Cell reports最新文献

Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data. iMetAct outperforms expression-based methods in predicting metabolite conversion rates by accounting for the effects of post-translational modifications. With iMetAct, we identify clinically significant subtypes of hepatocellular carcinoma with distinct metabolic preferences driven by dysregulated enzymes and metabolic regulators acting at both the transcriptional and non-transcriptional levels. Moreover, applying iMetAct to single-cell RNA sequencing data allows for the exploration of cancer cell metabolism and its interplay with immune regulation in the tumor microenvironment. An accompanying online platform further facilitates tumor metabolic analysis, patient stratification, and immune microenvironment characterization.

Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.

Triggering receptor expressed on myeloid cells 1 (TREM-1) has been shown to amplify inflammatory signals, such as Toll-like receptor signaling, after infection and sterile injury. While previous studies have demonstrated that TREM-1 activation in circulating immune cells promotes injury, the role of TREM-1 signaling in tissue-resident cells in the context of sterile inflammation remains poorly understood. Here, we used a cardiac transplantation model to dissect how Trem1/3 expression on heart-resident cells regulates sterile inflammation. TREM-1 is expressed in heart-resident C-C chemokine receptor 2 (CCR2)⁺ macrophages in mice and humans. TREM-1/3 signaling in tissue-resident CCR2⁺ macrophages promotes C-C motif chemokine ligand 3 (CCL3) production and is critical for recruiting neutrophils and CCR2⁺ monocytes after heart transplantation. We demonstrate prolonged allograft survival after transplantation of Trem1/3-deficient compared with wild-type hearts. We identify TREM-1/3 signaling in donor grafts as a potential future therapeutic target to blunt inflammation after myocardial ischemia-reperfusion injury.

Episodic memory requires remembering the temporal sequence of events, a process attributed to hippocampal "time cells." However, the distributed nature of brain areas supporting episodic memory suggests that temporal representations may extend beyond the hippocampus. To investigate this possibility, we trained mice to remember the identity of an odor for a specific duration. Using mesoscale two-photon imaging of neuronal activity across the neocortex, we reveal a striking area-specific temporal representation. The retrosplenial cortex (RSC), a hippocampal target area, exhibits time-dependent sequential neuronal firing that encodes both odor identity and elapsed time, with decreasing accuracy over time. By contrast, temporal coding is far less prominent in areas surrounding the RSC, including the posterior parietal cortex and visual, somatosensory, and motor areas, highlighting functional specialization. Our results establish the RSC as a key temporal processing hub for episodic memory, supporting conjunctive "what" and "when" coding models.

Bacteriophages are crucial in bacterial communities and can be used for therapy of multidrug-resistant pathogens such as Staphylococcusaureus. However, the host range of new phages remains difficult to predict. We identified the receptor-binding proteins (RBPs) of 335 S. aureus-infecting phages, yielding 8 distinct RBP clusters. Recombinant representative RBPs of all clusters, including several subclusters, were analyzed for binding to S. aureus strains differing in potential phage receptor structures. Notably, most of the phages encoded two separate RBPs, and all RBPs used S. aureus wall teichoic acid (WTA) polymers as receptors, albeit with varying preference for WTA glycosylation patterns and backbone structures. Based on these findings, a sequence-based tool for predicting the adsorption of new phages was developed. Moreover, one of the RBPs proved useful for identifying S. aureus-type WTA in other bacterial species. These findings facilitate the characterization of phage and bacterial isolates and the development of phage therapies.

A robust index of gut microbiome taxa encompassing their association with host health and microbiome resilience would be valuable for development and optimization of microbiome-based therapeutics. Here we present a single ranked order for 201 taxa, the Health-Associated Core Keystone (HACK) index, derived using their association strengths with prevalence/community association in non-diseased subjects, longitudinal stability, and host health. The index was derived based on 127 discovery cohorts and 14 validation datasets (cumulatively encompassing 45,424 gut microbiomes, subject age >18 years, representing 42 countries, 28 disease categories, and 10,021 longitudinal samples). We show that this index is reproducible regardless of microbiome profiling strategies and cohort lifestyle. Specific consortia of high HACK index taxa respond positively to Mediterranean diet interventions and reflect immune checkpoint inhibitor responsiveness and associated with specific functional profiles at the genome level. The availability of HACK indices provides a rational basis for comparing microbiomes and facilitating selection and design of microbiome-based therapeutics.

The motilin receptor (MTLR) is a key target for treating gastrointestinal (GI) disorders like gastroparesis, yet developing effective agonists remains challenging due to drug tolerance and signaling bias. We present cryoelectron microscopy (cryo-EM) structures of MTLR bound to azithromycin, a macrolide antibiotic, and DS-3801b, a non-macrolide agonist. Distinct ligand recognition mechanisms are revealed, with azithromycin binding deeply within the orthosteric pocket and DS-3801b adopting a special clamp-like conformation stabilized by a water molecule. We also highlight the critical role of extracellular loop 2 (ECL2) in ligand specificity and signaling pathway activation, affecting both G-protein and β-arrestin signaling. Additionally, the "D^2.60R^2.63S^3.28" motif and interactions around transmembranes 6/7 (TM6/7) are identified as key drivers of signaling selectivity. These findings offer insights into the structural dynamics of MTLR, laying the groundwork for the rational design of next-generation GI prokinetic drugs with enhanced efficacy and safety.

Plant-unique RNA polymerase IV (RNA Pol IV) governs the establishment of small RNA (sRNA)-directed DNA methylation (RdDM). In dicotyledon, elevated RdDM activity is often associated with embryogenesis; however, the loss of RdDM frequently results in indiscernible phenotypes. Here, we report that the absence of SlNRPD1, encoding the largest subunit of RNA Pol IV, leads to diminished RdDM and abnormal embryogenesis in tomato (Solanum lycopersicum). Hypermethylation at pericentric transposable elements (TEs) and a burst of 21/22-nt siRNA from the distal and pericentric genes are observed in slnrpd1 embryos. The specific activation of endoribonuclease Dicer-like 2 (SlDCL2b/c/d) is correlated with 21/22-nt sRNA accumulation. Auxin and WUSCHEL-related homeobox (WOX) signaling gene expression is altered by mCHH hypomethylation, which may lead to defective embryos. Due to improper maturation, the slnrpd1 embryos cannot withstand post-harvest desiccation. This study provides insights into how DNA methylation regulates plant embryogenesis.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.