Biology subjects

Lu, J.

Publications and source records attributed to Lu, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

An open-access CT-based 3D anatomical dataset of extant sharks across all major lineages

0Sharks exhibit extraordinary morphological diversity across a wide range of ecological niches, yet large-scale, high-resolution digital datasets of their internal anatomy remain limited. Here we present an open-access 3D shark anatomical repository derived from published X-ray computed tomography (CT) data, featuring manually segmented and systematically annotated models of the chondrocranium, visceral arches, axial skeleton, musculature, and viscera in standard STL format. The dataset comprises 117 individuals, representing 72 species across 25 families and all nine extant shark orders, with 115 full-body reconstructions and two head-only models. This open-access dataset offers a comprehensive resource for comparative anatomy, biomechanical simulations, evolutionary developmental biology and biomimetics research of extant sharks.

evolutionary biology↗

bioRxiv2026

ROS Impair Mitophagy via PARylation of PINK1

Mitophagy is the process of selective autophagic clearance of damaged mitochondria and is closely implicated in neurodegenerative disease. PTEN-induced kinase 1 (PINK1) and a RBR E3 ubiquitin-protein ligase (Parkin) constitute a positive feedback loop in mitophagy initiation. It is known that reactive oxygen species (ROS) modulate mitophagy, while the exact regulatory mechanism remains largely elusive. Here, we found that exogenously applied ROS effectively block mitophagy induced by acute mitochondrial damage agents, which could be reversed by antioxidants. Mechanistically, ROS activate poly(ADP-ribose) polymerase 1 (PARP1), and suppression of PARP1 eliminates the inhibitory effect of ROS on mitophagy. Notably, PARP1 directly interacts with PINK1 and mediates its PARylation at residue E417, thereby negatively regulating PINK1 function. Collectively, our study identifies PARylation as a new form of post-translational modification of PINK1 and reveals a novel mechanism underlying the regulatory role of ROS in mitophagy by PARP1 activation and PARylation of PINK1. In briefGao et al. demonstrate that exogenous ROS inhibit mitophagy. Mechanistically, ROS activate PARP1, which mediates PARylation of PINK1, a central regulator of mitophagy, leading to its functional impairment. This study reveals a novel regulatory mechanism of ROS on mitophagy through PARP1 activation and identifies PARylation as a novel form of post-translational modification of PINK1. HighlightsO_LIROS block PINK1-Parkin-mediated mitophagy. C_LIO_LIROS activate PARP1. C_LIO_LIPARP1 suppression eliminates the inhibitory effect of ROS on mitophagy. C_LIO_LIPARylation of PINK1 by PARP1 impairs its activity and mitophagy. C_LI

Cell Biology↗

bioRxiv2026

Identification of the complete pathway for conversion of bilirubin to urobilinogen by human gut bacteria

Bilirubin, the predominant product of heme catabolism in mammals, enters the intestine via the hepatobiliary system and subsequently is metabolized by the gut microbiome. This process consumes bilirubin and generates multiple downstream derivatives, such as urobilinogen and stercobilinogen. Levels of bilirubin and its derivatives are associated with susceptibility to inflammatory and metabolic disorders, but the microbial species and enzymes that metabolize bilirubin have remained largely unknown. Here, demonstrate that metabolism of bilirubin to urobilinogen requires two separate reactions that can occur in either order and identify novel enzymes and pathway intermediates required for conversion. We find that bilirubin reductase (BilR), an enzyme that was recently discovered and proposed to convert bilirubin to urobilinogen, is specific for reducing the methine bridges of bilinoids, converting bilirubin to the novel intermediate divinylurobilinogen and mesobilirubin to urobilinogen. Using transcriptomic profiling, we identify the bilinoid vinyl reductase (BilV) responsible for reducing the vinyl groups of bilirubin and divinylurobilinogen. BilV is a flavin-dependent oxidoreductase of the Old Yellow Enzyme (OYE) superfamily with a broad distribution across human gut bacteria that overlaps with but does not completely mirror the distribution of BilR. These findings establish the complete pathway for bacterial conversion of bilirubin to urobilinogen, enabling defined studies to interrogate how this metabolism contributes to human health and disease.

microbiology↗

bioRxiv2026

Long-read RNA-seq resolves isoform-level and context-specific regulatory architecture of complex traits in cattle

Traditional short-read RNA-seq lacks the resolution to fully capture full-length isoforms and complex alternative splicing, leaving a "missing regulation" gap in existing molecular atlases. Here, we present a population-scale, multi-omics dissection of bovine complex traits using matched deep whole-genome sequencing (30x), long-read (ONT) and short-read RNA-seq, as well as metabolome data from 432 dairy cows across four distinct lactation stages. We expanded the bovine transcript atlas with 13,177 novel isoforms and fine-mapped 1,088,900 regulatory effects across 11 diverse molecular phenotypes. Notably, long-read mapping uncovered 606 genes with isoform expression quantitative trait loci (12.8%, eQTL) and 1,116 genes with detailed splicing QTL (sQTL) (31.8%) that were missed by conventional short-read mapping. We further showed that lactation-specific regulation was profoundly mediated by the metabolic microenvironment (46.8%) and cellular composition (4.3%). Across genome-wide associations (GWAS) of 90 bovine complex traits, isoform-level and context-specific regulatory effects captured GWAS loci missed by short-read eQTL and sQTL analyses, increasing colocalized loci from 35.2% to 60.3%. These regulatory variants also exhibited evolutionary constraints with human immune and metabolic loci. Our study establishes an invaluable resource (https://cattleblr.farmgtex.org) demonstrating that long-read transcriptomics is essential for resolving the complexity of regulatory mechanisms underlying mammalian physiology.

genetics↗

bioRxiv2026

Divergent scalp-to-region distance alteration patterns in autism spectrum disorders, Parkinson's disease and Alzheimer's disease

Brain stimulation is increasingly recognized as an effective and important therapeutic intervention for many brain diseases. Distance between the scalp and other brain regions is a pivotal variable for neurostimulation planning and the development of new techniques, but alterations in the distance between the scalp and other regions in brain diseases are largely unknown. In this study, we developed an automatic pipeline to calculate scalp-to-region distance (SRD) values from T1 MR images and applied it to a total of 1382 participants, including patients with autism spectrum disorder (ASD), Parkinsons disease (PD), Alzheimers disease (AD), and cognitively normal controls (CNs). Cloud points were uniformly sampled on the automatically extracted scalp surface and cortex surface, on which the point-wise distance maps were generated. The brain was then coregistered with the BCI-DNI atlas, and SRD value for each brain region was extracted. Analysis of covariance (ANCOVA) was performed for SRD in each brain region, with age and sex as covariates. Compared with CNs, ASD patients showed widespread SRD decreases across the brain with prominent involvement of the frontal lobe, especially the orbitofrontal cortex and adjacent regions. In contrast, in AD patients, significantly increased SRD values were observed in various regions of the frontal gyrus. No significant SRD alteration was found in PD patients after correction. The automatic SRD calculation pipeline and the different patterns of SRD alterations in these diseases might be helpful for future neurostimulation planning in clinical practice. HighlightsO_LIAutomatic pipeline enables scalp-to-region distance (SRD) measurement, facilitates brain stimulation planning. C_LIO_LIASD patients show widespread SRD decreases, especially in the orbitofrontal cortex and adjacent regions. C_LIO_LIAD patients present increased SRD in the frontal gyrus and decreased SRD in the parahippocampal gyrus. C_LI

neuroscience↗

bioRxiv2026

Dual-view Guided Context-aware Network for Automated Bone Lesion Segmentation and Quantification in Whole-body SPECT

Whole-body SPECT bone scintigraphy reflects skeletal metabolic activity throughout the body and plays an indispensable role in the screening, treatment evaluation, and prognostic assessment of bone metastases in tumors. However, the automatic detection and segmentation of hypermetabolic bone lesions remain challenging due to low contrast, limited spatial resolution, and complex lesion distributions. In this study, we proposed Bone-Segnet, a dual-view guided automatic segmentation network for hypermetabolic bone lesions that integrated multi-scale feature modeling, global context modeling, and view-conditioned modulation. Pixel-level annotated anterior and posterior whole-body bone scintigraphy images were used for model training and prediction. The proposed network enhanced the recognition of low-contrast and small-scale lesions through small-lesion enhancement and multi-scale contextual modeling. A Transformer module was further introduced to strengthen global feature representation, while cross-view collaborative modeling was achieved by incorporating the complementary characteristics of anterior and posterior imaging. Experimental results demonstrated that the proposed method outperformed existing approaches across multiple evaluation metrics, with the Dice score improving from 0.7440 to 0.8750, indicating a substantial improvement in segmentation performance. Further quantitative analysis based on the segmentation results revealed significant differences among disease types in lesion count, pixel burden, and spatial distribution patterns, reflecting the heterogeneity of disease-related skeletal metabolic activity. Overall, the proposed method improved automatic lesion segmentation performance and enabled quantitative analysis of lesion burden and spatial distribution patterns, providing objective data support for the assessment of related diseases. Index Terms--Whole-body SPECT, bone lesion segmentation, dual-view modeling, quantitative analysis.

bioinformatics↗

bioRxiv2026

Histone modifications analysis reveals enhancers reprogramming during maternal-to-zygotic transition

Enhancers are important epigenetic regulatory components that coordinate spatiotemporal gene expression and play a crucial role in mammalian development, gene regulation, and illness. During early mammalian embryogenesis, histone modifications including H3K4me1, a canonical enhancer mark, and H3K27ac, which identifies active enhancers, are still poorly understood. This study profiles the genome-wide H3K4me1 and H3K27ac patterns in mouse oocytes and pre-implantation embryos using low-input CUT&RUN (cleavage under targets and release using nuclease) with input as low as 50 cells. Both markers are enriched in distal regions and exhibit distinct sequence preferences and reprogramming dynamics in pre-implantation embryos. H3K27ac, a mark of active enhancers, is reprogrammed at the 2-cell stage, whereas H3K4me1 is remodeled at the 4-cell stage and overlaps with H3K27ac, coinciding with accessible chromatin regions. Interestingly, H3K4me1 and H3K27ac are co-localized in promoter regions, where they are mutually exclusive to H3K4me3. Enhancers are dynamically remodeled during maternal-to-zygotic transition (MZT). there are three enhancer types: active enhancers (H3K4me1/H3K27ac), primed enhancers (H3K4me1), and poised enhancers (H3K4me1/H3K27me3). Active enhancers increase significantly after zygotic genome activation. Further, super-enhancers are present across the genome and are mainly enriched in promoters. The specific motifs enriched by super-enhancers may be associated with the variations of gene expressions at different stages.

developmental biology↗

bioRxiv2026

Guidance for high-quality functional gene embeddings from large language models

Large language models (LLMs) are increasingly used to generate gene embeddings, yet systematic benchmarks of prompting strategies and practical guidance for obtaining biologically meaningful representations remain limited. Here we present GEbench, an evaluation framework for assessing LLM-derived gene embeddings across different tasks, prompting strategies, and LLM architectures. GEbench revealed that embedding quality depends primarily on whether the input text contains explicit functional information, rather than on sparse gene identifiers or model size. Identifier-based embeddings showed weak biological organization, whereas embeddings derived from functional descriptions consistently achieved stronger functional separation and predictive performance. Notably, Self-Des, which extracts embeddings from model-generated gene function descriptions, enabled locally deployable LLMs to generate high-fidelity representations that approach the quality of expert-curated databases. Genome-scale analyses further supported these findings, indicating that explicit functional descriptions are an effective design principle for generating high-quality gene embeddings from LLMs.

bioinformatics↗

bioRxiv2026

A digital twin of pancreatic islet differentiation predicts cell fate

The controlled generation of mature stem cell-derived islets (SC-islets) remains a barrier to scalable cell therapy for diabetes. Here, we develop a predictive digital model defining the cell-state-specific regulatory logic governing fate specification during human SC-islet differentiation. We integrate 400,603 cells from 9 original single-cell multiomic datasets and 52 public single-cell RNA-seq and ATAC-seq datasets across 4 cell lines and 7 differentiation protocols. This model resolves transcriptional and chromatin accessibility dynamics while enabling time-resolved inference and in silico perturbation of cell-state-specific gene regulatory networks. We identify regulators across trajectories from endoderm progenitors to pancreatic exocrine and endocrine lineages, nominating new candidate regulators. Among these candidates, we validate previously unreported roles for STAT1 as an exocrine driver and ZEB1 as a dynamic regulator of early endocrine specification and later off-target serotonergic islet cell fate. This work provides an experimentally supported predictive framework and an interactive resource comprising 1,116 simulations to prioritize transcription factors and intervention windows for refining SC-islet differentiation.

cell biology↗

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

Dissociating the Hallucinogenic and Neuroplastic Effects of Psilocybin

It is unclear how serotonin 2A receptors (5-HT2ARs) in cortical layer 5 pyramidal neurons (L5 PyrNs) differentially contribute to psilocybin-induced hallucinations versus neuroplasticity. Here we show that psilocybin promotes synapse formation and maturation while accelerating the elimination of pre-existing synapses. Cell type-specific manipulation further demonstrated that 5-HT2AR signaling in L5 PyrNs is necessary and sufficient for psilocybin-induced synaptic remodeling but dispensable for the head-twitch response, a rodent proxy of hallucination.

neuroscience↗

bioRxiv2026

Ultra-large targeted DNA integrations in primary human cells

Genetic engineering experiments and therapies are constrained by the size of DNA integrations into human cells genomes. Existing AAV, lentiviral, and non-viral methods rapidly decrease in integration efficiency beyond [~]5kb of sequence. Through systematic evaluation of non-viral DNA template formats, we identified circular ssDNA and dsDNA as capable of mediating >5kb integrations. Large circular DNA delivery efficiency and its impacts on cell viability and payload expression could be significantly improved with small DNA "helper" plasmids, mRNA-encoded nucleases, and sequence design optimizations. Collectively, these modifications enabled ultra-large--up to 10 kb DNA--integrations at >20% efficiency in primary human T cells at the TRAC locus and at >60% efficiency in human iPSCs at the AAVS1 locus. Finally, we demonstrate that GMP clinical-manufactured T cells with ultra-large integrations are functional in vitro and in vivo. Overall, we identified optimal template architectures, delivery modes, and sequence design rules for ultra-large DNA integrations in both research and clinical settings to accelerate basic genetic research and next-generation cellular therapies.

genetics↗

bioRxiv2026

Spike-in probe-enhanced single-cell RNA-seq reveals post-infusion transcriptomic remodeling of "prime-and-kill" synNotch-CAR-T cells

We previously developed synthetic Notch (synNotch)-chimeric antigen receptor (CAR)-T cells to improve the safety and efficacy of CAR-T therapy for glioblastoma. In this system, an anti-EphA2/IL13R2-dual-CAR is expressed only upon recognition of tumor- or brain-specific "priming" antigens, EGFRvIII (termed E-SYNC cells) or brevican (B-SYNC), respectively, with E-SYNC currently under phase I clinical evaluation (NCT06186401). However, tracking and profiling these engineered cells in vivo remain challenging, limiting our understanding of their activity and therapeutic potential. To address this gap, we developed a single-cell RNA-sequencing (scRNA-seq) workflow with custom spike-in probes for synNotch-CAR transcripts, enabling simultaneous detection of engineered cells and transcriptomic profiling. In vitro, integration of multiple probes using machine-learning-assisted classifiers detected 78.2% of E-SYNC cells and 60.0% of B-SYNC cells with 98.0% specificity. In a xenograft model, synNotch-positive cells were detected across the spleen, lung, and brain, with the highest frequency and most robust priming and activation observed in the brain. Single-cell transcriptomic analyses revealed tissue-specific differentiation programs, including cytotoxicity, proliferation, metabolic activity, and acquisition of tissue-resident memory phenotypes, shaped by both environmental cues and synNotch-mediated antigen recognition. In summary, this spike-in probe-enhanced scRNA-seq workflow enables robust detection and high-resolution characterization of synNotch-CAR-T cell dynamics and provides a broadly applicable platform for monitoring engineered immune cells in diverse clinical contexts. One Sentence SummaryOur spike-in probe-enhanced single-cell RNA-sequencing method enables analysis of tissue-dependent activation and transcriptional states of synNotch-CAR-T cells, providing a robust and scalable platform for in vivo tracking and transcriptomic profiling of engineered cell therapies.

cancer biology↗

bioRxiv2026

The translatome of quiescent Plasmodium falciparum gametocytes reveals parasite pyridoxal 5'-phosphate (PLP) biosynthesis is essential for efficient mosquito stage development

The ability of Plasmodium falciparum gametocytes to remain quiescent within the vertebrate host but poised for rapid onward development in the mosquito is an adaptation essential to maximise the onward spread of malaria. In this dormant state, mature infectious stage V gametocytes are largely unaffected by most antimalarial drugs and our limited understanding of how gametocytes prepare for mosquito transmission has hindered the identification of new molecular targets for transmission-blocking therapeutics. In this study, we move beyond the total proteome of gametocytes and define the translatome of mature stage V gametocytes using L-azidohomoalanine incorporation into nascent proteins, click chemistry purification and proteomic analysis. We identify the proteins and pathways that gametocytes sustain in preparation for transmission during this dormant period and through genetic disruption, we validate this approach by demonstrating the importance of parasite pyridoxal 5-phosphate biosynthesis for mosquito transmission.

microbiology↗

bioRxiv2026

The enhanced multi-tissue atlas of regulatory effects in cattle

Cattle are integral to global food security, yet the molecular architecture of their complex traits remains poorly understood. Here, we present the Cattle Genotype-Tissue Expression (CattleGTEx) Phase 1 resource (https://cattlegtex.farmgtex.org/), a substantial expansion of the pilot study. By leveraging 12,422 RNA-seq profiles across 43 tissues and 82 breeds, we characterized 433,972 primary and 161,428 non-primary regulatory effects spanning seven molecular phenotypes. This high-resolution atlas resolves 75% of GWAS signals for 44 complex traits, significantly addressing the "missing regulation" in livestock. We propose a genetic regulatory model demonstrating how variants across multiple biological layers interact with specific biological contexts to shape phenotypic variation. Furthermore, CattleGTEx elucidates mechanisms underlying adaptive evolution between Bos taurus and Bos indicus, as well as artificial selection in dairy and beef breeds. Finally, by mapping evolutionary constraints on these regulatory effects, we demonstrate the translational value of this resource for prioritizing causal variants in human complex diseases. Together, Phase 1 of CattleGTEx provides a transformative framework for functional genomics, precision breeding, and comparative genetics.

genetics↗

bioRxiv2026

CHPT1-LCAT rewires lipolysis towards ferroptosis

Ferroptosis is driven by iron-dependent lipid peroxidation, yet how metabolic flux through central lipid pathways is selectively routed towards pro-ferroptotic lipid species remains unclear. Here, through an unbiased chemical-genetic screen targeting core metabolic enzymes, we identify diacylglycerol (DAG) as a licensing lipid intermediate whose pro-ferroptotic activity depends on its intracellular routing. Systematic manipulation of lipolytic flux reveals that ferroptotic vulnerability is not determined by bulk lipolytic output or downstream intermediates, but by the selective channelling of DAG into a distinct metabolic fate. Mechanistically, DAG is selectively routed through a previously unrecognized intracellular metabolic axis composed of choline phosphotransferase 1 (CHPT1) and lecithin-cholesterol acyltransferase (LCAT). We uncover an enzymatically active intracellular pool of LCAT (iLCAT) that cooperates with CHPT1 on Golgi-trans-Golgi network membranes to generate polyunsaturated cholesteryl esters that execute ferroptosis. Functionally, enforced DAG routing through this axis suppresses tumour growth via ferroptosis in vivo, whereas hepatocyte-specific inhibition of the CHPT1-iLCAT axis attenuates lipid peroxidation and disease progression in metabolic dysfunction-associated steatohepatitis. Together, these findings establish subcellular lipid routing, rather than lipid abundance per se, as a fundamental determinant of ferroptotic vulnerability.

cell biology↗

bioRxiv2026

Subclonal Complete Loss of CDKN1B as a Common Genomic Alteration in Prostate Cancer: Associations with Race and Prostate Cancer Outcomes

BackgroundHomozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. Experimental DesignWe used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy. ResultsIPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. IPPL was associated with [≥]pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease. ConclusionsSubclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males.

cancer biology↗

bioRxiv2026

Dissociable frequency regimes in human temporal cortex integrate facial and acoustic cues during natural speech

Face-to-face communication relies on the seamless integration of visual and acoustic cues, yet the spatiotemporal principles governing how the human brain dynamically represents and combines these multisensory streams remain largely unresolved. To address this, we recorded high-density electrocorticography (ECoG) from eight participants perceiving matched audiovisual, audio-only, and video-only continuous natural Mandarin speech. Using time-frequency-resolved encoding models, we reveal complementary, frequency-dependent integration regimes across the temporal lobe. We show that the superior temporal gyrus (STG) implements a feature-selective, auditory-dominant strategy, utilizing visual input to selectively strengthen low-frequency representations of lip-reading kinematics. Conversely, the middle temporal gyrus (MTG) acts as a higher-order multisensory hub, employing a frequency-selective strategy to broadly integrate diverse facial and articulatory features. Crucially, we demonstrate that access to visual information during perception significantly improves the acoustic and lexical accuracy of neural speech decoding and re-synthesis, with the MTG driving the largest gains in linguistic intelligibility. These findings uncover the dissociable neural architectures supporting robust multisensory perception, providing critical mechanistic insights for the development of next-generation, multimodal brain-computer interfaces.

neuroscience↗