Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

Elucidating the potential carcinogenic molecular mechanisms of parabens in head and neck squamous cell carcinoma through network toxicology and molecular docking

ObjectiveThis study aims to systematically investigate the molecular mechanisms through which parabens may contribute to head and neck squamous cell carcinoma (HNSCC) carcinogenesis using integrated network toxicology and molecular docking. Materials and MethodsSix commonly used parabens (ethyl-, propyl-, methyl-, heptyl-, butyl-, and benzylparaben) were selected for toxicity prediction via ProTox 3.0 and ADMETlab2.0. Their potential targets were retrieved from Swiss Target Prediction, ChEMBL, and the Similarity Ensemble Approach (SEA). HNSCC-related targets were collected from GeneCards, OMIM, and CTD, while differentially expressed genes (DEGs) were identified using TCGA-HNSC data. Functional enrichment, protein-protein interaction (PPI) network construction, hub gene identification, molecular docking, and immune infiltration analyses were performed using DAVID, STRING, Cytoscape, CB-DOCK2, and TIMER2.0. ResultsWe identified 80 common targets through which parabens may exert toxic effects in HNSCC. Among these, 12 hub genes (CCNB1, CDK1, CCNA2, CDK2, CDK4, TYMS, AURKA, CCNA1, CHEK1, CCNB2, PLK1, CDC25A) were significantly overexpressed in HNSCC tissues and were primarily enriched in cell cycle regulation, p53 signaling, and viral carcinogenesis pathways. CCNA1 was further validated as an independent prognostic factor associated with poor survival. Molecular docking revealed strong binding affinities between parabens and hub proteins. Immune infiltration analysis indicated a negative correlation between CCNA1 expression and CD8+ T cell and B cell infiltration. ConclusionsParabens may promote HNSCC progression by disrupting cell cycle regulation and immune responses via direct interactions with key hub genes. These findings provide a novel mechanistic basis for the carcinogenic potential of parabens in HNSCC and underscore the need for further experimental and epidemiological validation.

pharmacology and toxicology↗

bioRxiv2025

Human SerRS/SIRT2 complex structure reveals cross regulation between translation and NAD+ metabolism

Life at the cellular level depends on effective coordination between diverse processes. Here we uncover a novel cross-regulation between metabolism and translation through a 3.2 [A] cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) bound to sirtuin-2 (SIRT2), an NAD+-dependent deacetylase. This interaction, naturally triggered by the NAD+ metabolite ADP-ribose (ADPR), resembles substrate binding and block SIRT2s active site. Interestingly, SerRS acetylation is not required for this interaction. SIRT2 binding sterically and allosterically impedes tRNA binding to SerRS, lowering charged tRNASer level and protein synthesis activity. Key interaction residues in both proteins emerged simultaneously in vertebrates, suggesting co-evolution for cross-regulation. Given ADPRs accumulation under stress, the ADPR-induced SerRS/SIRT2 interaction likely serves as a cell-protective response.

molecular biology↗

bioRxiv2025

Deciphering acquired resistance mechanisms to sustained auxin-inducible protein degradation in cells and mice

Targeted protein degradation is a favorable strategy for studying the immediate downstream effects of protein loss-of-function. An appealing platform among these technologies is the auxin-inducible degron (AID) system. Although this system has been applied extensively to cell and animal models, degradation resistance to long-term auxin treatment has not been studied. With the advent of the new AID2 system, cellular toxicity due to the high concentrations of auxin required in the original AID1 system is no longer a concern, making it possible to study protein degradation over extended periods. In this study, we derived multiple miniAID-tagged knock-in human cell lines and a Ctcf-miniAID knock-in mouse strain to investigate mechanisms of degradation resistance. We revealed four independent resistance mechanisms, including a nonsense mutation in the CTCF coding sequence that removed the miniAID peptide, a missense point mutation in the miniAID coding region that disrupted ubiquitin complex targeting, and silencing of the OsTIR1 adaptor protein. Resistance to auxin degradation was also acquired in mouse primary CtcfminiAID/miniAID knock-in B-ALL cells through missense mutations of the OsTIR1(F74G) protein in vivo and ex vivo. In summary, our innovative study expands our understanding of the AID system and cautions careful consideration of design for future applications in mammalian system.

cell biology↗

bioRxiv2025

Optimized Ex Vivo Differentiation of CD103⁺ Dendritic Cells and High-Efficiency Retroviral Transduction of Mouse Bone Marrow HSCs

CD103+ conventional dendritic cells (cDC1s) are key drivers of antitumor immunity, but their scarcity and resistance to genetic manipulation make them difficult to study. We optimized a two-stage ex vivo culture system using key cytokines and growth factors to efficiently generate CD103+ cDC1-like cells from mouse bone marrow progenitors. These cells closely mimicked their in-vivo counterparts, displaying CD103 expression, robust cytokine production, and functional responses to immune stimulation. Additionally, we established a high-efficiency retroviral transduction method using ecotropic pseudotyped virus and retronectin-coated plates, significantly improving gene delivery into mouse hematopoietic stem cells. This integrated platform provides a powerful approach for dissecting CD103+ cDC1 biology and advancing dendritic cell-based immunotherapy research.

immunology↗

bioRxiv2025

Chromosomal Restructuring and Subgenome Divergence Drive Post-Polyploid Adaptive Diversification in Sinocyclocheilus Cavefish

Allopolyploidy generates extensive genomic potential, yet its role in adaptive diversification remains poorly understood. We assembled phased chromosome-level genomes of cave and surface ecotypes of Sinocyclocheilus, a rapidly diversifying cavefish lineage, the most species-rich in the world. Our analyses show that all species derive from the ancestral allotetraploidisation event common to all cyprinids without subsequent polyploidisation. Instead, diversification has been driven by chromosomal rearrangements and the emergence of subgenome asymmetry. The dominant D subgenome maintains more genes, exhibits higher expression, and is enriched for adaptive functions, while the submissive S subgenome is inclined towards housekeeping roles. This asymmetry is further reinforced by the accumulation of transposable elements near genes exhibiting expression biased toward the S-subgenome. We also identify a derived epigenetic mechanism in the cave ecotype, i.e., differential methylation of these elements, absent in the surface ecotype. These findings show how structural, regulatory, and epigenetic processes have interacted following allopolyploidy to produce ecological and phenotypic diversity in Sinocyclocheilus. Our findings also offer quantitative evidence that cave adaptation is a complex process characterised by an evolutionary trade-off - the regression of energetically expensive traits combined with the remodeling of neural and developmental pathways driven by natural selection.

evolutionary biology↗

bioRxiv2025

Probing the genomic and proteomic basis of encystment in Oxytricha granulifera

Protozoan encystment is a crucial survival strategy for resisting environmental stresses, yet its molecular mechanisms remain poorly understood due to limited genomic resources and lack of integrated multi-omics analyses in model ciliates. In this study, we aimed to elucidate the molecular mechanisms underlying the encystment process in Oxytricha granulifera by sequencing and assembled its genome, and by conducting comprehensive transcriptome, proteome and morphology analyses to reveal gene expression and morphologic changes between vegetative and cyst stages. Morphological observation revealed ciliary dedifferentiation and cyst-wall formation during encystment, events respectively supported by the downregulation of microtubule dynamics related genes and the upregulation of vesicle transport related genes in cyst stage. Expanded gene families for carbohydrate metabolism, autophagy and cellular acidification align with the species mucocyst signature and their observed autophagic clearance, hinting at previously unrecognized mechanisms underlying cyst formation. Elevated expression of the ubiquitin-proteasome system and autophagy pathways facilitates protein turnover, and upregulation of antioxidant enzymes genes helps mitigate oxidative damage, while a rewired post-transcriptional regulation that increases spliceosome activity and alternative splicing frequency--each trend validated at the protein level. Concurrently, the methyltransferases responsible for DNA N6-adenine methylation (6mA), with homologous genes of AMT1 and AMT6/7 significantly downregulated. These results suggesting a multilayered regulation of ciliate encystment and the first integrated evidence that alternative splicing modulates dormancy. Our findings establish the first multi-omics framework for O. granulifera encystment, offering baseline data and tentative clues to the dormancy mechanism that will inform future inquiries into how single-celled eukaryotes endure adverse environments. IMPORTANCEOxytricha species are widely distributed in freshwater and terrestrial ecosystems, playing significant ecological roles in microbial communities. Their ability to undergo encystment provides a powerful model for studying cellular differentiation and stress adaptation in microbial eukaryotes. This study presents the first multi-omics analysis of encystment in Oxytricha granulifera, revealing microbial survival strategies through enhanced protein turnover, autophagy, alternative splicing, and DNA methylation reprogramming. These findings offer fundamental insights into dormancy mechanisms and environmental adaptation in protists, advancing our understanding of microbial resilience, evolutionary innovation, and ecological success in fluctuating environments.

genomics↗

bioRxiv2025

Olfactory Bulb Pinprick Induction of Cortical Spreading Depolarizations

Cortical spreading depolarization (CSD) is a wave of cellular depolarization followed by prolonged depression of neuronal activity and is associated with a broad array of neurological diseases, including migraine with aura, traumatic brain injury, and stroke. Traditional CSD induction methods for animal studies have included pinprick, concentrated potassium chloride (KCl) application, and electrical stimulation. These methods are invasive and can cause injury to the cortex. Recently, a non-invasive approach using optogenetics has become available, but requires the use of transgenic mice or transfection of an optogene, which limits its wide adoption. Here, we describe a novel approach using olfactory bulb needle insertion in rodents to induce CSD. We also included KCl-induced CSDs as a comparator in the same mice. Olfactory bulb pinprick resulted in CSDs on every attempt (n = 18/18) as confirmed with optical intrinsic signal imaging. Histological analysis revealed that needle disruption in the caudal olfactory bulb, which is continuous with the cerebral cortex, may account for the propagation of CSD from the olfactory bulb to the cortex. Olfactory bulb pinprick reliably induces CSD and is non-invasive with respect to cortex. The approach may prove to be useful in rodent studies where maintenance of cortical integrity is important.

neuroscience↗

bioRxiv2025

Differential Regulation of NHE3 Expression in Type 1 and Type 2 Diabetic Intestine: Impaired Endosomal Regulation of NHE3 Expression in Type 1 Diabetes

Chronic diarrhea is a frequent gastrointestinal complication in both type 1 (T1D) and type 2 diabetes (T2D), though the underlying mechanisms differ: T1D is linked to autonomic neuropathy and disrupted transporter regulation, while T2D is often linked to medications and intestinal inflammation. Using streptozotocin-induced mouse models of T1D and T2D, we observed increased luminal fluid in the small intestine of both. Given the role of Na+/H+ exchanger 3 (NHE3) in fluid absorption and its loss in most diarrheal diseases, we examined NHE3 expression across intestinal segments. In T1D, NHE3 protein was significantly reduced in the duodenum and jejunum without changes in mRNA, suggesting post-transcriptional regulation. In contrast, T2D mice exhibited reduced NHE3 protein and mRNA, restricted to the proximal colon. To investigate mechanisms underlying NHE3 loss in T1D, we evaluated endosomal scaffolding proteins involved in NHE3 trafficking. While our previous work showed that the Sorting Nexin-27 (SNX27)-retromer complex does not regulate NHE3 protein stability, we found that SNX17 was significantly decreased in the small intestine of T1D mice but unchanged in T2D. SNX17 knockdown in SK-CO15 cells reduced NHE3 activity and stability. A GST pull-down assay showed that SNX17 interacts with the C-terminus of NHE3. Mutation of the NHE3 distal NPxY motif disrupted this interaction, leading to reduced NHE3 expression and increased degradation. These findings reveal segment-specific and mechanistically distinct causes of diabetic diarrhea in T1D versus T2D, and identify SNX17 loss as a contributor to reduced NHE3 stability and activity in T1D, likely promoting diabetic diarrhea. New and NoteworthyThis study identifies distinct mechanisms of impaired sodium absorption contributing to diabetic diarrhea in type-1 and type-2 diabetes. We identify SNX17 as a novel regulator of NHE3 in the small intestine, showing that SNX17 loss in T1D contributes to post-translational NHE3 destabilization. In contrast, T2D-associated NHE3 downregulation is transcriptional and confined to the colon. These findings reveal disease- and region-specific regulatory pathways that drive impaired fluid absorption in diabetes, with direct implications for the development of targeted therapies. Graphical abstract Schematic overview of differential NHE3 regulation in diabetic diarrhea.In Type 1 Diabetes (T1D), reduced SNX17 expression in the small intestine causes increased degradation of NHE3 and impaired sodium absorption. In Type 2 Diabetes (T2D), SNX17 levels remain unchanged in the small intestine, but NHE3 expression is transcriptionally downregulated in the proximal colon. These distinct mechanisms contribute to segment-specific differential regulation of NHE3 in T1 and T2D diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/675364v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@eabf0aorg.highwire.dtl.DTLVardef@1a46891org.highwire.dtl.DTLVardef@cd2d5corg.highwire.dtl.DTLVardef@5d185b_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

DNA Data Storage Architecture via Ligation of Dynamic DNA Bytes

The explosive growth of digital data is overwhelming conventional storage media, creating an urgent need for more efficient solutions. DNA offers immense potential for digital data storage, yet most systems remain static and archival. Here, we present a modular DNA storage architecture based on dynamic DNA bytes (DynaBytes)-- pre-fabricated DNA segments that can be ligated into reconfigurable information units. Utilizing core, functional and control DynaBytes, we stored 210,776 bits (26,347 bytes) of digital information organized within a file-system, and demonstrated CRUD (Create-Read-Update-Delete)-like operations, hierarchical access and nanopore-based realtime retrieval. Robust data recovery was achieved under [~]100x error-prone sequencing using streamlined error correction and fuzzy decoding. By relying on in vitro ligation of standardized components, DynaBytes reduces cost, scales efficiently, and allows interactive, rewritable storage. These features advance DNA storage beyond passive archiving toward a reconfigurable framework, opening new possibilities for dynamic, practical and large-scale DNA-based data systems.

synthetic biology↗

bioRxiv2025

Bioactive 3D-bioprinted scaffolds with endothelial progenitor cells and Zn2+-enhanced SFMA/HisMA/nHAP for healing of infected bone defect

Infected bone defects remain one of the greatest challenges in orthopedics, as bacterial contamination and insufficient vascularization severely compromise regeneration. Here, we report the development of a multifunctional 3D-bioprinted scaffold composed of zinc ion (Zn{superscript 2}{square}) functionalized silk fibroin methacryloyl (SFMA), histidine methacryloyl (HisMA), and nano-hydroxyapatite (nHAP), further loaded with endothelial progenitor cells (EPCs) to promote simultaneous antibacterial, angiogenic, and osteogenic responses. The photocrosslinkable SFMA/HisMA bio-ink reinforced with nHAP provided mechanical stability, controlled swelling and degradation, while Zn{superscript 2}{square} coordination endowed strong antibacterial activity against E. coli and S. aureus. EPCs adhered and proliferated on the scaffolds, and in co-culture with bone marrow stromal cells (BMSCs) markedly enhanced osteogenic differentiation, as evidenced by increased expression of OCN, RUNX2, COL1, and OPN. Proteomic profiling further revealed that EPC-loaded scaffolds modulated osteoblast protein expression patterns consistent with both immunoregulation and active extracellular matrix reconstruction to promote tissue regeneration. In a murine femoral infected defect model, EPC-loaded scaffolds suppressed pro-inflammatory cytokines (IL-6, TNF-), stimulated angiogenesis, and supported robust new bone formation, leading to accelerated defect repair confirmed by {micro}CT and histological analyses. Together, these findings demonstrate that the EPC-loaded Zn{superscript 2}{square} functionalized SFMA/HisMA/nHAP scaffold integrates antibacterial defence with vascular and osteogenic stimulation, offering a promising translational strategy for the treatment of complex infected bone defects. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/676384v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1a75a57org.highwire.dtl.DTLVardef@1c32b6org.highwire.dtl.DTLVardef@1456159org.highwire.dtl.DTLVardef@1fa5321_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic illustration of materials synthesis and application. Silk fibroin was modified with glycidyl methacrylate (GMA) to obtain silk fibroin methacryloyl (SFMA), while histidine was functionalized with acryloyl chloride to generate histidine methacryloyl (HisMA). SFMA and HisMA were then combined and coordinated with Zn{superscript 2}{square} ions and incorporated with nHAP to form the full-component bioactive scaffold (SFMA/HisMA/nHAP/Zn{superscript 2}{square}). The resulting material can be 3D-printed and loaded with endothelial progenitor cells (EPCs) to yield a multifunctional scaffold with antibacterial activity, pro-osteogenic and pro-angiogenic properties, favorable physicochemical characteristics, and excellent biocompatibility, making it a promising candidate for the treatment of infected bone defects.

bioengineering↗

bioRxiv2025

Redefining Parkinson's Disease by Dysregulated Genetic Networks in Distinct Cell Types

Parkinsons disease (PD) is classically linked to dopaminergic neuron loss, but emerging evidence suggests broader cellular involvement. Here we show that PD risk variants converge on distinct molecular networks across specific brain cell types, enabling stratification of patients into six subgroups: dopaminergic, oligodendrocyte progenitor cells (O), excitatory (E), dopaminergic/excitatory, dopaminergic/oligodendrocyte and other. While all subgroups exhibit motor symptoms, the E-group individuals also display more severe non-motor symptoms, including dementia, hyposmia, and REM sleep behavior disorder. The O-group individuals exhibit reduced myelin integrity, as demonstrated by diffusion tensor imaging, implicating NRG6 (formerly C1orf56), a previously uncharacterized high-risk PD gene. We show that NRG6 encodes a conserved epidermal growth factor-like domain structurally and functionally analogous to neuregulin-1, which is critical for oligodendrocyte development and myelination. These findings redefine the cellular architecture of PD vulnerability and identify neuregulin-like signaling in oligodendrocytes as a potential contributor to non-motor symptoms.

neuroscience↗

bioRxiv2025

HERITABILITY AND QTL MAPPING OF AERIAL ROOTS AND OTHER YIELD COMPONENT TRAITS WITH IMPLICATIONS FOR N2 FIXATION IN ZEA MAYS

Zea mays L. spp. mays (hereafter maize) populations from an indigenous community of Mexico have been reported to perform well using traditional cultivation practices that exclude industrial fertilizers despite low soil nitrate levels. The local maize cultivar is characterized by extended maturity, tall stature, and presence of thick aerial roots that secrete an abundance of polysaccharide-rich root exudate, or mucilage, that is implicated in the recruitment of diazotrophic microbes to facilitate biological nitrogen fixation. Here we estimate the broad sense heritability of traits related to nitrogen fixation in a panel of Zea entries spanning pre-domestication, post-domestication and post-improvement, and identify QTL via F2:F3 families for traits including aerial root node counts and various other yield related traits (i.e. germination rate, time to reproductive maturity, total biomass and nitrogen content of shoot and grain). Across two separate field studies, aerial root node count (AR) demonstrates heritability of 64% and 73%, and genetic mapping reveals three distinct QTL distributed on chromosomes 1 and 9. Further, we report novel QTL for germination rate via stand counts after direct sowing (SC), Plant Total Nitrogen (PTN), Plant Dry Mass (PDM), and a joint QTL for Grain Total Nitrogen (GTN) and Grain Dry Mass (GDM). Finally, we identify overlap between QTL for multiple traits (including AR and SC) and regions of elevated introgression from wild Zea mays L. spp. mexicana (hereafter mexicana) into Totontepec maize, with a greater degree of overlap than expected under a uniform genomic distribution suggesting adaptive introgression from mexicana. Given its pronounced aerial root morphology, we propose that mexicana is the ancestral source for prominent aerial roots and corresponding abundant mucilage production in Totontepec maize and other maize traditional varieties. ARTICLE SUMMARYZea mays aerial roots (AR) and mucilage have been implicated in diazotrophic recruitment. This study estimates heritability and identifies QTL for AR and yield components via a diverse panel of Zea entries and F2:F3 mapping populations. Genetic mapping reveals three QTL for AR and several QTL for other yield traits, both novel and previously reported. This study also compares QTL and regions of elevated introgression from wild Zea mays L. spp. mexicana (hereafter mexicana) into a native cultivar. For AR QTL, enrichment for mexicana-derived haplotypes is greater than expected under a uniform genomic distribution, suggesting adaptive introgression from mexicana.

genetics↗

bioRxiv2025

A Mammalian Genomic Signature Shaped by Single Nucleotide Variants Controlling Transcriptome Integrity and Diversity

BackgroundMany functional features of mammalian genomic sequences remain poorly defined, especially how sequence motifs and genetic variants within non-coding regions (NCRs) regulate transcriptome integrity and diversity. We have shown that G-tracts unusually positioned between the polypyrimidine tract and 3' AG repress usage of the AG and are enriched at cryptic splice sites in cancer cells but their broader role across the extensive NCRs of mammalian genomes is unknown. ResultsHere, we identify a widely evolved genomic signature, G-tract-AG motifs consisting of guanine tracts closely upstream of AG dinucleotides, which is significantly associated with single-nucleotide variants (SNVs) identified in genome-wide association studies, particularly within NCRs. Approximately 9,000 such G-tracts within human genes are disrupted by variants of the cis-splicing quantitative trait loci in the Genotype-Tissue Expression project. Functionally, G-tracts repress splicing at the adjacent 3' AG, primarily by stalling the second transesterification step. Disruption of G-tracts by SNVs relieves this repression, enabling splicing and generating novel transcript isoforms. These G-tract-disrupting SNVs are in cis across the majority of protein-coding genes and are among thousands of rare variants causing genetic diseases. ConclusionsG-tract-AG signatures are widespread bipartite motifs with dual functions: G-tracts repress AG usage to safeguard transcriptome integrity, while SNV-induced disruption releases AGs for splicing to promote transcriptome diversity. Our findings provide mechanistic insights into the regulation of transcriptome integrity and diversity by a mammalian genomic signature, particularly for NCR SNVs associated with diverse traits and a new framework for their functional annotation.

genetics↗

bioRxiv2025

MiR-34a deficiency enhances nucleic acid sensing and type I IFN signaling in a mouse model of Alzheimer's disease

MiR-34a is implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. In order to investigate the role of miR-34a in Alzheimers disease (AD), we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble A{beta}42 to A{beta}40 and with increases in soluble and insoluble A{beta}40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified "cellular response to type I interferon" and "type I interferon signaling pathway" as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 microglia. These results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.

neuroscience↗

bioRxiv2025

Neural Subspaces Encode Sequential Working Memory, but Neural Sequences Do Not

The neural mechanisms of multiple-item working memory are not well understood. In the current study, we address two competing hypotheses about the neural basis of sequential working memory: neural subspaces versus neural sequences. Using broadband MEG data from human participants, we applied dimensionality reduction and multivariate decoding techniques to test whether sequential items are maintained during the retention period through the reactivation of individual items in sequence (neural sequences), or by organizing them into distinct low-dimensional subspaces (neural subspaces). Our results revealed behaviorally relevant, low-dimensional neural subspaces that organized memory representations during the retention period but not during stimulus encoding, supporting the neural subspaces hypothesis. In contrast, we found no evidence of sequential neural replay during the delay period, contrary to predictions from the neural sequences hypothesis. Together, our findings suggest that sequential working memory is maintained through structured geometric organization in low-dimensional representational space, rather than through the sequential reactivation of individual items.

neuroscience↗

bioRxiv2025

Hybrid In Vivo Breast Cancer Model Reveals Transcriptomic Insights into Cancer Progression with Age

Aging is a key risk factor for breast cancer, yet the independent role of the extracellular matrix (ECM) in tumor progression remains understudied. Recent studies have investigated healthy mammary tissue and aging to understand their relationship; however, the independent effects of the aged ECM remain understudied. Herein, we describe a hybrid in vivo model where MCF10A ductal carcinoma (DCIS.com) cells - with or without knockdown of select targets - were seeded onto decellularized ECM from aged murine mammary glands and implanted into the mammary fat pads of young Rag1-/- mice. Knockdown of selected targets, IL1B and LOX, reduced tumor growth on aged matrices in vivo and P4HA1 knockdown enhanced tumor growth. Additionally, analysis of LOX on aged ECM highlighted LOX as a driver of tumor progression where knockdown reduced transcriptomic programs related to invasion and cellular stress. To isolate the individual ECM influence on tumor growth, MCF10A cells were seeded atop young or aged matrices where it was found that tumors grown on the aged ECM after implantation exhibited significantly greater volume and a larger tumorigenic region when compared to those from the young ECM. Furthermore, single cell RNA-sequencing revealed transcriptional enrichment of inflammatory and invasive genes within the aged matrix. Together, these results identify LOX as a driver of tumor progression and potential therapeutic target, and demonstrate that the aged ECM alone can promote breast cancer progression

bioengineering↗

bioRxiv2025

The cow udder is a potential mixing vessel for influenza A viruses

The incursion of high pathogenicity avian influenza A virus (IAV) into US dairy cows is unprecedented in the era of molecular diagnosis and pathogen sequencing. This raises questions over the likelihood of further outbreaks and whether dairy cattle could be a "mixing vessel" for novel strains of IAV. Using a panel of BSL2-safe reassortant viruses representing clade 2.3.4.4b H5 epizootic lineages circulating since 2020, we found that a cow B3.13 isolate displayed enhanced replication in cow mammary gland cells, along with increased viral polymerase activity and stronger interferon antagonism in cow cells compared to an earlier EA-2020-C genotype virus. However, multiple avian and mammalian IAV strains, including other clade 2.3.4.4b high pathogenicity genotypes, were replication competent in bovine cells, particularly those of the mammary gland, suggesting that there is a diverse circulating IAV pool with the potential to infect cows. Moreover, we show that cow mammary cells co-express -2,3 and -2,6 - linked sialic acids, and are susceptible to co-infection with human and avian IAVs. We conclude that the US cow influenza outbreak does not simply reflect a unique adaptation of the B3.13 genotype virus; rather, the bovine udder represents a permissive niche for IAV and a plausible site for reassortment, underscoring its potential role in generating novel influenza viruses with pandemic risk.

microbiology↗

bioRxiv2025

Beyond the Anterior Temporal Lobe: Domain-Related Degeneration of Cortical Language Network Dynamics in Semantic Dementia

Semantic dementia (SD) is a neurodegenerative disorder marked by a progressive decline in semantic memory, mainly due to focal atrophy in the anterior temporal lobe (ATL). As the disease advances, atrophy spreads to the perisylvian regions, accompanied by non-semantic language impairments. Despite these clinical findings, the network mechanisms behind cross-domain linguistic deficits remain poorly understood. In this study, we used our recently developed meta-networking framework of cortical language network dynamics to systematically examine domain-specific network disruptions in SD. Using resting-state functional MRI (fMRI) and comprehensive neuropsychological tests across several language domains, we analyzed data from SD patients at two timepoints: baseline (n = 42) and a 2-year follow-up (n = 24). Our findings showed that the framework successfully identified domain-specific language network degeneration. Beyond the ATL, progressive atrophy disrupted the dynamic separation of language networks involved in semantic processing, phonological processing, and speech production. These disruptions were characterized by state-specific hypo- and hyper-connectivity patterns that related to distinct language impairments. At follow-up, atrophy extended to posterior temporal and prefrontal regions, worsening network function. Importantly, the patterns of language network disruption predicted individual language deficits, providing a mechanistic link between structural degeneration, functional network changes, and clinical symptoms.

neuroscience↗