Biology subjects

Chang, W.-T.

Publications and source records attributed to Chang, W.-T..

10 recordsLinked to original sources

bioRxiv2026

Single-shot simultaneous BOLD and velocity-encoding MRI for functional and slow-flow imaging

Cerebrospinal fluid (CSF) motion is coupled with global blood oxygenation level-dependent (BOLD) fluctuations, but the spatial relationship between regional brain activity and CSF dynamics remains poorly understood. Here, we developed a single-shot BOLD-VENC sequence that combines gradient-echo BOLD imaging with spin-echo velocity encoding following the same RF excitation, enabling simultaneous measurement of brain-wide BOLD activity and spatially resolved slow CSF velocity at 3T. The velocity measurement was validated in a slow-flow phantom and in five healthy participants using paced-breathing, breath-holding, and visual-stimulation experiments. Phantom measurements showed strong agreement with prescribed velocities over 0.1-1.0 mm/s (R2 = 0.93-0.98). In vivo measurements demonstrated respiratory- and cardiac-dependent changes in CSF velocity magnitude and direction across the ventricles and cortical subarachnoid spaces (SAS). The established coupling between the negative derivative of the global BOLD signal and fourth-ventricle CSF inflow was reproduced, with a peak lag of 0.9 s. Global BOLD fluctuations were also coupled with spatially distributed CSF velocity changes across ventricular and cortical CSF spaces, with a similar peak lag of 1.2 s. During visual checkerboard stimulation, BOLD-CSF velocity coupling was localized primarily to the SAS surrounding the activated visual cortex, demonstrating a regional relationship between local BOLD activity and nearby CSF motion. These findings establish the feasibility of simultaneous BOLD and slow CSF velocity imaging and extend BOLD-CSF coupling from a global measure toward spatially resolved assessment of hemodynamic-CSF interactions.

neuroscience↗

bioRxiv2025

TXNDC5 Governs Extracellular Matrix Homeostasis in Pulmonary Hypertension

BACKGROUNDPulmonary hypertension (PH) is characterized by vascular remodeling without effective treatments. Thioredoxin domain containing 5 (TXNDC5), a member of the protein disulfide isomerases (PDI) family, regulates protein folding and vascular homeostasis, yet its role in PH remains unknown. METHODSLabel-free proteomics profiled protein expression in lungs from PH patients. TXNDC5 was analyzed by single-cell RNA sequencing, immunofluorescence, and Western blot. Endothelial gain- and loss-of-function approaches were applied in Sugen5416/hypoxia (SuHx)-induced rodent PH models. RNA sequencing and protein-protein interaction analysis were used to investigate underlying mechanisms. RESULTSTXNDC5 was significantly upregulated in the lungs of patients with PH and in experimental PH models, with predominant localization in endothelial cells (ECs) of remodeled distal pulmonary arteries. Endothelial TXNDC5 overexpression exacerbated pulmonary vascular remodeling, elevated right ventricular systolic pressure, and promoted right ventricular hypertrophy, whereas global or endothelial-specific TXNDC5 deficiency conferred protection against SuHx-induced PH. Hypoxia-induced factor (HIF)-2 transcriptionally activated TXNDC5 to drive PH development. Single-cell RNA sequencing identified a distinct subpopulation characterized by TXNDC5high extracellular matrix (ECM)-producing ECs. Bulk RNA sequencing combined with protein-protein interaction analysis revealed that TXNDC5 regulated ECM homeostasis through biglycan (BGN). Pharmacological inhibition of TXNDC5 with E64FC26 and endothelial-targeted TXNDC5 gene therapy significantly attenuated PH severity in rats. CONCLUSIONSOur study reveals that TXNDC5 is a main modulator to regulate ECM homeostasis and may serve as a promising target for the treatment of PH.

molecular biology↗

bioRxiv2025

SORDINO for Silent, Sensitive, Specific, and Artifact-Resisting fMRI in awake behaving mice

Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has revolutionized our understanding of the brain activity landscape, bridging circuit neuroscience in animal models with noninvasive brain mapping in humans. This immensely utilized technique, however, faces challenges such as acoustic noise, electromagnetic interference, motion artifacts, magnetic-field inhomogeneity, and limitations in sensitivity and specificity. Here, we introduce Steady-state On-the-Ramp Detection of INduction-decay with Oversampling (SORDINO), a transformative fMRI technique that addresses these challenges by maintaining a constant total gradient amplitude while acquiring data during continuously changing gradient direction. When benchmarked against conventional fMRI on a 9.4T system, SORDINO is silent, sensitive, specific, and resistant to motion and susceptibility artifacts. SORDINO offers superior compatibility with multimodal experiments and carries novel contrast mechanisms distinct from BOLD. It also enables brain-wide activity and connectivity mapping in awake, behaving mice, overcoming stress- and motion-related confounds that are among the most challenging barriers in current animal fMRI studies.

neuroscience↗

bioRxiv2024

Cell wall arabinogalactan is responsible for Fungitell(R) cross reactivity in nocardiosis

Nocardiosis is a serious infection in immunosuppressed patients, especially transplant recipients. The slow-growing phenotype of the bacterium and the variety of symptoms complicate diagnosis and delay antimicrobial therapy, which results in high mortality rates despite effective treatments. Incidentally, some nocardiosis patients test positive in fungal diagnostics that detect (1,3) {beta}-D-glucan (the Fungitell(R) assay), but the basis for this cross-reactivity remains unknown. We demonstrate that nocardial cell wall arabinogalactan is a cryptic antigen responsible for cross reactivity in the Fungitell(R) assay and that this antigen is revealed in vivo following bacterial cell lysis. We further show that the reactivity results from {beta}-glucose substitution of the galactan domain, a modification specific to Nocardia, and identify the optimal antigen as a tetramer of the trisaccharide repeating unit. By providing structural evidence for Fungitell(R) cross-reactivity during nocardiosis, this work paves the way for developing specific diagnostic tools that are presently lacking.

microbiology↗

bioRxiv2023

Enabling brain-wide mapping of directed functional connectivity at 3T via layer-dependent fMRI with draining-vein suppression

Layer-dependent functional magnetic resonance imaging (fMRI) is a promising yet challenging approach for investigating layer-specific functional connectivity (FC). Achieving a brain-wide mapping of layer-specific FC requires several technical advancements, including sub-millimeter spatial resolution, sufficient temporal resolution, functional sensitivity, global brain coverage, and high spatial specificity. Although gradient echo (GE)-based echo planar imaging (EPI) is commonly used for rapid fMRI acquisition, it faces significant challenges due to the draining-vein contamination. In this study, we addressed these limitations by integrating velocity-nulling (VN) gradients into a GE-BOLD fMRI sequence to suppress vascular signals from the vessels with fast-flowing velocity. The extravascular contamination from pial veins was mitigated using a GE-EPI sequence at 3T rather than 7T, combined with phase regression methods. Additionally, we incorporated advanced techniques, including simultaneous multi-slice (SMS) acceleration and NOise Reduction with DIstribution Corrected principal component analysis (NORDIC PCA) denoising, to improve temporal resolution, spatial coverage, and signal sensitivity. This resulted in a VN fMRI sequence with 0.9-mm isotropic spatial resolution, a repetition time (TR) of 4 seconds, and brain-wide coverage. The VN gradient strength was determined based on results from a button-pressing task. Using resting-state data, we validated layer-specific FC through seed-based analyses, identifying distinct connectivity patterns in the superficial and deep layers of the primary motor cortex (M1), with significant inter-layer differences. Further analyses with a seed in the primary sensory cortex (S1) demonstrated the reliability of the method. Brain-wide layer-dependent FC analyses yielded results consistent with prior literature, reinforcing the efficacy of VN fMRI in resolving layer-specific functional connectivity. Given the widespread availability of 3T scanners, this technical advancement has the potential for significant impact across multiple domains of neuroscience research.

neuroscience↗

bioRxiv2023

Microbially Driven Reversible Actuation and Color Changing Materials

A common feature of natural living systems that is underexplored in the field of engineered living materials (ELMs) is macroscale mechanical actuation, as driven by active cellular processes. Here we demonstrate an ELM wherein Escherichia coli drives the reversible swelling and de-swelling actuation of a pH-responsive hydrogel by producing or consuming acidic metabolites. We covalently incorporated a novel synthetic pH indicator dye into the hydrogel network that complements the hydrogel actuation with coordinated color change. Acid production or consumption is controlled by media composition and multiple hydrogel form factors are explored. This approach represents a new form of biologically driven actuation that could be compatible with a range of responsive hydrogel applications.

bioengineering↗

bioRxiv2020

Brain-wide functional networks associated with anatomically- and functionally-defined hippocampal subfields using ultrahigh-resolution fMRI

The hippocampus is critical for learning and memory and may be separated into anatomically-defined hippocampal subfields (aHPSFs). Many studies have shown that aHPSFs, and their respective functional networks, are differentially vulnerable to a variety of disorders. Hippocampal functional networks, particularly during resting state, are generally analyzed using aHPSFs as seed regions, with the underlying assumption that the function within a subfield is homogeneous, yet heterogeneous between subfields. However, several prior studies that have utilized aHPSFs and assessed brain-wide cortical connectivity have observed similar resting-state functional connectivity profiles between aHPSFs. Alternatively, data-driven approaches offer a means to investigate hippocampal functional organization without a priori assumptions. However, insufficient spatial resolution may lead to partial volume effects at the boundaries of hippocampal subfields, resulting in a number of caveats concerning the reliability of the results. Hence, we developed a functional Magnetic Resonance Imaging (fMRI) sequence on a 7T MR scanner achieving 0.94 mm isotropic resolution with a TR of 2s and brain-wide coverage to 1) investigate whether hippocampal functional segmentation with ultrahigh-resolution data demonstrate similar anatomical, lamellar structures in the hippocampus, and 2) define and compare the brain-wide FC associated with fine-grained aHPSFs and functionally-defined hippocampal subfields (fHPSFs). Using a spatially restricted hippocampal Independent Component Analysis (ICA) approach, this study showed that fHPSFs were arranged along the longitudinal axis of the hippocampus that were not comparable to the lamellar structures of aHPSFs. Contrary to the anatomically defined hippocampal subfields which are bilaterally symmetrical, 13 out of 20 fHPSFs were unilateral. For brain-wide FC, the fHPSFs rather than aHPSFs revealed that a number of fHPSFs connected specifically with some of the functional networks. The visual and sensorimotor networks preferentially connected with different portions of CA1, CA3 and CA4/DG. The DMN was also found to connect more extensively with posterior subfields rather than anterior subfields. Finally, the frontoparietal network (FPN) was anticorrelated with the head portion of CA1. The investigation of functional networks associated with the fHPSFs may enhance the sensitivity of biomarkers for a range of neurological disorders, as network-based approaches take into account disease-related alterations in brain-wide interconnections rather than measuring the regional changes of hippocampus.

neuroscience↗

bioRxiv2020

Mutant glucocorticoid receptor binding elements on Interleukin-6 promoter regulate dexamethasone effects

Glucocorticoid has been widely used as an important modulator for clinical infectious and inflammatory disease. Glucocorticoid receptor (GR) is a transcription factor belonging to the family of nuclear receptors, regulated anti-inflammatory process and the release of pro-inflammatory cytokines. Five putative GR and other transcription factor binding sites on interleukin (IL)-6 promoter were identified and dexamethasone could reduce LPS-induced IL-6 release. Among them, the mutant transcriptional factors NF-{kappa}B, AP-1, and Sp1-2 site decreased the basal and effects of lipopolysaccharide (LPS)-induced IL-6 promoter activities in different responses. GR2/3 seemed to be an important role in both basal and inducible promoter activities in LPS-induced inflammation. We concluded that the selective GR2/3 modulators may have agonistic and antagonistic combined effects and activate important signaling pathway during LPS-stimulated inflammatory process.

immunology↗

bioRxiv2019

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

neuroscience↗

bioRxiv2017

Drug discovery to counteract antinociceptive tolerance with mu-opioid receptor endocytosis

Morphine antinociceptive tolerance is highly correlated with its poor ability to promote mu-opioid- receptor (MOR) endocytosis. Our objective was to discover a novel positive allosteric modulator of MOR to enhance morphine-induced MOR endocytosis. We used high-throughput screening to identify several cardiotonic steroids as positive allosteric modulators of morphine-induced MOR endocytosis having high potency and efficacy, independently of Na+/K+-ATPase inhibition. Convallatoxin was found to enhance morphine-induced MOR endocytosis through an adaptor protein 2/clathrin-dependent mechanism without regulating G protein- or {beta}-arrestin-mediated pathways. Both F243 and I292 residues of MOR were essential to the effect of convallatoxin on MOR endocytosis. Co-treatment with chronic morphine and convallatoxin reduced morphine tolerance in animal models of acute thermal pain and chronic inflammatory pain. Acute convallatoxin administration reversed morphine tolerance in morphine-tolerant mice. These findings suggest that cardiotonic steroids are potentially therapeutic for morphine side effects and open a new avenue for the study of MOR trafficking.

neuroscience↗