Biology subjects

Yu, J.

Publications and source records attributed to Yu, J..

At least 127 records · Page 7Linked to original sources

bioRxiv2025

A spatially-resolved human brain proteome atlas for understanding function and disease

While the brain performs specialized functions across distinct regions, the spatial organization of the human brain proteome remains largely uncharted. Here we present a comprehensive spatially-resolved proteome atlas of the human brain, analyzing over two thousand MRI- guided locations across four individuals. Proteome analysis integrated with transcriptomics reveals extensive post-transcriptional regulation, with cortical regions showing markedly higher protein diversity than transcript. Unsupervised molecular clustering defines distinct brain territories that transcend anatomical boundaries, instead reflecting metabolic demands and functional specialization patterns. Application to epilepsy brain tissue uncovered disrupted astrocyte metabolism, protein homeostasis and therapeutic targets including the seizure-associated purinergic receptor P2RX7. This resource bridges molecular and systems neuroscience to accelerate neurological drug discovery.

neuroscience↗

bioRxiv2025

PhysioMotion Artifact: A Task-Driven EEG Dataset with Channel-Level Motion Artifact Annotations

Physiological artifacts pose persistent challenges in electroencephalo-gram (EEG) data acquisition, often compromising interpretation and post-analysis of EEG signals across research and clinical applications. To address such limitations, including various artifact types, insufficient annotations, and low spatial resolutions, we present PhysioMotion Artifact, a large-scale, task-driven EEG dataset with channel-level artifact annotations. EEG data was acquired from 30 healthy participants performing 16 systematically designed single-type and multi-type movement tasks, inducing 14 distinct types of physiological artifacts. To demonstrate the utility of the dataset, we implemented a Convolutional Neural Networks-Transformer hybrid model for artifact detection and classification, achieving 98% accuracy in binary classification and 85% in 14-class classification tasks.

neuroscience↗

bioRxiv2025

Enhanced splicing modulation by NMA-modified antisense oligonucleotides

Aberrant RNA splicing contributes to many human diseases, and splice-switching antisense oligonucleotides (SSOs) are ideally suited as a therapeutic strategy to modulate splicing and restore normal gene expression. Nusinersen (Spinraza) has revolutionized the treatment of spinal muscular atrophy. It is a splice-switching oligonucleotide (SSO) that is modified with 2-O-methoxyethyl (MOE) modifications. Here, we introduce a next-generation ribose modification, 2'-O-[2-(methyl-amino)-2-oxoethyl] (NMA), which enhances the pharmacological properties of SSOs. We identified a long-lasting NMA-modified human candidate SSO, salanersen, that is 3-4-fold more potent than nusinersen in human SMN2 transgenic mice. To evaluate the generality of the NMA chemistry, we applied it to modulation of SCN1A exon 20N splicing, a therapeutic strategy for Dravet syndrome. An NMA-modified SSO is 3.5-fold more potent than STK-001, a MOE-modified SSO currently in clinical trials. Our data establish the NMA chemistry as a broadly applicable ribose modification that markedly improves the pharmacological profile of SSOs, supporting its development as a next-generation platform for splicing modulation therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC="FIGDIR/small/680653v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@122e426org.highwire.dtl.DTLVardef@1b0a56eorg.highwire.dtl.DTLVardef@3ce4e8org.highwire.dtl.DTLVardef@1d86378_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

The effects of increasing renal perfusion pressure on renal hemodynamics, microcirculation，and oxygen metabolism in a septic shock model

BackgroundThe optimal target for mean arterial pressure (MAP) during clinical management of septic shock remains a topic of debate. This study investigates how elevating MAP, and thereby increasing renal perfusion pressure (RPP, defined as MAP-CVP), influences renal hemodynamics, microcirculation, and oxygen metabolism in a septic shock model. MethodsSixteen New Zealand rabbits of either sex and similar weight were randomly assigned to sham group (n=8) and septic shock group (n=8). Renal blood flow (RBF), microcirculatory blood flow and velocity in the kidney, as well as tissue oxygen pressure in the renal cortex and medulla, were assessed at four distinct time points: baseline (T0), model establishment (T1), restoration of MAP to baseline levels (T2), and an increase in MAP by more than 15% above baseline (T3). ResultsWithin the septic shock group, although MAP and consequent RPP were increased, RBF markedly decreased from 17.63{+/-}2.50 to 8.50{+/-}1.93 ml/min (p < 0.05). No significant changes in microcirculation blood flow or flow velocity were observed between T2 and T3. Tissue oxygen pressure in the renal cortex and medulla declined significantly from 21.20{+/-}1.80 to 17.14{+/-}1.72 (p < 0.05) and from37.74{+/-}4.85 to 24.34{+/-}3.74 (p < 0.05), respectively. ConclusionElevating RPP does not improve RBF, renal microcirculation, or tissue oxygen pressure in the renal cortex or medulla in septic shock. Elevating RPP does not improve RBF, renal microcirculation, or tissue oxygen pressure in the renal cortex or medulla in septic shock. We advocate restoring MAP to the baseline level rather than increasing it further to enhance renal perfusion pressure.

systems biology↗

bioRxiv2025

Ancestral Origin of the CXCL17-GPR25 System Traced to the Lobe-Finned Fish Latimeria chalumnae

The roles of C-X-C motif chemokine ligand 17 (CXCL17) and its receptor, G protein-coupled receptor 25 (GPR25), in immune regulation are gaining recognition, but their evolutionary origins and phylogenetic distributions have yet to be determined. In this study, we identified a CXCL17 gene in the lobe-finned fish Latimeria chalumnae (coelacanth), a close living relative of tetrapods. This gene produces two alternatively spliced secretory proteins, designated Lc-CXCL17a and Lc-CXCL17b, which display limited sequence similarity to known CXCL17s from mammals or ray-finned fishes. Recombinant forms of Lc-CXCL17a and Lc-CXCL17b were generated via bacterial overexpression, purification, and enzymatic processing. Functional assays, including NanoLuc Binary Technology (NanoBiT)-based {beta}-arrestin recruitment, ligand-receptor binding, and chemotaxis assays, demonstrated that both proteins tightly bound to and potently activated coelacanth GPR25 in a manner dependent on their C-terminal residues, because removal of these residues markedly diminished activities. These findings provide the first evidence that a functional CXCL17-GPR25 system exists in lobe-finned fishes, supporting the hypothesis that this ligand-receptor pair originated in ancient fishes and was transmitted to vertebrate lineages through lobe-finned fish ancestors. This work broadens understanding of chemokine evolution and highlights the coelacanth as a valuable model for tracing conserved immune signaling pathways.

biochemistry↗

bioRxiv2025

Disruption of theta-timescale spiking impairs learning but spares hippocampal replay

The ability to rapidly learn and retrieve salient information about new environments is critical for survival. In mammals, the hippocampus plays a crucial role in that learning. Specialized features of hippocampal population coding, including network-level theta oscillatory activity, location-specific firing of principal cells, and reactivation of experience during immobility (replay), have been implicated in rapid storage and retrieval of spatial information. Disruptions of theta and replay jointly, or replay alone, are sufficient to impair learning; however, the specific contribution of theta-associated temporal structure during locomotion remains unknown. In this study, we manipulated hippocampal spiking activity in rats specifically during locomotion by optogenetically activating septal parvalbumin-expressing GABAergic neurons. We developed a closed-loop, theta phase-specific stimulation protocol that reliably reduced theta power shortly after stimulation onset. This manipulation preserved the place codes of individual cells but disrupted the fine temporal structure of endogenous spatio-temporal representations (i.e., theta sequences) at the pairwise and population level. Theta disruption during locomotion was also sufficient to cause pronounced deficits in learning the more cognitively challenging component of a spatial alternation task, even though disruption was applied on only [~]66% of trials. Notably, network effects accompanying theta disruption were restricted to locomotor periods; we did not observe changes in replay rate, length, or content during immobility. Together, these results demonstrate the importance of the precise temporal microstructure of locomotion-associated spatial representations in the hippocampus for learning.

neuroscience↗

bioRxiv2025

Class A PBPs reinforce the septal cell wall following initial synthesis by SEDS-bPBP pairs during bacterial cytokinesis

Bacterial cytokinesis requires the coordinated action of septal peptidoglycan (PG) synthases to ensure efficient and accurate septum formation. Two major types of synthases contribute: SEDS-bPBP and bifunctional class A PBPs (aPBPs). How their activities are organized in space and time has remained unclear. Using Deinococcus radiodurans, which often contains both constricting and closed septa in the same cell, we show that septal PG synthesis proceeds through distinct steps at different regions. Primary synthesis at the leading edge by SEDS-bPBP pairs drives constriction, whereas aPBPs act later at the lagging edge and in closed septa to thicken the wall, enhance cross-linking, and reinforce septal integrity. At the single-molecule level, both synthase types move directionally to perform processive PG synthesis at distinct sites. We also observed spatiotemporal separation of SEDS-bPBP and aPBP synthases in Staphylococcus aureus, suggesting that secondary septal PG synthesis is a conserved mechanism securing successful cytokinesis.

microbiology↗

bioRxiv2025

Flippable Siamese Differential Neural Network for Differential Graph Inference

Differential graph inference is a critical analytical technique that enables researchers to accurately identify the variables and their interactions that change under different conditions. By comparing two conditions, researchers can gain a deeper understanding of the differences between them. Currently, the mainstream methods in differential graph inference are mathematical optimization algorithms, including sparse optimization based on Gaussian graphical models or sparse Bayesian regression. These methods can eliminate many false positives in graphs, but at the cost of heavy reliance on the prior distributions of data or parameters, and they suffer from the curse of dimensionality. To address these challenges, we introduce a new architecture called the Flippable Siamese Differential Neural Network (FSDiffNet). We originally established the concept of flippability and the theoretical foundation of flippable neural networks, laying the groundwork for building a flippable neural network. This theoretical framework guided the design of architecture and components, including the SoftSparse activation function and high-dilation circular padding diagonal convolution. FSDiffNet uses large-scale pre-training techniques to acquire differential features and perform differential graph inference. Through experiments with simulated and real datasets, FSDiffNet outperforms existing state-of-the-art methods on multiple metrics, effectively inferring key differential factors related to conditions such as autism and breast cancer. This proves the effectiveness of FSDiffNet as a solution for differential graph inference challenges.

bioinformatics↗

bioRxiv2025

Identification and functional characterization of two CXCL17 paralogs from zebrafish

C-X-C motif chemokine ligand 17 (CXCL17) and its receptor G protein-coupled receptor 25 (GPR25) have been identified as a significant pair in regulating immunity, but CXCL17 orthologs have not yet been identified from non-mammalian vertebrates. This study aimed to identify and characterize non-mammalian CXCL17 orthologs based on key features of mammalian CXCL17s, such as a C-terminal Xaa-Pro-Yaa motif, a signal peptide, and six cysteine residues. Two possible CXCL17 paralogs were identified from zebrafish (Danio rerio): Dr-CXCL17 (encoded by zgc:158701) and Dr-CXCL17-like (encoded by si:dkey-112a7.5). Both are previously uncharacterized proteins with unknown functions because they lack overall sequence similarity to known mammalian CXCL17s. For functional characterization, recombinant Dr-CXCL17 and Dr-CXCL17-like were prepared via overexpression in Escherichia coli and subsequent in vitro refolding and their activity was tested using NanoLuc Binary Technology (NanoBiT)-based {beta}-arrestin recruitment assays, NanoBiT-based ligand{square}receptor binding assays, and chemotaxis assays. The results showed that both Dr-CXCL17 and Dr-CXCL17-like tightly bound to and efficiently activated zebrafish GPR25 (Dr-GPR25) and induced chemotactic movement in transfected human embryonic kidney (HEK) 293T cells expressing the receptor. Deletion of three C-terminal residues in both paralogs almost eliminated their binding, activation, and chemotactic effects, which suggests that this fragment is crucial for their function. Homologs of Dr-CXCL17 or Dr-CXCL17-like were retrieved from several other ray-finned fish species, indicating that two CXCL17 paralogs are present in certain fish species and function as endogenous agonists for the fish GPR25 receptor. The identification of fish CXCL17 orthologs suggests that the CXCL17{square}GPR25 pair likely originated in ancient fishes and was conserved across vertebrate lineages. This work represents the first identification of CXCL17 orthologs in non-mammalian vertebrates, paving the way for future functional studies of this ligand{square}receptor pair.

biochemistry↗

bioRxiv2025

Comprehensive analysis of metabolic reprogramming-related gene signaturesmetabolic reprogramming related gene signature for predicting ovarian cancer prognosis, immune landscape, and potential treatment options

Ovarian cancer (OV) is the most lethal gynecologic malignancy. Metabolic reprogramming is a distinctive feature of cancer and is associated with tumorigenesis and progression. It could be a potential therapeutic target for cancer treatments and a biomarker for assessing cancer prognosis. In this study, we identified metabolic reprogramming-related differentially expressed genes (MRRDEGs) in OV through differential gene expression analysis and conducted a comprehensive characterization of these MRRDEGs. Based on the MRRDEGs, we constructed an effective prognostic risk model including five model genes for OV. The risk score was a valid independent prognostic factor that could more accurately predict the survival of OV patients. It could classify OV patients into distinct risk groups with significant differences in survival. We observed significant differences between risk groups in biological pathway activity, immune cell infiltration patterns, and immunotherapy responses. Specifically, the low-risk group demonstrated superior immunotherapy response compared to the high-risk group. These findings significantly advance our understanding of the relationship between metabolic reprogramming and OV pathogenesis, progression, prognosis, and immunotherapy response, laying a foundation for developing novel biomarkers and therapeutic targets in the future and providing an important reference for the formulation of precision medicine strategies.

bioinformatics↗

bioRxiv2025

Multi-omics reveals lipid metabolism, mitochondrial and extracellular matrix dysregulation of diabetic cardiomyopathy in the human heart

Diabetic cardiomyopathy (DbCM) is a condition characterized by myocardial dysfunction in diabetes. Although the clinical recognition of DbCM is increasing, its underlying molecular mechanisms remain poorly understood. We aimed to conduct a comprehensive multi-omics analysis of heart tissue from cardiomyopathy patients (both with and without diabetes),alongside tissue from healthy donors, by integrating transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic data. Differential analyses revealed a significant metabolic pattern in patients with DbCM, characterized by increasing utilization of triglyceride-derived fatty acids. Correlation analyses highlighted impaired BNIP3L-mediated mitophagy as a potential contributor to the disruption of fatty acid metabolism and mitochondrial dysfunction in DbCM. Protein interaction and fibrotic trichrome analyses showed that patients with DbCM had impaired cardiac matrix repair compared to patients with cardiomyopathy without diabetes. These findings provide a system-level understanding of DbCM and reveal molecular signatures driving its progression, offering insights for targeted therapeutic strategies against diabetic heart disease.

bioinformatics↗

bioRxiv2025

Symptomatic treatment by a BBB-permeable AAV engineered to restore TDP-43 function slows motor neuron disease and prevents paralysis

TAR DNA-binding protein 43kDa (TDP-43) dysfunction is an early pathogenic mechanism that underlies amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder that lacks disease modifying therapies. We previously developed a mouse model in which TDP-43 is selectively deleted from motor neurons (ChAT-Cre;Tardbpf/f) that mimics the early stages of ALS. Here, we demonstrate that intravenous delivery of a blood-brain-barrier (BBB) permeable AAV capsid expressing our rationally designed splicing repressor CTR (AAV-PHP.eB-CTR) in symptomatic ChAT-Cre;Tardbpf/f mice markedly slowed disease progression and prevented paralysis. Systemic delivery of AAV-PHP.eB-CTR led to transduction of [~]80% of spinal motor neurons, repression of TDP-43-associated cryptic exons within motor neurons expressing CTR, and attenuation of motor neuron loss. Notably, the addition of the TARDBP 3UTR autoregulatory element to CTR maintained its expression within a physiological range. In control littermates that received AAV-PHP.eB-CTR and were monitored for >20 months, grip strength and body weight remained normal, and no histopathological abnormalities were observed, underscoring a favorable safety profile for this gene therapy. These results provide preclinical proof-of-concept that BBB-crossing AAV delivery of CTR can rescue motor neuron disease through the restoration of TDP-43 function, offering a promising mechanism-based therapeutic strategy for ALS.

neuroscience↗

bioRxiv2025

Distinct goal location beta frequency dynamics in hippocampus and prefrontal cortex across learning

Neural activity at goal locations contributes to learning by providing feedback on the success of preceding actions. This period engages neocortical and hippocampal networks, which serve distinct functions in reward processing and in forming associations between experience and reward. A neocortical network signature for reward feedback processing is beta oscillations (15-30 Hz). Beta oscillations are thought to coordinate distributed neural processes across brain regions. However, it is unknown whether beta oscillations coordinate hippocampal-neocortical networks during the goal period, or how their dynamics relate to learning. Here, we show that beta oscillations occur in both hippocampal CA1 and the prefrontal cortex (PFC) when rats reach goal locations in spatial navigation tasks. Despite the presence of beta oscillations in both regions after goal entry, beta activity in each region differed in spectral and temporal properties. These differences suggest that the hippocampus and PFC are weakly coupled at the beta frequency. We found that across learning, the strengths of PFC and CA1 beta oscillations were inversely related: PFC beta power increased and CA1 beta power decreased. Beta burst properties in PFC also had an inverse relationship to those of hippocampal sharp wave-ripples (SWRs), a prominent hippocampal process required for learning. We found a subset of PFC neurons modulated by both beta and hippocampal SWRs, which had distinct task-related firing patterns. Our results suggest that during outcome processing at goal locations, the neocortex and hippocampus are locally modulated at the beta frequency and then become coordinated for memory-related processes during SWRs.

neuroscience↗

bioRxiv2025

Approaching an Error-Free Diploid Human Genome

Complete human genomes now resolve regions long inaccessible to genetic analysis, yet repetitive and structurally complex sequences remain prone to assembly errors because of limitations in current assembly algorithms. We introduce a support-based framework founded on the principle that each sequencing read provides independent evidence for the underlying genome sequence. Implemented through Sufficient Alignment Support (SAS), the framework identifies regions lacking concordant read support, localizes residual errors, and guides correction. Applying SAS to T2T-YAO, a haplotype-resolved Han Chinese genome, produced a support-validated assembly in which nearly all sequences outside unresolved rDNA arrays and long homopolymer tracts are supported by independent sequencing evidence. This work establishes a scalable framework for genome validation and provides a support-validated East Asian diploid reference for investigating human genomic diversity.

genomics↗

bioRxiv2025

Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient

Amyloid transthyretin-derived (ATTR) amyloidosis is a degenerative, systemic disease characterized by transthyretin fibril deposition in organs like the heart, kidneys, liver, and skin. We report the first cryo-EM structure of transthyretin fibrils isolated from skin tissue of a living patient carrying a rare genetic mutation (ATTRv F64S). The structure adopts a highly conserved fold previously observed in other ATTR fibrils from different tissues or genetic variants. Mass spectrometry was used to evaluate fibril content and identify post-translational modifications. The structural consistency between ATTR filaments validates non-invasive skin biopsy as a diagnostic tool.

biochemistry↗

bioRxiv2025

Inertial sensing of water content in tumor spheroids

Cellular water content governs the concentration of all biomolecules inside a cell, thereby influencing the physical and functional properties of the cell. However, measurements of water content in physiologically relevant cell culture models remain largely unavailable, particularly in 3D models such as tumor spheroids and organoids. Here, we achieve such measurements using a commercially available, industrial-grade, steel tube. The steel tube functions as a mechanical resonator that inertially senses the buoyant mass of particles. For microgram-scale particles [≥]400 {micro}m in diameter, we achieve <1% precision error in buoyant mass with a 5-minute acquisition interval. By sequentially measuring the buoyant mass of individual, glioblastoma patient-derived tumor spheroids in media of different densities and cell permeabilities, we determine the absolute and fractional (v/v) water content of the spheroids, along with their dry mass, volume, and density properties. We achieve ~0.4% precision error in fractional water content with a throughput of 3 spheroids per hour. This enables us to detect both inter-spheroid variability in fractional water content and acute responses to kinase inhibition. Overall, we establish a simple and accessible technique for quantifying water content in living 3D cell culture models, opening new avenues for studying biophysical regulation in multicellular systems.

bioengineering↗

bioRxiv2025

Graph pangenome reveals structural variation dynamics during cucumber breeding

Structural variants (SVs) represent a significant yet underexplored component of plant genome diversity. Analyzing SV dynamics is important for understanding their contributions to phenotypic variation and their influence on genome evolution. Here, we present a graph-based pangenome for cucumber, constructed from 39 reference-level genome assemblies. The pangenome captures 171,892 high-confidence SVs and enables genotyping of these SVs across 443 cucumber accessions, representing diverse geographic origins and spanning wild progenitors, landraces, and modern cultivars. Our analyses reveal that during cucumber domestication, a substantial portion of mildly deleterious SNPs are retained, whereas SVs are consistently purged, highlighting their potentially highly deleterious nature. During the geographic expansion of cucumber, a reduction in SV burden and a younger age of SVs than SNPs were observed, suggesting stronger purifying selection acting on SVs. Additionally, notable gene flow from wild population to African and European populations was detected, resulting in an increased SV burden, potentially due to hitchhiking effects. Importantly, incorporating SV burden into genomic prediction models improved the prediction accuracy for several agronomically important traits. This study illuminates the dynamics of SVs during cucumber domestication and improvement, highlights the complex interplay between SVs and selection pressures, and underscores the extensive implications of SVs for future cucumber breeding.

plant biology↗

bioRxiv2025

MTARC1 Regulates Lipid Droplet Degradation via Phospholipid Remodeling in Metabolic Fatty Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of liver disease, including simple fatty liver, hepatic steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, with limited treatment options. MTARC1 p.A165T variant is associated with reduced risk of MASLD. We previously showed that this variant promotes MTARC1 protein degradation, suggesting MTARC1 inactivation may represent a potential therapeutic strategy. Here, we report that global or liver specific Mtarc1 knockout markedly suppresses diet-induced hepatic TG accumulation, liver injury, inflammation, and fibrosis in a manner dependently on lipolysis and lipophagy. MTARC1 inactivation post-transcriptionally upregulates PEMT and CEPT1 expression, consequently elevating GPL levels, including PC, PE, and lyso-PE, three major GPLs of hepatic LDs. Furthermore, we observed that MTARC1-deficient hepatocytes exhibited smaller but more numerous LDs compared to controls, under comparable cellular TG levels during lipolysis/lipophagy inhibition. Importantly, inhibition of CEPT1 or PEMT could attenuated the hepatoprotective effect of MTARC1 deficiency. Mechanistically, subcellular GPL remodeling induced by MTARC1 deficiency reduce LD size while increase their surface-to-volume ratio, which in turn promote TG degradation through lipolysis and lipophagy. Collectively, our findings identify MTARC1-GPL biosynthesis-LD degradation axis as a key regulator of fatty liver disease and highlight MTARC1 inhibition as a promising therapeutic strategy for MASLD.

cell biology↗