Biology subjects

Ye, S.

Publications and source records attributed to Ye, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗

bioRxiv2026

Generalisable tissue-wide molecular reconstruction from histology

Spatial transcriptomics technologies measure gene expression within intact tissues but remain difficult to scale across large tissue sections and patient cohorts. Consequently, many studies rely on tissue microarrays (TMAs) or sparse spatial profiling designs, where molecular measurements are available for only limited tissue regions and are often generated using heterogeneous gene panels. Existing H&E to spatial gene expression prediction methods remain challenged by sparse molecular measurements, partially overlapping gene panels and tissue-wide reconstruction across heterogeneous spatial datasets. Here, we present GHIST+, a framework for tissue-wide reconstruction of single-cell molecular states from H&E histology. GHIST+ integrates cellular morphology, local tissue context and shared tissue representations to extend sparse molecular measurements into tissue-wide molecular maps across heterogeneous spatial datasets. Across multiple cancer types and GTEx breast tissues, GHIST+ reconstructs biologically meaningful tissue-wide molecular organisation from sparse TMA-derived measurements while preserving spatial tissue structure, cell-type organisation and age-associated tissue states across cancer and non-cancer settings. GHIST+ establishes a scalable framework for transforming sparse spatial profiling experiments into tissue-wide molecular maps, enabling cohort-scale molecular reconstruction from routine histology under heterogeneous spatial transcriptomic settings.

bioinformatics↗

bioRxiv2026

Inter-organ communication shapes human metabolic tissue states and resolves anti-diabetic drug response modes in a six-tissue microphysiological system

Systemic glucose regulation depends on coordinated signaling among metabolically specialized tissues, yet most human in vitro models capture only limited portions of this network. Here, we developed and benchmarked a perfused human six-tissue MPS by combining AnthroHive, a recirculating perfusion platform, with MOTIVE-6, a six-compartment Multiorgan Tissue Interaction Vessel, to culture human gut epithelium, pancreatic islets, liver organoids, adipocytes, skeletal muscle, and midbrain-patterned brain organoids in a microphysiological system. Shared perfusion redirected engineered tissue states toward tissue-aligned metabolic, endocrine, absorptive, contractile, and neural-associated programs while reducing selected isolation-associated stress and remodeling signatures. Under High nutrient conditions, however, multi-tissue interaction shifted liver and islet responses toward inflammatory and nutrient-stress-associated gene expression, indicating context-dependent effects of cross-compartment signaling. Graded nutrient exposure resolved a staged circuit trajectory: Low nutrient conditions supported maintenance-associated programs, Mid nutrient exposure induced compensatory endocrine and anabolic remodeling with declining net glucose depletion, and High nutrient exposure shifted the system toward stress-associated metabolic dysfunction. Under High conditions, metformin and semaglutide produced distinct response modes. Metformin preserved circuit-level glucose handling without increasing insulin or C-peptide accumulation, while semaglutide remodeled gut, brain organoid, islet, and liver organoid transcriptional programs linked to nutrient sensing, epithelial maintenance, endocrine signaling, and neurometabolic state. Together, this study establishes a benchmarked human six-tissue MPS resource, paired with tissue-resolved transcriptomic, shared-media metabolomic, functional, endocrine, and inflammatory datasets, for investigating how tissue interaction, nutrient availability, and metabolic therapies reshape glucose-regulatory networks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/726943v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@181cdfforg.highwire.dtl.DTLVardef@fb211eorg.highwire.dtl.DTLVardef@13b7284org.highwire.dtl.DTLVardef@1db7543_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Trapecar, M. (2026) https://BioRender.com/a4tl7nv

bioengineering↗

bioRxiv2026

Structural Basis of Ligand-Specific Orthosteric-Allosteric Coupling and Sensory Tuning in the Human Bitter Taste Receptor TAS2R14

The bitter taste receptor TAS2R14 recognizes hundreds of structurally diverse ligands, yet the mechanisms governing its broad promiscuity, graded agonist efficacy, and multi-site regulation remain unclear. Here, we report cryo-EM structures of TAS2R14-Gi1 complexes bound to 3,5-diiodosalicylic acid (DA), flufenamic acid (FA) and aristolochic acid (AA) at resolutions of 2.44 [A], 2.39 [A], and 2.69 [A], with a clear efficacy hierarchy of AA > FA > DA. Transmembrane helix 6 (TM6) acts as a core regulatory hub, with agonist binding triggering 12 [A] lever-like TM6 rearrangements to reshape receptor interfaces and modulate G-protein coupling strength. We also identify cholesterol hemisuccinate (CHS) as a new TAS2R14 orthosteric agonist, selectively potentiating DA-mediated signaling potency by [~]5-fold via allosteric-orthosteric coupling without affecting FA or AA. Our findings show TM6 dynamics unify TAS2R14s key functional features, advancing insights into bitter receptor activation and sterol regulation.

molecular biology↗

bioRxiv2026

Multidimensional Mechanistic Study of Panax Notoginseng Saponins in the Treatment of Alcohol-Induced Osteonecrosis of the Femoral Head: Integrating Network Pharmacology, Molecular Dynamics Simulation and In Vivo Validation

BackgroundAlcohol-induced osteonecrosis of the femoral head (AIONFH) is an orthopedic disorder from chronic alcohol abuse, characterized by disrupted femoral head blood supply, osteocyte death and structural collapse. Current hip-preserving therapy is unsatisfactory, and most patients eventually require total hip arthroplasty. Panax Notoginseng Saponins (PNS), the core active component of Panax notoginseng, exerts pro-angiogenic and anti-osteocyte apoptosis effects, but its specific therapeutic mechanism remains unclear. ObjectiveThis study used network pharmacology, molecular dynamics simulation and animal experiments to identify PNSs active components, core targets and key pathways for AIONFH, verify its in vivo efficacy, and provide a scientific basis for clinical application. MethodsPNS active components, their targets and AIONFH-related targets were screened from databases; intersection targets constructed an interaction network, core targets were screened by three machine learning algorithms, with concurrent GO and KEGG analysis. Molecular docking was performed between core targets and PNS components; Gromacs 2022 conducted 100 ns simulation to evaluate complex stability. AIONFH rat models were grouped with 4-week intragastric intervention; pathology, immunofluorescence and PCR were used for detection. Results and DiscussionNetwork pharmacology identified 127 PNS targets and 18 intersections with 672 AIONFH targets. Six core targets (including FGF2, HSD11B1) were screened; KEGG indicated VEGF pathway as key. Ginsenoside Re bound HSD11B1 with the lowest binding energy (-12.4 kcal/mol), and 100 ns simulation confirmed complex stability. Animal experiments showed PNS improved trabecular structure and regulated osteocyte activity. PNS treats AIONFH via multi-component, multi-target mode, core mechanism being osteocyte apoptosis inhibition. Results and DiscussionNetwork pharmacology screening identified 127 potential targets of PNS, and 18 potential intersection targets were obtained by overlapping with 672 AIONFH-related targets. Six core targets including FGF2 and HSD11B1 were screened out by machine learning, and KEGG analysis indicated that the VEGF pathway and other pathways were the key signaling pathways for PNS action. Molecular docking showed that Ginsenoside Re had the lowest binding energy with HSD11B1 (-12.4 kcal/mol), and 100 ns molecular dynamics simulation confirmed the stable conformation of this complex. Animal experiments demonstrated that PNS could improve trabecular bone structure and regulate osteocyte activity. In summary, PNS exerts a therapeutic effect on AIONFH through a multi-component, multi-target and multi-pathway mode, with the core mechanism of inhibiting osteocyte apoptosis.

pharmacology and toxicology↗

bioRxiv2026

Organization of functional brain networks architecture during negative movie watching in late adulthood

Most evidence on age-related network topology derives from resting-state paradigms, leaving unclear how aging alters brain organization during naturalistic processing and whether graph-theoretical metrics relate to emotional and cognitive functioning in ecologically valid contexts. We analyzed movie-fMRI and behavioral data from 72 younger and 68 older adults, examining global (small-worldness, clustering coefficient, characteristic path length), network (participation coefficient), and nodal (degree centrality, betweenness centrality, nodal efficiency) properties. Regression models were used to test associations between nodal measures and both the Emotional Resilience Index (ERI) and the Cognitive Function Index (CFI), while mediation analyses were conducted to test whether nodal measures mediate the relationship between age and ERI. Older adults exhibited increased characteristic path length and clustering coefficient, indicating reduced global integration and greater local segregation. Although small-world organization was preserved in two groups, there was less pronounced small-world architecture in older adults compared to younger adults, suggesting a shift toward more regularized, locally clustered networks and reduced long-range connections during dynamic stimuli. Participation coefficient values were higher in the somatomotor, frontoparietal, and default mode networks, and lower in the subcortical network, among older adults reflecting greater between-network integration in cortical networks but diminished subcortical coordination in aging. Five key nodes, two thalamic regions, hippocampus, and two insular regions, showed reduced centrality and efficiency in older adults during the negative movie, indicating weakened dominance of subcortical hubs under emotional salience condition. Right thalamic nodal properties were negatively associated with ERI and CFI and served as mediators in the relationship between age and emotional resilience. These findings suggest that reduced thalamic hub centrality may reflect adaptive recalibration of salience emotional processing, linking network reorganization to improved emotional resilience in aging. Key pointsO_LIOlder adults showed higher path length and clustering, suggesting reduced integration. C_LIO_LIReduced small-worldness reflects weaker balance of segregation and integration with age. C_LIO_LIOlder adults showed higher cortical but lower subcortical participation coefficients. C_LIO_LIKey nodes showed reduced centrality during negative stimuli, indicating weaker hubs. C_LIO_LIRight thalamus changes linked to resilience, mediating age-emotion relationships. C_LI

neuroscience↗

bioRxiv2026

Porcine extended pluripotent stem cell-derived somite-like mesoderm cells with Dox-driven PAX7 are robust seed cell resource for facilitating production of cultured meat

Cultured meat technology, with its significant advantages of shortening meat production cycles, reducing natural resource consumption, minimizing the risk of zoonotic disease transmission, and enabling precise control over nutritional composition and texture, offers a novel alternative source for human meat consumption. One of the major challenges to produce cultured meat in large scale is how to establish high.quality seed cells, which should have long term proliferative capacities and are able to differentiate into muscles efficienuy with simple procedures. Here, we first established an engineered porcine expanded potential stem cells (Tet-On-PAX7 EPSCs) containing Tet-On regulated PAX7 gene. Then the Tet-On-PAX7 EPSCs were induced to somite-liKe mesodermal cells. These somite-liKe mesodermal cells can be expanded over 1025-fold even after 40 passages in-vitro culture while retaining strong myogenic potential. The somite-like mesodermal cells treated with DOX for one day would differentiate into muscle stem cells (Muses), and the later were able to differentiate into muscles with an efficiency of up to 90% within just 7 days in 11-FSDeDa without Dox. Moreover, when somite-liKe mesodermal cells were seeded on patterned scaffolds, microcarrier scaffolds, or cultured in anchorage-independent suspension, they maintained high efficiency in muscle differentiation, confirming their potential to be used as seed cells for scaled cultured meat production.

developmental biology↗

bioRxiv2026

Age-related reconfiguration of locus coeruleus-cortical functional organization

The locus coeruleus (LC) regulates attention, arousal, and adaptive behavior via widespread noradrenergic projections to cortex, yet its large-scale cortical organization and age-related vulnerability remain poorly understood. Using 7T MRI during naturalistic movie-viewing with neutral and negative emotional valence, study-specific LC delineation, and PET-derived receptor-transporter maps, we characterized LC-linked cortical organization in younger and older adults. Functional gradient analysis revealed two dominant axes: a stable primary gradient anchored by catecholaminergic receptor-transporter distributions, and a context-sensitive secondary gradient aligning with the visual-somatomotor (V-S) axis in neutral movie-viewing and the sensorimotor-association (S-A) axis in negative movie-viewing. During negative movie-viewing, older adults exhibited higher global and within-frontoparietal control network dispersion, indicating reduced functional differentiation, a pattern further associated with poorer emotional wellbeing. By revealing chemoarchitectural and context-sensitive LC-linked cortical organization, current work identifies mechanisms underlying age-related LC-linked cortical reorganization with consequences for mental health.

neuroscience↗

bioRxiv2026

Functional connectivity profile of the amygdala subfields associates with emotional well-being in aging

Amygdala-related functional connectivity plays a crucial role in human emotion, cognition, and mental well-being. The amygdala is a highly heterogeneous structure, with subregions that have both distinct and overlapping functions. However, the connectivity patterns of different amygdala subregions--and how these associations vary with age--remain poorly understood. Functional MRI data were analyzed from 68 younger adults and 66 older adults during movie watching in a 7T MRI scanner. Partial least squares (PLS) analysis was used to identify latent variables capturing variance associated with age-related differences in the functional connectivity patterns of three amygdala subregions: the basolateral (BLA), centromedial (CMA), and superficial (SFA) nuclei. In addition, covariance between behavioral measures, such as emotional resilience and cognitive function, and functional connectivity of these subregions was examined. We further explored the associated cognitive processes, correspondence with large-scale brain networks, and the underlying chemoarchitecture of the identified connectivity patterns of the BLA, CMA, and SFA. Multivariate analyses revealed age-related and subregion-specific functional connectivity patterns. Functional connectivity patterns of amygdala subregions were further associated with emotional resilience, which largely overlapped across widespread brain regions; however, their associations differed by age. Stronger coupling of amygdala subregions predicted higher resilience in older adults but lower resilience in younger adults. The identified connectivity patterns were linked to the salience, control, and default mode networks and showed spatial correspondence with mGluR5 and 5-HT6 receptor distributions. These findings highlight age-dependent reorganization of amygdala-related networks that support emotional resilience and provide novel insights into how functional and neurochemical changes of the amygdala subregions contribute to adaptive emotional and cognitive functions in aging.

neuroscience↗

bioRxiv2026

Lab-on-a-3D-Printer for Democratized Reconfigurable Digital Microfluidics

Automation in the life sciences remains dominated by expensive, centralized robotic systems, leaving most laboratories unable to access precision robotic liquid handling. Here we present the Lab-on-a-3D-Printer (Lo3DP), a reconfigurable robotic microfluidic platform that repurposes the motion control, thermal regulation, and open-source programmability of consumer 3D printers to deliver laboratory-grade automation at a hardware cost below $500. By replacing the extruder with a multifunctional magnetic toolhead, Lo3DP actuates ferrofluid droplets with sub-100 {micro}m positioning accuracy and programmable volume control spanning 0.5-25 {micro}L, enabling the full repertoire of digital microfluidic operations within inexpensive laser-cut chips (<$3). We quantitatively validate system performance through long-term droplet transport exceeding 40,000 s without degradation, automated serial dilutions with high linearity (R{superscript 2} [≥] 0.99), and fully automated colorimetric nucleic acid amplification assays whose results match conventional benchtop workflows under tightly regulated isothermal conditions (CV {approx} 0.3%). By harnessing the global economies of scale of consumer 3D printers, Lo3DP provides accurate, reproducible, and programmable assay automation at a fraction of the cost and footprint of conventional systems, establishing a practical path toward desktop-scale, democratized laboratory robotics.

bioengineering↗

bioRxiv2025

Neutrophil-neuronal crosstalk drives arthritis-induced pain

Pain in rheumatoid arthritis (RA) often persists despite effective control of inflammation, suggesting distinct mechanisms driving nociception. In both patients and animal models, pain severity does not strongly correlate with the degree of inflammation1,2. Sensory neurons, with cell bodies located in the dorsal root ganglia (DRG), innervate peripheral tissues, including joints, and transmit pain signals to the central nervous system. Crosstalk between sensory neurons and immune cells occurs at all of these sites. While sensory neurons can be directly activated by immune mediators, it remains unclear whether pain-like behaviour in antibody-induced arthritis models arises independently of immune cell activity, or which immune cell populations and mediators are required to activate pronociceptive mechanisms. Through temporal profiling of the CAIA joint-DRG transcriptomic axis, we identified SEMA4D and OSM signalling as candidate molecular mediators of neutrophil-neuron communication and neuronal sprouting. The joint-DRG atlas also revealed persistent changes in the fibroblast-immune cellular composition of the joint, along with molecular changes in DRG neurons. We showed that mechanical and cold hypersensitivity, as well as sprouting of CGRP+ nociceptive fibers in synovial tissue of mice with collagen antibody-induced arthritis (CAIA), require neutrophils but not macrophages. Analysis of publicly available datasets showed that neutrophils from the synovium of RA patients express high levels of SEMA4D and OSM, and corresponding expression of their receptors, PLEXINB1 and OSMR, in human DRG neurons, underscoring the translational relevance of this axis. Both murine and human-derived DRG neurons sprout in response to OSM. Our findings demonstrate that neutrophils produce molecules that act as cues for nociceptor sensitization and structural remodelling. Targeting these molecules could improve the efficacy of RA treatments by reducing pain while simultaneously preventing disease progression.

immunology↗

bioRxiv2025

Stalling of elongating Pol II triggers Ser7 phosphorylation in trans to drive transcription recovery

DNA is scattered with obstacles that stall RNA polymerase II (Pol II) and block the production of full-length transcripts. Two mechanisms are known to resolve stalled Pol II: transcription-coupled nucleotide excision repair (TC-NER) and the "last resort" Pol II ubiquitylation-degradation pathway. Here, we uncover a third, distinct mechanism that alerts incoming Pol II molecules to roadblocks ahead and primes them for efficient elongation. We show that transcription stalling triggers GSK3-mediated phosphorylation of Ser7 residues (Ser7P) on the Pol II C-terminal domain. Unexpectedly, this phosphorylation occurs in trans: obstacles in gene bodies induce Ser7P on Pol II complexes at gene beginnings. This modification enables processive transcription while restraining excessive Pol II degradation by the "last resort" pathway. Our findings reveal an adaptive system that preserves transcriptional homeostasis by coordinating polymerase behavior across the gene in response to elongation stress.

molecular biology↗

bioRxiv2025

A novel method to sort and enrich sensory neurons

Peripheral sensory neurons, residing in the dorsal root ganglia (DRG), relay sensory information from the periphery to the central nervous system. Although single-cell transcriptomic studies have identified over 20 distinct sensory neuron subtypes, functional analysis and assessment of subtype-specific pathological changes remain difficult. Effective isolation and enrichment of sensory neurons are challenging yet essential for functional studies. Therefore, we used single-cell transcriptomic data from DRG to identify a panel of neuronal surface markers, including Nrxn2 and Pirt. Using these markers, we developed a fluorescence-activated cell sorting (FACS) panel for neuronal enrichment and analysis that does not rely on transgenic mouse strains and can be broadly applied. The panel was validated by microscopy and single-cell RNA (scRNA) sequencing, which also revealed broad representation of neuronal subtypes. Expression of these markers in human DRG underscores the translational value of this isolation method for sensory and pain studies. Overall, this study provides a valuable tool for isolating DRG neurons, advancing research on sensory neuron function and pain biology, and facilitating neuroimmune studies.

neuroscience↗

bioRxiv2025

Dissecting the Cellular Genetics of Cardiovascular Disease Through Endothelial and Immune Compartments Profiling

BackgroundNon-communicable diseases such as coronary artery disease, atrial fibrillation, type 2 diabetes, hypertension, and others share endothelial dysfunction as one of their underlying features. The endothelium, as the interface between blood and vasculature, shapes disease onset and progression through its response to environmental cues. However, while the genetic component of these diseases has been captured by genome wide association studies (GWAS), which also highlighted a shared immune component, it remains unclear which of these disease loci exerts their effects through endothelial cells. This study identifies, and quantifies, the genetic determinants of endothelial cells molecular traits and their overlap to the common genetic variation component of these diseases. MethodsWe generated genotype, RNA-sequencing, H3K27ac ChIP-sequencing, ATAC-sequencing, and endothelial cells barrier stimuli response measurements for 100 samples of human umbilical vein endothelial cells. These were used to identify quantitative trait loci (QTL) for gene expression, transcriptional isoform usage, splice junction usage, chromatin activity and barrier response. We applied statistical colocalisation to identify the overlap between data layers, and to explain molecular QTLs contribution to GWAS disease loci. ResultsWe used molecular QTLs to identify the regulatory features of 8,214 genes, representing 36% of all expressed genes in endothelial cells. We also identified the molecular mechanisms underlying 815 loci across 16 disease GWAS. These represent between 29% and 40% of all loci for each disease, compared to the previous average of 23%. This is due to the choice of a cell type often underrepresented in tissue level data, and the inclusion of isoform, splicing and chromatin activity datasets. Furthermore, we compared the endothelial cells molecular QTLs with similar datasets in monocytes, neutrophils and CD4 T lymphocytes to shed light on the interplay between the endothelial and the immune compartments in these diseases. We identified loci acting through both the endothelial and the immune compartment, mostly with the same directionality of effect, and endothelial specific ones. ConclusionsThis work expands the knowledge of the mechanisms and genes underlying the effect of common genetic variation on non-communicable diseases having endothelial dysfunction as a shared feature. It also illustrates the interplay between endothelial cells and immune cell types in these diseases, highlighting shared and unique pathways.

genomics↗

bioRxiv2025

Resolving Heterogeneity in Major Depression: Overcoupling and Undercoupling Subtypes Exhibit Differential Treatment Response and Molecular Pathways

Major depressive disorder (MDD) exhibits significant heterogeneity whose neurobiological mechanisms remain elusive. Alterations in morphological-functional coupling (MFC) have been observed in MDD. This study aims to investigate MDD subtypes based on MFC alterations and their associations with clinical symptoms and molecular basis. We identified two clinically distinct MDD subtypes in multi-center neuroimaging data (Discovery: 828 MDD/776 healthy controls; Validation: 236 MDD/86 healthy controls) by using a semi-supervised machine learning approach based on MFC changes, which were validated and robustly repeated in the validation dataset. Differences among subtypes were then examined in relation to clinical assessments, gene expression patterns, neurotransmitter and cell density, and treatment response. Subtype I (overcoupling) showed elevated MFC in high-order association cortices, linking to synaptic transmission activity and severe symptoms. Subtype II (undercoupling) demonstrated reduced MFC in primary cortices, associated with cell cycle regulation and treatment resistance. Both subtypes shared molecular signatures (cell types: astrocytes and oligodendrocytes; neurotransmitter systems: serotonergic and GABAergic receptors). Crucially, longitudinal data (33 MDD undergoing Escitalopram monotherapy) revealed that undercoupling subtype exhibited better response, implying a potential mechanism of the drug via increasing the MFC. Our work deciphers MFC-driven MDD phenotypes with distinct molecular profiles and differential treatment outcomes, suggesting potential pathways for personalized diagnosis and treatment strategies in MDD, advancing precision psychiatry.

neuroscience↗

bioRxiv2025

Dynamic Spiral Artery Remodeling in Early Human Pregnancy: An Analysis of Specimens Collected with a Standardized Protocol

Human uterine spiral artery remodeling (SAR) is a tightly regulated process involving complex interactions between interstitial and endovascular extravillous trophoblasts (iEVTs and enEVTs) and diverse maternal decidual cell populations. However, the intrinsic spatiotemporal dynamics of SAR in human placentation remain poorly understood, largely due to the limited availability of high-quality maternal-fetal interface specimens. Electively terminated early pregnancies offer a valuable resource for studying SAR in situ, yet inconsistent methods for distinguishing fragmented villous and decidual tissues have hindered reproducibility and interpretation. Herein we present a standardized protocol for the classification and characterization of high-quality maternal-fetal interface specimens from elective terminations by integrating stereomicroscopic evaluation with confirmation by immunohistochemistry and immunofluorescence microscopy. Combined with multiplex immunofluorescence imaging with cell-type- specific markers, this approach enabled precise spatial mapping and quantification of key morphological and cellular events in SAR from gestational weeks 5 to 10. Our analyses reveal that SAR initiates as early as week 5 with extraluminal recruitment of natural killer (NK) cells, followed by the formation of tightly packed EVT plugs within the lumens of spiral arteries in the decidua compacta; these plugs progressively extend deeper into the vessels and gradually loosen as gestation progresses. Notably, enEVTs appear to acquire NK cell-like phenotypes that may facilitate the displacement of endothelial and smooth muscle cells, promoting progressive vessel dilation. In summary, we provide a robust and reproducible method for assessing physiological SAR in early human pregnancy, supporting the adoption of our methodology in future studies of pathological SAR and related pregnancy disorders. Summary SentenceA standardized protocol for classifying maternal-fetal interface specimens from electively aborted materials at gestational weeks 5-10 was developed to quantify the spatiotemporal spiral artery remodeling dynamics in early human pregnancy. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/682615v2_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@ad6f1eorg.highwire.dtl.DTLVardef@5a3dcborg.highwire.dtl.DTLVardef@8f06b7org.highwire.dtl.DTLVardef@1f877_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

Integrated mesenchymal and extracellular cues drive bioengineered liver tissue formation and function

Human liver tissue engineering holds promise for creating physiological in vitro models but faces challenges replicating liver complexity. In the present study, we created bioengineered liver tissues (BLTs) utilizing three different cell types; human intrahepatic cholangiocyte organoids (ICOs), hepatic stellate cells (HSCs), and mesenchymal stromal cells (MSCs). Co-culturing with HSCs and MSCs accelerated growth and spontaneous fusion, resulting in complex liver-like tissue structures. In a dynamic suspension culture, BLTs had a more compact morphology and higher expression of hepatic markers, including ALB, CYP3A4, and MRP2. We further showed that animal-derived Matrigel can be replaced by a synthetic polyisocyanide (PIC)-based hydrogel for BLTs. Importantly, PIC-based hydrogel further promoted the maturation of BLTs assessed by parameters as intracellular protein levels, morphological analysis, and metabolic activity. Transcriptomic analyses revealed mechanisms underlying tissue formation and function. To conclude, our strategy yields functional liver tissues suitable for disease modelling, drug screening, and toxicity tests, and forms an important basis for future development of larger liver tissues for in vivo transplantation.

bioengineering↗

bioRxiv2025

Modeling structural variations sequencing information to address missing heritability and enhance risk prediction

Missing heritability remains a significant challenge in genome-wide studies focused on single nucleotide polymorphisms (SNPs) when analyzing the genetic basis of complex traits. Structural variations (SVs), which span broader genomic regions and often exert larger functional impacts than SNPs, hold promise for capturing this heritability. Although graph-based pangenomes have advanced SV detection and association analysis, traditional SNP-centric frameworks typically overlook detailed SV sequence information, treating overlapping SVs as independent variants and leading to reduced statistical power. To overcome this limitation, we developed SVrefiner, an algorithm that aligns overlapping SVs and partitions them into non-overlapping refined SVs (rSVs) based on sequence congruence. By generating precise genotype matrices, SVrefiner enables more accurate association studies. When applied to human, tomato, and pig genomes, SVrefiner delineated 48,712 rSVs from 77,696 human SVs, 6,607 rSVs from 51,561 tomato SVs, and 5,237 rSVs from 142,784 pig SVs. Incorporating rSVs alongside SNPs, indels, and unrefined SVs enhanced heritability estimates by up to 24.47%. Further, refined analysis revealed that gene expression traits are often influenced by specific SV subregions rather than entire SVs. Notably, integration of rSVs in human datasets increased total eQTLs by 71.56%, with cis- and trans-eQTLs rising by 21.3% and 94.4%, respectively. Mean risk prediction accuracy across over 16,000 traits improved by as much as 16.8%. These findings deepen the understanding of complex trait heritability and demonstrate the utility of rSVs for genetic improvement and disease risk assessment.

genetics↗