The Ediacara biota represents Earth’s earliest complex macroscopic organisms, but their biology and ecology remain poorly understood. Here we report Dengyingia pennata gen. et sp. nov., an exceptionally preserved frondose fossil from the late Ediacaran ( ~550–543 Ma) Shibantan limestone of South China. Dengyingia possesses a unique body plan: a bifoliate petalodium of unconstrained, flexible primary branches with pronounced two-sided differentiation—a smooth obverse surface and a reverse surface covered by secondary and tertiary modules. This innovation represents a key morphological advance among Ediacaran fronds. Its architecture, basal growth pattern, and suspension-feeding strategy align with those of modern sea pens (pennatulacean cnidarians), reflecting adaptations for dynamic filter-feeding in currents. Dengyingia bridges the ecological gap between the Ediacara biota and Phanerozoic suspension-feeding animals, demonstrating that complex, animal-like ecological strategies emerged before the Cambrian explosion. These findings expand Ediacaran diversity and provide insights into early animal functional differentiation. An exceptionally preserved Ediacaran frond, Dengyingia pennata, from South China shows a unique branched body plan and functional convergence with modern sea pens, suggesting complex suspension-feeding strategies evolved prior to the Cambrian diversification.
The rapid emergence of multidrug-resistant Escherichia coli highlights the urgent need for effective, host-compatible antibacterial strategies. Targeting bacterial redox homeostasis represents a promising non-antibiotic paradigm, yet rational synergistic approaches remain poorly defined. We show that zinc combined with vitamin K3 exhibits potent antibacterial activity against pathogenic E. coli, including enterotoxigenic ETEC K88, by selectively disrupting redox regulation. Mechanistically, Zn²⁺ targets the redox-sensitive transcription factor SoxR, inactivating the SoxR-SoxS pathway and suppressing the downstream superoxide dismutase (SOD) antioxidative axis, thereby impairing the bacterial adaptive response to oxidative stress and rendering the pathogen highly susceptible to oxidative damage. This effect is further amplified by vitamin K3-mediated superoxide generation, resulting in synergistic bactericidal activity. In the present study, the Zn²⁺-vitamin K3 combination was validated across multiple infection models, including in vitro systems, a Galleria mellonella infection model, and an ETEC K88-induced murine diarrhea model, where it reduced bacterial burden, improved host survival, and alleviated intestinal pathology. Importantly, gut microbiota analysis revealed partial restoration of infection-associated dysbiosis without broad microbial depletion. These findings establish redox homeostasis disruption as a microbiota compatible antibacterial strategy against multidrug-resistant E. coli.
Despite positive outcomes for novel targeted therapy screens in preclinical studies, the majority of follow on GBM clinical trials fail to meet their primary endpoints. This translational gap is partly due to models that do not accurately recapitulate the human GBM-TME and therefore fail to accurately predict patient treatment response. Here, we investigated the NFPp10a/NF5310 syngeneic mouse model of mesenchymal GBM, to assess its translational relevance for evaluating TME-targeting agents. Young and aging C57BL/6 mice bearing orthotopic NFPp10a/NF5310-Luc2 tumours underwent treatment with temozolomide (TMZ), tumour resection, anti-PD1 checkpoint blockade, and/or regorafenib (REGO). TME composition was evaluated using the murine microenvironment cell population (mMCP) counter method and multiplexed immunohistochemistry (multiple iterative labelling by antibody neodeposition). To assess translational relevance and conserved human response patterns, immune cell composition and gene expression changes were directly compared to primary human mesenchymal GBM tumours via further hypothesis generating MILAN analysis and by studying publically available ICI clinical trial data. NFPp10a/NF5310-Luc2 tumour-bearing mice showed resistance to monotherapy and neoadjuvant anti-PD1, with limited response also observed to REGO treatment. mMCP analysis revealed modest increases in CD8+ T-cells, B cells, and monocytes following anti-PD1 and REGO treatment. MILAN analysis further indicated increased cytotoxic T-cells following anti-PD1 therapy. Comparison to untreated-primary GBM and ICI-treated human GBM suggested similar exhausted CD8+ T-cell phenotypes, suggesting the NFPp10a/NF5310 TME reflects the mesenchymal GBM T-cell compartment. Overall, the NFPp10a/NF5310 model recapitulates the GBM-TME architecture and therapeutic resistance patterns observed in human GBM, supporting its use in evaluating select TME-targeting therapies. The NFPp10a/NF5310 glioblastoma model demonstrates clinically relevant response patterns and key tumour microenvironment features of mesenchymal glioblastoma, supporting its utility as a translational platform for therapeutic development.
Triple-negative breast cancer (TNBC), as the most aggressive subtype of breast cancer, has a poor prognosis because of its heterogeneity and complicated molecular mechanism. RAD21, a key component of cohesin complex, play vital roles in cellular functions and regulation of cell identity gene expression in cancer cells. However, it remains incompletely understood how RAD21 regulates tumorigenesis and metastasis in TNBC. Here, we present data suggesting that RAD21 was commonly highly expressed in TNBC and was correlated with poor outcome in invasive breast cancer. RAD21 depletion induced autophagy and suppress proliferation, invasion and xenograft tumor growth of TNBC cells, while RAD21 overexpression promoted lung metastasis. Mechanistically, RAD21 bound to the promoter region of the YAP and RAD21 knockdown increased YAP transcription level and the YAP nuclear accumulation in TNBC cells. Subsequently, YAP promoted a transcriptional program leading to enhanced autophagy flux to restrain TNBC cells proliferation and invasiveness. These findings uncover RAD21 as a promoter of TNBC tumorigenesis and metastasis and suggest a new function of RAD21 in regulating TNBC cells autophagy driven by YAP. RAD21 is linked to poor breast cancer outcomes. RAD21 is here found to drive TNBC tumor growth and invasion in vitro and in vivo by suppressing YAP transcription and YAP-mediated autophagy, revealing a novel YAP-dependent role.
The success of trypanosomes in transitioning between hosts and life stages depends on their ability to manipulate host metabolism, immunity, and behavior. Pathogen-favoring behaviors often link tsetse flies’ host behavioral plasticity and sensory adaptations, but the underlying mechanisms remain unclear. To uncover the molecular basis regulating neuronal sensitivity and transmission behavior in tsetse flies, we applied transcriptomics, metabolomics and validated by RT-qPCR and behavioral assays. Uninfected Glossina pallidipes were more attracted to Trypanosoma congolense-infected mice and metabolites from infected cow urine than to healthy ones. T. congolense infection alters host metabolic pathways, modifying the composition of volatile organic compounds in mice and cattle, which enhanced fly attraction. Infection modulated cellular signaling across multiple sensory modalities, including olfaction, vision, taste, thermosensation, and immunity in G. pallidipes. Trypanosome associated odors doubled the catch of infected G. pallidipes in the field, reducing infected flies by 75% and diseases prevalence in cattle by 40% based on agent-based model. These findings reveal the molecular interaction between T. congolense, G. pallidipes, and cattle, highlighting how the parasite manipulates multiple pathways to enhance adaptation, multiplication, and transmission. Muti-omics investigation reveals how trypanosomes manipulate their vertebrate host metabolites and tsetse flies’ multiple sensory modalities and immunity to enhance its survival and transmission.
The dorsolateral prefrontal cortex contributes to cognitive–affective pain regulation, but the optimal frequency and individualization strategy for high-definition transcranial alternating current stimulation remain unclear. Here we show, across three double-blind experiments in healthy human participants using a capsaicin-induced tonic pain model, that analgesia depends on stimulation frequency and the brain state used for frequency selection. Study 1 compares 10-Hz stimulation of the dorsolateral prefrontal cortex with 10-Hz stimulation of the primary sensorimotor cortex in 40 participants. Study 2 compares 7-Hz theta and 10-Hz alpha stimulation over the dorsolateral prefrontal cortex in 40 participants. Study 3 compares fixed 7-Hz stimulation with individualized theta frequencies derived from pain-free or pain-persistent oscillatory profiles in 28 participants. Participants receive 30 minutes of high-definition transcranial alternating current stimulation during tonic pain with continuous pain ratings. Alpha-band dorsolateral prefrontal cortex stimulation produces stronger acute and sustained analgesia than primary sensorimotor cortex stimulation. Theta-band stimulation produces greater and longer-lasting analgesia than alpha stimulation and is accompanied by increased prefrontal beta- and low-gamma activity. Individualized theta stimulation derived from pain- persistent states yields greater analgesia than fixed-frequency or pain-free-state-based stimulation. These findings identify frequency and brain state as key determinants of analgesic responses to dorsolateral prefrontal cortex stimulation. Three double-blind experiments test how frequency and brain state influence analgesia during tonic pain. Prefrontal theta stimulation tailored to brain activity during pain produces the strongest and most sustained pain relief.
Telomeric DNA replication involves coordinated action of telomerase and DNA polymerase α-primase (Polα/primase), which synthesize the G-strand and C-strand, respectively. The conserved Cdc13-Stn1-Ten1 (CST) complex critically regulates this process by both terminating telomerase activity and stimulating Polα/primase. While telomerase-mediated G-overhang synthesis is well studied, how CST-Polα/primase is recruited to telomeres for C-strand fill-in remains poorly understood. Structural analysis reveals an evolutionary diversity of CST interaction with Polα/primase across organisms. Here, using a combination of AlphaFold3 structural modeling with genetic assays, we unveil the assembly mechanism of CST-Polα/primase for telomere maintenance in Saccharomyces cerevisiae. We structurally characterize the uniqueness and specific determinants of the Stn1-Pol12 interaction in the S. cerevisiae CST-Polα/primase complex. The Cdc13-Pol1 and Stn1-Pol12 interactions together mediate CST-dependent recruitment of Polα/primase to telomeres. Functional analyses reveal that disruption of the CST-Polα/primase interaction shows distinct telomere phenotypes compared to CST disassembly, supporting the model that CST recruits Polα/primase after telomerase elongation is terminated. Together, our findings not only resolve the longstanding question on the assembly mechanism of the CST and Polα/primase complexes at yeast telomeres, but also hint that CST-Polα/primase-dependent C-strand fill-in likely governs recombination-based telomere structure maintenance via controlling 3’ overhang length.
The human auditory system represents sounds at multiple levels, from low-level acoustic features to abstract category- and object-level information. Although selective attention enables listening in complex natural soundscapes, it remains unclear which representational levels are modulated by attention and how this depends on scene structure. Using functional magnetic resonance imaging, representational similarity analysis, and cross-experiment decoding, we examined attentional modulation of auditory representations under three conditions: 1) listening to isolated sounds, 2) attending to one of three overlapping sounds from different categories, or 3) one of three overlapping sounds from the same category. We show that attentional modulation is task-dependent: when competing sounds could not be distinguished by category, attention enhanced low-level acoustic feature processing, whereas in cross-category scenes it targeted abstract category-level representations. Object-identity representations were modulated by attention across both scene types, with category-specific differences, demonstrating flexible, task-dependent targeting of auditory features. Varis et al. use fMRI to study how attention shapes auditory representations in scenes of overlapping natural sounds. Attention enhances acoustic features when competing sounds share a category and categorical features when they differ.
Dominant individuals often structure group organization, but less is known about how social networks reorganize in their absence and how variation among subordinates contributes to collective outcomes. Bumble bees (Bombus impatiens) provide an ideal system to study these dynamics: queens typically monopolize reproduction, but in some contexts, individual workers can adopt queen-like social roles. Using multi-animal pose tracking, we compare matched queenright and queenless partitions from the same source colonies, quantifying over 80 million social interactions. Queenless colonies exhibit increased behavioral variation and contain a subset of highly influential workers with elevated movement, spatial centrality, and reproductive activity that is absent in queenright conditions. The emergence of these individuals coincides with a shift from centralized to decentralized, efficient network architectures. These results demonstrate that queen presence constrains latent worker variation, revealing how individual behavioral differences can scale up to reshape collective social organization in hierarchical societies. Automated tracking of bumble bee colonies shows that queen loss unmasks latent worker variation, allowing a subset of workers to become highly influential and reorganize colony social networks.
Within host-microbiome-pathogen systems, the host chemical microenvironment is often overlooked despite its inherent role in host physiology. We used a multifaceted experimental approach encompassing culture-dependent and -independent methods, genomic and metagenomic analyses, and deep neural network modeling to assess the impact of host skin chemistry and the bacterial microbiome on the growth of Ophidiomyces ophidiicola (ophidiomycosis, snake fungal disease). Results suggest that host skin lipid chemistry (e.g., oleic acid, squalene) and bacteria isolated from wild snake skins (e.g., Chryseobacterium sp. and Stenotrophomonas maltophilia) suppress O. ophidiicola growth. Notably, the O. ophidiicola genome contains biosynthetic gene clusters (BGCs) that encode metabolites that may suppress host lipid production, facilitating fungal pathogenicity. A contrastive deep neural network produced a near-perfect alignment of snake skin lipid and microbiome profiles for both individual snakes and disease states. BGCs from bacterial genomes isolated from snake skin overlap with metagenome profiles from wild snakes and are associated with disease state. We highlight antifungal activity found in the diverse lipid milieu of snake skin and bacterial-fungal interactions that structure the skin microbiome. Our results illustrate a strong relationship among a fungal pathogen, the microbiome, and host skin lipid chemistry that may underpin disease susceptibility. Deep learning models accurately align multimodal data including snake skin lipid chemistry and microbiome-pathogen interactions in the snake fungal disease system.
Cells are the basic unit of life. In multicellular organisms, cells are organized into tissues. This enables a division of labor where tissues perform complex tasks via coordinated actions of specialized cell types. Accordingly, the cellular collective determines tissue function. A comprehensive overview of which cell types exist in solid tissues is lacking. Using skeletal muscle as a model, we discuss basic principles for cell type classification, summarize 62 unified definitions of cell types in terms of lineage, molecular signatures, and function from the literature, and discuss how these cell types contribute to muscle function. For cell types for which quantitative data was available, we compare abundances in immunohistology and single cell and single-nucleus RNA sequencing data, revealing cell types that are commonly over- or underrepresented in each method. The result is a cell type resource that will serve as a benchmark for single-cell studies of skeletal muscle.
Magnetic susceptibility in brain white matter is anisotropic because of the ordered arrangement of myelin lipids, whereas paramagnetic iron is generally not considered a source of susceptibility anisotropy. Whether spatially organized paramagnetic sources also contribute to tissue-level susceptibility anisotropy remains unclear. Here we analyze multi-orientation gradient-echo MRI and diffusion MRI data from a paraformaldehyde-fixed postmortem adult male western chimpanzee (Pan troglodytes verus) brain and use DECOMPOSE-QSM to separate paramagnetic and diamagnetic susceptibility components before tensor reconstruction. The diamagnetic component shows the expected anisotropy in white matter and aligns with major diffusion-based fiber orientations. The paramagnetic component also shows coherent anisotropy, most prominently in deep gray matter and in parts of white matter. Numerical modeling further supports that an ordered spatial arrangement of otherwise isotropic paramagnetic sources can produce orientation-dependent susceptibility. These results suggest that source-separated susceptibility tensor imaging provides complementary information about tissue-specific susceptibility organization beyond conventional susceptibility tensor imaging. Source-separated susceptibility tensor MRI in a postmortem chimpanzee brain reveals distinct paramagnetic and diamagnetic anisotropy patterns, providing complementary views of primate brain microstructure.
Many clinically important bacterial pathogens, including Pseudomonas, Vibrio, Neisseria, and Acinetobacter species, employ dynamic extracellular appendages called type IV pili (T4P) to facilitate virulence through cyclical extension and retraction of pilus filaments. To dissect how T4P dynamics govern pathogenesis, we engineered a genetic system to precisely tune pilus length across a continuum. We demonstrate that pilus length determines four major T4P-dependent virulence traits in P. aeruginosa (motility, surface sensing, biofilm formation, and phage infection) and reveal a hidden subpopulation of pili that are unable to interact with environmental substrates or host cells, rendering them non-contributing to T4P-mediated functions. Integrating molecular dynamics simulations, we show that low inner-membrane abundance of the major pilin forces the extension mechanism into transient idle states, restricting both velocity and final length. Molecularly, this finding reveals how two key biophysical parameters, pilin abundance and diffusion, impose a fundamental physical constraint on T4P assembly, and that regulating pilin abundance presents a strong lever over regulating pilus count for controlling the amount of functionally contributing filaments. Contrary to the view that retraction force dictates T4P-mediated behaviors, our results establish extension dynamics as the overlooked bottleneck constraining retraction-enabled virulence traits, with population heterogeneity in length possibly enabling risk mitigation. The availability of the major pilin PilA limits extension of type IV pili and directly impacts pilus-dependent virulence behaviors.
The sustained human-to-human transmission of Clade IIb monkeypox virus (MPXV) during the 2022 outbreak underscores the need to define host determinants of viral fitness across species. ISG15 encodes a ubiquitin-like modifier with antiviral activity, yet its role in MPXV infection and host adaptation remains unclear. Using representative strains from Clades Ib and II, we identify a striking species-specific difference in ISG15-mediated restriction. In murine cells, ISG15 deficiency primarily increases viral protein accumulation with minimal effects on infectious viral production, indicating limited antiviral restriction. In contrast, in human cells, ISG15 restricts replication of recent epidemic strains since ISG15 deficiency enhances viral growth, establishing ISG15 as a restriction factor in humans. ISGylome profiling identifies candidate viral and host substrates underlying this effect. Together, these findings reveal species-specific ISG15-dependent control of MPXV infection and support a model in which rodents serve as permissive reservoirs while humans represent a more restrictive host due at least in part to the antiviral activity of human ISG15. We study ISG15 during MPXV infection in human and murine cells. ISG15 deficiency increases infectious virus production in human cells but alters viral protein accumulation in murine cells, and ISGylome analysis identifies ISGylated viral proteins.
Enhancer editing is widely proposed as a strategy to modulate gene dosage therapeutically. EKLF/KLF1, a master erythroid transcription factor, is an attractive target because haploinsufficiency is benign and associated with hereditary persistence of fetal hemoglobin (HPFH). Here we test whether enhancer disruption can recapitulate this state by targeting two KLF1 regulatory elements, EHS1 and INT1. EHS1 editing reduces KLF1 expression and increases γ-globin, and combined INT1/EHS1 targeting produces additional increases in some samples, although responses are variable. In xenotransplantation models, edited cells engraft and retain indels but fail to sustain consistent γ-globin induction. Epigenetic profiling across the KLF1 genetic locus reveals a remarkable resistance to loss of hypersensitive sites. These results establish a key principle: the transcriptional consequences of enhancer editing are strongly constrained by local genomic architecture. Attempts to mimic KLF1 haploinsufficiency by non-coding indels are blunted by dense regulatory architecture, enhancer redundancy, and long-range interaction. Thus, it may be difficult to develop KLF1 as a target for gene therapy for hemoglobinopathies until tools for recapitulating natural mutations via heterozygous edits are developed. Our findings underscore the observation that disruption of non-coding elements may not always recapitulate the biology of haploinsufficiency from heterozygous loss-of-function mutations. Structural and epigenetic properties of the human KLF1 locus constrain the in vivo effects of efficient editing at its non-coding regulatory elements, providing a cautionary tale for the design of functional enhancer modifications.
Abstract Neuronal variability is a fundamental feature of neuronal coding. In spiking activity, across-trial variance (ATV) normalized by mean spike count (i.e., the Fano factor) shows stimulus-induced quenching. ATV has also been studied in electro/magneto-encephalography (E/MEG) without normalization, revealing effects of stimulation and cognition. Here we show that outside of event-related potentials (ERPs), ATV for both EEG and local field potential (LFP) is nearly identical to intra-trial variance (ITV), which equals signal power. ATV–ITV correlation decreases during ERPs, proportional to how much the ERP explains total power. While EEG ATV shows post-stimulus quenching, LFP ATV does not, particularly in the gamma band, where power increases after stimulus onset. To provide an independent variability measure, we introduce CV(power), the coefficient of variation of signal power, as a mean-normalized metric. CV(power) is the inverse of the signal-to-noise ratio of power and thus related to decodability, offering a variability measure applicable to E/MEG and LFP.
Peripheral myelination requires precise axon-glia communication, yet the neuronal intrinsic machinery that governs the release of axonal signals remains incompletely understood. Here, we discover that RhoA, a classic cytoskeletal regulator, is highly expressed in postnatal spinal motoneurons and unexpectedly governs this axon-glia communication. RhoA conditional knockout in postnatal motoneurons causes profound peripheral hypomyelination without affecting neuronal survival, dendrites, or axonal caliber. Mechanistically, RhoA deficiency in postnatal spinal motoneurons attenuates ROCK2/p-Erk/SP1/BACE1 signaling and NRG1-Ⅲ secretion, then disrupts Schwann cells differentiation, lipid biosynthesis, and myelin formation. Together, this study reveals a novel, non-cell-autonomous role for RhoA and provides further insights into the complexity of neuronal control over peripheral myelination. This study used motoneuron-specific conditional knockout mice to explore the role of neuronal RhoA in postnatal myelination. Results revealed that neuronal RhoA deficiency down-regulates axonal NRG1-Ⅲ secretion via ROCK2/p-Erk/SP1/BACE1 axis which leads to hypomyelination in peripheral nerve.
Tactile adaptation, the adjustment of neural and behavioural responses to repeated stimulation, is crucial for interacting with our environment and is often affected in neurodevelopmental conditions. While GABA and glutamate, the main inhibitory and excitatory neurotransmitters, are essential for sensory encoding, their dynamic responses during tactile stimulation and their influence on perception remain unclear. Using functional magnetic resonance spectroscopy (fMRS), we investigated in vivo GABA and glutamine+glutamate (Glx) dynamics during repetitive tactile stimulation in healthy individuals. Here we found that repetitive stimulation markedly altered GABA–Glx coupling, suggesting an association with underlying adaptation processes. Moreover, during tactile stimulation, incorporating early Glx dynamics significantly improved prediction of GABA+ responses, while higher baseline Glx was associated with reduced feedforward inhibition, thereby linking excitatory tone to sensory processing. These findings highlight the critical role of GABA + /Glx interplay in shaping sensory processing. fMRS shows that repetitive touch alters GABA–Glx coupling, with early Glx changes predicting GABA+ responses. Baseline Glx shapes feedforward inhibition, linking neuronal excitatory tone to tactile adaptability
SWIFT (Single-organoid Workflow for quantitative Imaging classiFication and Tracking) is a fast and modular pipeline for quantitative, time-resolved organoid analysis from brightfield images. Requiring only minimal training annotations, SWIFT combines YOLOv8, SAM, and application-specific object classification to deliver accurate single-organoid segmentation, phenotyping, and tracking. The workflow is robust across organoid types and microscope systems. Applied to intestinal organoids, SWIFT uncovers dynamic Wnt-dependent morphological transitions, enabling scalable, high-throughput studies of epithelial plasticity.
Inflammation-induced osteoblast death disrupts bone homeostasis. However, how pro-survival bone morphogenetic protein (BMP) signaling intersects with the tumor necrosis factor (TNF)–NF-κB pathways remains unclear. Here we show that BMP4 protection of mouse osteoblasts from TNF-α–triggered inflammatory cell death requires Smad4 and NF-κB p65. ChIP-seq and ATAC-seq under TNF-α and BMP4 co-stimulation reveal broad overlap of Smad4 and p65 binding. Peak-shape–based quality scoring ranks two Samd9l-proximal accessible elements as the top candidates among ~20,000 peaks. These elements contact the Samd9l promoter, act as TNF-α–responsive enhancers and are required for Samd9l induction. One element mediates BMP4–Smad4-dependent attenuation of TNF-α–driven output. Samd9l depletion reduces TNF-α–induced cell-death-associated responses, and enhances ectopic bone formation in vivo. The corresponding mouse elements map to a regulatory region near the human SAMD9L locus. Together, these data delineate an enhancer-resolution BMP4–Smad4 brake on inflammatory NF-κB output that limits Samd9l-dependent osteoblast death, providing a mechanistic framework for supporting osteoblast survival during inflammation. Integration of ChIP-seq, ATAC-seq, 4C-seq and targeted chromatin perturbation to define how BMP4–Smad4 and TNF-α–NF-κB signals converge in osteoblasts. Smad4 restrains p65-dependent Samd9l enhancer output, limits inflammatory osteoblast death and supports bone-forming capacity.
