Nature Communications最新文献

Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 10²² compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets.

Obesity is regarded as a chronic inflammatory disease involving adipose tissue macrophages (ATM), but whether immunometabolic reprogramming of ATM affects obesity remains unclarified. Here we show that in ATM glutaminolysis is the fundamental metabolic flux providing energy and substrate, bridging with AMP-activated protein kinase (AMPK) activity, succinate-induced interleukin-1β (IL-1β) production, and obesity. Abrogation of AMPKα in myeloid cells promotes proinflammatory ATM, impairs thermogenesis and energy expenditure, and aggravates obesity in mice fed with high-fat diet (HFD). Conversely, IL-1β neutralization or myeloid IL-1β abrogation prevents obesity caused by AMPKα deficiency. Mechanistically, ATP generated from glutaminolysis suppresses AMPK to decrease phosphorylation of the β subunit of succinyl-CoA synthetase (SUCLA2), thereby resulting in the activation of succinyl-CoA synthetase and the overproduction of succinate and IL-1β; by contrast, siRNA-mediated SUCLA2 knockdown reduces obesity induced by HFD in mice. Lastly, phosphorylated SUCLA2 in ATM correlates negatively with obesity in humans. Our results thus implicate a glutaminolysis/AMPK/SUCLA2/IL-1β axis of inflammation and obesity regulation in ATM.

Environmental surveillance of antibiotic resistance genes (ARGs) is critical for understanding and mitigating the spread of antimicrobial resistance. Current short-read-based ARG profiling methods are limited in their ability to provide detailed host information, which is indispensable for tracking the transmission and assessing the risk of ARGs. Here, we present Argo, a novel approach that leverages long-read overlapping to rapidly identify and quantify ARGs in complex environmental metagenomes at the species level. Argo significantly enhances the resolution of ARG detection by assigning taxonomic labels collectively to clusters of reads, rather than to individual reads. By benchmarking the performance in host identification using simulation, we confirm the advantage of long-read overlapping over existing metagenomic profiling strategies in terms of accuracy. Using sequenced mock communities with varying quality scores and read lengths, along with a global fecal dataset comprising 329 human and non-human primate samples, we demonstrate Argo’s capability to deliver comprehensive and species-resolved ARG profiles in real settings.

Neutrophil extracellular traps (NETs) play a critical role in acute myocardial infarction (AMI) and the externalization of S100 family members. Here, we show the effects of S100A12 on NETs formation and myocardial injury following AMI. S100A12 expression increases rapidly in neutrophils and peaks on day 1 after AMI, promoting NETs production and exacerbating myocardial injury. DNase I, an inhibitor of NETs, reduces apoptosis of cardiomyocytes induced by S100A12. Mechanistically, the interaction of S100A12 and Annexin A5 (ANXA5) enhances calcium influx and promotes NETs formation. Blockage of ANXA5 effectively attenuates heart function impairment after AMI. Finally, we show that plasma S100A12 levels correlate with dsDNA concentration, and this correlation is associated with an increased risk of all-cause mortality during the 1-year follow-up of AMI patients. These findings, derived from male mice, reveal the S100A12-ANXA5-calcium influx axis as a potential therapeutic target and biomarker for AMI.

Cellular agriculture is a novel platform for addressing the issues of protein scarcity, environmental pressures, and food safety. However, expanding seed cells at a large scale remains a prerequisite for achieving industrial cultured meat production. We here propose the production of large-pore-sized edible porous microcarriers (EPMs) by using NaCl to precisely control ice crystal growth during cryogenic crosslinking. Muscle satellite cells (SCs) and adipose-derived stem cells (ASCs) from large yellow croakers exhibit remarkable adhesion, proliferation, and differentiation on gelatin-based EPMs. Following consecutive expansion, SCs and ASCs densities reach 6.25 × 10⁵ and 5.77 × 10⁵ cells/mL, leading to a 499-fold and 461-fold increase in cell numbers, respectively. Subsequently, the mature microtissues are incorporated into a bioink, thereby enabling successful three-dimensional printing of cultured fish fillets with sensory properties similar to native fish fillets. EPM-based cell expansion and food structuring techniques are promising in facilitating large-scale cultured fish meat production.

Applying full-waveform methods to image small-scale structures of geophysical interest buried within the Earth requires the computation of the seismic wavefield over large distances compared to the target wavelengths. This represents a considerable computational cost when using state-of-the-art numerical integration of the equations of motion in three-dimensional earth models. “Box Tomography” is a hybrid method that breaks up the wavefield computation into three parts, only one of which needs to be iterated for each model update, significantly saving computational time. To deploy this method in remote regions containing a fluid-solid boundary, one needs to construct artificial sources that confine the seismic wavefield within a small region that straddles this boundary. The difficulty arises from the need to combine the solid-fluid coupling with a hybrid numerical simulation in this region. Here, we report a reconciliation of different displacement potential expressions used for solving the acoustic wave equation and propose a unified framework for hybrid simulations. This represents a significant step towards applying ’Box Tomography’ in arbitrary regions inside the Earth, achieving a thousand-fold computational cost reduction compared to standard approaches without compromising accuracy. We also present examples of benchmarks of the hybrid simulations in the case of target regions at the ocean floor and the core-mantle boundary.

Apart from the classic features, it is almost unknown whether there exist other new pathological features during pre-metastatic niche formation in hepatocellular carcinoma (HCC). Our previous works have highlighted the contribution of increased matrix stiffness to lung pre-metastatic niche formation and metastasis in HCC. However, whether increased matrix stiffness influences glucose metabolism and supply of lung pre-metastatic niche remains largely unclear. Here we uncover the underlying mechanism by which matrix stiffness-tuned exosomal miRNAs as the major contributor modulate glucose enrichment during lung pre-metastatic niche formation through decreasing the glucose uptake and consumption of lung fibroblasts and increasing angiogenesis and vascular permeability. Our findings suggest that glucose enrichment, a new characteristic of the lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs, is essential for the colonization and survival of metastatic tumor cells, as well as subsequent metastatic foci growth.

Understanding the interaction between genetic and epigenetic variation remains a challenge due to confounding environmental factors. We propose that human induced Pluripotent Stem Cells (iPSCs) are an excellent model to study the relationship between genetic and epigenetic variation while controlling for environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data from iPSC lines and three iPSC-derived cell types (neural stem cell (NSC), motor neuron, monocyte) from three healthy donors. We find that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in differentiated cells. Additionally, cell type is a stronger source of epigenetic variation than genetic variation. Further, we elucidate a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell types in which they may be acting.

The reverse piezoelectric effect allows for the conversion of an electrical input signal into mechanical displacement and forms the basis for the operation of positioners and actuators. Addressing the practical need for cost-effective sensitive materials, we introduce erbium-doped lead magnesium niobium titanate ceramics which exhibit exceptionally high strain (3.19% bipolar and 0.8% unipolar) under a very low applied field of 2 kV mm⁻¹, resulting in record-breaking piezoelectric coefficients (d₃₃* values of 15,950 and 4014 pm V⁻¹, respectively). These exceptional properties stem from a combination of factors including the sensitivity of polar nanoregions to the applied field in this relaxor ferroelectric system, the thickness of the sample, and the energetic availability of polymorphs with different polar structures where a change in polarisation direction occurs at the field induced phase transition. Surpassing the performance of single crystal materials, our findings establish a benchmark in piezoelectric performance with implications for many diverse applications.

The hadal zone, >6 km deep, remains one of the least understood ecosystems on Earth. We address bioturbational structures in sediment cores from depths exceeding 7.5 km, collected during the IODP Expedition 386 in the Japan Trench. Micro-CT imaging on 20 core sections allowed to identify biogenic sedimentary structures (incipient trace fossils) and their colonization successions within gravity flow deposits. Their frequency, and consequent changes in substrate consistency, oxygenation and organic matter delivery and remineralization controlled the endobenthic colonization. The gravity-flow beds show recurring bioturbation successions: The initial colonization is characterized by deposit-feeding structures such as Phycosiphon, Nereites and Artichnus generating typically 20 cm thick intensively bioturbated fabrics. The final colonization stage comprises slender spiral, lobate and deeply penetrating straight and ramifying burrow systems such as Gyrolithes, Pilichnus and Trichichnus, interpreted to include burrows of microbe farming and chemosymbiotic invertebrates. The main factor precluding colonization is soupy substrate. Organic matter degradation and post-event upward expansion of the anoxic zone drive the change from deposit feeding to microbe-dependent feeding strategies.