Biomedical subjects

Xiaoping Hu

Publications and source records attributed to Xiaoping Hu.

At least 19 recordsLinked to original sources

PubMed2025

A First-in-Class Chemical-Induced Proximity System Achieves Dose-Dependent Control of Tumor Protein P53 Gene Activation in Preclinical Models of Gastric Cancer.

The tumor protein P53 (TP53) gene has long been studied in cancer research with genomic and epigenetic aberrations playing a driving role in cancer pathology, yet even after decades of work, only a few methods have been developed to specifically target TP53 therapeutically. Some cancers are driven by loss-of-function TP53 mutations, while others have wild-type TP53 in a transcriptionally repressed state; the latter is exploitable by advances in epigenome editing. In our previous work, we demonstrated that deactivated CRISPR/Cas9 systems (dCas9), combined with an FK-506-binding protein (FKBP) recruitment protein tag and chemical epigenetic modifier (CEM) small molecules, can elicit gene-specific changes in expression in a dose-dependent manner. Here, we describe the development, application, and characterization of the dCas9-FKBP-CEM technology to increase TP53 expression. We demonstrate that catalyzing increased TP53 expression via dCas9-FKBP-CEM87 induced apoptosis, cell cycle arrest, and tumor growth inhibition in a dose-dependent manner in preclinical models of gastric cancer.

CRISPR↗

PubMed2003

Spin-echo fMRI in humans using high spatial resolutions and high magnetic fields.

The Hahn spin-echo (HSE)-based BOLD effect at high magnetic fields is expected to provide functional images that originate exclusively from the microvasculature. The blood contribution that dominates HSE BOLD contrast at low magnetic fields (e.g., 1.5 T), and degrades specificity, is highly attenuated at high fields because the apparent T(2) of venous blood in an HSE experiment decreases quadratically with increasing magnetic field. In contrast, the HSE BOLD contrast is believed to arise from the microvasculature and increase supralinearly with the magnetic field strength. In this work we report the results of detailed and quantitative evaluations of HSE BOLD signal changes for functional imaging in the human visual cortex at 4 and 7 T. This study used high spatial resolution, afforded by the increased signal-to-noise ratio (SNR) of higher field strengths and surface coils, to avoid partial volume effects (PVEs), and demonstrated increased contrast-to-noise ratio (CNR) and spatial specificity at the higher field strengths. The HSE BOLD signal changes induced by visual stimulation were predominantly linearly dependent on the echo time (TE). They increased in magnitude almost quadratically in going from 4 to 7 T when the blood contribution was suppressed using Stejskal-Tanner gradients that suppress signals from the blood due to its inhomogeneous flow and higher diffusion constant relative to tissue. The HSE signal changes at 7 T were modeled accurately using a vascular volume of 1.5%, in agreement with the capillary volume of gray matter. Furthermore, high-resolution acquisitions indicate that CNR increased with voxel sizes < 1 mm(3) due to diminishing white matter or cerebrospinal fluid-space vs. gray matter PVEs. It was concluded that the high-field HSE functional MRI (fMRI) signals originated largely from the capillaries, and that the magnitude of the signal changes associated with brain function reached sufficiently high levels at 7 T to make it a useful approach for mapping on the millimeter to submillimeter spatial scale.

Adult↗

PubMed2003

Microvascular BOLD contribution at 4 and 7 T in the human brain: gradient-echo and spin-echo fMRI with suppression of blood effects.

The BOLD signal consists of an intravascular (IV) and an extravascular (EV) component from both small and large vessels. Their relative contributions are dependent on field strength, imaging technique, and echo time. The IV and EV contributions were investigated in the human visual cortex at 4 and 7 T using spin-echo and gradient-echo BOLD fMRI with and without suppression of blood effects. Spin-echo acquisition suppresses EV BOLD from large veins and reflects predominantly blood T(2) changes and EV BOLD signal from small blood vessels. At a short echo time (32 ms), diffusion gradient-based suppression of blood signals resulted in a 75% and 20% decrease in spin-echo BOLD changes at 4 T and 7 T, respectively. However, at echo times (55-65 ms) approximating tissue T(2) typically used for optimal BOLD contrast, these gradients had much smaller effects at both fields, consistent with the decreasing blood T(2) with increasing field strength. Gradient-echo BOLD percent changes, with relatively long echo times at both fields, were virtually unaffected by gradients that attenuated the blood contribution because the EV BOLD surrounding both large and small vessels dominated. These results suggest that spin-echo BOLD fMRI at 4 and 7 T, with TE approximating tissue T(2), significantly reduces nonspecific mapping signals from large vessels and significantly accentuates microvasculature contributions.

Brain↗

PubMed2003

The evaluation of preprocessing choices in single-subject BOLD fMRI using NPAIRS performance metrics.

This work proposes an alternative to simulation-based receiver operating characteristic (ROC) analysis for assessment of fMRI data analysis methodologies. Specifically, we apply the rapidly developing nonparametric prediction, activation, influence, and reproducibility resampling (NPAIRS) framework to obtain cross-validation-based model performance estimates of prediction accuracy and global reproducibility for various degrees of model complexity. We rely on the concept of an analysis chain meta-model in which all parameters of the preprocessing steps along with the final statistical model are treated as estimated model parameters. Our ROC analog, then, consists of plotting prediction vs. reproducibility results as curves of model complexity for competing meta-models. Two theoretical underpinnings are crucial to utilizing this new validation technique. First, we explore the relationship between global signal-to-noise and our reproducibility estimates as derived previously. Second, we submit our model complexity curves in the prediction versus reproducibility space as reflecting classic bias-variance tradeoffs. Among the particular analysis chains considered, we found little impact in performance metrics with alignment, some benefit with temporal detrending, and greatest improvement with spatial smoothing.

Adult↗

PubMed2003

A functional MRI study of high-level cognition. II. The game of GO.

GO is a board game thought to be different from chess in many aspects, most significantly in that GO emphasizes global strategy more than local battle, a property very difficult for computer programs to emulate. To investigate the neural basis of GO, functional magnetic resonance imaging (fMRI) was used to measure brain activities of subjects engaged in playing GO. Enhanced activations were observed in many cortical areas, such as dorsal prefrontal, parietal, occipital, posterior temporal, and primary somatosensory and motor areas. Quantitative analysis indicated a modest degree of stronger activation in right parietal area than in left. This type of right hemisphere lateralization differs from the modest left hemisphere lateralization observed during chess playing.

Brain Mapping↗

PubMed2003

A functional MRI study of high-level cognition. I. The game of chess.

Chess is a game that involves many aspects of high level cognition and requires sophisticated problem solving skills. However, there is little understanding of the neural basis of chess cognition. This study employed functional magnetic resonance imaging (fMRI) to identify cortical areas that are active during the analysis of chess positions compared with a spatial task with matched visual stimuli. Bilateral activation was revealed in the superior frontal lobes, the parietal lobes, and occipital lobes. Some small areas of activation were observed unilaterally in the left hemisphere. The left hemisphere showed more activation than the right. Results are discussed in relation to a similar brain imaging study on the game Go.

Adult↗

PubMed2003

Spatial dependence of the nonlinear BOLD response at short stimulus duration.

Most functional magnetic resonance imaging studies use linear models to predict the measured response by convolution of an impulse response with the stimulus profile. Using very short visual presentation times (<2 s), deviation from the linear model in the measured BOLD data from the human brain was found for the response integral, amplitude, and width. In this study, high temporal and spatial resolution were used to quantify nonlinear effects and investigate the spatial dependence. Data at 4 Tesla showed at short stimulus duration a nonlinearity, i.e., deviation from a linear model, with an index up to 400%, whereas data at 7 Tesla exhibited a nonlinearity index up to 40%. The effect was more pronounced for response amplitude than for response area. A reduced width and sharpening of responses at shorter stimulus duration was also found. A voxel-based analysis of 7 Tesla data with 1.2 x 1.2 x 2 mm(3) resolution revealed a correlation between response onset and nonlinearity index. This suggests that the nonlinearity effects are a tissue-specific phenomenon and are likely to be more localized to the site of neuronal activity. The observed magnetic field dependence and the demonstrated nonlinearity in the response width support the hypothesis that the source of the nonlinearity at short stimulus duration has a considerable hemodynamic contribution. The nonlinearity was modeled as a "switch"-type initial hemodynamic response onset. Understanding these nonlinearities in the BOLD response is important for design and the analysis of rapid event-related fMRI experiments with brief stimulus presentations.

Brain Mapping↗

PubMed2003

A base-line survey on birth defects in Gansu province, West China.

We report a study to determine the incidence, types and rank order of congenital anomalies and related fetal and infant mortality in Gansu province in China to provide a base-line for an intervention project directed at reducing birth defects in Gansu. Forty-two communities in four counties of Gansu were randomly selected by cluster sampling, based on economic and geographical features of the province. All infants born between 1 January 2001 and 1 January 2002 (live and stillborn) were investigated in departments of gynaecology and obstetrics, in birth control centres and in facilities for women and children in county and community hospitals. The types of birth defect were classified by the diagnostic standardisation ICD-9. The overall incidence of birth defects in Gansu was 15.4/1000 births (102/6621): 6.7/1000 (44) neural tube defects, 4.7/1000 (31) low birthweight infants, 2/1000 (13) limb defects, 0.8/1000 (five) cleft lip and palate and 0.5/1000 (three) Down's syndrome. The infant mortality rate was 14.8/1000 (98), to which birth defects contributed 7.3/1000 (48). We conclude that the incidence of birth defects in Gansu is one of the highest in China, that birth defects are the leading cause of infant mortality and that neural tube defects cause most deaths.

China↗

PubMed2003

Mapping cortical areas associated with Chinese word processing using functional magnetic resonance imaging.

OBJECTIVES: To identify the cortical areas engaged during Chinese word processing using functional magnetic resonance imaging (fMRI) and to examine the reliability and reproducibility of fMRI for localization of functional areas in the human brain. METHODS: FMRI data were collected on 8 young, right-handed, native Chinese speakers during performance of Chinese synonym and homophone judgment tasks on two different clinical MRI systems (1.5 T GE Signa Horizon and 1.5 T Siemens Vision). A cross correlation analysis was used to statistically generate the activation map. RESULTS: Broca's area, Wernicke's area, bilateral extrastriate, and ventral temporal cortex were significantly activated during both the synonym and homophone activities. There was essentially no difference between results acquired on two different MRI systems. CONCLUSIONS: FMRI can be used for localizing cortical areas critical to Chinese language processing in the human brain. The results are reliable and well reproducible across different clinical MRI systems.

Adult↗

PubMed2002

Sustained negative BOLD, blood flow and oxygen consumption response and its coupling to the positive response in the human brain.

Most fMRI studies are based on the detection of a positive BOLD response (PBR). Here, we demonstrate and characterize a robust sustained negative BOLD response (NBR) in the human occipital cortex, triggered by stimulating part of the visual field. The NBR was spatially adjacent to but segregated from the PBR. It depended on the stimulus and thus on the pattern of neuronal activity. The time courses of the NBR and PBR were similar, and their amplitudes covaried both with increasing stimulus duration and increasing stimulus contrast. The NBR was associated with reductions in blood flow and with decreases in oxygen consumption. Our findings support the contribution to the NBR of (1) a significant component of reduction in neuronal activity and (2) possibly a component of hemodynamic changes independent of the local changes in neuronal activity.

Adult↗

PubMed2002

Correction of physiologically induced global off-resonance effects in dynamic echo-planar and spiral functional imaging.

In functional magnetic resonance imaging, a rapid method such as echo-planar (EPI) or spiral is used to collect a dynamic series of images. These techniques are sensitive to changes in resonance frequency which can arise from respiration and are more significant at high magnetic fields. To decrease the noise from respiration-induced phase and frequency fluctuations, a simple correction of the "dynamic off-resonance in k-space" (DORK) was developed. The correction uses phase information from the center of k-space and a navigator echo and is illustrated with dynamic scans of single-shot and segmented EPI and, for the first time, spiral imaging of the human brain at 7 T. Image noise in the respiratory spectrum was measured with an edge operator. The DORK correction significantly reduced respiration-induced noise (image shift for EPI, blurring for spiral, ghosting for segmented acquisition). While spiral imaging was found to exhibit less noise than EPI before correction, the residual noise after the DORK correction was comparable. The correction is simple to apply and can correct for other sources of frequency drift and fluctuations in dynamic imaging.

Adult↗

PubMed2002

Respiration-induced B0 fluctuations and their spatial distribution in the human brain at 7 Tesla.

In functional magnetic resonance imaging (fMRI), it is known that physiological influences such as cardiac pulsation, respiration, and brain motion can induce fluctuations in signal intensity and phase. Some of the mechanisms potentially involved in those phenomena are expected to be amplified at higher magnetic fields. This study addresses the issue of B(0) fluctuations induced by susceptibility changes during respiration attributed to movements of chest and diaphragm, and variations in the oxygen concentration. It is demonstrated that respiration-induced resonance offsets (RIROs) are significant at 7T. Data were acquired with an RF pulse (no gradients), multislice echo-planar imaging (EPI), and dynamic 3D fast low-angle shot (3D- FLASH) imaging. Three main observations summarize the experimental findings. First, in FIDs measured after a single RF pulse, a RIRO with a large amplitude was consistently detected, although the average amplitude varied between subjects from 1.45 Hz to 4 Hz. Second, in transverse EPI images obtained in the occipital lobe, the RIRO amplitude showed a monotonic increase along the z axis toward the lungs. Third, a more detailed spatial analysis with 3D-FLASH phase maps revealed that a previously published analytical model can accurately describe the spatial distribution of RIRO. Consequential apparent motions in the EPI series, as well as the implications of slice orientation for correction strategies are discussed.

Brain↗

PubMed2002

Perfusion-based high-resolution functional imaging in the human brain at 7 Tesla.

Perfusion-based MRI measures cerebral blood flow (CBF) at the capillary level and can be used for functional studies based on the tight spatial coupling between brain activity and blood flow. Obtaining functional CBF maps with high spatial resolution is a major challenge because the CBF signal is intrinsically low and the SNR is critical. In the present work, CBF-based functional imaging was performed at a considerably smaller voxel size than previously reported in humans. High-resolution CBF maps were obtained with voxel sizes as small as 0.9 x 0.9 x 1.5 mm(3) in the human brain. High sensitivity was made possible by signal-to-noise gains at the high magnetic field of 7 T and by using a novel RF combination coil design. In addition, a reduction of the field-of-view was critical to achieve 0.9-mm in-plane resolution with gradient-echo echo-planar imaging in a single shot. Functional CBF data were compared with functional BOLD data to reveal that, for CBF, large contrast- to-noise gains were obtained at high spatial resolution, indicating that the functional CBF response was more localized. High-resolution functional CBF imaging is significant for neuroscience research because it provides better localization and more specific information than BOLD for monitoring brain function.

Cerebrovascular Circulation↗

PubMed2002

High-resolution, spin-echo BOLD, and CBF fMRI at 4 and 7 T.

With growing interest in noninvasive mapping of columnar organization and other small functional structures in the brain, achieving high spatial resolution and specificity in fMRI is of critical importance. We implemented a simple method for BOLD and perfusion fMRI with high spatial resolution and specificity. Increased spatial resolution was achieved by selectively exciting a slab of interest along the phase-encoding direction for EPI, resulting in a reduced FOV and number of phase-encoding steps. Improved spatial specificity was achieved by using SE EPI acquisition at high fields, where it is predominantly sensitive to signal changes in the microvasculature. Robust SE BOLD and perfusion fMRI were obtained with a nominal in-plane resolution up to 0.5 x 0.5 mm(2) at 7 and 4 Tesla, and were highly reproducible under repeated measures. This methodology enables high-resolution and high-specificity studies of functional topography in the millimeter to submillimeter spatial scales of the human brain.

Adult↗

PubMed2002

Zoomed functional imaging in the human brain at 7 Tesla with simultaneous high spatial and high temporal resolution.

Functional neuroimaging in the human brain using noninvasive magnetic resonance methods has the potential of providing highly resolved maps of neuronal activation. Decreasing the voxel size and obtaining simultaneously high temporal resolution is a major challenge and is mainly limited by sensitivity. Here, signal-to-noise gains at high magnetic fields (7 Tesla) and an optimized surface coil setup are combined with a novel approach for zoomed functional imaging in the visual cortex. For echoplanar imaging, the acquisition time and segmentation was shortened fourfold by using a reduced field-of-view. An adiabatic outer-volume suppression method, BISTRO, was used to obliterate signal outside the area-of-interest achieving effective suppression even for inhomogeneous B1-fields. A single-shot acquisition was performed at submillimeter resolution in the human brain, while simultaneously maintaining a high temporal resolution of 125 ms. Functional studies with and without field-of-view reduction were performed. Activation and percent change maps were compared with respect to spatial extent, t values and percentage changes of the BOLD contrast. The detection of functional activation was found to be equal within the inter-series variability for the two acquisition schemes. Thus, single-trial BOLD responses were detected for the first time robustly at a 500 x 500 microm2 in plane and 250 ms temporal resolution, significantly expanding the possibilities of event-related functional imaging in the human brain. The magnetization transfer effect induced by the outer-volume suppression pulses was investigated and found to be increased during neuronal activity.

Algorithms↗

PubMed2002

Truncation artifact reduction in spectroscopic imaging using a dual-density spiral k-space trajectory.

Truncation artifacts arise in magnetic resonance spectroscopic imaging (MRSI) of the human brain due to limited coverage of k-space necessitated by low SNR of metabolite signal and limited scanning time. In proton MRSI of the head, intense extra-cranial lipid signals "bleed" into brain regions, thereby contaminating signals of metabolites therein. This work presents a data acquisition strategy for reducing truncation artifact based on extended k-space coverage achieved with a dual-SNR strategy. Using the fact that the SNR in k-space increases monotonically with sampling density, dual-SNR is achieved in an efficient manner with a dual-density spiral k-space trajectory that permits a smooth transition from high density to low density. The technique is demonstrated to be effective in reducing "bleeding" of extra-cranial lipid signals while preserving the SNR of metabolites in the brain.

Artifacts↗

PubMed2002

Node merging in Kohonen's self-organizing mapping of fMRI data.

In this paper, Kohonen's self-organizing mapping (SOM) is used as a data-driven technique for analyzing functional magnetic resonance imaging (fMRI) data. Upon the completion of an SOM analysis, a cluster merging technique, based on examining the reproducibility of the fMRI data across epochs, is utilized to merge SOM nodes whose feature vectors are sufficiently similar to one another. The resulting 'super nodes' give time course templates of potential interest. These templates can be subsequently used in traditional template-based analysis methods, such as cross-correlation analysis, yielding statistical maps and activation patterns. This technique has been demonstrated on two fMRI datasets obtained from a visually-guided motor paradigm and a visual paradigm, respectively, showing satisfactory results.

Algorithms↗

PubMed2002

Human hippocampal activation in the delayed matching- and nonmatching-to-sample memory tasks: an event-related functional MRI approach.

The delayed matching-to-sample (DMS) and delayed nonmatching-to-sample (DNMS) memory tasks are standard tools used to probe visual recognition memory in human and nonhuman primates. Previous research indicates that structures within the medial temporal lobe, including the hippocampus, make up a crucial memory circuit for successful performance on these tasks. In the present investigation, event-related functional magnetic resonance imaging was used to examine activation in the hippocampus proper during these memory tasks relative to a perceptuomotor task involving the same stimuli. The results indicate that both memory tasks elicited greater activation in the right hippocampus during the encoding phase. These findings are consistent with the work from human patients and animal studies, indicating hippocampal involvement in the DMS and DNMS tasks.

Adult↗