Biology subjects

Liu, S.

Publications and source records attributed to Liu, S..

At least 163 records · Page 9Linked to original sources

bioRxiv2026

Distinct modes of sequence evolution and epigenetic modifications underpin the origins of Starship-mediated variation in Pyricularia fungal plant pathogens

Fungal pathogens display remarkable variation in genome content and organization that directly impacts their survival and host interactions. Although numerous models have been proposed to explain the origins of this variation, they generally fail to explain or predict the mechanisms that generate the genome variation observed in natural populations. Starships are a recently discovered group of giant fungal transposons that carry dozens of genes as cargo and horizontally transfer both within and between species. Here, we identify the features of a newly defined "Starship compartment" in the major fungal plant pathogen Pyricularia oryzae. We test the hypothesis that the Starship compartment makes distinct contributions to fungal genome evolution by explicitly comparing its transferability, mutability, and epigenetic modifications with those of the canonical core and accessory compartments. To enable this, we developed an updated and user-friendly version of the annotation tool stargraph for the comprehensive annotation of Starships and Starship-like regions. Using this approach, we identified two distinct families of Starships and related Starship-like regions in P. oryzae that differ in their activity, impacts on genome organization, modes of sequence evolution, and epigenetic modifications. Elements from the more active family exhibit higher rates of structural variation than all other genomic compartments in the predominantly clonal isolates infecting rice. Both families of Starships encode specific suites of known effector sequences that contribute to plant disease and Starship activity accounts for avirulence gene turnover, which suggests that evolutionary change within the Starship compartment may subsequently impact the evolution of plant-fungal interactions. Starships from the more active family have repeatedly transferred across the Pyricularia genus and tend to be depleted in heterochromatic histone modifications and repeat-induced point mutations. However, contrasting histone modification profiles in this family suggests a genomic conflict between silencing or maintaining Starship activity. Our findings demonstrate that variation in the mode of sequence diversification and epigenetic modification within the Starship compartment underpins the impacts of these giant transposons on fungal genome evolution. We argue for the explicit consideration of not only the Starship compartment but of element-specific dynamics when investigating the evolution of host-fungal interactions.

genomics↗

bioRxiv2026

Targeting Circulating FABP4 Ameliorates Obesity-Associated Hepatic Steatosis

Obesity is a major driver of hepatic steatosis, yet the molecular link between excess adiposity and hepatocellular lipid accumulation remains incompletely defined. Here, we identify circulating fatty acid-binding protein 4 (FABP4) as a key mediator of adipocyte-hepatocyte lipid crosstalk in obesity. Analyses of human liver specimens and mouse models reveal aberrant accumulation of FABP4 protein--but not transcript--in hepatocytes during steatosis, indicating an extrinsic source. Genetic deletion of FABP4, specifically in adipocytes, protects against high fat diet-induced hepatic steatosis without altering obesity or systemic lipid levels. Mechanistically, circulating FABP4 directly binds to hepatocytes, facilitating free fatty acid uptake. Furthermore, we developed a high-affinity humanized monoclonal antibody that selectively neutralizes circulating FABP4, blocks hepatocyte binding, suppresses fatty acid uptake, and markedly attenuates hepatic steatosis in multiple obese mouse models. These findings establish circulating FABP4 as a pathogenic lipid chaperone and a promising therapeutic target for obesity-associated hepatic steatosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/701451v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@5b91d5org.highwire.dtl.DTLVardef@1c34892org.highwire.dtl.DTLVardef@1d17ea9org.highwire.dtl.DTLVardef@d2b43c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHepatocytic accumulation of extrinsic FABP4 links adiposity to liver lipid deposition. C_LIO_LISpecific deletion of FABP4 in adipocytes prevents hepatic steatosis without affecting systemic lipid levels or obesity. C_LIO_LICirculating FABP4 derived from adipocytes directly binds hepatocytes to facilitate free fatty acid transfer. C_LIO_LIBlocking circulating FABP4 with a high-affinity anti-FABP4 monoclonal antibody inhibits hepatocyte lipid uptake and attenuates steatosis in multiple obese mouse models. C_LI

pathology↗

bioRxiv2026

BRD8 Disruption Unlocks Retrotransposon-Driven Tumor-Intrinsic Immunogenicity via Redistribution of Histone Acetylation in Liver Cancer

Overall response rate for immune checkpoint blockade (ICB) therapy remains limited in advanced hepatocellular carcinoma (HCC). Epigenetic perturbation has been shown to enhance tumor-intrinsic immunogenicity and thus reverse resistance to immunotherapy in multiple cancer types. Here, through domain-focused CRISPR/Cas9 genetic screens targeting chromatin regulators, we identified the bromodomain-containing protein 8 (BRD8) as a novel epigenetic factor that functions to suppress tumor-intrinsic immunity through BRD8/EP400 chromatin remodeling complex in HCC. Depletion of BRD8 potently induces anti-tumor immune responses and sensitizes tumors to ICB therapy in mouse tumor models. Mechanistically, BRD8 knockout leads to partial redistribution of H3K27ac to repetitive elements, activating double-stranded RNA (dsRNA) accumulation and subsequent type I interferon (IFN) response, leading to tumor rejection via remodeling the tumor microenvironment. The first-in-class selective chemical probe DN02 targeting the bromodomain of BRD8 also exhibits immunomodulatory and anti-tumor effects. In line with these findings, low BRD8 expression correlated with enriched interferon signatures, elevated immune cell infiltration, and prolonged survival in HCC patients. Together, this study reveals BRD8 as a selective epigenetic vulnerability for promoting tumor immunogenicity, and its bromodomain as a druggable target to overcome immunotherapy resistance in liver cancer patients. SignificanceThe induction of viral mimicry by epigenetic interference could trigger tumor-intrinsic immune response and enhance immunotherapy efficacy. Here, through domain-focused CRISPR/Cas9 screening, we identify BRD8 complex as a regulator involved in the suppression of repetitive elements by controlling H3K27ac distribution and propose BRD8 as a novel target to enhance anti-tumor immunity.

cancer biology↗

bioRxiv2026

Global trends in human birth and death seasonality suggest temperature-dependent shifts in birth months

Despite growing evidence that climate change affects public health, it remains unclear whether recent global warming has directly altered fundamental aspects of human biology at large scales. Here, we analyzed long-term trends in human birth and death seasonality, using demographic data from >100 regions worldwide. We found that both births and deaths followed remarkably persistent seasonal cycles. Births peaked through spring to fall, whereas deaths peaked in mid-winter, especially among older individuals. Across latitude, death seasonality diminished near the equator; birth seasonality remained strong across all latitudes but peaked progressively later at lower latitudes. Strikingly, birth seasonality in high-latitude regions showed synchronized phase delays in recent decades, with peak timing delayed by 2-3 months during the 1970s-2000s, converging toward lower-latitude timing and stabilizing subsequently, while death seasonality remained stable. An unbiased analysis of key socioeconomic and climatic variables revealed that temperature was the predominant predictor of birth-peak timing. Estimated conception peaks shifted away from summer amid rising heatwaves and stabilized in cooler fall/winter months, consistent with known adverse effects of heat on reproduction. Together, these results suggest that recent climate warming has reshaped the seasonal timing of human reproduction.

physiology↗

bioRxiv2026

A drought stress-induced MYB transcription factor regulates pavement cell shape in leaves of European aspen (Populus tremula)

The leaf pavement cells of many plant species develop fascinating jigsaw puzzle-like shapes in which neighboring cells interdigitate with each other, providing an ideal model for the study of cell shape acquisition. We analyzed pavement cell shape complexity in a natural population of European aspen (Populus tremula) genotypes and then used a genome-wide association study (GWAS) approach to identify a new candidate gene in cell shape regulation, Potra2n8c18226, encoding the transcription factor MYB305a. We subsequently validated a role for MYB305a in regulating aspen leaf pavement cell shape. We then demonstrated that drought conditions strongly induced MYB305a promoter expression in these cells and provided evidence implying that MYB305a plays a role in simplification of the cell shape in response to drought stress. Finally, we demonstrated negative correlations of pavement cell shape complexity with water-use efficiency, as well as with average precipitation, latitude and longitude of the genotypes original sampling sites in the natural European aspen population. Taken together, our results suggest that climatic variables affect the shape complexity of pavement cells in aspen leaf and provide a first step towards unravelling the molecular mechanisms controlling pavement cell shape acquisition in this species in response to environmental conditions, by implicating the involvement of the transcription factor MY305a.

plant biology↗

bioRxiv2026

Locomotor savings relies on attentional control of walking in older, but not younger adults

The ability to recall learned movements and rapidly adapt to environmental changes, known as locomotor savings, is crucial for mobility in community-dwelling older adults. However, the influence of aging on locomotor savings and the underlying mechanisms remains poorly understood. Attentional compensation is a particularly relevant mechanism because the control of automatic motor behaviors like walking tend to recruit more attentional/executive resources with aging. We hypothesize that locomotor savings is diminished with age and relies on attentional rather than automatic control of walking. To test this, we compared savings of a novel walking pattern learned on a split-belt treadmill, where each leg moves at a different speed, across multiple days in 21 older and 21 younger adults. Attentional control of walking was assessed by overground dual-task walking while prefrontal cortex (PFC) activity was recorded using functional near-infrared spectroscopy (fNIRS). We found that older adults exhibited less locomotor savings than younger adults after practice. Older adults also relied more on attentional resources during dual-task walking. Importantly, greater locomotor savings was associated with higher attentional control of walking in older adults, suggesting that the use of attentional resources during challenging walking facilitates the recall of previously learned movements. These results indicate that cognitive compensation strategies utilizing attentional resources are important neural mechanisms modulating locomotor savings. Understanding the role of cognitive compensation in locomotor savings may inform rehabilitation design to enhance mobility in older adults ensuring movement corrections practiced in clinical settings are saved for long-term benefit in daily life.

neuroscience↗

bioRxiv2026

An additional site mutation in MITA/STING gain-of-function mutants abolishes the autoimmune SAVI phenotypes and directs a therapeutic strategy.

STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by gain-of-function mutations (GOFs) of MITA/STING and the most frequent GOFs for SAVI are MITAN154S and MITAV155M. However, how MITA GOFs are spontaneously activated remains incompletely understood. Here, we show that the activity of MITA hinge-region GOFs is compromised by an additional mutation at Lys150 and that the SAVI phenotypes of MITAN153S/WT mice are completely abolished in the MITAK150N/N153S (MITANS/NS) mice. Mechanistically, MITA GOFs constitutively associate with iRhom2 for the spontaneous ER-to-Golgi translocation, which is substantially inhibited by the introduction of a mutation at Lys150. Interestingly, cGAMP binds to MITANS, triggers the ER-to-Golgi translocation of MITANS as well as the MITANS-iRhom2 interaction, and induces the expression of downstream genes in MitaNS/NS cells similarly as in Mita+/+ cells. Consistently, structural studies demonstrate an inactive open conformation of apo-MITANS characterized by connector region crossover and a curved filament of cGAMP-bound MITANS characterized by parallel connector regions, similar to those observed in wild-type MITA. Furthermore, we design a SAVI-inhibitory peptide (SIP) that selectively inhibits the interaction between MITAN153S and iRhom2 and the activity of MITA GOFs and thereby abolishes the SAVI phenotypes of the MITAN153S/WT[->]WT chimeric mice. These findings reveal a previously uncharacterized mechanism for the spontaneous activation of MITA GOFs and highlight a potential therapeutic intervention for SAVI.

immunology↗

bioRxiv2026

Glucose is a ligand-like trigger for secretion of postprandial GLP-1

Glucagon-like peptide 1 (GLP-1) is secreted from the intestinal L cells in a glucose-dependent manner. However, the mechanism underlying how glucose stimulates the secretion remains unclear. Here, we found that glucose at postprandial concentrations near the Km of GK for glucose ([~]10 mM), as well as nonmetabolizable glucose analogs, triggers GLP-1 secretion by intestinal L cells through directly binding to glucokinase (GK), without increasing intracellular ATP levels. We also show that in postprandially high glucose, glucose-bound GK interacts and inhibits KATP, as assessed by immunoprecipitation and FRET-FLIM analyses, as well as patch clamping. In addition, we have utilized GK mutants identified in diabetics, demonstrating that those mutants defective in binding to glucose impair GLP-1 secretion in however high glucose, whereas mutants constitutively bound to glucose with defects in catalysis, promote GLP-1 secretion even in low glucose. Furthermore, the KATP mutant unable to bind to GK blocks GLP-1 secretion in high glucose. We have also provided evidence showing that sodium-glucose cotransporter 1 (SGLT1) plays an important role in the basal secretion of GLP-1, but not in high glucose. We have thus revealed that glucose the molecule itself and GK act as a ligand and the receptor, respectively, to induce GLP-1 secretion in response to high glucose, providing new therapeutic avenues targeting metabolic diseases.

biochemistry↗

bioRxiv2026

A plug-and-play ROI imaging module and deep-learning denoising framework extend three-photon microscopy to 1.7 mm depth

Three-photon microscopy (3PM) has extended optical imaging beyond the reach of two-photon microscopy (2PM), but its practical depth remains far below theoretical predictions because of low photon efficiency and severe noise contamination. Here we present an integrated hardware and software solution that addresses these limitations. We developed a plug-and-play region-of-interest (ROI) imaging module that selectively excites neuron-occupied regions to improve power efficiency and reduce photothermal stress. The module incorporates frame-partitioned accumulative (FPA) imaging for high signal-to-noise ratio (SNR) structural acquisition, automated neuron segmentation, and motion-robust registration for stable recordings. Complementing this, OptiCal is a cascaded deep-learning framework that removes mixed noise including periodic, motion-induced, and random components. Together, these innovations enable high-fidelity imaging to 1.7 mm depth, extending the practical limit of 3PM by about 400 {micro}m while maintaining low excitation power. Our results reveal reliable calcium activity and behavior-correlated dynamics in deep medial prefrontal cortex of awake mice.

neuroscience↗

bioRxiv2025

Kilohertz-rate two-photon voltage imaging of population dynamics in vivo

Understanding how neural circuits compute requires capturing voltage dynamics across large neuronal populations with millisecond resolution in vivo. However, two-photon voltage imaging remains fundamentally limited by a trade-off among imaging speed, field of view, and excitation efficiency. We introduce HS2PM, a hybrid scanning two-photon microscope that overcomes this bottleneck, enabling kilohertz-rate imaging over a 650 x 524 m2 field of view at single-cell resolution while preserving the photon efficiency of single-point excitation. HS2PM stably records deep-layer membrane potentials from over 160 neurons simultaneously, with minimal photobleaching and phototoxicity. It resolves both spikes and subthreshold voltage dynamics in vivo, revealing how these jointly shape sensory adaptation and population coding. Beyond voltage imaging, HS2PM supports high-speed fluorescence lifetime and vascular flow imaging, establishing a multimodal platform for dissecting fast circuit dynamics with precision previously inaccessible to optical methods.

neuroscience↗

bioRxiv2025

Residual blinking-driven channel alignment for multicolor single-molecule localization microscopy

Given the nanometer-scale resolution of single-molecule localization microscopy (SMLM), sequential multicolor SMLM is inherently challenged by inter-channel misalignment arising from unpredictable sample drift during channel switching. Traditional fiducial-based strategies are limited by added complexity in sample preparation. Here, we report a residual blinking-driven method for channel alignment in multicolor SMLM, termed ReBling alignment. By exploiting residual blinking events under dual-wavelength excitation, our method extracts shared localizations as intrinsic registration anchors and performs accurate cross-correlation-based alignment. We validated ReBling alignment across biological systems featuring distinct spatial patterns, including continuous patterned structures (mitochondria-microtubule co-imaging, dual-labeled microtubules), and discrete point-cluster assemblies (dual-color nuclear pore complex components), demonstrating its broad applicability and reliability. These results establish ReBling alignment as a practical, versatile, fiducial-free solution for accurate channel registration in sequential multicolor SMLM, enabling more precise and reliable characterization of complex cellular architecture and molecular interactions.

cell biology↗

bioRxiv2025

Combinatorial Protein Language Model-Guided Engineering of TEV Protease for Enhanced Stability and Production

Industrial enzyme engineering focuses on improvement of enzyme production yield, stability, catalytic activity, and substrate specificity, but often suffers from low efficiency with time-consuming and labor-intensive design and screening processes of massive libraries. Recent advances in AI and machine learning created protein language models trained by numerous datasets and shed new lights to speed up the enzyme engineering processes with high accuracy structural prediction. Here, we developed a highly efficient enzyme engineering strategy combining three protein language models (xTrimoMPNN-Thermo, ESM-IF, and MPNNsol) and use it to generate TEV protease variants with improved expression, stability, and function. The results indicated that a small number of TEV protease designs (<50 designs) were sufficient to develop variants with desired properties, demonstrating its high efficiency. Our strategy could be broadly applied to accelerate designing and engineering various industrial enzymes.

bioengineering↗

bioRxiv2025

Molecular insights into Profilin1-dependent regulation of cellular phosphatidylinositol-(4,5)-bisphosphate

Phosphatidylinositol (4,5)-bisphosphate (PIP2), the most abundant cellular poly-phosphoinositide (PPI) class of phospholipid, is a central plasma membrane (PM)-associated signaling hub that controls many cellular processes. In this study, we demonstrate that either deletion of the gene encoding actin-binding protein profilin1 (Pfn1) or disruption of Pfn1-actin interaction leads to downregulation of PM PIP2 content in cells. This is also phenocopied when F-actin is depolymerized implying that Pfn1-dependent PIP2 alteration is related to its actin-regulatory function. Phospholipase C (PLC) activity is critical for Pfn1-deficient cells to exhibit the PIP2-related phenotype. These findings, taken together with biochemical signatures of elevated PIP2 hydrolysis (higher baseline PM diacylglycerol-to PIP2 ratio and protein kinase C activity) exhibited by Pfn1-deficient cells, imply that PLC-mediated PIP2 hydrolysis plays a role in Pfn1-dependent regulation of PM PIP2. Furthermore, we unexpectedly found that Pfn1 loss leads to dramatic alterations in several other important forms of lipids, revealing a previously unrecognized role of Pfn1 as a broad regulator of cellular lipid environment that extends beyond PPI control. In conclusion, our study establishes Pfn1 as an important regulator of cellular lipid homeostasis. SUMMARY STATEMENTThis study uncovers a mechanism of how functional loss of Profilin1, a key regulator of actin cytoskeleton, can trigger downregulation of plasma membrane content of PIP2, an important class of phospholipid, in cells.

cell biology↗

bioRxiv2025

Evolutionary rates provide genomic insights into convergent and lineage-specific evolution in carnivorous plants

Carnivorous plants (CPs) are striking examples of convergent evolution across ecological, morphological, and molecular scales, making them ideal systems for investigating genomic adaptation to extreme environments. While genomic studies have shown that gene family expansion and functional recruitment underlie key carnivorous traits, the effects of these transitions on rates of sequence evolution remain incompletely understood. Here, we present a comparative framework to examine evolutionary rate shifts across 30 carnivorous and non-carnivorous eudicots in over 12,000 gene families. Analyzing branch-lengths and evolutionary rate covariation (ERC), we detect both lineage-specific and convergent acceleration in CPs for genes associated with stress response, stimulus signaling, and light perception. Accelerated genes often belong to expanded families and show relaxation of purifying selection pressure. Despite the limited number of specific genes or gene families showing convergent acceleration across CP lineages, we find strong convergence at the functional level. Distinct sets of accelerated genes in each CP lineage are enriched for similar functional pathways, particularly light and hormone responses. ERC network analysis identifies a stress- and stimulus-responsive gene community with lineage-specific acceleration in Sarraceniaceae species and moderate acceleration in other CP lineages. Hub genes in this network are also co-expressed in a distantly related non-CP model system, suggesting repeated co-option of an ancestral regulatory module for carnivorous functions. Together, our results show that convergent genomic rate accelerations in CPs primarily involve functionally equivalent or similar but lineage-distinct genes, shaped by gene duplication, relaxed selection, and co-option of stress-response networks.

evolutionary biology↗

bioRxiv2025

Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate

Cell fate transitions require signal-induced chromatin derepression, yet mechanisms governing transitions from repressed to active chromatin states are poorly understood. We discover, at fate-defining genes across immune cell types, a signal-induced histone code, and describe domains of H3 serine 28 phosphorylation (H3S28ph) spanning architectural features, often coincident with repressive H3 lysine 27 trimethylation (H3K27me3). Employing biophysical, single cell, and functional approaches to study signal-induced cell differentiation in the immune system, we uncover epigenomic transitions and cell fate choices precipitated by histone phosphorylation (H3ph). Mechanistically, H3ph overrides Polycomb Repressive Complex 2 (PRC2) chromatin repression, biophysically disrupts polynucleosome compaction, and promotes loss of H3K27me3, while increasing activating H3K27 acetylation and H3K36 dimethylation to drive domain interactivity and stabilize transcription. We demonstrate the activity of H3ph in several cell fate transitions and illuminate biophysical mechanisms enabling rapid signal-activated chromatin derepression, processes with general relevance for cellular differentiation and activation.

immunology↗

bioRxiv2025

Non-apoptotic death of the C. elegans linker cell is primed by MYRF-1 activation of pqn-41/polyQ

Linker cell-type death (LCD) is a morphologically conserved non-apoptotic cell-death process with features resembling polyglutamine-dependent neurodegeneration. In C. elegans development, LCD eliminates the male-specific linker cell following its long-range migration. Using single-cell mRNA sequencing of migrating and dying linker cells, we identify myrf-1, encoding a membrane-bound transcription factor implicated in human developmental disorders, as a key LCD regulator. MYRF-1 translocates to the linker cell nucleus during early migration and, surprisingly, its auxin-inducible degradation then, but not later, blocks LCD. MYRF-1 directly binds known LCD genes, including pqn-41, encoding an aggregation-prone polyglutamine protein. Deleting a bona fide MYRF-1-binding site within pqn-41 promotes linker cell survival. Our findings reveal that linker cell death is primed well before cell demise takes place, temporally uncoupling death commitment and execution.

cell biology↗

bioRxiv2025

ERAD Activity Distinguishes the Functional Heterogeneity of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) rely on precisely controlled proteostasis to sustain lifelong self-renewal, yet whether intrinsic proteostatic characteristics can prospectively define functional diversity within the HSC pool remains unknown. In this study, we developed a dual-fluorescence reporter system to visualize endoplasmic reticulum-associated degradation (ERAD) activity in vivo and discovered that ERAD activity can prospectively predicts the long-term reconstitution potential of HSCs. Remarkably, ERAD states were maintained through self-renewal, revealing an inheritable "proteostatic memory" within the HSC pool. Transcriptomic and functional analyses identified SOCS2 as a key regulator of this process: SOCS2 inhibits JAK2 signaling to sustain ERAD activity, whereas hyperactive JAK2 interacts with the ERAD E3 ligase Hrd1 and suppresses VCP-mediated misfolded substrate. These findings define a SOCS2-JAK2-ERAD axis that connects cytokine signaling to intrinsic proteostasis remodeling, establishing ERAD activity as a predictive and heritable marker of HSC function and providing a conceptual framework for understanding hematopoietic stem cell heterogeneity.

cell biology↗

bioRxiv2025

Dynamic alterations of DNA methylation and transcriptome in adaptation to and recovery from the space environment

Space exploration presents tremendous health challenges. Here, we report time series of multi-omic and phenotypic profiles of seventeen astronauts from six China Manned Space missions with continuous spaceflight durations ranging from 13 to 180 days. We revealed a key role of DNA methylation regulation in reshaping gene expression patterns to adapt to the space environment. Long-duration spaceflight showed more alterations in epigenetic modifications correlated with alternative splicing and protein acetylation. During recovery, an "overrange rebound" phenomenon was observed, furthermore, a mathematical model was established to describe this implying important phenomenon. Moreover, we revealed the correlations between molecular alterations and phenotypic changes such as coagulation activation and bone intensity loss. Additionally, we performed ground-based simulation experiments to estimate the impacts of individual stressors in the space environment on DNA methylation. In summary, our study highlights the importance and complexity of epigenetic regulation in adaptation to and recovery from the space environment.

genomics↗