Nature Communications最新文献

The initial fine-tuning processes are crucial for successful bone regeneration, as they guide skeletal stem cells through progenitor differentiation toward osteo- or chondrogenic fate. While fate determination processes are well-documented, the mechanisms preceding progenitor commitment remain poorly understood. Here, we identified a transcription factor, Zfp260, as pivotal for stem cell maturation into progenitors and directing osteogenic differentiation. Zfp260 is markedly up-regulated as cells transition from stem to progenitor stages; its dysfunction causes lineage arrest at the progenitor stage, impairing bone repair. Zfp260 is required for maintaining chromatin accessibility and regulates Runx2 expression by forming super-enhancer complexes. Furthermore, the PKCα kinase phosphorylates Zfp260 at residues Y173, S182, and S197, which are essential for its functional activity. Mutations at these residues significantly impair its functionality. These findings position Zfp260 as a vital factor bridging stem cell activation with progenitor cell fate determination, unveiling a element fundamental to successful bone regeneration.

HEPN–MNT, a type VII TA module, comprises the HEPN toxin and the MNT antitoxin, which acts as a nucleotidyltransferase that transfers the NMP moiety to the corresponding HEPN toxin, thereby interfering with its toxicity. Here, we report crystal structures of the Legionella pneumophila HEPN–MNT module, including HEPN, AMPylated HEPN, MNT, and the HEPN–MNT complex. Our structural analysis and biochemical assays, suggest that HEPN is a metal-dependent RNase and identify its active site residues. We also elucidate the oligomeric state of HEPN in solution. Interestingly, L. pneumophila MNT, which lacks a long C-terminal α4 helix, controls the toxicity of HEPN toxin via a distinct binding mode with HEPN. Finally, we propose a comprehensive regulatory mechanism of the L. pneumophila HEPN–MNT module based on structural and functional studies. These results provide insight into the type VII HEPN–MNT TA system.

While selective defunctionalizations are valuable in organic synthesis, hydrodeamination of primary amines poses challenges. Deuterodeamination, analogous to hydrodeamination, presents even greater difficulties due to its frequently slower deuteration rate, interference by hydrogenation and constraints in deuterated sources. This study introduces a reliable, robust, and scalable hydro- and deuterodeamination method capable of handling various primary amines. Defined by its mild reaction conditions, rapid completion, simplified purification facilitated by water-soluble byproducts, the method leverages deuterium oxide as a deuterium source and employs commercialized O-diphenylphosphinylhydroxylamine for deamination. Applied to a diverse range of biologically active molecules, it has consistently achieved high yields and efficient deuterium incorporation. By synergizing with site-selective C–H functionalization of primary aliphatic amines, our method reveals synthetic strategies utilizing nitrogen atom as a traceless directing group, encompassing deaminative alkylation, 1,1-deuteroalkylation, 1,1-dialkylation, 1,1,1-deuterodialkylation, C–H arylation, and 1,3-deuteroarylation. Emphasizing this innovation, the processes of deaminative degree-controlled deuteration have been developed.

Biofilm formation is an important mechanism of survival and persistence for many bacterial pathogens. These multicellular communities contain subpopulations of cells that display metabolic and transcriptional diversity along with recalcitrance to antibiotics and host immune defenses. Here, we present an optimized bacterial single-cell RNA sequencing method, BaSSSh-seq, to study Staphylococcus aureus diversity during biofilm growth and transcriptional adaptations following immune cell exposure. BaSSSh-seq captures extensive transcriptional heterogeneity during biofilm compared to planktonic growth. We quantify and visualize transcriptional regulatory networks across heterogeneous biofilm subpopulations and identify gene sets that are associated with a trajectory from planktonic to biofilm growth. BaSSSh-seq also detects alterations in biofilm metabolism, stress response, and virulence induced by distinct immune cell populations. This work facilitates the exploration of biofilm dynamics at single-cell resolution, unlocking the potential for identifying biofilm adaptations to environmental signals and immune pressure.

Multi-target single-molecule super-resolution fluorescence microscopy offers a powerful means of understanding the distributions and interplay between multiple subcellular structures at the nanoscale. However, single-molecule super-resolution imaging of whole mammalian cells is often hampered by high fluorescence background and slow acquisition speeds, especially when imaging multiple targets in 3D. In this work, we have mitigated these issues by developing a steerable, dithered, single-objective tilted light sheet for optical sectioning to reduce fluorescence background and a pipeline for 3D nanoprinting microfluidic systems for reflection of the light sheet into the sample. This easily adaptable microfluidic fabrication pipeline allows for the incorporation of reflective optics into microfluidic channels without disrupting efficient and automated solution exchange. We combine these innovations with point spread function engineering for nanoscale localization of individual molecules in 3D, deep learning for analysis of overlapping emitters, active 3D stabilization for drift correction and long-term imaging, and Exchange-PAINT for sequential multi-target imaging without chromatic offsets. We then demonstrate that this platform, termed soTILT3D, enables whole-cell multi-target 3D single-molecule super-resolution imaging with improved precision and imaging speed.

The Pacific islands and Island Southeast Asia have experienced multiple waves of human migrations, providing a case study for exploring the potential of ancient microbiomes to study human migration. We perform a metagenomic study of archaeological dental calculus from 102 individuals, originating from 10 Pacific islands and 1 island in Island Southeast Asia spanning ~3000 years. Oral microbiome DNA preservation in calculus is far higher than that of human DNA in archaeological bone, and comparable to that of calculus from temperate regions. Oral microbial community composition is minimally driven by time period and geography in Pacific and Island Southeast Asia calculus, but is found to be distinctive compared to calculus from Europe, Africa, and Asia. Phylogenies of individual bacterial species in Pacific and Island Southeast Asia calculus reflect geography. Archaeological dental calculus shows good preservation in tropical regions and the potential to yield information about past human migrations, complementing studies of the human genome.

Aldehydes are ubiquitous in star-forming regions and carbonaceous chondrites, serving as essential intermediates in metabolic pathways and molecular mass growth processes to vital biomolecules necessary for the origins of life. However, their interstellar formation mechanisms have remained largely elusive. Here, we unveil the formation of lactaldehyde (CH₃CH(OH)CHO) by barrierless recombination of formyl (HĊO) and 1-hydroxyethyl (CH₃ĊHOH) radicals in interstellar ice analogs composed of carbon monoxide (CO) and ethanol (CH₃CH₂OH). Lactaldehyde and its isomers 3-hydroxypropanal (HOCH₂CH₂CHO), ethyl formate (CH₃CH₂OCHO), and 1,3-propenediol (HOCH₂CHCHOH) are identified in the gas phase utilizing isomer-selective photoionization reflectron time-of-flight mass spectrometry and isotopic substitution studies. These findings reveal fundamental formation pathways for complex, biologically relevant aldehydes through non-equilibrium reactions in interstellar environments. Once synthesized, lactaldehyde can act as a key precursor to critical biomolecules such as sugars, sugar acids, and amino acids in deep space.

Neural preconfigured activity patterns (nPAPs), conceptualized as organized activity parcellated into groups of neurons, have been proposed as building blocks for cognitive and sensory processing. However, their existence and function in motor networks have been scarcely studied. Here, we explore the possibility that nPAPs are present in the motor thalamus (VL/VM) and their potential contribution to motor-related activity. To this end, we developed a preparation where VL/VM multiunitary activity could be robustly recorded in mouse behavior evoked by primary motor cortex (M1) optogenetic stimulation and forelimb movements. VL/VM-evoked activity was organized as rigid stereotypical activity patterns at the single and population levels. These activity patterns were unable to dynamically adapt to different temporal architectures of M1 stimulation. Moreover, they were experience-independent, present in virtually all animals, and pairs of neurons with high correlations during M1-stimulation also presented higher correlations during spontaneous activity, confirming their preconfigured nature. Finally, subpopulations expressing specific M1-evoked patterns also displayed specific movement-related patterns. Our data demonstrate that the behaviorally related identity of specific neural subpopulations is tightly linked to nPAPs.

Cardiopharyngeal mesoderm contributes to the formation of the heart and head muscles. However, the mechanisms governing cardiopharyngeal mesoderm specification remain unclear. Here, we reproduce cardiopharyngeal mesoderm specification towards cardiac and skeletal muscle lineages with gastruloids from mouse embryonic stem cells. By conducting a comprehensive temporal analysis of cardiopharyngeal mesoderm development and differentiation in gastruloids compared to mouse embryos, we present the evidence for skeletal myogenesis in gastruloids. We identify different subpopulations of cardiomyocytes and skeletal muscles, the latter of which most likely correspond to different states of myogenesis with “head-like” and “trunk-like” skeletal myoblasts. In this work, we unveil the potential of gastruloids to undergo specification into both cardiac and skeletal muscle lineages, allowing the investigation of the mechanisms of cardiopharyngeal mesoderm differentiation in development and how this could be affected in congenital diseases.

LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.