rodent models of endotoxic shock.

This study is to investigate the possible mechanism of beneficial effects of tetramethylpyrazine (TMP) on endotoxic shock which we showed in our preliminary study (Liao et al. 1998; Proc Natl Sci Counc Repub China B 22:46-54). Here, we have confirmed the beneficial effects of TMP on the hypotension, vascular hyporeactivity to noradrenaline (NA), release of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). In addition, we further examined the expression of inducible NO synthase in the lung and in the aorta from these rats and evaluated the effect of TMP on the 36-h survival rate in a murine model of endotoxaemia. Male Wistar-Kyoto rats were anaesthetised and instrumented for the measurement of mean arterial pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg(-1), i.v.) resulted in an acute fall followed by a substantial fall in MAP within 4 h and an increase in HR. In contrast, animals pretreated with TMP (10 mg kg(-1), i.p.; at 30 min prior to LPS) maintained a significantly higher MAP but the tachycardia was further enhanced at 1-2 h when compared to rats given only LPS (LPS rats). The pressor effect of NA (1 microg kg(-1), i.v.) was also significantly reduced after the treatment of rats with LPS. Similarly, the thoracic aorta obtained from rats at 4 h after LPS showed a significant reduction in the contractile responses elicited by NA (1 microM). Pretreatment of LPS rats with TMP partially, but significantly, prevented this LPS-induced hyporeactivity to NA in vivo and ex vivo. The injection of LPS resulted in a bell-shaped change in plasma TNF-alpha level which reached a maximum at 1 h, whereas the effect of LPS on the plasma level of nitrate (an indicator of NO formation) was increased in a time-dependent manner. This increment of both TNF-alpha and nitrate levels was significantly reduced in LPS rats pretreated with TMP. Endotoxaemia for 4 h caused a significantly increased protein expression of iNOS in the lung and the aorta. In LPS rats pretreated with TMP, iNOS protein expression in lung and aorta homogenates was attenuated by 75+/-3% and 57+/-6%, respectively. In addition, the lack of evidence of pressor effect of TMP on rats with endotoxaemia for 4 h suggested that TMP inhibits the induction of iNOS rather than directly inhibiting NOS activity. Treatment of conscious ICR mice with a high dose of endotoxin (60 mg kg(-1), i.p.) resulted in a survival rate of only 15% at 36 h (n=20). However, therapeutic application of TMP (10 mg kg(-1), i.p.; at 0, 6, 15 and 24 h after LPS) increased the 36 h survival rate to 55% (n=20). Thus, TMP inhibits the expression of iNOS and mitigates the delayed circulatory failure caused by endotoxic shock in the rat. In addition, TMP also improves survival in a murine model of severe endotoxaemia.

Animals↗

PubMed2003

Spectrally driven classification of high spatial resolution, hyperspectral imagery: a tool for mapping in-stream habitat.

Streams represent an essential component of functional ecosystems and serve as sensitive indicators of disturbance. Accurate mapping and monitoring of these features is therefore critical, and this study explored the potential to characterize aquatic habitat with remotely sensed data. High spatial resolution, hyperspectral imagery of the Lamar River, Wyoming, USA, was used to examine the relationship between spectrally defined classes and field-mapped habitats. Advantages of this approach included enhanced depiction of fine-scale heterogeneity and improved portrayal of gradational zones between adjacent features. Certain habitat types delineated in the field were strongly associated with specific image classes, but most included areas of diverse spectral character; spatially buffering the field map polygons strengthened this association. Canonical discriminant analysis (CDA) indicated that the ratio of the variability among groups to that within a group was an order of magnitude greater for spectrally defined image classes (20.84) than for field-mapped habitat types (1.82), suggesting that unsupervised image classification might more effectively categorize the fluvial environment. CDA results also suggested that shortwave-infrared wavelengths were valuable for distinguishing various in-stream habitats. Although hyperspectral stream classification seemed capable of identifying more features than previously recognized, the technique also suggested that the intrinsic complexity of the Lamar River would preclude its subdivision into a discrete number of classes. Establishing physically based linkages between observed spectral patterns and ecologically relevant channel characteristics will require additional research, but hyperspectral stream classification could provide novel insight into fluvial systems while emerging as a potentially powerful tool for resource management.

Ecosystem↗

PubMed2003

Clustered-charge to alanine scanning mutagenesis of the Mal63 MAL-activator C-terminal regulatory domain.

The MAL-activator genes of Saccharomyces cerevisiae encode regulatory proteins required for the expression of the structural genes encoding maltose permease and maltase. Residues within the C-terminal region of the Mal63 protein required for negative regulation were previously identified. Evidence suggested that the C-terminal domain is also involved in positive regulatory functions, such as inducer responsiveness and transactivation in the context of a full-length protein. Charged-cluster to alanine scanning mutagenesis of the regulatory domain of MAL63 and the constitutive MAL43-C were undertaken to identify distinct regions within Mal63p involved in positive functions and to define their roles in induction. Mutations that affect the ability to activate transcription in the inducible MAL63 but have no effect in the constitutive MAL43-C define regions that function in induction. Those that affect both the inducible and constitutive alleles define regions involved in activation more generally. Mutations in MAL63 fell into three classes, those that have little or no impact on activity, those that decrease activity, and those that enhance function. Mutations from these classes mapped to distinct regions of the protein, identifying a region of approximately 90 residues (residues 331-423) involved in maltose sensing and an approximately 50-residue region at the extreme C-terminus (residues 420-470) required for activation, such as the formation and/or maintenance of an active state. These studies support a model for MAL-activator function which involves complex protein-protein interactions and overlapping negative and positive regulatory regions.

Amino Acid Sequence↗

PubMed2002

Identification of a multicopy chromatin boundary element at the borders of silenced chromosomal domains.

The insulating properties required to delimit higher-order chromosomal domains have been shown to be shared by a variety of chromatin boundary elements (BEs). Boundary elements have been described in several species, from yeast to human, and we have previously reported the existence of a class of chromatin BEs in Drosophila melanogaster whose insulating activity requires the DNA-binding protein BEAF (boundary element-associated factor). Here we focus on the characterization of a moderately repeated 1.2 kb DNA sequence that encompasses boundary element 28 (BE28). We show that it directionally blocks enhancer/promoter communication in transgenic flies. This sequence contains a BEAF-binding sequence juxtaposed to an AT-rich sequence that harbors a strong nuclease-hypersensitive site. Using a combination of DNA-protein and protein blotting techniques, we found that this region is recognized by the A+T-binding D1 non-histone chromosomal protein of D. melanogaster, and we provide evidence that D1 and BEAF physically interact. In addition, the multicopy BE28 element maps to pericentric regions of the D. melanogaster 2L, 2R and X chromosome arms to which D1 has been shown to localize. In yeast, BEs that mark the periphery of silenced chromosomal domains have recently been shown to block the spreading of heterochromatin assembly. We propose that the BE28 repeat clusters could fulfill a similar function, acting as a local boundary between hetero- and euchromatin in a process involving interactions between the BEAF and D1 proteins.

AT Rich Sequence↗

PubMed2026

Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

Understanding how genetic variants influence disease risk through molecular mechanisms remains a central challenge in complex disease genetics. Nonsyndromic orofacial clefts (OFCs) exemplify this challenge, with most risk loci residing in non-coding regions. We hypothesized that common genetic variants influence OFC risk by modulating DNA methylation at regulatory elements through methylation quantitative trait loci (meQTLs). We analyzed 10 OFC-associated SNPs against genome-wide DNA methylation profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. Findings were validated using 358 cleft-discordant sibling pairs with MethyLight assays. We performed formal mediation analysis, genotype-tissue interaction and cross-referenced with the mQTL Database to assess developmental timing. Nine meQTLs were validated, including rs987525 (8q24)-cg16561172 (MYC) (P = 9.6 × 10⁻⁶), which mapped to a mesendoderm-active enhancer upstream of MYC. Genotype × tissue interaction confirmed tissue-specificity (P = 1.00 × 10- 3), with stronger effects in oral-derived tissue (saliva). Additional validated SNP-CpG associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4. While effect sizes correlated between tissues (r = 0.81), formal mediation analysis indicated individual CpG sites do not fully mediate SNP-phenotype relationships, suggesting coordinated epigenetic mechanisms. Most associations showed peak effects during childhood, while 8q24 showed unique adult-specific patterns. We identified genetic variants influencing methylation at craniofacial regulatory elements, and provided a mechanistic link for a major risk locus, 8q24, with tissue-specific effects in saliva. While individual CpG sites did not fully mediate the genetic risk, our findings identified specific regulatory regions where coordinated epigenetic changes may contribute to OFC susceptibility.

Humans↗