Biology subjects

Gu, Y.

Publications and source records attributed to Gu, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Charting structural brain asymmetry across the human lifespan

Lateralization is a fundamental principle of structural brain organization. In vivo imaging of brain asymmetry is essential for deciphering lateralized brain functions and their disruption in neurodevelopmental and neurodegenerative disorders. Here, we present a normative framework for benchmarking brain asymmetry across the lifespan, developed from an aggregated sample of 128 primary neuroimaging studies, including 177,701 scans from 138,231 individuals, jointly spanning the age range from 20 post menstrual weeks to 102 years. This resource includes comprehensive, hemisphere-specific brain growth charts for multiple neuroimaging phenotypes: regional cortical grey matter volume, thickness, surface area, and subcortical volumes. Our findings reveal distinct spatial patterns of asymmetry, with early leftward asymmetry observed in association cortices and late rightward asymmetry in sensory regions. These trajectories support theories of the neuroplasticity of asymmetry and the role of both genetic and environmental factors in shaping brain lateralization. Additionally, we provide tools to generate asymmetry centile scores, which allow the quantification of individual deviations from typical asymmetry throughout the lifespan and can be applied to unseen data or clinical populations. We demonstrate the utility of these models by highlighting group-level differences in asymmetry in autism spectrum disorder, schizophrenia, and Alzheimers disease, and exploring genetic correlations with hemispheric specialization. To facilitate further research, we have made this normative framework freely available as an interactive open-access resource (upon publication), offering an essential tool to advance both basic and clinical neuroscience.

neuroscience↗

bioRxiv2025

Xcr1+ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression

BackgroundAtherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and an inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1+ cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in the development of atherosclerosis remains highly controversial. ResultsWe first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mice, a novel and complex genetic model, in which cDC1 was constitutively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4+ and CD8+ subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1+ cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1+ cDC1 cells via Xcl1 by establishing Xcl1 and ApoE deficient mice. Xcl1 knockout mice exhibited decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation, indicating that Xcl1 contributes to cDC1-mediated atherosclerotic lesion development. ConclusionsOur results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.

immunology↗

bioRxiv2025

Enhancing Biomedical Optical Volumetric Imaging via Self-Supervised Orthogonal Learning

Optical volumetric imaging grapples with inherent noise problems arising from photon budget constraints, light scattering, and space-bandwidth product bottlenecks, all of which degrade structural fidelity and become even more pronounced than in planar imaging. While deep learning presents potential for denoising, supervised methods are hindered by the impracticality of paired dataset, and existing self-supervised approaches fail to fully exploit the intrinsic volumetric structural redundancy inherent to optical imaging. Here, we present a self-supervised Volumetric biomedicAL Imaging Denoiser (VALID) that leverages intrinsic three-dimensional spatial coherence for highly efficient volumetric denoising through a self-supervised orthogonal learning framework. VALID demonstrates robust denoising performance across diverse imaging modalities, including two- and three-photon microscopy, light-field microscopy, and optical coherence tomography, substantially enhancing structural fidelity in deep-tissue, multimodal, and dynamic imaging scenarios. By combining computational efficiency with zero-shot adaptability, VALID establishes a transformative approach to volumetric image enhancement with structure-aware precision.

neuroscience↗

bioRxiv2025

A Transcriptomic Atlas of Healthy Human Skin Links Regional Identity to Inflammatory Disease.

Human skin is not a uniform organ but a mosaic of anatomically distinct niches, with each site finely tuned to unique environmental demands and immune pressures. Yet, the molecular determinants that define these regional identities and their relationship to site-specific vulnerability to inflammatory disease remain poorly understood. Here, we generate a high-resolution single-cell atlas of human skin, profiling 274,834 cells from 96 healthy samples across 7 anatomically distinct sites (acral, arm, axilla, back, face, leg and scalp). Our analysis reveals striking region-specific transcriptional and cellular networks, uncovering how local immune-stromal crosstalk governs tissue homeostasis and underpins anatomical susceptibility to distinct inflammatory diseases such as such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis. These findings illuminate the tissue-intrinsic foundations of regional immune identity and provide a blueprint/resource for the development of precision therapies tailored to the distinct immunological microenvironments of specific anatomical skin sites.

systems biology↗

bioRxiv2025

Neuropeptide signalling and perineurial barrier generate a persistent stress-induced internal state in Drosophila

Although fear conditioning has elucidated cue-evoked acute fear responses, the mechanisms by which stress experiences induce generalized internal states linked to anxiety are poorly understood. Here, we report that robust stress induces a persistent behavioral change characterized by avoidance of a confined space, claustrophobia-like behavior in Drosophila. Unlike aversive memory formation, the development of claustrophobia-like behavior does not require dopamine receptors. Our neuronal screening determined that neuropeptide signalling via Allatostatin-A inactivates the downstream neurons via its receptor AstA-R1, causally inducing claustrophobia-like behavior. Moreover, gene expression profiling of individual fly heads revealed that immune response activation in perineurial barrier is involved in claustrophobia-like behavior. Our data demonstrate that stress-induced persistent behavioral change would not be related to a canonical mechanism of aversive memory formation, rather involves neuropeptidergic signalling and perineurial barrier, providing the mechanism determining internal states which persistently change behavioral modes.

neuroscience↗

bioRxiv2025

Single-cell alternative polyadenylation analysis reveals mechanistic insights of COVID-19-associated neurological and psychiatric effects

COVID-19 is associated with increased risks of neurological and psychiatric sequelae. Alternative polyadenylation (APA) is ubiquitous in human genes, resulting in mRNA diversity, and has been validated to play a pivotal regulatory role in the onset and progression of a variety of diseases, including viral infections. Here, we analyzed the APA usage across different cell types in frontal cortex cells from non-viral control group and COVID-19 patients, and identified functionally related APA events in COVID-19. According to our study, the poly(A) site (PAS) usage is different among cell types and following SARS-COV-2 infection. Moreover, we found the genes with significant PAS level changes affected pathways related to RNA splicing, and neuronal development and function, suggesting that survivors of COVID-19 will have a high risk of these diseases and that alternative splicing functions cause these changes. Additionally, APA usage and its correlation with gene expression levels varied across genes, some prefer short isoform that is more stable to produce more proteins, while others may be regulated by different mechanisms. A total of 267 risk genes targeted by microRNAs for common neurological and psychiatric disorders were found to undergo significant changes in APA following infection. In conclusion, our comprehensive analysis of APA in neural cells from COVID-19 patients at the single-cell level elucidated changes in APA levels in the brains of SARS-COV-2-infected patients and confirmed that these changes impair the function of the nervous system, providing important insights for COVID-19-associated sequelae. HighlightsO_LIWe analyzed the changes in single-cell APA level in the frontal cortex after SARS-COV-2 infection and found that PAS usage is different among cell types and changed after infection. C_LIO_LIWe find that APA changes are related to RNA splicing, and neuronal development and function, such as synaptic plasticity, nervous system development, learning or memory and cognition, and the brain function may be impaired due to global gene expression and APA changes. C_LIO_LIA total of 267 risk genes for common neurological and psychiatric disorders were found to undergo significant changes in APA following infection, implying that APA alterations in specific genes could be a potential therapeutic target and predictive biomarker for neurological and psychiatric disease. C_LIO_LIAPA in infection samples results in the removal/addition of miRNA target sites in the 3'-UTR of genes. A total of 2404 miRNAs were predicted which suggests that the miRNAs target site information can indicate the impact of APA events and has the potential to be used as a predictive biomarker. C_LI

bioinformatics↗

bioRxiv2025

Escherichia coli with a 57-codon genetic code

The near-universal genetic code of living organisms uses 64 codons to encode the 20 canonical amino acids in protein synthesis. Here we design and generate a variant of Escherichia coli with a 4 Mb synthetic genome in which we replace every known occurrence of six sense codons and a stop codon with synonymous codons. We thereby recode 105 codons to create an organism with a 57-codon genetic code; this organism - which we name Syn57 - uses 55 codons to encode the 20 canonical amino acids.

synthetic biology↗

bioRxiv2025

Optogenetic translocation to subcellular compartments through regulation of protein avidity

Inducible translocation to subcellular compartments is a common strategy for protein switches that control a variety of cell behaviors. However, existing switches achieve translocation through induced dimerization, requiring constitutive anchoring of one component into the target compartment and optimization of relative expression levels between the two components. We present a simpler, single-component strategy called Avidity-assisted targeting (Aviatar). Aviatar achieves translocation with only a single protein by converting low-affinity monomers into high-avidity assemblies through inducible clustering. We demonstrated the Aviatar concept and its generality using optogenetic clustering to drive translocation to the plasma membrane, endosomes, golgi, endoplasmic reticulum, and microtubules using binding domains for lipids or endogenous proteins that were specific to those compartments. Aviatar recruitment regulated actin polymerization at the cell periphery and revealed compartment-specific signaling of receptor tyrosine kinase fusions associated with cancer. Finally, GFP-targeting Aviatar probes allowed inducible localization to any GFP-tagged target, including endogenously-tagged stress granule proteins. Aviatar is a straightforward platform that can be rapidly adapted to a broad array of targets without the need for their prior modification or disruption.

bioengineering↗

bioRxiv2025

HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against hypoxia-induced neuronal injury

Hypoxia contributes to brain disorders by causing neuronal injury. However, in the early stage of stress, neurons initiate a series of compensatory pathways to resist cell damage, but the underlying mechanisms have not been fully elucidated. In this study, we found that hypoxia transiently activates PTEN-induced kinase 1 (PINK1)-dependent mitophagy in the early stage before cell damage and neurological dysfunction. PINK1 overexpression protects neurons and it knockdown exacerbates neuronal damage, highlighting the key role of PINK1-dependent mitophagy in hypoxic adaptation. Mechanistically, hypoxia promotes HIF-1 nuclear translocation, inducing transcription of stomatin like 2 (STOML2). STOML2 relocates to the mitochondrial membrane, aiding phosphoglycerate mutase 5 (PGAM5) cleavage, which triggers PINK1-dependent mitophagy. Silencing HIF-1, STOML2, or PGAM5 inhibits PINK1-dependent mitophagy and worsens neurological function under hypoxia. Notably, intermittent hypoxia, a hypoxic conditioning strategy for improving hypoxic tolerance, enhances PINK1-dependent mitophagy by activating HIF-1/STOML2 axis, and protects neurons against hypoxia. In conclusion, our study reveals a new "self-protection" mechanism of neurons against hypoxic stress and discovers that intermittent hypoxia is a potential therapeutic strategy against hypoxia-induced injury.

neuroscience↗

bioRxiv2025

Neural oscillations and top-down connectivity are modulated by object-scene congruency

The knowledge we have about how the world is structured is known to influence object recognition. One way this is demonstrated is through a congruency effect, where object recognition is faster and more accurate if items are presented in expected scene contexts. However, our understanding of the dynamic neural mechanisms that underlie congruency effects are under-explored. Using MEG, we examine how the congruency between an object and a prior scene results in changes in the oscillatory activity in the brain, which regions underpin this effect, and whether congruency results arise from top-down or bottom-up modulations of connectivity. We observed that prior scene information impacts the processing of visual objects in behaviour, neural activity and connectivity. Processing objects that were incongruent with the prior scene resulted in slower reaction times, increased low frequency activity in the ventral visual pathway, and increased top-down connectivity from the anterior temporal lobe and frontal cortex to the posterior ventral temporal cortex. Our results reveal that the recurrent dynamics within the ventral visual pathway are modulated by the prior knowledge imbued by our surrounding environment, suggesting that the way we recognise objects is fundamentally linked to their context.

neuroscience↗

bioRxiv2025

Immune Niche Formation in Engineered Mouse Models Reveals Mechanisms of Tumor Dormancy

Residual tumor cells can persist in a dormant state during clinical remissions that may last decades. The mechanisms that lead to such growth control vs. eventual reactivation and macroscopic tumor outgrowth remain unclear. Here, we report data from a mouse model that reveals a key role of host immunity and the cellular and molecular mechanisms that control tumor dormancy. Abrogation of myeloid-specific TGF-{beta}RII expression (T{beta}RIImyeKO) resulted in an IFN-{gamma} rich immune microenvironment. IFN-{gamma} in turn elevated KLF4-mediated SLURP1 production in malignant cells, which is critical to the tumor cell quiescent state through interruption of fibronectin-integrin signaling pathways. The dormant tumor lesions were located in spatially localized immune niches rich in NK cells, cDCs, monocytes, and neutrophils, concomitant with tumor cell inactivation of NK cell immune surveillance through a CD200-CD200R1 mechanism. Our studies identify the IFN-{gamma}-KLF4-SLURP1 and CD200-CD200R1 axes as critical molecular drivers in tumor dormancy regulated by immune-tumor crosstalk. These insights provide enhanced mechanistic understanding of tumor dormancy in a mouse model suitable for further investigation of cancer treatment resistance and prevention of metastatic spread.

cancer biology↗

bioRxiv2025

Energy predicts global mountain endemic plant richness better than environmental heterogeneity

The drivers of biodiversity in mountain ecosystems have long been a central focus in ecologists. Increasing evidence suggests that energy is a key determinant of mountain species diversity; however, whether this pattern holds universally across different mountain ecosystems remains unclear, especially as there may be differences between different plant taxa. To address this knowledge gap, we selected mountain endemic plant genera from global biodiversity hotspots to explore the main drivers of diversity of different taxa in the mountains. Our results indicate that energy is the key driver of endemic plant richness in mountain regions worldwide, particularly for endemic tree and shrub taxa, while endemic herb richness is shaped by both energy and environmental heterogeneity. Regional studies have shown that energy availability drives total endemic plant groups in 70% of mountain regions. Specifically, energy is the dominant driver for 86% of endemic tree groups and 67% of endemic shrub groups, whereas endemic herb groups are the least influenced by energy, with only 50% of mountain regions showing energy as the primary driver. Our findings indicate that energy availability is the predominant factor shaping the diversity of endemic plant groups in mountain ecosystems worldwide. Therefore, mountain ecological conservation efforts should focus extensively on energy input aspects. HighlightsO_LIClimate energy is the main driver of the richness of montane endemic plant taxa, especially for tree and shrub, whereas herb richness is determined by a combination of energy and environmental heterogeneity. C_LIO_LIEnvironmental heterogeneity predominantly drives endemic taxa richness in the Cape of Good Hope, whereas both climatic energy and environmental heterogeneity jointly influence endemic taxa richness in the Andes and Japan. In all other mountain ranges, climatic energy is the primary determinant. C_LIO_LIEndemic tree taxa have the highest number of mountains dominated by climatic energy, followed by endemic shrub taxa, and endemic herb taxa are more affected by environmental heterogeneity. C_LI

ecology↗

bioRxiv2025

A study of different pre-treatment methods for cigarettes and their aroma differences

The study innovatively utilized a combination of smoking machine and Cambridge filter to effectively extract the aroma compounds generated during smoking of cigarettes, and employed three different pretreatment methods to obtain optimal cigarette pretreatment procedures. In addition, the aroma components of different cigarettes were identified by different instruments such as gas chromatography-mass spectrometry. Combined with the calculation of Odor Activity Values (OAV), PCA analysis and sensory evaluation were performed on the five types of cigarettes to reveal differences and similarities in their aroma profiles.

biochemistry↗

bioRxiv2025

The entorhinal spatial map integrates visual identity information of landmarks

The location and identity of landmarks provide spatial and nonspatial information of an environment, respectively, to guide spatial navigation. While the medial entorhinal cortex (MEC) is essential for representing spatial information, it is unclear whether it also encodes landmark identity. Here, we conducted two-photon calcium imaging of the MEC when mice navigated in multiple virtual environments, and discovered a general ability of the MEC to encode landmark identity through cue cells, which responded to individual landmarks during virtual navigation. Cue cells represented landmark identity by exhibiting more distinct activity patterns between visually disparate landmarks than identical ones. The representation was modulated by the spatial shift of cue cell activity relative to landmark location. Moreover, the identity encoding by the same cue cell population changed between different environments but was maintained within the same environment despite increased experience. In contrast, landmark location encoding by cue cells was regulated by experience, suggesting different mechanisms underlying the encodings of landmark identity and location. Finally, compared to cue cells, grid cells weakly encoded landmark identity but more robustly encoded landmark location. Thus, the MEC integrates both spatial and nonspatial information during navigation, but potentially through different circuit mechanisms.

neuroscience↗

bioRxiv2025

UHRF1 is critical for tumor-promoting inflammation and tumorigenesis in retinoblastoma

Retinoblastoma, the most common pediatric intraocular malignancy, arises from RB1 inactivation, leading to uncontrolled proliferation of retinal progenitor cells. Epigenetic dysregulation a key driver of retinoblastoma progression, yet the underlying mechanisms are poorly understood. UHRF1, a regulator of DNA methylation and chromatin remodeling, has been implicated in oncogenesis but its role in retinoblastoma has not been fully characterized. To investigate Uhrf1s role in tumor initiation and progression, we generated a genetically engineered mouse model of retinoblastoma with conditional Uhrf1 knockout. Remarkably, Uhrf1 loss completely blocked tumor formation, despite persistent early oncogenic events. Transcriptomic and epigenomic profiling revealed that Uhrf1 is essential for tumor progression, facilitating oncogenic transcription, chromatin accessibility, and aberrant DNA methylation. Beyond its epigenetic role, we found Uhrf1 modulates the tumor immune microenvironment, promoting chemokine secretion and microglial infiltration, suggesting that Uhrf1 promotes immune cell recruitment. Mechanistically, Uhrf1 enhances chemokine expression through NF-{kappa}B signaling, establishing a novel connection between epigenetic regulation and tumor-associated immune responses. These findings establish Uhrf1 as a critical driver of retinoblastoma progression, essential for tumor maintenance but not initiation. By sustaining oncogenic transcriptional programs and shaping a pro-tumor immune microenvironment, Uhrf1 emerges as a promising therapeutic target for inhibiting tumor growth and immune evasion.

cancer biology↗

bioRxiv2025

De novo biosynthesis of cannabinoid and its analogs in Yarrowia lipolytica

Cannabis sativa has long been a cornerstone of both medicinal and cultural practices, with its therapeutic use spanning over 2,700 years. Central to its therapeutic effects are cannabinoids, which interact with the endocannabinoid system to influence various physiological processes such as anxiety, pain, and inflammation. Despite its benefits, cannabinoid production faces challenges and scarcity from plant extraction. This work leverages Yarrowia lipolytica as a platform for cannabinoid biosynthesis. By optimizing precursor supply, engineering biomolecular condensate-like dual prenyltransferase expression and expanding endogenous metabolism with a noncanonical polyketide synthase, we achieved the de novo biosynthesis of various cannabinoid and its analogs. Our engineered Y. lipolytica produced [~]3.5 mg/L of cannabigerolic acid, 18.8 mg/L of orsellinic acid, and 0.5 mg/L of cannabigerorcinic acid. Additionally, CBGA titer reached 15.7 mg/L with olivetolic acid supplement. This work demonstrates Y. lipolyticas versatility as a promising host for cannabinoid and its analogs production, which opens avenues for further research and medicinal applications.

synthetic biology↗

bioRxiv2025

Structural and Functional Insights into GGCX-FIX Interaction: Implications for Vitamin K-Dependent Bleeding Disorders

Gamma-carboxylation, catalyzed by {gamma}-glutamyl carboxylase (GGCX), is a critical post-translational modification essential for the biological activity of vitamin K-dependent proteins (VKDPs). Mutations in GGCX, depending on their specific location, result in vitamin K-dependent coagulation factor deficiency type 1 (VKCFD1), which encompasses a broad spectrum of clinical manifestations ranging from mild to severe, including bleeding disorders, osteoporosis, and vascular calcification. The limited knowledge of GGCXs structure and functional regions hinders our understanding of the consequences of GGCX mutations and the treatment for VKCFD1. This study aimed to identify key functional regions of GGCX and their interactions with VKDPs to better elucidate the molecular mechanisms underlying these diverse clinical symptoms. Using AlphaFold 3 and molecular dynamics simulations, we developed a complex binding model of GGCX, FIX, and reduced vitamin K, which revealed critical regions and residues involved in their interaction. Site-directed mutagenesis and cell-based assays further validated the model, confirming that multisite and regional cooperative binding of FIX to GGCX plays a key role in modulating {gamma}-carboxylation efficiency. Additionally, novel residues (I296, M303, M401, M402) were identified as essential for GGCXs dual enzymatic activities: carboxylation and vitamin K epoxidation. We further demonstrated that the spatial proximity of these active sites supports the hypothesis that GGCXs carboxylation and vitamin K epoxidation centers are interconnected, ensuring the efficient coupling of these processes. Our GGCX-FIX binding and carboxylation model aligns with known pathogenic GGCX mutations, providing valuable insights into the molecular basis of coagulation disorders caused by GGCX mutants.

pathology↗

bioRxiv2025

TaWUS2D regulates the number of grains per spikelet by enhancing the number of fertile ovaries in Multi-Ovary Wheat

Innovative genetic improvements in the staple crop Triticum aestivum (bread wheat) are urgently needed to address the growing global food security crisis. Here, we report the map-based cloning of TaWUS2D, the gene responsible for the dominant multi-ovary phenotype in wheat. Multi-ovary lines are characterized by the development of three fertile ovaries per floret that results in three grains, as opposed to wildtype single ovary wheat. We used HiFi long-reads to assemble a 14.48 Gbp genome scaffold assembly in the background of mutli-ovary wheat line MOV. Using high-resolution genetic mapping, combined with additional genomic resources, we defined the Mov-1 locus to a 135 Kbp region containing two genes. Using five independent deletion mutants and eight TILLING mutants, we demonstrate that a functional WUSCHEL-like protein, TaWUS2D, is required for the multi-ovary phenotype. TaWUS2D is upregulated in the MOV genetic background. This research lays the groundwork for developing new approaches to improve wheat production potential and sustainability in the face of current and future global food challenges.

plant biology↗