Biology subjects

Fu, Y.

Publications and source records attributed to Fu, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

CoV-UniBind: A Unified Antibody Binding Database for SARS-CoV-2

Since the emergence of SARS-CoV-2, numerous studies have investigated antibody interactions with viral variants in vitro, and several datasets have been curated to compile available protein structures and experimental measurements. However, existing data remain fragmented, limiting their utility for the development and validation of machine learning models for antibody-antigen interaction prediction. Here, we present CoV-UniBind, a unified database comprising over 75,000 entries of SARS-CoV-2 antibody-antigen sequence, binding, and structural data, integrated and standardised from three public sources and multiple peer-reviewed publications. To demonstrate its utility, we benchmarked multiple protein folding and inverse folding models across tasks relevant to antibody design and vaccine development. We expect CoV-UniBind to facilitate future computational efforts in antibody and vaccine development against SARS-CoV-2. Availability and implementationThe curated datasets, structures, model scores and antibody synonyms are free to download at https://huggingface.co/datasets/InstaDeepAI/cov-unibind. Folded structures are available upon request.

immunology↗

bioRxiv2025

Isoliensinine Ameliorates Pathological Cardiac Hypertrophy After Aerobic Exercise by Activating Cytochrome c Oxidase Subunit 6A2

Pathological cardiac hypertrophy is an abnormal remodeling process of the heart under chronic pressure overload, characterized by myocardial fibrosis, apoptosis, and progressive decline in cardiac function, ultimately leading to heart failure or death. Although aerobic exercise, particularly swimming, has been shown to alleviate pathological cardiac hypertrophy, its molecular mechanisms remain incompletely understood. In this study, metabolomic and transcriptomic analyses revealed the molecular mechanisms underlying swimming-induced improvement of pathological cardiac hypertrophy. Results showed that swimming training significantly altered the level of isoliensinine in animals. Further studies demonstrated that isoliensinine exerts cardioprotective effects by regulating the expression of Cytochrome C Oxidase Subunit 6A2 (COX6A2), establishing for the first time the critical role of the Isoliensinine-COX6A2 signaling axis in cardiac function regulation. To validate this axis, a pathological cardiac hypertrophy model was constructed in mice through transverse aortic constriction (TAC). Both swimming training and isoliensinine intervention significantly improved cardiac structure and function. In vitro experiments using isoproterenol (ISO)-induced hypertrophy in H9C2 cells further confirmed the essential role of this signaling axis in suppressing pathological hypertrophy and maintaining mitochondrial homeostasis. Our findings demonstrate that swimming mitigates pathological cardiac hypertrophy by enhancing COX6A2 expression by isoliensinine, thereby improving mitochondrial function. This study not only expands the understanding of exercise-mediated mechanisms in pathological cardiac remodeling but also highlights the cardioprotective potential of isoliensinine and COX6A2 as therapeutic targets for preventing and treating heart failure.

molecular biology↗

bioRxiv2025

Cerebellum metastasis model of HER2-positive breast cancer unveils key role of IL34-induced Arg1+ macrophages.

Brain metastases occur in up to 40% of Stage IV breast cancer patients. The cerebellum is a frequent location for metastases in HER2-positive breast cancer patients, but the mechanisms for this are unknown. Here, we developed a syngeneic, immunocompetent mouse model for breast cancer brain metastases by stereotactically injecting mouse HER2-overexpressing breast cancer organoids into the cerebellum. Growth of these cerebellar metastases was monitored by MRI and trastuzumab optical imaging using a near-infrared fluorophore conjugated to trastuzumab. Spatial transcriptomics identified interleukin-34 production by breast cancer cells inducing ARG1+ macrophages at the invading edge of the metastasis. Treatment with a blocking antibody to interleukin-34s receptor, CSF1R, produced tumor shrinkage. These findings have immediate translation potential as a CSF1R-blocking antibody is FDA-approved. Further, it demonstrates that cancer-associated inflammation bordering the brain metastasis promotes metastatic growth and offers a molecularly targeted strategy to treat inflammation in brain metastasis. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/660224v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9f1a50org.highwire.dtl.DTLVardef@178acc5org.highwire.dtl.DTLVardef@196d803org.highwire.dtl.DTLVardef@3fe631_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Rapid adaptive optics enabling near noninvasive high-resolution brain imaging in awake behaving mice

High-resolution imaging under physiological conditions is essential for studying biological mechanisms and disease processes. However, achieving this goal remains challenging due to optical aberrations and scattering from heterogeneous tissue structures, compounded by motion artifacts from awake animals. In this study, we developed a rapid and accurate adaptive optics system called multiplexing digital focus sensing and shaping (MD-FSS) for deep-tissue multiphoton microscopy. Under two-photon excitation, MD-FSS precisely measures the aberrated point spread function in approximately 0.1 s per measurement, effectively compensating for both aberrations and scattering to achieve subcellular resolution in deep tissue. Using MD-FSS integrated with two-photon microscopy, we achieved high-resolution brain imaging through thinned or optically cleared skull windows, two near noninvasive methods to access mouse brain, reaching depths up to 600 m below the pia in awake behaving mice. Our findings revealed significant differences in microglial functional states and microvascular circulation dynamics between awake and anesthetized conditions, highlighting the importance of studying brain function in awake mice through noninvasive methods. We captured functional imaging of fine neuronal structures at subcellular level in both somatosensory and visual cortices. Additionally, we demonstrated high-resolution imaging of microvascular structures and neurovascular coupling across multiple cortical regions and depths in the awake brain. Our work shows that MD-FSS robustly corrects tissue-induced aberrations and scattering through rapid PSF measurements, enabling near-noninvasive, high-resolution imaging in awake, behaving mice.

bioengineering↗

bioRxiv2025

Deconvolution of multiplexed peptidoform mass spectra enables high-resolution profiling of complex protein modification patterns

Combinatorial patterns of post-translational modifications (PTMs), like the histone code, play critical roles in regulating protein functionality. However, in bottom-up proteomics, isobaric modification peptidoforms (IMPs) frequently co-elute and co-fragment during liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), resulting in multiplexed mass spectra that cannot be properly analyzed by conventional protein identification and quantification methods. Existing solutions are either limited to highly narrow scenarios or unavailable for public use. Here, we introduce PTMdecoder, a robust and versatile software tool for discriminating and quantifying IMPs by deconvoluting their multiplexed MS/MS spectra and ion chromatograms without requiring a spectral library of individual peptidoforms. Tested on 34 samples of synthesized IMPs, PTMdecoder achieved an overall sensitivity of 95.7% for IMP identification and root mean square errors mostly <0.05 for quantification. In human histone samples, it detected and quantified 36.7-44.8% more IMPs than conventional methods, providing a higher-resolution view of histone modification patterns.

bioinformatics↗

bioRxiv2025

The decameric repeat (DR) of PSGL-1 functions as a basic antiviral unit in restricting HIV-1 infectivity

PSGL-1 (P-selectin glycoprotein ligand-1) is a dimeric, mucin-like surface glycoprotein that interacts with selectins on the endothelium, facilitating leukocyte tethering and rolling during transmigration. Previous studies have demonstrated that PSGL-1 acts as an HIV restriction factor, blocking HIV infectivity by hindering particle attachment to target cells. A large part of PSGL-1s extracellular region consists of a mucin-like domain, characterized by decameric repeats (DR), which comprise 14 to 16 DR tandems. Each DR is composed of 10 consensus amino acids (-A-T/M-E-A-Q-T-T-X-P/L-A/T-) and is notably rich in O-glycosylated threonines (30%) and prolines (10%). A proposed function of the DR is to elongate the protein backbone needed for selectin binding. However, the precise role of DR in PSGL-1s antiviral mechanisms has yet to be fully elucidated. In this study, we performed DR deletion mutagenesis and molecular modeling, systematically deleting from one DR to all DRs, and quantified their effects on PSGL-1s antiviral functions. Here, we demonstrate that DR is necessary for PSGL-1s antiviral activity. Deleting DR did not affect virion incorporation of PSGL-1, but diminished PSGL-1s ability to hinder virion attachment to target cells. We also discovered that individual single DR mutants retained 3.5 to 18% of the antiviral activity exhibited by full-length PSGL-1, and the basic antiviral activity of DR is cumulative; increasing the number of DRs correlates with heightened antiviral activity. Additionally, the intrinsic anti-HIV capability of DR was found to be transferrable; inserting the DR domain into the extracellular Ig-like domain of CD2 permitted the hybrid CD2-DR molecules to partially acquire the anti-HIV properties of PSGL-1. Further molecular modeling utilizing all-atom replica exchange molecular dynamics simulations highlighted a structure-function relationship between the anti-HIV potency of DR and the elongation of the DR backbone, as measured by DR backbone dihedral angles ({varphi}) and the radial distributions of peptide atom number density (rmax). These results collectively suggest that DR serves as an essential antiviral unit within the framework of PSGL-1s restriction mechanism against HIV.

immunology↗

bioRxiv2025

Breaking the Link: Neural Dissociation of Attention and Working Memory through Inhibitory Control

Attention and working memory (WM) encoding have traditionally been considered inseparable processes with shared neural mechanisms. Here, using an innovative experimental design and a multimodal approach, we provide the first direct neural evidence that attention and WM encoding are dissociable. Functional MRI identifies the supramarginal gyrus (SMG) as the key region enabling this dissociation, while dynamic causal modeling reveals the neural circuitry through which the SMG exerts inhibitory control over attentional representations, regulating their integration into WM. Furthermore, neuromodulation via transcranial direct current stimulation (tDCS) demonstrates that enhancing SMG activity strengthens this inhibitory control, providing causal evidence for the dissociation mechanism. A second tDCS experiment with varied stimuli confirms the generalizability of this mechanism and reinforces the robustness of our results. These findings challenge the long-standing view that attention and WM encoding form a continuous process, demonstrating instead that they constitute two dissociable neural processes of information selection.

neuroscience↗

bioRxiv2025

Single-Cell eQTL Mapping Reveals Cell Type-Specific Genetic Regulation in Lung Cancer

Genome-wide association studies (GWAS) have identified over 50 lung cancer risk loci; however, the precise cellular context of these genetic mechanisms remains unclear due to limitations in bulk tissue eQTL analyses. Here, we present the largest single-cell eQTL atlas of human lung tissue to date, profiling 222 donors using multiplexed scRNA-seq. We identified 16,785 eQTLs across 17 cell types, with over 90% of sc-eQTLs and 59% eGene being cell-type-specific, and fewer than 23% were detectable in paired bulk datasets. Integration with GWAS for non-small cell lung cancer highlighted epithelial and immune cells as key contributors to genetic susceptibility, identifying 28 candidate genes within known risk loci and 24 in novel regions. Notably, 47% of established NSCLC susceptibility loci exhibited cell-type-specific pleiotropic genetic regulation. This study provides a valuable resource of lung sc-eQTLs and illuminates how genetic variation modulates gene expression in a cell-type-specific fashion, contributing to lung cancer susceptibility.

genetics↗

bioRxiv2025

Disturbing immune homeostasis by neutrophil loss of Uba1 induces VEXAS-like autoinflammatory disease in mice

ObjectiveVEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an identified haemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells. We report Uba1 loss in various mouse hematopoietic cell types leads to diverse effects, with approximately 70% Uba1 depletion in neutrophils inducing non-lethal VEXAS-like symptoms. MethodsUsing nine different Cre/flox-mediated conditional-knockout (CKO) models, we interrogated the phenotypes caused by hematopoietic loss of Uba1. Neutrophil-specific depletion of Uba1 were validated and VEXAS-like phenotypes were examined. ResultsUba1 loss in HSCs induces extensive hematopoietic cell death while in B or T cells, or megakaryocytes induces corresponsive cell death but these mutants appear normal. Uba1 loss in monocytes and neutrophils failed to induce cell death and the mutants are viable. Among the models, only Uba1 loss in neutrophils manifests autoinflammatory symptoms including increased counts and percentage of neutrophils, increased proinflammatory cytokines, vacuoles in myeloid cells and dermatitis. Residual Uba1 is about 30% in the mutant neutrophils, which manifest disturbed cellular hemostasis. Genetic loss of Morrbid partially mitigated the VEXAS-like symptoms. ConclusionOur study reveals diverse effects of Uba1 loss in hematopoietic cells and establishes a VEXAS-like murine model, facilitating understanding and potential treatments for this syndrome prevalent in aged men. HIGHLIGHTSO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSVEXAS syndrome is a recently identified hematological and immunological disease prevalent in adult man but rarely in adult woman. Somatic mutations in the E1-enzyme encoding gene UBA1 in hematopoietic stem cells is the driver on the top of the genetic etiology of the disease. However, the major pathogenic cell type(s) for VEXAS syndrome has not been experimentally examined and mouse models recapitulating the disease are lacking. WHAT THIS STUDY ADDSO_LIUsing nine different conditional-knockout (CKO) murine models, we interrogated the pleiotropic phenotypes caused by loss of the ubiquitin activation enzyme Uba1 in different hematopoietic cell types; C_LIO_LIOur results demonstrated that among the nine tested CKO mutants, only neutrophil loss of Uba1 results in VEXAS-like autoinflammatory disease; C_LIO_LIThe VEXAS-like symptoms in the S100a8Cre-CKO mutant mice include: increased counts of white blood cells and neutrophils, increased percentage of neutrophils, increased serum level of proinflammatory cytokines (IL-1{beta}, IL-6 and TNF), observation of vacuoles, increased survival, and increased phagocytosis in mutant neutrophils; C_LIO_LIPharmacological treatments with IL-1 inflammatory pathway inhibitors Anakinra or Canakinumab or genetic loss of the myeloid pro-survival regulator Morrbid partially mitigated the VEXAS-like symptoms in the S100a8Cre-CKO mutants; C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe study reports a technical strategy of developing the murine models for VEXAS syndrome. In addition, the study dissects cellular and molecular mechanisms, especially the cell-type-dependent tolerance and pathogenicity of loss of function of Uba1, for the occurrence of the autoinflammation diseases in mice. The study provides translational implications in etiology and potential treatment choices for the newly-identified haemato-rheumatoid syndrome in clinical management.

immunology↗

bioRxiv2025

Self-contrastive learning enables interference-resilient and generalizable fluorescence microscopy signal detection without interference modeling

Every weak signal in fluorescence microscopy may contain critical biological information. However, the inter-ference resilience required to detect such signals has traditionally relied on task-specific interference modeling, which limits generalizability. Here, we present a self-contrastive learning-based signal detection solution that achieves interference resilience without the need for interference modeling, thereby offering high generalizability. The method, DEep PAttern Fitting (DEPAF), is a module that contrasts asynchronously generated data views from asymmetric model paths to extract signals from interference, while incorporating highly parallel signal recognition and localization in the process. Benchmarking shows that DEPAF substantially improves signal detection performance across diverse imaging modalities and dimensions, especially under challenging conditions such as low SNRs and ultra-high signal densities. It is also compatible with, and consistently enhances the performance of various imaging techniques, such as super-resolution imaging, spatial transcriptomic imaging, and two-photon calcium imaging. Notably, DEPAF relies only on image patches with signal patterns and one tunable hyperparameter to adapt to new tasks, making it accessible to users without domain-specific expertise and lowering the barrier to broader adoption. DEPAF is expected to advance the signal-centric fluorescence microscopy techniques and inspire further advancements, especially in the era of image-based multi-omics.

bioinformatics↗

bioRxiv2025

ALFIN-LIKE Proteins Orchestrate H3K4me3-H3K27me3 Crosstalk to Regulate Plant Embryogenesis

In multicellular organisms such as animals and plants, development requires the precise regulation of gene expression, mediated not only by transcription factors but also by chromatin-based mechanisms. Among these, histone modifications like H3K4me3 and H3K27me3 play opposing roles in gene activation and repression, respectively. In Arabidopsis thaliana, H3K27me3 is deposited by the Polycomb Repressive Complex 2 (PRC2), while Trithorax group (TrxG) proteins mediate H3K4me3 deposition. While the functions of these writer complexes have been extensively studied, far less is known about the histone mark readers that interpret these modifications during development. Here, we investigate the antagonistic interplay between H3K27me3 and H3K4me3 during Arabidopsis embryogenesis. We identify a developmentally specific interaction between the FIS-PRC2 complex and ALFIN-LIKE (AL) proteins--a family of plant-specific PHD domain proteins that read H3K4me3. Our findings reveal a dynamic competition between these two marks during early embryogenesis that helps shape the epigenomic landscape of the developing seed. Disruption of AL function leads to severe developmental defects and loss of cell identity in early embryos. Moreover, loss of ALs impairs H3K4me3 deposition, resulting in aberrant spreading of H3K27me3, misregulation of developmental genes, and defects that persist into adult plant traits. Together, our results show that proper embryonic development relies on a finely tuned antagonism between activating and repressive chromatin states--an interplay orchestrated not only by their writers but also by specific readers that translate these epigenetic cues into developmental outcomes.

plant biology↗

bioRxiv2025

Lymphatic Malformations with Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix Metalloproteinases

BACKGROUNDLymphatic malformations (LMs) are lesions due to inherited or somatic mutations that lead to a defective lymphatic vasculature. Activating KRAS mutations have been identified recently in LM patients with lymphedema, chylous ascites, or life-threatening chylothorax. In a LM mouse model, KRAS mutations are associated with a loss of lymphatic valves, which has been proposed to cause chylothorax via retrograde lymph flow into the pleural space. However, the mechanisms underlying the loss of lymphatic valves are unknown. METHODSTo investigate the mechanisms leading to valve loss, we combined the lymphatic-specific and tamoxifen-inducible Flt4CreERT2 with Kras-loxP-stop-loxP-G12D (Kras+/G12D) mice and Prox1GFP reporter mice to induce the restricted expression of KRAS-G12D and enable valve quantification in postnatal pups. Human dermal lymphatic endothelial cells (hdLECs) expressing KRAS-G12D were probed for changes in mRNA and protein expression with qRT-PCR, western blot, and gel zymography, and mechanistic studies were performed using 3D cell culture in collagen matrices. RESULTSOur data showed that lymphatic-specific expression of KRAS-G12D significantly attenuated valve development in the mesentery, diaphragm, and ear skin. qRT-PCR, western blot, and gel zymography using hdLECs expressing KRAS-G12D revealed the upregulation of the plasminogen activator (PA) pathway and matrix metalloproteinases (MMPs). The MMPs were sufficiently activated by plasmin, the product of the PA pathway, in hdLECs grown in a 3D collagen matrix, indicating a role for MMPs in the degradation of valve ECM core. Furthermore, a broad-spectrum MMP inhibitor given to Flt4CreERT2;Kras+/G12D mice rescued lymphatic valve development. CONCLUSIONSWe conclude that hyperactive KRAS signaling upregulates MMPs that become excessively activated by the upregulation of the PA pathway. MMPs then degrade the lymphatic valve ECM core preventing valve formation.

pathology↗

bioRxiv2025

Nanosecond pulsed electric field precisely manipulates cytoplasmic Ca2+ oscillations during oocyte activation

Oocyte activation deficiency (OAD) is a primary cause of fertilization failure following intracytoplasmic sperm injection (ICSI), a problem that can potentially be overcome through artificial oocyte activation (AOA). However, concerns persist regarding the safety and efficacy of AOA techniques in clinical practice. In this study, nanosecond pulsed electric field (nsPEF) is proposed as a safe and controllable method for oocyte activation in vitro by precisely manipulating Ca2+ signaling in the ooplasm. Mouse oocytes collected from oviducts were exposed to nsPEF stimulation at varying intensities to induce distinct Ca2+ signaling patterns. Subsequently, these oocytes underwent parthenogenetic activation and were cultured to assess developmental potential up to the blastocyst stage. The sperm-initiated physiological Ca2+ oscillations are successfully mimicked by one series of Ca2+ signals induced by nsPEF at low or medium intensities, and improve activation efficiency and developmental potential compared to calcium ionophore A23187. Low-intensity nsPEF pulses mediated repetitive extracellular Ca2+ influx in a non-invasive, electro-permeable manner. Medium-intensity nsPEF stimulation triggered periodic Ca2+ release from the endoplasmic reticulum (ER) via the PIP2-IP3-IP3R pathway, producing physiological-like Ca2+ oscillations. The non-invasive nsPEF method ensures safe oocyte activation by preserving cellular integrity and minimizing stress responses. The efficacy of nsPEF in precisely manipulating Ca2+ signaling patterns was further validated in human unfertilized oocytes. Our findings present a novel AOA approach with enhanced safety and efficacy, especially for patients experiencing repeated fertilization failures. It is anticipated that nsPEF is emerging as a promising technology for addressing male infertility issues, and may offer a potential alternative fertility treatment, bypassing sperm for initiation of oocyte activation.

developmental biology↗

bioRxiv2025

AlphaFold3 and RoseTTAFold All-Atom structures enable radiosensitizers discovery by targeting multiple DNA damage repair proteins

Radioresistance remains a primary obstacle in tumor radiotherapy, with no clinically approved radiosensitizers due to toxicity concerns. To identify effective and safe radiosensitizers, a natural products database containing 79,263 compounds are docked against a hybrid target library of four DNA damage response (DDR)-related proteins, comprising both experimental and artificial intelligence (AI)-predicted structures generated by AlphaFold3 and RoseTTAFold All-Atom models. Retrospectively, AI-modeled structures show comparable AUC and logAUC values to experimental structures. Prospectively, compounds screened by AI-modeled structures versus those by experimental structures exhibit limited overlap, e.g., 10% for ataxia telangiectasia mutated (ATM), 22.2% for ATM- and Rad3-related (ATR), 7.7% for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and 40% for Poly (ADP-ribose) polymerase 1 (PARP1). This highlights structural complementarity of AI-modeled structures when docking against small-scale compound libraries. Two compounds exhibiting lower binding free energy than the DNA-PKcs co-crystallized ligand were selected and validated as effective radiosensitizers in tumor cells. Proteomic analyses reveal shared DDR dysregulation but distinct repair pathway vulnerabilities behind both compounds, which activate TP53-associated apoptosis and senescence as cellular endpoints by modulating the synergistic interplay between DDR and spindle checkpoints. These findings highlight their potential as context-dependent radiosensitizers, providing novel candidates and strategies to overcome tumor radioresistance.

cancer biology↗

bioRxiv2025

DiNovo: high-coverage, high-confidence de novo peptide sequencing using mirror proteases and deep learning

Despite the recent advancements driven by deep learning, de novo peptide sequencing is still constrained by incomplete peptide fragmentation and insufficient protein digestion in current single protease-based proteomic experiments. Here, we present a software system, named DiNovo, for high-coverage and confidence de novo peptide sequencing by leveraging the complementarity of mirror proteases. DiNovo is empowered by several innovative algorithms, including a mirror-spectra recognition algorithm independent of pre-sequencing, two sequencing algorithms based on deep learning and graph theory, respectively, and target-decoy mapping, a method for sequencing result evaluation free of prior peptide identification. Compared with the trypsin protease used alone, DiNovo using two pairs of mirror proteases led to two to three times high-confidence amino acids sequenced. Compared with previous single-protease de novo sequencing algorithms, DiNovo achieved much higher sequence coverages. DiNovo also showed great potential as a powerful complement or alternative to database search for peptide identification with quality control.

bioinformatics↗

bioRxiv2025

Overexpression of alpha synuclein in Midbrain Dopamine Neurons Reduces Dopamine Release Without Cell Loss and Drives Mild Motor Deficits in Mice

It has proven challenging to faithfully recapitulate the key pathological, physiological, and behavioral features of Parkinsons Disease (PD) in animals. Here we used adeno-associated virus (AAV) vectors to achieve cell type-specific overexpression of wild-type human -synuclein (syn) and a fluorophore (mCherry) in midbrain dopamine neurons to model PD in mice. We found that AAVs drove selective expression of both syn and mCherry in midbrain dopamine neurons. In conjunction with approximately 2-fold overexpression of syn, we found several histopathological markers of PD-like pathology, including progressive accumulation of phosphorylated and aggregated syn, ubiquitin, and a reduction in the expression of tyrosine hydroxylase, without overt cell loss. In parallel, syn overexpression drove a profound loss of evoked dopamine release, without a substantive change in the intrinsic properties of dopamine neurons, nor in striatal dopamine content. Finally, syn overexpression led to mild locomotor deficits. Together, these findings suggest that moderate syn overexpression can mimic some aspects of premotor and early symptomatic phases of PD, including markers of Lewy Body-like pathology and functional loss of evoked dopamine release. This model may be useful for investigating cellular and circuit mechanisms related to PD pathogenesis and progression.

neuroscience↗

bioRxiv2025

Scale drop disease virus (SDDV) triggering ferroptosis both in vivo and in vitro facilitates virus infection via targeting transferrin receptor 1 (TfR1)

Scale drop disease virus (SDDV) is a distinct member in genus Megalocytivirus of family Iridoviridae, garnering increasing attention due to its significant threat to teleost. Ferroptosis is a new type of cell death discovered recently and involved in various viral infections. Knowledges on SDDV induced ferroptosis remains unclear. Here, we demonstrated that SDDV infection triggers ferroptosis, as evidenced by hallmark features such as iron overload, massive lipid peroxides accumulation, glutathione depletion and glutathione peroxidase 4 downregulation. SDDV-infected MFF-1 cells exhibited increased reactive oxygen species production and mitochondrial shrinkage. Treatment with Ferrostatin-1, a potent ferroptosis inhibitor, significantly attenuated SDDV replication in MFF-1 cells and could improve the survival of mandarin fish upon SDDV challenge. Treatment with an iron chelator mitigated ferroptosis and reduced the mortality of mandarin fish following SDDV infection, suggesting that SDDV-induced ferroptosis is iron-dependent. Finally, we demonstrated that SDDV infection could upregulate the expression of transferrin receptor protein 1 (TfR1), a critical iron transporter, to disrupt cellular iron homeostasis, induce ferroptosis, and then facilitate viral infection. Collectively, our findings provide compelling evidence that SDDV infection induces ferroptosis by targeting TfR1 to facilitate virus infection. Inhibiting ferroptosis represents a promising immunotherapeutic strategy for combating SDDV infection in aquaculture.

microbiology↗

bioRxiv2025

Le Petit Prince (LPP) Multi-talker: Naturalistic 7T fMRI and EEG Dataset

Prior neuroimaging datasets using naturalistic listening paradigms have predominantly focused on single-talker scenarios. While these studies have been invaluable for advancing our understanding of speech and language processing in the brain, they do not capture the complexities of real-world multi-talker environments. Here, we introduce the "Le Petit Prince (LPP) Multi-talker Dataset", a high-quality, naturalistic neuroimaging dataset featuring 40 minutes of electroencephalogram (EEG) and 7T functional magnetic resonance imaging (fMRI) recordings from 26 native Mandarin Chinese speakers as they listened to both single-talker and multi-talker speech streams. Validation analyses conducted on both EEG and fMRI data demonstrate the datasets high quality and robustness. Additionally, the dataset includes detailed transcriptions and prosodic and linguistic annotations of the speech stimuli, enabling fine-grained analyses of neural responses to specific linguistic and acoustic features. The LPP Multi-talker Dataset is well-suited for addressing a wide range of research questions in cognitive neuroscience, including selective attention, auditory stream segregation, and working memory processes in naturalistic listening contexts.

neuroscience↗