SEARCH · Search bioRxiv

Results for “pharmacology and toxicology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

299 records · Page 8Linked to original sources

bioRxiv2026

Comparative Transcriptional Responses of Human Blood to Neutron and Photon Irradiation

Despite the well-known health risks of neutron exposures, key gaps remain in understanding neutron-induced molecular responses and identifying reliable biodosimetric markers that distinguish neutrons from photon exposure. We provide the first genome-wide analysis of the human blood transcriptional response to an accelerator-derived fission-like spectrum of neutrons versus photons, evaluating transcriptomic relative biological effectiveness (RBE) and radiation quality-discriminating gene signatures. Whole blood from healthy donors was irradiated ex vivo with X-rays (140 kV, 0-4 Gy, n = 3) or neutrons (0.1-8 MeV, 0-1 Gy, n = 2), incubated for 6 h or 24 h, and processed for RNA sequencing from peripheral blood mononuclear cells (PBMCs). Neutrons were markedly more potent than X-rays at inducing differentially expressed genes (DEGs) at equal doses, showing a peak response 6 h post-irradiation followed by a decline. In contrast, X-rays caused a continuous increase in DEGs up to 24 h (neutrons vs. X-rays at 1 Gy: 1,449 vs. 121 DEGs at 6 h; 996 vs. 621 DEGs at 24 h). A universal p53-centered 34-gene signature, including FDXR, EDA2R, GADD45A, and ZMAT3, showed highly monotonic dose responses (Spearman correlation coefficient {approx} 1) across donors, radiation qualities, and timepoints. Additionally, difference-in-differences analysis identified radiation quality-discriminating genes only at 6 h, with transcriptional convergence observed by 24 h, suggesting a very narrow time window for biodosimetric differentiation. We identified a neutron-specific gene signature driven by cGAS-STING-NF-{kappa}B signaling (RELB, NFKB1, C3, MALAT1) and suppression of B-cell and myeloid identity genes (IGHD, TCL1A, CLEC7A, TLR2), defining a biologically coherent neutron quality index with distinct immunomodulatory effects. For the first time, we assessed neutron RBEs at the gene, pathway, and global transcriptomic levels in a human blood model, reporting a global transcriptomic neutron RBE of 1.30 (95% CI: 1.14-1.49) at 6 h and 1.21 (95% CI: 1.14-1.28) at 24 h, providing a valuable basis for biodosimetry in mixed-field exposure scenarios. Our findings advance the mechanistic understanding of neutron radiation responses and support the development of biodosimetric approaches for mixed-field exposure scenarios.

biophysics↗

bioRxiv2026

Invasive mosquito species Aedes aegypti and Aedes albopictus are competent vectors for Barmah Forest Virus

Barmah Forest Virus (BFV), an arthropod-born virus transmitted by mosquitoes, is of significant public health concern in Australia and regions in the Pacific. Recent climate change and globalization raise the potential for BFV to extend its geographic distribution. Despite the rising importance of BFV, its vector dynamics remain poorly understood, particularly concerning the vector competence of different mosquito species. This study aims to investigate the vector competence of BFV across various mosquito species, beyond those endemic to the Australasian region, especially focusing on global relevant vector species. No transmission was observed for Culex quinquefasciatus and Cx. torrentium as well as Anopheles stephensi. In contrast, both investigated Aedes species, Ae. aegypti as well as Ae. albopictus, exhibited BFV-positive saliva across all four temperature profiles (18{degrees}C, 21{degrees}C, 24{degrees}C or 27{degrees}C) examined. These two invasive mosquito species must therefore be classified as potential vectors for BFV, indicating the potential risk of BFV transmission outside of Australia.

molecular biology↗

bioRxiv2026

Pumping stations negatively affect the distribution of critically endangered European eel (Anguilla anguilla); a landscape-scale study using environmental DNA metabarcoding

Context Pumping stations pose a threat to fish globally through land use change, habitat fragmentation and entrainment risk, with the catadromous and critically endangered European eel particularly impacted. Objectives/methods Establish, model, assess and understand the present-day distribution of European eel and resident fishes in 152 pumping station catchments in a once extensive wetland (The Fens) using eDNA metabarcoding (855 samples over two and half years), with specific focus on anthropogenic influences on hydrological connectivity and habitat quality. A removal survey design maximised confidence in negative results while minimising time and consumable costs. Results Eel occurrence upstream of pumping stations was low (occupancy = 28.3%) and positively associated with catchment area, fish species richness and natural hydrological connectivity (gravity drainage or flooding) and negatively associated with distance from the tidal limit. Fish species richness replaced catchment area and improved model performance, potentially acting as a biotic indicator of habitat quality and connectivity. Pumped catchments with manually operated upstream water transfers had reduced eel presence, potentially linked to the direction of water flow or the timing of operation. By contrast, fish species richness increased in these catchments during summer, suggesting displacement into unsuitable long-term habitats. Physical habitat maintenance had no detectable effect on eel occurrence or fish species richness. Conclusions This study provides the first landscape-scale assessment of European eel distribution and drivers of occurrence in pumped river catchments. The highly novel and comprehensive insights have implications for European eel conservation as well as infrastructure and catchment management, including compliance with legislation (EC Regulation No. 1100/2007).

ecology↗

bioRxiv2026

Learning and forecasting shared evolutionary pathways to multi-drug resistance across global pathogens

Infections with bacteria which have evolved multi-drug resistance (MDR) cause millions of deaths worldwide. Large-scale efforts are gathering genotypic and phenotypic data on MDR bacteria, but methods for learning the structure, diversity, and predictors of evolutionary pathways to MDR have yet to take full advantage of these data. Here, we use evolutionary accumulation modelling (EvAM), an emerging class of machine learning methods with roots in cancer progression, to infer these evolutionary pathways across ESKAPEE pathogens (seven bacterial species that dominate health burdens), using a database of over 635k genotyped phenotypic observations from around the world. We identify global patterns in MDR evolutionary pathways, remarkably shared across multiple ESKAPEE species. Species-specific deviations from these stereotypical pathways are connected with geographical and demographic covariates, facilitating predictions of future MDR evolution. We verify these predictions with several hundred new phenotypes from ESKAPEE samples spanning decades of clinical infections in sub-Saharan Africa, demonstrating the capacity to forecast future MDR evolution from these inferred shared pathways.

evolutionary biology↗

bioRxiv2026

Differential expression of NEAT1 in the corneal endothelium increases susceptibility to oxidative stress in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a disease of the corneal endothelium (CE) characterized by the loss of corneal endothelial cells (CECs) and guttae formation, ultimately resulting in corneal edema and vision loss. FECD primarily affects the central CE while sparing the peripheral CE, however the underlying mechanism contributing to the spatial differences remain unknown. Oxidative stress has been increasingly recognized as a key contributor to the pathogenesis of FECD, with CECs being particularly susceptible to damage from reactive oxygen species (ROS), high metabolic activity and ultraviolet induced DNA damage. The non-proliferative nature of CECs, along with the accumulation of oxidative damage can ultimately lead to CEC loss, a key feature of FECD. In this study, we induced oxidative stress with hydrogen peroxide (H2O2) on ex-vivo corneal specimens and observe increased cell death in the central region compared to the peripheral CE. To investigate these underlying differences, we performed bulk RNA sequencing (RNA-seq) on the central and peripheral regions of CE from FECD and normal cadaveric donors. Pathway analysis identified an enrichment of genes involved in collagen and extracellular matrix between the central and peripheral regions of CE in both normal and FECD, as well as between normal and FECD CE. Intriguingly, we identified the long non-coding RNA (lncRNA), NEAT1 as a top differentially expressed gene, with reduced expression in the central CE compared to the peripheral CE and lower expression in FECD compared with normal CE. Using corneal endothelial cell lines and ex-vivo specimens from FECD patients and normal cadavers, we found decreased NEAT1 expression levels in FECD and increased susceptibility to H2O2-induced oxidative stress. We observed that NEAT1 knockdown in normal and FECD cells exacerbated H2O2-mediated oxidative stress, and that NEAT1 overexpression protected FECD cells. We report in this study, a novel insight in the spatial differences in gene expression in the CE and identify reduced expression of NEAT1 in the central CE as a potential contributor to oxidative stress-related cell death in FECD. These findings provide novel insight into FECD pathogenesis and why FECD pathology preferentially affects the central CE. Antioxidants targeting NEAT1 signaling could be developed into novel therapeutics aimed at preventing FECD pathogenesis.

cell biology↗

bioRxiv2026

Automatic bioinformatic software named entity recognition from literature

Bioinformatics software and databases are essential components of modern life science research, yet their mentions in the scientific literature are often inconsistent and difficult to systematically identify at scale. The lack of a comprehensive and up-to-date catalog of bioinformatics resources hinders efforts toward automated biomedical knowledge extraction and streamlined data analysis. Here we present SNAIL, a hybrid named entity recognition framework designed to automatically identify bioinformatics software and database (SW/DB) names from biomedical texts. SNAIL integrates complementary lexical and semantic modeling strategies. The lexical component captures orthographic patterns and contextual cues characteristic of SW/DB names, while the semantic component leverages contextual embeddings generated by transformer-based language models such as SciBERT, combined with an explicit token-masking strategy to enhance entity-focused representations. A large training corpus was constructed automatically through a hybrid pipeline that integrates citation-hinted extraction with large language model-assisted distillation. Evaluation on two independent benchmark datasets and real-world research articles demonstrates that SNAIL substantially outperforms existing approaches, including domain-specific methods such as bioNerDS2 and general-purpose large language models such as ChatGPT, Gemini, Grok and Claude. Applying SNAIL to large-scale literature analysis further reveals distinct journal-level preferences across bioinformatics subfields. These results demonstrate that SNAIL provides an accurate and scalable solution for identifying bioinformatics resources in scientific texts and enables systematic meta-analysis of tool usage and research trends.

bioinformatics↗

bioRxiv2026

Gene duplication of SNAPC1 generates transcription factors for snRNAs and sex-specific piRNAs

Piwi-interacting RNAs (piRNAs) are small non-coding RNAs essential for transposon silencing and germline integrity across metazoans. In many species, piRNA expression is sexually dimorphic, yet the molecular mechanisms underlying this sex specificity remain poorly understood. In Caenorhabditis elegans, sexually dimorphic piRNA expression is regulated at the transcriptional level. We previously identified SNPC-1.3, a paralog of the small nuclear RNA (snRNA) activating protein complex (SNAPc/SNPC) subunit SNAPC1, as a male-specific piRNA transcription factor. However, the factors governing female piRNA expression remained elusive. Here, we identify SNPC-1.2, a second SNPC-1 paralog, as a female-specific piRNA transcription factor. SNPC-1.2 interacts with the core piRNA transcriptional machinery, binds female piRNA loci, is required for female piRNA expression, and promotes hermaphrodite fertility. In contrast, a third paralog, SNPC-1.1, retains the ancestral SNAPc function in snRNA transcription and is dispensable for piRNA biogenesis. Together, these findings reveal how gene duplication and functional specialization within the snpc-1 gene family generate specificity factors that direct the core SNAP complex to distinct genomic targets, providing a molecular mechanism for sexually dimorphic piRNA expression while maintaining canonical snRNA transcription.

molecular biology↗

bioRxiv2026

Highly plastic macrophage niches orchestrate acquired quiescence and reactivation in breast-cancer bone metastasis

Recurrence and metastasis remain major causes of cancer mortality, sustained by therapy-resistant micrometastatic cells. Bone is a frequent site of breast-cancer relapse, yet the cues that reawaken disseminated cells remain poorly defined. We identify a previously unrecognized, highly plastic CXCL16 macrophage population that integrates tumor-associated macrophage programs found in distant metastatic sites such as lung and brain with non-tumor disease-associated traits in bone marrow. These CXCL16 macrophages establish a transient niche that restrains disseminated cancer-cell proliferation. Single-cell transcriptomics delineate functional remodeling of myeloid niches within the bone metastatic microenvironment: a CXCL16 macrophage niche that transiently constrains metastatic growth, and G-CSF macrophage and neutrophil niches that reignite tumor outgrowth. In primary tumors, cancer-associated fibroblasts (CAFs) aberrantly secrete G-CSF in response to cancer-cell signals, expanding G-CSF-receptor-positive subset of cancer cells with high metastatic potential. In advanced human bone metastases, CXCL16 macrophages localize to CAF-rich stroma but are excluded from cancer-cell clusters, indicating immune evasion. Together, these findings uncover CAF-bone-marrow cross-talk as a therapeutic target linking stromal inflammation, immune remodeling, and metastatic progression.

cancer biology↗

bioRxiv2026

Redundant information across functionally coupled cortical networks supports rapid perceptual decisions in the ferret

Coordinated activity across cortical areas transforms sensory inputs into perceptual decisions, yet how task-relevant information is distributed across sites and linked to functional interactions and behavior remains unclear. Conventional functional connectivity measures reveal statistical dependencies between neural signals but cannot distinguish information encoded uniquely at individual sites, shared redundantly across sites, or available only from their joint activity. Here, we used Partial Information Decomposition (PID) to characterize stimulus information during fast and slow correct decisions. We analyzed local field potentials (LFPs) extracted from mesoscale electrocorticographic recordings from auditory, visual, and parietal cortices in ferrets performing a visual and audiovisual spatial-detection task. Time- and frequency-resolved analyses of local field potential power and phase showed that stimulus-side information was strongest in the theta and alpha bands and greater during fast than slow responses. PID applied to pairs of recording sites revealed that fast responses were associated with earlier and stronger unique information and a greater relative contribution of redundancy, whereas synergistic contributions were smaller. During fast responses, redundancy was selectively associated with stronger LFP power-envelope coupling. These findings indicate that faster perceptual decisions involve a frequency-specific reorganization of cortical information, characterized by early local encoding and enhanced redundant information across functionally interacting sites.

neuroscience↗

bioRxiv2026

A mouse-adapted Staphylococcus aureus strain enables lifelong neonatal colonization and elicits a Th17-dominated immune response

The opportunistic pathogen Staphylococcus aureus persistently colonizes the anterior nares of up to 20% of the human population, yet there were no persistent mouse colonization models to study host-pathogen interaction. Using the mouse-adapted S. aureus strain JSNZ (CC88-MSSA), we established a neonatal S. aureus colonization model in C57BL/6N mice. Natural neonatal colonization was achieved by vertical transmission in a JSNZ-positive breeding colony. Offspring were followed for up to 69 weeks and found persistently colonized in the nose and cecum with high bacterial loads. Adult mice were colonized by intranasal inoculation of JSNZ; controls received PBS. The colonization patterns and the S. aureus-specific T cell responses were then monitored over a period of 28 days and compared between age-matched mice colonized as neonates or adults. The neonatal group remained persistently colonized in nose and gut with high bacterial densities. In contrast, mice colonized as adults had lower and declining bacterial loads in the nose. Some eliminated S. aureus from the nares, while all remained colonized in the gut. Neonatally colonized mice exhibited reduced nasal chemokine levels, which may have favored the prolonged S. aureus persistence. Ex vivo re-stimulation of cervical lymph node cells with an S. aureus antigen cocktail revealed a Th17-dominated antigen-specific T cell response in both colonized groups. The lymph node cells secreted large amounts of IL-17, but Th1-, Th2-associated and regulatory cytokines were also detected. The cytokine patterns were similar in both colonized groups except for IL-5, which was more abundant upon neonatal colonization. In conclusion, vertical transmission of the mouse-adapted S. aureus strain JSNZ reliably establishes persistent high-density neonatal colonization, providing a physiologically relevant model for the study of S. aureus host interactions. Route and timing of colonization do not fundamentally affect the T cell response to S. aureus.

immunology↗

bioRxiv2026

Sport expertise and motor imagery abilities shape sensorimotor rhythm modulations during visualisation tasks: Implications for neurofeedback-based cognitive training in athletes

Kinaesthetic motor imagery (kMI) is widely used in sport to enhance motor performance by engaging cortical sensorimotor networks. Neurofeedback may further support kMI, but the optimal neural target to reinforce remains unclear. Maximal sensorimotor event-related desynchronisation (SMR-ERD) represents a relevant target as it may index sensorimotor cortex engagement, yet sport expertise has been associated with reduced SMR-ERD, potentially reflecting neural efficiency. The optimal neurofeedback target may therefore depend on sport expertise, movement expertise, and individual kMI ability. This study examined how these factors influence sensorimotor activity during kMI. We compared 17 basketball players (Experts) and 16 individuals without formal basketball training (Novices). kMI ability and frequency of use were assessed using questionnaires, while SMR-ERD was quantified using electroencephalography (EEG) during kMI. Participants imagined either a basketball-specific movement (Free throw), for which only Experts had extensive experience, or a generic movement (Box lifting), familiar to both groups. Experts reported greater kMI ability and more frequent kMI use than Novices. Only Experts exhibited significant and sustained SMR-ERD during kMI. Moreover, SMR-ERD was stronger in Experts than Novices specifically during Free throw kMI, corresponding to their movement of expertise. Nonetheless, within the Expert group, higher kMI ability was associated with reduced SMR-ERD. These findings suggest that sport expertise initially enhances voluntary recruitment of sensorimotor networks during kMI, whereas greater kMI ability may subsequently promote neural efficiency, resulting in reduced overall sensorimotor cortical activation. These results highlight the need to tailor kMI-based neurofeedback training to users' sport expertise and kMI ability levels.

neuroscience↗

bioRxiv2026

Glutaminase contributes to MYC-induced cell-autonomous autophagy and to RasV12-dependent non-autonomous autophagy in the Drosophila wing disc epithelium

MYC-driven metabolic reprogramming supports rapid cell growth but also creates metabolic demands that require adaptive mechanisms to maintain cellular homeostasis. Here, combining clonal analysis in Drosophila wing imaginal discs with studies in Schneider S2 cells, we identify glutamine metabolism as a component of Myc-induced autophagy. Myc increased the expression of genes involved in glutamine utilization, including glutaminase (GLS), and enhanced ammonia production, a metabolic by-product of glutaminolysis. Genetic depletion of GLS in clones suppressed the accumulation of Myc-induced Atg8a-positive structures and reduced autophagic flux, demonstrating that glutaminase contributes to the autophagic response elicited by Myc. Exogenous NHCl was sufficient to induce Atg8a-positive structures and partially restored their accumulation following GLS depletion, supporting ammonia as a downstream contributor to this response. Mechanistically, Myc-induced autophagy in clones required the core autophagy factor Atg5 but was not suppressed by depletion of Rheb or Atg1, consistent with an autophagic program that can operate independently of canonical TOR-Atg1 signaling. We further found that Myc activity is required for RasV12-driven epithelial overgrowth and that RasV12 cells induce a pronounced non-cell-autonomous accumulation of Atg8a-positive structures in wild-type cells surrounding RasV12 clones. Depletion of either Myc or GLS in RasV12 cells strongly reduced this neighboring autophagic response, linking Myc-dependent glutamine metabolism in transformed cells to autophagy in the surrounding tissue. Together, our findings identify GLS-dependent glutamine metabolism as a previously unrecognized component of Myc-induced autophagy and extend this relationship to Ras-transformed epithelia, where Myc and Gls contribute to non-cell-autonomous autophagic responses in neighboring cells.

cell biology↗

bioRxiv2026

Resource supply dynamics control stability and chaos in complex ecosystems

Ecological interactions are often mediated by feedbacks between organisms and their resource environments. Yet, how resource supply dynamics dictate collective dynamical phases of an ecosystem remains unclear. Here, we analyse a generalised consumer--resource model with non-reciprocal interactions to demonstrate that self-renewing versus externally-supplied resources yield fundamentally different dynamical phase diagrams. As interactions become increasingly non-reciprocal, ecosystems relying on self-renewing resources transition from stable dynamics to chaos and ultimately to infeasibility. By contrast, ecosystems with externally-supplied resources remain stable over a broader parameter range and transition to infeasibility without experiencing an intervening chaotic phase. Using the cavity method, we derive a unified stability condition applicable to a broad class of resource supply functions, explaining why externally-supplied resources can expand the stable region. We show that stability hinges crucially on the susceptibility of resources to perturbations, which depends strongly on their supply. Further, we show that external resource supply suppresses chaos in the unstable region by drastically reducing the susceptibility of resources closest to extinction. Our findings demonstrate that resource dynamics fundamentally reshape the accessible dynamical behaviours of an ecosystem, with implications for interpreting microbial community experiments.

ecology↗

bioRxiv2026

Stochastic Biophysics of Cellular Radiosensitivity: From Molecular Noise and Repair Kinetics to Evolutionary Demographics

Radiation-induced DNA double-strand breaks (DSBs) drive cellular mortality, mutagenesis, and severe evolutionary bottlenecks. While classical phenomenological models, such as the Linear-Quadratic (LQ) framework, reliably predict macroscopic population survival, they obscure the intrinsic single-cell stochasticity that governs critical rare events like tumor recurrence or the emergence of radioresistant persisters. To bridge this divide, we develop a mathematically exact stochastic differential equation (SDE) framework that models continuous DSB induction and repair as a Feller square-root process. By deriving exact closed-form expressions for the foci moments, we establish a highly efficient Maximum Likelihood Estimation (MLE) pipeline that circumvents computationally exhaustive Monte Carlo simulations, allowing the direct extraction of deterministic repair velocities and intrinsic molecular noise from empirical single-cell $\gamma$-H2AX data. Integrating this kinetic model with a cumulative damage hazard via the Feynman-Kac formalism, our framework seamlessly recovers the classic macroscopic LQ survival topology from microscopic first principles. Furthermore, systematic sensitivity analysis uncovers a fundamental evolutionary duality: while initial physical damage operates additively, ultimate cellular fate is driven by a nonlinear survival response governed by the trade-off between the damage hazard rate and intrinsic molecular noise strength. Crucially, we demonstrate that this molecular noise inherently enhances population survival. Governed by Jensen's inequality, stochastic variance acts as a non-genetic bet-hedging mechanism that buffers the population by favoring cells with transiently low damage loads. Ultimately, this exact stochastic framework bridges microscopic biophysics and macroscopic demographics, offering deep mechanistic insights into the evolutionary roots of radioresistance.

biophysics↗

bioRxiv2026

Interactive downstream proteomics analysis with MiraProt using Mueller cell proteomes from equine recurrent uveitis

Mass spectrometry-based proteomics requires downstream analysis of processed protein abundance data, including data inspection, filtering, statistical testing, functional enrichment, protein set comparison, network analysis, and visualization. MiraProt was developed as a modular, metadata-aware R Shiny platform that integrates these steps in a single interactive workflow for processed protein-level proteomics data. Its metadata-aware design enables identifiers, sample information, experimental conditions, transformations, and derived data columns to be defined during data preparation and reused consistently across downstream analyses. To demonstrate its use, we reanalyzed a previously published label-free proteomic dataset of primary retinal Mueller cells from healthy horses and horses with equine recurrent uveitis (ERU). ERU is a naturally occurring autoimmune eye disease of horses characterized by recurrent intraocular inflammation triggered by autoreactive T-cells. Mueller cells are specialized retinal macroglia with various functions such as maintaining retinal ion homeostasis and supporting retinal neuron metabolism. Of 193 proteins with an adjusted p-value [≤] 0.05, 187 also showed at least a twofold abundance difference between ERU-derived and control Mueller cells. Functional enrichment highlighted nuclear RNA processing, chromatin-associated structures, DNA and RNA binding, interferon responses, and cell-cycle-associated programs. Gene set enrichment analysis identified positive enrichment of Interferon Alpha Response, Interferon Gamma Response, and MYC-, E2F-, and G2M-associated gene sets. Network analysis of shared proteins further linked this signature to DNA replication, mitotic checkpoint control, and RNA processing. ERU-derived Mueller cells also showed increased abundance of MHC class II-associated proteins. Together, these findings identified an interferon-responsive, cell-cycle-associated, and MHC class II-associated Mueller cell protein signature in ERU and generated experimentally testable hypotheses for further mechanistic studies. MiraProt provides an accessible, metadata-aware framework for reproducible downstream exploration of processed proteomic datasets and prioritization of candidate proteins and pathways for experimental follow-up.

bioinformatics↗

bioRxiv2026

The function of human PIF1 in G quadruplex formation and replication stress response at ALT telomeres

Cancers maintain their telomeres through two telomere maintenance mechanisms: 85-90% of cancers rely on telomerase (TEL+), while 10-15% of cancers adopt the Alternative Lengthening of Telomeres (ALT) pathway. The Break-Induced Replication (BIR) pathway plays a critical role in maintaining telomere length in the ALT+ cells. In both yeast and human, PIF1, a 5' to 3' helicase, is required for the robust activity of BIR. However, the extent of human PIF1 (hPIF1) involvement in the ALT pathway remains unknown. Here we showed that hPIF1 can be recruited to damaged telomeres in ALT+ cells. In addition, we demonstrated that inhibition of hPIF1 induced DNA damage and G quadruplex (G4) accumulation at ALT telomeres, leading to a moderate reduction of the mean telomere length. Most interestingly, we demonstrated that inhibition of hPIF1 also attenuates checkpoint activation, BLM recruitment, single-stranded DNA (ssDNA) formation, DNA damage, and G4s at telomeres in the FANCM deficient ALT+ cells. Finally, we showed that inactivation of hPIF1 affects the viability of both ALT+ and TEL+ cancers, suggesting that hPIF1 is a potential drug target for cancer therapy.

molecular biology↗

bioRxiv2026

Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology

Alzheimer's disease (AD) pathology involves amyloid deposition, reactive gliosis, and localized tissue alterations that coexist within the same brain regions, creating heterogeneous microstructural environments within individual imaging voxels. Conventional diffusion MRI averages these environments into aggregate measures, potentially obscuring their distinct contributions. Frequency-dependent multidimensional MRI ({omega}MD-MRI) resolves distributions of water components with different diffusion length scales, anisotropies, and relaxation properties, providing sensitivity to microstructural restriction, heterogeneity, and shape-size correlations within a voxel. Whether these measurements reveal microstructural complexity associated with AD pathology remains unclear. Here, we performed {omega}MD-MRI on ex vivo brain specimens from approximately 8-month-old 5xFAD and wild-type mice and interpreted the imaging findings alongside complementary histology. {omega}MD-MRI revealed widespread but spatially nonuniform differences between 5xFAD and wild-type brains. Measurements sensitive to microstructural restriction, heterogeneity, and shape-size correlations consistently indicated greater microstructural heterogeneity in 5xFAD brains, with the most prominent differences in the hippocampal formation and major cerebral white matter tracts. Complementary qualitative histology demonstrated extensive amyloid deposition and glial activation in affected regions, while overall cytoarchitecture and myelin organization remained largely preserved. Thus, the {omega}MD-MRI abnormalities occurred in tissue characterized by multiple coexisting pathological and relatively preserved microstructural environments rather than widespread structural degeneration. These findings demonstrate that {omega}MD-MRI can reveal the spatial and microstructural heterogeneity associated with amyloid pathology and provide a more comprehensive characterization of AD-related tissue alterations.

neuroscience↗

bioRxiv2026

Injury size regulates glucose allocation locally and systemically during vertebrate tissue regeneration

Tissue regeneration requires careful allocation of metabolic resources, yet how organisms adjust this allocation in response to varying amounts of tissue loss remains poorly understood. Here, we show that the regenerative metabolic response is not fixed: the size of an injury regulates how glucose is allocated at both local and organism-wide levels. We first demonstrate that tail regeneration requires glucose metabolism in the axolotl (Ambystoma mexicanum), a salamander capable of regenerating centimetre-scale tissues. We then mapped glucose uptake in axolotls regenerating from small or large tail injuries using positron emission tomography/magnetic resonance imaging (PET/MRI) and the radiolabelled glucose analogue [18F]FDG. Glucose uptake was elevated in regenerating tails compared to uninjured tails. During early regeneration, larger injuries induced higher glucose uptake than smaller injuries, correlating with faster regenerative outgrowth. Larger injuries also increased glucose uptake in distant organs, indicating a systemic metabolic response. Together, our findings suggest that metabolic responses tuned to injury size underlie faithful tissue regeneration and establish PET/MRI as a powerful approach for studying whole-body metabolic dynamics in large regenerating vertebrates.

developmental biology↗