Biology subjects

Shu, J.

Publications and source records attributed to Shu, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Medin-Induced Pro-inflammatory and Prothrombotic Activation of Coronary Artery Endothelial Cells: A Potential Novel Mediator Linking Aging and Atherosclerosis

BackgroundAge is the most important risk factor for coronary artery disease (CAD) independent of traditional risk factors. Aging induces classic pro-inflammatory and prothrombotic vascular phenotypic changes whose molecular mediators remain poorly understood. Medin is a common cleavage product protein that accumulates in vasculature with aging and shown to cause endothelial dysfunction. Its role in CAD is unknown. The study aimed to evaluate the effects of medin on human coronary artery endothelial cell (HCAEC) pro-inflammatory and prothrombotic activation and establish the relationship between medin and coronary atherosclerosis in human decedents. MethodsHCAECs were exposed to physiologic dose of medin (5 {micro}M) for 20 hours and ribonucleic acid sequencing (RNAseq) with signaling pathway analyses and reverse transcription polymerase chain reaction of select pro-inflammatory and prothrombotic genes performed. Corresponding protein expression was measured by Western blot or enzyme linked immunosorbent assay in HCAECs exposed to medin (5 {micro}M) without or with nuclear factor-{kappa}B (NF{kappa}B) inhibitor RO106-9920 (10 {micro}M). Coronary arteries from 40 deceased individuals underwent immunohistochemistry and medin and plaque burden were quantified and their relationship evaluated. ResultsRNAseq showed predominant pro-inflammatory gene expression changes induced by medin. HCAECs treated with medin showed increased phosphorylated NF{kappa}B, elevated protein expression of interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and plasminogen activator inhibitor (PAI)-1 and reduced protein expression of thrombomodulin; these changes were reversed by RO106-9920 co-treatment. In human tissues, coronary artery medin strongly correlated with plaque burden (R=0.76, p<0.0001) and coronary macrophage content (R=0.72, p<0.0001). Coronary arteries from decedents with myocardial infarction had higher medin than those without (5.53{+/-}2.67% versus 0.02{+/-}0.02%, p=0.0005). ConclusionsMedin induced NF{kappa}B-mediated endothelial cell pro-inflammatory and prothrombotic activation and was strongly associated with coronary plaque burden and inflammation. Medin is a novel candidate mediator linking aging and coronary atherosclerosis.

physiology↗

bioRxiv2026

Germline regulation of tumor evolutionary dynamics shapes multiple myeloma progression

Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-{kappa}B signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.

bioinformatics↗

bioRxiv2026

Nucleoporin1 maintains male germ unit organization and transport in Arabidopsis pollen tubes, likely through shaping nuclear morphology

The male germ unit (MGU) in Arabidopsis pollen is comprised of one vegetative nucleus (VN) and two sperm nuclei (SN). It is evolutionarily specialized to deliver immotile sperm nuclei to an ovule for fertilization. Despite some progress in research on MGU, its organization and transport remain only partially understood. Here, we identified Nucleoporin1/136 as a new player in the structural organization and positioning of MGU in pollen tubes. We and others have previously reported the reduced fertility of nup1-1 plants; however, the mechanism remains unknown. In this work, we further examined the role of NUP1 in fertility using two mutant alleles, nup1-1 and nup1-2-/+. The reciprocal crosses between the nup1 mutants and the Col-0 wild type indicate that the nup1 mutant pollen is defective. To study the effect of a complete NUP1 knockout on pollen, we generated a transgenic line that produces pollen with and without NUP1 expression. This work led to the surprising discovery that the NUP1 protein is inherited from the pollen mother cell to the daughter cell during microgametophyte development. Subsequent in vitro experiments showed that NUP1 is required for pollen germination and pollen tube elongation. Further microscopic studies demonstrated that NUP1 is highly expressed in VN and essential for maintaining nuclear shape and size. We also demonstrated that NUP1 is required for proper MGU organization and transport, likely through maintaining VN morphology. Notably, our finding of nuclear morphology-mediated regulation of MGU may also explain the mechanistic details underlying the defective MGU movement in previously reported mutants such as kaku4, wit, and wip, which have abnormal nuclear morphology.

plant biology↗

bioRxiv2026

Elamipretide reverses female fertility decline during reproductive aging via regulating VEGF in oocytes

Aging is one of the primary drivers for the decline of female fertility, and oocyte quality is the main cause for ovary aging, which is related with infertility. Although some effective anti-aging natural components have been reported, highly efficient strategies for reversing ovary aging remain lacking. In this study, we reported that peptide elamipretide reserved ovary function for female fertility during maternal aging. Our findings demonstrated that elamipretide improved aged human oocyte maturation and fertilization. Elamipretide injection increased the litter size of aged mice, and improved oocyte quality with the reverse of follicle and embryo development defect. Metabolomic and transcriptomic analyses demonstrated that multiple biological processes in oocytes were significantly reserved. Both nuclear maturation and cytoplasmic maturation of aged oocytes were improved, showing with enhancing cytoskeletal dynamics, mitochondrial metabolism and organelle rearrangement. In vitro supplementation during culture also restored oocyte developmental competence in both mouse and porcine oocytes. Mechanistic analysis suggested that elamipretide reversed age-related ovarian damage via synergistic activation of the Vitamin B6-VEGF axis. Therefore, our study proposed a new peptide therapy for aging-induced infertility, showing that elamipretide reverses aged oocyte quality for fertility by promoting both nuclear and cytoplasmic maturation through the coordination with VEGF signaling pathway.

developmental biology↗

bioRxiv2026

Noncanonical loops regulated by EMF1 and cohesin-associated factors shape the distinct 3D genome architecture in plants

In mammals, cohesin-mediated chromatin loop extrusion is blocked at boundaries, where CTCF, WAPL, and PDS5s co-bind and regulate cohesin, establishing an impermeable barrier with no exceptions. In contrast, our study revealed that in Arabidopsis, some noncanonical contacts have emerged between the boundary flanking regions, which suggest that cohesin is not absolutely blocked but enables sliding beyond boundaries. We identified these interactions as noncanonical loops and clarified their regulatory proteins. Firstly, the plant-specific boundary binding protein EMF1 is essential for noncanonical loops formation. Surprisingly, although both Arabidopsis WAPLs and PDS5s inhibit loop extension as mammals, PDS5s do not co-bind and cooperate with WAPLs at boundaries. Instead, PDS5s bind to boundary-flanking regions enriched with H3K4me1 through their Tudor domains, restricting further extension of noncanonical loops. Consequently, pds5a/b/c mutants lose noncanonical loops, resulting in emergence of larger canonical loops but anchored on boundaries and co-upregulation of anchored gene pairs. Collectively, our findings reveal that the plant-specific noncanonical loop, regulated by plant-specific EMF1 and PDS5 proteins, is the fundamental structure of the distinctive chromatin organization of plants, which provides novel mechanistic insights into eukaryotic chromatin architecture regulation.

plant biology↗

bioRxiv2025

VIP-OT: Dissecting Single-Cell Biochemical State Dynamics under Perturbation via Vibrational Painting and Optimal Transport

Dissecting the heterogeneous response of individual cells towards genetic and chemical perturbations is central to understanding the dynamic functions of cells and multicellular systems. However, characterizing and modeling how individual cells transition between different states remains a major challenge. Vibrational imaging provides high-content, biochemically informative, label-free molecular fingerprints of single cells but it remains at its infancy for dynamic or predictive analysis of cell state transition. Here, we introduce Vibrational Painting-Optimal Transport (VIP-OT), an integrated experimental-computational framework that overcomes this fundamental limitation. VIP-OT couples multiplexed infrared (IR) and Raman imaging with optimal transport to computationally reconstruct single-cell perturbation trajectories from unpaired population snapshots. When applying to over 22,000 single-cell spectra profiles from human breast adenocarcinoma cells under 16 drug treatments, this framework can retrospectively trace drug response heterogeneity back to baseline metabolic states. We leverage the inferred cell pairings to develop a machine learning model that accurately predicts the full post-treatment metabolic state of individual cells from their pre-treatment spectra. Furthermore, by modeling transitions across dose gradients, we introduce the concept of Spectral Velocity to map dynamic response trajectories and resolve drug combination effects into distinct, path-dependent molecular routes. Together, VIP-OT opens a new direction for dissecting heterogeneous perturbation responses at single cell resolution and serves as a foundation for building virtual simulators of cells under perturbations through high-throughput, high-content, and low-cost vibrational imaging, as well as interpretable in silico modeling.

bioengineering↗

bioRxiv2025

RamanOmics Decodes Spatial Vibrational-Molecular Architecture and Rewiring in Aging and Repair

Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and molecular architecture of aging and senescence directly in intact tissues. Applied to mouse lung and skin, RamanOmics generates spatially resolved biochemical-molecular maps revealing tissue-specific programs: lung senescent cells are enriched for extracellular matrix (ECM) remodeling and TGF-{beta} signaling (Serpine1, Dab2, Igfbp7), whereas skin senescence is dominated by keratinization and barrier homeostasis modules (Krt10, Lor, Sbsn). Across tissues, we identify a conserved branched-chain fatty-acid-linked biochemical profile and Raman signature (1131-1135 cm-{superscript 1}) that robustly marks p21 senescent cells. To unify these layers, we develop a machine learning derived "multimodal barcode" that quantitatively integrates biochemical and transcriptional features, enabling non-destructive identification of senescence in situ. In a wound-healing model, RamanOmics further reveals coordinated reactivation of barrier-repair programs in senescent cells, marked by upregulation of Krt10, Lor, Sbsn, Sfn, and Dmkn together with matching increases in lipid-associated Raman signatures, confirming biological generalizability beyond steady-state aging. By directly integrating gene programs to spatial vibrational-biochemical states, RamanOmics provides a general framework and resource for scalable, multimodal profiling of cellular states.

systems biology↗

bioRxiv2025

Competing Subclones and Fitness Diversity Shape Tumor Evolution Across Cancer Types

Intratumor heterogeneity arises from ongoing somatic evolution complicating cancer diagnosis, prognosis, and treatment. Here we present TEATIME (estimating evolutionary events through single-timepoint sequencing), a novel computational framework that models tumors as mixtures of two competing cell populations: an ancestral clone with baseline fitness and a derived subclone with elevated fitness. Using cross-sectional bulk sequencing data, TEATIME estimates mutation rates, timing of subclone emergence, relative fitness, and number of generations of growth. To quantify intratumor fitness asymmetries, we introduce a novel metric--fitness diversity--which captures the imbalance between competing cell populations and serves as a measure of functional intratumor heterogeneity. Applying TEATIME to 33 tumor types from The Cancer Genome Atlas, we revealed divergent as well as convergent evolutionary patterns. Notably, we found that immune-hot microenvironments constraint subclonal expansion and limit fitness diversity. Moreover, we detected temporal dependencies in mutation acquisition, where early driver mutations in ancestral clones epistatically shape the fitness landscape, predisposing specific subclones to selective advantages. These findings underscore the importance of intratumor competition and tumor-microenvironment interactions in shaping evolutionary trajectories, driving intratumor heterogeneity. Lastly, we demonstrate that TEATIME-derived evolutionary parameters and fitness diversity offer novel prognostic insights across multiple cancer types.

bioinformatics↗

bioRxiv2025

Defining the cell and molecular origins of the primate ovarian reserve

The primate ovarian reserve is established during late fetal development and consists of quiescent primordial follicles in the ovarian cortex, each composed of granulosa cells surrounding an oocyte in dictate. As late stages of fetal development are not routinely accessible for study with human tissue, we exploited the evolutionary proximity of the rhesus macaque to investigate primate follicle formation. Similar to human prenatal ovaries, the rhesus also develops multiple types of pre-granulosa (PG) cells, with the majority of primordial follicles derived from PG2 with small variable contributions from PG1. We observed that activated medullary follicles recruit fetal theca cells to establish a two-cell system for sex-steroid hormone production prior to birth, providing a cell-based explanation for mini puberty.

developmental biology↗

bioRxiv2024

RO8191, a new compound for initiating embryoimplantation in mice

During early pregnancy in mice, leukemia inhibitory factor (LIF) regulates embryo implantation by activating the JAK/STAT3 signaling pathway. The STAT3 pathway has been recognized to play a critical role in embryo implantation. However, it is not clear whether STAT3 activation itself can cause induction of embryo implantation. In this study, the effects of RO8191, a potential STAT3 activator, on embryo implantation were investigated through a series of studies with different mouse models. We found that the injection of RO8191 can induce embryo implantation by activating the STAT3 pathway in delayed implantation mice. Furthermore, RO8191 can initiate decidualization, which is essential for embryo implantation, in uterine epithelial-specific Stat3, Gp130, or Lifr conditional knockout (cKO) mice, which shows infertility due to embryo implantation failure. Histomorphological observations revealed that successful embryo implantation and embryonic development was seen in Lifr cKO mice. Increased epithelial detachment and vascularization were observed in Stat3 cKO mice, and excessive inflammatory response and embryo death were observed in Gp130 cKO mice. These results suggest that STAT3, Gp130 and LIFR each play a distinct role in embryo implantation and development. Although the specific mechanisms of RO8191 are not fully understood, the present study will provide insights to support the application of RO8191 in treating recuurent implantation failure.

developmental biology↗

bioRxiv2024

A conserved Pol II elongator SPT6L mediates Pol V transcription elongation to regulate RNA-directed DNA methylation in Arabidopsis

In plants, the plant-specific RNA polymerase V (Pol V) transcripts non-coding RNAs and provides a docking platform for the association of accessory proteins in the RNA-directed DNA methylation (RdDM) pathway. Various components have been uncovered that are involved in the process of DNA methylation, but it is still not clear how the transcription of Pol V is regulated. Here, we found that the conserved Pol II elongator, SPT6L, bound to thousands of intergenic regions in an RNA polymerase II (Pol II) independent manner. The intergenic enrichment of SPT6L, interestingly, co-occupied with the largest subunit of Pol V (NRPE1) and mutation of SPT6L led to the reduction of DNA methylation but not Pol V enrichment. Furthermore, the association of SPT6L at Pol V loci was dependent on the Pol V associated factor, SPT5L, rather than the presence of Pol V, and the interaction between SPT6L and NRPE1 was compromised in spt5l. Finally, Pol V RIP-seq revealed that SPT6L is required to maintain the amount and length of Pol V transcripts. Our findings thus uncovered the critical role of a Pol II conserved elongator in Pol V mediated DNA methylation and transcription, and shed light on the mutual regulation between Pol V and II in plants.

plant biology↗

bioRxiv2023

Deep learning reveals the role of copy number variation in the genetic architecture of a highly polymorphic sexual trait

The extraordinary variation in male guppy coloration has proven a powerful model for studying the interplay of natural and sexual selection. However, this variation has hampered the high-resolution characterization and determination of the genetic architecture underlying male guppy color, as well as clouded our understanding of how this exceptional level of diversity is maintained. Here we identify the heritability and genetic basis of male color variation using convolutional neural networks for high-resolution phenotyping coupled with selection experiments, controlled pedigrees and whole-genome resequencing for a Genome Wide Association Study (GWAS) of color. Our phenotypic and genomic results converge to show that color patterning in guppies is a combination of many heritable features, each with a largely independent genetic architecture spanning the entire genome. Autosomally-inherited ornaments are polygenic, with significant contributions from loci involved in neural crest cell migration. Unusually, our GWAS results suggest that gene duplicates from the autosomes to the Y chromosome are responsible for much of the sex-linked variation in color in guppies, providing a potential mechanism for the maintenance of variation of this classic model trait.

evolutionary biology↗

bioRxiv2023

Bering: joint cell segmentation and annotation for spatial transcriptomics with transferred graph embeddings

Single-cell spatial transcriptomics such as in-situ hybridization or sequencing technologies can provide subcellular resolution that enables the identification of individual cell identities, locations, and a deep understanding of subcellular mechanisms. However, accurate segmentation and annotation that allows individual cell boundaries to be determined remains a major challenge that limits all the above and downstream insights. Current machine learning methods heavily rely on nuclei or cell body staining, resulting in the significant loss of both transcriptome depth and the limited ability to learn latent representations of spatial colocalization relationships. Here, we propose Bering, a graph deep learning model that leverages transcript colocalization relationships for joint noise-aware cell segmentation and molecular annotation in 2D and 3D spatial transcriptomics data. Graph embeddings for the cell annotation are transferred as a component of multi-modal input for cell segmentation, which is employed to enrich gene relationships throughout the process. To evaluate performance, we benchmarked Bering with state-of-the-art methods and observed significant improvement in cell segmentation accuracies and numbers of detected transcripts across various spatial technologies and tissues. To streamline segmentation processes, we constructed expansive pre-trained models, which yield high segmentation accuracy in new data through transfer learning and self-distillation, demonstrating the generalizability of Bering.

bioinformatics↗

bioRxiv2023

NUCLEOPORIN1 mediates proteasome-based degradation of ABI5 to regulate Arabidopsis seed germination

NUCLEOPORIN1 (NUP1), a member of the Nuclear Pore Complex (NPC), is located on the inner side of the nuclear membrane. It is highly expressed in seeds; however, its role in seeds including germination has not been explored yet. Here, we identified an abscisic acid (ABA) hypersensitive phenotype of nup1 during germination. ABA treatment drastically changes the expression pattern of thousands of genes in nup1, including the major transcription factors (TFs) involved in germination, ABI3, ABI4, and ABI5. Double mutant analysis of NUP1 and these ABA-related genes showed that mutations in ABI5 can rescue the phenotype of nup1, suggesting that NUP1 acts upstream of ABI5 to regulate seed germination. ABI5, a key negative regulator of germination, is abundant in dry seeds and rapidly degrades during germination. However, its spatiotemporal regulation and interaction with other molecular players during degradation remained to be fully elucidated. We found that NUP1 is physically associated with ABI5 and the 26S proteasome. Mutation in NUP1 delayed ABI5 degradation through its post-translational retention in nucleolus under abiotic stress. Taken together, our findings suggest that NUP1 anchors the proteasome to NPC and modulates seed germination through proteasome-mediated degradation of ABI5 in the vicinity of NPC in the nucleoplasm.

plant biology↗

bioRxiv2023

Analyzing bivariate cross-trait genetic architecture in GWAS summary statistics with the BIGA cloud computing platform

As large-scale biobanks provide increasing access to deep phenotyping and genomic data, genome-wide association studies (GWAS) are rapidly uncovering the genetic architecture behind various complex traits and diseases. GWAS publications typically make their summary-level data (GWAS summary statistics) publicly available, enabling further exploration of genetic overlaps between phenotypes gathered from different studies and cohorts. However, systematically analyzing high-dimensional GWAS summary statistics for thousands of phenotypes can be both logistically challenging and computationally demanding. In this paper, we introduce BIGA (https://bigagwas.org/), a website that aims to offer unified data analysis pipelines and processed data resources for cross-trait genetic architecture analyses using GWAS summary statistics. We have developed a framework to implement statistical genetics tools on a cloud computing platform, combined with extensive curated GWAS data resources. Through BIGA, users can upload data, submit jobs, and share results, providing the research community with a convenient tool for consolidating GWAS data and generating new insights.

genetics↗

bioRxiv2023

A mouse-specific model to detect genes under selection in tumors

Mouse is a widely used model organism in cancer research. However, no computational methods exist to identify cancer driver genes in mice due to a lack of labeled training data. To address this knowledge gap, we adapted the GUST (genes under selection in tumors) model, originally trained on human exomes, to mouse exomes using transfer learning. The resulting tool, called GUST-mouse, can estimate long-term and short-term evolutionary selection in mouse tumors, and distinguish between oncogenes, tumor suppressor genes, and passenger genes using high throughput sequencing data. We applied GUST-mouse to analyze 65 exomes of mouse primary breast cancer models, leading to the discovery of 24 driver genes. The GUST-mouse method is available as an open-source R package on github (https://github.com/liliulab/gust.mouse).

bioinformatics↗

bioRxiv2023

Inference of single cell profiles from histology stains with the Single-Cell omics from Histology Analysis Framework (SCHAF)

Tissue biology involves an intricate balance between cell-intrinsic processes and interactions between cells organized in specific spatial patterns, which can be respectively captured by single cell profiling methods, such as single cell RNA-seq (scRNA-seq) and spatial transcriptomics, and histology imaging data, such as Hematoxylin-and-Eosin (H&E) stains. While single cell profiles provide rich molecular information, they can be challenging to collect routinely in the clinic and either lack spatial resolution or high gene throughput. Conversely, histological H&E assays have been a cornerstone of tissue pathology for decades, but do not directly report on molecular details, although the observed structure they capture arises from molecules and cells. Here, we leverage vision transformers and adversarial deep learning to develop the Single Cell omics from Histology Analysis Framework (SCHAF), which generates a tissue samples spatially-resolved whole transcriptome single cell omics dataset from its H&E histology image. We demonstrate SCHAF on a variety of tissues-- including lung cancer, metastatic breast cancer, placentae, and whole mouse pups--training with matched samples analyzed by sc/snRNA-seq, H&E staining, and, when available, spatial transcriptomics. SCHAF generated appropriate single cell profiles from histology images in test data, related them spatially, and compared well to ground-truth scRNA-Seq, expert pathologist annotations, or direct spatial transcriptomic measurements, with some limitations. SCHAF opens the way to next-generation H&E analyses and an integrated understanding of cell and tissue biology in health and disease.

bioinformatics↗

bioRxiv2023

Bovine milk glycoproteins inhibit SARS-CoV-2 and influenza virus co-infection

The attachment of S1 subunit of spike (S) protein to angiotensin-converting enzyme 2 (ACE2) is the first and crucial step of SARS-CoV-2 infection. Although S protein and ACE2 are heavily glycosylated, the precise roles of glycans in their interactions are still unclear. Here, we profiled the glycopatterns of S1 subunit of SARS-CoV-2 and ACE2, and found that the galactosylated glycoforms were dominant in both S1 subunit and ACE2. Interestingly, S1 subunit exhibited the property of glycan-binding protein (GBP) and adhered to the ACE2 via binding to the galactosylated glycans on the ACE2. Our earlier findings demonstrated that the sialylated glycoproteins isolated from bovine milk potently inhibit and neutralize viral activity against influenza A virus (IAV). Importantly, we proved further that the galactosylated glycans on isolated glycoproteins bind to the glycan recognition domains of S1 subunit and competitively inhibit binding of S1 subunit to ACE2 and ultimately impede the entry of SARS-CoV-2 pseudovirus into host cells. We provided a potential protein drug that could be multiple simultaneous inhibitor for coronavirus and IAV co-infection.

microbiology↗