Biology subjects

Choi, W.

Publications and source records attributed to Choi, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Sex-dependent metabolic remodeling of kidneys revealed by arteriovenous metabolomics

Sex is a fundamental biological variable important in biomedical research, drug development, clinical trials, and prevention approaches. Among many organs, kidneys are known to exhibit remarkable structural, histological, and pathological differences between sexes. However, whether and how kidneys display distinct metabolic activities between sexes is poorly understood. By developing kidney-specific arteriovenous (AV) metabolomics combined with transcriptomics, we report striking sex differences in both basal metabolic activities and adaptive metabolic remodeling of kidneys after a fat-enriched ketogenic diet (KD), a regimen known to mitigate kidney diseases and improve immunotherapy for renal cancer. At the basal state, female kidneys show highly accumulated aldosterone and various acylcarnitines. In response to the KD, aldosterone levels remain high selectively in females but the sex difference in acylcarnitines disappears. AV data revealed that, under KD, female kidneys avidly take up circulating fatty acids and release 3-hydroxybutyrate (3-HB) whereas male kidneys barely absorb fatty acids but consistently take up 3-HB. Although both male and female kidneys take up gluconeogenic substrates such as glycerol, glutamine and lactate, only female kidneys exhibit net glucose release. Kidney transcriptomics data incompletely predict these sex differences, suggesting post-transcriptional/translational regulation mechanisms. This study provides foundational insights into the sex-dependent and diet-elicited metabolic flexibility of the kidneys in vivo, serving as a unique resource for understanding variable disease prevalence and drug responses between male and female kidneys.

biochemistry↗

bioRxiv2024

MED26-enriched condensates drive erythropoiesis through modulating transcription pausing

The Mediator complex regulates various aspects of hematopoietic development, but whether composition of the Mediator complex undergoes dynamic changes for diversifying transcription and functional outputs is unknown. Here, we found that MED26, a subunit in the core Mediator complex, played a distinctive role in facilitating transcription pausing essential for erythroid development. While most Mediator subunits drastically decreased during this process, MED26 remained relatively abundant. Intriguingly, in the early stages, more than half of MED26 occupancy sites did not co-localize with MED1, a representative Mediator subunit, suggesting these subunits exert context-dependent gene regulation. We revealed that MED26-enriched loci were associated with RNA polymerase pausing. MED26 manifested a markedly preferential recruitment of pausing-related factors, leading to an increase in Pol pausing critical for genome-wide transcription repression during erythropoiesis. Moreover, MED26 exhibited pronounced condensate-forming capability, which was necessary for its function in promoting erythropoiesis and recruiting pausing-related factors. Collectively, this study provides mechanistic insights into the functional coordination of distinct Mediator subunits during development and highlights the switch of transcription condensates towards a MED26 enriched form, which modulates transcription pausing to facilitate transcription repression and erythroid development.

cell biology↗

bioRxiv2024

Loss of cell junctional components and matrix alterations drive cell desquamation and fibrotic changes in Idiopathic Pulmonary Fibrosis

The distal bronchioles in Idiopathic Pulmonary Fibrosis (IPF) exhibit histopathological abnormalities such as bronchiolization, peribronchiolar fibrosis and honeycomb cysts that contribute to the overall architectural remodeling of lung tissue seen in the disease. Here we describe an additional histopathologic finding of epithelial desquamation in patients with IPF, wherein epithelial cells detach from the basement membrane of the distal bronchioles. To understand the mechanism driving this pathology, we performed spatial transcriptomics of the epithelial cells and spatial proteomics of the basement membrane of the distal bronchioles from IPF patients and patients with no prior history of lung disease. Our findings reveal a downregulation of cell junctional components, upregulation of epithelial-mesenchymal transition signatures and dysregulated basement membrane matrix in IPF distal bronchioles, facilitating epithelial desquamation. Further, functional assays identified regulation between Collagen IV in the matrix, and the junctional genes JUP and PLEC, that is crucial for maintaining distal bronchiolar homeostasis. In IPF, this balanced regulation between matrix and cell-junctions is disrupted, leading to loss of epithelial adhesion, peribronchiolar fibrosis and epithelial desquamation. Overall, our study suggests that in IPF the interplay between the loss of cell junctions and a dysregulated matrix results in desquamation of distal bronchiolar epithelium and lung remodeling, exacerbating the disease. One Sentence SummaryTwo-way regulation of cell junctional proteins and matrix proteins drives cellular desquamation and fibrosis in the distal bronchioles of patients with Idiopathic Pulmonary Fibrosis.

pathology↗

bioRxiv2024

AIVE: accurate predictions of SARS-CoV-2 infectivity from comprehensive analysis

An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the Receptor Binding Motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in Variants of Concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 was detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.

genomics↗

bioRxiv2024

Code Multiplexed Nanocapacitor Arrays for Scalable Neural Recordings

Large scale neural recordings are redefining our understanding of the brain. However, simultaneously recording potentials from thousands of microelectrodes remains challenging. We overcome this limitation by measuring activity-induced changes in mutual capacitance. Code division multiplexing enabled simultaneous recordings of neural activity from 1,024 nanocapacitor electrodes at a density of 10k electrodes/mm.2 Features of neural activity i.e., action potentials, bursts, and local field potentials were measured in recordings, benchmarking our device against the state-of-the-art. SummaryCapacitive sensing of neural activity improves the scalability, fabrication, and miniaturization of microelectrode arrays.

neuroscience↗

bioRxiv2024

Human spinal cord activation during filling and emptying of the bladder

Recording neural activity from the spinal cord is crucial for gaining insights into how it functions. However, the neural activity of the human spinal cord is notoriously difficult to measure. The bony and fascial enclosures combined with the relatively small anatomic size of the spinal cord make it an unfavorable target for traditional functional neuroimaging techniques. Functional ultrasound imaging (fUSI) is an emerging neuroimaging technology that represents a new platform for studying large-scale neural dynamics with high sensitivity, spatial coverage and spatiotemporal resolution. Although it was originally developed for studying brain function, fUSI was recently extended for imaging the spinal cord in animals and humans. While these studies are significant, their primary focus is on the neuroactivation of the spinal cord in response to external sensory stimulations. Here, we combined fUSI with urodynamically-controlled bladder filling and emptying to characterize the hemodynamic response of the human spinal cord during the micturition cycle. Our findings provide the first practical evidence of the existence of bladder pressure-responsive regions, whose hemodynamic signal is strongly correlated with the bladder pressure.

neuroscience↗

bioRxiv2023

Immediate and Long-Term Electrophysiological Biomarkers of Antidepressant Behavioral Effects After Subanesthetic Ketamine and Medial Prefrontal Cortex Deep Brain Stimulation Treatment

1Ketamine and medial prefrontal cortex (mPFC) deep brain stimulation (DBS) are emerging depression treatments, however their mechanisms and efficacy biomarkers have not been established. This study investigates immediate and long-term mPFC electrophysiological correlates of their antidepressant effects, and explores the effects of combinatorial treatment. Local field potential electrodes were implanted into the mPFC of male Sprague Dawley rats, then corticosterone was administered for 21 days, except in the control group (n = 8). In the last week of depression induction, the remaining groups received mPFC DBS (n = 8), ketamine (n = 9), both (n = 9), or neither (n = 8). All groups then performed a behavioral assay. We found that DBS treatment immediately suppressed relative low gamma power and improved cognition in the long-term, which correlated with rescued apathy-like behavior in the Groom Test (GT). In contrast, ketamine treatment suppressed sample entropy in the long-term, which correlated with its immediate decrease in sample entropy as well as rescued GT behavior. In the combinatorial group these changes were inhibited, which correlated with a failure to fully rescue GT behavior. Despair-like behavior in the Forced Swim Test was rescued by all three treatments, which correlated with increased relative high frequency oscillation (HFO) power immediately after ketamine and combinatorial treatment. Our findings support the utility of low gamma and HFO power, sample entropy, and cognitive tests in the search for mechanisms and biomarkers of depression and novel treatments. 2 Significance StatementThere is growing interest in psychedelic pharmacological agents, such as ketamine, and direct neurostimulation techniques, like deep brain stimulation, as treatments for depression. However, their mechanisms are poorly understood, particularly those underlying their sustained benefits. Our study addresses this by correlating behavioral rescue with immediate and long-term changes in the function of the medial prefrontal cortex. These antidepressant correlates may represent therapeutically relevant functional changes, and therefore also have potential as biomarkers. Clinically, such biomarkers enable predicting and monitoring of treatment efficacy, and thereby contribute to the personalization of care. In research, utilizing these translatable biomarkers enhances the etiological validity of disease models, and enables the development of more targeted, next-generation treatment strategies.

neuroscience↗

bioRxiv2023

Comparison of image registration techniques in functional ultrasound imaging

Functional Ultrasound Imaging (fUSI) is an emerging hemodynamic-based functional neuroimaging technique that combines high spatiotemporal resolution and sensitivity, as well as extensive brain coverage, enabling a range of applications in both control and disease animal models. Based on power Doppler (pD) imaging, fUSI measures changes in cerebral blood volume (CBV) by detecting the back-scattered echoes from red blood cells moving within its field of view (FOV). However, the expansion of fUSI technology is partly limited by the challenge to co-register pD vascular maps acquired across different sessions or animals to one reference; an approach that could widen the scope of experimental paradigms and enable advanced data analysis tools. In this study, we seek to address this critical limitation. We evaluate six image registration techniques, predominantly used in other neuroimaging studies, using 2D sagittal whole-brain fUSI data from 82 anesthetized mice, and tested the quality of registration using multiple metrics. Our findings indicate a substantial enhancement in the alignment of fUSI images post registration. Among the tested techniques, the non-rigid registration algorithm Imregdeform yielded superior performance. We offer the first comparative study of image registration techniques for a 2D fUSI brain dataset, paving a way for improved utilization of fUSI in future pre-clinical research applications.

neuroscience↗

bioRxiv2023

Combined Mek inhibition and Pparg activation Eradicates Muscle Invasive Bladder cancer in a Mouse Model of BBN-induced Carcinogenesis

Bladder cancers (BCs) can be divided into 2 major subgroups displaying distinct clinical behaviors and mutational profiles: basal/squamous (BASQ) tumors that tend to be muscle invasive, and luminal/papillary (LP) tumors that are exophytic and tend to be non-invasive. Pparg is a likely driver of LP BC and has been suggested to act as a tumor suppressor in BASQ tumors, where it is likely suppressed by MEK-dependent phosphorylation. Here we tested the effects of rosiglitazone, a Pparg agonist, in a mouse model of BBN-induced muscle invasive BC. Rosiglitazone activated Pparg signaling in suprabasal epithelial layers of tumors but not in basal-most layers containing highly proliferative invasive cells, reducing proliferation but not affecting tumor survival. Addition of trametinib, a MEK inhibitor, induced Pparg signaling throughout all tumor layers, and eradicated 91% of tumors within 7-days of treatment. The 2-drug combination also activated a luminal differentiation program, reversing squamous metaplasia in the urothelium of tumor-bearing mice. Paired ATAC-RNA-seq analysis revealed that tumor apoptosis was most likely linked to down-regulation of Bcl-2 and other pro-survival genes, while the shift from BASQ to luminal differentiation was associated with activation of the retinoic acid pathway and upregulation of Kdm6a, a lysine demethylase that facilitates retinoid-signaling. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. That muscle invasive tumors are populated by basal and suprabasal cell types with different responsiveness to PPARG agonists will be an important consideration when designing new treatments.

cancer biology↗

bioRxiv2023

Machine learning assisted health viability assay for mouse embryos with artificial confocal microscopy (ACM)

The combination of a good quality embryo and proper maternal health factors promise higher chances of a successful in vitro fertilization (IVF) procedure leading to clinical pregnancy and live birth. Of these two factors, selection of a good embryo is a controllable aspect. The current gold standard in clinical practice is visual assessment of an embryo based on its morphological appearance by trained embryologists. More recently, machine learning has been incorporated into embryo selection "packages". Here, we report a machine-learning assisted embryo health assessment tool utilizing a quantitative phase imaging technique called artificial confocal microscopy (ACM). We present a label-free nucleus detection method with novel quantitative embryo health biomarkers. Two viability assessment models are presented for grading embryos into two classes: healthy/intermediate (H/I) or sick (S) class. The models achieve a weighted F1 score of 1.0 and 0.99 respectively on the in-distribution test set of 72 fixed embryos and a weighted F1 score of 0.9 and 0.95 respectively on the out-of-distribution test dataset of 19 time-instances from 8 live embryos.

bioengineering↗

bioRxiv2023

Frequency- and circuit- specific effects of septohippocampal deep brain stimulation in mice as measured by functional ultrasound imaging.

BackgroundDeep brain stimulation (DBS) has shown remarkable success in treating neurological and psychiatric disorders such as Parkinsons disease, dystonia, epilepsy, and obsessive-compulsive disorder. Despite this success, the underlying mechanism of action remains unknown. DBS is now being explored to improve functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e. schizophrenia). While DBS for movement disorders requires high-frequency continuous stimulation, there is evidence that intermittent low-frequency stimulation in neuropsychiatric conditions may have persisting cognitive benefits, necessitating a broader exploration of how DBS alters brain networks. ObjectiveWe characterize the effects of pharmacologic NMDA antagonism on the septohippocampal network and the impact of high- and low-frequency MSN DBS on cerebral blood volume (CBV) in brain structures within and outside of the septohippocampal network. MethodsIn this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice. ResultsImaging from a sagittal plane across a variety of brain regions, we find that MSN theta-frequency (7.7Hz) DBS has a larger effect on hippocampal CBV after stimulation offset. This is observed following an intraperitoneal (i.p.) injection of either saline vehicle or MK-801 (1 mg/kg). This effect is not present using standard high-frequency DBS stimulation parameters (i.e. gamma [100Hz]). ConclusionThese results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner that continues beyond the period of electrical stimulation.

neuroscience↗

bioRxiv2022

Adaptive Optical Coherent Raman Imaging of Axons through Mouse Cranial Bone

Coherent Raman scattering imaging has provided inherent chemical information of biomolecules without the need for any external labels.1-3 However, its working depth in deep-tissue imaging is extremely shallow because both the intrinsic scattering cross-section and image contrast are so small that even weak perturbation of the pump and Stokes beam focusing by the complex tissue causes the loss of the resolving power.4,5 Here, we propose a deep-tissue coherent Raman scattering (CRS) microscopy equipped with an advanced adaptive optics (AO) system measuring complex tissue aberration from elastic backscattering. Using this label-free AO-CRS microscopy, we demonstrate the vibrational imaging of lipid-rich substances such as myelin inside the mouse brain even through the thick and opaque cranial bones.

bioengineering↗

bioRxiv2022

Comparison of visual quantities in untrained deep neural networks

The ability to compare quantities of visual objects with two distinct measures, proportion and difference, is observed in newborn animals. Nevertheless, how this function originates in the brain, even before training, remains unknown. Here, we show that neuronal tuning for quantity comparison can arise spontaneously in completely untrained deep neural networks. Using a biologically inspired model neural network, we found that units selective to proportions and differences between visual quantities emerge in randomly initialized networks and that they enable the network to perform quantity comparison tasks. Further analysis shows that two distinct tunings to proportion and difference both originate from a random summation of monotonic, nonlinear responses to changes in relative quantities. Notably, we found that a slight difference in the nonlinearity profile determines the type of measure. Our results suggest that visual quantity comparisons are primitive types of functions that can emerge spontaneously in random feedforward networks. One sentence summaryThe ability to compare visual quantities arises spontaneously in untrained deep neural networks. Research HighlightsO_LIThe ability to compare visual quantity arises spontaneously in untrained networks C_LIO_LIDistinct tunings to measure proportion and difference of quantities are observed C_LIO_LIRandom wiring of monotonic, nonlinear activity induces quantity-comparison units C_LIO_LIThe nonlinearity pattern of the source unit determines the type of target measure C_LI

neuroscience↗

bioRxiv2022

A statistical genetics guide to identifying HLA alleles driving complex disease

The human leukocyte antigen (HLA) locus is associated with more human complex diseases than any other locus. In many diseases it explains more heritability than all other known loci combined. Investigators have now demonstrated the accuracy of in silico HLA imputation methods. These approaches enable rapid and accurate estimation of HLA alleles in the millions of individuals that are already genotyped on microarrays. HLA imputation has been used to define causal variation in autoimmune diseases, such as type I diabetes, and infectious diseases, such as HIV infection control. However, there are few guidelines on performing HLA imputation, association testing, and fine-mapping. Here, we present comprehensive statistical genetics guide to impute HLA alleles from genotype data. We provide detailed protocols, including standard quality control measures for input genotyping data and describe options to impute HLA alleles and amino acids including a web-based Michigan Imputation Server. We updated the HLA imputation reference panel representing global populations (African, East Asian, European and Latino) available at the Michigan Imputation Server (n = 20,349) and achived high imputation accuracy (mean dosage correlation r = 0.981). We finally offer best practice recommendations to conduct association tests in order to define the alleles, amino acids, and haplotypes affecting human traits. This protocol will be broadly applicable to the large-scale genotyping data and contribute to defining the role of HLA in human diseases across global populations.

genetics↗

bioRxiv2022

Npas4-mediated dopaminergic regulation of fear memory states

Amygdala circuitry encodes associations between conditioned stimuli and aversive unconditioned stimuli, and also controls fear expression (Pape and Pare, 2010). However, whether and how irrelevant information for unpaired conditioned stimuli (CS-) is discretely processed, and how it was influenced by stress remain unknown. CS- memory is retrievable immediately after fear conditioning, but then becomes silent after memory consolidation in mice. Synaptic pathway from the lateral to the anterior basal amygdala gates the expression of CS- memory, depending upon Npas4-mediated Drd4 synthesis. The upregulation of Npas4-Drd4 axis, which is precluded by corticosterone, shifts functional states of neural engrams for CS- memory toward silent states and limits its retrievability. In here, we demonstrate the cellular and molecular mechanisms regulating the functional states of neural engrams, which can be switched or maintained, supporting discriminative memory.

neuroscience↗

bioRxiv2022

Functional Ultrasound Imaging of the Human Spinal Cord

The integration of functional responses in the human spinal cord into the nervous system is not well understood. Herein we demonstrate the first in-human functional ultrasound imaging (fUSI) of spinal cord response to epidural electrical stimulation. fUSI is a minimally invasive neuroimaging technique that can record blood flow at a level of spatial and temporal precision not previously achieved in the human spinal cord. By leveraging fUSI and epidural electrical spinal cord stimulation in patients who underwent surgery, we recorded and characterized for the first-time hemodynamic responses of the human spinal cord to an electrical neuromodulatory intervention commonly used for treating pain, and increasingly used for sensory-motor and autonomic functions. We found that the hemodynamic response to epidural stimulation reflects a spatiotemporal modulation of the spinal cord circuitry not previously recognized. The impact of this analytical capability is significant for several reasons. It offers a mechanism to assess blood flow changes with a new level of precision which can be obtained in real time under in vivo conditions. Additionally, we demonstrate that fUSI can successfully decode the spinal cord state in a single trial, which is of fundamental importance for developing real-time closed-loop neuromodulation systems. Also, we show that spinal cord hemodynamic changes due to epidural electrical stimulation occur primarily at the level of small vessels. Overall, our work is a critical step towards developing a vital technique to study spinal cord function and understand the potential effects of clinical neuromodulation for spinal cord and other neurological disorders. One Sentence SummaryThe first in-human quantitative evaluation of spinal cord hemodynamics using functional ultrasound imaging (fUSI).

bioengineering↗

bioRxiv2022

Computational conjugate adaptive optics for longitudinal through-skull imaging of cortical myelin

We present a 1.3-m reflection matrix microscope and computational conjugate adaptive optics algorithm for label-free longitudinal imaging of cortical myelin through an intact mouse skull. The myelination processes of the same mice were observed from 3 to 10 postnatal weeks down to cortical layer 4 with a near-diffraction-limited resolution of 0.79 {micro}m. Our system will expedite the investigations on the role of myelination in learning, memory, and brain disorders.

neuroscience↗

bioRxiv2022

Characterizing dry mass and volume changes in human multiple myeloma cells upon treatment with proteotoxic and genotoxic drugs

Multiple myeloma (MM) is a cancer of terminally differentiated plasma cells. MM remains incurable, but overall survival of patients has progressively increased over the past two decades largely due to novel agents such as proteasome inhibitors (PI) and the immunomodulatory agents. While these therapies are highly effective, MM patients can be de novo resistant and acquired resistance with prolonged treatment is inevitable. There is growing interest in early, accurate identification of responsive versus non-responsive patients, however limited sample availability and need for rapid assays are limiting factors. Here, we test dry mass and volume as label-free biomarkers to monitor early response of MM cells to treatment with bortezomib, doxorubicin, and ultraviolet light. For the dry mass measurement, we use two types of phase-sensitive optical microscopy techniques: digital holographic tomography and computationally-enhanced quantitative phase microscopy. We show that human MM cell lines (RPMI8226, MM.1S, KMS20, and AMO1) increase dry mass upon bortezomib treatment. This dry mass increase after bortezomib treatment occurs as early as 1 hour for sensitive cells and 4 hours for all tested cells. We further confirm this observation using primary multiple myeloma cells derived from patients and show that a correlation exists between increase in dry mass and sensitivity to bortezomib, supporting the use of dry mass as a biomarker. The volume measurement using Coulter counter shows a more complex behavior; RPMI8226 cells increase the volume at an early stage of apoptosis, but MM.1S cells show the volume decrease typically observed with apoptotic cells. Altogether, this cell study presents complex kinetics of dry mass and volume at an early stage of apoptosis, which may serve as a basis for the detection and treatment of MM cells.

systems biology↗