Biology subjects

Xu, S.

Publications and source records attributed to Xu, S..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

RPRM (Reprimo) triggers SCF(FBXW11)-mediated DNA-PKcs degradation to block non-homologous end joining and radiosensitize tumors

Targeting DNA damage repair pathways represents a promising strategy in cancer radiotherapy, however, the limited insight into the regulation of the non-homologous end joining (NHEJ) repair pathway in cancer cells severely restricts the development of precise radiosensitization approaches. Here, we identify Reprimo (RPRM), a p53-inducible tumor suppressor, is a potent inhibitor of NHEJ in which RPRM promotes proteasomal degradation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylated at the T2609 site. Upon irradiation, RPRM quickly translocates into the nucleus to enhance the transcription of FBXW11, a F-box protein gene that encodes the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. In the nucleus, RPRM is also able to scaffold the assembly of the SCFFBXW11 E3 ligase complex by binding to both CUL1 and FBXW11. This complex can specifically ubiquitylate phosphorylated DNA-PKcs (T2609), leading to reduced levels of both phosphorylated DNA-PKcs (T2609) and total DNA-PKcs, thereby suppressing NHEJ-driven repair and enhancing tumor radiosensitivity. In consistence, inhibiting the SCFFBXW11 E3 ligase complex eliminates RPRM-mediated radiosensitization by protecting DNA-PKcs. Clinically, high RPRM expression in non-small cell lung cancer (NSCLC) predicts better patient prognosis. Moreover, RPRM expression correlates positively with FBXW11 and PRKDC (DNA-PKcs) in the tumor tissues of the NSCLC patient cohort. Significantly, high expression of RPRM protein is linked to enhanced radiosensitivity of patient-derived organoids (PDOs) from these NSCLC patients. These results establish RPRM as a key negative regulator in NHEJ repair pathway and the RPRM-SCFFBXW11-DNA-PKcs axis as a potential target to enhance cancer radiosensitivity.

cancer biology↗

bioRxiv2025

EMCF ecosystem: Towards pretrained foundation model for electron microscopy image analysis

Volume electron microscopy (vEM) enables nanoscale visualization of three-dimensional (3D) cellular ultrastructure, providing critical insights into physiological processes and pathological alterations. However, its application to large-scale biological tissues remains constrained by two major bottlenecks: prolonged image acquisition and inefficient data processing. Here, we present EMCF ecosystem (EMCFsys), an integrated ecosystem designed to overcome these challenges through three key components: a large-scale benchmark dataset (EMCFD) comprising 4,002,802 high-quality images across 14 EM modalities and 6 biological kingdoms; a foundation image restoration model (EMCellFiner); and a scalable image analysis foundation model (EMCellFound). Together, these modules systematically enhance image quality and substantially improve analysis efficiency. Our results show that EMCellFiner outperforms specialist models in restoring degraded images, even surpassing original ground truth sharpness in certain artifact regions, and reduces imaging time by 16-fold by enabling low-resolution and low dwell time acquisition. EMCellFound exhibits exceptional feature discriminability, outperforms specialist models in classification, semantic segmentation and instance segmentation. It also enables high-precision 3D reconstruction of organelles (e.g., endoplasmic reticulum) with minimal labeled data (0.01% of total volume). We validated the EMCFsys on unseen datasets across diverse biological contexts and imaging platforms. By publicly releasing both the dataset and models, we establish a scalable paradigm for automated, high-throughput vEM data interpretation, accelerating exploration of lifes nanoscale structure and function across biology.

cell biology↗

bioRxiv2025

Detection of CRISPR-Cas-induced mutations in Daphnia

CRISPR-Cas9 has established itself as a robust tool for conducting loss of function gene research in emerging model species including the freshwater zooplankton Daphnia. However, sensitive detection of mutations, especially in genetic mosaic and pooled samples, remains a challenge. In this study we evaluate two of the most widely used mutation screening techniques, the T7 Endonuclease I (T7EI) assay and Fragment Analysis (FA) for their sensitivity, accuracy, and practical use in detecting CRISPR-induced indels in four targeted genes, DNMT3A, DNMT3B, PERIOD2, and DMRT1 in Daphnia magna. Here, we show that T7EI, although it offers a quick and cost-effective screening method, often produces false positives, especially when examining pooled samples. Conversely, FA facilitates detecting allele size differences at a fine resolution, reproducibility in detecting indels, and distinguishing zygosity and is more reliable as a method to detect mutation. Our comparative analyses convey the importance of carefully selecting the appropriate screening methods depending on research questions.

genetics↗

bioRxiv2025

Acoustoluminescence in Transition Metal and Rare Earth Oxides Beyond 1800 nm for In Vivo Imaging

Acoustoluminescence (AL) is promising for molecular imaging in living tissue, but efficient acousto-optic conversion remains challenging due to the [~]108 times difference in quantum energy between phonons (1 MHz ultrasound) and photons (visible or near-infrared light). Here, we report AL in transition metal oxides (TMOs) and rare earth oxides (REOs) at wavelengths beyond 1800 nm in the short-wave infrared (SWIR) or near-infrared II (NIR-II, 1000-3000 nm) window, under ultrasound excitation at power densities 100-150-fold lower than those required for sonoluminescence in liquids. High-temperature N2/H2-mixed gas reduction was demonstrated as a safe and efficient method to regulate the AL spectra and brightness of TMOs and REOs. TMOs exhibited broadband NIR-II AL emission. Intrinsic emission peaks of rare earth ions and non-conventional luminescence were observed in the AL spectra of REOs under ultrasound excitation. NIR-II AL imaging enabled twice the penetration depth of fluorescence imaging. We developed a scanning focused ultrasound AL imaging system for in vivo tumor imaging through the intact hindlimb, achieving acoustic resolution and penetration depths exceeding one centimeter.

bioengineering↗

bioRxiv2025

An Expectation and Maximization Algorithm for Multivariate Genome-wide Association Studies (EMmvGWAS)

Genome-wide association studies (GWAS) commonly focus on one quantitative trait at a time, even when multiple traits are collected. However, joint analysis of multiple traits can increase the power to detect genetic associations by leveraging trait correlations. Multivariate GWAS is particularly important for identifying pleiotropic effects and uncovering shared genetic architecture underlying complex traits. Despite its great potential, multivariate GWAS methods face substantial computational challenges due to the high dimensionality of polygenic covariance structures and the cost of scanning genome-wide markers. We present EMmvGWAS, an efficient computational framework implemented as an R, which dramatically reduces computation time for multivariate GWAS involving a moderate number of traits. The algorithm estimates the genetic and environmental covariance matrices from a pure polygenic model using an Expectation-Maximization (EM) algorithm. To improve computational efficiency during genome-wide scanning, we use a semi-exact method that fixes the estimated covariance matrices and treats their ratio, defined as the genetic covariance matrix multiplied by the inverse of the environmental covariance matrix, as a known constant across all markers. This approach enables closed-form solutions for marker effects at each locus, dramatically reducing the computation time without compromising statistical power. We demonstrate the scalability and performance of our method through both simulation studies and real dataset analyses from rice, mouse and human populations. The method is implemented in R and is designed to support multivariate GWAS involving a moderate number of traits, while also accommodating univariate analyses as a special case. The R package is available at https://github.com/Jason-Teng/EMmvGWAS.

genomics↗

bioRxiv2025

Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans

Mitochondrial redox homeostasis is essential for cellular metabolism and organismal development. To investigate the consequences of disrupting redox homeostasis in this organelle in a metazoan organism, we generated a double mutant lacking mitochondrial glutathione reductase (gsr-1a) and thioredoxin reductase (trxr-2) genes in Caenorhabditis elegans. While gsr-1a or trxr-2 single mutants are phenotypically normal, double gsr-1a trxr-2 mutants displayed small body size, gonadal migration defects, reduced brood size, and prolonged egg-laying period, without developmental delay or lethality. Transcriptomic analysis revealed strong induction of ATFS-1-dependent stress and detoxification genes. Consistent with this, gsr-1a trxr-2 worms exhibited constitutive ATFS-1 nuclear localization and robust Phsp-6::gfp expression. Triple gsr-1a trxr-2; atfs-1 mutants were nonviable, demonstrating that unfolded protein response (UPRmt) activation is essential under mitochondrial redox stress. Despite the induction of a stress response at the transcriptional level, gsr-1a trxr-2 double mutants were not more resistant to oxidative or pathogen stressors. Moreover, these mutants maintained normal respiration, ATP and ROS production while displaying altered mitochondrial morphology in a tissue-specific manner, independent of mitophagy genes but dependent on mitochondrial fission or fusion machinery. Functionally, gsr-1a trxr-2 mutants showed impaired motility, reduced calcium uptake upon carbachol stimulation, enhanced hypodermal wound repair, and decreased fertilization efficiency associated with lower muscle exopher production. Overall, our data show that simultaneous loss of mitochondrial GSR-1a and TRXR-2 compromises growth, fertility and muscle performance and triggers a constitutive ATFS-1-dependent UPRmt that sustains viability revealing mitochondrial redox control as a core determinant of organismal proteostasis. HighlightsO_LIgsr-1a or trxr-2 single mutants have no overt phenotypes. C_LIO_LIgsr-1a trxr-2 double mutants are viable but show small size, gonad migration defects and reduced progeny. C_LIO_LILoss of both reductases in mitochondria triggers a constitutive ATFS-1-dependent UPRmt. C_LIO_LIATFS-1 is essential for gsr-1a trxr-2 worms survival. C_LIO_LIgsr-1a trxr-2 animals remodel mitochondrial morphology in a tissue-specific manner. C_LIO_LIgsr-1a trxr-2 double mutants exhibit impaired muscle and sperm function but enhanced wound healing. C_LI Graphical abstract (to be incorporated)

genetics↗

bioRxiv2025

The m6A reader protein YTHDF2 facilitates HTLV-1 infectious and mitotic propagation by stabilizing Tax RNA

N6-methyladenosine (m6A) is one of the important RNA modifications that affect RNA abundance and function and has also been implicated in viral infection. In this study, we identify a number of m6A modification sites within human T-cell leukemia virus type 1 (HTLV-1) RNAs, particularly in the RNA of the Tax oncogene. We demonstrate that YTH domain family, member 2 (YTHDF2), a key m6A reader protein that binds m6A-modified RNAs and influences RNA metabolism, is required for HTLV-1 replication in both de novo and persistently infected cells. Mechanistically, YTHDF2 interacts with and stabilizes Tax RNA in an m6A-dependent manner, thereby promoting Tax-driven HTLV-1 replication. Importantly, YTHDF2 activates oncogenic cellular pathways and promotes proliferation in HTLV-1 infected cells, aligning with the functions of Tax. Overall, our findings characterize YTHDF2 as a host factor critical to HTLV-1 RNA metabolism and viral propagation, offering novel insights into the understanding of HTLV-1 life cycle and the development of targeted interventions. Importancem6A is an RNA modification that plays crucial roles in physiological and pathological conditions; however, its roles in HTLV-1 infection are poorly understood. In this study, we identify that m6A modification is widely present in HTLV-1 RNAs including Tax. We demonstrate that YTHDF2, a prominent m6A reader protein, enhances the stability of Tax RNA, thereby promoting both de novo and persistent HTLV-1 replication. Our findings position YTHDF2 as an essential factor for HTLV-1 persistence and suggest it as a potential therapeutic target for viral clearance.

microbiology↗

bioRxiv2025

Visualization of photoreceptor outer segment renewal using AAV-delivered Dendra2-tagged rhodopsin

Visualization of photoreceptor outer segment (OS) renewal dynamics is essential for vision research but has proved difficult in mice due to the small size and dense packing of their photoreceptors. Lack of effective protein "trackers" and the time-consuming generation of transgenic reporter lines add to these challenges. In this study, we evaluated AAV-mediated delivery of photoconvertible Rhodopsin/Dendra2 and Peripherin2/Dendra2 fusion proteins as a means to track OS renewal in mouse photoreceptors. OS renewal was assessed by two approaches: (1) comparing the lengths of native (green) Dendra2 domains at two post-infection time points, and (2) using photoconversion of Dendra2 to distinguish newly synthesized discs from preexisting ones within the same cell. We validated this method in both wild type mice and a Tmem138-deficient ciliopathy mutant, in which a reduced OS renewal rate was observed. Taken together, this method offers a rapid genetic tool for "real-time" evaluation of OS renewal dynamics in mice, overcoming limitations posed by the compact and densely organized photoreceptor architecture.

cell biology↗

bioRxiv2025

Modulation of metabolic, inflammatory, fibrotic and cell death pathways by Resmetirom in metabolic dysfunction-associated steatohepatitis (MASH): A transcriptomic profiling study

Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global burden with limited therapeutic options, and the mechanisms driving disease regression remain incompletely understood. Resmetirom, a selective thyroid hormone receptor-{beta} (THR-{beta}) agonist, has been approved for MASH, yet its molecular actions require further clarification. In this study, we employed a diet-induced mouse model of MASH using fructose-palmitate-cholesterol (FPC) feeding and evaluated the therapeutic efficacy of Resmetirom. Resmetirom (5 mg/kg/day) treatment significantly improved systemic and hepatic lipid profiles. Histological analyses demonstrated marked attenuation of hepatic steatosis, inflammation, and fibrosis, accompanied by reduced hepatic cell death. Transcriptomic profiling of liver tissues further revealed a robust Resmetirom-induced reprogramming of metabolic and inflammatory pathways, with prominent downregulation of gene networks governing lipid accumulation, immune activation, extracellular matrix remodeling, and multiple forms of programmed cell death. Collectively, these findings provide mechanistic insight into the multifaceted actions of Resmetirom and establish a comprehensive preclinical framework for understanding how THR-{beta} activation ameliorates key pathological hallmarks of MASH. This work supports the therapeutic potential of Resmetirom and highlights critical molecular pathways that may inform future combination strategies for advanced metabolic liver disease.

pharmacology and toxicology↗

bioRxiv2025

Functional Characterization of Hsp110 in Drosophila Reveals its Essential and Dosage-Sensitive Role in Nervous System Integrity

The Hsp70 molecular chaperone system is the front line of defense in maintaining cellular proteostasis. In eukaryotes, ATP/ADP nucleotide exchange in the Hsp70 chaperone cycle is stimulated by Hsp110, a divergent member of the Hsp70 chaperone superfamily and co-chaperone of Hsp70. Hsp110 is also a known modifier of neurodegenerative and other protein misfolding-related disorders. Biochemical aspects of Hsp110 chaperone functions have been characterized in vitro, and pathway interactions have been extensively characterized genetically in yeast model systems; however, a detailed understanding of its physiological roles in metazoans, particularly in the nervous system has not been carried out. Taking advantage of the single Hsp110-encoding gene in the Drosophila genome, we conducted a comprehensive investigation of its expression and function in this animal model. Notably, Drosophila and human Hsp110 share significant similarity in their sequence, structure, and splicing variants. At the protein level, Hsp110 is ubiquitously expressed, with both cytosolic and nuclear distribution in a tissue-dependent manner. Functionally, while Hsp110 is dispensable for cell proliferation in developing larvae, it is essential for long-term cell survival and normal development of the nervous system, including non-autonomous effects on neuronal differentiation and glial cell migration. Furthermore, despite being identified as a potent suppressor of protein aggregation and neurotoxicity in multiple neurodegenerative diseases, higher levels of Hsp110 are detrimental in flies. Overexpression of Hsp40, another key co-chaperone of Hsp70, can mimic this effect. However, simultaneous overexpression of both Hsp40 and Hsp110 does not further exacerbate their detrimental effect. Together, these results demonstrate a critical role of Hsp110 in neuronal development and cell survival, and further suggest that in vivo, the levels and activities of Hsp110 and Hsp40 co-chaperones need to be properly balanced. Furthermore, this work supports the contention that the Hsp70 chaperone network must be considered as a whole when targeted for potential therapeutic purposes to meet the complex pathophysiological demands in multicellular organisms.

developmental biology↗

bioRxiv2025

A Syngeneic Immunocompetent Mouse Model of Gallbladder Cancer Reveals Tumorigenesis and Therapeutic Response

PurposeGallbladder cancer (GBC) is a rare but highly lethal malignancy with one of the poorest prognoses among cancers of the digestive system cancers. However, current experimental models of GBC face critical limitations, particularly their dependence on immunodeficient hosts, which precludes the investigation of the tumor microenvironment. We aimed to establish a novel syngeneic immunocompetent mouse model that recapitulates human GBC and enables the investigation of tumor-immune interactions. Experimental DesignWe engineered a murine cell line (mGBC1-ZH) from normal mouse gallbladder organoids expressing Kras and Trp53 (encoding mouse p53) mutations. Tumorigenic potential of mGBC1-ZH was evaluated by subcutaneous and orthotopic implantation. RNA-Seq and WES was used to demonstrate its characterization and similarity with human GBC. Immunohistochemistry, CCK8, and transwell assays wereused to investigate the role of CXCL5 in GBC. Therapeutic responses to standard first-line chemotherapeutic agents was evaluated in the syngeneic GBC model. ResultsThis model supports both subcutaneous and orthotopic tumor growth in immunocompetent C57BL/6J hosts while preserving hallmark features of human GBC, including biliary epithelial differentiation (CK7+/CK19+), aggressive histopathology, and an immunosuppressive "cold" tumor microenvironment. Genomic characterization revealed recurrent chromosomal instability and copy number alterations mirroring human GBC. Comprehensive transcriptomic profiling revealed profound gene expression changes during the model development, and resembled transcriptional features between mGBC1-ZH and human GBC cell lines and samples. CXCL5 was found to be upregulated in human GBC, and promote proliferation, metastasis, and neutrophils infiltration of GBC in the syngeneic mouse model. Functional validation of the syngeneic GBC model demonstrated therapeutic responsiveness to frontline chemotherapeutics gemcitabine and cisplatin with significant in vivo tumor regression. ConclusionsIn summary, we establised a novel syngeneic GBC mouse model, overcoming the limitations of traditional models by enabling studies in immunocompetent hosts. This model provides valuable insights into the molecular evolution from normal gallbladder cells to transformed cancer cells and establishes a robust platform for both mechanistic studies and therapeutic development.

cancer biology↗

bioRxiv2025

Deep learning reveals a microprotein atlas in maize and uncovers novel regulators of seed amino acid metabolism

Microproteins represent a vast and functionally important class of genes that remain largely unexplored in plant genomes. Here, we developed DeepMp, a deep learning framework that integrated multi-omics evidence and built the most comprehensive plant microprotein atlas to date, identifying 18,338 high-confidence candidates in maize. The majority of these appear to have originated de novo from regions previously annotated as noncoding, and they show hallmarks of rapid, lineage-specific evolution and pronounced tissue specificity. These novel microproteins were found integrated into core regulatory networks, particularly in organ development and nutrient storage. Focusing on the maize kernel, population-scale analyses linked microprotein expression to natural variation in amino acid content. We functionally validated three grain-filling-specific candidates originating from noncoding regions by CRISPR-Cas9 knockouts, which confirmed their roles as precise modulators of arginine, aspartate, and methionine levels, without pleiotropic effects on kernel morphology. Our study provides a foundational resource and analytical framework, establishes microproteins as a new and functionally important coding layer in maize, and uncovers a previously untapped source of targets for crop improvement.

genomics↗

bioRxiv2025

Chromosome-level genome assemblies of Nicotiana attenuata and Nicotiana obtusifolia

Nicotiana attenuata and Nicotiana obtusifolia are two wild tobacco species from the Solanaceae plant family, which are rich in producing diverse specialized metabolites and have been established as ecological model systems for studying plant-insect interactions. The previously published N. attenuata and N. obtusifolia genomes were draft assemblies and had low assembly contiguity, limiting comparative genomic analysis. Here, we performed chromosome-level genome assemblies and annotations of these two species using long-read sequencing and Hi-C data. Both N. attenuata and N. obutosifolia genomes were anchored to 12 chromosomes, with an assembled genome size of 2.19 Gb and 1.3 Gb, respectively. We achieved high BUSCO completeness at the protein level, with 99.3% for N. attenuata and 97.9% for N. obtusifolia. The reference genomes of N. attenuata and N. obtusifolia presented in this study will advance the understanding of metabolic innovations in Solanaceae plants.

genomics↗

bioRxiv2025

Structure-based engineering of a nutrient acquisition protein enhances neutralizing antibodies and protection for the development of a gonococcal vaccine

Gonorrhea is increasingly resistant to treatment and has been labelled an urgent threat due to the diminishing effectiveness of existing therapeutics. To address this challenge, we targeted the Neisseria gonorrhoeae transferrin binding protein B (TbpB), which is critical for iron acquisition and neisserial growth, as a vaccine target. Building on previous studies investigating the application of TbpB as an immunogen against various bacterial pathogens, we aimed to optimize this antigen for a broad protective effect. We compared the efficacy of wild type TbpB immunogens with engineered TbpB mutants that do not bind human transferrin (hTf) using infection studies in transgenic mice expressing hTf, which were required because the strict specificity of neisserial TbpB precludes its complexing with non-human transferrin. Comprehensive biophysical analyses confirmed that the introduced single residue mutations abolished hTf binding without compromising antigen structure. Immunization with the mutant antigens conferred increased resistance to infection by N. gonorrhoeae relative to that provided by the wild-type antigen in the humanized mice. When considering effector functions of the humoral response, we observed that the mutated antigen elicited more effective bactericidal and function-neutralizing activity. Through strategic mutations, we therefore enhanced vaccine effectiveness in a physiologically relevant model without significantly affecting the structure or immunogenicity of the antigen. This study highlights the use of rational structure-guided antigen design to drive effective immune responses and the potential interference of immunogen binding to host factors, and reinforces the utility of targeting TbpB in a gonococcal vaccine.

immunology↗

bioRxiv2025

Blood originates in hypoblasts during embryonic development

Blood is essential for oxygen supply throughout life. The emergence of blood in the human embryo remains poorly understood. Our study leverages multiple stem cell embryo models and advanced lineage barcoding to unveil that hypoblast, originally regarded as forming the yolk sac wall, is heterogeneous and contributes to CDX2+ extraembryonic mesoderm, followed by hemoglobin+ cells as the first blood cells. CDX2 marks the hypoblast-to-hemoglobin+ cell trajectory that functionally sustains oxygen levels in embryo models. These hemoglobin+ cells molecularly and functionally resemble phagocytes. We show that the erythro-core regulatory network is poised in hypoblasts, and its boost endows erythropoiesis to both hypoblasts and phagocytes. Hypoblasts are the origin of the first blood in humans and non-human primates, providing a conceptual framework that earlier blood generation than expected fills the gap in the establishment of circulation. Further, the hypoblast is a place where primates may repurpose the phagocyte program to carry oxygen throughout embryos. HighlightsO_LIBarcode-traced hypoblast fate in human embryo models; C_LIO_LIThe first blood comes from the hypoblast that contributes to hemoglobin+ phagocyte-like cells; C_LIO_LICDX2 marks hypoblast blood that sustains oxygen supply in embryos before heart formation; C_LIO_LIErythro-core regulatory network endows erythropoiesis to human hypoblasts and phagocytes. C_LI

developmental biology↗

bioRxiv2025

Cascade-Targeting Nanoparticles for Reversing Chemoresistance in Osteosarcoma

Osteosarcoma (OS) remains the most prevalent primary malignant bone tumor in adolescents, with chemotherapy resistance significantly limiting the efficacy of current treatments. To address the challenges of chemoresistance driven by DNA repair mechanisms and drug efflux, we developed a biomimetic cascade-targeting drug delivery system, TAT-mPDO@cRGD-M. This system combines a polydopamine (mPDA) core with strong photothermal and drug-loading capacities, enabling the co-delivery of cisplatin (CDDP) and olaparib (OLA). Surface functionalization with the nuclear localization peptide TAT and cloaking with osteosarcoma cell membranes modified with cRGD peptides allows for selective tumor recognition, nuclear targeting, and stimuli-responsive drug release. Upon near-infrared (NIR) irradiation, the platform enhances DNA damage, suppresses the PI3K-AKT signaling pathway, and promotes apoptosis while inhibiting epithelial-mesenchymal transition (EMT). In vitro and in vivo studies demonstrated that TAT-mPDO@cRGD-M exhibits potent antitumor activity against cisplatin-resistant osteosarcoma, maintaining strong therapeutic efficacy under low-power NIR irradiation without causing significant damage to normal tissues. This study highlights a highly specific and biocompatible therapeutic approach that offers promising potential for overcoming chemotherapy resistance in osteosarcoma and advancing clinical treatment strategies.

cancer biology↗

bioRxiv2025

Assessing molecular, cellular and transcriptomic bases of laminar perfusion and cytoarchitecture coupling in the human cortex

Understanding how cellular architecture organizes cortical function requires mesoscopic approaches that resolve structure-function coupling in vivo. Here we introduce cerebral blood flow (CBF) and cell-body staining intensity (CSI) similarity index (CCSI), a localized similarity index between the CBF estimates from ultra-high-field 7T arterial spin labeling images and CSI from the BigBrain histology images to serve as a quantitative marker of laminar perfusion-cytoarchitecture coupling. CCSI revealed a reproducible, region- specific alignment between laminar vascular and cellular profiles across the cortex. Going beyond CBF, CCSI selectively tracked mitochondrial respiratory capacity and colocalized with capillary endothelial and mature non-myelination oligodendrocyte populations forming neurovascular interfaces. Transcriptomic enrichment highlighted pathways related to vascular remodeling, oxidative metabolism, and lipid-myelin homeostasis, indicating that CCSI reflects integrated metabolic-structural specialization. At the systems level, CCSI strengthened structure-function gradient correspondence in transmodal cortices, such as the default mode network. Together, these findings establish CCSI as a physiologically grounded, non-invasive marker of perfusion-cytoarchitecture alignment, providing a cross-scale framework linking cortical microstructure, metabolism, and functional organization.

neuroscience↗

bioRxiv2025

KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS

Neuronal health depends on the precise transport and local translation of mRNAs to maintain synaptic function across highly polarized cellular architecture. While kinesin motor proteins are known to mediate mRNA transport, the specificity and direct involvement of individual kinesins as RNA-binding proteins (RBPs) remain unclear. Here, we demonstrate that KIF5A, a neuron-specific kinesin implicated in amyotrophic lateral sclerosis (ALS), functions as an RBP. We show that KIF5A directly binds mRNAs encoding synaptic ribosomal proteins and is required for their synaptic localization and for maintaining normal synaptic composition and function. Additionally, we show ALS-linked KIF5A mutations confer gain-of-function properties, enhancing mRNA binding, increasing synaptic ribosomal protein accumulation, inducing neuronal hyperexcitability, and impairing stress responses. These findings reveal a previously unrecognized mechanism by which mutant KIF5A disrupts synaptic homeostasis. Our work positions a kinesin motor protein as an RBP with critical roles in mRNA transport, local translation, and stress response. HighlightsO_LIKIF5A interacts with mRNA encoding synaptic ribosomal proteins C_LIO_LIKIF5A is required for normal synaptic composition and function C_LIO_LIKIF5A binds to G3BP1 and G3BP1 stress granule associated proteins C_LIO_LIKIF5A mutant ALS patient-derived motor neurons have abnormal synaptic function and stress response C_LI

neuroscience↗