iScience最新文献

Missense mutations disrupting N-glycosylation motifs can perturb protein folding and trafficking, yet the site-specific contributions of individual N-glycans to proteostasis remain poorly defined. Here, we delineated the functional hierarchy of three N-glycosylation sites in human prostatic acid phosphatase (ACP3). Glycoproteomic analysis showed that Asn94 and Asn220 carry predominantly complex-type N-glycans, whereas Asn333 is enriched in high-mannose structures. Glycan-deficient N94Q and N220Q variants were efficiently secreted and retained phosphatase activity, whereas N333Q and T335M accumulated intracellularly, formed endoplasmic reticulum aggregates, and lacked enzymatic activity. Molecular dynamics simulations revealed that the Asn333 high-mannose glycan forms persistent hydrogen-bond networks with surrounding residues and exhibits markedly reduced conformational flexibility, supporting a non-redundant structural role. Individuals harboring a heterozygous p.T335M variant presented severe neurodevelopmental abnormalities, linking Asn333 glycan loss to proteostasis failure in vivo. These findings establish a site-specific glycan-protein stabilizing mechanism with broad implications in glycoprotein folding and human disease.

Protein-protein interactions (PPIs) are fundamental to vast biological processes. Accurate prediction of mutation-induced changes in PPIs is crucial for protein engineering and drug discovery. Most existing PPI prediction approaches rely on refined physicochemical features or computationally intensive structural sampling. Here, we present delta-G message-passing-neural-network (DGMPNN), a message-passing neural-network framework for predicting the effects of mutations on PPIs. DGMPNN is pre-trained on an inverse protein folding (IPF) task and employs an adaptive residue-level attention pooling mechanism to enable effective transfer learning for predicting mutation-induced changes in protein binding affinity. The model achieves state-of-the-art performance on multiple benchmark datasets and deep mutational scanning (DMS) datasets. Experimental validation using computationally selected multi-site variants of the SARS-CoV-2 RBD-hACE2 complex showed strong agreement between predicted and experimentally measured binding affinities.

Induction of gastric ulcer by ethanol is associated with inflammation, oxidative stress, and impaired gastric mucosal defense. The current work was performed to determine the effect of lutein from Chlorella on ethanol-induced gastric ulcers in rats. Lutein caused significant decrease in gastric ulcer index and ulcer area (by 80.8%) and had beneficial effects on hematological and inflammatory status as seen from the 38% reduction in neutrophil, 57% reduction in myeloperoxidase activity, and 83% reduction in neutrophilic infiltration. At a dose of 200 mg/kg, lutein significantly lowered cyclooxygenase activity (50%), C-reactive protein (67%), prostaglandin E2 (55%), and nitric oxide (39%) levels. Lutein caused decrease in oxidative stress evidenced from 75% to 69% reduction in TBARS and hydrogen peroxide, and increase in the activities of superoxide dismutase, catalase, and glutathione peroxidase. Lutein exhibited dose-dependent inhibition of gastric H⁺K⁺ATPase activity and preservation of gastric mucosal integrity.

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid enriched in neuronal membranes and myelin, linked to cognitive performance. Yet, nutritional interventions show inconsistent cognitive benefits due to a limited understanding of the neural pathways connecting DHA status to human cognition. We studied 99 adolescents selected from both extremes of performance on a national scholastic examination. Participants completed assessments of intellectual ability, provided erythrocyte DHA samples, and underwent multimodal MRI. Using independent component analysis and Bayesian multivariate least absolute shrinkage and selection operator (LASSO) models, we identified brain components jointly associated with DHA and cognition. Across four MRI modalities, a single deep white-matter component consistently emerged as the strongest shared pathway. Tract-resolved analyses highlighted predominant contributions from the fornix and thalamus-temporal fasciculus, with additional subcortical and cortical involvement. These components predicted cognitive measures beyond DHA and other fatty acids, outlining a plausible neural pathway through which a modifiable dietary factor relates to adolescent learning.

Sulfur hexafluoride (SF₆) is extensively employed in high-voltage electrical equipment due to its exceptional dielectric properties, yet its potent greenhouse effect and extreme chemical inertness demand efficient abatement strategies. This study presents sulfate-modified ceria (CeO₂) photocatalysts designed to activate robust S-F bonds through surface Brønsted acid sites. Sulfate groups anchored on CeO₂ polarize SF₆ molecules and facilitate photogenerated electron injection into antibonding orbitals, enabling reductive bond cleavage under mild conditions. The optimized 0.5SCe catalyst achieves an SF₆ degradation amount of 7.41 mL g^-1 within 24 h under 365 nm LED irradiation, representing a 10.4-fold enhancement over pristine CeO₂. The catalyst maintains stable performance across consecutive cycles and 96 h of continuous operation. This surface acidity engineering strategy offers a sustainable pathway for controlling fluorinated greenhouse gas emissions.

Acute lung injury (ALI) is a critical disease with high mortality, yet its mechanisms remain incompletely elucidated. In this study, we investigated sulfonylurea receptor 1 (SUR1), the regulatory subunit of ATP-sensitive potassium (K_ATP) channels, in the progression of ALI. We observed elevated SUR1 protein levels in the bronchoalveolar lavage fluid (BALF) of patients with sepsis-associated ALI, as well as in BALF and lung tissues of ALI mouse models. Genetic deletion of SUR1, but not Kir6.2 (the pore-forming subunit of K_ATP channels), significantly alleviated ALI induced by cecal ligation and puncture (CLP) or by lipopolysaccharide (LPS) intratracheal instillation. Mechanistically, SUR1 interacted with poly (ADP-ribose) polymerase 1 (PARP1), impairing DNA damage repair and promoting apoptosis and NF-κB (nuclear factor kappa B) activation in bronchial epithelial cells. Notably, glibenclamide, a clinically approved SUR1 inhibitor, significantly alleviated ALI, at least in part, by disrupting the SUR1-PARP1 interaction. Our findings identify SUR1 as a new therapeutic target and highlight the potential repurposing of glibenclamide as a therapeutic drug in ALI.

Chimeric antigen receptor (CAR) T cell therapy provides substantial clinical benefits in hematologic malignancies. However, cell engineering using conventional viral vectors is costly, labor intensive, and prone to safety risks, while electroporation-induced cellular damage limits manufacturing scalability. This study reports a safe, high-efficiency, nonviral platform for generating mRNA-engineered CAR T cells. Herein, eight ionizable lipids are synthesized and formulated into lipid nanoparticles. Systematic screening and structural optimization identified lipid 6 as the lead candidate. Transfection efficiency is validated by delivering enhanced green fluorescent protein (eGFP) mRNA into DC2.4, peripheral blood mononuclear, dendritic, and natural killer cells. Murine models confirm robust in vivo expression and a favorable safety profile. Lipid 6-mediated delivery of MUC1 mRNA generates MUC1-CAR T cells characterized by high surface receptor expression and potent cytotoxicity against MUC1-positive tumor cells. These findings establish lipid 6 as a feasible strategy for primary human T cell engineering, facilitating functional CAR expression with minimal toxicity.

Resistance to cetuximab is a major challenge in colorectal cancer (CRC). Here, we show that IPO5, an importin mediating RASAL2 nuclear import, contributes to cetuximab resistance. Screening six CRC cell lines revealed an inverse correlation between IPO5 expression and cetuximab sensitivity, with higher IPO5 levels in resistant (RKO and SW620) than sensitive (LoVo and Caco2) cells. IPO5 knockdown in resistant cells restored cetuximab sensitivity, induced apoptosis (upregulated active caspase-3/BAX and downregulated BCL-2), and suppressed proliferation and xenograft growth, whereas IPO5 overexpression in sensitive cells reduced sensitivity. Mechanistically, IPO5 facilitates RASAL2 nuclear translocation via its nuclear localization signal, depleting cytoplasmic RASAL2 and increasing GTP-bound RAS to sustain AKT and MAPK activation. Consistently, IPO5 and downstream Ras effectors were elevated in resistant LoVo-CR cells. Collectively, our findings identify the IPO5/RASAL2 axis as a key contributor to cetuximab resistance in CRC by disrupting the cytoplasmic localization of RASAL2 and activating the RAS/MAPK and PI3K/AKT pathways.

Structure and function of lake microorganisms are sensitive to environmental disturbances; yet their differential responses to climatic and anthropogenic forcings over centennial scales remain poorly understood. Here, we analyzed a sediment core from Lake Daihai in northern China, combining metagenomics and stable isotope analyses. Our results revealed that microbial community assembly was dominated by deterministic processes, whereas stochasticity increased notably after 1850, coinciding with the termination of the Little Ice Age and intensified human impacts. Notably, microbial community structure evolved at a rate approximately one order of magnitude faster than community function. This decoupling was mediated by functional redundancy associated with bacterial keystone taxa, ultimately resulting in more negative sedimentary carbon and nitrogen isotopic compositions nearly a century later. Gene-level functional redundancy further buffered ecosystem function variability across biological scales. Collectively, our findings integrate omics and geochemical approaches to advance the understanding of lake ecological evolution under complex multi-forcing regimes.

Sarbecoviruses pose a substantial zoonotic threat, yet the determinants governing their host range remain incompletely defined. To systematically investigate host entry mechanisms, we generated a panel of vesicular stomatitis virus (VSV) pseudoviruses representing 46 sarbecoviruses and assessed their infectivity across 66 angiotensin-converting enzyme 2 (ACE2) orthologs. This analysis produced a high-resolution host-entry landscape with direct implications for cross-species transmission risk. We found that all severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) isolates, WIV1, and pangolin-derived sarbecoviruses demonstrated broad ACE2 usage, whereas no sarbecovirus utilized alternative entry factors including neuropilin-1, CD147, AXL, or TMEM106B. Notably, ACE2 orthologs from Rhinolophus affinis and Miniopterus schreibersii supported infection by nearly all clade 1 sarbecoviruses, identifying highly permissive host receptors. We also identified residues 27 and 42 of ACE2 as critical determinants of sarbecovirus host tropism. Together, these findings define host entry constraints relevant to receptor-based risk assessment and inform surveillance and pandemic preparedness.