INTAC endonuclease and phosphatase modules differentially regulate transcription by RNA polymerase II.

Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or promoter-proximal termination. Integrator-PP2A (INTAC) plays a crucial role in determining the fate of paused polymerases, but the underlying mechanisms remain unclear. Here, we establish a rapid degradation system to dissect the functions of INTAC RNA endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters and enhancers, yet differentially affect polymerase fate. The endonuclease module induces promoter-proximal termination, with its disruption leading to accumulation of elongation-incompetent polymerases and downregulation of highly expressed genes, while elongation-competent polymerases accumulate at lowly expressed genes and non-coding elements, leading to their upregulation. The phosphatase module primarily prevents the release of paused polymerases and limits transcriptional activation, especially for highly paused genes. Thus, both INTAC catalytic modules have unexpectedly general yet distinct roles in dynamic transcriptional control.

Partial coherence enhances parallelized photonic computing.

Advancements in optical coherence control1-5 have unlocked many cutting-edge applications, including long-haul communication, light detection and ranging (LiDAR) and optical coherence tomography6-8. Prevailing wisdom suggests that using more coherent light sources leads to enhanced system performance and device functionalities9-11. Our study introduces a photonic convolutional processing system that takes advantage of partially coherent light to boost computing parallelism without substantially sacrificing accuracy, potentially enabling larger-size photonic tensor cores. The reduction of the degree of coherence optimizes bandwidth use in the photonic convolutional processing system. This breakthrough challenges the traditional belief that coherence is essential or even advantageous in integrated photonic accelerators, thereby enabling the use of light sources with less rigorous feedback control and thermal-management requirements for high-throughput photonic computing. Here we demonstrate such a system in two photonic platforms for computing applications: a photonic tensor core using phase-change-material photonic memories that delivers parallel convolution operations to classify the gaits of ten patients with Parkinson's disease with 92.2% accuracy (92.7% theoretically) and a silicon photonic tensor core with embedded electro-absorption modulators (EAMs) to facilitate 0.108 tera operations per second (TOPS) convolutional processing for classifying the Modified National Institute of Standards and Technology (MNIST) handwritten digits dataset with 92.4% accuracy (95.0% theoretically).

The intra-individual reliability of 1 H-MRS measurement in the anterior cingulate cortex across 1 year.

Magnetic resonance spectroscopy (MRS) is the primary method that can measure the levels of metabolites in the brain in vivo. To achieve its potential in clinical usage, the reliability of the measurement requires further articulation. Although there are many studies that investigate the reliability of gamma-aminobutyric acid (GABA), comparatively few studies have investigated the reliability of other brain metabolites, such as glutamate (Glu), N-acetyl-aspartate (NAA), creatine (Cr), phosphocreatine (PCr), or myo-inositol (mI), which all play a significant role in brain development and functions. In addition, previous studies which predominately used only two measurements (two data points) failed to provide the details of the time effect (e.g., time-of-day) on MRS measurement within subjects. Therefore, in this study, MRS data located in the anterior cingulate cortex (ACC) were repeatedly recorded across 1 year leading to at least 25 sessions for each subject with the aim of exploring the variability of other metabolites by using the index coefficient of variability (CV); the smaller the CV, the more reliable the measurements. We found that the metabolites of NAA, tNAA, and tCr showed the smallest CVs (between 1.43% and 4.90%), and the metabolites of Glu, Glx, mI, and tCho showed modest CVs (between 4.26% and 7.89%). Furthermore, we found that the concentration reference of the ratio to water results in smaller CVs compared to the ratio to tCr. In addition, we did not find any time-of-day effect on the MRS measurements. Collectively, the results of this study indicate that the MRS measurement is reasonably reliable in quantifying the levels of metabolites.

Sperm-borne miR-202 targets SEPT7 and regulates first cleavage of bovine embryos via cytoskeletal remodeling.

In mammals, sperm-borne regulators can be transferred to oocytes during fertilization and have different effects on the formation of pronuclei, the first cleavage of zygotes, the development of preimplantation embryos and even the metabolism of individuals after birth. The regulatory role of sperm microRNAs (miRNAs) in the development of bovine preimplantation embryos has not been reported in detail. By constructing and screening miRNA expression libraries, we found that miR-202 was highly enriched in bovine sperm. As a target gene of miR-202, co-injection of SEPT7 siRNA can partially reverse the accelerated first cleavage of bovine embryos caused by miR-202 inhibitor. In addition, both a miR-202 mimic and SEPT7 siRNA delayed the first cleavage of somatic cell nuclear transfer (SCNT) embryos, suggesting that miR-202-SEPT7 mediates the delay of first cleavage of bovine embryos. By further exploring the relationship between miR-202/SEPT7, HDAC6 and acetylated α-tubulin during embryonic development, we investigated how sperm-borne miR-202 regulates the first cleavage process of bovine embryos by SEPT7 and demonstrate the potential of sperm-borne miRNAs to improve the efficiency of SCNT.

Potentially functional genetic variants in interferon regulatory factor family genes are associated with colorectal cancer survival.

Interferon regulatory factor (IRF) family genes play a critical role in colorectal cancer (CRC) development and impact patient survival. This study evaluated the influence of functional single nucleotide polymorphisms (SNPs) in IRF genes on CRC survival, including functional predictions and experimental validations. Multivariate Cox regression analysis identified three linked SNPs as significant survival predictors, with the rs141112353 T/T genotype in the 3'UTR region of IRF6 significantly associated with decreased survival (HR = 1.60, P = 6E-04). Expression quantitative trait loci (eQTL) analysis indicated that the rs141112353 TA > T alteration reduced IRF6 expression. Dual luciferase assays showed lower activity for the T allele in the presence of hsa-miR-548ap-3p. Data from The Cancer Genome Atlas (TCGA) and other databases confirmed lower IRF6 levels in CRC tissues, correlating with worse survival and inversely with M2 macrophage infiltration. In vitro, IRF6 overexpression inhibited CRC cell proliferation and M2 macrophage polarization by downregulating MIF expression. These findings suggest that the IRF6 rs141112353 TA > T variant significantly affects CRC survival, potentially by enhancing miR-548-ap-3p binding affinity.

Functional genetic variants of GEN1 predict overall survival of Chinese epithelial ovarian cancer patients.

BACKGROUND: Inherited variations in DNA double-strand break (DSB) repair pathway are known to influence ovarian cancer occurrence, progression and treatment response. Despite its significance, survival-associated genetic variants within the DSB pathway remain underexplored. METHODS: In the present study, we performed a two-phase analysis of 19,290 single-nucleotide polymorphisms (SNPs) in 199 genes in the DSB repair pathway from a genome-wide association study (GWAS) dataset and explored their associations with overall survival (OS) in 1039 Han Chinese epithelial ovarian carcinoma (EOC) patients. After utilizing multivariate Cox regression analysis with bayesian false-discovery probability for multiple test correction, significant genetic variations were identified and subsequently underwent functional prediction and validation. RESULTS: We discovered a significant association between poor overall survival and the functional variant GEN1 rs56070363 C > T (CT + TT vs. TT, adjusted hazard ratio (HR) = 2.50, P < 0.001). And the impact of GEN1 rs56070363 C > T on survival was attributed to its reduced binding affinity to hsa-miR-1287-5p and the resultant upregulation of GEN1 mRNA expression. Overexpression of GEN1 aggregated EOC cell proliferation, invasion and migration presumably by influencing the expression of immune inhibitory factors, thereby elevating the proportion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and then constructing an immunosuppressive tumor microenvironment. CONCLUSIONS: In conclusion, GEN1 rs56070363 variant could serve as a potential predictive biomarker and chemotherapeutic target for improving the survival of EOC patients.

Comparative study of ultrasound attenuation analysis and controlled attenuation parameter in the diagnosis and grading of liver steatosis in non-alcoholic fatty liver disease patients.

PURPOSE: To assess the diagnostic performance of Ultrasound Attenuation Analysis (USAT) in the diagnosis and grading of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD) using Controlled Attenuation Parameters (CAP) as a reference. MATERIALS AND METHODS: From February 13, 2023, to September 26, 2023, participants underwent CAP and USAT examinations on the same day. We used manufacturer-recommended CAP thresholds to categorize the stages of hepatic steatosis: stage 1 (mild) - 240 dB/m, stage 2 (moderate) - 265 dB/m, stage 3 (severe) - 295 dB/m. Receiver Operating Characteristic curves were employed to evaluate the diagnostic accuracy of USAT and determine the thresholds for different levels of hepatic steatosis. RESULTS: Using CAP as the reference, we observed that the average USAT value increased with the severity of hepatic steatosis, and the differences in USAT values among the different hepatic steatosis groups were statistically significant (p < 0.05). There was a strong positive correlation between USAT and CAP (r = 0.674, p < 0.0001). When using CAP as the reference, the optimal cut-off values for diagnosing and predicting different levels of hepatic steatosis with USAT were as follows: the cut-off value for excluding the presence of hepatic steatosis was 0.54 dB/cm/MHz (AUC 0.96); for mild hepatic steatosis, it was 0.59 dB/cm/MHz (AUC 0.86); for moderate hepatic steatosis, it was 0.73 dB/cm/MHz (AUC 0.81); and for severe hepatic steatosis, it was 0.87 dB/cm/MHz (AUC 0.87). CONCLUSION: USAT exhibits strong diagnostic performance for hepatic steatosis and shows a high correlation with CAP values.

N4-acetylcytidine of Nop2 mRNA is required for the transition of morula-to-blastocyst.

N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification is crucial for mRNA stability and translation efficiency, yet the underlying function in mammalian preimplantation embryos remains unclear. Here, we characterized the ac4C modification landscape in mouse early embryos and found that the majority of embryos deficient in ac4C writer-NAT10 failed to develop into normal blastocysts. Through single-cell sequencing, RNA-seq, acetylated RNA immunoprecipitation combined with PCR (acRIP-PCR), and embryonic phenotype monitoring, Nop2 was screened as a target gene of Nat10. Mechanistically, Nat10 knockdown decreases the ac4C modification on Nop2 mRNA and reduces RNA and protein abundance by affecting the mRNA stability of Nop2. Then, depletion of NOP2 may inhibit the translation of transcription factor TEAD4, resulting in defective expression of the downstream lineage-specific gene Cdx2, and ultimately preventing blastomeres from undergoing the trophectoderm (TE) fate. However, exogenous Nop2 mRNA partially reverses this abnormal development. In conclusion, our findings demonstrate that defective ac4C modification of Nop2 mRNA hinders the morula-to-blastocyst transition by influencing the first cell fate decision in mice.

Scalable High-Precision Trimming of Photonic Resonances by Polymer Exposure to Energetic Beams.

Integrated photonic circuits (PICs) have seen an explosion in interest, through to commercialization in the past decade. Most PICs rely on sharp resonances to modulate, steer, and multiplex signals. However, the spectral characteristics of high-quality resonances are highly sensitive to small variations in fabrication and material constants, which limits their applicability. Active tuning mechanisms are commonly employed to account for such deviations, consuming energy and occupying valuable chip real estate. Readily employable, accurate, and highly scalable mechanisms to tailor the modal properties of photonic integrated circuits are urgently required. Here, we present an elegant and powerful solution to achieve this in a scalable manner during the semiconductor fabrication process using existing lithography tools: by exploiting the volume shrinkage exhibited by certain polymers to permanently modulate the waveguide's effective index. This technique enables broadband and lossless tuning with immediate applicability in wide-ranging applications in optical computing, telecommunications, and free-space optics.

Nitrate Signaling and Its Role in Regulating Flowering Time in Arabidopsis thaliana.

Plant growth is coordinated with the availability of nutrients that ensure its development. Nitrate is a major source of nitrogen (N), an essential macronutrient for plant growth. It also acts as a signaling molecule to modulate gene expression, metabolism, and a variety of physiological processes. Recently, it has become evident that the calcium signal appears to be part of the nitrate signaling pathway. New key players have been discovered and described in Arabidopsis thaliana (Arabidopsis). In addition, knowledge of the molecular mechanisms of how N signaling affects growth and development, such as the nitrate control of the flowering process, is increasing rapidly. Here, we review recent advances in the identification of new components involved in nitrate signal transduction, summarize newly identified mechanisms of nitrate signaling-modulated flowering time in Arabidopsis, and suggest emerging concepts and existing open questions that will hopefully be informative for further discoveries.

LncRNAs in the Dlk1-Dio3 Domain Are Essential for Mid-Embryonic Heart Development.

The Dlk1-Dio3 domain is important for normal embryonic growth and development. The heart is the earliest developing and functioning organ of the embryo. In this study, we constructed a transcriptional termination model by inserting termination sequences and clarified that the lack of long non-coding RNA (lncRNA) expression in the Dlk1-Dio3 domain caused the death of maternal insertion mutant (MKI) and homozygous mutant (HOMO) mice starting from E13.5. Parental insertion mutants (PKI) can be born and grow normally. Macroscopically, dying MKI and HOMO embryos showed phenomena such as embryonic edema and reduced heart rate. Hematoxylin and eosin (H.E.) staining showed thinning of the myocardium in MKI and HOMO embryos. In situ hybridization (IHC) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) showed downregulation of lncGtl2, Rian, and Mirg expression in MKI and HOMO hearts. The results of single-cell RNA sequencing (scRNA-Seq) analysis indicated that the lack of lncRNA expression in the Dlk1-Dio3 domain led to reduced proliferation of epicardial cells and may be an important cause of cardiac dysplasia. In conclusion, this study demonstrates that Dlk1-Dio3 domain lncRNAs play an integral role in ventricular development.

ABTS as Both Activator and Electron Shuttle to Activate Persulfate for Diclofenac Degradation: Formation and Contributions of ABTS•+, SO4•-, and •OH.

The activation of peroxydisulfate (PDS) by organic compounds has attracted increasing attention. However, some inherent drawbacks including quick activator decomposition and poor anti-interference capacity limited the application of organic compound-activated PDS. It was interestingly found that 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonate) (ABTS) could act as both activator and electron shuttle for PDS activation to enhance diclofenac (DCF) degradation over a pH range of 2.0-11.0. Multiple reactive species of ABTS•+, •OH, and SO4•- were generated in the PDS/ABTS system, while only ABTS•+ and •OH directly contributed to DCF degradation. ABTS•+, generated via the reactions of ABTS with PDS, SO4•-, and •OH, was the dominant reactive species of DCF degradation. No significant decomposition of ABTS was observed in the PDS/ABTS system, and ABTS acted as both activator and electron shuttle. Four possible degradation pathways of DCF were proposed, and the toxicity of DCF decreased after treatment with the PDS/ABTS system. The PDS/ABTS system had good anti-interference capacity to common natural water constituents. Additionally, ABTS was encapsulated into cellulose to obtain ABTS@Ce beads, and the PDS/ABTS@Ce system possessed excellent performance on DCF degradation. This study proposes a new perspective to reconsider the mechanism of activating PDS with organic compounds and highlights the considerable contribution of organic radicals on contaminant removal.

Citrinin inhibits the function of Leydig cells in male rats in prepuberty.

Citrinin, a mycotoxin existing in fruits, has nephrotoxicity, hepatotoxicity and embryotoxicity. The effects of citrinin on Leydig cell development in prepuberty remains unclear. Male Sprague-Dawley rats were gavaged with 0, 1, 2.5, and 5 mg/kg citrinin from postnatal days 21-28. Citrinin at 5 mg/kg significantly decreased serum testosterone levels, while increasing serum LH and FSH levels. Citrinin at 1-5 mg/kg markedly downregulated Hsd17b3 and HSD17B3 expression, while upregulating Srd5a1 (SRD5A1) and Akr1c14 (AKR1C14) expression at 2.5 and/or 5 mg/kg. Citrinin at 5 mg/kg also significantly increased PCNA-labeling index in Leydig cells. Citrinin at 5 mg/kg significantly raised testicular MDA amount, whiling at 2.5 and 5 mg/kg downregulating SOD1 and SOD2 expression. Citrinin at 5 mg/kg markedly decreased the ratio of Bcl2 to Bax, in consistent with the increased apoptosis in Leydig cells judged by TUNEL assay. Enzymatic assay revealed that citrinin inhibited rat testicular HSD3B1 activity at 100 µM and HSD17B3 activity at 10-100 µM. Citrinin at 50 µM and higher also induced reactive oxygen species (ROS) and apoptosis of R2C cell line. In conclusion, citrinin inhibits Leydig cell development at multiple levels via different mechanisms and oxidative stress partially plays a role.

Potentially functional genetic variants of the notch signaling pathway genes predict survival of Chinese patients with esophageal squamous cell carcinoma.

BACKGROUND: The Notch signaling pathway is involved in the progression of esophageal squamous cell carcinoma (ESCC), although the roles of single nucleotide polymorphisms (SNPs) of the Notch signaling pathway genes in the process remain unknown. METHODS: The present study included 1009 patients with histopathologically diagnosed ESCC at Fudan University Shanghai Cancer Center. Two-stage multivariate Cox proportional hazards regression analysis was used to estimate associations between 13,248 SNPs in 103 Notch signaling pathway genes and overall survival of the patients. RESULTS: We found that overall survival of the patients was significantly associated with genotypes of HDAC9 rs1729318 (AT+TT vs. AA: hazard ratio = 1.44, 95% confidence interval = 1.16-1.80, pcombined  = 0.001) and HDAC9 rs1339555498 (GT + TT vs. GG: hazard ratio = 1.38, 95% confidence interval = 1.10-1.74, pcombined = 0.005). Further receiver operator characteristic (ROC) curve analysis indicated that the model with both available clinical factors and these two SNPs improved the area under the ROC curve compared to the model with clinical factors only (1-year: 0.66 vs. 0.64, p = 0.034). Additional expression quantitative trait loci analysis showed that the rs1729318 T variant genotypes were associated with increased mRNA expression levels of HDAC9 in normal esophageal muscular tissue (p = 0.003). CONCLUSIONS: The results suggest that these two potential functional SNPs on HDAC9 may serve as biomarkers for predicting survival of ESCC patients. However, further studies are needed to confirm these findings.

Potentially functional genetic variants of VAV2 and PSMA4 in the immune-activation pathway and non-small cell lung cancer survival.

BACKGROUND: Lung cancer has the highest mortality among cancers, represented by a low 5-year survival rate. The function of the immune system has a profound influence on the development and progression of lung cancer. Thus genetic variants of the immune-related genes may serve as potential predictors of non-small cell lung cancer (NSCLC) survival. METHODS: In the present study, we conducted a two-stage survival analysis in 1,531 NSCLC patients and assessed the associations between genetic variants in the immune-activation gene set and the overall survival (OS) of NSCLC patients. The validated variants were further subjected to functional annotation and in vitro experiments. RESULTS: We identified 25 SNPs spanning six loci associated with NSCLC OS after multiple-testing corrections in all datasets, in which two variants, PSMA4 rs12901682 A > C and VAV2 rs12002767 C > T, were shown to potentially affect lung cancer OS by cis-regulating the expression of the corresponding genes [(HR (95% CI) = 0.76 (0.65-0.89) and 1.36 (1.12-1.65), p = 4.29 × 10-4 and 0.002, respectively]. CONCLUSION: Our findings provide new insights into the role of genetic variants in the immune-activation pathway genes in lung cancer progression.

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer.

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10-6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10-8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

Flg22-induced Ca2+ increases undergo desensitization and resensitization.

The flagellin epitope flg22, a pathogen-associated molecular pattern (PAMP), binds to the receptor-like kinase FLAGELLIN SENSING2 (FLS2), and triggers Ca2+ influx across the plasma membrane (PM). The flg22-induced increases in cytosolic Ca2+ concentration ([Ca2+ ]i ) (FICA) play a crucial role in plant innate immunity. It's well established that the receptor FLS2 and reactive oxygen species (ROS) burst undergo sensitivity adaptation after flg22 stimulation, referred to as desensitization and resensitization, to prevent over responses to pathogens. However, whether FICA also mount adaptation mechanisms to ensure appropriate and efficient responses against pathogens remains poorly understood. Here, we analysed systematically [Ca2+ ]i increases upon two successive flg22 treatments, recorded and characterized rapid desensitization but slow resensitization of FICA in Arabidopsis thaliana. Pharmacological analyses showed that the rapid desensitization might be synergistically regulated by ligand-induced FLS2 endocytosis as well as the PM depolarization. The resensitization of FICA might require de novo FLS2 protein synthesis. FICA resensitization appeared significantly slower than FLS2 protein recovery, suggesting additional regulatory mechanisms of other components, such as flg22-related Ca2+ permeable channels. Taken together, we have carefully defined the FICA sensitivity adaptation, which will facilitate further molecular and genetic dissection of the Ca2+ -mediated adaptive mechanisms in PAMP-triggered immunity.

A long-wavelength activable AIEgen fluorescent probe for HClO and cell apoptosis imaging.

Hypochlorous acid (HClO) is an important bactericide, and adjusting the content of HClO helps to improve the host's innate immunity and resist microbial invasion. Aggregation-induced luminescence (AIE) is the opposite of aggregation-induced quenching (ACQ). Compounds with AIE properties emit weakly in a dispersed state in solution and they can emit strong fluorescence in an aggregated state. In this article, we proposed a new AIE fluorescent probe QM-ClO based on the quinoline-malononitrile (QM) fluorophore and dimethylthiocarbamate (DMTC) to detect HClO. The probe QM-ClO showed a fast response time, a low detection limit of 30.8 nM and a large Stokes shift (190 nm). Carbonyl cyanide metachlorophenyl-hydrazone (CCCP) was used to induce cell apoptosis, and then an increase in the HClO content was observed in the cell. It is proved that cell apoptosis can lead to the increase of the HClO content in the cell. This probe provides an effective tool for studying apoptosis-related diseases.

Chemistry and Pharmacological Activity of Sesquiterpenoids from the Chrysanthemum Genus.

Plants from the Chrysanthemum genus are rich sources of chemical diversity and, in recent years, have been the focus of research on natural products chemistry. Sesquiterpenoids are one of the major classes of chemical constituents reported from this genus. To date, more than 135 sesquiterpenoids have been isolated and identified from the whole genus. These include 26 germacrane-type, 26 eudesmane-type, 64 guaianolide-type, 4 bisabolane-type, and 15 other-type sesquiterpenoids. Pharmacological studies have proven the biological potential of sesquiterpenoids isolated from Chrysanthemum species, reporting anti-inflammatory, antibacterial, antitumor, insecticidal, and antiviral activities for these interesting molecules. In this paper, we provide information on the chemistry and bioactivity of sesquiterpenoids obtained from the Chrysanthemum genus which could be used as the scientific basis for their future development and utilization.

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations.

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10-8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10-9) and 4q28.1 (OR=1.14, p=3.33×10-11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.