Biology subjects

Wang, N.

Publications and source records attributed to Wang, N..

At least 91 records · Page 5Linked to original sources

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

Unpredictable circadian rhythm disruption in Wistar rats: biological and behavioural changes reflecting bipolar disorder pathophysiology

Circadian disturbances are implicated in dysregulation of arousal and general neurobiological function, contributing to conditions such as bipolar disorder (BD). However, the behavioural and biological consequences of circadian disruption on arousal dysfunction remain poorly quantified. Here, we developed a novel unpredictable circadian disruption (UCD) protocol - consisting of unpredictable exposure to light and sound - to investigate its impact on locomotor activity and its association with metabolic, inflammatory, stress, and circadian markers in the nucleus accumbens (NAc). Forty-eight Wistar rats were exposed to UCD or control conditions, with or without corticosterone administration, for five weeks. Body weight was tracked throughout the study. Locomotor activity was assessed over the final two weeks (nine sessions) in an open-field arena. Real-time PCR was used to quantify NAc gene expression of inflammatory, metabolic, stress, and circadian markers, while liquid chromatography-mass spectrometry (LC-MS) measured neurotransmitter and central carbon metabolite concentrations. UCD animals exhibited initial hyperactivity at three weeks, followed by hypoactivity at four weeks. UCD was associated with increased NAc expression of inflammatory, stress, and circadian markers. Male UCD animals showed significant weight gain, an effect reversed in females. UCD also induced increases in NAc insulin resistance markers and reductions in central carbon metabolites, indicating disrupted striatal glucose metabolism. These findings highlight the central effects of circadian disruption on locomotor behaviour, stress, and immunometabolic signalling, offering mechanistic insights into arousal dysfunction in BD. HighlightsO_LIUnpredictable circadian disruption (UCD) triggers a biphasic shift in locomotor behaviour C_LIO_LIUCD alters levels of striatal inflammatory, circadian, stress, and metabolic markers C_LIO_LIUCD has sex-specific effects on behaviour, weight, and molecular biomarkers C_LIO_LICorticosterone administration mitigates key molecular disruptions induced by UCD C_LI

neuroscience↗

bioRxiv2025

Structural insights and engineering of deep-sea halophilic PET hydrolytic enzymes

Pervasive use of polyethylene terephthalate (PET) poses tremendous challenges for global waste management and environmental sustainability, fueling growing interests in enzymatic degradation as an eco-friendly solution. While PET hydrolases hold significant promise, their industrial deployment is hindered by insufficient performance, particularly under high-salinity conditions raised from high substrate loads. Building on our previous discovery of three deep-sea PET hydrolases (dsPETase01, dsPETase05 and dsPETase06) with exceptional halophilicity and PET-degrading activity, we here present their three-dimensional structures and mechanistic characterization. Structural comparison, site-directed mutagenesis, and domain swapping reveal key structural features and the essential role of C-terminal acidic residues in salt tolerance. Integrating semi-rational protein design, Transformer-based modeling, and disulfide bond engineering, we synergistically enhance the thermostability and catalytic efficiency of dsPETase05. These findings elucidate the unique structural features and salt adaptation mechanisms of deep-sea halophilic PET hydrolases, and inform the future engineering of biocatalysts for application in harsh industrial environments.

molecular biology↗

bioRxiv2025

High-throughput 3D super-resolution ultrasound imaging

Capturing fast hemodynamics in deep organs is essential for understanding microvascular regulation of organ responses to physiological demands and pathological stress. However, non-invasive three-dimensional (3D) imaging of these microscale processes remains challenging due to trade-offs between spatial resolution, imaging speed, and penetration depth. Here, we present fluctuation-based high-order super-resolution acoustic microscope (FLAME), a tracking-free 3D ultrasound imaging technology capable of fast microvascular angiography and flow measurement. Using as few as 30 volumes, FLAME improves 3D ultrasound resolution by 8-fold ([~]50 m) and shortens data acquisition time by over two orders of magnitude, from tens of seconds to tens of milliseconds, compared with conventional tracking-based super-resolution approaches1-6. This high-throughput capability supports high-fidelity imaging of tissue functions under flexible experimental settings. FLAME achieves an unprecedented 3D super-resolution frame rate of [~]40 Hz, capturing transient hemodynamic responses to various physiological and pathological stimuli in different mouse organs, from the microvascular level to the whole-body scale. With open-sourced implementation, FLAME provides an accessible platform for real-time, in-depth hemodynamic monitoring across diverse biomedical applications and clinical translation.

bioengineering↗

bioRxiv2025

Tracking the Evolutionary Patterns of RNA Modifications from Bryophyte to Flowering Plants by Mass Spectrometry

RNA modifications are critical for the regulation of gene expression. Comprehensive profiling of RNA modifications is a prerequisite for unravelling their identities and functions. The plant hormone auxin plays pivotal roles in regulating plant growth, development, and environmental responses. In contrast to the extensive studies in animals, there is a paucity of knowledge regarding the existence and functions of RNA modifications in plants. This is due to the low abundance of modified ribonucleosides and the lack of accurate analytical methods. This study employs a state-of-the-art hydrophilic interaction liquid chromatography-tandem-mass spectrometry (HILIC-MS/MS) platform to achieve the sensitive detection of 12 nucleosides at the pM to nM level. Utilizing this platform, we were able to identify N4,2-O-dimethylcytidine (m4Cm) in plants by LC-MS/MS for the first time, which provided direct evidence for the widespread of this modification in plants. Moreover, a comprehensive investigation was undertaken to examine the 12 types of RNA modifications and their response patterns to auxin in a range of prototype plants, spanning from bryophyte (Marchantia polymorpha) to flowering plants (Arabidopsis thaliana, Oryza sativa, and Zea mays). The evolutionary patterns of the 12 RNA modifications were depicted from bryophyte to flowering plants, and their potential functions in plant growth, development, and auxin responses were revealed.

biochemistry↗

bioRxiv2025

Light-Activated Nucleic Acid Amplification Systems Using Photo-caged DNA Polymerase or Primers

Precise control over nucleic acid amplification is essential for achieving reliable, quantitative, high-throughput, and multiplexed molecular diagnostics, particularly in point-of-care and field settings. However, conventional isothermal amplification methods, especially rapid assays at ambient temperature such as recombinase-aided amplification (RAA), suffer from spontaneous initiation and lack of synchronization across parallel reactions. Here, we report light-activatable RAA systems employing two distinct photocaging strategies to achieve spatiotemporal control. In the first, a photocaged DNA polymerase was engineered via site-specific incorporation of p-azido-L-phenylalanine and conjugation with a 2-nitrobenzyl-modified ssDNA blocker through click chemistry. This approach offers high stability, making it advantageous for long-term storage and lyophilized formats. In the second, 5'-nitrobenzyl-modified primers were synthesized to block hybridization or extension until UV activation, offering operational simplicity and rapid integration into existing workflows. Both strategies independently suppressed background activity in the dark and restored full amplification efficiency upon 365 nm UV exposure. The systems exhibited high sensitivity, low background, and compatibility with portable diagnostics. A custom-built device integrating UV activation and real-time fluorescence detection enabled seamless, on-demand operation. This modular platform provides flexible light-gated amplification solutions, allowing the selection of polymerase- or primer-based caging according to storage stability or workflow requirements, thereby advancing precise and field-ready molecular diagnostics.

molecular biology↗

bioRxiv2025

Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2V617F Clonal Hematopoiesis

BackgroundThe Jak2V617F (Jak2VF) mutation is an important cause of both clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPN). Mouse models of Jak2VF CHIP and MPN show accelerated atherosclerosis progression, driven by macrophage inflammasome activation. We undertook the present study to assess the hypothesis that ongoing inflammation would impede atherosclerosis resolution in Jak2VF mice. Methods and ResultsChimeric Jak2VF/WT or control WT/WT bone marrow was transplanted into Ldlr-/-mice and, following 13-16 weeks of Western diet-induced atherosclerosis progression, cholesterol was lowered either moderately (to 200-300 mg/dl) or markedly (to 100 mg/dl). With moderate cholesterol lowering, there was impaired resolution of lesions in Jak2VFMPN mice compared to controls. However, with marked cholesterol lowering, progression of lesions was halted in both Jak2VF MPN and control mice while macrophage burden was decreased and lesional collagen was increased similarly in Jak2VFMPN and control mice. Two mechanisms of low-density lipoprotein (LDL) lowering-induced suppression of inflammation in plaques were implicated: 1) reversal of increased proliferation, DNA damage and Absent in Melanoma 2 (AIM2) inflammasome activation specifically in Jak2VF macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-myc expressing macrophages in both Jak2VF and control mice. ConclusionsAggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2VF MPN, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could reverse atherosclerotic cardiovascular disease (ACVD) risk in individuals with JAK2VFCHIP or MPN.

molecular biology↗

bioRxiv2025

Modular platform for therapeutic drug delivery using trifunctional bio-orthogonal macromolecular conjugates

Targeted delivery of macromolecular therapeutics holds great promise for overcoming the limitations of conventional small molecules, enabling modulation of protein-protein interactions and precise genome editing. However, efficient, safe, and cell type-specific delivery remains a major challenge. To address this, we developed a modular platform for synthesizing heterotrifunctional bio-orthogonal macromolecular conjugates (BMCs) by engineering diverse combinations of targeting ligands, cell-penetrating peptides (CPPs), and bioactive cargos. We optimized facile bioconjugation chemistries to generate BMCs with improved yields, structural integrity, and activity. Modular BMCs accommodate diverse components, including antibodies and receptor ligands for targeting, CPPs for intracellular trafficking, and optical probes, therapeutic peptidomimetics, and CRISPR-Cas9 nuclease as cargos to confer specific biological activities. We assayed their utility across multiple applications: BMCs with fluorescently labeled cargo revealed endosomal escape and intracellular accumulation; peptidomimetic MYB transcription factor inhibitor BMCs exhibited potent anti-leukemic activity against acute myeloid leukemia cells; and Cas9 BMCs achieved rapid delivery and cell type-specific gene editing in human cells. The BMC approach enables customizable delivery of functional macromolecules, nominating BMCs as a broadly applicable platform for biomedical applications. One-Sentence SummaryThe establishment of modular platform for synthesizing bio-orthogonal macromolecular conjugates (BMC) enabled fast and targeted delivery of membrane-impermeant macromolecular drugs.

biochemistry↗

bioRxiv2025

A Paracrine-to-Autocrine Shunt of GREM1 Fuels Colorectal Cancer Metastasis via ACVR1C

Tumor cells typically rely on paracrine stromal signals to guide malignant behaviors, but whether they acquire signaling autonomy to support metastasis remains unclear. We elucidate this in colorectal cancer (CRC) by uncovering a paracrine-to-autocrine shunt of Gremlin1 (GREM1), a canonical stromal-secreted antagonist of bone morphogenetic proteins (BMPs). We demonstrate that while GREM1 remains restricted to stromal cells in earlier-stage (I-III) CRC, its ectopic expression in tumor epithelium increases markedly in stage IV. Mechanistically, we identify ACVR1C as a novel, high-affinity epithelial receptor for GREM1. Their interaction activates SMAD2/3 signaling, which upregulates SNAI1 and GREM1, establishing a feedback loop that amplifies epithelial-mesenchymal transition (EMT). Disrupting this loop impairs CRC metastasis in vivo. Clinically, epithelial GREM1 or ACVR1C expression predicts metastasis and poor survival. These findings define a paradigm in which tumor cells hijack stromal GREM1 to establish a GREM1-ACVR1C autocrine loop that sustains EMT and metastasis, marking a shift toward signaling autonomy and revealing a targetable vulnerability in advanced CRC.

cancer biology↗

bioRxiv2025

Copper-Containing ROS-Scavenging Nanozyme Paradoxically Drives Alpha-Synucleinopathy by Amplifying Nitrosative Stress

Reactive oxygen and nitrogen species (RONS) are implicated in neurodegeneration, but their specific pathogenic roles remain unclear. Here, we developed a pair of iridium-based nanozymes with opposing functionalities to dissect these pathways. We show that a copper-tuned iridium nanozyme (Ir{square}Cu), despite being a superior ROS scavenger, paradoxically and dramatically exacerbated -synuclein (Syn) pathology in vivo. This pathology was causally linked to its ability to amplify RNS, as pharmacological inhibition of nitric oxide synthase (NOS) with L-NAME completely abrogated the pathology and reversed a human Parkinsons disease (PD)-like transcriptomic signature. In contrast, a copper-free, broad-spectrum RONS-scavenging iridium (Ir) nanozyme demonstrated substantial therapeutic efficacy across diverse brain-first, body-first, and Alzheimers disease with Lewy body co-pathology models. Our findings uncover the importance of the RNS pathway in driving -synucleinopathies and establish a critical design principle for nanomedicine, mandating caution in the use of redox-active copper for neuroprotective applications.

pathology↗

bioRxiv2025

Integrated landscape genomics reveals biogeography and climate-driven local adaptation in high-altitudes

High-elevation environments harbor unique species adapted to altitudinal and environmental extremes. However, due to logistical challenges of sampling such species throughout their distribution across steep and varied terrains, studies often lack comprehensive evidence to understand patterns of population divergence, local adaptation, and how current adaptations may influence future vulnerability. In this study, we utilized Tibetan Partridge (Perdix hodgsoniae), a high-altitude endemic bird found between 2800-5000 meters across the arid western and humid northeastern regions of the Sino-Himalayan landscape. This regions complex topography-characterized by tall mountains, deep valleys, and contrasting climatic conditions provided opportunities for investigating population divergence, local adaptation, and climate-related vulnerability. We integrated population-scale whole-genome sequencing with ecological, climatic, landscape, and morphological data to examine current patterns of local adaptation and forecast future risks. Our findings show that both biogeographic barriers and climatic variation drive rapid population divergence in P. hodgsoniae, reflected in distinct morphological traits and population genetic structure. Western populations, inhabiting dry and fragmented landscapes, exhibit adaptations to temperature extremes with low genetic diversity, reduced habitat suitability, limited gene flow, and weak connectivity--factors that increase their vulnerability to future environmental changes. In contrast, northeastern populations, living in more humid regions, show genetic adaptations linked to precipitation, maintain high genetic diversity and habitat connectivity, and may serve as evolutionary refugia under future climate scenarios. This study underscores the value of integrating genomic, ecological, and landscape data to reveal mechanisms of divergence and adaptation, and to develop robust predictions for conservation planning under rapidly changing environmental conditions.

evolutionary biology↗

bioRxiv2025

The 5-HT1A receptor antagonist WAY-100635 maleate reprograms metabolism to promote RGC differentiation and regeneration in retino-visual centers

Metabolic collapse of retinal ganglion cells (RGCs) onsets glaucoma, yet no approved drug directly protects these neurons. Through a live-cell mitochondrial screen in human stem-cell-derived hRGCs we uncovered WAY-100635 (WAY), a clinically tested 5-HT1A antagonist, as a systemic neuroprotectant. WAY triggers a reversible cyclic-AMP surge that activates PGC-1-driven reversible mitochondrial biogenesis and suppresses apoptosis. In glaucoma associated OPTNE50K hRGCs, WAY restores mitochondrial fitness, dampens excitotoxicity, and reprograms metabolism toward aerobic glycolysis, while in progenitors WAY boosts mitochondrial cristae maturation, oxidative phosphorylation, and cell-cycle exit to accelerate RGC specification. Daily intraperitoneal dosing preserves RGC bodies, neural activity, promotes axon regeneration into the optic nerve and vision centers after optic-nerve crush, as well as shows RGC protection and maintenance of visual acuity in chronic ocular hypertension glaucoma. As the non-invasive neuroprotective therapy with a human safety profile, WAY addresses a critical gap in glaucoma care and potentially for other mitochondrial optic neuropathies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/659983v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@131ff3eorg.highwire.dtl.DTLVardef@16c4e6borg.highwire.dtl.DTLVardef@190724eorg.highwire.dtl.DTLVardef@4067e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Single oocyte full-length isoform sequencing unveils the impact of transposable elements on RNA diversity and stability during oocyte maturation

The oocyte-specific isoforms play crucial roles in oocyte maturation, while current understanding of the oocyte transcriptome is mainly focused on gene level. Here, we utilized single cell full-length isoform sequencing based on third generation sequencing to detect entire transcripts in human and mouse oocytes. Isoform diversity during oocyte maturation was systematically profiled, including 6,736 and 4,902 putative novel human and mouse transcripts, respectively. More than half of novel isoforms were categorized as the novel-not-in-catalog (NNC) and may serve specific functions in oocytes, including novel isoforms of ARHGAP18, colocalized with microtubules and targeted knockdown disrupting oocyte maturation. Moreover, over 25% of NNC isoforms were derived from transposable elements (TEs), and their incorporation within transcripts could enhance isoform stability during oocyte maturation. Altogether, our findings represent a valuable resource showcasing the complexity and diversity of RNA isoforms in oocytes, as well as TE co-option for novel isoform generation and isoform stability enhancement.

developmental biology↗

bioRxiv2025

A Tunable Pulmonary Organoid Model Demonstrates Compositionally Driven Epithelial Plasticity and Immune Polarization

Summary/AbstractAberrant epithelial regeneration and immune remodeling are hallmarks of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), COPD, and post-viral syndromes. Yet how cellular context shapes these trajectories remains unresolved. We present a tunable, primary rat-derived lung organoid model that systematically varies immune, epithelial, and mesenchymal inputs to reveal how composition alone dictates epithelial plasticity and macrophage polarization. Across organoid conditions that varied by relative starting lineage ratios, we observed the spontaneous emergence of disease-relevant transitional cell states, including Sox9+ stressed progenitors, RAS-like intermediates, and hillock-like cells, alongside distinct macrophage activation profiles. In mesenchyme-rich contexts, epithelial-immune-mesenchymal crosstalk appeared to reinforce inflammatory signaling and stabilize transitional persistence, while immune-dominant inputs favored ATI-like repair and squamous remodeling. Hillock-like cells displayed context-specific polarization and expressed immune-regulatory genes, suggesting a role as epithelial orchestrators that help calibrate inflammatory response during regeneration. Connectomic analysis via NICHES revealed that regenerative outcomes were associated with dynamic multicellular signaling networks that integrate stress sensing, immune coordination, and epithelial resilience. This platform provides a tractable system for modeling milieu-specific repair and regenerative mechanisms and could inform therapeutic strategies aimed at redirecting epithelial fate in chronic lung disease.

bioengineering↗

bioRxiv2025

IL-18 inhibition enlarges lesions, necrotic cores and thickens fibrous caps in Jak2V617F clonal hematopoiesis-driven atherosclerosis.

BackgroundInflammasome activation promotes atherosclerosis in clonal hematopoiesis (CH). Active inflammasomes secrete both IL-1{beta} and IL-18. Plasma IL-18 levels are elevated in Jak2VFCH. Genetic deficiency of IL-18 has been shown to reduce atherosclerosis in non-CH murine models. However, whether IL-18 inhibition promotes atherosclerosis in control or Jak2VF CH is unknown. Methods and resultsLdlr-/- mice were transplanted with bone marrow (BM) from Mx1-cre Jak2VF (20%) and wild-type (80%) mice or with control BM, fed a Western-type diet (WTD) for 8, 10 or 16 weeks and administered control or IL-18 IgG from 4 weeks onwards. IL-18 antibody treatment increased plaque collagen content and cap thickness. Unexpectedly, IL-18 antibody treatment increased the size of early lesions and promoted formation of advanced lesions with large necrotic cores in Jak2VF CH mice. IL-18 antibody treatment was associated with diminished interferon (IFN)-{gamma} and AIM2 levels and reduced macrophage pyroptosis especially in Jak2VF CH mice. However, IL-18 antibodies increased cleaved Caspase-3 and TUNEL+ macrophages (indicating increased apoptosis) and reduced efferocytosis. Sc-RNA-seq analysis showed that IL-18 antibody treatment reduced expression of MHC class II genes, a marker of IFN-{gamma} signaling, and of genes mediating efferocytosis (Mertk and Axl), in resident-like macrophage subpopulations in Jak2VF CH mice. Consistently, IFN-{gamma} injection increased Axl and Mertk expression in resident peritoneal macrophages. ConclusionsDespite improvements in collagen and fibrous cap thickness in Jak2VF CH mice, IL-18 antibody treatment increased advanced necrotic lesions, reflecting a shift from pyroptotic to apoptotic cell death coupled with defective efferocytosis, events which were coordinated by reduced IFN-{gamma} signaling. These findings indicate a mixed atherosclerosis phenotype resulting from IL-18 inhibition, advocating for alternative therapeutic strategies. Inhibition of IL-18 has been considered as a novel therapeutic approach to reduce atherosclerosis and stabilize atherosclerotic plaques. We show that IL-18 antibodies have adverse effects on atherosclerotic lesional necrosis, calling this approach into question. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/657754v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@a93b2forg.highwire.dtl.DTLVardef@6cc057org.highwire.dtl.DTLVardef@1c7afc5org.highwire.dtl.DTLVardef@e4da82_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIInflammasome activation produces active IL-1 and IL-18 and worsens atherosclerosis in clonal hematopoiesis (CH) however the contribution of IL-18 is unknown. C_LIO_LIAntibody inhibition of IL-18 increased plaque collagen but also increased early lesion area and late lesions with large necrotic cores in Jak2VF CH mice. C_LIO_LIThere was a reversal of AIM2 inflammasome activation but a switch to apoptosis which along with reduced efferocytosis increased necrosis C_LIO_LIThese events appeared to be coordinated by reduced IFN-{gamma} which increased collagen but also decreased expression of efferocytotic genes. Our studies call into question whether inhibition of IL-18 would stabilize plaques in CH. C_LI

molecular biology↗

bioRxiv2025

Cardiac fibroblasts counterbalance cardiomyocytes in LMNA cardiomyopathy pathogenesis

Genetic cardiomyopathies arising from mutations in the LMNA gene, encoding nuclear intermediate filaments lamin A/C, display variable age of onset, severity, and fibrosis development. This variability suggests a fundamental element in disease pathogenesis that has yet to be elucidated. Given the central role cardiac fibroblasts play in fibrosis, we explored the relevance of lamin A/C in cardiac fibroblast function, as very little is known in this regard. Using primary cardiac fibroblasts and in vivo mouse models, we show that Lmna mutations impact various aspects of cardiac fibroblast function in response to myocyte damage. We show that both lamin A/C depletion and point-mutant variant expression impair cardiac fibroblast proliferation and contraction whereas other functions such as cell migration appears to be mutation dependent. In vivo depletion of lamin A/C simultaneously in cardiomyocytes and cardiac fibroblasts significantly delayed disease progression, improved cardiac function, and prolonged survival, indicating that lamin A/C mediate an opposing balance between cardiomyocytes and cardiac fibroblasts in driving disease pathogenesis. Our results elucidate previously unexplored roles of lamin A/C in cardiac fibroblasts and suggest that interactions between cardiac fibroblasts and cardiomyocytes are important determinants of the rate of progression and the severity of LMNA cardiomyopathy.

cell biology↗

bioRxiv2025

Mechanistic dissection of Candidatus Liberibacter Triggered Chronic Immune Disease

Immunity is generally considered critical for plant health against pathogen infection. Citrus Huanglongbing (HLB) caused by the phloem colonizing bacterial pathogen Candidatus Liberibacter asiaticus (CLas) was suggested to be a pathogen triggered chronic immune disease. However, the genetic evidence and mechanistic understanding for such a disease model is lacking. Here, we show CLas triggers phloem cell death, reactive oxygen species (ROS) production and callose deposition in photosynthesis tissues, but little or none in non-photosynthesis tissues of citrus. We further demonstrate that CLas triggers ROS production in chloroplasts. Overexpression of flavodoxin (Fld), an electron shuttle, in chloroplasts reduced ROS production, cell death and HLB symptoms, but not phloem callose deposition induced by CLas. Knockout, silencing, and overexpression of phloem callose synthase genes CsCalS7a, CsCalS7b, or CsCalS7c demonstrated that phloem callose deposition also caused phloem cell death. Trunk injection with 2-deoxy-d-glucose, a callose deposition inhibitor, reduced fruit drop and increased fruit yield of HLB symptomatic trees in field trials. Using tomato-Ca. L. psyllaurous (Lpsy) as a model, knockout of Eds1 and Pad4 but not RbohB, Bik1 and Sobir1 abolished ROS production, phloem callose deposition, cell death and disease damages caused by Lpsy. This study provides genetic evidence for Ca. Liberibacter-triggered immune disease and reveals that tuning plant immune responses converts Ca. Liberibacter into a benign endophyte, providing a promising strategy for precision breeding to enhance resistance/tolerance against HLB.

plant biology↗

bioRxiv2025

A complete reference genome assembly and annotation of the Black Redstart (Phoenicurus ochruros)

The Black Redstart (Phoenicurus ochruros) is one of the most widely distributed species, occupying diverse habitats and exhibiting remarkable altitudinal migration, making it suitable model for studying altitudinal migration and high-altitude adaptation. In this study, we present the first reference genome of Phoenicurus ochruros, generated using PacBio HiFi long-read sequencing. The nuclear genome is 1.37 Gb in length, assembled into 296 scaffolds with a scaffold N50 of 29.9 Mb. Multiple complementary genome validation approaches - including BUSCO analysis, mapping of raw PacBio HiFi reads, and comparative genomics analysis - confirmed the high contiguity and gene-space completeness of the genome. The Black Redstart genome contains one of the highest proportions of transposable elements among passerines (30.58%), second only to Bells Sparrow (Artemisiospiza belli), 31.2%. We further integrated RNA-seq data, protein homology evidence, and ab initio gene prediction to build high-quality genome annotation of 18,609 genes in the P. ochruros genome. This genomic resource provides invaluable resource for evolutionary genomics studies of passerines and explore genetic basis of high-altitude adaptation.

genomics↗