pH monitoring in high ionic concentration environments: performance study of graphene-based sensors.

Graphene-based pH sensors, acclaimed for their exceptional sensitivity to environmental variations, have garnered significant interest in scientific research. However, the sensor performance in high ionic concentration environments is limited, due to the Debye length ion screening effect. In this study, an innovative graphene channel pH sensing device was developed and modified by cross-linked poly(methyl methacrylate) (PMMA). Furthermore, even in high ionic concentrations, the pH value can be precisely measured by this sensor. The sensor has remarkable sensitivity, and high response rate of - 70.49 mV/pH within the pH range from 7 to 10. Notably, the sensors retain uniform response direction and sensitivity under different ionic concentrations environmental and maintain consistent reversibility and stability. This advancement in sensor technology paves the way for broader applications in complex ionic environments.

Proteomimetic polymer blocks mitochondrial damage, rescues Huntington's neurons, and slows onset of neuropathology in vivo.

Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington's disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.

Limited Variation in Codon Usage across Mitochondrial Genomes of Non-Biting Midges (Diptera: Chironomidae).

The codon usage patterns of mitochondrial genomes offer insights into the evolutionary and phylogenetic studies of species. Codon usage analysis has been conducted in a few Chironomidae species, and the codon usage patterns in other species remain ambiguous. We aim to reveal the codon usage differences in the mitochondrial genomes across this family. We sequenced the first mitochondrial genome of the genus Conchapelopia and the third mitochondrial genome of the subfamily Tanypodinae. Then, we analyzed its relative synonymous codon usage and effective number of codons with registered mitochondrial genomes from 28 other genera. The results indicated that there was limited variation in codon usage across five subfamilies, Chironominae, Orthocladiinae, Diamesinae, Prodiamesinae and Tanypodinae. While Parochlus steinenii from Podonominae presented a weaker codon bias, P. steinenii possessed the most genes experiencing natural selection. Additionally, ND1, ND2 and ND3 were found to be the most frequently selected genes across all species. Our findings contribute to further understanding the evolutionary and phylogenetic relationships of Chironomidae.

pH-driven fabrication of a caseinate-pectin polyelectrolyte complex as a promising carrier for lutein and zeaxanthin delivery: Microencapsulation, stability, and sustained release properties.

In this study, caseinate-pectin polyelectrolyte complexes and co-solutions were successfully fabricated at pH 3.0 and 7.0, respectively, to encapsulate bioactive molecules. During the fabrication process, the effect of the sequence in which each component was added on lutein/zeaxanthin (Lut/Zx) complexation with sodium caseinate (NaCas) was investigated. The protective effect of the polyelectrolyte complex and co-solution for Lut/Zx in liquid formulations was compared with that of a binary system containing only caseinate and Lut/Zx. Compared with the binary system, the polyelectrolyte complex at pH 3.0 further enhanced the chemical stability of Lut/Zx during storage, whereas the co-solution at pH 7.0 did not exhibit this ability. Unexpectedly, NaCas-Lut/Zx - pectin (NC-L/Z-P) with a theoretically sandwich structure did not exhibit better protection than NaCas-pectin-Lut/Zx (NC-P-L/Z). Fluorescence quenching spectra revealed that the addition of NaCas to Lut/Zx and ultimately to pectin resulted in the formation of a sandwich structure, which was soon followed by structural rebalancing. Finally, freshly prepared NC-L/Z-P complexes were lyophilized to stabilize their sandwich structure, resulting in improved encapsulation and sustained-release properties compared with those of the dried NC-P-L/Z. These results suggest that protein-polysaccharide complexes, combined with timely dehydration, enhance the combination of Lut/Zx with caseinate, leading to heightened protective effects.

Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US.

INTRODUCTION: Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. METHODS: We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. RESULTS: Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. DISCUSSION: These findings support further studies to assess semaglutide's potential in preventing AD. HIGHLIGHTS: Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.

Joint line convergence angle should be considered when constitutional alignment is predicted based on arithmetic hip-knee-ankle angle: a retrospective cross-sectional observational study.

Few studies have illustrated the role of the joint line convergence angle (JLCA) in the correlation between the arithmetic hip-knee-ankle angle (aHKA) and mechanical hip-knee-ankle angle (mHKA). We aimed to determine this role and to evaluate the effect of the JLCA in predicting constitutional alignment using the aHKA. A total of 107 normal participants (214 knees) and 246 patients (477 knees) with osteoarthritis(OA) were retrospectively examined using long-leg radiographs. The formula was calculated geometrically on plain radiographs of the knee based on the relationships among the mHKA, aHKA, and JLCA, and the distribution of the JLCA between the groups was determined. The effect of the JLCA on the prediction of constitutional alignment using the aHKA were evaluated. The geometric formula was determined to be 'mHKA=180°+aHKA - JLCA', and was verified. The median (quartile 1, quartile 3) JLCA was 2.0° (1.0°, 3.5°) and 2.5° (1.0°, 4.5°) in the normal and OA groups, respectively. The JLCA affected the prediction of constitutional alignment based on the aHKA. It should be considered when constitutional alignment is predicted based on the aHKA in patients with high JLCA values.

MGACL: Prediction Drug-Protein Interaction Based on Meta-Graph Association-Aware Contrastive Learning.

The identification of drug-target interaction (DTI) is crucial for drug discovery. However, how to reduce the graph neural network's false positives due to its bias and negative transfer in the original bipartite graph remains to be clarified. Considering that the impact of heterogeneous auxiliary information on DTI varies depending on the drug and target, we established an adaptive enhanced personalized meta-knowledge transfer network named Meta Graph Association-Aware Contrastive Learning (MGACL), which can transfer personalized heterogeneous auxiliary information from different nodes and reduce data bias. Meanwhile, we propose a novel DTI association-aware contrastive learning strategy that aligns high-frequency drug representations with learned auxiliary graph representations to prevent negative transfer. Our study improves the DTI prediction performance by about 3%, evaluated by analyzing the area under the curve (AUC) and area under the precision-recall curve (AUPRC) compared with existing methods, which is more conducive to accurately identifying drug targets for the development of new drugs.

Depicting Primate-Like Granular Dorsolateral Prefrontal Cortex in the Chinese Tree Shrew.

It remains unknown whether the Chinese tree shrew, regarded as the closest sister of primate, has evolved a dorsolateral prefrontal cortex (dlPFC) comparable with primates that is characterized by a fourth layer (L4) enriched with granular cells and reciprocal connections with the mediodorsal nucleus (MD). Here, we reported that following AAV-hSyn-EGFP expression in the MD neurons, the fluorescence micro-optical sectioning tomography revealed their projection trajectories and targeted brain areas, such as the hippocampus, the corpus striatum, and the dlPFC. Cre-dependent transsynaptic viral tracing identified the MD projection terminals that targeted the L4 of the dlPFC, in which the presence of granular cells was confirmed via cytoarchitectural studies by using the Nissl, Golgi, and vGlut2 stainings. Additionally, the L5/6 of the dlPFC projected back to the MD. These results suggest that the tree shrew has evolved a primate-like dlPFC which can serve as an alternative for studying cognition-related functions of the dlPFC.

Transcriptomic Analysis Reveals Dynamics of Gene Expression in Liver Tissue of Spotted Sea Bass Under Acute Thermal Stress.

The spotted sea bass (Lateolabrax maculatus), a eurythermal species, exhibits strong adaptability to temperature variations and presents an ideal model for studying heat stress-responsive mechanisms in fish. This study examined the liver transcriptome of spotted sea bass over a 24-h period following exposure to elevated temperatures, rising from 25 to 32 °C. The results revealed significant alterations in gene expression in response to this thermal stress. Specifically, we identified 1702, 1199, 3128, and 2636 differentially expressed genes at 3, 6, 12, and 24 h post-stress, respectively. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify specific gene modules responsive to heat stress, containing hub genes such as aco2, eci2, h6pd, suclg1, fgg, fga, fgb, f2, and apoba, which play central roles in the heat stress response. Enrichment analyses via KEGG and GSEA indicated that upregulated differentially expressed genes (DEGs) are predominantly involved in protein processing in the endoplasmic reticulum, while downregulated genes are primarily associated with the AGE-RAGE signaling pathways. Additionally, 272 genes exhibited differential alternative splicing, primarily through exon skipping, underscoring the complexity of transcriptomic adaptations. These findings provide deeper insights into the molecular responses to thermal stress and are crucial for advancing the breeding of heat-resistant strains of spotted sea bass.

Exploring temporal and sex-linked dysregulation in Alzheimer disease phosphoproteome.

This study aims to characterize dysregulation of phosphorylation for the 5XFAD mouse model of Alzheimer disease (AD). Employing global phosphoproteome measurements, we analyze temporal (3, 6, and 9 months) and sex-dependent effects on mouse hippocampus tissue to unveil molecular signatures associated with AD initiation and progression. Our findings reveal consistent phosphorylation of known AD biomarkers APOE and GFAP in 5XFAD mice, alongside candidates BIG3, CLCN6, and STX7, suggesting their potential as biomarkers for AD pathology. In addition, we identify PDK1 as a significantly dysregulated kinase at 9 months in females, and the regulation of gap junction activity as a key pathway associated with Alzheimer disease across all time points. AD-Xplorer, the interactive browser of our dataset, enables exploration of AD-related changes in phosphorylation, protein expression, kinase activities, and pathways. AD-Xplorer aids in biomarker discovery and therapeutic target identification, emphasizing temporal and sex-specific nature of significant phosphoproteomic signatures. Available at: https://yilmazs.shinyapps.io/ADXplorer.

Effect of three polysaccharides with different charge characteristics on the properties of highland barley starch gel.

Highland barley, a nutritious whole grain, faces limited market utilization due to the poor heating stability of its starch. The aim of this study was to investigate the effects of three differently charged ionic polysaccharides-guar gum (GG), xanthan gum (XG), and carboxymethyl chitosan (CMC)-on the gel properties of highland barley starch (HBS). GG and XG notably increased pasting viscosity, viscoelasticity, hardness, and strength of HBS gels. Conversely, CMC resulted in decreased gel properties. All three polysaccharides enhanced OH tensile vibration (3000-3800 cm-1), with GG and XG promoting denser honeycomb network structures and lower spin-spin relaxation time (T2), indicating improved structural integrity. In contrast, low concentrations of CMC led to disorder and loose structure. Hydrogen bonding and electrostatic interactions were the main forces by which polysaccharides influenced the properties of starch gels. This research contributes to enhancing the properties of HBS gel during heating and expanding its commercial applications. It also provides some insights to understand the interaction between different charged polysaccharides and starch.

Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity.

INTRODUCTION: Subtypes of the dipeptidyl peptidase (DPP) family, such as DPP4, are reportedly associated with memory impairment. DPP9 is widely distributed in cells throughout the body, including the brain. However, whether DPP9 regulates memory has not yet been elucidated. OBJECTIVES: This study aimed to elucidate the role of DPP9 in memory, as well as the underlying molecular mechanism. METHODS: We performed immunofluorescence on mouse brains to explore the distribution of DPP9 in different brain regions and used AAV vectors to construct knockdown and overexpression models. The effects of changing DPP9 expression on memory were demonstrated through behavioral experiments. Finally, we used electrophysiology, proteomics and affinity purification mass spectrometry (AP-MS) to study the molecular mechanism by which DPP9 affects memory. RESULTS: Here, we report that DPP9, which is found almost exclusively in neurons, is expressed and has enzyme activity in many brain regions, especially in the hippocampus. Hippocampal DPP9 expression increases after fear memory formation. Fear memory was impaired by DPP9 knockdown and enhanced by DPP9 protein overexpression in the hippocampus. According to subsequent hippocampal proteomics, multiple pathways, including the peptidase pathway, which can be bidirectionally regulated by DPP9. DPP9 directly interacts with its enzymatic substrate neuropeptide Y (NPY) in neurons. Hippocampal long-term potentiation (LTP) is also bidirectionally regulated by DPP9. Moreover, inhibiting DPP enzyme activity impaired both LTP and memory. In addition, AP-MS revealed that DPP9-interacting proteins are involved in the functions of dendritic spines and axons. By combining AP-MS and proteomics, DPP9 was shown to play a role in regulating actin functions. CONCLUSION: Taken together, our findings reveal that DPP9 affects the CNS not only through enzymatic activity but also through protein-protein interactions. This study provides new insights into the molecular mechanisms of memory and DPP family functions.

Impact of enhanced recovery after surgery on postoperative blood management following primary total knee arthroplasty: a propensity score-matched analysis.

PURPOSE: To evaluate the efficacy of blood management in patients underwent unilateral Total Knee Arthroplasty (TKA) under an enhanced recovery after surgery (ERAS) program. METHOD: Patients underwent unilateral TKA from January 2019 to October 2023 in a university hospital were retrospectively studied. A total of 200 cases were selected in the analysis. After matching with propensity scoring, 51 patients in each group were included. The postoperative Haemoglobin (Hb), albumin (Alb), C-reactive protein (CRP), total length of stay (LOS), and estimated blood loss after operation were compared between the two groups. Clinical outcomes including Western Ontario and McMaster Universities Arthritis Index (WOMAC), SF-12, and Oxford Knee Score (OKS) were also compared at six week and three month follow-up. RESULTS: The results showed that the Hb of the ERAS group was significantly higher than those of the non-ERAS group (P < 0.05) on the third postoperative. The mean CRP level was lower, LOS was shorter, and Alb level was higher in the ERAS group compared to that in the non-ERAS group (P < 0.05). The clinical outcomes such as WOMAC and OKS, SF-12 scores were higher in the ERAS group at both follow-up. CONCLUSION: ERAS protocol effectively minimizes perioperative blood loss and supports optimal nutrient levels in patients. ERAS management significantly contributes to the postoperative recovery of knee function in patients undergoing primary total knee arthroplasty.

Quantitative Determination of Endoplasmic Reticulum Viscosity during Immunogenic Cell Death by a Theranostic Rhenium Complex.

The endoplasmic reticulum (ER) is an important targeting organelle for metal-based immunogenic cell death (ICD) inducers. Metal complexes can induce ER stress by causing protein misfolding, which can be reflected by alternations in microenvironmental parameters, including viscosity. We present here a theranostic Re(I) complex (Re1) that shows viscosity-dependent emission intensity and lifetime. Re1 can trigger immunogenic cell death (ICD) in MDA-MB-231 cells by localizing in the ER and causing ER stress. We demonstrate that Re1 can simultaneously induce and monitor the gradual increase in the ER viscosity quantitatively.

Characteristics and health risks assessment of PM2.5-bound heavy metals during winter in urban areas of northern China: A case study in Kaifeng.

The health impact of heavy metals in atmospheric PM2.5 has garnered increasingly widespread attention. We have collected PM2.5 samples in a typical city (Kaifeng) within the Central Plains Urban Agglomeration in China during winter and measured the mass concentration of PM2.5-bound heavy metals. The pollution of As and Cr in the urban atmosphere requires significant attention. As PM2.5 concentrations increased, the enrichment factors (EFs) of Mn, Cu, Zn, As, and Pb also rose, suggesting a growing contribution from anthropogenic emissions. The analysis showed that the hazard quotient (HQ) for the non-heating and heating periods (HQ < 1) did not result in a cumulative non-carcinogenic health risk to humans. Regarding carcinogenic effects, As and Cr exhibit significant carcinogenic impacts on both children and adults (ELCR>1 × 10-6), indicating that the carcinogenic risks posed by As and Cr under PM2.5 exposure in Kaifeng could not be overlooked. It was found that industrial and biomass combustion are the primary sources of carcinogenic risk in Kaifeng city. From the non-heating to the heating period, the industrial carcinogenic risk increased from 37.12 % to 43.39 %, while the contribution of biomass burning remained at 25 %. This result was strongly correlated with the high proportions of heavy metal elements such as As, Mn, Pb, and Ni from the metal refinery industry. The results of this study revealed the equally important source of heavy metals, compared to coal combustion in North China Plain. In addition to residential coal combustion, industrial emissions are a major source of PM2.5-bound heavy metals in Kaifeng, contributing significantly to overall air pollution and providing a useful reference to mitigating human health risks in the area.

Unexpected increase in microalgal removal of doxylamine induced by bicarbonate addition: synergistic chem-/bio-degradation mechanisms.

Microalgae-based approaches serve as promising methods for the remediation of pharmaceutical contaminants (PCs) compared to conventional wastewater treatment processes. However, how to decrease hydraulic retention times of the microalgal system currently has been one of the main bottlenecks. This study constructed an unexpected synergistic extra-chemical/intra-biological degradation system by adding 5.95 mM bicarbonate to the microalgal system, which achieved complete removal (100%) of a representative PC, doxylamine (DOX) in 96 h, compared to that 192 h in the control. Removal capacities and mass balance analyses demonstrated that biodegradation rate per unit microalgal density was significantly increased by 207%. Further analyses using transcriptomic, enzymatic inhibiting tests, and high-resolution mass spectrometry revealed that after addition of bicarbonate for metabolism of DOX, a hydrolase (CYP97C1) and a primary amine oxidase (TynA) can transform DOX into doxylamine N-oxide and an intermediate (C15H17NO2) with a m/z of 244.1335. Meanwhile, bicarbonate reacted with microalgae-excreted hydrogen peroxide to form more oxidative radicals such as superoxide and hydroxyl radicals extracellularly, which promised the extracellular degradation of DOX according to the oxidative radical inhibiting tests. Further investigation showed addiing bicarbonate to the microalgal system improved the removal rate of 17 PCs by up to 500.8%. Therefore, this study not only developed an approach to enhance treatment efficiencies of diverse PCs by microalgae within a shorter time, but also carried unique mechanistic insights into the underlying principles.

Characteristics of heavy metal migration in the gasification-combustion process of rural solid waste: Influencing factors and mechanisms.

The miniaturized gasification-combustion model has potential advantages in treatment of rural solid waste (RSW) in China. In this study, the gasification-combustion technology concerning air-staged technology was employed in the treatment of seven combustible components in RSW, focusing on the analysis of heavy metal migration characteristics. Firstly, a comparison was made between combustion and gasification-combustion regarding the migration characteristics of heavy metals, demonstrating that gasification-combustion effectively reduces the volatilization rate of heavy metals. The largest reduction in volatility was 12.99 % for Cu. Secondly, this study explored reaction temperatures and oxygen concentration in the gasification zone, concluding that under experimental conditions mentioned herein, optimal gasification temperatures for curing heavy metals were determined to be 700 °C while maintaining an optimal ratio of air (RA) at 0.5 during gasification. Finally, the interaction of inorganic elements with different components on heavy metal migration was revealed by co-gasification-combustion of equal mass mixture of two components. The P, S, Cl contents and the inorganic mineralogical composition of the RSW are the key factors influencing the transport properties of heavy metals. The two-component synergistic effect of RSW studied in this paper has guiding significance for limiting the proportion of RSW components to control heavy metal emission in gasification-combustion process.

Machine learning methods to predict cadmium (Cd) concentration in rice grain and support soil management at a regional scale.

Rice is a major dietary source of the toxic metal cadmium (Cd). Concentration of Cd in rice grain varies widely at the regional scale, and it is challenging to predict grain Cd concentration using soil properties. The lack of reliable predictive models hampers management of contaminated soils. Here, we conducted a three-year survey of 601 pairs of soil and rice samples at a regional scale. Approximately 78.3% of the soil samples exceeded the soil screening values for Cd in China, and 53.9% of rice grain samples exceeded the Chinese maximum permissible limit for Cd. Predictive models were developed using multiple linear regression and machine learning methods. The correlations between rice grain Cd and soil total Cd concentrations were poor (R 2 < 0.17). Both linear regression and machine learning methods identified four key factors that significantly affect grain Cd concentrations, including Fe-Mn oxide bound Cd, soil pH, field soil moisture content, and the concentration of soil reducible Mn. The machine learning-based support vector machine model showed the best performance (R 2 = 0.87) in predicting grain Cd concentrations at a regional scale, followed by machine learning-based random forest model (R 2 = 0.67), and back propagation neural network model (R 2 = 0.64). Scenario simulations revealed that liming soil to a target pH of 6.5 could be one of the most cost-effective approaches to reduce the exceedance of Cd in rice grain. Taken together, these results show that machine learning methods can be used to predict Cd concentration in rice grain reliably at a regional scale and to support soil management and safe rice production.

Rapid and direct detection of m6A methylation by DNAzyme-based and smartphone-assisted electrochemical biosensor.

m6A methylation detection is crucial for understanding RNA functions, revealing disease mechanisms, guiding drug development and advancing epigenetics research. Nevertheless, high-throughput sequencing and liquid chromatography-based traditional methods still face challenges to rapid and direct detection of m6A methylation. Here we report a DNAzyme-based and smartphone-assisted electrochemical biosensor for rapid detection of m6A. We initially identified m6A methylation-sensitive DNAzyme mutants through site mutation screening. These mutants were then combined with tetrahedral DNA to modify the electrodes, creating a 3D sensing interface. The detection of m6A was accomplished by using DNAzyme to capture and cleave the m6A sequence. The electrochemical biosensor detected the m6A sequence at nanomolar concentrations with a low detection limit of 0.69 nM and a wide detection range from 10 to 104 nM within 60 min. As a proof of concept, the 3'-UTR sequence of rice was selected as the m6A analyte. Combined with a smartphone, our biosensor shows good specificity, sensitivity, and easy-to-perform features, which indicates great prospects in the field of RNA modification detection and epigenetic analysis.

Patient-derived organoids and mini-PDX for predicting METN375S-mutated lung cancer patient clinical therapeutic response.

Lung cancer as a molecularly and histologically high heterogonous disease, there is an urgent need to predict lung cancer patients' responses to anti-cancer treatment, and patient-derived organoids (PDOs) have been recognized as a valuable platform for preclinical drug screening. In this study, we successfully established 26 PDO lines from various subtypes of lung cancers including benign tumor, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large-cell carcinoma, and small-cell carcinoma. These PDOs were shown to retain the major genomic and histological characteristics of primary tumors and remain stable during long-term culture. With the help of targeted genomic sequencing, we found that lung cancer that harbors METN375S mutation is selectively sensitive to afatinib, and a combination of afatinib and gemcitabine induced synthetic lethality in PDO and mini-PDX models. In summary, our findings demonstrate the potential of PDO in predicting lung cancer drug response, and reveal a promising strategy for METN375S mutant lung cancer treatment.