Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 253 records · Page 14Linked to original sources

bioRxiv2025

From features to slice: parameter-cloud modeling of spatial transcriptomics for simulation and 3D interpolatory augmentation

Computational simulation and data augmentation of spatial transcriptomics (ST) are essential for quantitative benchmarking, reproducibility, and methodological innovation. Yet current models often lack flexibility in controlling spatial and transcriptional heterogeneity, fail to capture higher-order gene dependencies, and rarely extend to three-dimensional or alignment-aware contexts. Here we present FEAST, a computational infrastructure that models ST data within a parameter cloud - a latent manifold encoding gene-level mean, variance, and sparsity. By sampling and perturbing this manifold, FEAST generates high-fidelity synthetic slices with tunable spatial and transcriptional variation, enabling systematic evaluation of clustering, deconvolution, and spatial alignment algorithms. Beyond two dimensions, FEAST performs 3D parameter-cloud interpolation guided by optimal transport and benchmark alignment, reconstructing continuous tissue architectures while preserving molecular coherence. Together, these capabilities establish FEAST as a foundational platform for standardized benchmarking, data augmentation, and 3D reconstruction in spatial transcriptomics. The source code and tutorials for FEAST are publicly available at https://github.com/maiziezhoulab/FEAST, and can be installed via Pypi at https://pypi.org/project/FEAST-py/.

bioinformatics↗

bioRxiv2025

Identification of Patient Trajectories in Timeseries Clinical Transcriptomics Data

In clinical trials, it is common for only a subset of patients to respond to a given therapy. Such variability may arise from genetic differences, environmental influences, or the presence of distinct disease endotypes. Longitudinal transcriptomic profiles collected in phase 2a/2b studies provide a unique opportunity not only to investigate drug-induced biological mechanisms in humans, but also to understand why certain individuals fail to respond and to uncover previously unrecognized disease endotypes--ultimately informing the development of targeted therapeutics. However, analyzing these datasets is challenged by substantial patient heterogeneity, variability in disease severity at each visit, and the coarse temporal resolution due to sparse sampling. To address these limitations, we introduce a classification-guided autoencoder framework that jointly optimizes gene-expression reconstruction and classification objective to learn disease-relevant sample embeddings. Sample embeddings from all patients are leveraged to establish a continuous representation of disease dynamics, which can be clustered to delineate discrete disease states. We then construct a patient-sample graph in the learned latent space and apply a multi-commodity-flow based algorithm to infer patient trajectories through these states, enabling the identification of different patient trajectories. We evaluated our approach on three interventional datasets--ulcerative colitis, psoriasis, and atopic dermatitis, each containing both responders and non-responders. The method recapitulates known pathway perturbations associated with anti-IL17 and anti-IL6 therapies, identifies intermediate states reflecting disease/treatment progression, and reveals biologically meaningful patient trajectories within the patient population. Code and data are available in a public GitHub repository - https://github.com/Sanofi-Public/EndotypeDetection-Timeseries

bioinformatics↗

bioRxiv2025

Network-based analysis reveals microRNA regulation of oncogenic pathways in SOX10-depleted uveal melanoma

SOX10 is essential for melanocyte development and maintenance and plays a critical role in uveal melanoma (UM) initiation and progression. While SOX10s transcriptional regulation of protein-coding genes is well characterized, its role on microRNA (miRNA) regulatory landscape in UM remains unexplored. Here, we employed network-based modeling to systematically characterize miRNA regulatory functions following SOX10 depletion in UM. First, we profiled mRNA and miRNA expression levels in SOX10 wild-type and knockdown UM cells. Then, we integrated the transcriptomic data, a UM network, and a Bayesian model to quantify miRNAs regulatory activities and identify key miRNAs. Subsequently, we employed pathway enrichment analysis combined with literature mining to elucidate the functional roles of identified miRNAs through their target genes and associated signaling pathways in UM. We identified 17 miRNAs that show significant changes in regulatory activities following SOX10 knockdown in UM cells. These miRNAs regulate the expression of genes involved in cancer hallmark pathways, including cell cycle progression, mTORC1 signaling, and fatty acid metabolism. Notably, miR-34a, miR-25, miR-186, and miR-211 have tumor-suppressive potential by targeting genes involved in UM progression and metastasis. Our results suggested that SOX10 depletion in UM can activate tumor-suppressive mechanisms through regulating miRNAs.

cancer biology↗

bioRxiv2025

Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart

BACKGROUNDDisruption of mitochondrial homeostasis drives cardiomyopathy and heart failure, yet upstream regulatory mechanisms remain poorly defined. Neddylation, a reversible post-translational conjugation of the ubiquitin-like protein NEDD8 by E1/E2/E3 enzymes, is essential for cardiac morphogenesis, but its role in the adult heart is unknown. METHODSWe assessed the relevance of neddylation to human cardiac disease by gene set enrichment analysis of ischemic (ICM) and non-ischemic cardiomyopathy (NICM) datasets and by immunoblotting and qPCR of ventricular tissue from patients with ICM or dilated cardiomyopathy (DCM). In adult mice, we induced cardiomyocyte-restricted deletion of the NEDD8-activating enzyme 1 (NAE1) by tamoxifen injection and monitored cardiac function at baseline and after transverse aortic constriction (TAC). Bulk RNA-seq 4 weeks post-tamoxifen was combined with bioenergetic, biochemical, and ultrastructural analyses. To assess mitochondrial dynamics, we generated NAE1/MFN2 and NAE1/DRP1 double-knockout mice. Cullin activity, mitochondrial ubiquitination, and mitophagy were measured in hearts and cultured cardiomyocytes. RESULTSNeddylation pathways were dysregulated in human ICM and NICM datasets and in failing ICM/DCM myocardium. Cardiomyocyte-specific NAE1 deletion caused systolic dysfunction and heart failure by 10 weeks post-tamoxifen, culminating in premature death and exacerbating TAC-induced pressure-overload heart failure. At 4 weeks, NAE1 loss repressed metabolic and mitochondrial bioenergetic programs, reduced ATP production, and impaired respiration. Electron microscopy revealed elongated mitochondria and accumulated mitophagic vesicles, with dysregulation of DRP1, MFN2, PINK1, LC3-II, and p62. DRP1/NAE1 co-deletion accelerated systolic failure relative to either single knockout, whereas MFN2/NAE1 co-deletion did not alter early disease progression, implicating pathogenic mitochondrial hyperfusion. Genetic NAE1 depletion in vivo and pharmacologic NAE1 inhibition in vitro impaired mitophagic vesicle formation and flux, inactivated cullin scaffold proteins, reduced mitochondrial ubiquitination, and blunted mitophagic clearance. CONCLUSIONSCardiac neddylation preserves adult heart function by coordinating mitochondrial fusion-fission dynamics and sustaining cullin-dependent ubiquitination and turnover of damaged mitochondria. These findings identify neddylation as a key regulator of mitochondrial quality control and link its disruption to human cardiomyopathy. Therapeutically, targeting the neddylation-cullin axis may limit mitochondrial dysfunction, enhance mitophagy, and improve energetic reserve in failing hearts, while neddylation signatures in patient myocardium may help guide stratification and precision therapy for cardiomyopathy. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABS* Demonstrates for the first time that the NEDD8-activating enzyme (NAE1)driven neddylation pathway is indispensable for maintaining mitochondrial quality control in the adult heart. * Links loss of neddylation to mitochondrial hyperfusion, impaired mitophagy, and rapid progression to heart failure. * Reveals that neddylation promotes cullin-RING ligase-mediated ubiquitination of damaged mitochondria, coupling mitochondrial dynamics with turnover. What Are the Clinical Implications?* Restoring or enhancing cardiac neddylation may represent a novel therapeutic avenue for cardiomyopathies characterized by mitochondrial dysfunction. * Pharmacologic agents that bolster DRP1-dependent fission or activate cullin neddylation could potentially normalize mitochondrial dynamics and improve myocardial energetics. * Conversely, systemic neddylation inhibitors now in oncology trials warrant careful cardiac monitoring, as they may precipitate mitochondrial injury and heart failure. * Circulating or tissue markers of neddylation might help stratify patients at heightened risk for mitochondrial-driven cardiac disease and guide precision therapy.

physiology↗

bioRxiv2025

BrainBridge Characterizes Key Factors affecting Alzheimer's Disease and Associated Phenotypes

Single-cell RNA sequencing (scRNA-seq) has significantly advanced our understanding of Alzheimers disease and aging by revealing cellular heterogeneity and shifts in cell-type composition between diseased/old and healthy/young individuals. However, few existing studies utilize the rich information in single-cell transcriptomic atlases for robust patient-level modeling and biological feature selection. To address this gap, we present BrainBridge, a deep learning-based framework designed to integrate atlas-scale single-cell transcriptomic data with phenotypic information to model the biomolecular complexity of the human brain. BrainBridge functions both as a powerful predictor and an embedding model for representing sample-level expression profiles and covariates through comprehensive benchmarking. We also demonstrate its effectiveness in prioritizing key genes and cell types associated with disease progression, aging, and sex differences. We further validate our findings using external resources, including genome-wide and epigenome-wide association studies (GWAS and EWAS), spatial transcriptomics, and perturb-seq experiments. Finally, we deploy BrainBridge within an interactive, agent-powered interface that enables intuitive and user-friendly model interactions, promoting broader accessibility and application in biomedical research.

bioinformatics↗

bioRxiv2025

Molecular basis of high-torque transmission of the Vibrio polar flagellar motor

The bacterial flagellar motors are huge protein nanomachines that drive rotation of the flagellum for bacterial motility, and have considerable diversity in structure among bacterial species, which enables the transmission of different torques to the flagellar filaments to propel bacteria and renders various swimming abilities. Relative to the bacterial peritrichous flagellar motors, the polar flagellar motors are the faster rotational machines and transmit high torque to drive bacterial high-speed motility in liquid and empower swimming in viscous environments. However, the structural basis of high-torque transmission of the polar flagellar motors is still unclear. Here we present an atomic-resolution cryo-electron microscope structure of the polar flagellar motor in complex with the hook from Vibrio alginolyticus, comprising 295 subunits from 18 proteins. Extensive inter-subunit interactions and additional phospholipids generate the higher rigidity of the rod. The LP ring utilizes more electrostatic charges on the inner surface and less physical contacts to facility the higher-speed rotation of the rod. The additional HT ring tightly binds to the outer surface of the LP ring to enhance the LP-ring stability. A previously function-unknown component FlrP enhances the interactions of 15 FliF peptides of the MS ring with the rod and stabilizes the LPHT and MS rings. The hook has two different states, L- and R-state, which provides structural flexibility of the hook to drive the unique forward-reverse-flick motility of the bacteria in the flicking process. This study provides unprecedented molecular insights into evolution and structural adaptions of the bacterial polar flagellar motors for high-torque transmission.

microbiology↗

bioRxiv2025

Robust brain complexity measurement using T2* informed multivariate sample entropy from multi-echo BOLD fMRI

Sample entropy is a useful tool to analyze resting-state fMRI data and evaluate the complexity of neural activity. However, sample entropy computed from conventional BOLD signals is not highly resistant to artifacts. In contrast, T2* may be more sensitive to certain neural-related changes, and directly incorporating T2* information enables the detection of features that are often lost in BOLD-only sample entropy due to noise influences. To further improve the robustness and reliability of complexity estimation, we introduce a multivariate sample entropy approach that incorporates T2* signals derived from multi-echo BOLD signal. We applied this method to compare a cohort of 23 elder adults and 12 younger adults, and observed significant group differences in several brain regions. Notably, the proposed method yielded more pronounced group differences than conventional sample entropy computed without T2* information. Moreover, in regions with reduced neural activity due to ischemia, as well as in ventricular areas, our approach demonstrated superior performance. These results indicate that the proposed method enhances the ability to characterize the complexity of neural activity.

biophysics↗

bioRxiv2025

IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by A Low-Affinity Antibody

Mechanistic studies of viral neutralization typically prioritize high-affinity antibodies, relegating low-affinity binders to the sidelines. We report P5-1C8, a Class 1 SARS-CoV-2 antibody that exemplifies this underexplored "low-affinity yet high-potency" phenotype, retaining strong neutralization of Omicron JN.1 despite markedly weakened trimer binding (KD = 225 nM; IC50 = 0.06 nM). Structural and biophysical analyses reveal that P5-1C8 engages WT and BA.1 spikes through canonical intra-spike bivalency, but with JN.1 it induces aggregation. Using virion-like nanoparticles displaying multiple spikes, we show that IgG remains bound with no detectable dissociation and triggers pronounced aggregation. Coarse-grained molecular dynamics delineate the stepwise pathway in which weak IgG-spike contacts seed aggregation via transient inter-spike bridging. Together, these findings establish the first mechanistic framework demonstrating how weak-binding antibodies can nonetheless achieve potent neutralization through higher-order aggregation, thereby expanding the conceptual landscape of antibody function and opening new directions for antibody evaluation and design. Graphical AbstractLow-affinity antibodies are frequently disregarded in discovery pipelines. This work reports P5-1C8, a Class 1 SARS-CoV-2 antibody with weak trimer binding (KD-to-IC50 > 3,700-fold) yet potent neutralization of Omicron JN.1. Structural, biophysical, functional and coarse-grained simulations collectively demonstrate that transient inter-spike IgG bridging seeds higher-order aggregation, which in turn drives neutralization and provides a mechanistic framework. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/691454v1_ufig1.gif" ALT="Figure 1000"> View larger version (79K): org.highwire.dtl.DTLVardef@1d4f132org.highwire.dtl.DTLVardef@1274400org.highwire.dtl.DTLVardef@e186a6org.highwire.dtl.DTLVardef@4f1870_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Engineering an Anaerobic Microenvironment to Empower Hydrogenase-Catalyzed Hydrogen Therapy for Diabetic Wound Healing

The inherent oxygen sensitivity of hydrogenases has long restricted their applications to anaerobic systems. Here, we present a hybrid peptide-nanocluster hydrogel that establishes a self-sustaining anaerobic microenvironment to enable hydrogenase-catalyzed hydrogen therapy under aerobic conditions. This system integrates a custom-designed Fmoc-KYF peptide hydrogel with integrated silver nanoclusters (AgNCs), which host an engineered [NiFe]-hydrogenase (3S1C-Hyd-2). Mechanistic studies combining molecular dynamics simulations and spectroscopic analysis revealed that hydrophobic pockets within the peptide network trap oxygen molecules, while photoexcited AgNCs rapidly deplete invasive O2. Our design ensures stable hydrogen evolution, effectively overcoming the oxygen sensitivity that has long restricted hydrogenase applications in biomedical contexts. In vitro, the in-situ-generated hydrogen effectively scavenges reactive oxygen species, suppresses pro-inflammatory cytokine production. In a diabetic mouse model, this light-activated system markedly accelerates wound closure (87% by day 11), reduces oxidative stress, promotes macrophage polarization toward a reparative phenotype, enhances angiogenesis, and upregulates tissue repair pathways, as confirmed by transcriptomic profiling. Our work establishes a new bioengineering paradigm for constructing anaerobic microenvironments through synergistic material-enzyme-light interactions, offering a versatile platform for hydrogenase-enabled therapeutic interventions in oxidative stress-related diseases.

biochemistry↗

bioRxiv2025

Ethylene signal-driven plant-multitrophic synergy boosts crop performance

Efficient nutrient use in agriculture depends on the dynamic interplay between plant roots, soil, and microbial communities. The root-rhizosphere interface is central to nutrient uptake and serves as a key hub for interactions with beneficial microbes. Arbuscular mycorrhizal (AM) fungi, positioned at the nexus between plant roots and soil microbiota, play a critical role in enhancing crop performance under nutrient-limited conditions. In this study, we dissected the genetic and molecular basis of AM fungi-induced lateral root development in maize (Zea mays), focusing on the role of ethylene-responsive transcription factors (ERFs). We identified ERF genes as essential regulators of pericycle cell division, acting downstream of ethylene biosynthesis genes (ACS6 and ACS7) and AM fungal signaling. Our findings reveal that AM fungi promote lateral root initiation by activating ERF expression and reprogramming flavonoid metabolism, particularly reducing the accumulation of flavonols such as kaempferol and quercetin, which otherwise inhibit root development when over-accumulated. Furthermore, we demonstrated that Massilia, a beneficial rhizobacterium, synergizes with AM fungi to enhance lateral root formation by colonizing fungal hyphae, degrading flavonoids, and contributing to auxin production. Together, our results uncover a tripartite signaling network linking ethylene signaling, flavonoid-mediated microbial recruitment, and AM symbiosis. This study highlights ERFs as central integrators of plant-microbe interactions and provides a molecular framework for engineering root architecture and microbiome assembly to improve nutrient acquisition and support sustainable crop productivity.

plant biology↗

bioRxiv2025

Process optimization for enhanced enzymatic nylon deconstruction

Plastics such as polyamides (PAs) possess unique physicochemical properties that make them indispensable in modern society. However, their energy-intensive production and challenging end-of-life management highlight the urgent need for efficient recycling or remanufacturing solutions. Enzymatic depolymerization offers a promising route toward circular recycling, yet remains constrained by limited enzyme characterization, lack of validation under industrially relevant conditions, and overall performance. Here we optimized the reaction conditions for three recently discovered nylon-degrading enzymes. One of them, Nyl12, achieved product titers with PA6 and PA66 that exceed previously reported values, without enzyme engineering or substrate pretreatment. We further demonstrated the scalability of the process and its application to complex PA-based materials used in microelectronic components. Analysis of substrate features, including surface area and particle size, revealed key parameters governing enzymatic activity and provided a framework for future pretreatment and process optimization efforts. In combination, these efforts provide a new benchmark for enzymatic nylon recycling.

biochemistry↗

bioRxiv2025

Ferrapoptosis: Discovery of a Hybrid Programmed Cell Death

Traditional taxonomies classify ferroptosis and apoptosis as distinct forms of regulated cell death. Here, we challenge this view by defining and validating a previously unrecognized neuronal death entity in traumatic brain injury (TBI), which we term "Ferrapoptosis". This hybrid mode of death is characterized by the coexistence of ferroptotic and apoptotic molecular and ultrastructural features within the same neuron-- ultrastructural alterations that cannot be fully characterized by any known cell death modalities. By integrating single-cell transcriptomics with multi-layered functional assays, we show that Ferrapoptosis dominates in severe injury and the acute phase, and is critically driven by mitochondrial oxidative stress. Over time, its predominance is gradually replaced by death modes in which either ferroptosis or apoptosis alone becomes the major pathway. Genome-wide CRISPR screening further identifies Smg7 as a key regulator that synchronously activates both death programs to drive the hybrid phenotype, whereas genetic or viral inhibition of Smg7 reduces Ferrapoptosis and promotes neurological recovery after TBI in mice. Our work systematically delineates a previously unrecognized form of cell death and its pathogenetic mechanisms, providing experimental evidence to refine cell death classification, and suggesting a conceptual strategy for treating complex diseases such as TBI by targeting shared regulatory nodes. HIGHLIGHTSO_LIDefined and validated a previously unrecognized cell death modality, termed "Ferrapoptosis". C_LIO_LIElucidated the ordered pattern of Ferrapoptosis across key stages of TBI pathogenesis. C_LIO_LIRevealed mitochondrial oxidative stress as the pivotal hub integrating ferroptosis and apoptosis. C_LIO_LIIdentify Smg7 as a core driver of Ferrapoptosis and a promising neuroprotective target. C_LI

cell biology↗

bioRxiv2025

Improved spike-in normalization clarifies the relationship between active histone modifications and transcription

Spike-in normalization enables quantitative analysis of ChIP-sequencing (ChIP-seq) signal. Here we introduce a novel robust dual-spike-in normalization approach for ChIP-seq (ChIP-wrangler). We identify optimal conditions, such as the ratio between the spike-in species and the target, demonstrate the ability of this approach to detect technical artefacts, and use ChIP-wrangler to revisit recent claims that active histone marks are dependent on transcription. Concerned that previous studies improperly used spike-in normalization to arrive at their conclusions, we used ChIP-wrangler to show that acute depletion of RNA polymerase II (RNAPII) has only a modest impact on the levels of H3K4me3 and H3K27ac. In line with other studies, our results provide proof that the maintenance of histone acetylation is not merely a consequence of ongoing transcription. Further, we show that promoters and enhancers are differentially impacted by inhibiting transcription. Specifically, of the 5.9% peaks that showed a decrease in H3K27ac following depletion of RNAPII, 82% are promoter-distal and contain enhancer-related DNA binding motifs. Further, the small subset of regions that gain acetylation (0.35%) were enriched for stress response motifs. Our innovative ChIP-seq normalization approach provides increased rigor and "guardrails" for successful spike-in normalization, and as applied here refines the understanding of the intricate crosstalk between RNAPII activity and histone marks associated with transcription.

genomics↗

bioRxiv2025

GPR17 structure and agonism with small molecules and oxysterols

GPR17 is a class A orphan GPCR that regulates myelination in the central nervous system. Inhibiting GPR17 is a potential therapeutic mechanism to induce remyelination. The limited understanding of the structural basis of GPR17 agonism and antagonism is a challenge for GPR17 drug discovery. We present novel cryo-EM structures of GPR17 with bound orthosteric antagonist or agonist/G protein heterotrimer with biophysical and cellular characterization to inform rational drug discovery. Both ligands bind towards a lateral edge of the orthosteric pocket, while an exceptionally long extracellular loop 2 occupies and limits access to this site. In contrast, pharmacological and photoaffinity studies indicate that endogenous oxysterol agonists of GPR17 bind allosterically. Characterization of oxysterol agonism versus a known orthosteric ligand in oligodendrocytes further supports an allosteric mechanism. Therefore, the design of more potent orthosteric ligands is limited by pocket size and accessibility. Targeting allosteric binding offers an alternative approach to GPR17 antagonism.

biochemistry↗

bioRxiv2025

DNA Motors Powered by Exonuclease III for Autonomous Rolling Motion and Biosensing Applications

Nucleic acid-based synthetic motors emulate key behaviors of biological machines, enabling applications in biosensing and nanoscale actuation. Among the reported synthetic motors, RNase H-powered motors offer high speed and processivity with demonstrated applications in computation and viral sensing. However, these motors rely on RNA as "fuel" source, limiting their stability. Here, we report the development of a robust, RNA-free DNA motor powered by Exonuclease III. These motors exhibit self-avoiding rolling motion driven by enzymatic hydrolysis of surface-bound DNA fuel strands, consistent with a burnt-bridge Brownian ratchet mechanism of translocation. We systematically optimized motor performance by chemically tuning the fluorescence reporter, DNA sequence composition, and surface fuel density. Fluorescence and brightfield microscopy revealed super-diffusive and Levy-like stop-and-go dynamics under optimized conditions. Importantly, the established DNA-only architecture confers resistance to RNase degradation, and the system can be configured for motion-based biosensing via aptamer-functionalized components that selectively stall in response to viral targets. Beyond the significance of creating a chemically stable, tunable, and biosensing-compatible DNA motor platform, the work also establishes the modularity of the rolling motor platform and highlights how enzymatic diversity can expand their chemical and functional scope.

biophysics↗

bioRxiv2025

Nuclear factor kappa B subunits and IkappaB family are modulated in the ovine endometrium during early pregnancy

Pregnancy modulates the endometrial immune responses to establish maternal immune tolerance, and nuclear factor kappa B (NF-{kappa}B) subunits and I{kappa}B family are involved in the maternal innate and adaptive immune responses. It, nevertheless, is unclear if early pregnancy regulates the expression of NF-{kappa}B subunits and inhibitor of NF-{kappa}B (I{kappa}B) family in the ovine endometrium. In this study, ovine endometria were sampled at day 16 of the estrous cycle (N16), and at days 13, 16, and 25 of pregnancy (P13, P16, and P25), and mRNA and protein expression of NF-{kappa}B subunits and I{kappa}B family was analyzed by RT-qPCR, western blot, and immunohistochemistry. The results revealed that the expression of all NF-{kappa}B subunits was decreased at P25 compared with N16 both in mRNA and protein expression, but the expression of B cell leukemia-3, I{kappa}B, I{kappa}B kinase {gamma}, and I{kappa}B{delta} was increased at P25 compared with N16 both in mRNA and protein expression. I{kappa}B{beta}, however, was downregulated during early pregnancy, and the expression of I{kappa}B{varepsilon} and I{kappa}B{zeta} was decreased at P13 and P16 compared with N16 and P25 both in mRNA and protein expression. In summary, early pregnancy changed the expression of NF-{kappa}B subunits and I{kappa}B family in the ovine endometrium both in mRNA and protein expression, which may be essential for maternal immune tolerance and embryo implantation.

immunology↗

bioRxiv2025

Life-long behavioral screen reveals an architecture of vertebrate aging

Mapping behavior of individual vertebrate animals across lifespan is challenging, but if achieved, could provide an unprecedented view into the life-long process of aging. We created the first platform for high-resolution continuous behavioral tracking of a vertebrate animal across natural lifespan from adolescence to death--here, of the African killifish. This behavioral screen revealed that animals follow distinct individual aging trajectories. The behaviors of long-lived animals differed markedly from those of short-lived animals, even relatively early in life, and were linked to organ-specific transcriptomic shifts. Machine learning models accurately predicted age and even forecasted an individuals future lifespan, given only behavior at a young age. Finally, we found that animals progressed through adulthood in a sequence of stable and stereotyped behavioral stages with abrupt transitions suggesting a novel structure for the architecture of vertebrate aging.

animal behavior and cognition↗

bioRxiv2025

A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation

The SARS-CoV-2 spike protein binds its receptor ACE2 to initiate target-cell infection. To engage ACE2, at least one of the three receptor-binding domains (RBDs) of the spike must adopt the up orientation. Here we describe S22, a potent, bioavailable, and non-toxic inhibitor of BA.2 and all subsequent Omicron variants. Cryo-EM analyses showed that S22 assembled as a trimer in a previously uncharacterized pocket of the spike apex, stabilizing all three RBDs in the down orientation, thereby preventing ACE2 association. Binding studies, especially those using mixed S22-sensitive and -resistant spikes, imply a cooperative assembly of three S22 molecules with three RBDs, resulting in an unusually slow S22 off-rate. Consistent with its slow dissociation and favorable pharmacokinetics, S22 suppressed viral replication 100-fold in the lungs of XBB.1.5-infected mice. Thus, S22 potently inhibits Omicron entry through a distinct mechanism whereby a small compound assembles cooperatively as a trimer to stabilize spike in an inactive conformation.

microbiology↗