Poly(ADP-ribose) glycohydrolase (PARG) is a key enzyme involved in poly(ADP-ribose) (PAR) degradation and is considered a potential anticancer target. We previously investigated resistance mechanisms to the PARG inhibitor PDD00017273 in human colorectal cancer HCT116 cells and established an acquired PDD00017273-resistant HCT116RPDD cell line. In this study, we analyzed the protein levels of enzymes associated with PAR metabolism in both parental HCT116 cells and resistant HCT116RPDD cells using western blotting. PARG expression levels were similar between HCT116RPDD and HCT116 cells. However, the levels of PARP1 and ARH3 were reduced in HCT116RPDD cells compared to HCT116 cells. Nevertheless, intracellular PAR levels were elevated in HCT116RPDD cells. Interestingly, HCT116RPDD cells exhibited greater sensitivity to γ-ray irradiation and the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 than the parental HCT116 cells, yet showed comparable sensitivity to 5-FU, cisplatin, and PARP inhibitors olaparib, talazoparib, and veliparib. Furthermore, we observed that HCT116RPDD cells tended to maintain slightly higher levels of intracellular NAD+/NADH and ATP compared to parental HCT116 cells. These findings suggest that cancer cells employ a mechanism to regulate NAD+ and ATP levels, thereby avoiding cell death from intracellular PAR accumulation through coordinated PARP-PARG regulation.

Community-based natural resource governance is often promoted in the name of sustainability, yet long-term outcomes remain elusive. This study examines the impact of various types of trust as the underpinning factor for the long-term resilience of co-management arrangements. Using a four-type trust framework, dispositional, affinitive, rational, and procedural, the study compares trust trajectories across the prior to-, during-, and post-project phases of matsutake mushroom management in two communities within the S National Protected Area, Yunnan Province, China. Drawing on qualitative interviews and comparative case analysis, the study finds that while neither community sustained co-management mechanisms in full, X Village retained partial continuity through embedded procedural and rational trust. In contrast, Y village experienced accelerated institutional decline after project withdrawal, as market changes and weak enforcement undermined collective norms and trust in formal structures. These findings underscore that institutional resilience is shaped not only by institutional design but also by the evolution and interaction of trust types over time. By tracing trust trajectories across project stages, this study contributes a micro-level explanation of how trust mediates post-project governance outcomes. It emphasizes that trust layering, together with the distribution of multiple trust types across actors, enhances institutional resilience, particularly when these trust relations are embedded within local social and institutional practices. The findings highlight the need to consider how co-management strategies can support trust continuity after project withdrawal, particularly by acknowledging the underlying structural conditions that shape trust resilience. • Trust critically shapes co-management outcomes in conservation projects. • Two villages demonstrate divergent post-project governance outcomes despite undergoing similar interventions. • Procedural trust alone is fragile and requires reinforcement from other trust types. • Trust layering and distribution enhance long-term institutional resilience.

Peritoneal metastasis is the most lethal manifestation of gastric cancer, with a median survival of less than one year, highlighting the need for new therapeutic targets. Through an in vivo genome-wide CRISPR/Cas9 screen, we identified GRIA2, an AMPA-type glutamate receptor subunit, as a key driver of peritoneal metastasis. GRIA2 promotes gastric cancer cell migration, invasion, stemness, and adhesion to mesothelial cells in a glutamate-dependent manner. Mechanistically, glutamate activates GRIA2, enhancing its interaction with GSK-3β and inducing calcium influx, inhibiting GSK-3β kinase activity and stabilizing β-catenin, thereby activating the Wnt/β-catenin signaling pathway. Single-cell RNA sequencing revealed that cancer-associated fibroblasts are the primary source of glutamate in the peritoneal microenvironment, which establishes a paracrine axis that enhances GRIA2-driven metastasis. Pharmacological inhibition of AMPA receptors with NBQX and Selurampanel suppressed peritoneal metastasis in both cell line-derived and patient-derived organoid xenograft (PDOX) mouse models. In clinical analysis, GRIA2 expression in peritoneal metastases correlated with the levels of β-catenin and phosphorylated GSK-3β (serine 9), with high GRIA2 expression predicting poor prognosis. These findings suggest that GRIA2 is a novel therapeutic target, and AMPA receptor antagonists are promising agents for treating gastric cancer peritoneal metastasis.

Streptococcus pneumoniae commonly colonizes the nasopharynx asymptomatically, but certain conditions trigger its transition to invasive disease. The mechanisms driving this expansion are not fully understood. We used a murine model of pneumococcal nasopharyngeal colonization followed by respiratory syncytial virus (RSV) infection to investigate bacterial expansion. We measured bacterial loads in nasal and bronchoalveolar lavage fluids and analyzed growth arrest-specific protein 6 (Gas6) expression. The effect of the Axl receptor inhibitor BGB324 (bemcentinib) on RSV-mediated growth was assessed, and macrophage phenotypes were analyzed in vivo and in vitro. RSV infection increased bacterial loads and upregulated Gas6 expression in the nasal cavity. Inhibition of the Axl receptor with BGB324 effectively attenuated RSV-mediated pneumococcal growth. Furthermore, RSV infection decreased M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppresses M1 polarization, fostering an environment conducive to bacterial proliferation. Our findings reveal that the RSV-induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting this axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing severe pneumococcal infections exacerbated by RSV.

Cells can adapt to various environments by changing their biomolecular profiles while maintaining physiological homeostasis. What organizational principles in cells enable the simultaneous realization of adaptability and homeostasis? To address this question, we measure Raman scattering light from Escherichia coli cells under diverse conditions, whose spectral patterns convey their comprehensive molecular composition. We reveal that dimension-reduced Raman spectra can predict condition-dependent proteome profiles. Quantitative analysis of the Raman-proteome correspondence characterizes a low-dimensional hierarchical stoichiometry-conserving proteome structure. The network centrality of each gene in the stoichiometry conservation relations correlates with its essentiality and evolutionary conservation, and these correlations are preserved from bacteria to human cells. Furthermore, stoichiometry-conserving core components obey growth law and ensure homeostasis across conditions, whereas peripheral stoichiometry-conserving components enable adaptation to specific conditions. Mathematical analysis reveals that the stoichiometrically constrained architecture is reflected in major changes in Raman spectral patterns. These results uncover coordination of global stoichiometric balance in cells and demonstrate that vibrational spectroscopy can decipher such biological constraints beyond statistical or machine-learning inference of cellular states.

Sleep-wakefulness regulation dynamically evolves along development in a wide range of organisms. While the mechanism regulating sleep in adults is relatively well understood, little is known about its counterpart in early developmental stages. Here, we report a neuropeptidergic circuitry that modulates sleep in developing Drosophila larvae. Through an unbiased screen, we identified the neuropeptide Hugin and its receptor PK2-R1 as critical regulators of larval sleep. Our genetic and behavioral data suggest that HugPC neurons secrete Hugin peptides to activate insulin-producing cells (IPCs), which express a Hugin receptor PK2-R1. IPCs, in turn, release insulin-like peptides (Dilps) to regulate sleep. We further show that the Hugin/PK2-R1 axis is dispensable for adult sleep. Our findings thus reveal the neuromodulatory circuit that regulates developmental sleep in larvae and highlight differential impacts of the same modulatory axis on early-life sleep and adult sleep.

Catalyst supports are indispensable for efficient water dissociation since they play key roles in either indirectly enhancing catalysis activity by modifying electronic structures of catalysts or directly participating in catalytic reaction. MXene has recently emerged as a promising catalyst support for water dissociation by virtue of its rich surface electronic states that enable various electronic modifications of catalysts, but its potential of directly interacting with reactants or products to accelerate catalytic dynamics in water dissociation remains unexplored. Here we report our finding that phosphate anion-engineered MXene is capable of significantly accelerating water dissociation on single-atom ruthenium-copper (Ru-Cu) alloy, achieving a record-high mass-specific activity of 746 L gRu -1 min-1 under light conditions at room temperature. This is mainly enabled by the accelerated hydrogen spillover effect, which results from the phosphate anion-induced electronic modification of titanium sites on MXene following the light-enhanced activation of ammonia borane and water molecules on Ru-Cu active sites. This underlying mechanism is elucidated by a combination of in situ spectroscopic characterizations and density function theory calculations. This work unveils a previously unrecognized catalytic role of MXene-based supports and offers a new design strategy for enhancing water dissociation through tailored support-catalyst-reactant interactions.