Science Advances最新文献

Until now, Hippo pathway-mediated nucleocytoplasmic translocation has been considered the primary mechanism by which yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) transcriptional coactivators regulate cell proliferation and differentiation via transcriptional enhanced associate domain (TEAD)-mediated target gene expression. In this study, however, we found that TAZ, but not YAP, is associated with the Golgi apparatus in macrophages activated via Toll-like receptor ligands during the resolution phase of inflammation. Golgi-associated TAZ enhanced vesicle trafficking and secretion of proinflammatory cytokines in M1 macrophage independent of the Hippo pathway. Depletion of TAZ in tumor-associated macrophages promoted tumor growth by suppressing the recruitment of tumor-infiltrating lymphocytes. Moreover, in a diet-induced metabolic dysfunction-associated steatohepatitis model, macrophage-specific deletion of TAZ ameliorated liver inflammation and hepatic fibrosis. Thus, targeted therapies being developed against YAP/TAZ-TEAD are ineffective in macrophages. Together, our results introduce Golgi-associated TAZ as a potential molecular target for therapeutic intervention to treat tumor progression and chronic inflammatory diseases.

Bioluminescence, an optical marker that does not require excitation by light, allows researchers to simultaneously observe multiple targets, each exhibiting a different color. Notably, the colors of the bioluminescent proteins must sufficiently vary to enable simultaneous detection. Here, we aimed to introduce a method that can be used to expand the color variation by tuning dual-acceptor bioluminescence resonance energy transfer. Using this approach, we could visualize multiple targets with up to 20 colors through single-shot acquisition using a color complementary metal-oxide semiconductor camera. Overall, this method enables simple and simultaneous observation of multiple biological targets and phenomena.

Highly packable and deployable electronics offer a variety of advantages in electronics and robotics by facilitating spatial efficiency. These electronics must endure extreme folding during packaging and tension to maintain a rigid structure in the deployment state. Here, we present foldable and robustly deployable electronics inspired by Plantago, characterized by their tolerance to folding and tension due to integration of tough veins within thin leaf. The primary design approach for these electronics involves a high resistance to folding and tension, achieved through a thin multilayered electronic composite, which manages the neutral axis and incorporates tough Kevlar. The fabricated electronics can be folded up to 750,000 times without malfunctions and endure pulling an object 6667 times heavier than itself without stretching. Such robust electronics can be used as a deployable robot with sensor arrays, demonstrating practical applicability, as it maintains their mechanical and electrical properties during inflation from the packaged state.

Revealing the momentum-resolved electronic structure of infinite-layer nickelates is essential for understanding this class of unconventional superconductors but has been hindered by the formidable challenges in improving the sample quality. In this work, we report the angle-resolved photoemission spectroscopy of superconducting La_0.8Sr_0.2NiO₂ films prepared by molecular beam epitaxy and in situ atomic-hydrogen reduction. The measured Fermi topology closely matches theoretical calculations, showing a large Ni [Formula: see text]-derived Fermi sheet that evolves from hole-like to electron-like along k_z and a three-dimensional (3D) electron pocket centered at the Brillouin zone corner. The Ni [Formula: see text]-derived bands show a mass enhancement (m*/m_DFT) of 2 to 3, while the 3D electron band shows negligible band renormalization. Moreover, the Ni [Formula: see text]-derived states also display a band dispersion anomaly at higher binding energy, reminiscent of the waterfall feature and kinks observed in cuprates.

Human health is being threatened by environmental microplastic (MP) pollution. MPs were detected in the bloodstream and multiple tissues of humans, disrupting the regular physiological processes of organs. Nanoscale plastics can breach the blood-brain barrier, leading to neurotoxic effects. How MPs cause brain functional irregularities remains unclear. This work uses high-depth imaging techniques to investigate the MPs within the brain in vivo. We show that circulating MPs are phagocytosed and lead these cells to obstruction in the capillaries of the brain cortex. These blockages as thrombus formation cause reduced blood flow and neurological abnormalities in mice. Our data reveal a mechanism by which MPs disrupt tissue function indirectly through regulation of cell obstruction and interference with local blood circulation, rather than direct tissue penetration. This revelation offers a lens through which to comprehend the toxicological implications of MPs that invade the bloodstream.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site III_Qo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

Poor ambient air quality poses a substantial global health threat. However, accurate measurement remains challenging, particularly in countries such as India where ground monitors are scarce despite high expected exposure and health burdens. This lack of precise measurements impedes understanding of changes in pollution exposure over time and across populations. Here, we develop open-source daily fine particulate matter (PM_2.5) datasets at a 10-kilometer resolution for India from 2005 to 2023 using a two-stage machine learning model validated on held-out monitor data. Analyzing long-term air quality trends, we find that PM_2.5 concentrations increased across most of the country until around 2016 and then declined partly due to favorable meteorology in southern India. Recent reductions in PM_2.5 were substantially larger in wealthier areas, highlighting the urgency of air quality control policies addressing all socioeconomic communities. To advance equitable air quality monitoring, we propose additional monitor locations in India and examine the adaptability of our method to other countries with scarce monitoring data.

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. ¹³C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1^-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1^-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.

Mixed matrix membranes, with well-designed pore structure inside the polymeric matrix via the incorporation of inorganic components, offer a promising solution for addressing CO₂ emissions. Here, we synthesized a series of novel metal organic cages (MOCs) with aperture pore size precisely positioned between CO₂ and N₂ or CH₄. These MOCs were uniformly dispersed in the polymers of intrinsic microporosity (PIM-1). Among them, the MOC-Ph cage effectively modulated chain packing and optimized the microporous structure of the membrane. Remarkably, the PIM-Ph-5% membrane shows superior performance, achieving an excellent CO₂ permeability of 8803.4 barrer and CO₂/N₂ selectivity of 59.9, far exceeding the 2019 upper bound. This approach opens opportunities for improving the porous structure of polymeric membranes for CO₂ capture and other separation applications.

Tigilanol tiglate (EBC-46) is a selective modulator of protein kinase C (PKC) isoforms that is Food and Drug Administration (FDA) approved for the treatment of mast cell tumors in canines with up to an 88% cure rate. Recently, it has been FDA approved for the treatment of soft tissue sarcomas in humans. The role of EBC-46 and, especially, its analogs in efforts to eradicate HIV, treat neurological and cardiovascular disorders, or enhance antigen density in antigen-targeted chimeric antigen receptor-T cell and chimeric antigen receptor-natural killer cell immunotherapies has not been reported. Enabled by our previously reported scalable synthesis of EBC-46, we report herein the systematic design, synthesis, and evaluation of EBC-46 analogs, including those inaccessible from the natural source and their PKC affinities, ability to translocate PKC, nuclear factor κB activity, and efficacy in reversing HIV latency in Jurkat-Latency cells. Leading analogs show exceptional PKC affinities, isoform selectivities, and functional activities, serving as promising candidates for therapeutic applications.