Nature最新文献

The global spread of multidrug-resistant pathogenic fungi presents a serious threat to human health, necessitating the discovery of antifungals with unique modes of action¹. However, conventional activity-based screening for previously undescribed antibiotics has been hampered by the high-frequency rediscovery of known compounds and the lack of new antifungal targets². Here we report the discovery of a polyene antifungal antibiotic, mandimycin, using a phylogeny-guided natural-product discovery platform. Mandimycin is biosynthesized by the mand gene cluster, has evolved in a distinct manner from known polyene macrolide antibiotics and is modified with three deoxy sugars. It has demonstrated potent and broad-spectrum fungicidal activity against a wide range of multidrug-resistant fungal pathogens in both in vitro and in vivo settings. In contrast to known polyene macrolide antibiotics that target ergosterol, mandimycin has a unique mode of action that involves targeting various phospholipids in fungal cell membranes, resulting in the release of essential ions from fungal cells. This unique ability to bind multiple targets gives it robust fungicidal activity as well as the capability to evade resistance. The identification of mandimycin using the phylogeny-guided natural-product discovery strategy represents an important advancement in uncovering antimicrobial compounds with distinct modes of action, which could be developed to combat multidrug-resistant fungal pathogens.

Rapid learning confers significant advantages on animals in ecological environments. Despite the need for speed, animals appear to only slowly learn to associate rewarded actions with predictive cues^1,2,3,4. This slow learning is thought to be supported by gradual changes to cue representation in the sensory cortex^2,5. However, evidence is growing that animals learn more rapidly than classical performance measures suggest^6,7, challenging the prevailing model of sensory cortical plasticity. Here we investigated the relationship between learning and sensory cortical representations. We trained mice on an auditory go/no-go task that dissociated the rapid acquisition of task contingencies (learning) from its slower expression (performance)⁷. Optogenetic silencing demonstrated that the auditory cortex drives both rapid learning and slower performance gains but becomes dispensable once mice achieve ‘expert’ performance. Instead of enhanced cue representations⁸, two-photon calcium imaging of auditory cortical neurons throughout learning revealed two higher-order signals that were causal to learning and performance. A reward-prediction signal emerged rapidly within tens of trials, was present after action-related errors early in training, and faded in expert mice. Silencing at the time of this signal impaired rapid learning, suggesting that it serves an associative role. A distinct cell ensemble encoded and controlled licking suppression that drove slower performance improvements. These ensembles were spatially clustered but uncoupled from sensory representations, indicating higher-order functional segregation within auditory cortex. Our results reveal that the sensory cortex manifests higher-order computations that separably drive rapid learning and slower performance improvements, reshaping our understanding of the fundamental role of the sensory cortex.

Phonon polaritons are quasiparticles resulting from the coherent coupling of photons with optical phonons in polar dielectrics¹. Owing to their exceptional ability to confine electric fields to deep-subwavelength scales with low loss, they are uniquely poised to enable a suite of applications beyond the reach of conventional photonics, such as subdiffraction imaging² and near-field energy transfer^3,4,5. The conventional approach to exciting phonon polaritons through optical methods, however, involves costly light sources along with near-field schemes^6,7, and generally leads to low excitation efficiency owing to substantial momentum mismatch between phonon polaritons and free-space photons. Here we demonstrate that under proper conditions, phonon polaritons can be excited all-electrically by drifting charge carriers. Specifically, in hexagonal boron nitride (hBN)/graphene heterostructures, by electrically driving charge carriers in ultrahigh-mobility graphene out of equilibrium, we observe bright electroluminescence of hBN’s hyperbolic phonon polaritons (HPhPs) at mid-infrared frequencies, which shows a temperature and carrier density dependence distinct from black-body thermal emission. Moreover, the carrier density dependence of the HPhP electroluminescence spectra reveals that HPhP electroluminescence can arise from both interband transition and intraband Cherenkov radiation⁸ of charge carriers in graphene. The HPhP electroluminescence offers avenues for realizing electrically pumped mid-infrared and terahertz phonon-polariton light sources.

Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ^1,2. Mouse lungs follow a stereotyped sequence of fibrogenesis-to-resolution after bleomycin injury³, and we reasoned that profiling post-injury histological stages could uncover pro-fibrotic versus anti-fibrotic features with functional value for human fibrosis. Here we quantified spatiotemporally resolved matrix transformations for integration with multi-omic data. First, we charted stepwise trajectories of matrix aberration versus resolution, derived from a high-dimensional set of histological fibre features, that denoted a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally enriched ‘ECM-secreting’ (Csmd1-expressing) and ‘pro-resolving’ (Cd248-expressing) fibroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial–transcriptional neighbourhoods by fibroblast subtype, identifying distinct fibrotic versus non-fibrotic biomolecular milieu. Critically, pro-resolving fibroblast instillation helped to ameliorate fibrosis in vivo. Furthermore, the fibroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis at protein level additionally uncovered analogous fibroblast subtypes and neighbourhoods in human disease. Collectively, these findings establish an atlas of pro- and anti-fibrotic factors that underlie lung matrix architecture and implicate fibroblast-associated biological features in modulating fibrotic progression versus resolution.