Browse Articles

Identification of cellular intermediates unveils unique enzymes for flagellar glycan biosynthesis in <i>Clostridioides difficile</i>

Glycosylation of bacterial surface proteins, such as flagellin (FliC), is important for their function and is often involved in virulence of pathogens. Glycans can be further modified by so-called postglycosylation modifications (PGMs), often resulting in exclusive molecular structures. In Clostridioides difficile, a unique glycan structure (Type A) decorates FliC (which forms the flagellar filament) that consists of an O -linked N -acetyl-β- d -glucosamine (GlcNAc) modified with an N -methyl-L-threonine via a phosphodiester linkage. This PGM is synthesized by a set of four enzymes encoded in one operon ( ftaABCD ), but the exact biosynthesis pathway and biosynthetic intermediates remain unknown. In this study, we chemically synthesized two hitherto undescribed biosynthetic intermediates that we predicted based on bioinformatic analyses, CDP-threonine and CDP- N -methylthreonine. We showed that they are involved in the Type A PGM biosynthesis, as evidenced by mass spectrometric analyses of extracts of a set of C. difficile mutant strains. Furthermore, we characterized FtaC to be a SAM-dependent CDP-threonine N -methyltransferase that installs the methyl group on CDP-threonine prior to transfer of the PGM to GlcNAc-FliC, and we revealed FtaD as the CDP- N -methylthreonine:GlcNAc N -methylthreoninephosphotransferase. Finally, using recombinantly expressed FtaC and FtaD in combination with synthetic CDP-threonine, we reconstituted the biosynthesis pathway of the Type A PGM in vitro. Overall, our results open avenues to explore these unique biosynthesis enzymes in molecular detail to provide new points of entry for the development of biosynthesis inhibitors and tools to study the role of this PGM in virulence and flagellar function.

Sensory nerve-derived signaling coordinates oropharyngeal structural organization that supports suckling and vocalization in neonatal mice

Probing anharmonic and heterogeneous carrier dynamics across sublattice melting in a minimal model superionic conductor

Despite decades of research, the microscopic origin of sublattice melting and fast ion transport in superionic conductors remains elusive. Here, we introduce a chemically neutral minimal binary model consisting of a rigid host lattice stabilized by short-range steric repulsion and a soft carrier sublattice interacting via long-range Wigner-type forces. This contrast naturally produces distinct melting temperatures and an intermediate sublattice-melting phase in which carriers become fluidlike while the host remains crystalline. Molecular dynamics simulations identify multiple dynamical regimes–crystalline, sublattice-melt, and fully molten–marked by sharp changes in diffusivity, structural correlations, and dynamical heterogeneity. Near sublattice melting, carrier motion is strongly anharmonic and spatially heterogeneous, beyond mean-field hopping descriptions. By tuning the density, we demonstrate that sublattice melting can be continuously controlled, establishing a direct link between lattice softness, anharmonicity, and collective ion transport. Comparison with conventional long-range Coulombic models confirms that our minimal model reproduces the key dynamical signatures of superionicity, providing a unified microscopic foundation for designing mechanically robust superionic conductors.

Synergistic interfacial-mechanical binder design for high-areal-capacity and long-lifespan Si-based negative electrodes in practical pouch cells

Covalent phytobilin adducts of GUN4 implicate a photoprotective mechanism in chlorophyll biosynthesis

In the green alga Chlamydomonas reinhardtii, loss of chlorophyll synthesis under light stress is associated with degradation of the porphyrin-binding H-subunit (CHLH1) of magnesium chelatase (MgCh). This degradation is exacerbated by the absence of GENOMES UNCOUPLED 4 protein (GUN4) or its phycocyanobilin (PCB) ligand. PCB is synthesized from heme via the action of heme oxygenase HMOX1 followed by a ferredoxin-dependent bilin reductase (FDBR), a ubiquitous enzyme family in oxyphototrophs. We show that C. reinhardtii cells lacking GUN4 and/or HMOX1 accumulate the MgCh substrate protoporphyrin IX (PPIX), a potent generator of singlet oxygen ( 1 O 2 ). CHLH1 is unstable in gun4 or hmox1 mutants, phenotypes that can be rescued by deletion of known cytosolic 1 O 2 response proteins SAK1 or SOR1. GUN4 Trp residues are oxidized in the presence of PPIX and near-ultraviolet light (nUV), and spectroscopic changes in GUN4 seen in the presence of PCB are ablated by PPIX and nUV. The combination of PPIX, PCB, and nUV result in formation of covalent GUN4–bilin adducts. Such adducts are formed both in vivo and in vitro and are also formed in GUN4 proteins from cyanobacteria and plants. In GUN4 variants, loss of adduct formation correlates with Chlamydomonas growth defects under light stress. We propose that phytobilin adduct formation provides a mechanism for detoxifying 1 O 2 and sustaining chlorophyll synthesis in the presence of light and oxygen, thereby explaining the ubiquity of FDBRs in eukaryotic algae.

Molecular basis of DosR-dependent transcription activation in Mycobacterium tuberculosis

<i>Arabidopsis</i> BSL phosphatases regulate zygote polarity through a brassinosteroid-independent essential function in MAP kinase signaling

The main axis of the plant body is established in early embryogenesis. Polar growth and asymmetric division of the Arabidopsis zygote require the Mitogen-Activated Protein (MAP) kinase kinase kinase YODA and the MAP kinases MPK3/MPK6, but regulation of this signaling cascade is not well understood. Here, we show that three BSU1-LIKE phosphatases (BSL1-3) are essential positive regulators: A combined loss causes closely similar defects to loss of the YODA MAP kinase cascade, resulting in nonpolar embryos; transcriptional profiling and cell-fate markers confirm that BSL phosphatases and the MAP kinase cascade regulate the same process. Unexpectedly, the founding member of the family, BSU1, appears dispensable. These results cast doubt on the view of BSU1-family phosphatases as core components of brassinosteroid hormone signaling. MPK3 activity shows striking sensitivity to BSL dosage, and genetic interactions with activated MPK3 suggest that BSL phosphatases function downstream of YODA and either in conjunction with or downstream of MPK3/MPK6, implying a novel mechanism of MPK regulation.

Potential-mediated enol-keto equilibrium in phenol electro-hydrogenation on platinum

Transregional astrocyte-dependent metaplasticity in the hippocampus

Learning-related synaptic plasticity is regulated by metaplasticity, which adjusts plasticity thresholds in an activity-dependent manner. We have previously described a heterodendritic form of metaplasticity whereby priming stimulation in stratum oriens (SO) inhibits subsequent long-term potentiation (LTP) in the neighboring stratum radiatum of the hippocampal CA1 region. Here, we report that this metaplasticity is transregional, in that the SO priming stimulation also inhibits later LTP induction at dentate gyrus (DG) middle molecular layer (MML) synapses, both in vitro and in vivo. This effect operates across the hippocampal fissure and occurs in the absence of CA3, highlighting a previously unappreciated reverse-direction and long-distance hippocampal crosstalk. Our findings demonstrate an essential role of astrocytes as SO priming elicited an increase in the frequency of calcium (Ca 2+ ) events in astrocytes in the DG MML, while the metaplasticity effect was blocked by calcium-buffering in MML astrocytes. It could be triggered by either activation of M1 muscarinic acetylcholine receptors or group II metabotropic glutamate receptors, and was critically dependent on inositol 1,4,5-trisphosphate receptor type 2 signaling. The transregional inhibition of LTP was mediated by astrocytic release of tumor necrosis factor (TNF), which likely acts in an autocrine fashion on astrocytic TNF type 1 receptors (TNFR1s). Downstream of TNF-TNFR1 signaling, the inhibition of MML LTP was mediated by the activation of GluN2B-containing N-methyl-D-aspartate receptors. Thus, a complex, bidirectional neuron–glia signaling cascade orchestrates long-distance metaplasticity across hippocampal subregions, providing a framework for understanding how hippocampal neuronal networks dynamically regulate plasticity thresholds across space and time.

Self-heating-induced blocking in nanopores enables neuromorphic ionic computing

The structure of correlated variability reflects task-relevant information in sensory neurons

Shared trial-to-trial variability across sensory neurons is reliably reduced when perceptual performance improves, yet this variability is low dimensional, so it could be ignored by an optimal readout mechanism. Why then is it so consistently related to behavior? We propose that shared variability both reflects circuit structure and reveals the information communicated to downstream areas. In this framework, the same connectivity that shapes signal propagation also shapes shared variability. Using a circuit model, we show that when sensory signals align with shared variability, behaviorally relevant information is amplified without compromising coding fidelity. Analyses of neural population recordings from multiple brain areas and tasks reveal that the dominant axis of shared variability consistently aligns with task-relevant stimulus features and action plans. Finally, the behavioral impact of microstimulation can be explained by the extent to which it changes projections onto the shared variability axis. These findings suggest that shared variability may illuminate, rather than obscure, the neural dimensions that guide behavior.

Dorsal horn DCC amplification loop induced by endplate osteoclasts generates chronic nociplastic low back pain in male mice

Intracellular structural modifications of natural peptidoglycan fragments preceding NOD2 signaling in mammalian cells

Bacterial peptidoglycan fragments (PGNs) are pathogen-associated molecular patterns that activate the mammalian innate immune system, particularly through NOD2 signaling pathways. Since NOD2 is a cytosolic sensor in mammalian cells, cellular assays are commonly used to identify bioactive PGNs that elicit NOD2 response, with muramyl dipeptide (MDP) long recognized as the minimal NOD2 agonist. However, recent studies have highlighted the intracellular phosphorylation of MDP by mammalian N -acetylglucosamine kinase (NAGK) as a critical prerequisite for NOD2 activation, emphasizing the need for further investigation into other host-mediated processing of PGNs. In this study, we examined how various bacterial PGNs, differing in saccharide and stem peptide length, undergo intracellular structural modifications within mammalian cells. Our findings show that disaccharide PGNs are processed through intracellular glycosidic cleavage to generate monosaccharide MurNAc-containing PGNs intracellularly, followed by NAGK-dependent phosphorylation, uncovering an additional essential step that precedes NOD2 activation. To identify the glycosidase responsible for disaccharide PGN cleavage, we provide biochemical and cellular observations that human O -GlcNAcase functions as a promiscuous glycosidase capable of processing certain disaccharide PGNs and potentially modulate their NOD2 activation. Furthermore, we demonstrate that PGNs with a lysine-type tripeptide stem are specifically cleaved into dipeptides and that phosphorylated PGNs are subjected to dephosphorylation in mammalian cells. Together, these findings offer insights into the metabolism and intracellular processing of PGNs in mammalian cells, which are crucial in shaping the host innate immune responses.

Universal energy-space localization and stable quantum phases against time-dependent perturbations

Abstract Stability against perturbations is a defining property of quantum many-body phases of matter. However, most rigorous stabilities are only established for static perturbations; whether any system can remain stable against generic time-dependent perturbations is largely elusive. Here, we identify a universal phenomenon, where the evolving state driven by time-dependent q -local Hamiltonians can be exponentially localized in an energy window of instantaneous spectrum, and prove its survival under generic time-dependent perturbations. Applying such energy-space localization to classical and quantum LDPC codes whose codewords are separated by extensive energy barriers, we show that the system remains localized near the original codeword for an exponentially long time under generic time-dependent perturbations. For classical optimization problems with clustered solution spaces, the stability becomes an obstacle for quantum Hamiltonian-based algorithms to escape local minima. Our work provides a new lens for analyzing quantum non-equilibrium dynamics and tools for establishing stability and designing quantum algorithms.

Morphological and functional diversity of spatially resolved vestibular ganglion neuron cell types

Vestibular ganglion neurons (VGNs) are the primary sensory neurons of the vestibular system, a relatively understudied sensory modality that is essential for maintaining visual stability and postural balance. Compared with other sensory systems, our understanding of the molecular heterogeneity of VGNs and its contribution to the diverse functions of the vestibular system remains limited. Using single-cell and spatial transcriptomics, we defined five transcriptionally distinct VGN cell types with discrete spatial distributions across the ganglion. These VGN cell types demonstrate organ-specific innervation patterns, target defined zones within each organ, and form characteristic synaptic endings. To probe their functional roles, we generated genetic tools that selectively label each VGN cell type. Leveraging these tools, we identified a cell type contributing to gravity sensing and otolith-dependent vestibulo-ocular reflexes, revealing a cell type–specific basis for modality-selective vestibular computations.

Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and prevents post-ablation HCC relapse

Controlled generation of 3D vortices in driven atomic Josephson junctions

We propose an ac-driven atomic Josephson junction as a clean and tunable source of three-dimensional (3D) solitary waves in quantum fluids. Depending on the height of the junction barrier, the emitted excitations appear as vortex rings at low velocity or vorticity-free rarefaction pulses near the sound velocity, thus spanning the complete Jones-Roberts family of solitons. The Shapiro-step phenomenon renders the emission deterministic: on the first, second, third Shapiro steps, the junction ejects one, two, and three solitary excitations per drive cycle. This enables controlled generation of single- and multiexcitation configurations, allowing detailed studies of the full crossover between vortex rings and rarefaction pulses and their interaction dynamics. By Shapiro phase locking, multiexcitations are emitted in succession and interact, revealing leapfrogging motion of two and three coaxial rings and their decay via boundary-assisted, sound-mediated processes. This ac-driven protocol establishes a compact and reproducible platform for generating, classifying, and controlling 3D solitonic excitations, paving the way for precision studies of nonlinear vortex dynamics, dissipation, and quantum turbulence in trapped superfluids.

DiscERN: an automated genome mining tool for the discovery of evolutionarily related natural products

Abstract Targeted genome mining to expand known families of natural products is a powerful strategy for discovering bioactive compounds, yet it remains a significant bioinformatics challenge. While tools exist for de novo biosynthetic gene cluster identification and large-scale unsupervised clustering, dedicated methods for the targeted, hypothesis-driven expansion of user-defined BGC families are lacking. Here, we present DiscERN (Discoverer of Evolutionarily Related Natural products), a user-friendly tool designed to address this gap. DiscERN leverages a multi-modal ensemble method that integrates four complementary algorithms classifying biosynthetic gene clusters based on Pfam content, sequence homology, and predicted product structure. This approach allows users to strategically balance discovery sensitivity with predictive precision to suit diverse research goals. We demonstrate DiscERN’s utility by applying it to a large collection of actinomycete genomes and validating its predictive power through the successful isolation of discomycin A, a new calcium-dependent lipopeptide antibiotic, from a silent biosynthetic gene cluster. DiscERN provides a robust and accessible platform that streamlines the path from genomic data to a prioritised list of candidate biosynthetic gene clusters, effectively bridging the gap between in silico prediction and bioactive compound discovery.

Shared neurogenetic substrates of nonplanning impulsivity and procrastination

Procrastination has a maladaptive impact on health and survival, yet it remains moderately heritable, presenting a biological paradox. Procrastination has been conceptualized as a byproduct of impulsivity, explaining its prevalence despite no discernible adaptive benefit. However, their shared neurobiological substrates have yet to be elucidated. Using a longitudinal twin cohort ( N = 154), we show that nonplanning impulsivity (NPI) during late adolescence and early adulthood is prospectively associated with procrastination in later life. This effect was independently replicated in two cross-sectional cohorts ( N = 327; N = 1,543). Twin modeling using an additive genetic and nonshared environmental (AE) framework, together with a meta-analysis of twin studies ( N = 3,656 twin pairs), revealed significant shared genetic contributions ( r g = 0.51). Beyond genetic overlap, neuroimaging meta-analysis ( NeuroSynth meta-analysis for impulsivity: k = 198 studies, 5855 loci; mini meta-analysis for procrastination: k = 5 studies, 7 independent samples, N cumulative = 893 participants), normative modeling ( N = 37,407), and seed-based d mapping (SDM) converged on the left dorsolateral prefrontal cortex (DLPFC) as the region of maximal overlap between NPI and procrastination. The transcriptional profiles of the left DLPFC and impulsivity-associated genes exhibited functional convergence on regulation of biological and cellular processes. These genes showed brain-specific expression and associations with cortical metabolism, neurodegenerative disease, and developmental expression peaks, indicating a shared molecular basis for the neurogenetic architecture of procrastination. Together, our findings delineate a cross-scale characterization of the shared neurogenetic substrates linking NPI and procrastination, offering empirical evidence that elucidates the biological origins of procrastination.

Distinct molecular subgroups in pediatric and young-onset meningiomas require age-adapted risk stratification

Abstract Meningiomas in pediatric and adolescent/young adult patients are poorly characterized biologically and clinically, and risk stratification is largely extrapolated from adult tumors. We analyze 293 tumors from patients aged 0–39 years using integrated histopathological and molecular profiling. Youth-onset meningiomas are enriched for NF2 and SMARCE1 alterations and exhibit a gain-dominated copy-number landscape, including recurrent chr17q gain, whereas canonical adult high-risk features, such as chr1p loss, lack prognostic significance. Adult-derived prognostic frameworks, including WHO grade, methylation-based stratification and integrated risk scores, fail to predict progression in patients ≤21 years of age. Tumors segregate into age-enriched epigenetic clusters defined by SMARCE1 , NF2 and BAP1 alterations. Among NF2 -altered tumors, patterns of Merlin inactivation, shaped by germline status and co-occurring copy-number variations, delineate biologically divergent subsets. In patients ≤21 years, extent of resection is the dominant predictor of outcome, while molecular features further refine risk assessment. These findings define pediatric and young adult meningiomas as a distinct molecular entity and support age-adapted risk refinement that integrates molecular features with strong clinical determinants.