Cell reports最新文献

The common neural mechanisms underlying the reduction of consciousness during sleep and anesthesia remain unclear. Previous studies have examined changes in network structure by only using recordings with limited spatial resolution, which has hindered the investigation of the critical spatial scales for the reduction of consciousness. To address this issue, we recorded calcium signals from approximately 10,000 neurons across multiple cortical regions in awake, sleeping, and anesthetized mice and compared network structure at different spatial scales by leveraging single-cell resolution and wide-field two-photon microscopy. At the single-cell scale, both sleep and anesthesia exhibit higher network modularity than an awake state, indicating a segregated network, but modules are spatially intermixed in all three states. In contrast, at the mesoscale, there are no consistent differences in modularity between states, and modules are spatially localized. Our multi-scale analysis challenges the traditional view of network segregation during unconsciousness and indicates a scale-dependent network organization.

Although many chemotherapeutic agents induce neutrophil extracellular trap (NET) formation, how NETs affect therapeutic efficacy across different cancer types remains poorly understood. Here, we report that irinotecan-induced NETs exhibit differential cytotoxicity against cancer cells through the proteolytic activity of cathepsin G (CTSG), with colon cancer cells exhibiting high sensitivity while liver cancer cells demonstrating marked resistance. Through bioinformatic analysis and siRNA-mediated knockdown validation, we identified SERPINA3, a serine protease inhibitor, as a key factor in this resistance. Mechanistically, SERPINA3 inhibits CTSG-mediated cleavage of the anti-apoptotic protein 14-3-3ε, thereby protecting cells from NET-induced apoptosis. Interestingly, the NF-κB signaling pathway governs SERPINA3 expression in liver cancer cells, with activated p65 directly binding to its promoter. Targeting SERPINA3 with antisense oligonucleotides successfully sensitized liver cancer cells to irinotecan therapy. These findings elucidate a critical mechanism of chemoresistance in liver cancer and propose targeting SERPINA3 as a promising therapeutic strategy to enhance chemotherapy efficacy.

Behavioral choices of uncertain rewards suggest that agents construct subjective reward value by combining the basic value components of utility and weighted probability. Despite the general acceptance of this evaluation mechanism for explaining economic choice, knowledge about its neuronal implementation is fractionated and remains essentially unknown. We investigate, in monkeys, whether reward signals in dopamine neurons represent subjective reward value based on these two fundamental value components. At the population level, the dopamine signal reliably represents the axiomatically defined integration of utility and weighted probability into subjective value in a way that closely matches animal-specific choice behavior. In particular, we find a crucial contribution of subjectively weighted probability to the dopamine signal of subjective reward value. These data demonstrate a neuronal implementation of subjective value constructed from the two most basic subjective reward components.

Borrelia burgdorferi, the bacteria causing Lyme disease, has a complex genome comprising a linear chromosome and multiple linear and circular plasmids. The atypical hairpin telomeres and the highly paralogous plasmids complicate genome assembly. We develop a genome assembly pipeline using both long and short reads to overcome these challenges. Using long reads, we assemble the hairpin telomeres of the linear replicons, an lp28-1a plasmid subtype, and circular plasmids of nine B. burgdorferi strains from five regions across Northwest Ontario and Manitoba, Canada. Although similar across the core conserved genomic regions, all strains carry a ∼2-10 kb right telomeric end identical to lp28-1, leading to variability in telomere length and gene content. Additionally, we observe diversity at the linear chromosome hairpin telomeric sequences, ospC types, and plasmid profiles, highlighting the genomic diversity among the geographically proximate strains and suggesting such variations as possible mechanisms of rapid evolution.

Calcium (Ca²⁺) influx through the Ca²⁺ release-activated Ca²⁺ (CRAC) channel is triggered by binding of the Ca²⁺ sensor STIM1 to the pore-forming Orai1 complex, primarily to its cytosolic C termini. These C termini connect to transmembrane (TM) domain 4 via the flexible nexus region, which has been proposed to transmit the activation signal toward the central pore via concentrically arranged TM domains. However, the conformational dynamics of the nexus-TM3 interface required for channel gating remain elusive. Here, we combine unnatural amino acid (UAA)-based photocrosslinking and chemical crosslinking with site-directed mutagenesis to investigate this interface. We report that a widening of the nexus-TM3 interface is an essential step within the cascade of conformational rearrangements underlying STIM1-mediated pore opening, while hydrophobicity and charges in this interface are further determinants contributing to signal propagation to the pore. These findings underscore the relevance of the nexus-TM3 dynamics for proper Orai1 function.

Navigating the emerging pollutant crisis appears increasingly daunting, with the interaction between micro- and nanoplastics (M/NPs) and antimicrobial resistance (AMR) in complex microbial consortia remaining poorly understood. Here, mixed-culture microcosms are subjected to polymer- and size-resolved plastic exposures, and resistome and mobilome dynamics are quantified using phenotyping and multi-omics. M/NP exposure increases AMR gene abundance and reshapes resistance profiles in a polymer-dependent manner, dominated by efflux and target alteration. Particle miniaturization amplifies resistome diversity and gene mobility, and nanoplastics show the highest horizontal gene transfer activity and strongest co-localization of AMR genes with mobile genetic elements, forming dense cross-phylum transfer networks. Mechanistically, nanoplastics elevate ROS and membrane damage, activate the SOS response, and upregulate conjugation, competence, and transposase functions. Increased ATP generation and efflux activity sustain stress tolerance and energy-intensive DNA exchange, turning nanoplastics into hotspots of transferable resistance with implications for microbial evolution and ecological resilience.

Bevacizumab (Bev) resistance limits therapeutic efficacy in ovarian cancer (OC) patients. We identified ESM1 as a key gene in Bev-resistant OC. ESM1 secreted by OC-resistant cell lines activates the ITGB1/FAK axis to induce neovascularization and Bev resistance. Additionally, ESM1 overexpression promoted the growth and Bev resistance of OC, lung, intestinal, and hepatocellular carcinoma tumors. Then, we identified TRIM28 as an upstream regulator that stabilizes ESM1 by promoting SUMOylation, inhibiting its proteasomal degradation. In OC mice, TRIM28 overexpression promotes angiogenesis and Bev resistance via ESM1-mediated ITGB1/FAK activation. This work unveils a new molecular pathway underlying Bev resistance in OC and proposes TRIM28 and ESM1 as potential therapeutic targets.

Despite the crucial roles of GATA-3 in lymphocyte biology, little is known about its intracellular distribution and the mechanisms regulating its nuclear import. Single-cell analyses on confocal microscopy images revealed that GATA-3 was enriched in the nucleus of naive and T helper (Th)2 cells, whereas Th1 cells preferentially accumulated it in the cytoplasm. This GATA-3 compartmentalization was mirrored in innate lymphoid cells ex vivo. In vitro or in vivo reprogramming of Th1 and Th2 cells reversed the subset-specific GATA-3 localization and triggered the acquisition or loss of GATA-3-dependent effector functions, respectively. We identified importin-β as the transporter mediating GATA-3's nuclear import. In Th2 cells, the subtle cytoplasmic accumulation of GATA-3 following importin-β blockade disrupted the GATA-3 autoactivation loop and impeded type 2 cell features. This sensitivity was explained by the prompt nuclear degradation of GATA-3, thus emphasizing that Th2 cell function depends on continuous and maximal nuclear import of GATA-3. Our results highlight the control of GATA-3 import into the nucleus as a fundamental rheostat of lymphocyte biology.

Circulating tumor cells (CTCs) face challenges to their survival, including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade is not well understood. Here, we find that cancer cells exposed to brief pulses of high-level fluid shear stress (FSS) exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer cells exposed to FSS rapidly alter their metabolism in a manner that promotes survival by providing energy for cytoskeletal remodeling and contractility as well as reducing equivalents to counter oxidative stress associated with cell detachment. Thus, exposure to FSS may provide CTCs with an unexpected survival benefit that promotes metastatic colonization.

Copper (Cu) is essential for innate immunity; however, how neutrophils regulate Cu homeostasis to support their functions remains unclear. We found that myeloid progenitors express abundant Cu-transporter ATP7B targeted to distinct vesicles and store Cu in vesicles. During neutrophil differentiation, ATP7B is downregulated, whereas ATP7A, LOXL2, and SLC31A2 are induced, suggesting a coordinated switch from Cu storage to utilization. As mature neutrophils exit the bone marrow, cellular Cu levels drop markedly, indicating Cu release during late maturation or egress. Myeloid-specific deletion of Atp7b in mice uncouples lineage commitment from functional maturation: Atp7b-deficient cells differentiate into neutrophils but fail to mature fully, showing more mitochondria, fewer lysosome-like structures, lower abundance of Cebp-ε and Ngal, reduced tubulin levels, and disrupted microtubules. Following lipopolysaccharide injection, Atp7b-deficient bone marrow releases fewer neutrophils into the bloodstream. Together, these findings reveal a previously unrecognized role of the Cu-transport network in neutrophil maturation and egress.