Biology subjects

Cho, H.

Publications and source records attributed to Cho, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

APIPred Web 1.0: A Web Platform to Predict Potential Aptamer Sequences for Protein targets

Aptamers are short single-stranded nucleic acids that bind protein targets with high specificity and are increasingly used in diagnostics and therapeutics, yet experimental discovery remains slow and variable in success. This creates a demand for computational systems that not only score candidate binders but also generate experimentally usable libraries under biologically meaningful constraints. Here, we present APIPred Web 1.0, a unified web platform that integrates constraint-aware aptamer library generation, machine learning- based aptamer- protein interaction prediction, and DNA secondary-structure analysis within a user-facing workflow. Users submit a target protein aminoacid sequence and define an aptamer template in a PREFIX - [VARIABLE] - SUFFIX format with real-time validation of key biological constraints (GC content and homopolymer limits). On the backend, sequences are converted into model- compatible features via optimized k-mer encodings (aptamer) and pseudo amino acid composition (PAAC) descriptors (protein), followed by inference with a trained XGBoost predictor. APIPred Web 1.0 improves the computational efficiency by applying precomputed protein features, vectorized batch processing (hundreds of sequences per batch), optimized XGBoost DMatrix inference, and a bounded heap that retains only the top 25 candidates during generation. The platform then computes minimum free energy (MFE) structures using ViennaRNA with parallel folding and returns ranked list of the top candidates with log-transformed interaction scores, complete sequences (variable region highlighted), dot-bracket structures, MFE values, and interactive 2D visualizations via persistent result links. In a demonstration study targeting CD64 protein, the platform produced 25 putative binders from a custom 40- nucleotide library and enabled selection of structurally diverse candidates for experimental testing. Flow cytometry showed specific binding to CD64-expressing THP-1 cells with minimal signal in Ramos control cells. Collectively, APIPred Web 1.0 offers a reproducible, structure-informed, and computationally efficient pipeline for rapid generation of aptamer candidates against target proteins for downstream experimental validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=50 SRC="FIGDIR/small/697194v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1c1ca4dorg.highwire.dtl.DTLVardef@1c8b23dorg.highwire.dtl.DTLVardef@12dfe2dorg.highwire.dtl.DTLVardef@8a7c8f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Simulated drought with Polyethylene-Glycol (PEG) decreases above-ground performance and increases nodulation in the legume Medicago lupulina

Under climate change, understanding how plants and crops respond to drought is essential for basic research in ecology and evolution, and improving agricultural resilience. One common method of simulating drought in experimental conditions is by applying polyethylene glycol (PEG) to plants. We investigated drought growth responses in Medicago lupulina (black medic) using PEG to simulate drought stress. We grew Medicago lupulina plants inoculated with Sinorhizobium meliloti in Magenta boxes under controlled conditions and randomly assigned them to one of three treatments: a control, PEG applied to the bottom (PEG added to the bottom-watering container of a magenta box), or PEG applied from the top (PEG poured over the growth media). After 60 days, we measured true leaf number, nodule count, and below- and above-ground dry biomass. PEG treatments significantly reduced above-ground growth, including total biomass and leaf number, but unexpectedly increased nodulation. Our results suggest that while PEG effectively simulates drought stress on above-ground growth parameters, it may not accurately simulate drought effects on rhizobial symbiosis. PEG treatments had no effect on below-ground biomass, suggesting that increased nodulation is not a result of increased plant investment in below-ground growth under simulated drought. We hypothesize that PEG, as a persistent liquid that plants do not absorb, created conditions favorable for nodulation. Overall, these results highlight the importance of interpreting PEG-simulated drought experiments with caution when assessing mutualistic interactions.

plant biology↗

bioRxiv2025

The Human Cell Line Phosphoproteome Atlas: A Deep Empirical Resource Revealing Kinase Activity Landscapes

Protein phosphorylation orchestrates cellular signaling and controls diverse biological processes, with its dysregulation driving diseases, notably cancer. Comprehensive, high-throughput phosphoproteomics remains limited by detection sensitivity, data completeness, and computational bottlenecks, especially in low-input settings. We present the deepest empirical human phosphoproteome resource to date, regrouping over 200,000 class I phosphosites across 33 diverse human cell lines, and demonstrate that this spectral library dramatically improves single-shot phosphoproteomics with 30-fold faster data processing compared to library-free approaches and enhanced confidence in phosphosite localization even from minimal sample input. Integrating proteome and phosphoproteome data, we developed a combined kinase activity score, revealing cell line- and cancer-specific signaling vulnerabilities, many correlating with drug sensitivity. This resource accelerates deep, reproducible phosphoproteomics, enabling systematic functional mapping of cellular signaling networks, and empowers precision oncology by highlighting actionable kinase targets in diverse cell states.

biochemistry↗

bioRxiv2025

Glucocorticoid-induced proteome and phosphoproteome changes in breast cancer cell lines

Glucocorticoids (GCs) are steroid hormones that bind to glucocorticoid receptor (GR) as ligands to initiate systemic anti-inflammatory effects. GCs are commonly administered alongside chemotherapy to reduce treatment-related side effects in breast cancer patients. However, GC administration has been shown to promote metastasis in breast cancer. In this study, we used quantitative mass spectrometry-based approaches to analyze proteome and phosphoproteome of three breast cancer cell lines following GC treatments. By comparing MCF7, MDA-MB-231, and MDA-MB-436 cells, we suggest that the level of GR significantly affects GC-mediated responses. Additionally, we identify noncanonical transcription factors (TFs) and kinases that are regulated by GCs in different cell lines. Together, our data present GC-induced modulations and modifications at protein level, indicating that breast cancer metastasis occurs via TF- and kinase-dependent signaling pathways. These findings highlight the need for careful consideration of GC use in breast cancer therapy and identify potential molecular targets for mitigating adverse effects. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/690354v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1c9ff8borg.highwire.dtl.DTLVardef@a8172forg.highwire.dtl.DTLVardef@18a4b85org.highwire.dtl.DTLVardef@6413cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

NeuroTest: a benchtop testbed for evaluating sensing-capable electrophysiology and neurostimulation systems

ObjectiveThe development of increasingly complex implantable neuromodulation devices requires extensive benchtop validation and testing prior to in vivo implementation. Our goal is to enable this in vitro testing by creating a benchtop system that is accessible, easy-to-use, and functions reliably across academic and industry environments, reducing discordant results that arise from discordant approaches. Furthermore, such a system paves the way for standardizing benchtop characterization of future implantable systems by establishing a repeatable and comparable methodology for validating these devices and their capabilities. ApproachWe describe the NeuroTest Board (NTB), a low-cost, open-source device that combines a low-noise current source waveform generator with a high-precision data acquisition system. We provide information on its architecture, operation, and performance as an initial benchmark of the potential capabilities of the system. Main resultsWe demonstrate the use of the NTB to assess electrophysiology systems in two separate applications. In one case, we assess a commonly used laboratory system (the RHD2132 headstage and Open Ephys data acquisition system), while the second case characterizes an investigational neuromodulation device in development for human use (the CorTec Brain InterChange). Following this initial sensing characterization, we explore stimulation-related artifacts that would hamper in vivo data collection. With the NTB, we develop and evaluate artifact mitigation strategies for each system, thus demonstrating an example application of this benchtop testbed. SignificanceThe ability to test neuromodulation devices against a common benchmark will enable faster development of novel therapeutics by increasing inter-institutional reliability and decreasing troubleshooting time.

bioengineering↗

bioRxiv2025

Human-specific features of the cerebellum and ZP2-regulated synapse development

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

neuroscience↗

bioRxiv2025

EED Maintains the Small Cell Lung Cancer Neuroendocrine Phenotype and Drives Lung Cancer Histological Transformation

Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). While typically distinct, combined LUAD/SCLC histology tumors occur, and LUAD can transform into SCLC as a resistance mechanism to targeted therapies, especially in EGFR-Mutant LUADs with RB1/TP53-inactivation. Although PRC2 complex expression increases during this transformation, its functional role has remained unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we demonstrate that inactivation of EED, the core PRC2 scaffolding subunit, impairs SCLC tumorigenesis and drives histological transformation from ASCL1-positive SCLC to LUAD through a transient NEUROD1-positive intermediate state. Mechanistically, EED loss de-represses bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes, to promote transformation to LUAD. Consistently, these same signaling genes are bivalently repressed in human SCLC patient-derived xenograft (PDX) tumors, suggesting a conserved PRC2-dependent mechanism to repress LUAD lineage oncogenic signaling to maintain the SCLC neuroendocrine identity. In a complementary EGFR-mutant LUAD GEMM with RB1/TP53 inactivation, EED was required for LUAD-to-SCLC transformation and distant metastasis upon EGFR withdrawal. These findings identify the PRC2 complex as a key epigenetic enforcer of SCLC neuroendocrine identity and nominate EED inhibition as a potential strategy to block SCLC transformation in high-risk LUAD.

cancer biology↗

bioRxiv2025

Quantitative proteomics and phosphoproteomics reveal glucocorticoid stimulation of TLR and Rho GTPase signaling in neutrophil-like cells

BackgroundGlucocorticoids (GCs) are corticosteroid hormones that are commonly used for treating systemic inflammatory diseases and acute infections. Immunosuppressive effects of GCs have been studied in many cell types, particularly macrophages and T cells. Despite the importance and abundance of neutrophils in the human immune system, GC responses remain understudied in neutrophils. ResultsHere, we performed quantitative mass-spectrometry (MS)-based proteomics of neutrophil-like cells (NLCs) differentiated from human HL-60 promyelocyte cells. Proteome and flow cytometry analysis showed that NLCs share features of neutrophils. Quantitative proteomics and phosphoproteomics of NLCs treated with two synthetic GC compounds, the clinical drugs dexamethasone (DEX) and prednisolone (PRED), identified higher numbers of significantly regulated proteins and phosphosites compared to parental HL-60 cells. GC treatments triggered abnormal neutrophil activation and aging by promoting toll-like receptor (TLR) signaling and CXCR4 serine phosphorylation. We also identified RIPOR2 as a novel target protein of GC which stimulates Rho GTPase signaling networks and upregulates actin cytoskeletal proteins. ConclusionsOur results not only reveal unconventional regulatory mechanism of GCs in the human immune system but also provide valuable resources for discovering novel GC-responsive protein targets.

cell biology↗

bioRxiv2025

CPT1B-Mediated Fatty Acid Oxidation Induces Pigmentation in Solar Lentigo

IntroductionCellular senescence is associated with altered lipid metabolism, including increased cellular lipid uptake, upregulated lipid biosynthesis, and deregulated lipid breakdown. Previous studies have reported that carnitine palmitoyltransferase (CPT), the rate-limiting enzyme in fatty acid oxidation that catalyzes the conversion of acyl-CoA to acylcarnitine, is involved in various senescence-related diseases. Although solar lentigo (SL) is an age-related pigmentary disorder characterized by the accumulation of senescent cells, its role in metabolic dysregulation has rarely been investigated. Methods and ResultsIntegrated transcriptomic profiling of SL skin samples, combining mRNA sequencing, differential gene expression, pathway enrichment analyses, metabolic flux simulations, and protein-protein interaction analysis, was conducted to demonstrate the molecular alterations in SL compared to perilesional normal skin. We found transcriptomic alterations in mitochondrial energy metabolism-associated genes. Metabolic flux simulations revealed that carnitine-associated reactions involved in fatty acid oxidation were upregulated. Using a multi-omics approach, CPT1B was selected as a potential marker for SL, which was confirmed via its overexpression in immunohistochemical studies. Using a zebrafish model, CPT1B was implicated in melanogenesis. DiscussionCPT1B-mediated metabolic alteration is a key driver of SL pathogenesis. Targeting CPT1B and the associated lipid metabolism pathways is a novel therapeutic approach for managing SL and age-related pigmentation disorders. Research HighlightsSolar lentigo (SL) exhibits altered mitochondrial metabolism and fatty acid oxidation. CPT1B activation regulates pigmentation, suggesting that targeting CPT1B may offer a novel therapy for SL and other age-related pigmentary disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/659823v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@81fce3org.highwire.dtl.DTLVardef@1bf3forg.highwire.dtl.DTLVardef@b2c119org.highwire.dtl.DTLVardef@1a38b23_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

Study of combination CAR T-cell treatment for glioblastoma using mathematical modeling

Glioblastoma is a highly aggressive and difficult-to-treat brain cancer that resists conventional therapies. Recent advances in chimeric antigen receptor (CAR) T-cell therapy have shown promising potential for treating glioblastoma; however, achieving optimal efficacy remains challenging due to tumor antigen heterogeneity, the tumor microenvironment, and T-cell exhaustion. In this study, we developed a mathematical model of CAR T-cell therapy for glioblastoma to explore combinations of CAR T-cell treatments that take into account the spatial heterogeneity of antigen expression. Our hybrid model, created using the multicellular modeling platform PhysiCell, couples partial differential equations that describe the tumor microenvironment with agent-based models for glioblastoma and CAR T-cells. The model captures cell-to-cell interactions between the glioblastoma cells and CAR T-cells throughout treatment, focusing on three target antigens: IL-13R2, HER2, and EGFR. We analyze tumor antigen expression heterogeneity informed by expression patterns identified from human tissues and investigate patient-specific combination CAR T-cell treatment strategies. Our model demonstrates that an early intervention is the most effective approach, especially in glioblastoma tumors characterized by mixed antigen expression. However, in tissues with clustered antigen patterns, we find that sequential administration with specific CAR T-cell types can achieve efficacy comparable to simultaneous administration. In addition, spatially targeted delivery of CAR T-cells to specific tumor regions with matching antigen is an effective strategy as well. Our model provides a valuable platform for developing patient-specific CAR T-cell treatment plans with the potential to optimize scheduling and locations of CAR T-cell injections based on individual antigen expression profiles.

systems biology↗

bioRxiv2025

Adaptive Evolution of Gene Regulatory Networks in Mammalian Neocortical Neurons

Mammals have evolved a plethora of adaptations that have enabled them to thrive in diverse environments. Among the most significant is the emergence of a more complex brain, exemplified by the dramatic transformation of the dorsal cortex from a single layer of excitatory projection neurons (ExNs) in ancestors to a multilayered cerebral neocortex enriched with diverse intratelencephalic (IT) and extratelencephalic (ET) ExN subtypes. These ExNs established specialized projection systems, such as the corticospinal tract and corpus callosum, enhancing brain connectivity and functionality. However, the evolutionary mechanisms underlying these mammalian-specific adaptations remain elusive. By comparing the landscape of gene expression and cis-regulatory elements (CREs) in mouse ExN subtypes and by cross-species examination of mammalian and non-mammalian CREs, we identified mammalian-specific CREs and expression patterns. The mammalian-specific CREs include a subset bound by ZBTB18 that are associated with genes defining IT and ET subtypes and connectivity. Both ZBTB18 and these target genes have previously been implicated in intellectual disability and autism. Deletion of Zbtb18 in mouse ExNs dysregulated target gene expression, reduced molecular diversity, diminished corticospinal and callosal projections, and increased intrahemispheric cortico-cortical association projections to the prefrontal cortex, resembling features of non-mammalian dorsal pallium. Interestingly, ZBTB18 binding motifs are highly enriched in callosally projecting IT-biased CREs, where they show higher conservation specifically in mammals. This study uncovers critical components and mammalian-specific evolutionary adaptations within a regulatory node essential for neocortical ExN identity and connectivity, with implications for neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Sub-second Fluctuation between Top-Down and Bottom-Up Modes Distinguishes Diverse Human Brain States

Information continuously flows between regions of the human brain, exhibiting distinct patterns that dynamically shift across states of consciousness, cognitive modes, and neuropsychiatric conditions. In this study, we introduce Relative Phase Analysis (RPA), a method that leverages phase-lead/lag relationships to reveal the real-time dynamics of dominant directional patterns and their rapid transitions. We demonstrate that the human brain switches on a sub-second timescale between a top-down mode-where anterior regions drive posterior activity-and a bottom-up mode, characterized by reverse directionality. These dynamics are most pronounced during full consciousness and gradually become less distinct as awareness diminishes. Furthermore, we find from simultaneous EEG-fMRI recordings that the top-down mode is expressed when higher-order cognitive networks are more active while the bottom-up mode is expressed when sensory systems are more active. Moreover, comparisons of an attention deficit hyperactivity disorder (ADHD) inattentive cohort with typically developing individuals reveal distinct imbalances in these transition dynamics, highlighting the potential of RPA as a diagnostic biomarker. Complementing our empirical findings, a coupled-oscillator model of the structural brain network recapitulates these emergent patterns, suggesting that such directional modes and transitions may arise naturally from inter-regional neural interactions. Altogether, this study provides a framework for understanding whole-brain dynamics in real-time and identifies sub-second fluctuations in top-down versus bottom-up directionality as a fundamental mechanism underlying human information processing.

neuroscience↗

bioRxiv2025

Role of IL10 signaling in the circadian control of host response to Influenza infection

We have previously demonstrated that the circadian clock regulates the host response to influenza A virus (IAV) infection, conferring a time-of-day-specific protection -infection at dawn resulted in a threefold increase in survival and reduced immunopathology compared to infection at dusk. While IL10 is well-known for its immunoregulatory function, its role in IAV remains unclear, with studies reporting both protective and detrimental effects. Given the diurnal rhythmicity of IL-10 receptor (Il10ra) expression in the lung, we investigated the contribution of IL-10 signaling to time-of-day-specific IAV protection. We found that blocking IL10 signaling abrogated the time of day protection, leading to increased immunopathology characterized by enhanced lymphocyte infiltration and global immune activation (transcriptomic analysis). Interestingly, while later, IL-10R blockade also eliminated the time-of-day difference in IAV outcomes, it improved the outcome of dusk-infected mice. Furthermore, natural killer (NK) cell depletion suppressed IL-10 levels in bronchoalveolar lavage, suggesting a role for NK cells in regulating IL-10 signaling. In conclusion, incorporating the circadian context has not only clarified the IL-10 role in IAV infection but also underscored the pivotal influence of circadian regulation on immune responses.

immunology↗

bioRxiv2025

Mathematical Modeling of Neural Stem Cell Migration within Brain using Multi-Fiber Tractography

An agent-based model of therapeutic neural stem cell (NSC) migration is developed and used to predict the migration of NSCs in naive mouse brain. The model utilizes generalized q-sampling imaging which resolves white matter fibers that cross in the brain and is shown to better account for variations in NSC migration patterns as compared to diffusion tensor imaging. In calibrating the model to experimental data, we show that the model is able to reproduce the distribution of NSCs in the mouse brain. In addition, we show that the distribution of NSCs in the mouse brain is sensitive to the location of NSC injection. Persistent distribution of NSCs to the olfactory bulb, consistent with developmental pathways including the rostral migratory stream, suggests that future models of therapeutic NSCs in the naive brain may need to include other factors such as chemotaxis or blood flow to account for variations in NSC migration paths. The results highlight the usefulness of the model in predicting which injection locations may provide the best distribution of NSCs to a given target location.

systems biology↗

bioRxiv2025

Phosphorus Availability Modulates Flowering Time Through Subcellular Reprogramming of bGLU25 and GRP7 in Flowering Plants

The transition from vegetative to reproductive growth is vital for plant fitness and crop yield and is strongly influenced by nutrient availability. While nitrogen deficiency accelerates flowering, phosphorus (P) limitation delays it. However, the molecular basis for how P availability regulates flowering time remains unclear. Here, through genome-wide association mapping in Arabidopsis, we uncover genetic variation in {beta}-GLUCOSIDASE 25 (bGLU25) that modulates flowering under P-limited conditions. In P-sufficient environments, bGLU25 localizes to the endoplasmic reticulum. Under P limitation, however, bGLU25 translocates to the cytosol, a process mediated by P-regulated SERINE CARBOXY PEPTIDASE 50 (SCP50). In the cytosol, bGLU25 binds to JACALIN-LECTIN LIKE1 (AtJAC1), preventing the nuclear translocation of the Flowering Locus C (FLC) regulator GLYCINE-RICH RNA-BINDING PROTEIN 7 (GRP7). This cytosolic sequestration of GRP7 under P-deprivation elevates FLC expression, delaying flowering. Moreover, in the monocot rice, the homologs of bGLU25 also modulate flowering responses to P availability, indicating a conserved role for bGLU25 across flowering plants. Our findings provide a molecular framework for breeding strategies aimed at optimizing flowering time in response to P levels.

plant biology↗

bioRxiv2024

Cellular cartography reveals mouse prostate organization and determinants of castration resistance

Inadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single-cell RNA sequencing, single-cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta-analysis of human prostates and prostate cancer, we identified cellular orthologs and key determinants of ADT response and resistance. Our findings reveal that mouse prostates harbor lobe-specific luminal epithelial cell types distinguished by unique gene regulatory modules and anatomically defined androgen-responsive transcriptional programs, indicative of divergent developmental origins. Androgen-insensitive, stem-like epithelial populations - resembling human club and hillock cells - are notably enriched in the urethra and ventral prostate but are rare in other lobes. Within the ventral prostate, we also uncovered two additional androgen-responsive luminal epithelial cell types, marked by Pbsn or Spink1 expression, which align with human luminal subsets and may define the origin of distinct prostate cancer subtypes. Castration profoundly reshaped luminal epithelial transcriptomes, with castration-resistant luminal epithelial cells activating stress-responsive and stemness programs. These transcriptional signatures are enriched in tumor cells from ADT-treated and castration-resistant prostate cancer patients, underscoring their likely role in driving treatment resistance. Collectively, our comprehensive cellular atlas of the mouse prostate illuminates the importance of lobe-specific contexts for prostate cancer modeling and reveals potential therapeutic targets to counter castration resistance. Significance StatementAndrogen deprivation therapy is a mainstay in prostate cancer treatment, yet many patients eventually develop castration-resistant disease--a lethal progression driven by poorly understood cellular mechanisms. Our study provides a comprehensive cellular map of the prostate, identifying key determinants of normal organization and castration-induced remodeling. By pinpointing the cell types and molecular programs that confer ADT responsiveness or resistance, our findings offer new directions for prostate cancer modeling and pave the way toward novel therapeutic strategies aimed at enhancing ADT efficacy and preventing the emergence of castration-resistant prostate cancer.

cancer biology↗

bioRxiv2024

Anatomical Region-Specific Transcriptomic Signatures and the Role of Epithelial Cells in Pterygium Inflammation: A Multi-Omics Analysis

BackgroundThe anatomy of pterygium consists of the head, neck, and body. Prior studies have examined the three parts collectively, yet the treatment methods and their success rates differ based on the anatomical characteristics. In this study, we divide the pterygium tissue into Main (head and neck) and Acc (body) to investigate its pathogenesis across regions. PurposesThis study aims to understand the pathogenesis and identify potential therapeutic targets of pterygium. Through a robust multi-omics analysis of bulk and single-cell RNA sequencing (RNA-seq) data from pterygium patients, we focus on the expression of inflammatory and mitochondrial energy pathways and identify potential genes responsible for the upregulated pathways in pterygium. MethodsWe collected bulk RNA-seq data from six pterygium patients and single-cell RNA-seq data from two pterygium patients. We then investigated the pathway enrichment, pathway correlation, differential gene expressions, protein-protein interactions, and cell-cell communications of pterygium. ResultsFrom the analysis of bulk RNA-seq data, the distribution of sample points from the principal component analysis plot and the pathways enriched from the Gene Ontology analysis showed distinct expression patterns in the Acc group compared to the Main and control groups. This suggested the need to separate the Main and Acc regions within pterygium samples and utilize single-cell RNA-seq data to understand the differences between the Main and control groups that the bulk data could not capture. The annotation of integrated single-cell data revealed a cluster of epithelial cells containing only pterygium samples. Cells from this cluster exhibited significant contributions to the ANGPTL, IL1, and KLK signaling networks in the cell-cell communication analysis. We also observed significant upregulation of the cells in the inflammatory pathways related to integrated stress response and the renin-angiotensin-aldosterone system, both of which showed high correlations with energy metabolism pathways. Significant changes in the expression of multiple pro-inflammatory, antioxidant, and immune-related genes were also identified. ConclusionThe different expression patterns between the Main and Acc groups suggest the need to consider different anatomical regions separately in future studies of pterygium. Additionally, the significant role epithelial cells from the Main group play in the inflammation of pterygium presents a potential clinical approach to the disease.

bioinformatics↗

bioRxiv2024

Molecular Specification of Claustro-Amygdalar and Paleocortical Neurons and Connectivity

The ventropallial excitatory neurons (ExNs) in the claustro-amygdalar complex and piriform cortex (PIR; part of paleocortex) form crucial reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that result in adaptive behaviors. Early-life disruptions in these circuits are linked to neuropsychiatric disorders, highlighting the importance of understanding their development. Our study uncovers that transcription factors SOX4, SOX11, and TFAP2D play a pivotal role in the development, identity, and PFC connectivity of these neurons. Using mouse models, we demonstrate that the absence of transcription factors SOX4 and SOX11 in post-mitotic ExNs dramatically reduces the size of the basolateral amygdala complex (BLC), claustrum, and PIR. SOX4 and SOX11 control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including humans, identified conserved Tfap2d expression in developing ExNs of BLC, claustrum, paleocortex including PIR, and the associated transitional areas of the frontal, insular and temporal cortex. While the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat behaviors, differences emerge in the manifestation of Tfap2d dosage, particularly in terms of changes observed in BLC size and the connectivity pattern between the BLC and PFC. This underscores the significance of Tfap2d dosage in orchestrating developmental shifts in BLC-PFC connectivity and behavioral modifications reminiscent of symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial ventropallial ExNs and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

neuroscience↗