Biology subjects

Cho, C. J.

Publications and source records attributed to Cho, C. J..

6 recordsLinked to original sources

bioRxiv2026

Preferred visual experiences provide intuitive descriptions of the functional properties of the cortical navigation network

Complex, high-dimensional brain representations are often difficult to understand intuitively. Recent advances in generative neural networks have made it possible to predict the optimal stimulus that maximizes the activity in a specific brain region. Because these stimuli are in image space, they provide an intuitive understanding of the functional properties of that region. Previous work on optimized stimuli has focused on passive perceptual tasks. Yet real-world perception operates in a closed loop with cognition and action, and so passive stimuli are unlikely to be optimal for many brain regions. In a previous study, we used fMRI to record BOLD activity from participants actively navigating through a virtual world. We identified a network of 11 cortical regions that support active navigation and are tuned for complex feature combinations. Here, we used a variational autoencoder to generate video clips predicted to correspond to maximal activity in each region. These preferred visual experiences capture dynamic scenes that incorporate both world events and participant actions. These preferred visual experiences provide intuitive descriptions of the functional properties of each region, and suggest that these regions are more engaged during dynamic than static scenes. These patterns also generate novel, data-driven hypotheses for future study.

neuroscience↗

bioRxiv2026

Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism

The ability of epithelial cells to cope with injury and undergo regeneration depends on tightly coordinated cellular responses. IFRD1 is a stress-responsive protein that is evolutionarily conserved and required for the cellular regeneration program paligenosis; however, how IFRD1 works in paligenosis is not known. Here we demonstrate that IFRD1 is primarily a cytosolic ribosome-binding protein, specifically binding 80S monosomes that are not actively engaged in translation. Using multiple in vivo and in vitro injury models, including cerulein-induced pancreatitis in mice and tunicamycin-induced ER stress in cell culture, we demonstrate that IFRD1 acts as a ribosome-salvaging factor, preventing ribosomes from degradation. In the absence of IFRD1 during ER stress, non-translating 80S ribosomes were unstable and prone to disassembly and selective degradation. The resulting accumulation of degraded ribosomal subunits overwhelmed cellular autophagic machinery, as evidenced by accumulation of the autophagy-tagging protein p62, even though overall autophagic flux remained unaffected. Ultimately, cells lacking IFRD1 showed reduced mTORC1 activity followed by increased cell death, consistent with patterns observed in cells lacking IFRD1 during paligenosis. Thus, we detail a previously unrecognized cellular function for IFRD1 in stabilizing and preserving the mature ribosome pool during metabolic and translational transitions such as paligenosis.

cell biology↗

bioRxiv2024

Inhibition of Ribosome Biogenesis in vivo Causes p53-Dependent Death and p53-Independent Dysfunction

Ribosomes are critical for cell function; their synthesis (known as ribosome biogenesis; "RiBi") is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cells in vivo in adult tissue. Here, we generated mice with conditional deletion of Nat10, an essential gene for RiBi and translation, to investigate effects of RiBi blockade in vivo. We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis. We observed a surprising latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death, which was associated with translocation of ribosomal proteins RPL5 and RPL11 into acinar cell nucleoplasm. Indeed, deletion of Trp53 could rescue acinar cells from apoptotic cell death; however, Nat10{Delta}/{Delta}; Trp53{Delta}/{Delta} acinar cells remained morphologically and functionally abnormal. Moreover, the deletion of Trp53 did not rescue the lethality of inducible, globally deleted Nat10 in adult mice nor did it rescue embryonic lethality of global Nat10 deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion of Nat10 in acinar cells blocked Kras-oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translation in vivo.

cell biology↗

bioRxiv2024

A new role for IFRD1 in regulation of ER stress in bladder epithelial homeostasis

A healthy bladder requires the homeostatic maintenance of and rapid regeneration of urothelium upon stress/injury/infection. Several factors have been identified to play important roles in urothelial development, injury and disease response, however, little is known about urothelial regulation at homeostasis. Here, we identify a new role for IFRD1, a stress-induced gene that has recently been demonstrated to play a critical role in adult tissue proliferation and regeneration, in maintenance of urothelial function/ homeostasis in a mouse model. We show that the mouse bladder expresses IFRD1 at homeostasis and its loss alters the global transcriptome of the bladder with significant accumulation of cellular organelles including multivesicular bodies with undigested cargo, lysosomes and mitochondria. We demonstrate that IFRD1 interacts with several mRNA-translation-regulating factors in human urothelial cells and that the urothelium of Ifrd1-/- mice reveal decreased global translation and enhanced endoplasmic reticulum (ER) stress response. Ifrd1-/- bladders have activation of the unfolded protein response (UPR) pathway, specifically the PERK arm, with a concomitant increase in oxidative stress and spontaneous exfoliation of urothelial cells. Further, we show that such increase in cell shedding is associated with a compensatory proliferation of the basal cells but impaired regeneration of superficial cells. Finally, we show that upon loss of IFRD1, mice display aberrant voiding behavior. Thus, we propose that IFRD1 is at the center of many crucial cellular pathways that work together to maintain urothelial homeostasis, highlighting its importance as a target for diagnosis and/or therapy in bladder conditions.

cell biology↗

bioRxiv2021

Expression of fatty acyl-CoA ligase drives one-pot de novo synthesis of membrane-bound vesicles in a cell free transcription-translation system

Despite the central importance of lipid membranes in cellular organization, it is challenging to reconstitute their de novo formation from minimal chemical and biological elements. Here we describe a chemoenzymatic route to membrane-forming non-canonical phospholipids in which cysteine-modified lysolipids undergo spontaneous coupling with fatty acyl-CoA thioesters generated enzymatically by a fatty acyl-CoA ligase. Due to the high efficiency of the reaction, we were able to optimize phospholipid membrane formation in a cell-free transcription-translation (TX-TL) system. Combining DNA encoding for the fatty acyl-CoA ligase with suitable lipid precursors, enabled spontaneous one-pot de novo synthesis of membrane-bound vesicles. Non-canonical sphingolipid synthesis was also possible by using a cysteine-modified lysosphingomyelin as a precursor. When the sphingomyelin-interacting protein lysenin is co-expressed alongside the acyl CoA ligase, the in situ assembled membranes were spontaneously modified with protein. Our strategy of coupling gene expression with membrane lipid synthesis in a one-pot fashion could facilitate the generation of proteoliposomes and brings us closer to the bottom-up generation of synthetic cells using recombinant synthetic biology platforms.

synthetic biology↗

bioRxiv2021

Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury

BACKGROUND & AIMSAcinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression. METHODSAcinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate upon injury. Transcripts of over 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared to gastric metaplasia, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining. RESULTSscRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison to KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype. CONCLUSIONSUnder conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. KrasG12D expression is sufficient to drive neoplasia from injury-induced ADM and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.

cell biology↗