Biology subjects

Wang, T.-Y.

Publications and source records attributed to Wang, T.-Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Monocyte-Mimetic Nanoparticle Delivery of Verteporfin Promotes Plaque-Stabilizing Remodeling in Atherosclerosis

Background: Despite advances in lipid-lowering and anti-inflammatory therapies, pharmacological strategies that act directly within established atherosclerotic lesions to suppress plaque progression remain limited. We recently developed a monocyte-mimetic nanoparticle (MoNP) platform that selectively targets inflamed endothelium and delivers Verteporfin (VP), termed MoNP-VP, to suppress YAP/TAZ-associated endothelial activation and plaque development. Here, we extend this biomimetic nanotherapy by defining the pharmacological effects of MoNP-VP within atherosclerotic vessels and evaluating its therapeutic efficacy in pre-existing plaques under distinct lipid burden. Methods: MoNP-VP were formulated by encapsulating VP in polymeric cores followed by cloaking with mouse monocyte membranes. Partial ligation was performed in ApoE-deficient mice, and single-cell RNA sequencing was used to define pharmacodynamic responses in carotid lesions. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function was induced in wild-type mice to generate pre-existing aortic lesions, followed by continued high-fat-diet or switching to chow to evaluate MoNP-VP efficacy under persistent hyperlipidemia and lipid-lowering conditions. Results: Single-cell analysis revealed that MoNP-VP remodeled the plaque microenvironment in carotid arteries, selectively reducing foamy macrophage populations while enriching vascular stromal populations associated with fibrotic remodeling. In mice with pre-existing aortic plaques, MoNP-VP suppressed lesion progression and reduced macrophage content under persistent hyperlipidemia. Following diet-induced lipid lowering, MoNP-VP further reduced macrophage accumulation despite no significant change in plaque size. Across both settings, MoNP-VP increased fibroblast-like cell populations and collagen deposition accompanied by activation of TGF{beta} signaling, features consistent with a more stable plaque. Importantly, repeated MoNP-VP administration was well tolerated and elicited no overt systemic toxicity. Conclusion: These findings bridge mechanistic insight and therapeutic efficacy in pre-established plaques by demonstrating that MoNP-VP remodels the inflammatory plaque microenvironment and promotes lesion stabilization, supporting its translational potential as a precision nanotherapy for atherosclerosis.

molecular biology↗

bioRxiv2026

FAM136A is an essential chaperone for mitochondrial membrane protein biogenesis

The metabolic and signaling function of mitochondria rely on a network of chaperones within the inner membrane space (IMS) that regulate the biogenesis of nascent mitochondrial proteins. Using a genome wide CRISPRi screen we found that in human cells FAM136A is required for biogenesis of all three voltage-dependent anion channel (VDAC) paralogs, an abundant and essential family of {beta}-barrel metabolite transporters in the outer mitochondrial membrane (OM). FAM136A is a ubiquitously expressed essential gene, that is conserved in metazoa and plants. Using a combination of experiments in human cells and in vitro reconstitution, we determined that FAM136A associates with unfolded VDACs in the IMS; solubilizes nascent VDAC through a direct interaction; and facilitates insertion of VDAC into the OM. FAM136A also binds and chaperones a subset of -helical subunits of the electron transport chain. We therefore conclude that FAM136A is an IMS-resident chaperone, necessary and sufficient to maintain nascent membrane proteins in a folding-competent state to mediate their integration into the bilayer.

molecular biology↗

bioRxiv2026

Assembling and annotating the Tainung 67 rice genome to trace its japonica and indica ancestries

Here we reported the 409.0 Mb assembly of the Tainung 67 (TNG67) genome, an early hybrid of japonica and indica cultivars. We used different platforms to sequence the TNG67 genome with a total coverage of 209.8x, from a combination of Illumina paired-end reads, Illumina mate-pair reads, and Oxford Nanopore Technology long reads. The assembly has an N50 of 32.3 Mb with the longest scaffold = 45.2 Mb. We have annotated 38,938 genes where 28,376 (72.9%) finished with the Blast2GO annotation stage. There were 4,821 genes, (98.4%) of the total gene count that have complete BUSCOs. 48.33% (197.5Mb) of the TNG67 genome is composed of repeats. We predicted a total of 527 blast-resistant genes in TNG67. We also analyzed a total of 20 grain size genes and 38 photoperiod-related genes of TNG67, Nipponbare and TN1, and grouped them in terms of whether the TNG67 genes are more similar to Nipponbare, more similar to TN1, hybrid, same, or unique. We also determined whether the sequences of the TNG67 genome were derived from its japonica or indica ancestors. This TNG67 genome may help rice researchers improve yield, develop resistance against biotic and abiotic stress, and understand the evolution of a hybrid cultivar of japonica and indica.

genomics↗

bioRxiv2026

Biomimetic MRI Nanoprobe for Mapping Cerebrovascular Inflammation After Traumatic Brain Injury

Cerebrovascular inflammation is a critical driver of secondary injury following traumatic brain injury (TBI), yet no noninvasive tool currently exists to map its spatial heterogeneity across the injured brain. Here, we report MoNP-SPION, a monocyte-mimetic nanoprobe that selectively targets activated cerebrovascular endothelium after TBI and enables quantitative MRI of spatiotemporally heterogeneous cerebrovascular inflammation. MoNP-SPION binding to inflamed brain endothelium scaled with activation state, enabling rapid, spatially heterogeneous targeting of injured cerebral vasculature. MoNP-SPION-enhanced MRI revealed dynamic reductions in T2* throughout the brain that extended beyond the injury penumbra and captured both subacute vascular injury and therapy-induced recovery. Importantly, spatiotemporal reductions in T2* strongly correlated with VCAM1 upregulation, supporting MoNP-SPION as a molecularly specific readout of endothelial activation. Together, these findings establish MoNP-SPION as a promising platform for longitudinal, noninvasive monitoring of cerebrovascular inflammation in TBI and other neurological disorders involving vascular dysfunction. TEASERCell-mimicking MRI nanoprobe maps cerebrovascular injury and recovery dynamics following brain trauma.

bioengineering↗

bioRxiv2026

Monocyte-Mimetic Nanoprobe Enables Longitudinal MRI of Atherosclerotic Inflammatory Dynamics

Noninvasive monitoring of plaque inflammatory dynamics remains an unmet need. We previously developed a monocyte-mimetic nanoprobe, termed MoNP-SPION, for MRI detection of atherosclerotic lesions. Here we demonstrate MoNP-SPION enables longitudinal tracking of plaque inflammatory status in a clinically relevant mouse model. Following 16 weeks of plaque induction, mice were maintained on high-fat diet or switched to chow for 6 weeks to model persistent versus resolving plaque inflammation. MoNP-SPION-enhanced MRI was performed at 3- and 6-weeks post-adjustment, and arterial tissue was collected for histological assessment. Mice maintained on high-fat diet exhibited persistent hypointense T2* signal at the carotid bifurcation and aortic root, whereas chow-transitioned mice showed progressive signal attenuation, consistent with histological evidence of reduced plaque burden and inflammation. These findings establish MoNP-SPION as an effective molecular MRI probe for longitudinal assessment of plaque inflammatory dynamics, supporting its potential for monitoring atherosclerosis progression and therapeutic response.

bioengineering↗

bioRxiv2026

Glucose selectively drives a rapid oxidative burst and immunometabolic reprogramming in human neutrophils during Mycobacterium tuberculosis infection

Neutrophil functions have been linked to tuberculosis (TB)-associated tissue damage; however, the mechanisms driving immunopathology in the human TB lung remain poorly understood, due partly to the scarcity of human tissue for study. Here, we examine the metabolic and bioenergetic reprogramming of human neutrophils in response to Mycobacterium tuberculosis (Mtb) infection. In human necrotic TB granulomas, levels of NETosis-associated proteins are increased and co-localize with GLUT3, linking nutrient uptake to tissue damage. In vitro, Mtb elicits an immediate, contact-dependent oxidative burst in human neutrophils, and the magnitude of this response is carbon source-dependent. Glucose enables the most robust responses, indicating that glucose metabolism is a key driver of neutrophil-mediated inflammatory damage during TB. Mtb-induced responses are distinct from those induced by PMA, non-tuberculous mycobacteria, or other pathogenic intracellular bacteria, and are mediated through multiple neutrophil surface receptors. Notably, our data show that while the oxidative burst is carbon source-dependent, cytokine production is not. Further, Mtb infection reprograms neutrophil metabolism from glycolysis to the pentose phosphate pathway (PPP), generating NADPH required for the oxidative burst. Inhibiting G6PD, NADPH oxidase, or PAD4 significantly reduces this response, highlighting the PPP as a promising host target for mitigating TB immunopathology.

microbiology↗

bioRxiv2026

IGF2BP2 links m6A-modified HMGA1 mRNA stability to mitochondrial metabolism and cell proliferation

Chinese hamster ovary (CHO) cells serve as the primary host for industrial therapeutic protein production, yet enhancing their productivity remains a significant challenge. Epigenetic regulation, particularly RNA N6-methyladenosine modification, offers a promising strategy. Here, we show that the m6A reader protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) positively regulates recombinant protein yield in CHO cells. IGF2BP2 expression was elevated in high-producing clones, and its stable overexpression promoted cell proliferation, increased the S-phase cell proportion, and boosted titers and specific productivity of recombinant proteins--adalimumab, vitronectin, and donanemab--by 2.0-, 1.6-, 2.6-fold and 1.8-, 1.4-, 2.1- fold, respectively. Mechanistically, IGF2BP2 recognized m6A sites on HMGA1 mRNA, enhancing its stability and expression. Integrated analyses of oxidative stress, mitochondrial function, and metabolomics, along with inhibitor validation, revealed that IGF2BP2 also strengthens antioxidant defense, promotes mitochondrial ATP production and utilization, and reshapes cellular redox and metabolic homeostasis. These findings highlight IGF2BP2 as a critical regulator of recombinant protein expression and mitochondrial oxidative metabolism in CHO cells, illustrating how RNA methylation cooperates with mitochondrial function and proliferation to enhance protein production.

bioengineering↗

bioRxiv2026

TXNDC15 modulated quality control at the endoplasmic reticulum shapes ciliogenesis

At the endoplasmic reticulum (ER), membrane protein quality control is tightly regulated to ensure excess subunits are recognized and degraded to protect cellular homeostasis. Using genome wide CRISPR screens, we identified a factor of unknown function, thioredoxin domain containing protein 15 (TXNDC15), and showed that it regulates membrane protein stability by tuning the activity of the E3-ubiquitin ligase, MARCHF6. TXNDC15 modulates MARCHF6 in two opposing ways: first, it enhances the binding, ubiquitination, and degradation of membrane protein subunits with soluble cytosolic domains; and second, it prevents the inappropriate recruitment and ubiquitination of subunits with globular lumenal domains. Patient mutations to TXNDC15 that cause the ciliopathy Meckel-Gruber syndrome, disrupted its binding to MARCHF6, allowing degradation of critical ciliary proteins as they transit through the ER leading to defects in ciliogenesis. The regulatory function of TXNDC15 therefore exemplifies how protein quality control maintains the integrity of the proteome to prevent disease.

molecular biology↗

bioRxiv2026

Integrin Activation Enhances Lesion-Specific Targeting of Monocyte-Mimetic Nanoparticles in Atherosclerosis

PurposeEndothelial cell (EC) activation, characterized by upregulation of adhesion molecules that drive monocyte recruitment, contributes to plaque progression while also providing an opportunity for targeted therapeutic delivery. Leveraging the cell membrane cloaking strategy, we recently developed a monocyte-mimetic nanoparticle (MoNP) platform that exploits the natural inflammatory tropism of monocytes for site-specific delivery to atherosclerotic vessels. Recognizing that integrin activation is a key determinant of monocyte adhesion to ECs, this study investigates whether pre-activating integrins on MoNP enhances their binding affinity and accumulation at atherosclerotic lesions. MethodsMouse bone marrow-derived monocytes were pretreated with CCL2 or Mn2{square} to activate membrane integrins. Isolated monocyte plasma membranes were cloaked onto fluorescently labeled polymeric cores to generate integrin-activated MoNPs (IA@MoNPs). The targeting capability of IA@MoNPs toward endothelial ligands, inflamed ECs, and atherosclerotic lesions was evaluated using in vitro and in vivo models. ResultsIA@MoNPs exhibited markedly enhanced binding to VCAM1, the primary endothelial ligand mediating integrin-dependent monocyte adhesion, and significantly increased uptake by ECs under atheroprone conditions compared to standard MoNPs. In vivo, IA@MoNPs demonstrated enhanced accumulation in atherosclerotic arteries without increasing nonspecific binding, and blocking {beta}1-integrins on IA@MoNPs abolished this targeting effect. Importantly, integrin activation on IA@MoNPs did not compromise circulatory stability or induce immune or organ toxicity. ConclusionIntegrin activation represents a simple yet effective strategy to enhance MoNP targeting to inflamed ECs and atherosclerotic lesions. This mechanism-driven approach improves targeting performance while maintaining specificity and safety, advancing the translational potential of the biomimetic nanomedicine platform for atherosclerosis.

bioengineering↗

bioRxiv2025

Deep Learning for RNA Secondary Structure Determination: Gauging Generalizability and Broadening the Scope of Traditional Methods

The diverse regulatory functions, protein production capacity, and stability of natural and synthetic RNAs are closely tied to their ability to fold into intricate structures. Determining RNA structure is thus fundamental to RNA biology and bioengineering. Among existing approaches to structure determination, computational secondary structure prediction offers a rapid and low-cost strategy and is thus widely used, especially when seeking to identify functional RNA elements in large transcriptomes or screen massive libraries of novel designs. While traditional approaches rely on detailed measurements of folding energetics and/or probabilistic modeling of structural data, recent years have witnessed a surge in deep learning methods, inspired by their tremendous success in protein structure prediction. However, the limited diversity and volume of known RNA structures can impede their ability to accurately predict structures markedly different from the ones they have seen. This is known as the generalization gap and currently poses a major barrier to progress in the field. In this Perspective article, we gauge method generalizability using a new benchmark dataset of structured RNAs we curated from the Protein Data Bank. We also discuss the emergence of deep learning methods for predicting structure probing data and use a new dataset to underscore generalization challenges unique to this domain along with directions for future improvement. Expanding beyond improving predictive accuracy, we review how advances in deep learning have recently enabled scalable and accessible optimization of traditional structure prediction methods and their seamless integration with modern neural networks.

bioinformatics↗

bioRxiv2025

Determining Multivalent Interactomes of Intrinsically Disordered Proteins in Phase-Separated Condensates in Live Cells

Many intrinsically disordered protein regions (IDRs) can form liquid-liquid phase separation (LLPS) condensates via multivalent interactions, but how the interaction behaviors contribute to specific cellular functions remains unclear due to the unknown composition of the condensates. Here, we report phase-separation-induced interactome detection (PhaseID), a new method that determines the protein components within the LLPS condensates driven by any given IDR in live human cells. Using PhaseID, we demonstrated that transactivation IDRs each have unique multivalent interactomes, thereby executing transactivation through distinct pathways. In-depth analyses of PhaseID-determined IDR interactomes revealed that LLPS tunes the interaction selectivity of IDRs, enabling them to play new roles in specific cellular processes, and different LLPS condensates recruit proteins with distinct physicochemical properties encoded in their sequences.

molecular biology↗

bioRxiv2025

ATM promotes reversed fork processing during DNA interstrand cross-link repair

During replication-coupled DNA interstrand cross-link (ICL) repair, fork reversal is thought to enable the Fanconi anemia (FA) pathway to resolve the ICL through nucleolytic incisions. Subsequent fork restoration then allows nascent DNA strand extension past the lesion. Although these fork remodeling events are crucial for ICL repair, their regulation remains poorly understood. Here, we use cell-free Xenopus egg extracts to investigate fork dynamics during ICL repair by the FA pathway. We find that the ataxia telangiectasia-mutated (ATM) kinase is activated concomitantly with fork reversal and promotes resection of the reversed fork intermediate. This resection depends on the coordinated activities of the EXO1 and DNA2 nucleases. Our data indicate that EXO1 initiates 5 to 3 resection of nascent lagging strands in the regressed arm, while DNA2 performs 5 to 3 resection of recessed lagging strands. We further show that the inhibition of protein phosphatase 2A (PP2A) during ICL repair results in ATM hyperactivation, reversed fork over-resection, and formation of aberrant end-joining products, indicating that PP2A counteracts ATM signaling to constrain reversed fork resection. Taken together, this work implicates reversed forks as substrates for ATM activation and reveals a phospho-regulatory circuit that governs reversed fork processing during ICL repair.

molecular biology↗

bioRxiv2025

Eco-genomic analysis uncovers precision-conservation targets for the western Pacific's southernmost salmonid

Understanding how isolated small populations persist and adapt in adverse environments is instrumental to evolutionary and conservation biology. We combine a chromosome-level genome assembly, population resequencing and forward-time simulations to reconstruct the history and viability of the Formosan landlocked salmon (Oncorhynchus formosanus), now restricted to a handful of high-mountain headwaters in Taiwan. We estimate that this lineage has diverged from Japanese masu salmon over one million years ago and has no detectable gene flow for [~]50,000 years. It has accumulated extensive chromosome fusions and expansions of cold-adaptation gene families, qualifying it as a new species rather than a subspecies of Japanese masu salmon. Whole-stream sampling reveals an overlooked Hehuan-Creek population that retains high heterozygosity and has gained unique alleles. Life-table simulations show that the Hehuan population has a notably lower extinction risk and can persist or even grow under low-to-moderate typhoon frequency, whereas Qijiawan-Creek population would decline precipitously under the same or higher frequency . These findings contradict the notion that peripheral populations are likely genetically depleted and support stream-specific "precision conservation" in place of broad, untargeted translocations that could erode local adaptation potential. Thus, our genomic-ecological analysis has uncovered hidden strong resilience in a critically endangered, climate-threatened salmonid lineage.

genomics↗

bioRxiv2025

stk32a links sleep homeostasis to suppression of sensory and motor systems

Sleep is regulated by a homeostatic process and associated with an increased arousal threshold, but the genetic and neuronal mechanisms that implement these essential features of sleep remain poorly understood. To address these fundamental questions, we performed a zebrafish genetic screen informed by human genome-wide association studies. We found that mutation of serine/threonine kinase 32a (stk32a) results in increased sleep and impaired sleep homeostasis in both zebrafish and mice, and that stk32a acts downstream of neurotensin signaling and the serotonergic raphe in zebrafish. stk32a mutation reduces phosphorylation of neurofilament proteins, which are co-expressed with stk32a in neurons that regulate motor activity and in lateral line hair cells that detect environmental stimuli, and ablating these cells phenocopies stk32a mutation. Neurotensin signaling inhibits specific sensory and motor populations, and blocks stimulus-evoked responses of neurons that relay sensory information from hair cells to the brain. Our work thus shows that stk32a is an evolutionarily conserved sleep regulator that links neuropeptidergic and neuromodulatory systems to homeostatic sleep drive and changes in arousal threshold, which are implemented through suppression of specific sensory and motor systems.

neuroscience↗

bioRxiv2025

Multi-omics integration uncovers host-microbiota crosstalk underlying sexual differentiation in the shortfin eel Anguilla bicolor pacifica

The global decline in anguillid eel populations has intensified interest in understanding their biology for conservation and aquaculture. While host-gut microbiota interactions are well-characterized in homeotherms, these relationships remain poorly understood in poikilotherms during sexual differentiation. We examined gut microbiota dynamics across developmental stages in the shortfin eel Anguilla bicolor pacifica, which exhibits early sexual differentiation and a relatively short life cycle. Glass eels were cultivated in controlled freshwater conditions for three years, with sampling at key stages: glass eel, elver, sex-undetermined eel, and sex-determined eel. Full-length 16S rRNA gene sequencing revealed significant compositional shifts during development, with higher bacterial richness in adults versus younger eels. Early stages were dominated by Pseudomonadota, while sex-determined adults showed increased Deinococcota abundance. Network analysis identified Deinococcus, Sphingomonas, and Variovorax as key genera in sex-determined eels, with positive correlations between anti-Mullerian hormone gene expression and these taxa. We isolated 66 gut bacterial strains capable of metabolizing sex hormones under microaerobic conditions. These isolates, representing 22 genera across four phyla, demonstrated diverse metabolic capabilities from partial oxidation to complete steroid mineralization. Multiple strains achieved complete estradiol degradation as single isolates--a rare metabolic capability of environmental microorganisms. Comparative genomic analysis revealed widespread steroid-metabolizing genes, with Deinococcus species showing previously unreported hormone degradation capabilities. Our multi-omics analysis demonstrates that gut microbiota composition and function are intimately linked to eel sexual development, suggesting bidirectional host-microbe interactions influencing reproductive physiology. These findings advance understanding of host-microbiota interactions in aquatic vertebrates and provide implications for eel aquaculture and conservation.

microbiology↗

bioRxiv2025

Massive Chromosome Fission and Speciation in Asian River Chub: Integrating Kinetochore Reproduction Theory with Transposable Element Dynamics

Chromosomal speciation poses a paradox: if rearrangements cause postmating isolation, how do they persist and spread? We propose that centromere remodeling, driven by transposable element accumulation, provides a mechanistic solution. In Opsariichthys, a hyper-diverse lineage of Asian river chub with 2N = 76-78 chromosomes, we identify [~]15 fission events coinciding with TE-fueled centromeric DNA expansion, potentially linked to a mutation in the PIWI1 protein. These expansions enable neokinetochore formation, allowing fissioned chromosomes to segregate faithfully, while subsequent rearrangements disrupt pairing and reduce gene flow. Comparative genomics reveals that fissioned chromosomes exhibit lower migration and greater divergence, acting as reproductive barriers. Our findings show that TE-mediated kinetochore duplication can facilitate extensive chromosome fission without meiotic disruption, providing a viable and previously underappreciated path to rapid speciation.

genomics↗

bioRxiv2025

Reducing Cofilin dosage makes embryos resilient to heat stress

In addition to regulating actin dynamics, Cofilin also senses and responds to physiological stress and can determine cell survival outcomes. Yet, the full picture of Cofilin's role in stress response is lacking. Here, we used imaging and RNA-seq methods to show that exposing early Drosophila melanogaster embryos to either acute or chronic heat stress (32{degrees}C) induces a Cofilin-mediated Actin Stress Response (ASR) and leads to upregulation of genes associated with both heat shock and Endoplasmic Reticulum (ER) unfolded protein responses. Reducing cofilin gene dosage (cofilin+/-) in heat-stressed embryos modulates all observed stress responses and partially rescues embryo survival. Unexpectedly we find that heat shock- and ER- stress response modulation arises because non-stressed cofilin+/- embryos already show upregulation of heat shock- and ER- stress response genes, prior to heat exposure. Our data support a model whereby cofilin heterozygosity activates specific stress responses associated with reduced protein homeostasis, thus priming embryos to be more resilient when they encounter subsequent heat stress. We conclude that Cofilin dosage serves as a determinant of stress outcomes, impacting both the actin cytoskeleton and inducible stress response pathways. In the embryo, we identify Cofilin as a novel link between inducible stress response and thermotolerance.

developmental biology↗

bioRxiv2024

A Genomic Language Model for Chimera Artifact Detection in Nanopore Direct RNA Sequencing

Chimera artifacts in nanopore direct RNA sequencing (dRNA-seq) can significantly distort transcriptome analyses, yet their detection and removal remain challenging due to limitations in existing basecalling models. We present Deep-Chopper, a genomic language model that precisely identifies and removes adapter sequences from base-called dRNA-seq long reads at single-base resolution, operating independently of raw signal or alignment information to effectively eliminate chimeric read artifacts. By removing these artifacts, DeepChopper substantially improves the accuracy of critical downstream analyses, such as transcript annotation and gene fusion detection, thereby enhancing the reliability and utility of nanopore dRNA-seq for transcriptomics research.

genomics↗