Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 577 records · Page 32Linked to original sources

bioRxiv2025

Brain-derived neurotrophic factor supports pericyte and vascular homeostasis in the aging brain

Microvascular circulation in the brain is often impaired in connection with the loss of pericytes in old age. The neurotrophic factor BDNF also decreases in the aging brain. We hypothesized that BDNF regulates the homeostasis of cerebral pericytes and microvasculature. We used differently aged C57BL/6J mice, and C57BL6 mice with conditional knockout of Bdnf gene. Collagen IV-positive microvessels and PDGFR{beta}-positive pericytes in the brain were counted after immunological staining. Pericytes were also quantified by Western blot of PDGFR{beta} and CD13 in isolated cerebral microvessels. The level of BDNF and TrkB phosphorylation was determined in brain homogenates. To demonstrate the direct effect of BDNF on pericytes, TrkB and pericytes were co-stained in brain tissue, single-cell sequencing and transcriptomic analysis were used to identify and characterize Ntrk2-expressing pericytes, and TrkB was also detected in the pericyte cell line by Western blot. Cultured pericytes were further treated with recombinant BDNF in the presence and absence of an Akt inhibitor and examined for PDGFR{beta} expression. The length and branching of microvessels and pericytes decreased in conjunction with the reduction in mature BDNF and TrkB phosphorylation in aging brains. Deficiency of BDNF in neurons or astrocytes was sufficient to reduce cerebral microvessels, PDGFR{beta} and CD13 concentrations and Akt and Erk1/2 phosphorylation in isolated blood vessels. A subset of pericytes in the brain and cultured pericytes expressed TrkB. BDNF treatment increased PDGFR{beta} expression along with Akt and Erk1/2 phosphorylation in cultured cells. The effect of BDNF on PDGFR{beta} expression was abolished by treatment with Akt inhibitor. Therefore, BDNF induces the expression of PDGFR{beta} and CD13 by activating Akt signaling in pericytes, promoting the homeostasis of pericytes and microvasculature in the aging brain. Our study identified a BDNF-mediated mechanism that regulates microvascular integrity in the aged brain.

neuroscience↗

bioRxiv2025

MECP2 Mutations Rewire Human ESC Fate and Bias Cortical Lineage Commitment

Rett syndrome arises from loss-of-function mutations in the X-linked chromatin regulator MECP2, yet the earliest molecular derailments in human development remain poorly defined. Using isogenic hESC models carrying three patient-derived MECP2 mutations, we followed the transcriptome from pluripotency through neuro-ectoderm, neural stem, and neural progenitor stages and into three-month cerebral organoids. Stage dominated transcriptional variance, but mutants shared a secondary program enriched for synaptic-membrane and extracellular-matrix genes. Single-cell profiling revealed a naive-like, hyper-proliferative state marked by up-regulation of ZFP42 at ESC stage. Strikingly, EMX1, a cortical radial-glia determinant, was consistently suppressed from the earliest stage onward, and cerebral organoids subsequently generated fewer excitatory neurons in favour of inhibitory and glial lineages. These data chart a continuous developmental trajectory for MECP2-mutant human cells and nominate ZFP42 and EMX1 dysregulation as tractable entry points for dissecting Rett pathogenesis.

neuroscience↗

bioRxiv2025

p53 activity licenses transcriptional regulation by YAP/TAZ-TEAD to shape expression landscapes during tumorigenesis

The tumor suppressor p53 is the most frequently disabled gene in cancer, where its inactivation promotes the transition between transcriptionally distinct pre-malignant and malignant disease. How p53 action shapes these stage-dependent expression landscapes is poorly understood. Using a mouse model where p53 function is restored in advanced pancreatic cancer, we demonstrate that p53 dependent gene expression is determined by regulation of YAP/TAZ-TEAD transcriptional complexes at multiple levels of molecular control. Restoration of p53 activity in pancreatic cancer cells expands transcriptional regulation by reorganizing TEAD binding at newly accessible enhancer landscapes, resulting in distinct TEAD-driven gene regulatory networks when p53 is inactivated versus engaged. Furthermore, p53 potentiates expression of newly licensed TEAD targets by increasing TAZ levels in response to the actin remodeling associated with cell cycle arrest and senescence. Thus, p53 activity controls the qualitative and quantitative output of YAP/TAZ-TEAD, including secretory programs involved in tumor-immune communication and remodeling of the microenvironment. Our work nominates regulation of YAP/TAZ-TEAD via p53 as a mechanism that determines stage dependent transcriptional landscapes during stepwise tumorigenesis.

cancer biology↗

bioRxiv2025

Multi-Scale Kinetics Modeling and Advanced Assay for mRNA-Lipid Nanoparticle Potency Assessment

mRNA lipid nanoparticle (mRNA-LNP) technology has attracted global attention, especially in vaccine development, due to its superior delivery efficiency, molecular stability, and safety profile. However, evaluating mRNA-LNP potency--defined as the quantifiable biological response elicited by the product--remains costly and time-consuming when relying solely on in vitro experiments. Rapid and reliable potency assessment is hindered by limited mechanistic understanding of delivery processes and sparse experimental data. To address these challenges, we present a mechanism-informed, multi-scale kinetic modeling framework that quantitatively captures the coupled dynamics across particle-level, cellular, and macroscopic scales. This model incorporates variability in LNP-cell interactions and accounts for critical factors such as dosage, LNP and cell size distributions, and cell proliferation dynamics--all of which influence delivery efficiency and response variability. By integrating advanced multi-omics assays--such as single-molecule fluorescent in situ hybridization (smFISH), which enables single-cell resolution of mRNA and protein expression--our framework leverages heterogeneous, multi-scale data to support mechanistically grounded modeling of mRNA delivery and enable robust predictions of therapeutic potency. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/679406v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1f3ec2borg.highwire.dtl.DTLVardef@1163893org.highwire.dtl.DTLVardef@1dc530borg.highwire.dtl.DTLVardef@1d0264a_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

scRGP: Prediction of Single-cell Genetic Perturbation Transcriptional Responses based on Rank in Multiple Scenarios

Single-cell perturbation sequencing technologies (e.g., Perturb-seq, CROP-seq), which integrate CRISPR-based gene editing with single-cell transcriptome profiling, have revolutionized the analysis of transcriptomic changes induced by genetic perturbations at single-cell resolution. These technologies serve as a powerful tool for identifying key genes that inhibit tumor growth or reverse cancer cell phenotypes. However, they face two major challenges: data explosion with high experimental costs, and data complexity characterized by high dimensionality, noise, sparsity, and heterogeneity. To address these challenges, we developed the single-cell Rank-based Genetic Perturbation predictor (scRGP), the first deep learning framework leveraging gene expression rank-order information for this task. scRGP demonstrates superior performance in terms of robustness, cross-cell-line perturbation prediction, and high-throughput screening. Specifically, scRGP achieves an approximately 10-16 percentage points improvement in Pearson correlation coefficient (PCC) over state-of-the-art methods (e.g., GEARS and scFoundation) for single- and double-gene perturbation predictions, while also extending prediction capability to triple-gene perturbations. Furthermore, it outperforms these methods by approximately 5-9 percentage points in cross-cell-line predictions. These advancements promise to shift the paradigm of single-cell perturbation studies from experiment-driven to computation-driven approaches, providing new support for functional genomics and precision medicine.

bioinformatics↗

bioRxiv2025

Enhancing protein structure prediction accuracy by prioritizing important residues using protein language models

Accurate prediction of protein tertiary structures from amino acid sequences remains a fundamental challenge in computational biology. Although AlphaFold2 represents a major advance, systematic discrepancies persist between its predictions and experimentally determined structures. Given that individual residues contribute differentially to protein function, we hypothesized that incorporating residue-specific importance metrics could improve prediction accuracy. Here, we develop i-Fold (importanceFold), an enhanced neural architecture enhances the AlphaFold2 architecture by integrating protein language model ESM-derived residue importance scores (RIS) as dynamic positional weights during training. Our approach dynamically weights amino acids using RIS during structure prediction, thereby directing computational attention toward functionally critical residues and regions. Evaluation on a benchmark test set of 3,559 protein structures reveals that i-Fold significantly improves accuracy (reduction in r.m.s.d., p = 0) and achieves a higher prediction success rate (7.6% improvement: 55.1% [->] 62.7%). Notably, i-Fold demonstrates particular improvements for targets that are typically challenging for AlphaFold2, including ribosomal proteins, membrane proteins, and orphan proteins. Consistent results were obtained on a completely independent test set of 167 recently released protein structures, where i-Fold again exhibited a higher prediction success rate (6.0% improvement: 43.7% [->] 49.7%) compared to AlphaFold2. Our findings indicate that explicit integration of RIS can advance the state-of-the-art in protein structure prediction, producing more accurate and generalizable models without substantially increasing computational cost.

bioinformatics↗

bioRxiv2025

NQO1 phase condensation promotes stress granule assembly to facilitate pancreatic carcinogenesis

G3BP1 promotes pancreatic ductal adenocarcinoma (PDAC) tumorigenesis driven by oncogenic KRAS mutations through liquid-liquid phase separation (LLPS)-mediated assembly of stress granules (SGs). However, the regulatory mechanisms remain elusive. We identify the antioxidant enzyme NAD(P)H quinone dehydrogenase 1 (NQO1) as a novel SG regulator that enhances SG assembly in pancreatic cancer cells independently of reactive oxygen species (ROS). Mechanistic studies reveal that NQO1 does not regulate the expression of G3BP1 or other SG-associated genes. Instead, NQO1 undergoes LLPS dependent on its RNA-binding K homology (KH) like domain. Further analysis demonstrates that residues 121-131 of NQO1 directly interact with G3BP1s RNA-binding domain (RBD), enhancing the multivalency of G3BP1 complexes to potentiate LLPS-driven SG assembly. This interaction accelerates cell proliferation, KRAS mutation-induced acinar-to-ductal metaplasia (ADM), and pancreatic carcinogenesis. Notably, the interaction between NQO1 residues 121-131 and G3BP1s RBD is essential for NQO1 phase condensation under stress condition. Integrative analysis of human PDAC transcriptomic datasets reveals a weak association between NQO1 and G3BP1 levels. Importantly, both NQO1 and G3BP1 formed biological condensates and co-localized in the lesions of human PDAC tissue sections. Our study uncovers a novel KRAS mutation-driven mechanism of pancreatic carcinogenesis through the lens of phase separation, transcending conventional gene expression regulation and offering new insights into non-canonical KRAS-NQO1-G3BP1-SG regulatory networks in PDAC initiation.

cancer biology↗

bioRxiv2025

Hepatic cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): Topological determinants and cellular partnerships that dictate the preferential P450 proteolytic sorting into macroautophagy rather than UPS.

Many N-terminally endoplasmic reticulum (ER)-anchored cytochrome P450 proteins (P450s) turn over proteolytically via ER-associated degradation (ERAD), others via ER-to-lysosomal-associated degradation (ERLAD), and yet others via both pathways. What precisely dictates their differential proteolytic turnover is unknown. Herein, we employed rabbit liver CYPs 1A1 and 1A2, which reportedly reside in liquid-disorded (ld)- and detergent-resistant, liquid-ordered (lo)-ER-microdomains, respectively, governed by their specific N-terminal (NT) signal-anchor (SA) subdomains. We now report that this precise SA-dependent ER-topology not only determines the proclivity of CYP1A1 towards ERAD and CYP1A2 towards ERLAD, but also their differential lifespans. We further document that the detergent-resistant lo-ER-membranes (DRMs) are morphologically quite similar to mitochondria-associated ER-membranes (MAMs), documented cellular platforms for autophagic-initiation complexes. DRMs and MAMs, composed of saturated fatty-acids, glycosphingolipids and cholesterol, harbor many common morphological markers including the ER-specific prohibitin, erlin-1. Herein employing SURF, a split fluorogenic bifunctional complementation assay, we show that intracellularly, erlin-1 and CYP1A2 interact closely via their ER NT-SAs. siRNA-knockdown (KD) of erlin-1 in HepG2-cells, not only relocated CYP1A2 from DRMs to non-DRMs, but also impaired its ERLAD, resulting in insoluble cellular CYP1A2 aggregates. Upon erlin-1 KD, CYP1A2 ERLAD could be rescued by co-expression of a siRNA-resistant intact erlin-1 or just its NT-1-30 residue SA-domain. Our findings are the first to reveal that the CYP1A2 lifespan and preferential proclivity towards ERLAD is determined by its close association with erlin-1 within DRMs/MAMs. As proof of concept, we document that the ERLAD-proclivity of CYP2B1 is also similarly dependent upon erlin-1-DRM-association. SIGNIFICANCE STATEMENTThe endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) incur ER-associated degradation (ERAD) and/or ER-to-lysosomal-associated degradation (ERLAD). What determines their preferential proteolytic turnover is unknown. Here, employing P450s CYP1A1 and CYP1A2 that reside in their N-terminal signal anchor-determined liquid-disordered (ld)- and detergent-resistant, liquid-ordered (lo)-ER-microdomains, respectively, we documented that in HepG2-cells these ER-microdomains determine the CYP1A proteolytic preferences for ERAD vs ERLAD as well as their lifespans. More importantly, we discovered that its intimate interaction with the ER-specific prohibitin erlin-1 colocalized in these lo-ER-microdomains, specifically dictates CYP1A2s ERLAD-preference. Accordingly, siRNA-elicited erlin-1-knockdown disrupted CYP1A2-ERLAD, which was rescued upon coexpression of either a siRNA-resistant erlin-1 or just its N-terminal 1-30 residues. As proof of concept, we document similar characteristics for CYP2B1, another ERLAD-targeted P450.

cell biology↗

bioRxiv2025

Deletion of Cd248 in Postn positive myofibroblast Fails to Attenuate Cardiac Remodeling and Fibrosis in a Murine Model of Pressure-Overload Cardiomyopathy

BackgroundCardiac fibrosis, driven by activated Periostin (Postn)-expressing myofibroblasts, is a key pathophysiological feature of heart failure induced by pressure overload. The clinic trial tested tumor vascular regulator CD248 has been validated as a potential anti-fibrotic target in ischemic heart injury. We therefore tested the hypothesis that targeting Cd248 specifically in Postn+ myofibroblasts ameliorates pressure-overload cardiomyopathy. MethodsSingle-cell RNA-sequencing data from murine hearts subjected to transverse aortic constriction (TAC) were analyzed to quantify the Cd248+/Postn+ fibroblast population. Subsequently, Postn+ myofibroblast-specific inducible Cd248 knockout mice were subjected to TAC. Gene deletion was induced with tamoxifen from the day of surgery. Cardiac remodeling and function were analyzed 8 weeks after TAC. ResultsAnalysis of scRNAseq data confirmed that about 1/3 of the fibroblasts in the 14-day TAC heart are Cd248+Postn+ fibroblasts. However, comprehensive echocardiographic analysis revealed no significant differences in key parameters of cardiac function or dimensions, including left ventricular ejection fraction, ventricular volumes, wall thickness and global muscle strain between PostnMCM+/-;Cd248fl/fl and PostnMCM+/- controls. Histological analysis at 8 weeks also showed no significant alteration in the extent of interstitial or perivascular fibrosis, myocardial vessel density, or cardiomyocyte hypertrophy. ConclusionThe specific deletion of Cd248 in Postn-expressing myofibroblasts does not mitigate pathological remodeling or fibrosis in response to chronic pressure overload. These findings suggest the role of Cd248 in this cell lineage is not a primary driver of pressure-overload pathology. Therefore, a better understanding of the context-dependent functions of CD248 is critical to successfully guide the clinical translation of CD248-based anti-fibrotic therapies.

pathology↗

bioRxiv2025

Phosphoantigen-Driven Dissociation of Butyrophilin Oligomers Activates γδ T Cells

{gamma}{delta} T cells represent a promising avenue for cancer immunotherapy. The V{gamma}9V{delta}2 T cell receptor (TCR), expressed by the predominant subset of {gamma}{delta} T cells, responds to phosphoantigen (pAg)-engaged butyrophilins (BTNs) on various cancer cells. However, the molecular mechanism underlying pAg-mediated activation of V{gamma}9V{delta}2 TCRs remains a subject of debate. Here, we employed an integrative approach to elucidate the mechanism of pAg reactivity in V{gamma}9V{delta}2 T cells. Our results demonstrate that BTNs form higher-order oligomers in the absence of pAg. Upon pAg binding, these oligomers dissociate into tetramers, enabling V{gamma}9V{delta}2 TCR engagement. This pAg-induced dissociation of higher-order BTN complexes is critical for pAg-mediated activation of {gamma}{delta} T cells. Our findings reveal a mechanism of BTN dissociation-driven pAg sensing, providing valuable insight for future immunotherapeutic strategies.

immunology↗

bioRxiv2025

Dual Targeting of IKKβ and NR4A1 for AML Therapy

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKK{beta}-NF-{kappa}B pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKK{beta} has been limited by serious toxicities, including neutrophilia. Here we identify IKK{beta} and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKK{beta} and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKK{beta} and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrols ability to bind both IKK{beta} and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase-dependent degradation of IKK{beta} and/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKK{beta} and NR4A1 as a promising therapeutic strategy. Plain language summaryAcute myeloid leukemia (AML) is a predominant form of blood cancer with devastating consequences in both young and adult populations. Despite some advances in AML treatment over the last decade, there is still an unmet medical need to develop new drugs for difficult-to- treat AMLs. We discover that two proteins, namely IKK{beta} and NR4A1, play important roles in promoting the AML disease and could be associated with more severe AML subtypes. To target and destroy those proteins within AML cells, we employ a novel targeted protein degradation approach, which involved design, synthesis, and screening of PROTAC drugs, to discover a drug possessing pronounced AML cell killing activity by virtue of IKK{beta} and NR4A1 degradations. The drug also significantly reduces AML progression in mice without any noticeable adverse effects. Our current efforts involve more comprehensively testing the benefit of the drug (and its analogs) in a wide range of clinically relevant AML models. Key PointsO_LIIKK{beta} and NR4A1 are clinically relevant drivers of AML pathogenesis. C_LIO_LIA novel celastrol-based PROTAC can effectively degrade IKK{beta} and/or NR4A1 to potentially treat AML. C_LI

cancer biology↗

bioRxiv2025

Complex Assembly and Activity States as Multifaceted Protein Attributes Explaining Phenotypic Variability

Cell function studies primarily focus on measuring overall molecular abundances while often overlooking critical clues--including protein modifications and molecular interaction networks--that critically determine the functional properties of the cell. In prior work, we introduced a suite of methods to reveal context-specific transcription factor-gene regulatory networks, kinase-substrate networks, and protein interaction networks and leveraged them to gain deeper insights into transcriptional regulation and signal transduction. However, the complex interdependencies between these networks are still elusive. To address this challenge, we introduce a multi-omics framework, aimed at harnessing measured or inferred protein activity in context-specific networks, which yields deeper functional insights into mechanisms underlying molecular phenotypes, compared to protein abundance alone. As proof of concept, we utilized progressively differentiated instances of HeLa CCL2 and Kyoto cell lines to explore the role of protein complexes and interactions in cell doubling time and susceptibility to Salmonella Typhimurium infection. Notably, this analysis underscores the pivotal role of protein interaction networks in linking molecular profiles to phenotypic outcomes, thus providing a highly generalizable framework for multi-omics dataset analysis.

systems biology↗

bioRxiv2025

OT-RMSD: A Generalization of the Root-Mean-Square Deviation for Aligning Unequal-Length Protein Structures

The Root-Mean-Square Deviation (RMSD) metric, coupled with the Kabsch algorithm for optimal superposition, represents a cornerstone of quantitative structural biology. However, its application is fundamentally limited to the comparison of structures with a pre-defined, one-to-one correspondence of equal length, precluding its direct use for the vast majority of biologically relevant comparisons involving proteins of different lengths or unknown equivalences. To overcome this limitation, we introduce OT-RMSD, a novel, parameter-light method that generalizes the RMSD for comparing unequal-length protein structures without a pre-defined alignment. Our approach recasts the correspondence problem as an Optimal Transport (OT) task, utilizing a fundamental, distance-based cost function to identify the most economical mapping between two protein structures. This transport plan is then used as a soft-weighting scheme within an iterative Sinkhorn-Kabsch framework to simultaneously solve for correspondence and optimal superposition. We test our method on a benchmark dataset of 40 challenging protein pairs and demonstrate its superiority over both the widely-used PyMOL align command and a more complex, heuristic-driven variant of our own framework. On average, OT-RMSD identifies larger and more accurate alignment cores, achieving a significantly lower RMSD. We conclude that OT-RMSD provides a mathematically principled, robust, and effective extension of the classic RMSD concept, offering a powerful tool for modern structural analysis.

bioinformatics↗

bioRxiv2025

Colorectal cancer-associated PCBP1 mutations disrupt protein stability in a dominant negative manner

Mutations in RNA-binding proteins are increasingly identified in cancers through tumor sequencing and are correlated with disease progression, therapy response, and overall patient outcomes, underscoring the need to study them. Here, we focus on the RNA-binding protein Poly-C binding protein 1 (PCBP1), which binds target RNAs through K-homology (KH) domains to regulate RNA fate. PCBP1 is a tumor suppressor gene and hotspot missense mutations at leucine residues 100 and 102 are observed in colorectal cancer (CRC). PCBP1 mutations have been recurrently reported in CRC genome-wide mutation studies and are associated with poor clinical outcomes; however, their effects on PCBP1 expression and function remain largely unexplored. We show that cancer-associated mutations substituting leucine 100 and 102 with glutamine, proline, or arginine destabilize PCBP1, leading to increased protein turnover. The L100/L102 residues occur at the interface of the RNA-binding KH1 and KH2 domains, and our molecular dynamics simulations show that mutations at these residues disrupt the secondary structure of PCBP1. Additionally, these mutants display increased cytoplasmic localization. Importantly, mutant PCBP1 physically interacts with wild type PCBP1 and suppresses its expression through a dominant-negative mechanism. Together, our data demonstrate that CRC-associated PCBP1 mutations destabilize the protein and act as dominant-negative variants, revealing a novel mechanism of tumor suppressor inactivation in colorectal cancer.

cancer biology↗

bioRxiv2025

Cryo-EM structure of influenza polymerase bound to the cRNA promoter provides insights into the mechanism of virus replication

Influenza virus polymerase (FluPol) synthesizes the complementary RNA (cRNA) and the viral RNA (vRNA) using distinct de novo initiation strategies during genome replication, known as internal and terminal initiation, respectively. The de novo initiation mechanisms, especially the internal initiation process, which includes a template realignment process, is still not well understood. Here, we present a cryo-electron microscopy structure of H5N1 FluPol bound to the cRNA promoter. In combination with structural analyses and structure-guided mutagenesis studies, we identified several previously unreported structural features of FluPol essential for internal initiation. The B loop adopts an "open" conformation, allowing translocation of the 3' terminus of cRNA (3'-cRNA) template into the catalytic cavity. The dynamic of incoming 3'-cRNA template is limited by the priming and realignment loop (PR loop), which facilitates the cRNA template realignment process. An asparagine cluster above the catalytic cavity is required for polymerase activity. Our findings provide structural insights into the mechanism of replication internal initiation of FluPol.

microbiology↗

bioRxiv2025

Chromosomal Restructuring and Subgenome Divergence Drive Post-Polyploid Adaptive Diversification in Sinocyclocheilus Cavefish

Allopolyploidy generates extensive genomic potential, yet its role in adaptive diversification remains poorly understood. We assembled phased chromosome-level genomes of cave and surface ecotypes of Sinocyclocheilus, a rapidly diversifying cavefish lineage, the most species-rich in the world. Our analyses show that all species derive from the ancestral allotetraploidisation event common to all cyprinids without subsequent polyploidisation. Instead, diversification has been driven by chromosomal rearrangements and the emergence of subgenome asymmetry. The dominant D subgenome maintains more genes, exhibits higher expression, and is enriched for adaptive functions, while the submissive S subgenome is inclined towards housekeeping roles. This asymmetry is further reinforced by the accumulation of transposable elements near genes exhibiting expression biased toward the S-subgenome. We also identify a derived epigenetic mechanism in the cave ecotype, i.e., differential methylation of these elements, absent in the surface ecotype. These findings show how structural, regulatory, and epigenetic processes have interacted following allopolyploidy to produce ecological and phenotypic diversity in Sinocyclocheilus. Our findings also offer quantitative evidence that cave adaptation is a complex process characterised by an evolutionary trade-off - the regression of energetically expensive traits combined with the remodeling of neural and developmental pathways driven by natural selection.

evolutionary biology↗

bioRxiv2025

Generation of Valvular Interstitial Cells from Human Pluripotent Stem Cells

Heart valves are living structures whose sophisticated functions are mediated by a specialized population of mesenchymal cells known as valvular interstitial cells (VICs). Given their central role in valve homeostasis, VICs represent a promising cell population for studying heart valve diseases and developing novel therapies to treat them. Here, we describe a strategy for generating VICs from human pluripotent stem cells (hPSCs) by stage-specific manipulation of developmental signalling pathways. Our results demonstrate that hPSC-derived VICs show a high transcriptional similarity to primary human fetal VICs and can secrete key proteins of the valve extracellular matrix. We further investigate the heterogeneity of hPSC-derived VICs and identify two major subpopulations with distinct molecular and functional properties, mirroring the cellular diversity observed in vivo. Finally, we utilize an in vitro model of Noonan syndrome to demonstrate that hPSC-derived VICs can accurately recapitulate key aspects of valve disease. Collectively, these findings provide a reproducible method for the scaled generation of bona fide hPSC-derived VICs and establish their utility in disease modelling and tissue engineering applications. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- We established a robust platform to generate bona fide valvular interstitial cells (VICs) from human pluripotent stem cells (hPSCs), recapitulating native VIC identity and function. - We delineated signaling pathways that promote the development of two distinct VIC subsets and identified a surface marker to distinguish between them. What are the clinical implications?- A renewable, human-specific source of VICs enables precise mechanistic studies of valve development and disease that are not possible with limited surgical specimens or animal models. - This platform creates opportunities for therapeutic applications, including drug discovery and tissue engineering approaches for valve repair.

cell biology↗

bioRxiv2025

ProTDyn: a foundation Protein language model for Thermodynamics and Dynamics generation

AO_SCPLOWBSTRACTC_SCPLOWMolecular dynamics (MD) simulation has long been the principal computational tool for exploring protein conformational landscapes and dynamics, but its application is limited by high computational cost. We present ProTDyn, a foundation protein language model that unifies conformational ensemble generation and multi-timescale dynamics modeling within a single framework. Unlike prior approaches that treat these tasks separately, ProTDyn allows flexible independent and identically distributed (i.i.d.) ensemble sampling and dynamic trajectory simulation. Across diverse protein systems, ProTDyn yields thermodynamically consistent ensembles, faithfully reproduces dynamical properties over multiple timescales, and generalizes to proteins beyond its training data. It offers a scalable and efficient alternative to conventional MD simulations. Code is available at: https://github.com/Harrydirk41/ProTDyn.

biochemistry↗