Biology subjects

Chan, K. L.

Publications and source records attributed to Chan, K. L..

11 recordsLinked to original sources

bioRxiv2026

Participant-specific macromolecule information improves quantification of GABA-edited spectra at 3T

Purpose: To evaluate the effects of different MM fitting strategies on gamma-aminobutyric acid (GABA) estimates using MEGA-PRESS at 3T. Methods: Thirteen healthy individuals were scanned in the parietal lobe and centrum semiovale. GABA-edited scans were performed at TE=64ms (GABA+MMs) and TE=80ms (MM-suppressed GABA). MM-edited spectra were acquired using MEGA-PRESS with an inversion pre-pulse. MM peaks at 3.0 (MM3.0), 2.05 (MM2.05), and 0.94 (MM0.94) ppm were parameterized to form five MM basis categories. Cohort-mean/individual MM basis sets were constructed with all MM peaks combined (MMtogether), or with MM2.05 fit separately from MM0.94+MM3.0 (MM2+1). Simulated-MM bases were scaled by a participant-specific MM0.94/MM3.0 amplitude-ratio estimated from 64-224 transients. Fit quality numbers (FQNs) between the five MM parameterization methods were calculated to compare fit quality. Intraclass and Pearson's correlations were calculated to assess for agreement of GABA concentrations between the MM-suppressed GABA scan and the GABA+ scan with MMs fit out. Results: GABA concentrations derived from fitting with simulated-/individual-MM bases and MM2.05 fit separately lead to good--excellent agreements and high correlations with MM-suppressed GABA concentrations. Fit quality was significantly (51--63%) worse when fit with the MMtogether methods. GABA concentrations derived from fitting with a simulated MM basis demonstrated strong agreement with MM-suppressed GABA concentrations even when estimating the MM0.94/MM3.0 amplitude-ratio from a reduced number of transients (64--112). Conclusion: A participant-specific MM basis with MM2.05 excluded/fit separately yielded accurate GABA concentrations and superior fits. An accurate estimation of the MM0.94/MM3.0 amplitude-ratio can be achieved from a short 3-minute MM scan.

bioengineering↗

bioRxiv2026

Deep Learning-Based Reconstruction: Model Comparison for Variable-Density GRAPPA 1H MRSI

Proton magnetic resonance spectroscopic imaging (1H MRSI) enables quantitative mapping of brain metabolites, but its clinical use remains limited by long acquisition time. The goal of this work to improve the applicability of high-resolution 1H FID-MRSI at 7T by enhancing GRAPPA-based acceleration through deep learning-driven k-space reconstruction. In particular, compared with conventional GRAPPA, MultiNet PyGRAPPA enables substantially higher in-plane acceleration while suppressing residual lipid aliasing and preserving metabolite map fidelity in non-lipid-suppressed MRSI. Building on the MultiNet PyGRAPPA framework, we introduce a comprehensive comparison of advanced machine-learning models for predicting missing k-space points. Multiple architectures--including multilayer perceptrons, convolutional neural networks, and several U-Net variants--were trained within a variable-density k-space undersampling scheme to support acceleration factors of R = 4, 6, and 7. The proposed U-Net model extends the MultiNet concept by leveraging nonlinear hierarchical feature extraction, thereby improving reconstruction fidelity while maintaining robustness to noise.The methods were evaluated in vivo using retrospectively undersampled 7T 1H FID-MRSI datasets from healthy volunteers and patients. Quantitative analyses demonstrate that the U-Net outperforms the original MultiNet approach, offering improved SNR retention rate, reduced lipid RMSE, and higher structural similarity of major metabolites. Metabolite maps reconstructed with the U-Net showed reduced lipid artifacts and improved anatomical consistency. In conclusion, integrating deep convolutional networks into GRAPPA-based k-space prediction provides a more reliable and higher-fidelity reconstruction pipeline. When combined with variable-density undersampling, this approach enables faster acquisition of high-resolution 1H MRSI without compromising spectral quality or metabolite quantification.

bioengineering↗

bioRxiv2026

Molecular dissection of protein complexes isolated from sections of human brain

Molecular studies of brain receptors and transporters have typically relied on recombinant systems, limiting insight into their organization in native tissue. Here, we develop nanobody-based immunoprecipitation coupled with native mass spectrometry to interrogate endogenous protein assemblies from post-mortem mouse and human brain sections. We exemplify our approach by characterizing the synaptic proteins VGluT1 and mGluR2. From a single mouse brain, we discover mGluR2/3 heterodimers, alongside mGluR2 homodimers. Considering regions of human brain heterodimeric mGluR2/3 is highly abundant in the OFC and sgACC ([~]70% and 50%, respectively) and forms regional-specific interactions with additional synaptic proteins. In a modest cohort of biobanked human tissue, associated with depression and suicide, we find increased mGluR2/3 in the OFC. Consistent with this, mice exhibit similar associations between heterodimer levels and stress-susceptibility. Overall, our approach provides a direct means for establishing molecular-behavioural links at the level of receptor organization in brain.

biochemistry↗

bioRxiv2025

Restoration of MAIT cell function in healthcare-associated bacterial infections supports recovery of carbapenem efficacy against resistant bacteria

Antimicrobial resistance (AMR) presents a major clinical challenge to patients with healthcare-associated infections (HAIs), particularly among immunocompromised individuals and patients with comoribidites, who often exhibit an impaired mucosa-associated invariant T (MAIT) cell pool. MAIT cells are innate-like T cells enriched in mucosal tissues, possess potent antibacterial activity, and restoration of their function may offer a host-directed strategy against drug-resistant pathogens. We evaluated how stimulation with cognate antigen in combination with various cytokines, modulates MAIT cell cytotoxicity and enhances carbapenem activity. Under optimal conditions, MAIT cells exhibited increased expression of antimicrobial cytolytic proteins and efficiently killed cells pulsed with MAIT cell antigen. IL-15 or IL-2 plus IL-7 were particularly effective in promoting polyfunctional cytotoxic responses. Secretomes from cytokine-stimulated MAIT cells restored the activity of imipenem against engineered E. coli expressing the clinically relevant carbapenemases blaNDM-1, blaKPC-2, and blaOXA-48, strongly reducing bacterial growth, viability, and metabolic activity. Notably, IL-2 plus IL-7 stimulation enabled expansion and functional restoration of MAIT cells from HAI patients, whose baseline MAIT cell numbers and responses were diminished. These findings demonstrate that tailored stimulation can reinvigorate MAIT cell effector function and augment antibiotic efficacy, supporting a role for MAIT cells in adjunct immunotherapeutic strategy to combat AMR in vulnerable patient populations. Category of manuscript: Research Article.

immunology↗

bioRxiv2024

Astrocyte-derived extracellular matrix proteins regulate synapse remodeling in stress-induced depression

Major depressive disorder (MDD) is a common mood condition affecting multiple brain regions and cell types. Changes in astrocyte function contribute to depressive-like behaviors. However, while neuronal mechanisms driving MDD have been studied in some detail, molecular mechanisms by which astrocytes promote depression have not been extensively explored. To uncover astrocyte contributions to MDD, we subjected male mice to chronic social defeat stress precipitated by encounters with a dominant male. Animals exposed to this treatment exhibit symptoms indicative of MDD, including reduced social interactions, anxiety, despair, and anhedonia. We then measured astrocyte translating mRNA expression changes in mice that underwent chronic social defeat and control animals using ribosome affinity purification. Bioinformatic analyses reveal significant alterations in the prefrontal cortex (PFC), consistent with previous studies implicating this brain region in MDD. Expression of genes encoding extracellular matrix (ECM) proteins, cell-cell interaction proteins, and proteins controlling glutamatergic synaptic function are significantly altered. These changes correlate with perturbation of glutamatergic transmission, measured by electrophysiology, and increased synaptic cleft size. Among ECM genes, increased expression of mRNA encoding the synaptic remodeling protein secreted protein acidic and rich in cysteine (Sparc) correlates the most with the depressive phenotype. Furthermore, presence of SPARC and other ECM proteins in synaptosomes is also increased and overexpressing Sparc in PFC partially alleviates stress symptoms. Our results raise the possibility that increased expression of Sparc may be a natural protective mechanism against stress-induced synaptic dysfunction in depression.

neuroscience↗

bioRxiv2024

ProFit-1D for quantifying J-difference edited data at 3T

Reproducible and accurate fitting of the magnetic resonance spectrum is critical for estimating metabolite concentrations. We have previously developed a fitting software called ProFit-1D which was shown to fit 9.4T semi-LASER data from the human brain with high accuracy and precision. In this study, we adapted ProFit-1D to fit J-difference edited spectra acquired at a clinical field strength of 3T and to assessed its performance in simulated and in vivo data. ProFit-1D was adapted to fit J-difference edited data with alterations to the fitting range to exclude the 1.3 ppm lipid resonance, starting T2 relaxation constants, initial fit parameters, and adaptive spectral baseline determination. The accuracy of ProFit-1D was systematically evaluated on simulated GABA-edited and 2-hydroxyglutarate-edited (2HG-edited) data with different types of in vivo parameter variations and compared to that of LCModel and Gannet, two software commonly used to fit J-difference edited data. The precision of ProFit-1D was also evaluated in GABA-edited spectra acquired in vivo in the occipital cortex (OCC) and medial prefrontal cortex (mPFC) of healthy participants at 3T using subsets of averages and compared to that of LCModel and Gannet. The 2HG fit error was also evaluated for ProFit-1D in 2HG-edited spectra acquired in glioma patients and compared to that of LCModel. Overall, it was found that ProFit-1D generally produced fits with low parameter fit errors across a variety of parameter variations. GABA, glutamate plus glutamine (Glx), and 2HG levels were also more accurately estimated with ProFit-1D than with LCModel and Gannet across different spectral disturbances and simulated concentrations. ProFit-1D was found to be as precise as LCModel and more precise than Gannet in estimating GABA and Glx. 2HG fit errors were 45% lower with ProFit-1D than with LCModel. Thus, ProFit-1D was found to produce high-quality fits to J- difference edited data with high accuracy and precision.

bioengineering↗

bioRxiv2024

Hydrolysis of palm kernel meal fibre using a newly isolated Bacillus subtilis F6 with high mannanase activity

High fibre content is the main limitation of using mannan-rich palm kernel meal (PKM) in feeding non-ruminant livestock. Microbial fermentation stands out as a cost-effective and environmentally friendly approach for hydrolysing fibre in lignocellulosic biomass. In this study, a Bacillus subtilis strain F6 with high mannanase secretion capability was isolated from an environmental source. Fermentation of PKM using strain F6 resulted in at least a 10% reduction in its neutral detergent fibre content. Notably, the strain exhibited a rapid response to PKM, with significant mannanase activity detected as early as 6 h, enabling fibre hydrolysis within a short fermentation period. Subsequent transcriptome analysis uncovered potential enzymes involved in PKM fibre degradation, and the purified recombinant enzymes were generated to assess their activity on PKM fibre degradation. {beta}-mannanase GmuG demonstrated strong hydrolysis activity of PKM fibre, and its biochemical properties were determined. Overall, the study reported the isolation of a B. subtilis strain suitable for fibre hydrolysis of mannan-rich biomass, followed by an investigation to identify and characterize the enzyme responsible for fibre degradation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/599806v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@50b8c8org.highwire.dtl.DTLVardef@1937688org.highwire.dtl.DTLVardef@4b0ab6org.highwire.dtl.DTLVardef@ac727a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Chemokine receptor 5 signaling in PFC mediates stress susceptibility in female mice

Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.

animal behavior and cognition↗

bioRxiv2021

History of winning and hierarchy landscape influence stress susceptibility in mice

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, though gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.

neuroscience↗

bioRxiv2020

Hippocampal and striatal responses during motor learning are modulated byprefrontal cortex stimulation

While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof- of-concept study employed a comprehensive multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and striatum during motor learning. Our results indicate that stimulation influenced task-related connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus.

neuroscience↗

bioRxiv2019

Black sea cucumber (Holothuria atra Jaeger, 1833) protects Caenorhabditis elegans against Pseudomonas aeruginosa infection

A strategy to circumvent the problem of multidrug resistant pathogen is consumption of functional food rich in anti-infectives targeting bacterial virulence or host immunity. The black sea cucumber (Holothuria atra) is a tropical marine sea cucumer species traditionally consumed as remedy for many ailments. There is a paucity of knowledge the anti-infectives capacity of H. atra and the underlying mechanisms involved. The objectives of this study were to utilize the Caenorhabditis elegans-P. aeruginosa infection model to assess the anti-infective properties of H. atra. We first showed the capacity of a H. atra extract and fraction in promoting survival of C. elegans during a customarily lethal P. aeruginosa infection. The same chemical entities also attenuate the production of several P. aeruginosa virulence factors and biofilm. Treatment of infected transgenic lys-7::GFP worms with H. atra fraction restored the repressed expression of lys-7, a defense enzyme, indicating improved host immunity. QTOF-LCMS analysis revealed the presence of aspidospermatidine, an indole alkaloid and inosine. Collectively, our finding shows that H. atra confers survival advantage in C. elegans against P. aeruginosa infection through inhibition of pathogen virulence and eventually, the restitution of host lys-7 expression.

pharmacology and toxicology↗