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Using gas and rock samples from major petroliferous basins in the world, the helium content, composition, isotopic compositions and the U and Th contents in rocks are analyzed to clarify the helium enrichment mechanism and distribution pattern and the exploration ideas for helium-rich gas reservoirs. It is believed that the formation of helium-rich gas reservoirs depends on the amount of helium supplied to the reservoir and the degree of helium dilution by natural gas, and that the reservoir-forming process can be summarized as “multi-source helium supply, main-source helium enrichment, helium-nitrogen coupling, and homogeneous symbiosis”. Helium mainly comes from the radioactive decay of U and Th in rocks. All rocks contain trace amounts of U and Th, so they are effective helium sources. Especially, large-scale ancient basement dominated by granite or metamorphic rocks is the main helium source. The helium generated by the decay of U and Th in the ancient basement in a long geologic history, together with the nitrogen generated by the cracking of the inorganic nitrogenous compounds in the basement rocks, is dissolved in the water and preserved. With the tectonic uplift, the ground water is transported upward along the fracture to the gas reservoirs, with helium and nitrogen released. Thus, the reservoirs are enriched with both helium and nitrogen, which present a clear concomitant and coupling relationship. In tensional basins in eastern China, where tectonic activities are strong, a certain proportion of mantle-derived helium is mixed in the natural gas. The helium-rich gas reservoirs are mostly located in normal or low-pressure zones above ancient basement with fracture communication, which later experience substantial tectonic uplift and present relatively weak seal, low intensity of natural gas charging, and active groundwater. Helium exploration should focus on gas reservoirs with fractures connecting ancient basement, large tectonic uplift, relatively weak sealing capacity, insufficient natural gas charging intensity, and rich ancient formation water, depending on the characteristics of helium enrichment, beyond the traditional idea of searching for natural gas sweetspots and high-yield giant gas fields simultaneously.

Abstract Background Immune checkpoint blockade (ICB) has been improving the patient outcome in multiple cancer types. However, not all patients respond to ICB. Biomarkers are needed for selecting appropriate patients to receive ICB. CD74 is an important chaperone that regulates antigen presentation for immune response. However, the relationship between CD74 expression and ICB response remains elusive. Methods The unified normalized pan-cancer dataset was downloaded from the UCSC database. Wilcoxon Rank Sum Rank Tests were used to analyze the expression differences between normal and tumor samples in each tumor type. Then, the prognostic value of CD74 was determined using univariable Cox proportional hazards regression analysis. The STRING database was utilized to construct the protein-protein interaction (PPI) network of CD74 and the signal pathways were analyzed as well. The correlation of CD74 expression with immune cells and immune regulating genes was investigated in the TIMER database. The TIDE framework was utilized to evaluate the relationship between CD74 expression and the response to immunotherapy. Moreover, the localization of CD74 in the tumor immune microenvironment was verified using multiplex immunohistochemistry. Clinically annotated samples from 38 patients with esophageal cancer treated with neoadjuvant chemotherapy combined with ICB were analyzed for CD74 expression using immunohistochemistry. Results In this study, we investigated the prognostic and predictive value of CD74 in different types of cancer. Compared with normal tissue, the expression of CD74 was higher in tumor tissue in various cancers. High expression of CD74 was associated with improved patient prognosis in the majority of cancers. CD74 and its interacting proteins were mainly enriched in the immune-related pathways. The expression of CD74 was significantly positively correlated with B cells, CD4 T-cells, CD8 T-cells, neutrophils, macrophages and dendritic cells. TIDE analysis showed that tumors with high CD74 expression may have better responses to immunotherapy and improved patient survival. In patients with esophageal cancer who had received ICB, higher intratumoral CD74 expression was associated with improved response to ICB. Conclusions The findings of this study suggest that the high expression of CD74 may be a potential predictive biomarker of response to ICB.

Abstract Background Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. Methods We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. Results Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. Conclusion We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

Abstract The human gut microbiota significantly impacts health, including liver conditions like liver cirrhosis (LC) and spontaneous bacterial peritonitis (SBP). Immunoglobulin A (IgA) plays a central role in maintaining gut microbial balance. Understanding IgA's interplay with gut microbiota and liver health is crucial. This study explores the relationship between fecal IgA levels, gut microbiota, and liver injury severity. A total of 69 LC patients and 30 healthy controls were studied. Fecal IgA levels were measured using ELISA, and IgA‐coated bacteria were quantified via flow cytometry. Microbiota diversity and composition were assessed through 16S rRNA sequencing. Liver injury severity was graded using the Child–Pugh score. Statistical analyses determined correlations. LC patients had higher fecal IgA levels than controls, correlating positively with liver injury severity. Microbiota diversity decreased with severity, accompanied by shifts in composition favoring pro‐inflammatory species. Ralstonia abundance positively correlated with liver injury, whereas Faecalibacterium showed a negative correlation. Specific microbial markers for SBP were identified. Functional profiling revealed altered microbial functionalities in LC and SBP. Elevated fecal IgA levels, coupled with microbiota alterations, correlate with liver injury severity in LC patients. Modulating gut microbiota could be a promising strategy for managing liver‐related conditions. Further research is needed to understand underlying mechanisms and translate findings into clinical practice, potentially improving patient outcomes.

Abstract Background Considering that changes in the choroidal thickness are closely related to ocular growth, we studied the choroidal thickness (CT) and the blood flow features in children with unilateral myopic anisometropia (UMA) as well as investigating the relationship between choroidal changes and myopia. Methods Subjective refractive, axial length (AL), and biometric parameters were measured in 98 UMA children (age: 8–15 years). CT and choroidal blood-flow features, including the choroidal vessel volume (CVV), choroidal vascularity index (CVI), and choriocapillaris perfusion area (CCPA), were measured through swept-source optical coherence tomography angiography. The macular region was categorized into four concentric circles of diameters 0–1 mm (central fovea), 1–3 mm (parafovea), 3–6 mm (perifovea), and 6–9 mm (extended), and further categorized into superior (S), inferior (I), temporal (T), and nasal (N) quadrants. Results The aforementioned four regions of myopic eyes displayed significantly lower CT, CVV, and CVI than those of non-myopic eyes. CCPA changes differed across different regions of both the eyes (parts of N and T quadrants). There was an inverse association between CT and the interocular AL difference (central and other regions S, T quadrant). No correlation was noted between CVV and CVI with interocular AL difference. CT and CVV were positively correlated in the 0–6-mm macular region of myopic eyes (Spearman correlation coefficient = 0.763, P

Abstract Background In 2021, an EULAR task force published a definition of difficult-to-treat rheumatoid arthritis (D2T RA). Our current knowledge of D2T RA with the EULAR definition is based on European and Asian cohorts, and no North American cohort has yet to be published. The aim of this study was to compare D2T RA patients to non-D2T RA who are good responders to advanced therapy, and to describe their evolution in an university health center patient cohort. Methods This is a retrospective single centre study of the medical records of all adults with RA on at least one biologic or target synthetic DMARD (b/tsDMARD). D2T RA group was defined according to the EULAR definition of D2T RA. The non-D2T RA group was defined as a b/tsDMARD good responder who had low-disease activity or remission for at least one year on 1 or 2 b/tsDMARD mechanism of action. We compared the patients’ comorbidities, and history of b/tsDMARD use. Descriptive statistics and proportions were calculated. Kaplan-Meier analysis with log-rank test was used to estimate and compare median survival. Results Among the 417 patients, 101 (24%) were D2T RA and 316 (76%) were non-D2T RA. D2T RA group was slightly younger (63 ± 9 years versus 65 ± 12 years, p = 0.045), more likely to have concomitant non-inflammatory pain (28% versus 8%, p

The lifetime of Si-based environmental barrier coatings (EBCs) is constrained by thermally grown SiO2 oxide layer (SiO2-TGO), which can cause premature cracking and spalling. To address this issue, a new approach for surface modification using aluminum is proposed. The oxidation performance was examined in a 50 vol% H2O–50 vol% O2 environment at 1350 °C for up to 300 h. The results indicate that a dense ytterbium aluminum garnet (YbAG) layer was formed after modification, decreasing the porosity by 80%. Due to the elimination of fast diffusion channels and the low oxygen permeability of YbAG, aluminum modification significantly reduced the growth rate of SiO2-TGO by nearly two orders of magnitude. Consequently, its thickness decreased by more than 70% after 300 h of exposure. A diffusion-controlled oxidation mechanism indicates that the modified dense surface is equivalent to an initial SiO2 layer with a specific thickness, causing a shift in the oxidation time and increasing the oxidation resistance. This research provides valuable insights for designing Si-based EBC with improved lifetimes.

This study investigates the influence of accumulative roll bonding (ARB) cycles on the microstructure and room temperature (RT) mechanical properties of AT31/ATX3105 magnesium (Mg) alloy composite sheet. It is observed that, as the number of rolling passes increases, the interface between ATX3105 and AT31 layers exhibits stronger bonding. Furthermore, after five cycles of ARB treatment, the grain sizes of AT31 and ATX3105 layers are refined to ∼5.1 μm and ∼4.2 μm, respectively. With the increasing number of ARB passes, the strength of the composite sheets gradually increased, while their ductility showed a wave-like trend. It is particularly noteworthy that the ductility reached an optimal level of ∼17.0% after four ARB cycles. The composite sheet after five ARB cycles demonstrates the best comprehensive mechanical properties, with yield strength (YS), ultimate tensile strength (UTS), and elongation (EL) at ∼ 205.4 MPa, ∼274.9 MPa and ∼15.4%, respectively. The strength improvement mainly comes from grain boundary strengthening and heterogeneous deformation-induced (HDI) strengthening due to the layered grain structure of alternating coarse and fine grains. The results of hetero-structured Mg alloy sheet produced by ARB provides a reference for the development of Mg alloy sheet with good mechanical properties.

[Objective] Rural resettlement areas are the key areas to consolidate the effective connection between poverty alleviation achievements and rural revitalization. Based on the theory of new endogenous development, the analysis of the influencing factors and extension mechanism of the evolution of the agricultural industry chain is of great significance for preventing the return to poverty and promoting rural revitalization in an all-round way. [Methods] Based on the field research data of Tuanjie Village, a typical resettlement area in Ningxia Hui Autonomous Region in 2023, this study used the random forest model to identify the key factors of the evolution of the agricultural industry chain, and further described the extension mechanism of the agricultural industry chain with the help of the actor network theory. [Results] (1) The driving role of village collective organizations, the downstream sales and services of the industrial chain, the planting income of farmers, the age of respondents, the level of education and the proportion of agricultural income had important effects on the evolution of the agricultural industrial chain. (2) The village collective was the key actor in the extension of the agricultural industry chain in Tuanjie Village, and it relied on land, technology, and other resources to recruit, mobilize, and provide feedback to human actors such as the government, farmers’ cooperatives, enterprises, and farmers, and non-human actors such as land, capital, market, and technology, to eliminate objections, forming a relatively stable heterogeneous actor network. (3) In the process of rural industrial development, guided by the reasonable flow and allocation of factors such as people-land-industry-finance between urban and rural areas, the rural economic scale was expanded and the industrial layout was optimized through the fiv drivers of policy guarantee, capacity improvement, service guarantee, capital investment, and product research and development; With agricultural resources as the base of the industrial chain, the extension mechanism of multi-force cooperation and collaboration should be built to realize the orderly extension of the rural agricultural industry chain. [Conclusion] In the process of rural industrial development in resettlement areas, a network of actors with village collective organizations as the core has formed, which provides strong support for the extension of rural agricultural industry chain and promotes the high-quality development of rural industries.

Abstract The introduction of single-atom catalysts (SACs) into Fenton-like oxidation promises ultrafast water pollutant elimination, but the limited access to pollutants and oxidant by surface catalytic sites and the intensive oxidant consumption still severely restrict the decontamination performance. While nanoconfinement of SACs allows drastically enhanced decontamination reaction kinetics, the detailed regulatory mechanisms remain elusive. Here, we unveil that, apart from local enrichment of reactants, the catalytic pathway shift is also an important cause for the reactivity enhancement of nanoconfined SACs. The surface electronic structure of cobalt site is altered by confining it within the nanopores of mesostructured silica particles, which triggers a fundamental transition from singlet oxygen to electron transfer pathway for 4-chlorophenol oxidation. The changed pathway and accelerated interfacial mass transfer render the nanoconfined system up to 34.7-fold higher pollutant degradation rate and drastically raised peroxymonosulfate utilization efficiency (from 61.8% to 96.6%) relative to the unconfined control. It also demonstrates superior reactivity for the degradation of other electron-rich phenolic compounds, good environment robustness, and high stability for treating real lake water. Our findings deepen the knowledge of nanoconfined catalysis and may inspire innovations in low-carbon water purification technologies and other heterogeneous catalytic applications.

Abstract Zero‐dimensional (0D) hybrid manganese halides have gained wide attention for the various crystal structures, excellent optical performance and scintillation properties compared with 3D lead halide perovskite nanocrystals. In this work, a new family of 0D hybrid manganese halides of A2MnBr4 (A = BzTPP, Br‐BzTPP, and F‐BzTPP) based on discrete [MnBr4]2− tetrahedral units is reported as highly efficient lead‐free scintillators. Excited by UV or blue light, these hybrids emit bright green light originating from the d–d transition of Mn2+ with near‐unity PLQY (99.5%). Significantly, high PLQY and low self‐absorption render extraordinary radioluminescence properties with the highest light yield of 80,100 photons MeV−1, which reached the climax of present hybrid manganese halides and surpassed most commercial scintillators. The radioluminescence intensity features a linear response to X‐ray doses with a detection limit of 30 nGyair s−1, far lower than the requirement of medical diagnostic (5.5 µGyair s−1). X‐ray imaging demonstrates ultrahigh spatial resolution of 14.06 lp mm−1 and short afterglow of 0.3 ms showcasing promising application prospects in radiography. Overall, we demonstrated new hybrid manganese halides as promising scintillators for advanced applications in X‐ray imaging with multiple superiorities of nontoxicity, facile‐assembly process, high irradiation light yield, excellent resolution, and stability.

Background Microangiogenesis and lymphangiogenesis are essential for tumor growth in the tumor microenvironment, contributing to tumor invasion and metastasis. Limited literature exists on these processes in esophageal squamous cell carcinoma (ESCC). Therefore, the purpose of this study is to explore the impacts of microangiogenesis and lymphangiogenesis on the occurrence, progression, and prognosis assessment of ESCC. Methods Surgical specimens and paraffin-embedded human tissues were procured from ESCC patients, encompassing 100 ESCC tissues and 100 cancer-adjacent normal (CAN) tissues. CD34 and D2-40 were utilized as markers for microvessel endothelial cells and lymphatic vessel endothelial cells, respectively. Microvascular density (MVD) and lymphatic vessel density (LVD) were evaluated through immunohistochemical quantification. Results We found that tumor tissues in ESCC patients had significantly higher MVD and LVD than cancer-adjacent normal (CAN) tissues. High MVD and LVD were associated with lymph node metastasis and advanced tumor clinical stages. Additionally, both high MVD and high LVD were strongly linked to poorer prognosis among cancer patients. Furthermore, a positive correlation was found between high MVD and high LVD (p < 0.05). The presence of these markers individually indicated a worse prognosis, with their combined assessment showcasing enhanced prognostic value. Conclusions Overall, the increased MVD and LVD indicates higher invasion and metastasis of ESCC, closely correlating with unfavorablefor poor prognosis of ESCC patients.

Abstract Background Knee osteoarthritis (KOA) is a chronic musculoskeletal disorder characterized by pain and functional impairment. Blood flow restriction (BFR) with low-load resistance training (LLRT) demonstrates a similar improvement in clinical outcomes to high-load resistance training (HLRT) in treating KOA. It has not been established whether intermittent blood flow restriction (iBFR) with LLRT can lead to clinical outcomes that are comparable to those produced by continuous blood flow restriction (cBFR) with LLRT and HLRT. The aim of the proposed study is to evaluate the efficacy of iBFR with LLRT on pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), muscle strength, muscle mass, physical function, perceptions of discomfort and effort, and adherence in KOA patients. Methods This is a three-arm, non-inferiority, randomized controlled trial utilizing blinded assessors. Two hundred thirteen participants will be randomly allocated to one of the following three groups: iBFR group—receiving 4 months of LLRT with iBFR, twice weekly (n = 71); cBFR group—receiving 4 months of LLRT with cBFR, twice weekly (n = 71); or HLRT group—receiving 4 months of HLRT without BFR, twice weekly (n = 71). The primary outcome is pain. The secondary outcomes include the WOMAC, muscle strength, muscle mass, physical function, perceptions of discomfort and effort, and adherence. Pain and WOMAC will be measured at the baseline and 4 and 12 months after randomizations. Muscle strength, muscle mass, and physical function will be measured at the baseline and 4 months after randomizations. The perceptions of discomfort and effort will be measured during the first and final sessions. Discussion BFR with LLRT has a similar improvement in clinical outcomes as HLRT. However, cBFR may cause elevated ratings of perceived exertion and local discomfort, compromising patient tolerability and treatment adherence. If iBFR with LLRT could produce improvement in clinical outcomes analogous to those of HLRT and iBFR with LLRT, it could be considered an alternative approach for treating patients with KOA. Trial registration Chinese Clinical Trial Registry ChiCTR2300072820. Registered on June 26, 2023.

Abstract Objective Sotos syndrome (SOTOS) is an uncommon genetic condition that manifests itself with the following distinctive features: prenatal overgrowth, facial abnormalities, and intellectual disability. This disorder is often associated with haploinsufficiency of the nuclear receptor-binding SET domain protein 1 (NSD1)gene. We investigated four pediatric cases characterized by early-onset overgrowth and developmental delay. The primary objective of this study was to achieve accurate genetic diagnoses. Design&Methods A sequential analysis approach comprising chromosomal karyotyping, whole exome sequencing, and microarray analysis was conducted. Results All four cases exhibited variations in the NSD1 gene, with the identification of four previously unreported de novo variants, each specific to one case.Specifically, Case 1 carried the NSD1 (NM_022455): c.2686 C > T(p.Q896X) variant, Case 2 had the NSD1 (NM_022455): c.2858_2859delCT(p.S953X) variant, Case 3 displayed a chromosomal aberration, chr5: 5q35.2q35.3(176,516,604–176,639,249)×1, which encompassed the 5′-untranslated region of NSD1, and Case 4 harbored the NSD1 (NM_022455): c.6397T > G(p.C2133G) variant. Conclusion This study not only provided precise diagnoses for these cases but also supplied significant evidence to facilitate informed consultations. Furthermore, our findings expanded the spectrum of mutations associated with SOTOS.

Objective To explore the value of blood flow resistance index of both kidneys plus visceral adipose tissue-derived serine protease inhibitor (Vaspin) in predicting renal function in patients with type 2 diabetic nephropathy (T2DN). Methods From August 2021 to August 2022, 108 T2DN patients were recruited. Color ultrasonography was performed after admission for measuring renal indices. They were divided into two groups of elevated blood flow resistance index (n=40) and normal renal index (n=68). Serum level of Vaspin was detected by MeAP immunosorbent assay. The relevant clinical data were recorded. The risk factors affecting an elevation of renal indices were analyzed by univariate and multivariate Logistic regression. Pearson’s method was employed for examining the relationship between renal indices, Vaspin and renal function. Receiver operating characteristic (ROC) curve was plotted according to renal indices and Vaspin. And the area under the curve (AUC) was utilized for evaluating its predictive value of renal function in T2DN patients. Results No significant inter-group differences existed in gender, stage of diabetic kidney disease, quantitative urinary protein, blood albumin, glycosylated hemoglobin, blood uric acid, urinary albumin to creatinine ratio, urinary α1 microglobulin or urinary β2 microglobulin (P>0.05). Age [(56.33±5.19) year vs (50.78±5.24) year], duration of diabetes [(12.58±3.42) years vs (10.13±3.25) years] and hypertension (87.50% vs 61.76%) were higher in elevated renal blood flow resistance index group than those in normal group. Triglyceride [(1.72±0.45) mmol/L vs (2.11±0.58) mmol/L], low-density lipoprotein (LDL) [(2.33±0.57) mmol/L vs (2.61±0.62) mmol/L], hemoglobin [(102.39±21.64) g/L vs (113.76±28.45) g/L], left kidney volume [(76.58±15.33) cm3 vs (81.35±17.16) cm3], right kidney volume [(71.62±12.39) cm3 vs (80.47±16.51) cm3], estimated glomerular filtration rate (eGFR) [(40.37±12.58) mL·min−1·(1.73 m2)−1 vs (52.14±13.26) mL·min−1·(1.73 m2)−1] and serum level of Vaspin [(1.52±0.38) μg/L vs (1.74±0.43) μg/L] were lower than those in normal group (P

The lifetime of Si bond coatings in environmental barrier coatings is constrained by phase-transition-induced cracking of the SiO2 scale. In this study, Si–HfO2 dual-state duplex composite materials are proposed to address this issue by partially forming HfSiO4 and minimizing the SiO2 content. The as-prepared composite exhibited a structure comprising discrete HfO2 “bricks” embedded in a continuous Si “mortar”, while the oxidized state transformed into discrete HfSiO4 “bricks” within continuous thin SiO2 “mortars”. The results indicate that continuous thin SiO2 contributes to reducing the oxidation rate to a level comparable to that of pure Si, and discrete HfSiO4 particles aid in relieving phase transition-induced stress and inhibiting crack propagation, thereby enhancing oxidation and cracking resistance simultaneously. Consequently, the composite with 20 mol% HfO2 and a mean particle size of ~500 nm at 1370 ℃ exhibited a service lifetime 10 times greater than that of pure Si. This research provides valuable insights for designing Si-based bond coatings with improved service lifetime.

Alisma L. is a medicinally important genus of aquatic and wetland plants consisting of c. 10 recognized species. However, largely due to polyploidy and limited taxon and gene sampling, the phylogenomic relationships of Alisma remain challenging. In this study, we sequenced 34 accessions of Alismataceae, including eight of the ten species of Alisma, one species of Echinodorus and one species of Luronium, to perform comparative analyses of plastid genomes and phylogenetic analyses. Comparative analysis of plastid genomes revealed high sequence similarity among species within the genus. Our study analyzed structural changes and variations in the plastomes of Alisma, including IR expansion or contraction, and gene duplication or loss. Phylogenetic results suggest that Alisma is monophyletic, and constitutes four groups: (1) A. lanceolatum and A. canaliculatum; (2) the North American clade of A. subcordatum and A. triviale; (3) A. wahlenbergii and A. gramineum; and (4) A. plantago-aquatica from Eurasia and northern Africa with the eastern Asian A. orientale nested within it. Hence the results challenge the recognition of A. orientale as a distinct species and raise the possibility of treating it as a synonym of the widespread A. plantago-aquatica. The well-known Alismatis Rhizoma (Zexie) in Chinese medicine was likely derived from the morphologically variable Alisma plantago-aquatica throughout its long history of cultivation in Asia. The plastome phylogenetic results also support the tetraploid A. lanceolatum as the likely maternal parent of the hexaploid eastern Asian A. canaliculatum.

Introduction: Elevated glucagon levels are a characteristic feature of type 2 diabetes. This abnormal increase in glucagon can lead to an accelerated rate of gluconeogenesis. Glucagon also stimulates hepatic metabolism of amino acids, particularly promoting the formation of urea. The specific role of carbamoyl phosphate synthetase 1 (CPS1), a rate-limiting enzyme in the urea cycle, in the development versus the persistence of glucagon-induced hyperglycemia has not been previously established.Methods: The study employed both in vivo and in vitro approaches to assess the impact of CPS1 modulation on glucagon response. CPS1 was knockdown or overexpression to evaluate its influence on hepatic gluconeogenesis. In addition, an in-silico strategy was employed to identify a potential CPS1 inhibitor.Results: Knockdown of CPS1 significantly reduced the glucagon response both in vivo and in vitro. Conversely, overexpression of CPS1 resulted in an overactive hepatic gluconeogenic response. Mechanistically, CPS1 induced the release of calcium ions from the endoplasmic reticulum, which in turn triggered the phosphorylation of CaMKII. The activation of CaMKII then facilitated the dephosphorylation and nuclear translocation of FOXO1, culminating in the enhancement of hepatic gluconeogenesis. Furthermore, cynarin, a natural CPS1 inhibitor derived from the artichoke plant, had the capacity to attenuate the hepatic glucagon response in a CPS1-dependent manner.Discussion: CPS1 played a pivotal role in mediating glucagon-induced hepatic gluconeogenesis. The discovery of cynarin as a natural inhibitor of CPS1 suggested its potential as a therapeutic agent for diabetes treatment.