Biology subjects

Fan, Y.

Publications and source records attributed to Fan, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

A hierarchy of causes of death in senescent C. elegans

In experimental gerontology, lifespan is often interpreted as a metric of the rate of the overall aging process. However, interventions that increase lifespan can result from suppression of one or more individual late-life pathologies. Here we show how, in the nematode Caenorhabditis elegans, such pathologies can compete in a hierarchical fashion to cause death, such that removal of one cause of death can unmask another. Under standard culture conditions, a major cause of death in elderly C. elegans is infection by their bacterial food source. We report that only when such infection is prevented is lifespan extended by suppression of a second senescent pathology, teratoma-like uterine tumors. Thus, as in mammals, lifespan in wild-type C. elegans can be limited by naturally-occurring neoplasia. By contrast, blocking bacterial infection attenuated the life-shortening effects of vitellogenesis, and did not unmask a life-shortening effect of distal gonad degeneration. Thus, depending on the masking or unmasking of competing causes of mortality in the hierarchy of causes of death, nematode lifespan limitation in different contexts can reflect action of distinct life-limiting senescent pathologies. This underscores how increases in lifespan do not necessarily reflect a reduction in overall aging rate.

pathology↗

bioRxiv2025

Coupled SDE-ODE Modeling of Tumor-Immune Dynamics to Infer Biomarker Release

Tumor-immune interactions are central to cancer progression and treatment response, driving cell death through immune-mediated killing and resource-limited competition. In early-stage disease or following effective treatment, cancer populations are often small and difficult to observe directly. Disease monitoring therefore relies on the detection of biomarkers such as circulating tumor DNA (ctDNA) as noisy proxies to cancer size. However, existing approaches lack robust frameworks to infer tumor burden from these signals when populations approach detection thresholds. To address this, we present a coupled deterministic-stochastic framework that links tumor-immune dynamics to biomarker release. A two-prey, one-predator Lotka-Volterra model captures interactions between immune cells and competing tumor subpopulation under shared resource constraints. Biomarker production is modeled using a linear stochastic differential equation, incorporating ctDNA release from both apoptotic death (immune-mediated) and necrotic death (due to intra-tumor competition). We derive analytical solutions for the resulting biomarker trajectories, including mean detection time under a minimal detection threshold. These results show how volatility in measured biomarker signal, disease heterogeneity, and immune pressure jointly shape signal emergence and persistence. Finally, to model situations in which the observer has access to future information--such as the terminal biomarker signal or sampling time in retrospective studies--we adopt an anticipative theoretic perspective. Using anticipative stochastic calculus, we derive path solutions to the resulting anticipating stochastic differential equation, capturing how future observations influence the inferred biomarker dynamics. This approach links the dynamics of underlying tumor-immune interactions to the corresponding detectable biomarker levels, with implications for early detection, immune monitoring, and retrospective reconstruction of disease progression.

biophysics↗

bioRxiv2025

An improved SIFT algorithm based method for detecting of tumor tissue movement in respiratory motion

BackgroundThis paper intends to make use of the excellent performance of the SIFT algorithm to accurately calculate the displacement of tumor tissues during respiratory movement. Material and methodFirst, we moved phantoms to up,down,right,left respectively to simulate the different directions of movement during respiratory. And rotated phantom to left and right respectively by the angle of 5,10,30,45. Then, used SIFT and cross-correlation algorithms to search the phantoms. Last, use the t-test to check the differences between different directions. ResulThe t-test result proved that there was no significant difference in the detection of moving phantom in all directions. There was no statistical difference between the SIFT of the moving motif and the cross-correlation. The detection results of rotating phantom indicated that the SIFT test results could be used to detect distortion. ConclusionSIFT algorithm can be used to calculate the distortion caused by the thoracic tissue during respiratory movement.

biophysics↗

bioRxiv2025

Hedyotis Diffusae Herba Mitigates Rotenone-Induced Neurotoxicity via Akt Pathway in SH-SY5Y Cells

Hedyotis Diffusae Herba (HDH), known in traditional Chinese medicine for its heat-clearing and detoxifying properties, has been widely used to manage inflammation-related conditions. However, its neuroprotective potential and mechanism in the context of Parkinsons disease (PD) remain unclear.Network pharmacology and molecular docking were applied to predict the interactions between HDH components and PD-associated targets. Molecular dynamics simulations assessed the binding stability of major compounds to core targets. Rotenone-induced SH-SY5Y cell injury served as an in vitro PD model to evaluate HDHs biological effects. Cell viability, reactive oxygen species (ROS), IL-6 secretion, and Akt phosphorylation were assessed by CCK-8 assay, ROS detection kit, ELISA, and western blot, respectively. MK2206, an Akt inhibitor, was used to validate pathway involvement.Seven bioactive compounds were identified in HDH, among which stigmasterol and quercetin exhibited strong binding affinities with AKT1, IL-6, and JUN. Simulations confirmed stable interactions. HDH significantly increased cell viability and decreased intracellular ROS and IL-6 levels in rotenone-treated SH-SY5Y cells. Akt phosphorylation was restored by HDH, and the effect was blocked by MK2206, indicating Akt pathway participation.HDH exerts neuroprotective effects against rotenone-induced toxicity via antioxidant and anti-inflammatory activities and Akt pathway activation. These findings provide mechanistic insight and pharmacological support for HDH as a potential candidate in complementary therapy for PD.

cell biology↗

bioRxiv2025

Myeloid cell differentiation within extracorporeal membrane oxygenators in patients with ARDS

Extracorporeal membrane oxygenation is a last-resort rescue therapy for patients with acute respiratory distress syndrome (ARDS). The membrane oxygenator (MO) is prone to coagulation and dysfunction. Studies have shown that circulating cells can be retained within the MO, however, it is unclear what their cellular identity is. Here, we used single cell-RNA sequencing to characterize MO-resident and incoming venous PBMCs from ARDS patients. We find that MO contain both undifferentiated monocytes and differentiated macrophages, characterized by increased SPP1 expression. These results indicate that myeloid retention and differentiation occurs within MO, which might contribute to MO dysfunction.

cell biology↗

bioRxiv2025

Prediction of cellular morphology change under perturbations with transcriptome-guided diffusion model

Investigating the cell morphology change after perturbations with high-throughput image-based profiling is of growing interest, considering its wide applications in phenotypic drug discovery, including MOA (Mechanism Of Action) prediction, compound bioactivity prediction, and drug repurposing. However, the vast space of chemical and genetic perturbations makes it infeasible to fully explore all the potential perturbations with image-profiling technologies. Consequently, developing a powerful in-silico method to simulate high-fidelity cell morphological response under perturbations can reduce the experiment costs and accelerate drug discovery. Motivated by this, we proposed MorphDiff, a transcriptome-guided latent diffusion model for accurately predicting the cell morphology response to perturbations. We applied MorphDiff to two large-scale datasets, including one drug perturbation and one genetic perturbation cell morphology dataset covering thousands of diverse perturbations. Extensive benchmarking and comparison with baseline methods show the remarkable accuracy and fidelity of MorphDiff in predicting cell morphological changes under unseen perturbations. Furthermore, we explored the utilities of MorphDiff in identifying and retrieving the MOAs of drugs, which is a crucial application in phenotypic drug discovery. With the designed pipeline for MOA retrieval, we demonstrated MorphDiffs capability to boost the retrieval of the drugs MOAs (Mechanism Of Actions) by generating realistic cell morphology profiles. The average MOA retrieval accuracy of MorphDiff-generated morphology is comparable with that of the ground truth cell morphology, and consistently outperforms the baseline method and gene expressionbased retrieval by 29.1% and 9.7% respectively. We also validated that complementary information provided by cell morphology generated by MorphDiff can help discover drugs with dissimilar structures but the same MOAs. In summary, with its strong capabilities in generating high-fidelity cell morphology on unseen perturbations, we envision MorphDiff as a powerful tool in phenotypic drug discovery by accelerating the phenotypic screening of vast perturbation space and improving MOA identification.

cell biology↗

bioRxiv2025

DR5 CAR-T cells target solid tumors and suppress MDSCs with minimal toxicity

Chimeric antigen receptor (CAR) T cell therapies have poor efficacy in solid tumors due to limited target specificity and an immunosuppressive tumor microenvironment. We investigated death receptor 5 (DR5) as a CAR target based on its high expression in both solid tumors and myeloid- derived suppressor cells (MDSCs). We engineered agonistic DR5-specific CAR constructs and evaluated their activity in multiple models, demonstrating DR5-expression-dependent tumor killing, confirmed by knockout and overexpression experiments. DR5-targeting single-chain variable fragments retained their pro-apoptotic activity when expressed on non-effector cells or extracellular vesicles. Among multiple CAR designs, we identified a construct with optimized binding affinity that maintained T cell viability while preserving strong tumor and MDSC-killing potency. To assess safety and efficacy in an immunocompetent setting, we also developed a murine DR5-targeted CAR. In multiple xenograft and syngeneic mouse models, DR5 CAR-T cells reduced tumor growth, prolonged survival, and did not cause detectable toxicity. In patient- derived organoids and tissue slices, DR5 CAR-T cells infiltrated tumor tissues, reduced MDSCs, boosted CD8+ T cell activity, and inhibited tumor growth. These findings support DR5-targeted CAR-T therapy as a promising strategy for treating solid tumors, which combines direct tumor cytotoxicity with immune activation and minimizes off-target effects. TeaserDR5 CAR-T cells eliminate tumor cells and MDSCs and activate tumor-resident CD8+ T cells within the TME.

cancer biology↗

bioRxiv2025

E2F deregulation compromises ER homeostasis by attenuating IRE1 activity

The E2F family of transcription factors are key regulators of the cell cycle in all metazoans. While they are primarily known for their role in cell cycle progression, E2Fs also play broader roles in cellular physiology, including the maintenance of exocrine tissue homeostasis. However, the underlying mechanisms that render exocrine cells particularly sensitive to E2F deregulation remain poorly understood. The Drosophila larval salivary gland (SG), like its mammalian counterpart, is an exocrine tissue that produces large quantities of "glue proteins" in the endoplasmic reticulum (ER). Here, we show that E2F activity is important for the exocrine function of the Drosophila SG. The loss of de2f1b, an alternatively spliced isoform of Drosophila E2F1, leads to elevated DNA damage and accumulation of cytoplasmic DNA (cytoDNA) in the SGs. Surprisingly, we found that IRE1, a key sensor of the unfolded protein response, is required not only for ER homeostasis but also for preventing cytoDNA accumulation in the SG. Importantly, we found evidence demonstrating that IRE1 activity is attenuated in de2f1b-deficient SGs, contributing to both ER dysfunction and cytoDNA accumulation. Together, these findings reveal an unanticipated link between ER homeostasis and cytoDNA processing and offer mechanistic insight into why exocrine tissues are particularly vulnerable to E2F deregulation. Author SummaryWe discovered an unexpected consequence of E2F deregulation in ER homeostasis. The loss of de2f1b in the Drosophila salivary gland impedes physiological activation of an ER-resident protein, IRE1, a central component of the unfolded protein response. We show that IRE1 is required not only for ER homeostasis but also for preventing DNA accumulation in the cytoplasm, a phenotype observed in de2f1b deficient salivary glands. Our study reveals a previously uncharacterized role of IRE1-dependent ER function and offers new perspectives on why exocrine tissues are particularly vulnerable to the loss of E2Fs.

developmental biology↗

bioRxiv2025

Engineering novel AAV capsids by global de-targeting and subsequent muscle-specific tropism in mice and NHPs

Recombinant adeno-associated viral (rAAV) vectors are a potent tool, but their clinical application is restricted by insufficient target tissue transduction and liver toxicity. We employed a novel two-step engineering strategy to create novel rAAV capsids with global tissue de-targeting, then produced strong tissue-specific expression by adding a peptide sequence. We created a novel capsid, AAV.Zero1, with globally de-targeted transduction by loop swapping domains from AAV9 into AAV2. Making an R585A substitution (AAV.Zero2) re-targeted tissues but deleting residues 585-587 (AAV.Zero3) abrogated transduction. Inserting a myogenic peptide into AAV.Zero3 produced a novel capsid (AAV.eM) with strong muscle-specific transgene expression while maintaining minimal off-target expression, including in liver, which was conserved in two mouse strains and non-human primates. AAV.eM showed similar expression as the leading myotropic vector MyoAAV.4A but had a more favorable safety profile. Importantly, AAV.eM was able to functionally rescue a mouse model of Duchenne Muscular Dystrophy following systemic delivery of a micro-dystrophin gene. Thus, AAV.eM is an improved myotropic rAAV capsid that de-targets other tissues, especially the liver, and proof-of-concept for a platform to create capsids with specific properties that translate across species by addition of peptides onto low transduction backbones.

bioengineering↗

bioRxiv2025

β-Glucan Modulates Monocyte Plasticity and Differentiation Capacity to Mitigate DSS-Induced Colitis

Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this proinflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with {beta}-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from {beta}-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1 macrophages derived from Ly6Chi monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how {beta}-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/653036v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1b969c2org.highwire.dtl.DTLVardef@1ce603dorg.highwire.dtl.DTLVardef@10582forg.highwire.dtl.DTLVardef@10d7de6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

LOXL2 Deletion Triggers TMJ Osteoarthritis While Overexpression Protects Against NF-κB-Induced Chondrocyte Apoptosis

Temporomandibular joint osteoarthritis (TMJ-OA) affects a significant proportion of the population worldwide. However, there has been no substantial progress in the development of FDA-approved drugs for treatment due to a lack of understanding of the specific factors regulating key TMJ-OA molecular mechanisms. Lysyl Oxidase Like-2 (LOXL2) promotes knee joint cartilage protection, and it is downregulated in TMJ-OA animal model. We evaluated the role of LOXL2 in TMJ cartilage, its molecular mechanism and gene networks using in vivo Loxl2 knockout mice (Acan-Cre; Loxl2flox/flox) and ex vivo goat TMJ cartilage. Our results show that Loxl2 knockout in mice cartilage upregulates Il1b, Mmp9, Mmp13, Adamts4, and Adamts5, whereas it reduces the levels of aggrecan and proteoglycan. Loxl2 deleted TMJ cartilage show a higher enrichment of inflammatory response, TNFA signaling via NF-kB, extracellular matrix (ECM), and collagen degradation pathway network. Conversely, LOXL2 treatment reduces interleukin-1 beta (IL-1{beta})-induced expression of Mmp13, protects mitochondrial function and ECM from degeneration. Importantly, LOXL2 attenuates IL-1{beta}-induced chondrocyte apoptosis via phosphorylation of NF-{kappa}B and expression of pain-related gene PTGS2 (encodes COX2). Taken together, Loxl2 knockout mice exacerbate TMJ-OA through cartilage/ECM degradation, mitochondrial dysfunction, chondrocyte apoptosis, and inflammatory gene expression, whereas LOXL2 treatment mitigates these effects. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/653519v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@cb7540org.highwire.dtl.DTLVardef@17ebe2eorg.highwire.dtl.DTLVardef@1f7fd59org.highwire.dtl.DTLVardef@19fdd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Magnetic Resonance Imaging for Improved Brain Tumor Detection

Precise demarcation of brain tumor boundaries is critical for optimizing treatment strategies and improving patient outcomes. In vivo characterization of tumor using PET/CT and MRI is clinical standard. PET/CT highlights the metabolic aspects of the tumor, while MRI provides information on functional, metabolic and structural changes. Even with technological advancements in both PET/CT and MRI, a method that can precisely delineate infiltrative tumor boundaries from normal-appearing brain regions (NABR) in vivo is still lacking. To address this limitation, we explored a relatively new MR imaging method, the Nuclear Overhauser Effect Magnetization Transfer Ratio (NOEMTR), in conjunction with a gadolinium-based contrast agent (Gd-DOTA), to precisely delineate the tumor boundaries in a rat model of infiltrative gliosarcoma. NOEMTR imaging was performed in the rat model (n=5) before and after Gd-DOTA administration. The post-Gd-DOTA NOEMTR map was subtracted from the pre-Gd-DOTA map and compared with contrast-enhanced T1-weighted images and immuno-histological findings. The resulting NOEMTR difference map clearly highlighted both the tumor core and infiltrative boundaries, which was not discernible on the post-contrast T1-weighted images. The extended tumor boundaries observed on the NOEMTR difference map corroborated with the IHC image, which confirmed the presence of infiltrative tumor cells and macrophages in these regions. Guided by the NOEMTR difference map, regions of interest (ROI) were drawn to quantify NOEMTR signal changes in the tumor core, tumor boundaries, and NABR post-Gd-DOTA. Tumor core showed a significant [~]43% reduction in NOEMTR signal (plJ=lJ0.003), while the tumor periphery exhibited a moderate reduction of [~]10%, (plJ=lJ0.045). No appreciable change in was observed in the NABR (plJ=lJ0.371). In contrast, the post contrast T1-weighted signal changes in tumor core, tumor periphery and NABR were, 33.32% (p = 0.092), 3.8% (p = 0.478), and 8.7% (p = 0.464) respectively. These findings suggest that NOEMTR imaging provides enhanced tumor contrast, particularly at the infiltrative tumor margins, where conventional contrast enhanced T1-weighted MRI may underestimate tumor extent. Histological validation confirmed the presence of infiltrative tumor cells and macrophages in the tumor periphery, as highlighted by the NOEMTR difference map. Overall, NOEMTR imaging, in combination with Gd-DOTA administration, demonstrates superior delineation of brain tumor boundaries compared to conventional MRI. As NOEMTR imaging is a fast acquisition scan (under 10 minutes) and performed on standard 3 Tesla, it can be easily integrated into clinical protocols. By improving visualization of tumor infiltration and distinguishing tumor regions from NABR, NOEMTR imaging holds promise for advancing neuro-oncological diagnostics and treatment planning.

bioengineering↗

bioRxiv2025

SLFN11 Loss-Induced Chemoresistance is Associated with Overexpression of Glycerophospholipid Biosynthesis in Ewing Sarcoma.

Ewing sarcoma (EWS) is an aggressive cancer in adolescents and young adults with frequent relapse rates and poor outcomes in recurrent or metastatic cases. Schlafen family member 11 (SLFN11) gene is associated with the sensitivity to DNA-damaging agents (DDAs). The knockout of SLFN11 is associated with acquired chemoresistance in both cell lines and preclinical models. Here, we aimed to elucidate the metabolic underpinnings of SLFN11-loss associated chemoresistance in patient derived cell lines of EWS. Our integrated transcriptomic and metabolomic analyses revealed downregulation of mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2) gene, which was accompanied by the upregulation of glycerophospholipid (GPL) biosynthesis pathway. Further, therapeutic targeting of lipid synthesis with the glycerol-3-phosphate acyltransferase 1 (GPAT1) inhibitor (FSG67) enhanced the efficacy of the DDA (SN-38) in SLFN11-/- cells. These findings indicate that SLFN11 loss-mediated chemoresistance can be targeted by blocking GPL biosynthesis in addition to DDA administration.

cancer biology↗

bioRxiv2025

Embryonic Durotaxis: A Mechanical Framework for Understanding Cesarean Scar Pregnancy

Cesarean scar pregnancy (CSP) is an increasingly common complication associated with the rise in cesarean section rates, yet its underlying mechanisms remain poorly understood. In this study, we identified a stiffness gradient between healthy and scarred uterine tissues in both human cesarean samples and mouse uterine scar models. By employing gradient stiffness hydrogels, we demonstrated that mouse embryos and human trophoblast spheroids exhibit durotaxis, migrating preferentially toward stiffer areas. This migration occurs through three-dimensional complex behaviors--translation, swinging, and rolling--characterized by periodic patterns that align with cavity oscillations. Embryonic durotaxis is initiated from asymmetric adhesion forces and is driven by embryonic protrusive forces, generated from Marangoni-like tissue flows. The intrinsic cavity oscillations further amplify and sustain embryonic durotaxis. Finally, pharmacological inhibition of embryonic durotaxis significantly reduced CSP incidence in the mouse model. Our findings establish the concept of embryonic durotaxis, which may provide novel therapeutic avenues for CSP prevention.

developmental biology↗

bioRxiv2025

AAVs Targeting Human Carbonic Anhydrase IV Enhance Gene Delivery to the Brain

Clinically approved gene therapies based on natural adeno-associated virus (AAV) serotypes have restricted applications, particularly in the brain, due to their poor targeting, high dose requirements, and resulting safety concerns. Directed evolution of enhanced AAV capsids in mice or non-human primates (NHPs) has resulted in markedly improved performance in those species, but inter-species differences present a serious challenge for translating these vectors into human therapies. Here, we engineer AAVs to target human carbonic anhydrase IV (CA-IV), a recently identified blood-brain barrier (BBB) transcytosis receptor. Among known transcytosis receptors, CA-IV is notable for its relatively specific expression in brain endothelial cells and the potency of AAVs that target it in mice. CA-IVs AAV binding site, and thus the mouse vectors enhanced brain potency, is not conserved across species, so we employed a two-phase engineering strategy to identify AAVs optimized for human CA-IV-dependent gene delivery to the brain. We first used in vitro receptor-based selection of a vast AAV library to exclude capsids that do not bind human CA-IV, followed by in vivo selection in "humanized" mice expressing human CA-IV in brain endothelial cells. Notably, we find that human CA-IV binding capsid variants that were poorly enriched in the pull-down selection outperform strong binders in vivo. The most promising vector, AAV-hCA4-IV77, engages human CA-IV to achieve 100-fold greater brain transduction than AAV9, with robust neuronal and astrocytic coverage throughout multiple brain regions. These results advance our understanding of receptor-targeted capsid design and support the therapeutic potential of human CA-IV-engaging AAVs.

bioengineering↗

bioRxiv2025

Uncovering Shared and Tissue-Specific Molecular Adaptations to Intermittent Fasting in Liver, Brain, and Muscle

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16-hour daily fasting regimen (IF16) over four months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

molecular biology↗

bioRxiv2025

LPS/TLR4-Activating Exosomes from M1-Polarized Avian Macrophages Enhances IBV Vaccine-Induced Protective Immunity in Chickens

Infectious bronchitis virus (IBV) presents a substantial economic burden to poultry production due to extensive serotypic diversity and limited cross-protection afforded by conventional vaccines. This study evaluated exosomes derived from M1-polarized chicken macrophages (HD11M1-exo) as a novel adjuvant for IBV vaccination. HD11M1-exo, isolated from LPS-activated HD11 macrophages via ultracentrifugation, demonstrated significant immunomodulatory properties across multiple experimental systems. In vitro analyses revealed HD11M1-exo enhanced macrophage phagocytosis and cellular immune activation via the LPS/TLR4 signaling pathway. In embryonated eggs, HD11M1-exo pre-treatment induced TNF- upregulation, enhanced viral resistance, and reduced pathological damage. In chickens, HD11M1-exo administration elevated CD80/CD86 and TGF-{beta}4 expression in respiratory tissues and increased secretory IgA in lacrimal fluid. When combined with H120 vaccine, HD11M1-exo significantly augmented both humoral immunity (elevated serum IgY and mucosal IgA) and cellular responses (increased CD80/CD86 expression), surpassing commercial adjuvants in efficacy. Following viral challenge, HD11M1-exo+H120 immunized chickens exhibited significantly reduced viral loads and attenuated histopathology compared to controls. These data collectively suggest that exosome-based formulations may serve as effective adjuvants for enhancing poultry vaccine immunogenicity and protective efficacy.

immunology↗

bioRxiv2025

Mapping individualized multi-scale hierarchical brain functional networks from fMRI by self-supervised deep learning

The brains multi-scale hierarchical organization supports functional segregation and integration. Characterizing the hierarchy of individualized multi-scale functional networks (FNs) is crucial for understanding these fundamental brain processes. It provides promising opportunities for both basic neuroscience and translational research in neuropsychiatric illness. However, current methods typically compute individualized FNs at a single scale and are not equipped to quantify any possible hierarchical organization. To address this limitation, we present a self-supervised deep learning (DL) framework that simultaneously computes multi-scale FNs and characterizes their across-scale hierarchical structure at the individual level. Our method learns intrinsic representations of fMRI data in a low-dimensional latent space to effectively encode multi-scale FNs and their hierarchical structure by optimizing functional homogeneity of FNs across scales jointly in an end-to-end learning manner. A DL model trained on fMRI scans from the Human Connectome Project successfully identified individualized multi-scale hierarchical FNs for unseen individuals and generalized to two external cohorts. Furthermore, the individualized hierarchical structure of FNs was significantly associated with biological phenotypes, including sex, brain development, and brain health. Our framework provides an effective method to compute multi-scale FNs and to characterize the inter-scale hierarchy of FNs for individuals, facilitating a comprehensive understanding of brain functional organization and its inter-individual variation.

neuroscience↗