Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 253 records · Page 14Linked to original sources

bioRxiv2026

Mechanism of substrate recognition and catalysis in a mammalian phosphatidylserine synthase 2

Mammalian phosphatidylserine synthase-1 and -2 synthesize phosphatidylserine (PS) by replacing the headgroup of either phosphatidylcholine (PC, PTDSS1) or phosphatidylethanolamine (PE, PTDSS2) with a serine. We determined structures of PTDSS2 from Equus caballus in complex with either PE or serine substrates to resolutions of 2.8-3.2 [A]. The structures define substrate binding sites and reveal that the phosphate group of PE is coordinated by two Ca2+. In addition, we found that PTDSS2 has significant phospholipase D (PLD) activity in the absence of serine, which was not reported previously, and that Ca2+ is required for the PLD activity. These discoveries enrich our knowledge in the mechanism of mammalian PTDSS.

biochemistry↗

bioRxiv2026

The BELL-type homeobox transcription factor RLC3/OsBLH4 controls leaf rolling and drought tolerance via KNOX-BELL-lignin regulatory network in rice

O_LIModerate leaf rolling in rice is crucial for plant architecture and stress adaptation, but its molecular regulation remains unclear. We investigated the role of RLC3/OsBLH4, a BELL-type homeobox transcription factor, in controlling leaf rolling and drought tolerance, addressing gaps in lignin biosynthesis and cell wall development mechanisms. C_LIO_LIWe used gene map-based cloning (rlc3-1, rlc3-2), CRISPR/Cas9 knockout lines (rlc3-ko#11, rlc3-ko#12), and allelic complementation to validate RLC3s function. Additionally, we employed biochemical assays, gene expression analysis, and protein interaction studies to explore its regulatory network. C_LIO_LIRLC3 mutations impaired lignin biosynthesis and secondary cell wall formation, reducing bulliform cells area and causing midrib defects. These structural abnormalities accelerated water loss, leading to excessive leaf rolling and compromised drought tolerance. Mechanistically, RLC3 directly activates lignin synthesis genes (OsPAL5, OsCOMT5, OsCCR4, OsCAld5H1) and interacts with KNOX transcription factors (OSH1, OSH45, OSH71) to form a KNOX-BELL complex, further regulating lignin content and cell wall development. C_LIO_LIRLC3 orchestrates lignin deposition and secondary cell wall development to control leaf rolling, water transport, and drought tolerance. This study reveals a novel KNOX-BELL-lignin regulatory module governing leaf morphology and stress adaptation, offering targets for crop improvement under drought conditions. C_LI

plant biology↗

bioRxiv2026

Mutant FGFR3 restricts bone yet expands cortex via ERK-mediated self-repression

FGFR3 gain-of-function mutations cause achondroplasia 1,2, the most common form of dwarfism, yet trigger paradoxical cerebral overgrowth and skeletal stunting 3-9. Here, we demonstrate that Fgfr3-K644E mutant drives enhanced ERK activation, which then represses Fgfr3 expression and downregulates ERK signaling. In the developing cortex, this mechanism transiently expands cortical stem cells by activating ERK, then shifts signaling to downregulate Fgfr3/ERK/PKA and enhance YAP/TAZ, promoting cerebral overgrowth and premature ependymal maturation. In growing bones, Fgfr3-K644E mutant first elevates ERK to inhibit chondrocyte pre-hypertrophy, then downregulates Fgfr3/ERK/PKA and upregulates YAP/TAZ to accelerate premature hypertrophy and ossification. Our findings establish that FGFR3 mutations limit bone yet expand cortical size via an ERK negative feedback loop, revealing a unified disease mechanism and novel therapeutic targets.

developmental biology↗

bioRxiv2026

Reaction-enabled, highly sensitive super-resolution imaging

Super-resolution microscopy breaking the optical diffraction limit has led to success in illuminating the complexity of biology with fluorescence--light-excited luminescence1,2. Here, we propose another approach for super-resolution imaging with electrochemiluminescence (ECL)--reaction-excited luminescence3,4. While featuring high sensitivity in molecular analytics owing to its laser-free excitation, the current reaction-driven imaging suffers from limited resolution due to low photon budget4. Efficient ECL imaging of intracellular organelles remains elusive. To meet this challenge, we develop RIED (Reaction-based super-resolution Imaging via Entropy-weighted correlation combined with Deconvolution), which builds upon two pivotal advancements: (i) unprecedented ECL intracellular organelles imaging through a 1,000-fold enhancement in ECL emission, and (ii) the super-resolution ECL imaging by the spatiotemporal acquisition and efficient utilization of highly dynamic ECL profiles. RIED allows for the first three-dimensional super-resolution ECL imaging with a spatial resolution of {bsim}97 nm in the lateral dimension and {bsim}235 nm in the axial dimension. This allows to reveal outer mitochondrial membrane topology and distinct microtubule organizations in different mitosis phases, offering a chemistry-based imaging capability for high-throughput imaging and highly sensitive interfacial imaging, which provides a new dimension into biology.

biochemistry↗

bioRxiv2026

Balance between DNA repair, LINE1 suppression and lifespan in mice with SIRT6 Serine 10 mutations

Sirtuin 6 (SIRT6) is an important regulator of DNA repair, metabolism, chromatin maintenance and longevity. SIRT6 Serine 10 phosphorylation controls SIRT6 recruitment to the sites of DNA damage. To explore the effect of SIRT6 Serine 10 phosphorylation on lifespan, we generated two SIRT6 mutant mouse strains: phospho-null S10A and phosphomimetic S10E. The S10E mutant mice demonstrated enhanced DNA repair capacity, elevated LINE1 expression and reduced lifespan in male mice compared to the wild-type and S10A mice. This result suggests that SIRT6 S10E mutation enhances DNA repair capacity at the expense of reduced LINE1 silencing leading to shorter lifespan. While both SIRT6 functions in DNA repair and chromatin maintenance are important for longevity, our results suggest that when the balance between these functions is shifted, diminished of LINE1 control has a stronger impact on lifespan than enhanced DNA repair.

molecular biology↗

bioRxiv2026

Ophiuchus-Ab: A Versatile Generative Foundation Model for Advanced Antibody-Based Immunotherapy

Antibodies exhibit extraordinary specificity and diversity in antigen recognition and have become a central class of therapeutics across a wide range of diseases. Despite this clinical success, antibody design remains fundamentally challenging. Antibody function emerges from intricate and highly coupled interactions between heavy and light chains, which complicate sequence-function relationships and limit the rational design of developable antibodies. Here, we reveal that modeling antibody sequence space at the level of paired heavy and light chains is essential to faithfully capture inter-chain dependencies, enabling a deeper understanding of antibody function and facilitating antibody discovery. We present Ophiuchus-Ab, a generative foundation model pre-trained on largescale paired antibody repertoires within a diffusion language modeling framework, unifying antibody generation and representation learning in a single probabilistic formulation. This framework excels diverse antibody design tasks, including CDR infilling, antibody humanization, and light-chain pairing. Beyond generation, diffusion-based pre-training yields transferable representations that enable accurate prediction of antibody properties, including developability, binding affinity, and specificity, even in low-data regimes. Together, these results establish Ophiuchus-Ab as a versatile foundation model for modeling antibodies, providing a foundation for next-generation antibody-based immunotherapy.

bioinformatics↗

bioRxiv2026

Direct interactions of CEACAM1 and CD36 with LPS and each other

Micellar lipopolysaccharide (mLPS), a major shed product of gram-negative bacteria in the intestine, may result in TLR4-mediated sepsis in the circulation. CEACAM1 and CD36, expressed on both epithelia and immune cells, regulate TLR4 signaling and inflammation, suggesting a shared role in innate immunity. Furthermore, CEACAM1 associates with CD36 on hepatocytes, regulating lipid storage and bile acids (BAs) in the liver, where LPS detoxification occurs. Using E. coli mLPS-Ra as a model and soluble forms sCEACAM1 or sCD36, we assessed their direct binding to mLPS by SPR, SEC, and TEM. SPR derived steady state affinity constants (KD= 1.47 x 10-6 M and KD= 2.23 x 10-6 M) were obtained for mLPS-Ra binding to sCEACAM1 and sCD36, respectively. mLPS-Ra binding to sCEACAM1 and sCD36 was reduced by bile acids in order of sodium deoxycholate > sodium cholate. mLPS exhibited dose dependent binding to sCEACAM and sCD36 by SEC and the isolated complexes formed well defined micelles on TEM. A KD of 5.28 x 10-8 M was obtained for sCEACAM1 binding to immobilized sCD36. Antibody-based-proximity ligation assays (PLA) demonstrated the association of the ectodomains of CEACAM1 and CD36 on hepatic (P< 0.001) and HEK cells (P< 0.018), while biotin-based PLA demonstrated association of the cytoplasmic domains of CEACAM1 and a CD36-BioID2 fusion protein in HEK cells. Alpha Fold predicted CD36 binding in cis to CEACAM1 in a membrane model, in agreement with the results of the PLAs. Based on the SPR, SEC and TEM binding studies, CEACAM1 and CD36 share a cooperative mLPS binding function distinct from their regulation of TLR4 binding.

biochemistry↗

bioRxiv2026

An atlas of human histological diversity

Descriptions of tissues by histopathologists rest on verbal statements limited by quantitative inaccuracies and personal cognitive biases. Here we propose an unsupervised computational framework that transposes to histology the concepts and methods of RNA-seq gene expression analysis, setting histology on an unbiased quantitative ground. Leveraging this framework and the GTEx dataset, we built an atlas surveying the histological diversity of 40 organs from 946 non-diseased individuals and documenting 11,125,747 associations between 2,560 morphemes--the histological analogs of genes in our framework--and 9 layers of patho-clinical and multi-omic molecular data, providing a rich context to interpret histology. In contrast with the ideally healthy normal specimens depicted in histology textbooks, the atlas reveals the influence of age, sex, genetics and sub-clinical pathologies on tissue structures. For example, we report that female eccrine sweat glands are surrounded by more adipocytes than their male counterparts, and that distinct calcification-associated aorta morphemes are driven by either smoking or genetic polymorphisms. Cross-organ analyses also delineate the systemic histological impact of diabetes and other conditions and establish the power of blood gene expression to predict disease-related morphemes. The atlas is released as an interactive web resource aimed at researchers.

pathology↗

bioRxiv2026

Near completely reversing the γ- to β-globin switch by enhancer release, retargeting and reinforcing

The {gamma}- to {beta}-globin switch is intricately regulated during human ontogeny, and this process is manipulated for therapeutic approaches to treat {beta}-hemoglobinopathies by activating {gamma}-globin expression. Several genetic strategies to reactivate HbF have partially reversed the {gamma}- to {beta}-globin switch and ameliorated the clinical symptoms of {beta}-hemoglobinopathies. However, whether the {gamma}- to {beta}-globin switch can be completely reversed remains unknown. Completely reversing the {gamma}- to {beta}-globin switch requires a thorough redirection of the locus control region (LCR) from interacting with the {beta}-globin gene (HBB) to interacting with the {gamma}-globin gene (HBG). Here, we found that disrupting the KLF1-mediated HBB-LCR interaction by mutating the CACCC motif in HBB leads to the release of the LCR and its retargeting to other {beta}-like globin genes. Moreover, simultaneously disrupting the KLF1-mediated HBB-LCR interaction and the epigenetic repression of HBG by combined editing of the CACCC motif in HBB and the TGACCA motif in HBG reinforces the HBG-LCR interaction, resulting in almost exclusive {gamma}-globin expression while nearly absent {beta}-globin expression, achieving near complete reversal of the {gamma}- to {beta}-globin switch. This finding demonstrates the comprehensive regulation of the {gamma}- to {beta}-globin switch by gene competition and gene silencing mechanisms. This finding also suggests that silenced genes can be fully activated through the redirection of enhancer-promoter contacts and that the specificity of enhancer-promoter contact within chromosomal domains is achieved through the transcription factor clusters binding to enhancers and promoters. Combined editing of the CACCC&TGACCA motifs also offer a more optimal therapeutic strategy for {beta}-hemoglobinopathies.

molecular biology↗

bioRxiv2026

Tissue-to-Analysis Framework Enables Multiscale Mapping of the Architectural and Cellular Organization in the Human Dorsal Root Ganglion

Transcriptomic studies have helped us understand the dorsal root ganglias cellular milieu, yet our knowledge of protein expression and spatial organization/architecture remains less defined. Here we establish a comprehensive resource from processing through analysis of hDRG tissue. We optimize tissue-handling strategies and evaluate 114 antibodies targeting neuronal and non-neuronal cell types, identifying protocols that preserve neuronal morphology and antigen retain specificity. Integrating these workflows with our Deep Learning-assisted image analysis pipelines, we quantify size, expression, and spatial organization across 35,721 neurons from 15 donors. Female donors exhibited significantly larger neuronal somata, indicating sexual dimorphism. Neuronal subpopulations display clear spatial clustering. We further characterized the perineuronal niche, marked by dense vascularization, nuclear remodeling in perineuronal cells, and age-related increased turnover of neuron-associated macrophages. Together, this resource provides standardized methodologies and quantitative frameworks for reproducible protein-level interrogation of human sensory biology and pain mechanisms.

neuroscience↗

bioRxiv2026

Nab-paclitaxel fused with the de novo designed receptor binder exhibits enhanced tumor targeting and therapeutic efficacy

Chemotherapy has been widely used in cancer treatment, but most of the chemotherapeutic drugs rely mainly on passive accumulation due to lack of target specificity, which may lead to systemic toxicity and limited clinical utility. Recent advances in artificial intelligence-based protein design provide new opportunities for developing precision therapeutics. Here we modify the albumin-bound paclitaxel (Nab-PTX), one of the most widely used drugs in chemotherapies, by applying the fusion proteins of albumin with the de novo designed protein binders targeting human EGFR or HER2. The resulting particles, EGFRmb-Nab-PTX and HER2mb-Nab-PTX, retain the similar physicochemical properties of Nab-PTX while acquiring the receptor-specific binding capacities. The in vitro assays show that both binder-modified Nab-PTX particles have increased uptake and inhibitory effects significantly in the cancer cell lines with high receptor expression levels. Furthermore, the data from a xenograft model, including tumor growth, excised tumor analysis, organ histology, and fluorescence imaging, show that the binder-modified Nab-PTX enhances tumor accumulation, improves tumor suppression, and reduces off-target toxicity compared with the conventional Nab-PTX, suggesting that they may have promising clinical potential in cancer treatment. Overall, this strategy provides an adaptable modular platform for generating albumin-based chemotherapeutic drugs with target specificities, which can be readily customized with diverse target binders to enable precise cancer therapies.

cancer biology↗

bioRxiv2026

ProMeta: A meta-learning framework for robust disease diagnosis and prediction from plasma proteomics

The plasma proteome offers a dynamic window of human health, capturing the real-time intersections between genetics and physiology. However, the application of deep learning to proteomics is currently hindered by a reliance on large-scale labeled datasets, rendering standard models ineffective for rare or novel diseases where patient samples are inherently scarce. Here, we present ProMeta, a meta-learning framework designed to enable robust disease modeling under extreme data restrictions. By integrating knowledge-guided pathway encoding with bi-level meta-optimization, ProMeta projects unstructured proteomic profiles into biologically interpretable functional tokens. This architecture allows the model to learn a global initialization containing transferable biological priors from biobank-scale data, facilitating rapid adaptation to novel tasks. Through comprehensive benchmark experiments, ProMeta consistently outperformed transfer learning and traditional machine learning baselines in both disease diagnosis and prediction tasks. In the most challenging 4-shot scenarios (utilizing only 2 cases and 2 controls), the model achieved robust generalization with an average AUROC of [~] 0.69, representing a 24.6% relative improvement over the best-performing baseline methods. Mechanistic investigation revealed that ProMeta disentangles cases from controls in the latent space prior to task-specific adaptation, confirming the acquisition of universal biological rules rather than rote memorization. Furthermore, gradient-based interpretation identified disease-specific protein biomarkers and functional pathways consistent with known pathophysiology. Collectively, ProMeta overcomes the data-scarcity bottleneck in precision medicine, providing a scalable, interpretable framework for characterizing the full spectrum of human diseases, particularly for rare conditions lacking extensive clinical cohorts.

bioinformatics↗

bioRxiv2026

Melatonin alleviates acid-induced stress in peanut (Arachis hypogaea L.) through physiological, antioxidative regulation and molecular defense mechanisms

Acidic stress severely restricts crop growth by disrupting nutrient uptake, redox homeostasis, and membrane stability, yet mitigation strategies remain limited. Here, we investigated the role of melatonin (MT) in regulating growth, photosynthesis, oxidative stress, antioxidant defense and proton transport in peanut seedlings under controlled hydroponics acidic (pH 4.0) and near-optimal (pH 6.5) conditions, and validated these findings in naturally acidic field soil (pH 4.3-4.5). Acid stress markedly reduced biomass accumulation, chlorophyll content, and redox balance, while enhancing ROS (H2O2) and lipid peroxidation (MDA). Exogenous MT application, particularly at 50-100 {micro}M, significantly improved shoot and root biomass, restored chlorophyll pigments and reduced H2O2 and MDA accumulation, with more pronounced effects under pH 4.0 than pH 6.5. MT strongly activated antioxidant enzymes (SOD, CAT, APX), while POD activity declined, reflecting melatonins dual role as both a direct ROS scavenger and a regulator of enzymatic redox networks. Notably, MT induced strong, dose-dependent upregulation of HL-ATPase genes (AH1 and AH2) in both leaves and roots under acidic conditions, suggesting enhanced proton extrusion, intracellular pH homeostasis, and stress adaptation. The soil validation experiment confirmed the agronomic relevance of these findings, where MT dose-dependent concentrations improved germination, vegetative growth, chlorophyll fluorescence (Fv/Fm), and yield-related traits under natural acidic conditions. Although MT also conferred benefits at pH 6.5, responses were generally moderate compared with acid stress. Collectively, these results demonstrate that MT enhances peanut tolerance to acid stress across both controlled and natural field-relevant environments, highlighting its potential application for sustainable crop production on low-pH soils.

plant biology↗

bioRxiv2026

An Advanced Humanized Systemic Lupus Erythematosus Model Enables Parallel Profiling of B Cell-Targeted Therapies

B cell-targeted therapies represent a transformative frontier for systemic lupus erythematosus (SLE) intervention, yet clinical recommendation of specific treatment is hampered by the challenge to perform head-to-head comparisons of efficacy-toxicity trade-offs and tissue-specific impacts in patients. To address this gap, an advanced Toll-like receptor 7 (TLR7) agonist-induced SLE model is developed in a NCG-M (NOD-Prkdcem26Cd52Il2rgem26Cd22Rosa26em1Cin(hCSF2&IL3&KITLG)/Gpt) human immune system (HIS) mice. This model enables parallel evaluation of multiple B cell-directed therapies within a controlled cohort study. It recapitulates core SLE pathologies--including immune effector cell augmentation, autoantibody production and glomerulonephritis--within 2 months, demonstrating greater severity and clinical fidelity than conventional pristane-induced systems. Validated through replication of clinical responses to rituximab and belimumab, the platform directly compares two emerging modalities: universal chimeric antigen receptor-T cells (UCAR-T) elicits delayed but profound B-cell reset correlating with superior reduction in renal pathology and autoantibodies, while T cell engagers (TCEs) mediate rapid yet partial B-cell depletion and transient efficacy. UCAR-T concurrently induces greater acute inflammatory responses, aligning with its distinct toxicity profile. By resolving therapy-specific effects on human immune dynamics and symptom control, this study empowers context-specific therapeutic selection for SLE, advancing tailored management strategies.

immunology↗

bioRxiv2026

Enhancing interpretability of cryo-EM maps with hybrid attention Transformers

Cryo-electron microscopy (cryo-EM) has become a central technique for determining the structures of macromolecular complexes. However, experimental cryo-EM density maps often exhibit limited interpretability due to noise and heterogeneous, anisotropic resolution, complicating downstream atomic model construction. Here we present DEMO-EMReF, a Swin Transformer-based framework specifically designed for cryo-EM density map refinement that integrates channel attention with hybrid spatial attention. By combining local window-based attention with grid-based sparse global attention, DEMO-EMReF captures fine-grained local density features while modeling long-range, cross-region spatial dependencies, enabling more robust density refinement in heterogeneous and anisotropic map regions. DEMO-EMReF was systematically evaluated on large benchmark sets of both primary maps and half-maps spanning resolutions of 3.0-8.0 [A] and was compared against multiple state-of-the-art map enhancement methods. DEMO-EMReF consistently improves resolution-related metrics, map-model correlations, and local atomic resolvability, with particularly robust gains in challenging heterogeneous or anisotropic cases. Importantly, the refined maps facilitate more accurate and efficient automated atomic model building. Together, DEMO-EMReF provides a robust approach for enhancing cryo-EM density maps and enabling more reliable downstream studies.

bioinformatics↗

bioRxiv2026

Fibroblast-specific Deletion of Yap/Taz Impairs Mouse Postnatal Dermal Development by Suppressing Collagen Production and Deposition

The Hippo pathway effectors YAP and TAZ are key regulators of cell proliferation, apoptosis, and differentiation, thereby maintaining tissue homeostasis and controlling organ size. While their roles in epithelial tissues and cancer are well established, their role in dermal fibroblast extracellular matrix (ECM) regulation is less understood. Here, we investigated the role of Yap/Taz during postnatal skin dermis development. During postnatal growth, mouse skin steadily grows and undergoes significant surface expansion. Postnatal deletion of Yap/Taz in dermal fibroblasts, the primary cells responsible for dermal ECM homeostasis, significantly impaired dermal maturation, as evidenced by marked deficiencies in collagen synthesis and deposition. Isolated fibroblasts from Yap/Taz knockout mice showed reduced proliferation and diminished expression of Yap/Taz target genes (Ccn2, Col1a1), which were rescued by reintroduction of active Yap/Taz. RNA-seq, and spatial transcriptomics and proteomics of Yap/Taz knockout skin revealed substantial downregulation of matrisome genes, including type I (Col1a1, Col1a2) and type III (Col1a3) collagens, which together constitute more than 90% of the skins collagen content. These findings demonstrate that Yap/Taz are essential for dermal ECM homeostasis, highlighting their therapeutic potential in skin regeneration, fibrosis, and aging-related ECM decline.

cell biology↗

bioRxiv2026

Direct evidence from kinetic D2O-MRI modeling that the choroid plexus is not the major source of cerebrospinal fluid

The role of the choroid plexus (CP) as the primary source of cerebrospinal fluid (CSF) remains controversial. Here, we used dynamic indirect D2O magnetic resonance imaging (MRI) at 9.4T to investigate whole-brain CSF dynamics in rats. Spin-echo echo-planar imaging (SE-EPI) was performed during intravenous D2O infusion with a temporal resolution of 10.69 s and an in-plane resolution of 150 x 150 {micro}m. An echo time of 150.0 ms was employed to effectively suppress signals from brain parenchyma, blood, and interstitial fluid, resulting in preferential visualization of CSF. The ambient and supracerebellar cisterns (AC+SC) exhibited the greatest signal attenuation, reaching 47.32 {+/-} 15.70% of baseline, whereas the lateral ventricles (LV1, LV2) showed smaller reductions (68.73 {+/-} 18.72%-72.64 {+/-} 15.07% of baseline). CSF production rates were quantified using a one-compartment perfusion model. Estimated secretion rates were 0.11 and 0.13 {micro}L/min in the lateral ventricles and 1.30 {micro}L/min in the AC+SC region, indicating a 5.42-fold higher CSF production outside the ventricles. These findings provide direct in vivo evidence that the lateral ventricles are not the primary site of CSF production. The proposed D2O-based dynamic SE-EPI approach is safe, non-invasive, cost-effective, and suitable for widespread application.

neuroscience↗

bioRxiv2026

An Efficient Constant-Coefficient MSAV Scheme for Computing Vesicle Growth and Shrinkage

We present a fast, unconditionally energy-stable numerical scheme for simulating vesicle deformation under osmotic pressure using a phase-field approach. The model couples an Allen-Cahn equation for the biomembrane interface with a variable-mobility Cahn-Hilliard equation governing mass exchange across the membrane. Classical approaches, including nonlinear multigrid and Multiple Scalar Auxiliary Variable (MSAV) methods, require iterative solution of variable-coefficient systems at each time step, resulting in substantial computational cost. We introduce a constant-coefficient MSAV (CC-MSAV) scheme that incorporates stabilization directly into the Cahn-Hilliard evolution equation rather than the chemical potential. This reformulation yields fully decoupled constant-coefficient elliptic problems solvable via fast discrete cosine transform (DCT), eliminating iterative solvers entirely. The method achieves O(N2 log N) complexity per time step while preserving unconditional energy stability and discrete mass conservation. Numerical experiments verify second-order temporal and spatial accuracy, mass conservation to relative errors below 5 x 10-11, and close agreement with nonlinear multigrid benchmarks. On grids with N [≥] 2048, CC-MSAV achieves 6-15x overall speedup compared to classical MSAV with optimized preconditioning, while the dominant Cahn-Hilliard subsystem is accelerated by up to two orders of magnitude. These efficiency gains, achieved without sacrificing accuracy, make CC-MSAV particularly well-suited for large-scale simulations of vesicle dynamics.

biophysics↗