Biology subjects

Xie, X.

Publications and source records attributed to Xie, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Whole-Brain Convergence of Real-World Visual Expertise beyond Faces: Meta-Analytic Evidence for Core-Adaptive Neural Architecture

Visual expertise--the ability to discriminate highly similar exemplars quickly and accurately within a category--supports skilled performance across real-world domains and is supported by distributed neural systems. We focus on non-face expertise to test cross-domain convergence in acquired real-world visual skills, treating faces separately because socially embedded, sensitive-period-constrained processing could blur this inference. It remains unresolved whether non-face expertise across heterogeneous domains converges on a shared, domain-general whole-brain architecture, or instead recruits domain-contingent neural configurations that vary with task and stimulus demands. We conducted a coordinate-based meta-analysis of 22 task-fMRI studies spanning 11 real-world non-face expertise domains (579 participants, 210 peak-activation foci). Primary analysis revealed a robust, right-lateralized parieto-temporo-occipital circuit centered on the middle occipital gyrus, middle temporal gyrus, angular gyrus and adjoining inferior parietal lobule. We propose that this circuit constitutes a domain-general neural core that integrates fine-grained visual features with semantic associations while supporting attention-guided recognition of visually similar objects in expert performance. Subgroup and meta-regression analyses uncovered a complementary adaptive component, the engagement of which varied systematically with representational and contextual factors. Pictorial stimuli and expert-novice contrasts reliably strengthened recruitment of the right-hemisphere core, whereas symbolic stimuli engagement toward left temporal regions while selectively re-engaging right-core nodes. In addition, male-skewed samples showed attenuated left-hemisphere activation. Together, these findings delineate a stable right-hemisphere neural scaffold underlying non-face visual expertise, flexibly supplemented by left-hemisphere systems as a function of stimulus format, task demands, and demographic context, providing a whole-brain reference framework for future studies. HighlightsO_LIA coordinate-based meta-analysis integrates 22 whole-brain task-fMRI studies of real-world non-face visual expertise. C_LIO_LIResults delineate a core-adaptive architecture supporting non-face expertise across domains. C_LIO_LIA right-lateralized parieto-temporo-occipital core (AG, MOG, MTG, adjoining IPL) shows convergent recruitment across non-face domains. C_LIO_LIAdaptive left-hemisphere regions (MTG/STG/ITG/IFG; plus FG/IOG/insula) are flexibly engaged with task and stimulus demands. C_LIO_LIFindings refine neurocognitive accounts of perceptual expertise and provide a domain-spanning whole-brain reference framework for future studies. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/696823v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14119a6org.highwire.dtl.DTLVardef@fb04cforg.highwire.dtl.DTLVardef@1f8cd35org.highwire.dtl.DTLVardef@168798a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

A gastric microbial chromatin remodeler drives gastric cancer progression and immune evasion by reprogramming the host epigenome

Emerging evidence highlights the crucial role of microbial communities in modulating cancer development and progression. In gastric cancer (GC), we identify Streptococcus anginosus (SA) as a tumor-resident oncobacterium that drives both tumor progression and immune evasion. We define a novel mechanism in which SA secretes extracellular vesicles (saEVs) that translocate the bacterial chromatin remodeler saSNF2 into host cell. There, saSNF2 partners with host transcription factor TEAD1--through its ATPase activity and participation in BAF complex assembly--to coordinately activate oncogenic transcription. This transkingdom interaction upregulates the palmitoyltransferase ZDHHC11, which in turn stabilizes PD-L1 via palmitoylation to establish an immunosuppressive niche, while also amplifying other TEAD1 target genes to fuel tumor progression. Functionally, saEVs promote tumor growth and limit CD8+ T-cell infiltration in vivo. Strikingly, pharmacological inhibition of ZDHHC11 reverses immune evasion and synergizes with anti-PD-1 checkpoint blockade. Our results establish SA as a multifaceted driver of GC and reveal the saSNF2-ZDHHC11 axis as a promising target to potentiate immunotherapy.

cancer biology↗

bioRxiv2025

MisTIC: Missegmented Transcript Inference Correction for Improved Spatial Transcriptomics Analysis

Imaging-based spatially resolved transcriptomics (SRT) technologies, such as 10X Xenium, MERSCOPE, and CosMx, have revolutionized our ability to study gene expression within the spatial context of tissues at single-cell resolution. The acquisition of such data relies heavily on cell segmentation algorithms, which often produce imperfect boundaries, leading to transcript misassignment. These misassignments can significantly affect downstream analyses, including cell type identification, differential expression analysis, cell-cell communication, and RNA localization. We present MisTIC (Missegmented Transcript Inference Correction), a variational Bayesian model designed to correct transcript misassignment errors without requiring resegmentation. In benchmarking analyses using synthetic data with simulated transcript misassignment, MisTIC demonstrated high sensitivity and specificity in removing misassigned transcripts. In real data applications, MisTIC effectively enhances cell type identification, reduces ambiguity in differential expression analysis, and improves the detection of cell-cell communication. Furthermore, RNA localization analysis based on data corrected by MisTIC revealed that, in T cells located near cancer-associated fibroblasts compared to those farther away, genes involved in T cell activation, inflammation, and cytotoxicity were depleted from cytoplasmic regions despite not being differentially expressed between the two T cell subsets. In conclusion, MisTIC is a powerful tool for correcting transcript misassignment in SRT data. It not only improves the accuracy of routine analyses but also enables novel investigations that provide deeper insights into the dynamics of gene expression.

bioinformatics↗

bioRxiv2025

Synchronized Latency Reversal and Immune Clearance by a Multifunctional Fusion Protein Enables HIV-1 Reservoir Reduction

Strategies that concurrently reactivate latent reservoirs and enhance immune-mediated clearance hold significant promise for achieving an HIV cure. Here, we developed hyperIL-15xsCD4-Fc (15xsCD4-Fc), a fusion protein that integrates latency reactivation, targeted immune engagement, and effector-mediated killing into a single molecule. This agent not only potently reverses HIV-1 latency in CD4+ T cells from people living with HIV-1 (PLWH) through coordinated IL-15 receptor signaling and sCD4-mediated HIV-1 envelope (Env) engagement, but also enhances antigen-specific CD8+ T cell response in PBMCs derived from PLWH. Furthermore, 15xsCD4-Fc enables Env-specific elimination of reactivated latently infected cells by NK cells while preventing off-target cytotoxicity. In PBMCs from PLWH, 15xsCD4-Fc reduced replication-competent HIV-1 DNA by 93.8%. In antiretroviral treated HIV-1-infected humanized mice, the molecule demonstrated both safety and efficacy in diminishing viral reservoir in lymphoid organs. This spatiotemporally coupled approach to reservoir exposure and immune recognition establishes a clinically viable strategy for clearing the HIV-1 reservoir. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/693434v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@8f8f0org.highwire.dtl.DTLVardef@10f63f7org.highwire.dtl.DTLVardef@16c1de2org.highwire.dtl.DTLVardef@11e1787_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

ERAD Activity Distinguishes the Functional Heterogeneity of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) rely on precisely controlled proteostasis to sustain lifelong self-renewal, yet whether intrinsic proteostatic characteristics can prospectively define functional diversity within the HSC pool remains unknown. In this study, we developed a dual-fluorescence reporter system to visualize endoplasmic reticulum-associated degradation (ERAD) activity in vivo and discovered that ERAD activity can prospectively predicts the long-term reconstitution potential of HSCs. Remarkably, ERAD states were maintained through self-renewal, revealing an inheritable "proteostatic memory" within the HSC pool. Transcriptomic and functional analyses identified SOCS2 as a key regulator of this process: SOCS2 inhibits JAK2 signaling to sustain ERAD activity, whereas hyperactive JAK2 interacts with the ERAD E3 ligase Hrd1 and suppresses VCP-mediated misfolded substrate. These findings define a SOCS2-JAK2-ERAD axis that connects cytokine signaling to intrinsic proteostasis remodeling, establishing ERAD activity as a predictive and heritable marker of HSC function and providing a conceptual framework for understanding hematopoietic stem cell heterogeneity.

cell biology↗

bioRxiv2025

Loss of Complement Factor D suppresses alternative pathway activation but fails to reduce lipofuscin accumulation in the retinal pigmented epithelium of Abca4-/- mice

Stargardt disease (STGD1) is the most common inherited macular dystrophy, caused by loss-of-function mutations in ABCA4 that result in bisretinoid-containing lipofuscin accumulation in the retinal pigment epithelium (RPE), and progressive photoreceptor degeneration. Oxidative stress and complement system activation have been implicated as contributors to disease pathogenesis, but the requirement for alternative pathway activation in STGD1 remains unclear. To directly assess this, we used a genetic approach to generate pigmented mice deficient for both Abca4 and Cfd, an essential serine protease for alternative pathway initiation and amplification. Complement protein analysis revealed increased total C3 immunolabeling in the RPE and choroid of Cfd-/- mice, while C3d deposition at the RPE basal labyrinth and apical microvilli was markedly reduced, consistent with impaired alternative pathway activity. Western blotting confirmed altered C3 fragment profiles in Cfd-/- backgrounds, supporting a constitutive role for the alternative pathway in RPE complement activation. However, loss of Cfd did not prevent lipofuscin accumulation in the RPE of Abca4-/- mice. Under light-induced stress, we unexpectedly observed a modest attenuation of outer nuclear layer thinning in Abca4-/- that was unchanged by Cfd loss, which independently also showed a comparable rescuing effect. Together, these findings demonstrate that while the alternative pathway is a major driver of complement activation in the RPE and contributes only modestly to photoreceptor degeneration under light stress, its inhibition is insufficient to alter lipofuscin accumulation in pigmented Abca4-/-mice.

genetics↗

bioRxiv2025

Enterococcus faecalis delivers Obg GTPase via extracellular vesicles to instigate mTOR activity and promote HCC tumorigenesis

Hepatocellular carcinoma (HCC) is a malignant tumor that has been associated with dysbiosis of the gut microbiota. However, how the gut microbiota plays an oncogenic role in HCC remains largely unknown. Here, we show that Enterococcus faecalis (E. faecalis) is highly enriched in liver tumor tissues and is positively correlated with pathogenesis of HCC. E. faecalis promotes liver cancer cell proliferation, protein translation, cell migration and tumorigenesis. Mechanistically, we found that EF-derived extracellular vesicles (EF-EVs) deliver EF-Obg GTPase to activate host mTOR, thereby promoting liver cancer progression. Intriguingly, the EF-Obg protein exerts its influence on the mTOR pathway via a Ras-like G domain involved in GTP binding. EF-Obg exhibits a striking homology with the G1 site of the G domain of Rheb, a key positive regulator of mTOR. Obg gene is critical for E. faecalis to activate mTOR to promote hepatocarcinogenesis based on an engineered obg knockdown strain by CRISPR interference experiment. Clinically, abundant EF-Obg protein expression is correlated with enhanced activation of mTOR, leading to poor overall survival in HCC patients. Significantly, treatment of mTOR inhibitor Everolimus confers effectiveness in EF-colonized liver cancer orthotopic model, suggesting that Everolimus therapeutic approach can be effective for liver cancer patients with enriched E. faecalis. Taken together, we provide mechanistic and functional evidence to verify a direct causal relationship between tumor-resident E. faecalis enrichment and liver carcinogenesis, revealing that EF-Obg functions as a previously unidentified cross-kingdom activator of mTOR to promote liver tumorigenesis.

cell biology↗

bioRxiv2025

Potentiating CAR-T bystander killing by enhanced Fas/FasL signaling mitigates antigen escape in heterogeneous tumors

Antigen (Ag) escape is a frequent mechanism of relapse after CAR-T therapy, even though only [~]1% of leukemic and [~]0.1% of lymphoma cells are Ag- at baseline. In this study, we modeled extreme Ag heterogeneity (>20%) to define how Fas/FasL-dependent bystander killing contributes to tumor clearance. Across patient cohorts, Fas expression predicted survival after CD19 CAR-T therapy, particularly in CD19-low disease. In both murine and human systems, Fas-dependent bystander killing required Ag stimulation and cell contact, operated within a defined therapeutic window, and could eradicate large fractions of Ag- tumors in vivo. Pharmacologic potentiation with inhibitor of apoptosis protein antagonists or genetic stabilization of CAR-T membrane-bound FasL enhanced bystander killing but simultaneously induced CD4 T cell fratricide, which was rescued by CAR-T Fas knockout. Importantly, Fas sensitization also enabled bispecific antibody-redirected T cells to mediate bystander killing in resistant tumors. Finally, targeting tumor-associated macrophages triggered Fas-dependent clearance of neighboring tumor cells. These findings establish Fas-mediated bystander killing as a generalizable and therapeutically actionable axis to prevent Ag escape and broaden the scope of targeted T cell therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/677496v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@11bedorg.highwire.dtl.DTLVardef@d09d07org.highwire.dtl.DTLVardef@1f53c1dorg.highwire.dtl.DTLVardef@13d96f9_HPS_FORMAT_FIGEXP M_FIG C_FIG Fas-mediated bystander killing can be potentiated by IAP inhibition and FasL stabilization, and further improved by decoupling CD4 T cell fratricide via Fas knockout. Schematic representation of CAR-T bystander killing across three mechanistic states. Left (Baseline): Antigen-positive (CD19) tumor cells activate CAR-T cells, leading to FasL-mediated cytotoxicity of neighboring antigen-negative (CD19-) tumor cells via membrane-bound FasL. Limited FasL expression and ADAM10-mediated shedding constrain bystander killing, and CD4 T cells are largely spared. Middle (Potentiated): Enhancing Fas signaling through IAP inhibition (IAPi), increasing FasL expression, and reducing FasL shedding result in improved bystander killing but also increased CD4 T cell fratricide. Right (Potentiated & Decoupled): Combining IAPi with FasL stabilization and CAR-T Fas knockout (FasKO) augments bystander killing while eliminating CD4 T cell fratricide.

immunology↗

bioRxiv2025

VSA-2, a novel plant-derived adjuvant for SARS-CoV-2 subunit vaccine

QS-21, a key component of several licensed vaccines is facing limited supply, dose-limiting toxicity and other drawbacks which together limit its broader usage. Development of saponin alternatives to QS-21 that retain its desirable adjuvant activity without its drawbacks is in high need. Incorporating an amide side chain into the more sustainable Momordica saponins (MS) I and II led to the recent discovery of two semisynthetic immunostimulatory adjuvants VSA-1 and VSA-2. Here, we showed that the receptor-binding protein (RBD) of ancestral SARS-CoV-2 adjuvanted with VSA-2 (VSA-2-RBD) induced high titers of SARS-CoV-2-specific humoral and T helper-1 prone immune responses in mice comparable to that triggered by QS-21-RBD. Vaccination with VSA-2-RBD provided strong protection against SARS-COV-2, Delta and Omicron variants infection and the virus-induced lung inflammation and pathology similarly as QS-21-RBD vaccination. Overall, our results suggest that VSA-2 adjuvant can potentially complement the clinically proven saponin adjuvant QS-21 in vaccines against infectious diseases.

microbiology↗

bioRxiv2025

Molecular architecture of OXGR1 reveals evolutionary conserved mechanisms for metabolite surveillance

The ability of cells to sense and respond to metabolic signals is fundamental to life, yet the molecular mechanisms underlying metabolite surveillance remain incompletely understood. Here, we elucidate the structural basis of metabolite recognition by OXGR1, a GPCR that monitors key intermediates in the tricarboxylic acid cycle (TCA). Using cryo-electron microscopy, we determined four cryo-EM structures of OXGR1 bound to -ketoglutarate (AKG), itaconate (ITA), and structural related succinate (SUC) and maleate (MA). These structures reveal a positively charged binding pocket and an extensive hydrogen-bond network critical for OXGR1 recognizing dicarboxylic acids. In addition, we identify a distinct arrangement of hydrophobic residues that modulates ligand potency and selectivity. Mutational analysis and molecular dynamics simulations further demonstrate that non-canonical micro-switch motifs, including FRY and NLxxY, are essential for ligand recognition and receptor activation. Comparative structural and evolutionary analyses indicate that these mechanisms are conserved across species, underscoring the critical role of OXGR1 in maintaining metabolic homeostasis. Together, our findings provide a mechanistic framework for metabolite sensing via OXGR1 and suggest potential strategies for therapeutic modulation of metabolic and inflammatory diseases.

molecular biology↗

bioRxiv2025

GSDME unlocks astrocyte-driven neurotoxicity in Alzheimer's Disease

Astrocytic calcium dysregulation and reactivity precede A{beta} deposition in amyloid-{beta} deposition in Alzheimers disease (AD) but the neurotoxic mechanisms remain unclear. We show that GSDME acts as a switch, linking MAM-mediated calcium release to astrocyte-driven neurotoxicity. Specifically, A{beta}-activated microglial signals activate astrocytic GSDME, releasing its N-terminal fragment, which targets MAMs and triggers ER calcium efflux. This induces biphasic CaMKII phosphorylation, initially boosting NRF2 defenses, then activating NF-{kappa}B-driven inflammation, shifting astrocytes from protective to toxic states. GSDME activation also drives astrocyte-derived exosomes (ADEs) to carry neurotoxic tau, proinflammatory miRNAs, and toxic lipids, propagating toxicity. GSDME deletion in AD mice reduces A{beta} burden, restores NF-{kappa}B/NRF2 balance, reprograms astrocytes and ADEs to protective states, and rescues cognition. Multi-omics profiling of serum ADEs from AD patients reveals a disease-specific signature with central neurotoxicity and peripheral immune regulation. These findings position GSDME as a promising dual diagnostic and therapeutic target for early AD invention.

neuroscience↗

bioRxiv2025

First Whole-Genome Chikungunya Virus Sequence Detected in Mosquitoes during the 2025 Foshan Outbreak: Evidence of Field Vector Infection and Transmission Potential in China

BackgroundSince July 2025, an outbreak of mosquito-borne chikungunya fever occurred in Foshan City, Guangdong Province, China. This was the second outbreak in China following the one that occurred in Dongguan City, Guangdong Province, in 2010. Moreover, the intensity of this outbreak was significantly greater than that of the previous one. Updates to 23 August, more than 10,000 human cases had been reported. Here, we present the first full genome sequence of the chikungunya virus (CHIKV) derived from field-trapped mosquitoes during the outbreak. MethodsAdult Aedes albopictus were BG-trap captured from residences and parklands in three hotspot towns with high density of confirmed human cases. Mosquitoes were morphologically identified and pooled by species, sex and environment types. RNA was extracted, screened by CHIKV RT-qPCR, then positive pools underwent sanger and whole-genome sequencing for complete sequences. Lineage and mutational profiles were inferred by maximum likelihood phylogenetic and comparison against human and mosquito genomes. The distribution of amino acid site mutations in different protein coding regions was also analyzed. ResultThrough 11 days of collection using 10 BG-traps, 2,803 mosquitoes were captured. 1569 (55.97%) female Ae. albopictus were divided into 77 pools and 9.09% (7/77) of the pools tested positive for CHIKV. The local Ae. albopictus minimum infection rate (MIR, per 1000 females) was 4.46, while the MIR for residences in Lecong Town was the highest at 9.17. The MIR for parklands was slight higher than for residences (4.60 vs. 4.30). All the 5 Ae. albopictus-derived complete CHIKV genome clustered within ECSA-Indian Ocean lineage genotype, closely related to human-derived genomes on 2025 Reunion Island. Amino-acid mutations E1-A226V/E2-L210Q were detected in the strains, which enhanced adaptability to Ae. albopictus and increased the transmission capacity. Novel mutation observed on E1 and E2 were totally consist to the patient-derived CHIKV in 2025 Reunion Island. ConclusionsIt was the first mosquito-derived CHIKV whole-genome during the 2025 Foshan outbreak, filling a critical gap between human case and entomological surveillance. Ae. albopictus was confirmed as the primary vector during the outbreak. The current outbreak CHIKV strain with particular amino-acid mutations had adapted to Ae. albopictus transmission. Compared to previous Chikungunya outbreaks over the past decade, the Foshan outbreak occurred earlier (early July), in a larger urban area (with a population of over 9.5 million), and with abundant breeding sites for the vector mosquito Ae. albopictus. However, the outbreak was quickly brought under control, with daily case numbers consistently decreasing, which is closely linked to the strong vector control measures implemented by the Chinese government in the early stages of the outbreak. Moreover, this event once again underscores the necessity of early monitoring of vector mosquitoes and the importance of implementing highly effective vector intervention measures as soon as possible after an outbreak occurs.

microbiology↗

bioRxiv2025

Construction of a novel 3D urinary bladder mucosa model and its application in toxicity assessment of arsenicals

The urinary bladder is a major target organ for environmental toxicants, including arsenic. The objects of this study were two-fold. First, we constructed a novel 3D urinary bladder mucosa model that incorporated an overlying epithelium and a supporting subepithelial layer, referred to as the 3D-UBMM. Primary human bladder urothelial and fibroblast cells were immortalized by introducing the human CDK4R24C and TERT genes. The subsequent construction of the 3D-UBMM involved incorporating the immortalized fibroblast cells into a collagen raft, while the immortalized urothelial cells were cultured at the air-liquid interface of the raft. This 3D-UBMM closely resembles the human urinary bladder epithelium in terms of morphology and marker protein expression, including uroplakin 1b, P63, and cytokeratin 5. Second, using the 3D-UBMM we investigated the cytotoxicity of sodium arsenite (iAsIII) and dimethylarsenic acid (DMAV). Exposure to iAsIII and DMAV resulted in increased urothelial cell necrosis and increased {gamma}-H2AX-positive cells along with a reduction of P63-positive cells, and each of these effects was induced in a dose-response manner. These findings affirm that this novel 3D-UBMM closely resembles the human urinary bladder epithelial layer, offering a practical in vitro model for the evaluation of the toxicity of arsenic and other bladder carcinogens and the role of cancer-related genes in bladder carcinogenicity. In addition, by identifying mechanisms of carcinogenesis this model will aid in hazard identification and risk assessment of potential bladder carcinogens.

pharmacology and toxicology↗

bioRxiv2025

Macrophages drive a fibrogenic gene program of periductal fibroblasts in pediatric primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is an autoimmune, cholestatic liver disease characterized by inflammation and fibrosis surrounding bile ducts. The cellular crosstalk driving periductal fibrosis remains poorly defined. This study applied a multi-omics approach integrating MERSCOPE spatial transcriptomics, bulk RNA-seq, and SomaScan proteomics to characterize fibrotic periductal regions and their cell-cell communications. Macrophages (MP) expressing moderate-to-high CD163 were found co-localized with cholangiocytes, T cells, and collagen-producing hepatic stellate cells (HSC). Cell niche analysis identified periductal regions with elevated fibrotic signals, in which cell-cell communication analysis revealed MP-HSC interactions involving 17 fibrotic driver genes in MP (e.g., IFNGR1, CSF1R, CD163) and six fibrotic effector genes in HSC (e.g., COL1A2, VCAN, MMP2). In validation analyses, bulk RNA-seq data showed higher driver and effector gene scores in PSC with established fibrosis compared to early-stage PSC and autoimmune hepatitis (AIH). Plasma proteins encoded by MP driver genes were elevated in autoimmune liver disease (AILD) and in patients with elevated ([≥]3.29 kPa) liver stiffness on MR elastography. These findings suggest that macrophages engage in localized crosstalk with HSC, activating fibrotic gene programs and contributing to periductal fibrosis in PSC, thereby identifying potential molecular targets for therapeutic intervention.

immunology↗

bioRxiv2025

Pathology-Specific Modulation of Corticostriatal Circuitry by Chronic Alcohol Consumption in Alzheimers Disease Mouse Models

Chronic alcohol use is a major modifiable risk factor for Alzheimers disease (AD), yet the mechanisms by which it modulates AD pathophysiology remain unclear. Here, we examined circuit-level and pathological changes in two distinct AD mouse models, humanized A{beta} knock-in (hAPP-KI) (A{beta}-driven) and PS19 (tau-driven), subjected to a chronic intermittent alcohol exposure paradigm. In hAPP-KI mice, alcohol increased A{beta} accumulation and excitatory transmission in the medial prefrontal cortex (mPFC) while reducing corticostriatal transmission and striatal cholinergic output. These alterations were accompanied by enhanced recruitment of microglia around A{beta} plaques. In contrast, alcohol-exposed PS19 mice displayed elevated mPFC-to-dorsomedial striatum (DMS) glutamatergic transmission and increased tau phosphorylation without significant changes in microglial activation or local mPFC excitatory drive. In wild-type mice, microglial depletion enhanced glutamatergic transmission onto cortical neurons, suggesting a homeostatic role for microglia in maintaining excitatory balance. Together, these findings reveal pathology-specific effects of alcohol on circuit dysfunction and propose microglia as an important modulator of alcohol-induced synaptic remodeling in the early stage of AD. HighlightsO_LIChronic alcohol exposure modulates glutamatergic transmission and neuroimmune responses in pathology-specific manners across A{beta}- and tau-driven Alzheimers disease mouse models. C_LIO_LIIn hAPP-KI mice, alcohol increases mPFC excitatory input, A{beta} plaque burden, and microglial activation, while impairing corticostriatal transmission and striatal cholinergic signaling. C_LIO_LIIn PS19 mice, alcohol enhances mPFC-to-striatum excitatory transmission and tau phosphorylation without altering local microglial activation or mPFC excitability. C_LIO_LIMicroglial depletion in wild-type mice recapitulates alcohol-induced glutamatergic changes in hAPP-KI mice, revealing a homeostatic role for microglia in regulating cortical excitatory balance. C_LI

neuroscience↗

bioRxiv2025

f-BGM enables fungi-specific genome mining in high accuracy and interpretability

Emerging artificial intelligence (AI)-based genome mining methods have revolutionized the paradigm of bacterial secondary metabolite (SM) discovery. Fortunately, recent data accumulation of fungal biosynthetic gene clusters (BGC) fairly offers opportunities for systematic development and evaluation of fungi-specific pipelines. In this work, we proposed a deep learning framework termed as f-BGM specifically for fungal genome mining. By designing a novel self-attention-based architecture to augment inter-domain associations in local genomic contexts, f-BGM exhibits superior performance over existing AI-based methods in both in-distribution and out-of-distribution benchmark tests for BGC detection. Further analyses demonstrate that f-BGM is of decent interpretability on deciphering single-domain and -protein importance, as well as inter-domain partnership. By establishing additional binary classification models, f-BGM also achieves high-quality identification of core enzymes within given BGCs. Finally, case studies of f-BGM-driven genome mining in marine fungi uncovers biosynthetic potential underestimated by the rule-based method antiSMASH, as supported by experimental and computational validation.

bioinformatics↗

bioRxiv2025

Interprotomer Communication and Functional Asymmetry in H/ACA snoRNPs

H/ACA small nucleolar ribonucleoproteins (H/ACA snoRNPs) facilitate essential cellular processes such as RNA modification, folding, and stability. Here, we present multiple cryo-EM structures of endogenous, catalytically active insect H/ACA snoRNPs containing two protomers assembled on a two-hairpin H/ACA snoRNA. By characterizing key protein-protein and protein-RNA interactions, we reveal the coordination of pseudouridylation activity across the two protomers which explains the predominance of two-hairpin structures in eukaryotic H/ACA snoRNAs. Moreover, we discovered that several mutations in H/ACA proteins associated with Dyskeratosis congenita directly impair pseudouridine formation suggesting how these mutations disrupt RNA modification and ribosome biogenesis in this disease. Additionally, we uncover coordinated structural changes between Nop10, Nhp2 and the N-terminal extensions of Cbf5 in the 3' protomer that resemble active and inactive conformations and may regulate H/ACA snoRNP activity. In summary, this study provides detailed insight into the structure and function of RNA modification-competent, asymmetric H/ACA snoRNPs, which play pivotal roles in cellular processes including ribosome biogenesis, rRNA folding, (m)RNA modification, and telomere maintenance. Significance statementH/ACA snoRNPs are critical for numerous RNA processes as they utilize different H/ACA snoRNAs to introduce pseudouridines in ribosomal and other non-coding RNAs as well as mRNAs. In addition, H/ACA snoRNPs stabilize and fold RNA thereby contributing to ribosome biogenesis and telomere maintenance. Mutations in H/ACA snoRNP subunits such as dyskerin (pseudouridine synthase), Nhp2, and Nop10 cause the genetic disorder Dyskeratosis congenita. Here, we present cryo-EM structures of active eukaryotic H/ACA snoRNPs, revealing an asymmetric, dimeric complex of two protomers. We identify the key inter-protomer contact hotspots and biochemically characterize mutations at these interfaces. Our findings emphasize the importance of inter-subunit interactions for snoRNP stability and activity, providing mechanistic insight into H/ACA snoRNP function and Dyskeratosis congenita pathogenesis.

biochemistry↗

bioRxiv2025

bstinence and Extinction Drive Opposing Changes in Striatal Activity and Dopamine Signaling During Alcohol Relapse

Relapse remains a major obstacle in the treatment of alcohol use disorder, often driven in part by enduring neuroadaptations. However, how different treatment strategies--such as abstinence versus extinction training--modulate the underlying neural circuits and synaptic mechanisms that shape relapse vulnerability remains poorly understood. In this study, we demonstrate that abstinence and extinction distinctly influence dorsomedial striatal (DMS) direct-pathway medium spiny neuron (dMSN) activity and dopamine signaling during cue-induced reinstatement of alcohol seeking. Using in vivo fiber photometry in D1-Cre rats expressing calcium or dopamine sensors, we found that abstinence enhanced dMSN calcium responses and dopamine release during reinstatement, whereas extinction normalized these neural signals and suppressed relapse-like behavior. Furthermore, bidirectional optogenetic modulation of medial prefrontal cortex (mPFC)-to-dMSN synapses revealed a causal role for corticostriatal plasticity in determining relapse propensity. Inducing long-term depression (LTD) in the abstinent state attenuated reinstatement, while inducing long-term potentiation (LTP) after extinction training reinstated alcohol seeking. Together, these findings identify distinct neural adaptations shaped by abstinence versus extinction and highlight corticostriatal plasticity as a potential target for relapse prevention. HighlightO_LIAbstinence enhances striatal dMSN activity and dopamine signaling during cued relapse. C_LIO_LIExtinction training normalizes dMSN dynamics and reduces dopamine release during cued relapse. C_LIO_LIOptogenetic mPFC-to-dMSN long-term depression after abstinence reduces relapse. C_LIO_LIOptogenetic mPFC-to-dMSN long-term potentiation after extinction invigorates relapse. C_LI

neuroscience↗