Biology subjects

Zhou, X.

Publications and source records attributed to Zhou, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

White-matter-microstructure-informed whole-brain models reveal localized excitation-inhibition imbalance in schizophrenia

Providing early diagnosis and personalized treatment for psychiatric disorders like schizophrenia remains challenging, due to important interpersonal differences and still elusive neuronal mechanisms. Whole-brain network models show promising results with clinical relevance for individualized treatment recommendations in neurological disorders. However, their applicability to psychiatry is still limited as models fail to account for inter-individual differences in the correlation structure of brain dynamics. What physiological mechanisms should models incorporate to better account for individual profiles of brain dynamics in schizophrenia patients and healthy controls? Our study compares various metrics of white matter structure and microstructure to inform connection weights between regions. To do so, we inferred regional parameters of whole-brain mean-field models with The Virtual Brain simulator to account for empirical functional connectivity from resting-state functional magnetic resonance imaging of schizophrenia patients and healthy controls. We found that using global fractional anisotropy or apparent diffusion coefficient of white matter fibers to inform the weights in neural mass models can drastically improve model performance. The data-model correlations of simulated and empirical data were significantly improved (from 0.2 to 0.7) over using the number or density of fibers as in many state-of-the-art methods. This approach allows us to uncover personalized maps of excitation-inhibition imbalance, hypothesized to underlie symptoms in schizophrenia. These maps prove meaningful in that they can predict diagnosis better than model-independent neuroimaging benchmarks. Our findings highlight the importance of white matter microstructure in whole-brain modeling. The novel white-matter-informed models reveal mechanisms that can cause altered brain dynamics in schizophrenia and could inform treatment in personalized psychiatry.

neuroscience↗

bioRxiv2026

Box H/ACA snoRNP regulates lipid storage through insulin signaling pathway in Drosophila melanogaster

Text abstractsLipid homeostasis is essential for organismal physiology, and its disruption contributes to metabolic disorders. Using an unbiased genetic modifier screen in Drosophila, we identified GAR1, a core component of the box H/ACA small nucleolar ribonucleoprotein complex, as a pivotal regulator of systemic lipid storage. We show that the H/ACA snoRNP complex is essential for maintaining lipid droplet morphology in adipose tissue and preventing ectopic fat accumulation. Moreover, null mutants of Gar1 or Dkc1 exhibit severe developmental defects, including reduced body size and larval lethality. RNA-seq analysis revealed that Gar1 dysfunction triggered widespread alternative splicing defects, specifically targeting key transcripts within the insulin signaling cascade, including chico, Pi3K92E, sgg, and Lip4. Furthermore, knockdown of Gar1 impaired insulin signaling, as evidenced by the reduced membrane localization of the tGPH fluorescence. Genetic epistasis further positions GAR1 upstream of the lin-28/foxo axis, as knocking down lin-28 or foxo fully rescues the lipometabolic defects in GAR1-deficient animals. These findings reveal a previously unrecognized link between the snoRNP machinery and metabolic process, establishing the box H/ACA complex as an important coordinator that integrates RNA processing with insulin-mediated nutrient sensing to ensure developmental and lipid homeostasis. Article summaryLipid metabolism is tightly controlled by multiple factors. To find new regulators, the authors performed a genetic screen and identified a small nucleolar protein GAR1 participate in fat storage and larval development. They demonstrated a critical role of box H/ACA snoRNP complex in modulating alternative splicing and balancing insulin cascade. Blocking two insulin-related genes reversed the lipid defects caused by Gar1 loss. These findings revealed the box H/ACA complex integrates RNA processing with insulin-mediated nutrient sensing to ensure developmental and lipid homeostasis, offering a perspective for understanding the metabolic regulation network.

genetics↗

bioRxiv2026

Bacterial endosymbionts enhance fungal virulence by disrupting the disease-suppressive rhizobiome

The mechanisms by which bacterial endosymbionts (bacteria living within fungal cells) enhance the fitness and virulence of fungal pathogens remain poorly understood. Here, we report that the tomato Fusarium wilt pathogen Fusarium oxysporum f. sp. lycopersici (FOL) hosts Achromobacter sp. endosymbionts that enhance fungal virulence. This virulence potentiation is partially dependent on interactions with the native rhizosphere microbiota. We show that bacterial endosymbiont-harboring FOL reshapes the rhizosphere bacterial community during pathogen infection and decreased the abundance of disease{square}suppressive bacteria, including Streptomyces sp. taxa. This inhibitory effect is mediated by bacterial endosymbiont{square}stimulated production of beauvericin (an antibacterial cyclic hexadepsipeptide) by FOL. Together, our findings reveal a tripartite interaction in which a fungal pathogen leverages its bacterial endosymbiont to weaken rhizosphere microbiome{square}based disease suppression by inhibiting plant-protective bacterial taxa. This work highlights how cross{square}kingdom symbioses can modulate pathogen ecology and virulence in soil environments.

microbiology↗

bioRxiv2026

Single-cell transcriptomic atlas of mouse oocyte development from growth to ovulation

Oocyte growth and maturation depend on tightly coordinated programs within oocytes and their surrounding granulosa cells, yet defining the transcriptional continuum of growing oocytes has been challenging due to their large size and the limitations of current droplet-based and spatial transcriptomic platforms. Here, we optimized a high-density array-based platform called Stereo-cell for high-throughput dual-modality profiling of large mouse oocytes, allowing for both the preservation of morphology and transcript capture. By integrating unsupervised transcriptomic clustering with cell morphological features, we delineated successive temporal windows from growing oocytes to metaphase II and uncovered stage-linked shifts from early programs toward later programs. We also profiled the ovarian somatic fraction, reconstructed granulosa-cell subtype relationships, and placed ovarian cell states in tissue context using single-cell-resolution spatial data.

developmental biology↗

bioRxiv2026

Benchmarking zero-shot single-cell foundation model embeddings for cellular dynamics reconstruction

Reconstructing cellular trajectories from time-resolved single-cell transcriptomics is fundamental to understanding processes from embryonic development to cancer progression. While single-cell foundation models (scFMs) promise universal biological representations through large-scale pretraining, their capacity to capture the non-linear dynamics governing cell-fate decisions remains uncharacterized. Here we systematically benchmark multiple scFMs across challenging biomedical scenarios involving branching lineages and continuous state transitions. By coupling zero-shot scFM embeddings with dynamic optimal transport, we evaluated their performance against a traditional highly variable gene (HVG) baseline in backtracking progenitor states, interpolating transition intermediates, and extrapolating future fates. We find that zero-shot scFM embeddings underperform the HVG baseline across diverse biological systems, particularly in recovering the distributional complexity of unobserved cells. Mechanistic analysis reveals that current scFM architectures tend to over-compress subtle temporal signals, causing an artificial "linearization" of branched biological structures that may obscure critical divergence points in disease progression. Our findings suggest that while scFMs provide unified cell-state views, the HVG baseline remains more robust for trajectory inference, identifying a fundamental "temporal-compression" bottleneck that must be addressed to develop next-generation, dynamics-aware foundation models.

bioinformatics↗

bioRxiv2026

Exploring the Influence of Chemical Exposures in Breast Cancer Disparities: High-Throughput Transcriptomic Analysis in Normal Breast Cells from Diverse Donors

Racial disparities in the incidence of, and mortality from, aggressive breast cancers are a pressing public health issue. Many factors have been investigated in these inequities; however, the role of toxicant exposures is not well characterized. We and others have identified substantial inequities in chemical biomarker concentrations by race. The goal of this study was to test the hypothesis that exposure to these chemicals is linked to biological changes relevant to aggressive breast cancers, such as dysregulation of the Hallmarks of Cancer. We used high throughput transcriptomic profiling of normal primary human breast epithelial cells from diverse donors (n=6) to test effects of 8 chemicals (cadmium, lead, arsenic, copper, PFNA, BPA, BPS, p,p-DDE) with documented exposure disparities by race/ethnicity across 3 concentrations (100nM, 1{micro}M, 10{micro}M). Across chemicals, we identified that pathways related to cell cycle regulation and protein secretion were commonly affected. Through bioinformatic estimation of cell type proportions, we found that metals like lead and cadmium induced cell-type shifts, consistent with the dysregulated cellular plasticity cancer hallmark. Lead and arsenic response genes were enriched for genes associated with poor breast cancer survival in the Cancer Genome Atlas. Integrating concentration-response modeling and chemical biomonitoring data, BPA, p,p-DDE, copper, and lead elicited expression changes at concentrations relevant to the US population. Finally, we identified substantial interindividual heterogeneity in response to organic compounds, but less so in metals. These findings highlight the value of high-throughput transcriptomics as a New Approach Methodology (NAM) in quantifying how common exposures may impact aggressive breast cancer associated biological processes.

pharmacology and toxicology↗

bioRxiv2026

Vagus Nerve Stimulation Ameliorates Epilepsy via a Gut Microbiota-Butyrate-Vagus Nerve-Brain Axis

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical-translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve-dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid-producing bacteria, including Akkermansia muciniphila, Prevotella, Alistipes, and Odoribacter. Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota-butyrate-vagal pathway essential for the therapeutic effects of VNS, highlighting the gut-brain axis as a target for epilepsy treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/707138v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@8243e6org.highwire.dtl.DTLVardef@37f0e6org.highwire.dtl.DTLVardef@a8b321org.highwire.dtl.DTLVardef@1887342_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIVagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. C_LIO_LIVNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila, in both humans and mice. C_LIO_LITransplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. C_LIO_LIAkkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway. C_LI

neuroscience↗

bioRxiv2026

Fluorescence Properties of Collagen Types I-V: A Comprehensive Study of Spectral and Lifetime Characteristics

SignificanceCollagen autofluorescence provides valuable intrinsic contrast for assessing tissue structure, composition, and pathology. However, a comprehensive understanding of the fluorescence properties across different collagen types remains limited. This knowledge gap may limit the development of advanced label-free fluorescence spectroscopy and imaging techniques for specific tissue characterization and diagnostic applications. AimThis study aims to comprehensively characterize the fluorescence intensity excitation-emission matrices (I-EEMs) and time-resolved excitation-emission matrices (TR-EEMs) of collagen standards from Types I, II, III, IV, and V obtained from various organ sources under both dry and hydrated conditions, to identify optimal excitation-emission parameters for each collagen type discrimination, and to establish a reference dataset that supports future research in label-free tissue characterization. ApproachWe employed a time-resolved fluorescence spectroscopy system equipped with an optical parametric oscillator laser (excitation: 200-2000 nm, pulse width: 30 ps) as an excitation source to generate I-EEMs and TR-EEMs of human and bovine collagen Types I-V. The fluorescence light was obtained by a multichannel plate photomultiplier tube through a monochromator (spectral range: 200-1000 nm). Measurements were conducted using collagen standards, under both dry and hydrated states. Additionally, photobleaching effects were assessed to ensure the reliability and reproducibility of fluorescence data. ResultsEach collagen type exhibited distinct I-EEM and TR-EEM signatures, with fluorescence lifetimes ranging from 2.5 ns (Type III, bovine skin) to 5.3 ns (Types II and V). Fibrillar collagens (Types I and V) displayed broader I-EEMs, whereas basement membrane collagen (Type IV) showed the narrowest spectral distribution. Organ-source-dependent variations were evident within the same collagen type. Type I collagen from human placenta exhibited an inverse lifetime-emission wavelength relationship compared to bovine sources. Hydration consistently red-shifted emission peaks into the 395-420 nm range and reduced fluorescence lifetimes across all collagen types (e.g., Type I bovine Achilles tendon: 3.2-5.0 ns dry vs. 3.0-4.5 ns hydrated). Despite excitation wavelength- and fluence-dependent photobleaching of fluorescence intensity, fluorescence lifetimes remained relatively stable, confirming the robustness of lifetime-based measurements. ConclusionsThis study establishes a comprehensive reference dataset for the fluorescence properties of collagen Types I-V and demonstrates the potential of combined I-EEMs and TR-EEMs analysis for tissue characterization. The results highlight species-, organ-, type-, and environment-specific optical fingerprints of similar collagens, which must be considered before implementing more in-depth studies on how the optical properties of collagen change in different medical applications.

bioengineering↗

bioRxiv2026

Experimental Time Points Guided Transcriptomic Velocity Inference

Time-series single-cell RNA sequencing enables longitudinal tracking of biological processes, yet cellular trajectory reconstruction informed by experimental time remains challenging. Existing trajectory inference methods either perform de novo reconstruction without leveraging experimental time points, or prioritize transitions between time points while paying less attention to intra-time-point dynamics. To reconcile experimental time points with local precision, we present CellDyc, a semi-supervised learning framework that leverages experimental time-point supervision to reconstruct transcriptomic velocities and recover an intrinsic gene-embedded time. CellDyc consistently outperforms existing approaches in reconstructing cellular trajectories across development, disease, and reprogramming contexts. Biologically, CellDyc provides novel insights, such as resolving temporal heterogeneity in erythroid maturation and quantitatively demonstrating that the immunosuppressive environment delays monocyte differentiation in glioblastoma. CellDyc integrates seamlessly with downstream tools like CellRank and remains robust even when only inferred temporal information is available. Collectively, CellDyc offers a rigorous, data-driven solution for deciphering time-resolved cellular dynamics.

bioinformatics↗

bioRxiv2026

Local Confinement within Plasma Membrane Nanodomains Drives Constitutive Activity of GPCRs

Many G protein coupled receptors (GPCRs) exhibit constitutive (basal) activity, where they can signal in the absence of ligand binding through spontaneous conformational transitions that facilitate G protein coupling and downstream signaling. This intrinsic baseline activity is critical for cellular homeostasis and can be modulated by the receptors conformational ensemble, membrane organization, and interactions with intracellular effectors. In this study, we use live-cell signaling assays, fluorescence cross-correlation spectroscopy (FCCS), and single-particle tracking (SPT) to investigate how membrane organization influences the basal activity of two class A GPCRs: the M1 muscarinic receptor (M1R) and the adenosine A2A receptor (A2AR). In live-cell signalling assays, M1R showed minimal agonist-independent Ca{superscript 2} responses, while A2AR exhibited significant basal cAMP production that was eliminated by an inverse agonist. FCCS showed that, without ligand, only a small portion of M1R co-diffuses with its cognate G11 protein, whereas a much larger fraction of A2AR co-diffuses with the GS protein. SPT revealed that A2AR, but not M1R, is enriched in slowly diffusing, confined states with spatial scales around 150-200 nm and sensitivity to cholesterol- and raft-modulating agents, consistent with localization in lipid-raft nanodomains. Dual-color tracking and diffusion mapping demonstrated that a significant portion of A2AR and GS share confinement domains under basal conditions, while M1R and G11 only show such co-confinement in the active state. These findings support a model where the co-confinement of GPCRs and G proteins within plasma membrane nanodomains--rather than stable pre-coupled RG complexes-- determines the level of constitutive GPCR activity.

biophysics↗

bioRxiv2026

TCR signal strength determines Treg instability and discrimination of self versus non-self antigens

Regulatory T cells (Tregs) expressing autoreactive T-cell receptors (TCRs) maintain immune self-tolerance, yet their fate upon antigen encounter remains unclear. Although selected in the thymus for high-affinity self-recognition, the cross-reactive nature of the TCR repertoire allows some Tregs to also recognize foreign antigens with high affinity. Here, we identify cross-reactive destabilization, a process in which high-affinity recognition of foreign antigens erodes Treg stability and redirects lineage fate. Using a thymic-derived Treg (tTreg) TCR capable of recognizing both self and foreign antigens distinct from the self-ligand that mediated its thymic selection, we show that stimulation with high-affinity non-self agonists induces Foxp3 loss and conversion into effector-like ex-Tregs, whereas self-antigen stimulation preserves lineage stability. Treg instability also increases with age and correlates with activation, suggesting that cumulative foreign-antigen exposure drives this process. These findings reveal a signal-strength-dependent model in which strong TCR engagement induces cross-reactive destabilization to balance immune responsiveness and self-tolerance. One Sentence SummaryForeign antigen-driven destabilization of Treg cells balances immunity and tolerance

immunology↗

bioRxiv2026

Mitochondrial Retrograde Signaling in Arabidopsis thaliana: heterogenous, spatial and polarised aspects

Organelle retrograde signaling studies have exclusively relied on bulk tissues, obscuring cell-type specificity, spatial organization, and heterogeneity within cell types. Here, we use single-nucleus and spatial RNA sequencing to define the cellular and spatial architecture of mitochondrial stress signaling in Arabidopsis thaliana. Inhibition of the mitochondrial electron transport chain by antimycin A and myxothiazol rapidly redistributed nuclei among transcriptional states within epidermal, leaf pavement, and mesophyll lineages, revealing that mitochondrial dysfunction reshapes cell identity trajectories rather than eliciting a uniform response. Stress-associated clusters were already present at low frequency in untreated samples, but the numbers of cells increased following stress treatments, indicating that stress increases the proportion of nuclei occupying pre-existing, primed transcriptional states. Gene-level analyses revealed distinct temporal dynamics and variable cell-state penetrance of the canonical mitochondrial stress markers and identified broadly responsive genes absent from earlier marker sets. Spatial transcriptomics resolved tissue-scale responses, spanning from pan-tissue induction to cell-type- and cluster-restricted activation, and uncovered pronounced adaxial-abaxial polarity in gene expression. Cell identity and spatial inferences were supported by extensive experimental validation using a custom 465-probe 10x Xenium panel and 52 promoter-GFP reporter lines. Together, these data provide a high-resolution framework for organelle-to-nucleus signaling and a resource of cell-type markers and spatial maps to dissect mitochondrial stress signaling and its integration with developmental and environmental pathways.

plant biology↗

bioRxiv2026

Exercise-conditioned tear fluid suppresses myopia progression

Myopia represents a major global public health challenge with rapidly rising prevalence. It is thus important to explore novel therapeutics for the treatment of myopia. Here we predicted tear fluid after (TA) but not before (TB) moderate-intensity aerobic exercise might protect against myopia using reverse transcriptomic analysis. To experimentally validate this hypothesis, TA or TB was administered by periocular injection in a guinea pig model of form-deprivation myopia. As a result, TA treatment significantly attenuated myopic refractive shifts and suppressed vitreous chamber depth and axial length elongation, whereas TB showed no protective effects. This study proposes a novel therapeutic avenue for myopia intervention and also suggests a previously unrecognized tear fluid-mediated mechanism linking exercise to myopia.

bioinformatics↗

bioRxiv2026

p300/CBP-Driven Acetylation Stabilizes PARP7 to Reinforce Negative Feedback on IFN-I Signaling

Immune suppression within the tumor microenvironment (TME) remains a major barrier to effective immunotherapy, yet the molecular mechanisms that constrain type I interferon (IFN-I) signaling in tumor cells are incompletely understood. PARP7 (also known as TIPARP), a mono-ADP-ribosyltransferase, has been reported to suppress IFN-I signaling by modifying TBK1. Here, we identify PARP7 as a previously unrecognized acetylation substrate of the histone acetyltransferases p300 and CBP. We show that p300/CBP-mediated acetylation of PARP7 at lysine 32 markedly enhances its stability, thereby reinforcing repression of the TBK1-IRF3-STAT1 axis and suppressing IFN-{beta}-induced expression of interferon-stimulated genes, including CXCL10. Beyond their established function as transcriptional co-activators that support tumor cell proliferation, our findings uncover a direct role for p300/CBP in shaping innate antitumor immunity. Pharmacological inhibition of p300/CBP catalytic activity by A-485 abolishes PARP7 acetylation, accelerates its proteasomal turnover, and restores IFN-I signaling. In immunocompetent tumor models, this is accompanied by enhanced CD8+ T-cell infiltration and effector function. Together, these findings define a p300/CBP-PARP7 regulatory axis, uncover a non-canonical role for p300/CBP in innate immune suppression, and nominate this pathway as a tractable target for restoring antitumor immunity.

cancer biology↗

bioRxiv2026

Exploring protein conformational ensembles using evolutionary conditional diffusion

Protein conformational ensembles encode the dynamic landscapes underlying biological function, regulation, and allostery. Accurately reconstructing such ensembles while balancing conformational distributions accuracy and physical plausibility remains a fundamental challenge in structural biology, particularly when dynamic data is scarce. Here, we propose DiffEnsemble, a diffusion-based framework designed for modeling protein conformational ensembles. DiffEnsemble learns latent dynamical representations from static protein structures in the Protein Data Bank, integrated with the structural profile derived from the AlphaFold Protein Structure Database as conditional guidance during the diffusion process. Benchmarking on 72 protein targets from the ATLAS molecular dynamics simulation dataset demonstrates that DiffEnsemble outperforms existing methods, including BioEmu and AlphaFLOW. Compared with AlphaFLOW, DiffEnsemble achieves improvements of 28.9% and 11.3% in Pearson correlation coefficients for ensemble pairwise root mean square deviation and root mean square fluctuation, respectively. Importantly, DiffEnsemble successfully captures the dominant motions for 42% of the targets. These results demonstrate that latent dynamical information embedded in static structural data can effectively support the modeling of protein conformational ensembles.

bioinformatics↗

bioRxiv2026

Ybx1 Deficiency Causes ROS-Driven IBD-Like Intestinal Inflammation and Postnatal Lethality

Y box-binding protein 1 (YB-1; Ybx1/ybx1) is essential for zebrafish development. Maternal ybx1-/- mutants exhibited embryonic lethality, whereas zygotic mutants (Zybx1-/-) showed high postnatal mortality between 10 and 20 dpf, although a small fraction survived to adulthood. Western blot and immunohistochemical analysis revealed strong, transient expression of Ybx1 in intestinal enterocytes from 3 to 5 days post-fertilization (dpf), followed by rapid ubiquitin-mediated degradation at 6 dpf, coinciding with defective intestinal development and compromised gut homeostasis. RNA-seq analysis identified elevated reactive oxygen species (ROS) and upregulation of matrix metalloproteinases mmp9 and mmp13a in Zybx1-/- larvae. Antioxidant treatment with ascorbic acid rescued postnatal lethality and alleviated intestinal defects, whereas prooxidant exposure exacerbated them. Pharmacological inhibition of Mmp9 or Mmp13a similarly prevented lethality, highlighting a ROS-MMP axis driving tissue damage. By 30 dpf, surviving mutants exhibited progressive intestinal impairment and severe pathology. These findings demonstrate that Ybx1 deficiency triggers ROS-dependent intestinal inflammation, MMP-mediated gut damage, and postnatal lethality, establishing Ybx1-deficient zebrafish as a robust model for studying inflammatory bowel disease (IBD)-like intestinal disorders.

developmental biology↗

bioRxiv2026

Is torpor a quiescent state? Periodic motility and transient brain activation during daily torpor in Djungarian hamsters

Torpor is a hypometabolic state employed by many mammalian and non-mammalian species to cope with harsh environments. When exposed to a short photoperiod, Djungarian hamsters (Phodopus sungorus) enter daily torpor with body temperatures dropping to as low as 15{degrees}C. Despite the widely-held notion that torpor is a form of deep sleep, torpid animals are not completely inactive but exhibit occasional movements reflected in an increase in EMG tone. Little is known about these EMG events during torpor and whether they have a functional role during the torpid state. We here analysed EEG, EMG, and brain temperature data from Djungarian hamsters, and used an automatic detection algorithm to identify periods of EMG activation during spontaneous daily torpor. The hamsters exhibited regular periods of motility that were invariably initiated during a decline in brain temperature and were followed by a brain temperature increase. The frequency of EMG events exhibited a negative correlation with brain temperature, such that lower brain temperature was associated with a higher frequency of EMG events. In addition, EMG events were associated with a pronounced increase in EEG power, especially between 9.5-15.5 Hz, which often started with an EEG pattern similar to an evoked potential preceding the increase in the EMG activity. On the contrary, micro-arousals during normothermic NREM sleep were associated with a decrease in EEG power, a decrease in brain temperature and were of shorter duration than torpor EMG events, indicating that the two phenomena may serve different purposes. We speculate that periodic motility associated with increased brain activity during torpor may play a role in thermoregulation, and help retain vigilance to potentially mitigate predation risk during this hypometabolic state.

neuroscience↗

bioRxiv2026

Radiosynthesis and Evaluation of Novel Cholesterol 24-Hydroxylase Positron Emission Tomography Tracers

Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a pivotal enzyme in brain cholesterol metabolism and has emerged as a therapeutic and imaging target in neurodegenerative disorders. Although [18F]Cholestify ([18F]CHL-2205) has shown promise as a positron emission tomography (PET) tracer for imaging of CYP46A1, the impact of cyclopropyl moiety conformation on binding and imaging performance remains unexplored. Here, we report the rational design and preliminary evaluation of novel CYP46A1 PET tracers, in which the left-side cyclopropyl group was modified into bridged, spirocyclic, and fused bicyclic architectures to probe steric and conformational effects. All compounds 9-11 exhibited high CYP46A1 affinity (IC50 = 0.19-0.28 nM). Radiosynthesis of [18F]9-11 was achieved via copper-mediated [18F]fluorination, providing practical non-decay-corrected radiochemical yields of 10-34% with excellent radiochemical purity (>98%). In vitro autoradiography in rat brain sections demonstrated specific and regionally selective binding, comparable to that observed for [18F]CHL-2205. These cyclopropyl-derived scaffolds establish a scaffold-driven strategy for PET tracer development, providing a robust framework for further structure-activity relationship studies and the rational optimization of CYP46A1 PET tracers.

pharmacology and toxicology↗