Nature最新文献

Glioblastoma is incurable and in urgent need of improved therapeutics¹. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death². Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin–adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD⁺ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD⁺ pocket³. In vivo, gliocidin penetrates the blood–brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.

The binding of multiple transcription factors (TFs) to genomic enhancers drives gene expression in mammalian cells¹. However, the molecular details that link enhancer sequence to TF binding, promoter state and transcription levels remain unclear. Here we applied single-molecule footprinting^2,3 to measure the simultaneous occupancy of TFs, nucleosomes and other regulatory proteins on engineered enhancer–promoter constructs with variable numbers of TF binding sites for both a synthetic TF and an endogenous TF involved in the type I interferon response. Although TF binding events on nucleosome-free DNA are independent, activation domains recruit cofactors that destabilize nucleosomes, driving observed TF binding cooperativity. Average TF occupancy linearly determines promoter activity, and we decompose TF strength into separable binding and activation terms. Finally, we develop thermodynamic and kinetic models that quantitatively predict both the enhancer binding microstates and gene expression dynamics. This work provides a template for the quantitative dissection of distinct contributors to gene expression, including TF activation domains, concentration, binding affinity, binding site configuration and recruitment of chromatin regulators.

T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection¹. In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the microanatomical underpinnings of this process in pre- and early postnatal stages, we established a quantitative morphological framework for the thymus—the Cortico-Medullary Axis—and used it to perform a spatially resolved analysis. Here, by applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions by the beginning of the the second trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall’s corpuscles and identify divergence in the timing of medullary entry between CD4 and CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation and OrganAxis construction (TissueTag), which can be applied to any tissue.

Since Hampé’s classic developmental experiments in the mid-twentieth century^1,2, the reduced avian fibula has sparked sustained curiosity^3,4,5,6. The fibula transformed throughout dinosaur evolution from a columnar structure into its splint-like avian form, a change long thought to be of little biomechanical consequence^3,6. Here we integrated comparative three-dimensional kinematic analyses with transitional morphologies from the fossil record to refute this assumption and show that the reduced fibula serves a crucial function in enabling extreme knee long-axis rotation (LAR). Extreme LAR is fundamental to avian locomotion and is regularly exploited by living birds to execute complex terrestrial manoeuvres⁷. We infer that the evolution of this capacity was preceded by restriction of the knee to hinge-like motion in early theropod dinosaurs, driven by the origin of a mid-shank articulation⁸ that precluded ancestral patterns of tibiofibular motion. Freeing of the fibula from the ankle joint later enabled mobilization of this initially static articulation and, in doing so, established a novel pattern of tibiofibular kinematics essential to the extreme levels of LAR retained by modern birds. Fibular reduction thus ushered in a transition to LAR-dominated three-dimensional limb control, profoundly altering the course of theropod locomotor evolution.