Biology subjects

Luo, Q.

Publications and source records attributed to Luo, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

In Utero MRI of Radial Glial Fibers Highlights Their Role in Modulating Fetal Cortical Folding

The process of cortical folding is fundamental to early human brain development. While the differential growth of the cortical layers is a known driver, the biomechanical contribution of key cellular microstructures remains unclear, and there is a lack of direct in vivo markers of cortical microstructures for time-resolved observations. Using a multimodal approach combining in utero and ex vivo fetal brain MRI, histology, and computational mechanical simulation, we investigated whether developmental reorganization of cortical radial microstructures, particularly the radial glial cell (RGC)-associated scaffold, is linked to cortical folding and may modulate its mechanical progression. We characterized this radial organization noninvasively using diffusion MRI-based radial fiber density (FDrad). ex vivo fetal brain MRI and histology supported that regional variations in FDrad were strongly associated with vimentin-labelled radial architecture. Our in utero MRI data revealed closely coordinated developmental changes in cortical FDrad and curvature, with their regional timings and spatial patterns significantly coupled across the cortex. Longitudinal in utero MRI data further supported the synchronized within-individual co-development of FDrad and curvature. Furthermore, biomechanical simulations showed that reducing radial reinforcement modulated differential-growth-driven buckling, producing earlier folding and a greater cortical curvature under otherwise matched model conditions. Collectively, this study introduces FDrad as a noninvasive in utero MRI measure sensitive to radial glial fibers. By integrating spatial, temporal, histological, and computational evidence, our findings suggested a model in which developmental disassembly of the radial scaffold may modulate the mechanical response of the fetal cortex to differential growth, thereby contributing to cortical folding.

neuroscience↗

bioRxiv2026

Biologically inspired alignment reveals distributed and directionally asymmetric correspondence between rat and human cortices

Rodent models enable causal interrogation of brain circuits, but translating their systems-level organization to humans requires correspondence beyond one-to-one anatomical homology. Guided by the view that cortical areas are characterized by their relationships within distributed functional networks, we developed BrainMapping, a biologically inspired framework for aligning rat and human cortex using resting-state functional MRI. The framework combined a shared representation with optimal transport to derive probabilistic, bidirectional maps. These alignments revealed distributed, many-to-many correspondences that generalized to held-out subjects and preserved functional connectivity architecture, cortical gradients, and graph topology. Organizational preservation was directionally asymmetric. Human-to-rat mapping preserved organization more uniformly across rat cortical systems, whereas rat-to-human mapping showed stronger preservation in human association-related networks than in primary sensory and motor networks. The maps recovered literature-consistent default-mode and salience-system correspondences and generated testable non-canonical predictions. These findings provide a framework for expressing rat functional organization in human functional-network coordinates.

neuroscience↗

bioRxiv2026

Distinct Spatial Immune Architectures in Tumor and Tumor-Adjacent Tissues of Early-Stage Non-Small Cell Lung Cancer

Background: Lung cancer remains the leading cause of cancer-related deaths in the United States with over 124,000 estimated deaths for 2026. Previous studies have found that tumor-adjacent lung tissues may provide additional insight into the immune microenvironment of early-stage NSCLC. Methods: Multiplex immunofluorescence (mIF) imaging was performed on 192 tissues from 101 early-stage non-small cell lung cancer patients including 91 matched tumor-adjacent pairs, using three mIF panels. Spatial analyses were performed to identify distinctions between tissues and identify associations with clinical and genomic features. Results: Tumor tissue showed significantly higher densities of T cells, macrophages, B cells, and memory/regulatory populations than adjacent tissue (p<0.001). Tumors exhibited greater spatial heterogeneity, with higher prevalence of spatial patterning (47.7% vs. 31.2%) and more consistently localized organization, whereas adjacent tissue showed stronger individual-cell clustering. Pairwise colocalization (Ripley's L-cross) revealed selective spatial segregation in tumors (including B-cells from memory/regulatory cells and among cytotoxic T-cell subsets) and reduced immune proximity to malignant cells relative to the strong immune-epithelial association in adjacent tissue. Spatial features were linked to genomic features or patient outcomes: tumor neoantigen burden exhibited a positive association with CD3+ T cells in the tumor, while colocalization between CD45RO+CD57+GZMB+ cells and CD57+GZMB+ cells was negatively associated with overall survival outside the tumor. Conclusion: Tumor and adjacent tissues harbor distinct spatial immune architectures, with spatial features displaying associations with genomic features or patient outcomes. These findings highlight immune microenvironment reorganization and the importance of incorporating spatial context from both compartments into risk assessment in NSCLC.

immunology↗

bioRxiv2026

Inhibition of Pseudomonas aeruginosa-secreted protease IV reduces lung

The opportunistic pathogen Pseudomonas aeruginosa secretes numerous proteases that disrupt host defenses. Among them, the lysyl endopeptidase PrpL has been implicated in virulence, but its role in inflammatory responses has remained unclear. This study shows that purified PrpL activates the AP-1 transcription factors following instillation into mouse lungs, and drives robust production of IL-1{beta}, IL-6, and TNF, as well as clinical symptoms. A proteolytically inactive mutant of PrpL fails to elicit these responses. Structural analysis of the complex of PrpL and its natural inhibitory propeptide (PrpLPP) using X-ray crystallography revealed the inhibitory mechanism of PrpLPP, which guided the identification of a pre-existing dipeptide inhibitor (LasBi) that blocked PrpL activity and restricted AP-1-driven cytokine induction and clinical symptoms in vivo. This study shows that the alkaline protease AprA degrades PrpLPP and functions redundantly with LasB to liberate mature, active PrpL. Our findings: 1) establish PrpL as a key virulence factor that triggers AP-1-mediated inflammatory signaling, 2) provide structural and functional insights into PrpL inhibition, and 3) identify AprA as a novel upstream PrpL activator. Together, these results highlight PrpL as a promising anti-virulence therapeutic target. Given the functional redundancy of inflammatory effectors produced by P. aeruginosa, strategies aimed at mitigating P. aeruginosa-induced lung inflammation through PrpL inhibition would likely need to be combined with approaches targeting additional pro-inflammatory bacterial factors. Author SummaryWe identify PrpL as a critical Pseudomonas aeruginosa protease that activates the inflammatory transcription factor AP-1 and drives potent lung inflammation. Structural analysis of a natural PrpL inhibitor guided development of an existing dipeptide inhibitor that significantly reduced the production of proinflammatory cytokines and clinical responses in vivo. Moreover, discovery of the AprA protease as an additional PrpL activator refines the activation model and suggests potential upstream therapeutic strategies. These findings highlight PrpL as both a driver of pathogenesis and a promising therapeutic target for treating P. aeruginosa infections.

microbiology↗

bioRxiv2026

ProtBLIP2-SST: Protein Function Prediction via BLIP2 with Sequence, Structure, and Text

Protein function prediction traditionally relies on structured gene ontology (GO) labels or multi-label classifiers. However, these labels or classifiers cannot flexibly describe molecular function, biological process, cellular component, and free-text functional narratives in a single output. In comparison, generation-based approaches offer an intuitive paradigm for flexible free-text protein annotation, with large language models (LLMs) as a representative method for protein-text modeling. Recent efforts on utilizing LLMs for protein semantic understanding and annotation generation have adopted sequence-only encoding or sequence-text contrastive alignment paradigms, yet without explicit consideration of three-dimensional structural information. To address these limitations in current protein function prediction methods, we present ProtBLIP2-SST, a two-stage framework built on the BLIP2 model architecture that bridges protein sequence, structure, and text for open-ended protein functional caption generation. Specifically, we first integrate sequence and structure information through SaProt, a protein language model (PLM) with a structure-aware vocabulary that fuses residue tokens with Foldseek-derived 3Di structural tokens. To empower the LLM to understand protein semantics, we employ a Q-Former (a querying transformer in BLIP2) with learnable query tokens as the cross-modal projector to align protein features from the frozen SaProt encoder and text features from a frozen BiomedBERT via protein-text contrasting, protein-text matching, and protein captioning objectives. After alignment, the protein features are linearly projected and prepended to the prompt embeddings of the LLM for protein captioning fine-tuning with LoRA. Trained on 441k protein-text pairs from Swiss-Prot with corresponding structures from the AlphaFold Database, our ProtBLIP2-SST outperforms sequence-only and sequence-text alignment baselines on protein captioning metrics, with ablation studies demonstrating the effectiveness of integrating structure with sequence information for improved protein understanding. Through a unified two-stage alignment-and-generation pipeline, ProtBLIP2-SST integrates protein sequence and structural information, overcomes the rigidity of traditional GO-centric classification, generating open-ended captions that jointly describe molecular function, subcellular location, and homology context in one single output.

bioinformatics↗

bioRxiv2026

ProtAug: An Empirical Investigation of pLM-Guided Data Augmentation for Protein Sequence Prediction Tasks

Protein language models (pLMs) offer great potential for protein sequence analysis, yet the scarcity of labeled data often limits their effectiveness in fine-tuning. Data augmentation is a promising remedy, but systematic evaluation of augmentation strategies for protein sequences remains limited, and the conditions under which augmentation confers downstream benefits are not well understood. In this paper, we systematically investigate pLM-guided substitution-based augmentation across seven protein prediction tasks. We propose ProtAug, a framework that leverages encoder-based (ESM-2) and autoregressive (ProtGPT2) pLMs to generate augmented sequences with user-controlled variation levels. Our investigation focuses on four questions: (Q1) whether pLM-synthesized sequences preserve more original signals than simpler methods, (Q2) to what extent augmentation improves prediction performance, (Q3) how variation levels affect downstream accuracy across tasks and models, and (Q4) whether biological plausibility is a necessary condition for achieving improvement. Our experimental results show that: (1) ProtAug Esm generally preserves motifs and structural similarity better than simple substitution, often comparable to homology retrieval; (2) augmentation yields consistent but task-dependent improvements, with ProtAug Esm achieving the best or second-best performance in 5 out of 7 tasks at 10% variation; (3) low-to-moderate variation levels (2-30%) perform best overall, although high-variation augmentation can benefit certain structure-related tasks; (4) the necessity of biological plausibility is task- and variation-dependent--while semantic preservation correlates with performance at low-to-moderate variation levels, improved generalization at high variation levels suggests that regularization effects, rather than label preservation, can also drive performance gains.

bioinformatics↗

bioRxiv2026

Heterogeneous transmission estimation and strategy optimization for Chikungunya: a vector-borne modeling study differentiating age and sex

Against the backdrop of global climate change and accelerating population mobility in 2025, chikungunya fever (CHIKF) exhibited a trend of worldwide spread, significantly increasing the difficulty of controlling tropical mosquito-borne diseases. To enhance the precision of intervention strategies, this study developed an age- and sex-structured human-mosquito interaction dynamic model based on data from the largest CHIKF outbreak ever recorded in China, and conducted a targeted analysis of prevention and control strategies. By decomposing the basic reproduction number and examining population heterogeneity, asymptomatic males aged 15-59 years were identified as the core transmission group. Optimal control analysis revealed that the synergistic implementation of three measures-- reducing the effective human-to-mosquito transmission rate, reducing the effective mosquito-to-human transmission rate, and suppressing mosquito population density--could reduce the overall infection rate by 95.7586%. Among these, mosquito population suppression should be prioritized as a universal core strategy; however, its protective effect on females aged 60 years and above was relatively weak, warranting particular attention. The study further demonstrated that asymmetric intensity combinations targeting these three intervention pathways--such as intensity profiles of "10%, 90%, 90%" or "60%, 80%, 90%"--could achieve effective outbreak control. This research elucidates population-specific transmission patterns and key pathways for intervention intensity, providing a theoretical and strategic foundation for the precise control of mosquito-borne diseases. It also provides actionable operational insights to support rapid response and strategy optimization for future emerging outbreaks. Author summaryCHIKF is a mosquito-borne viral disease that is gradually spreading from tropical regions to other areas. To achieve more precise control of this disease, we developed an age- and sex-structured analytical model based on the largest CHIKF outbreak in China, aiming to provide a scientific basis for responding to potential future outbreaks with inherent uncertainties. The study found that asymptomatic males aged 15-59 years were the primary drivers of transmission and should be prioritized as a key population for reducing viral spread in prevention efforts. When evaluating the effectiveness of different intervention strategies, females aged 60 years and above were the least affected by the implemented measures, indicating that this group should strengthen personal protection to lower their infection risk. Among all control measures, mosquito suppression was the most effective, suggesting that vector control strategies should be prioritized in future outbreak responses.

pathology↗

bioRxiv2026

MTB-KB: A Curated Knowledgebase of Mycobacterium tuberculosis Related Studies

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), has regained its position as the worlds leading killer among infectious diseases. Despite extensive research progress across epidemiology, diagnosis, drug development, treatment regimens, vaccines, drug resistance, virulence factors, and immune mechanisms, MTB-related knowledge remains fragmented across thousands of publications, limiting its effective use. To address this gap, we present MTB-KB, a literature-curated knowledgebase that systematically integrates high-impact findings from eight major sections of TB research. The current release contains 75,170 associations from 1,246 publications, covering 18,439 entities standardized using authoritative databases and WHO-endorsed classifications. A central feature is the interactive knowledge graph, which links cross-section associations to reveal and infer MTB-host interactions, treatment strategies, and vaccine development opportunities. MTB-KB also provides a user-friendly interface with browsing, advanced search, and statistical visualization. Overall, by consolidating dispersed MTB knowledge into a structured and accessible platform, MTB-KB provides a valuable resource for researchers, clinicians, and policymakers, supporting both basic and clinical TB research, enabling evidence-based TB prevention, diagnosis, and treatment, and contributing to global elimination efforts. MTB-KB is accessible at https://ngdc.cncb.ac.cn/mtbkb/.

bioinformatics↗

bioRxiv2026

MiCBuS: Marker Gene Mining for Unknown Cell Types Using Bulk and Single Cell RNA-Seq Data

Identifying cell type-specific expressed genes (marker genes) is essential for understanding the roles and interactions of cell populations within tissues. To achieve this, the traditional differential analysis approaches are often applied to individual cell-type bulk RNA-seq and single-cell RNA-seq data. However, real-world datasets often pose challenges, such as heterogeneous bulk RNA-seq and incomplete scRNA-seq. Heterogeneous bulk RNA-seq amalgamates gene expression profiles from multiple cell types and results in low resolution, while incomplete scRNA-seq does not capture some cell types from the tissue, leading to unknown cell types. Traditional methods fail to identify marker genes for such unknown cell types. MiCBuS addresses this limitation by generating Dirichlet-pseudo-bulk RNA-seq based on bulk and incomplete single-cell RNA-seq data. By performing differential analysis of gene expressions on bulk and Dirichlet-pseudo-bulk RNA-seq samples, MiCBuS can identify the marker genes of unknown cell types, enabling the identification and characterization of these elusive cellular components. Simulation studies and real data analyses demonstrate that MiCBuS reliably and robustly identifies marker genes specific to unknown cell types, a capability that traditional differential analysis methods cannot achieve. Availability and implementationMiCBuS is implemented in the R language and freely available at https://github.com/Shanshan-Zhang/MiCBuS.

bioinformatics↗

bioRxiv2026

Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined small cell lung cancer

Combined small-cell lung cancer (cSCLC) is a rare and aggressive subtype of small-cell lung cancer (SCLC) characterized by mixed histology comprising SCLC and non-small cell lung cancer (NSCLC) or large cell neuroendocrine carcinoma (LCNEC) components. Despite its histological heterogeneity and even poorer prognosis than de novo SCLC, cSCLC is clinically managed as pure SCLC, largely due to the lack of molecular insights into its biology, lineage plasticity, and tumor microenvironment (TME). Here, we perform multi-omics profiling, including spatially-resolved whole-exome sequencing (WES), spatial transcriptomics (ST) and single-nucleus RNA sequencing (snRNA-seq), across 19 treatment-naive cSCLC tumors spanning all major histological subtypes. Our analysis reveals that SCLC and NSCLC/LCNEC components share a monoclonal origin, with histological divergence characterized by distinct mutation and copy number alteration patterns. ST and snRNA-seq uncover spatially exclusive or interspersed tumor domains, with distinct TME compositions and immune landscapes. Notably, fibroblast-rich regions enriched for an aggressive fibroblast subtype form boundaries between tumor domains, potentially influencing immune TME and treatment responses. We identify extensive lineage plasticity within cSCLC, including active LUAD-to-SCLC transdifferentiation and SCLC subtype coexistence, suggesting transitional cellular states not captured by traditional diagnostics. Leveraging these insights, we developed the cSCLC Detector, a sensitive mutation-based diagnostic assay that improves the detection of cSCLC in tissue and liquid biopsy samples. Our findings offer critical insights into cSCLC lineage plasticity, cellular evolution, and microenvironmental interactions, underscoring the need for tailored treatment strategies and diagnostic frameworks for this aggressive cancer subtype.

cancer biology↗

bioRxiv2025

Developing High-Yield and Safe Therapeutic EVs by Ablating Tissue Factor-Mediated Toxicity

The clinical translation of extracellular vesicles (EVs) as next-generation drug delivery vehicles is currently stalled by two interrelated challenges: the difficulty of manufacturing EVs at an industrial scale ("the yield problem") and the risks of toxicity associated with systemic administration of high doses ("the safety ceiling"). In this comprehensive study, we present a two-pronged genetic engineering strategy to overcome these limitations. First, we discovered that overexpression of glycosylphosphatidylinositol (GPI)-anchored proteins, such as CD55 and CD59, significantly enhances EV production in HEK293T and Expi293F cells. By engineering a truncated CD55 variant (TR3) that retains the GPI-anchor but lacks functional domains, we developed the ExoBoost cell line, which boosts EVs yield by approximately 50-fold without altering vesicle morphology. Second, we observed acute toxicity in mice following intravenous administration of high-dose ExoBoost EVs, with symptoms resembling venous thromboembolism. Through comparative analysis of EVs derived from other cell types, including keratinocyte stem cells (KSCs) and mesenchymal stem cells (MSCs), we identified Tissue Factor (TF/F3) as the critical causative agent of this lethal response. Moreover, we completely abolished this toxicity by generating a F3-knockout cell line (ExoBoost2.0) using CRISPR/Cas9, thereby raising the safe dose to as high as 1.5E12 particles per mouse, as quantified by nano flow-cytometry (nFCM). Finally, using a novel CD46-nanoluciferase reporter system, we demonstrated that high-dose administration of these safe EVs saturates hepatic and splenic clearance pathways, leading to a dramatic increase of systemic EVs accumulation, particularly in hard-to-target tissues such as the brain ([~]10,000-fold) and muscle ([~]1,000-fold). Additionally, repeated high-dose administration of ExoBoost2.0 EVs did not upregulate inflammatory cytokines or production of IgG and IgM. In summary, these findings establish a scalable, safe, and highly biocompatible EVs platform, potentially revolutionizing the drug delivery system in clinical application.

bioengineering↗

bioRxiv2025

Structural basis for BCL7B-mediated ncBAF-nucleosome engagement

The mammalian SWI/SNF family of chromatin remodelers comprises BRG1/BRM-associated factor (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF) complexes, which slide and disassemble nucleosomes to regulate gene expression and chromatin structure dependent on ATP hydrolysis energy. While the chromatin engagement mechanisms of cBAF and PBAF have been structurally resolved, the molecular architecture governing ncBAF interaction with chromatin remains elusive. In this study, by integrating cryo-electron microscopy, biochemical assays and cross-linking mass spectrometry, we resolved the conformational transition of ncBAF-nucleosome complexes from nucleotide-free to nucleotide-bound states. Our analyses establish BCL7 proteins as dynamic molecular tethers connecting the ARP module to the nucleosomal acidic patch and demonstrate that BCL7B promotes ncBAF-mediated nucleosome remodeling, with BRG1-catalyzed ATP hydrolysis triggering conformational changes that modulate BCL7-mediated histone association. Structurally and biochemically, we further demonstrate that {beta}-actin within the BCL7-containing ARP module retains ATP hydrolysis activity, rendering its exposed pointed end structurally compatible with incorporation into the barbed end of nuclear actin filaments, which provides a potential molecular basis for coordinating nuclear actin networks with chromatin remodeling. Collectively, our findings unravel a dynamic role of BCL7 in regulating ncBAF-mediated chromatin remodeling and establish a distinct chromatin engagement mode of ncBAF from that of cBAF/PBAF.

molecular biology↗

bioRxiv2025

IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer

Tumor-associated macrophages (TAMs) are major contributors to immunosuppression and therapeutic resistance, including resistance to PARP inhibitors (PARPi) in BRCA1-deficient breast cancer. However, the mechanisms underlying TAM-mediated PARPi resistance remain unclear. Here, we demonstrate that TAM-derived glutathione (GSH) impairs the efficacy of PARPi by protecting tumor cells from DNA damage and ferroptosis while suppressing STING-mediated immune activation. Mechanistically, STAT5-driven upregulation of the IRG1/itaconate axis in TAMs rewires mitochondrial metabolism and activates NRF2-dependent GSH biosynthesis. GSH is subsequently released into the tumor microenvironment, where it is taken up by tumor cells, protecting them from PARPi-induced cytotoxicity and dampening immune responses. Pharmacological inhibition of IRG1 reverses these effects, restoring PARPi sensitivity and enhancing anti-tumor immunity in BRCA1-deficient tumor models. Collectively, these findings uncover a TAM-specific immunometabolic program that limits PARPi efficacy and highlight the IRG1/NRF2/GSH axis as a promising therapeutic target to improve treatment outcomes in BRCA1-associated breast cancer.

cancer biology↗

bioRxiv2025

Brain-derived neurotrophic factor supports pericyte and vascular homeostasis in the aging brain

Microvascular circulation in the brain is often impaired in connection with the loss of pericytes in old age. The neurotrophic factor BDNF also decreases in the aging brain. We hypothesized that BDNF regulates the homeostasis of cerebral pericytes and microvasculature. We used differently aged C57BL/6J mice, and C57BL6 mice with conditional knockout of Bdnf gene. Collagen IV-positive microvessels and PDGFR{beta}-positive pericytes in the brain were counted after immunological staining. Pericytes were also quantified by Western blot of PDGFR{beta} and CD13 in isolated cerebral microvessels. The level of BDNF and TrkB phosphorylation was determined in brain homogenates. To demonstrate the direct effect of BDNF on pericytes, TrkB and pericytes were co-stained in brain tissue, single-cell sequencing and transcriptomic analysis were used to identify and characterize Ntrk2-expressing pericytes, and TrkB was also detected in the pericyte cell line by Western blot. Cultured pericytes were further treated with recombinant BDNF in the presence and absence of an Akt inhibitor and examined for PDGFR{beta} expression. The length and branching of microvessels and pericytes decreased in conjunction with the reduction in mature BDNF and TrkB phosphorylation in aging brains. Deficiency of BDNF in neurons or astrocytes was sufficient to reduce cerebral microvessels, PDGFR{beta} and CD13 concentrations and Akt and Erk1/2 phosphorylation in isolated blood vessels. A subset of pericytes in the brain and cultured pericytes expressed TrkB. BDNF treatment increased PDGFR{beta} expression along with Akt and Erk1/2 phosphorylation in cultured cells. The effect of BDNF on PDGFR{beta} expression was abolished by treatment with Akt inhibitor. Therefore, BDNF induces the expression of PDGFR{beta} and CD13 by activating Akt signaling in pericytes, promoting the homeostasis of pericytes and microvasculature in the aging brain. Our study identified a BDNF-mediated mechanism that regulates microvascular integrity in the aged brain.

neuroscience↗

bioRxiv2025

Development and Application of a Filamentous Phage-Based Rapid Detection Tool for Ralstonia pseudosolanacearum

Bacterial wilt caused by the Ralstonia solanacearum species complex (RSSC) is a devastating plant disease with a broad host range. Early detection is critical for disease management, yet conventional methods lack speed and specificity. This study developed a rapid detection system using engineered filamentous phages (RSCq) expressing bioluminescence genes (luxAB, nanoluc, and luxSit-i). Among the constructs, RSCqluxAB demonstrated optimal performance, detecting R. pseudosolanacearum at 1.58x103 CFU/mL within 12 hours, with minimal background noise. The phage retained stability for six months at 4{degrees}C, proving suitable for field applications. These findings highlight its potential for early pathogen monitoring, quarantine enforcement, and precision agriculture, though further validation in soil/plant samples is needed.

microbiology↗

bioRxiv2025

Long-term Dietary Fat Intervention Affects Retinal Health in APOE Mice

The APOE genotype influences metabolic and neurodegenerative outcomes, with APOE4 carriers at higher risk for Alzheimers disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/ function in APOE3-knock-in (KI, neutral for AD) and APOE4-KI mice. Humanized APOE3 and APOE4-KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in APOE4 mice (2 months); APOE3 mice showed impairment only after prolonged exposure (6-12 months). Notably, WD-fed APOE3 mice exhibited more pronounced hyperlipidemia than APOE4 mice. APOE4 CD mice displayed early retinal thinning (6 months), while APOE4 WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in APOE4 mice, with increased tortuosity and reduced vascular area. Elevated Il1b expression in WD-fed APOE4 mice confirmed inflammation-associated retinal dysfunction. APOE4 mice showed heightened vulnerability to diet, with WD worsening metabolic, retinal, and vascular impairments. While CD improved glucose metabolism, it did not prevent retinal dysfunction. These findings underscore genotype-specific dietary strategies to mitigate APOE4-associated risks.

neuroscience↗

bioRxiv2025

Fully Automated and Scalable Pipeline for Macaque Brain Registration

With the rapid development of various whole-brain ex vivo imaging technologies, there is a growing need to develop cross-modal 3D image registration methods to integrate multimodal imaging datasets. While comprehensive cross-modality registration tools such as D-LMBmap and mBrainAligner have been successfully implemented for mouse brains, macaque whole-brain registration presents unique challenges. These include more pronounced non-uniform deformations in larger ex vivo specimens, greater modality-specific contrast differences relative to standard space, and increased inter-individual variability. To address these challenges, we developed Macaca-Star, which incorporates deep learning models and self-individual MRI to tackle cross-modal and ex vivo sample deformation challenges in macaque whole-brain registration. Macaca-Star provides fully automated alignment of fMOST and 2D fluorescent slice images to the NMT MRI standard space, allowing for comprehensive integration of anterograde axonal projections and retrograde-traced neuronal soma profiles.

neuroscience↗

bioRxiv2025

Gut miRNA regulates gut microbiome and Alzheimer pathology in App-knock-in mice

Alzheimers disease (AD) alters the gut microbiome. It remains unclear whether manipulation of miRNA could modulate the gut microbiome and AD pathologies. Depletion of gut miRNA in App-knock-in mice by conditional knockout of Dicer1 gene in intestinal epithelial cells: 1) decreased the absolute number and changed the composition of bacteria in both the gut and brain; 2) reduced cerebral A{beta} load by inhibiting {beta}-secretase activity and increasing the expression of LRP1 and ABCB1 at the blood-brain barrier; 3) increased Il-10 transcription and decreased the transcription of Ccl-2 gene, and that of Ndufa2 and Ndufa5 genes encoding mitochondrial respiratory enzymes in the brain; and 4) induced anxiety symptoms without affecting cognitive function in AD mice. Thus, manipulating miRNA in the gut can modify AD pathogenesis. Future studies should focus on identifying AD-specific miRNAs in the gut that can be therapeutically exploited (e.g. by oral administration) to prevent the progression of AD.

neuroscience↗