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Abstract Background Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy. Although previous research has explored associations between plasma proteins and CLL, the causal relationships remain unclear. This study used Mendelian randomization (MR) to investigate the causal relationship between 7156 plasma proteins and CLL risk. Methods A two-sample MR analysis assessed the impact of specific plasma proteins on CLL risk, using data from the Finngen Proteomics project (analyzing 828 participants) and the UK Biobank. Additional analyses included colocalization, phenomenon-wide MR, and protein–protein interaction networks. Results The study identified nine plasma proteins significantly associated with CLL risk. Increased levels of Peptidyl-prolyl cis-trans isomerase E (PPIE) (OR = 1.66, 95% CI 1.22–2.27, P = 0.001) were associated with an increased risk of developing CLL, whereas Protein O-Mannosyltransferase 2 (POMGNT2) (OR = 0.62, 95% CI 0.41–0.91, P = 0.017) and C–C Motif Chemokine Ligand 14(CCL14) (OR = 0.80, 95% CI 0.67–0.94, P = 0.010) were associated with a reduced risk of CLL. Colocalization analysis suggested that PPIE may share pathogenic variants with CLL (PP.H4 = 0.758). Phenomenon-wide MR analysis of PPIE also indicated associations with other clinical features, including rheumatic diseases and type 2 diabetes. Protein–protein interaction and drug-gene interaction analyses highlighted CDC5L and SNW1 as potential therapeutic targets. Conclusion This study identifies nine plasma proteins linked to CLL risk, with PPIE offering new insights into the disease's pathogenesis. Further research is needed to validate these findings and explore their potential as therapeutic targets.

Abstract Background With advances in endoscopic submucosal dissection (ESD) technique, an increasing number of the Chinese population are being diagnosed with early gastric cancers (EGCs) at gastric angulus. However, the relationship between gastric angulus and EGCs remains obscure. Objectives We aimed to unveil the unreported location characteristics of gastric angulus in Chinese EGC patients and the correlation between the degree of submucosal fibrosis and ESD outcomes. Methods We retrospectively reviewed the medical records of EGC patients treated with ESD from January 2010 to March 2023. We retrospectively investigated and analyzed 740 EGC patients using multiple analyses. Results Following gastric antrum (53.1%), the gastric angulus (21.8%) emerged as the second-most prevalent site for EGCs. It had highest incidence of severe submucosal fibrosis and ulceration than the other parts. Multivariate analysis showed independent associations of submucosal fibrosis at the angulus with ulceration (OR: 3.714, 95% CI: 1.041–13.249), procedure duration (OR: 1.037, 95% CI: 1.014–1.061), and perforation complication (OR: 14.611, 95% CI: 1.626-131.277) (all P

BackgroundDyslipidemia is a known independent risk factor for Nonalcoholic fatty liver disease (NAFLD). However, the relationship between NAFLD and the serum non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio remains unclear. This study examined the association between the non-HDL-C to HDL-C ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population.MethodsWe conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018, including 4798 participants. Liver ultrasound and Transient Elastography (TE) were used to assess fibrosis and steatosis. Adjusted multivariable regression analyses, subgroup analyses based on BMI and sex, and a generalized additive model were employed to investigate the relationship between the non-HDL-C/HDL-C ratio and NAFLD.ResultsAmong the 4798 participants, 39.27% (n = 1,884) had NAFLD. Significant positive correlations between non-HDL-C/HDL-C and NAFLD risk were found across all models, with sex-stratified analyses indicating higher risk in men. Liver fibrosis was also associated with non-HDL-C/HDL-C ratios. The Receiver operating characteristic (ROC) analysis shows non-HDL-C/HDL-C as a better predictor for NAFLD than non-HDL-C or HDL-C alone.ConclusionElevated non-HDL-C/HDL-C levels are independently associated with increased NAFLD and liver fibrosis risk in the American population, suggesting its utility in predicting NAFLD and related liver fibrosis.

BackgroundPrior research suggests a potential link between ABO blood types and susceptibility to various malignancies. The correlation between ABO blood types and hematological myeloid neoplasms, however, remains inadequately explored.ObjectiveThis study investigates the association between ABO blood groups and the incidence of hematological myeloid neoplasms in adolescents and adults.MethodsIn this retrospective clinical study, 1,022 adolescent and adult cases of myeloid neoplasms diagnosed at our institution were initially considered. After excluding conditions potentially linked to ABO blood types from prior studies, 792 eligible cases were analyzed. These cases were categorized based on disease subtypes and compared with a control group for blood type distribution.ResultsOur findings reveal a significantly higher prevalence of blood type A in patients with myeloid neoplasms compared to the control group, except for chronic myelocytic leukemia and myeloproliferative neoplasms. Conversely, the prevalence of blood type AB in myeloid neoplasms was notably lower than in the control group.ConclusionThe study suggests a potential association between ABO blood types and the risk of developing hematological myeloid neoplasms in adolescents and adults. Further research is warranted to elucidate the underlying mechanisms of this relationship.

Abstract Background Research on the fatty acid metabolism related gene SLC27A2 is currently mainly focused on solid tumors, and its mechanism of action in hematological tumors has not been reported. Method This study aims to explore the pathological and immune mechanisms of the fatty acid metabolism related gene SLC27A2 in hematological tumors and verify its functional role in hematological tumors through cell experiments to improve treatment decisions and clinical outcomes of hematological tumors. Result This study identified the fatty acid metabolism related gene SLC27A2 as a common differentially expressed gene between DLBCL and AML. Immune microenvironment analysis showed that SLC27A2 was significantly positively correlated with T cell CD4 + , T cell CD8 + , endothelial cells, macrophages, and NK cells in DLBCL. In AML, there is a significant negative correlation between SLC27A2 and B cells, T cell CD8 + , and macrophages. SLC27A2 participates in the immune process of hematological tumors through T cell CD8 + and macrophages. The GESA results indicate that high expression of SLC27A2 is mainly involved in the fatty acid pathway, immune pathway, and cell cycle pathway of DLBCL. The low expression of SLC27A2 is mainly involved in the immune pathway of AML. Therefore, SLC27A2 is mainly involved in the pathological mechanisms of hematological tumors through immune pathways, and cell experiments have also confirmed that SLC27A2 is involved in the regulation of DLBCL cells. Conclusion In summary, our research results comprehensively report for the first time the mechanism of action of SLC27A2 in the immune microenvironment of DLBCL and AML, and for the first time verify the cycle and apoptotic effects of the fatty acid related gene SLC27A2 in DLBCL cells through cell experiments. Research can help improve the treatment of AML and DLBCL patients.

This review comprehensively surveys the latest advancements in surface modification of pure magnesium (Mg) in recent years, with a focus on various cost-effective procedures, comparative analyses, and assessments of outcomes, addressing the merits and drawbacks of pure Mg and its alloys. Diverse economically feasible methods for surface modification, such as hydrothermal processes and ultrasonic micro-arc oxidation (UMAO), are discussed, emphasizing their exceptional performance in enhancing surface properties. The attention is directed towards the biocompatibility and corrosion resistance of pure Mg, underscoring the remarkable efficacy of techniques such as Ca-deficientca-deficient hydroxyapatite (CDHA)/MgF2 bi-layer coating and UMAO coating in electrochemical processes. These methods open up novel avenues for the application of pure Mg in medical implants. Emphasis is placed on the significance of adhering to the principles of reinforcing the foundation and addressing the source. The advocacy is for a judicious approach to corrosion protection on high-purity Mg surfaces, aiming to optimize the overall mechanical performance. Lastly, a call is made for future in-depth investigations into areas such as composite coatings and the biodegradation mechanisms of pure Mg surfaces, aiming to propel the field towards more sustainable and innovative developments.

At present, GPX4's role in the occurrence and development of diffuse large B lymphoma (DLBCL) is rarely reported. This study's purpose is to explore GPX4's significance in the diagnosis, treatment, and pathological mechanisms of DLBCL. The TIMER 2.0, GEPIA, and GEO databases were used to analyze GPX4's expression levels in DLBCL tissue, peripheral blood, and single cells, and evaluate its potential performance as a therapeutic and diagnostic marker. Cell experiments validate GPX4's role in DLBCL cells. And revealed the potential mechanism of GPX4's action from three aspects: immunity, pathogenic gene expression, and protein interaction. The results indicate that GPX4 can be used as a biomarker for treatment and diagnosis (FC > 1.5, P 0.8, KM-P value

Abstract The often immune-suppressive tumor microenvironment (TME) may hinder immune evasion and response to checkpoint blockade therapies. Pharmacological activation of the STING pathway does create an immunologically hot TME, however, systemic delivery might lead to undesired off-target inflammatory responses. Here, we generate a small panel of esterase-activatable pro-drugs based on the structure of the non-nucleotide STING agonist MSA-2 that are subsequently stably incorporated into a liposomal vesicle for intravenous administration. The pharmacokinetic properties and immune stimulatory capacity of pro-drugs delivered via liposomes (SAProsomes) are enhanced compared to the free drug form. By performing efficacy screening among the SAProsomes incorporating different pro-drugs in syngeneic mouse tumor models, we find that superior therapeutic performance relies on improved delivery to the desired tumor and lymphoid compartments. The best candidate, SAProsome-3, highly stimulates secretion of inflammatory cytokines and creates a tumoricidal immune landscape. Notably, upon application to breast cancer or melanoma mouse models, SAProsome-3 elicits durable remission of established tumors and postsurgical tumor-free survival while decreasing metastatic burden without significant systemic toxicity. In summary, our work establishes the proof of principle for a better targeted and more efficient and safe STING agonist therapy.

Acute myeloid leukemia (AML) is a blood cancer that is diverse in terms of its molecular abnormalities and clinical outcomes. Iron homeostasis and cell death pathways play crucial roles in cancer pathogenesis, including AML. The objective of this study was to examine the clinical significance of genes involved in iron-related cell death and apoptotic pathways in AML, with the intention of providing insights that could have prognostic implications and facilitate the development of targeted therapeutic interventions. Gene expression profiles, clinical information, and molecular alterations were integrated from multiple datasets, including TCGA-LAML and GSE71014. Our analysis identified specific molecular subtypes of acute myeloid leukemia (AML) displaying varying outcomes, patterns of immune cell infiltration, and profiles of drug sensitivity for targeted therapies based on the expression of genes involved in iron-related apoptotic and cell death pathways. We further developed a risk model based on four genes, which demonstrated promising prognostic value in both the training and validation cohorts, indicating the potential of this model for clinical decision-making and risk stratification in AML. Subsequently, Western blot analysis showed that the expression levels of C-Myc and CyclinD1 were significantly reduced after CD4 expression levels were knocked down. The findings underscore the potential of iron-related cell death pathways as prognostic biomarkers and therapeutic targets in AML, paving the way for further research aimed at understanding the molecular mechanisms underlying the correlation between iron balance, apoptosis regulation, and immune modulation in the bone marrow microenvironment.

Background: Co-stimulatory molecules have been shown to enhance antitumor immune responses, but their role in Diffuse Large B-cell Lymphoma (DLBCL) remains unexplored. Methods: This study aimed to explore the molecular typing of DLBCL with co-stimulatory molecule genes and to construct a prognostic profile to improve treatment decisions and clinical outcomes. Results: We conducted the first comprehensive analysis of co-stimulatory molecules in DLBCL patients and identified five co-stimulatory molecule genes with prognostic and diagnostic values. Consensus cluster analysis based on these five co-stimulatory molecule genes revealed that the two identified clusters had different distribution patterns and prognostic differences. Co-stimulatory molecular correlation signatures were then constructed based on these five co-stimulatory molecular genes and validated in an external dataset, showing good performance in predicting patient prognosis. The signature is an independent risk factor for DLBCL patients and significantly correlates with clinical factors in patients and can be used as a complement to clinical factors. Furthermore, the signature was associated with the tumor immune microenvironment. Patients identified as being at high risk according to our signature exhibit high levels of immune cell infiltration microenvironment. Conclusions: In conclusion, our signature can provide clinicians with prognostic predictions and help guide the treatment of patients with DLBCL.

Crowdsourced testing is an emerging trend in software testing, which takes advantage of the efficiency of crowdsourced and cloud platforms. Crowdsourced testing has gradually been applied in many fields. In crowdsourced software testing, after the crowdsourced workers complete the test tasks, they submit the test results in test reports. Therefore, in crowdsourced software testing, checking a large number of test reports is an arduous but unavoidable software maintenance task. Crowdsourced test reports are numerous, complex, and need to be sorted to improve inspection efficiency. There are no systematic methods for prioritizing reports in crowdsourcing test report prioritization. However, in regression testing, test case prioritization technology has matured. Therefore, we migrate the test case prioritization method to crowdsourced test report prioritization and evaluate the effectiveness of these methods. We use natural language processing technology and word segmentation to process the text in the test reports. Then we use four methods to prioritize the reports: total greedy algorithm, additional greedy algorithm, genetic algorithm, and ART. The results show that these methods all perform well in prioritizing crowdsourced test reports, with an average APFD of more than 0.8.

Abstract Background Combinatorial systemic chemotherapy is a powerful treatment paradigm against cancer, but it is fraught with problems due to the emergence of chemoresistance and additive systemic toxicity. In addition, coadministration of individual drugs suffers from uncontrollable pharmacokinetics and biodistribution, resulting in suboptimal combination synergy. Methods Toward the goal of addressing these unmet medical issues, we describe a unique strategy to integrate multiple structurally disparate drugs into a self-assembling nanococktail platform. Conjugation of a polyunsaturated fatty acid (e.g., linoleic acid) with two chemotherapies generated prodrug entities that were miscible with tunable drug ratios for aqueous self-assembly. In vitro and in vivo assays were performed to investigate the mechanism of combinatorial nanococktails in mitigating chemoresistance and the efficacy of nanotherapy. Results The coassembled nanoparticle cocktails were feasibly fabricated and further refined with an amphiphilic matrix to form a systemically injectable and PEGylated nanomedicine with minimal excipients. The drug ratio incorporated into the nanococktails was optimized and carefully examined in lung cancer cells to maximize therapeutic synergy. Mechanistically, subjugated resistance by nanococktail therapy was achieved through the altered cellular uptake pathway and compromised DNA repair via the ATM/Chk2/p53 cascade. In mice harboring cisplatin-resistant lung tumor xenografts, administration of the nanococktail outperformed free drug combinations in terms of antitumor efficacy and drug tolerability. Conclusion Overall, our study provides a facile and cost-effective approach for the generation of cytotoxic nanoparticles to synergistically treat chemoresistant cancers.

The crustal velocity structure in the South Yellow Sea (SYS) Basin is crucial for understanding the basin’s geological structure and evolution. OBS (ocean-bottom station) data from the OBS2013 line have been used to determine the crustal velocity structure in the SYS. The velocity model of the upper crust in the northern SYS was determined using first-arrival traveltime tomography. The model showed a higher resolution shallow crustal velocity structure but a lower resolution middle-lower crustal velocity structure. The crustal velocity structure, together with the Moho discontinuity in the SYS Basin, was also constructed using a human–computer interactive traveltime simulation, and the result was highly dependent on the prior knowledge of the operator. In this study, we reconstructed a crustal velocity model in the SYS Basin using a joint tomographic inversion of the traveltime and its gradient data of the reflected and refracted waves picked from the OBS data. The resolution of the inverted velocity structure from shallow-to-deep crust was improved. The results revealed that the massive high-velocity body below the Haiyang Sag of the Jiaolai Basin extends to the Qianliyan Uplift in the SYS; the low-velocity Cretaceous strata directly cover the pre-Sinitic metamorphic rock basement of the Sulu orogenic belt; and the thick Meso-Paleozoic marine strata are retained beneath the Meso–Cenozoic continental strata in the northern depression. The Moho depth in the SYS Basin ranges from 28 to 32 km.

Imaging is of great importance in everyday life and various fields of science and technology. Conventional imaging is achieved by bending light rays originating from an object with a lens. Such ray bending requires space-variant structures, inevitably introducing a geometric center to the lens. To overcome the limitations arising from the conventional imaging mechanism, we consider imaging elements that employ a different mechanism, which we call reciprocal lenses. This type of imaging element relies on lateral ray shifting, enabled by momentum-space-variant phase modulations in periodic structures. As such, it has the distinct advantage of not requiring alignment with a geometric center. Moreover, upright real images can be produced directly with a single reciprocal lens as the directions of rays are not changed. We realize an ultrathin reciprocal lens based on a photonic crystal slab. We characterize the lateral ray shifting behavior of the reciprocal lens and demonstrate imaging. Our work gives an alternative mechanism for imaging and provides a new way to modulate electromagnetic waves.

Abstract Inferring the properties of a scattering objective by analyzing the optical far-field responses within the framework of inverse problems is of great practical significance. However, it still faces major challenges when the parameter range is growing and involves inevitable experimental noises. Here, we propose a solving strategy containing robust neural-networks-based algorithms and informative photonic dispersions to overcome such challenges for a sort of inverse scattering problem—reconstructing grating profiles. Using two typical neural networks, forward-mapping type and inverse-mapping type, we reconstruct grating profiles whose geometric features span hundreds of nanometers with nanometric sensitivity and several seconds of time consumption. A forward-mapping neural network with a parameters-to-point architecture especially stands out in generating analytical photonic dispersions accurately, featured by sharp Fano-shaped spectra. Meanwhile, to implement the strategy experimentally, a Fourier-optics-based angle-resolved imaging spectroscopy with an all-fixed light path is developed to measure the dispersions by a single shot, acquiring adequate information. Our forward-mapping algorithm can enable real-time comparisons between robust predictions and experimental data with actual noises, showing an excellent linear correlation (R 2 > 0.982) with the measurements of atomic force microscopy. Our work provides a new strategy for reconstructing grating profiles in inverse scattering problems.

Aerospace control software is the most important part of aerospace software. Since its potential defects endanger life and safety, there are strict requirements on product quality. Therefore, efficient and reliable software testing is essential. The traditional testing method has been challenging to meet its development requirements, and software automation testing has gradually become the main tool for testing aerospace control software. For the automation testing of aerospace control software, the core problem is to locate the GUI widgets on the software screenshots and identify their intent, which directly affects the accuracy of the test. Because of this, we use the widget recognition technology based on image matching and use the image understanding and analysis technology to extract the widget image in the screenshots. After obtaining the widget image, we use a convolutional neural network to extract image features and use the encoder module to encode the extracted information features as a tensor. The decoder module generates a word sequence conditional on tensor and previous output based on the encoded information. We also conduct an empirical study to evaluate the accuracy of widget recognition and intention generation. For widget recognition, our average IoU reached 0.81. For widget intent generation, our model BLEU-1 is 0.567, BLEU-2 is 0.356, BLEU-3 is 0.261, BLEU-4 is 0.131. The results show that our method is very effective.

BackgroundInflammation appears to have a critical role in carcinogenesis tumor growth according to emerging research. The platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and plasma C-reactive protein (CRP) are considered to reflect the systemic inflammatory response and clinical prognosis. The prognostic value of inflammatory indices in myelodysplastic syndrome (MDS) patients remains unclear.MethodsA total of 213 MDS patients were enrolled for the study. Univariate and multivariate analyses were performed to determine the prognostic significance of various indicators, including PLR, NLR, and CRP.ResultsMDS patients with higher PLR, NLR, and CRP levels had significantly shorter overall survival (OS). Based on univariate analysis, age (≥60 years), gender (men), lower hemoglobin level (5%), poorer karyotype, and higher Revised International Prognostic Scoring System (IPSS-R) score were significantly associated with shorter OS. Patients with higher CRP levels had shorter leukemia-free survival (LFS, P = 0.041). However, higher PLR and NLR had no significant influence on LFS (P > 0.05). Multivariate Cox proportional hazards regression analysis indicated that high PLR and CRP were also independent adverse prognostic factors for OS in MDS.ConclusionsElevated PLR and CRP predict poor prognosis independent of the IPSS-R and provide a novel evaluation factor for MDS patients.

In recent years, the ongoing impact of the COVID-19 epidemic, irregular closed school life and frequent online teaching have negatively impacted the mental health and academic performance of many college students. Doing horticultural activities is an effective way to promote physical and mental health and enhance academic performance. This paper explores the relationship between horticultural activities participation, academic self-efficacy and positive mental characters under the perspective of disciplinary integration, with a view to promoting the mental health status and academic performance of college students and the application of horticultural therapy on college campuses. Questionnaires such as the Positive Mental Characters Scale for Chinese College Students (PMCS-CCS) and Academic Self-Efficacy Scale (ASES) are used to investigate 160 college students from four universities in China. The results show that horticultural activity participation is significantly positively correlated with academic self-efficacy (r = 0.345; p < 0.01) and positive mental characters (r = 0.298; p < 0.01), and horticultural activity participation can positively affect positive mental characters (B = 0.135, p < 0.01). At the same time, academic self-efficacy has a partial mediating effect between horticultural activity participation and positive mental characters. Universities can actively carry out campus horticultural activities to enhance students’ horticultural activity participation, which in turn promotes academic self-efficacy and further enhances the positive psychological level of college students.

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Helicobacter pylori infection can induce GC through a serial cascade of events, with emerging evidence suggesting the important role of epigenetic alterations in the development and progression of the disease. Here, we report on mechanisms responsible for Jumonji AT-rich interactive domain1B (JARID1B) upregulation in GC and its role in the malignant transformation induced by H. pylori infection. We found that upregulation of JARID1B was associated with poorer prognosis, greater tumor purity, and less immune cell infiltration into the tumor. Mechanistically, we showed that the upregulation of JARID1B in human GC was attributed to JARID1B amplification and its induction by H. pylori infection. Furthermore, we identified miR-29c as a negative regulator of JARID1B in GC. H. pylori caused downregulation of miR-29c in human GC and thereby contributed to JARID1B upregulation through relieving posttranscriptional regulation. Functionally, we showed that knockdown of JARID1B reduced GC cell proliferation induced by H. pylori infection. Subsequently, cyclinD1 (CCND1), a key molecule in GC, was shown to be a target gene of JARID1B. In conclusion, these results suggest that JARID1B may be an oncogene upregulated in human GC and could represent a novel therapeutic target to prevent malignant transformation induced by H. pylori infection.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide. Patients with poorly differentiated OSCC often exhibit a poor prognosis. AUNIP (Aurora Kinase A and Ninein Interacting Protein), also known as AIBp, plays a key role in cell cycle and DNA damage repair. However, the function of AUNIP in OSCC remains elusive. Methods: The differentially expressed genes (DEGs) were obtained using R language. Receiver operating characteristic curve analysis was performed to identify diagnostic markers for OSCC. The effectiveness of AUNIP in diagnosing OSCC was evaluated by machine learning. AUNIP expression was analyzed in publicly available databases and clinical specimens. Bioinformatics analysis and in vitro experiments were conducted to explore biological functions and prognostic value of AUNIP in OSCC. Findings: The gene integration analysis revealed 90 upregulated DEGs. One candidate biomarker, AUNIP, for the diagnosis of OSCC was detected, and its expression gradually increased along with malignant differentiation of OSCC. Bioinformatics analysis demonstrated that AUNIP could be associated with tumor microenvironment, human papillomavirus infection, and cell cycle in OSCC. The suppression of AUNIP inhibited OSCC cell proliferation and resulted in G0/G1 phase arrest in OSCC cells. The survival analysis showed that AUNIP overexpression predicted poor prognosis of OSCC patients.Interpretation: AUNIP could serve as a candidate diagnostic and prognostic biomarker for OSCC and suppression of AUNIP may be a potential approach to preventing and treating OSCC. Fund: Taishan Scholars Project in Shandong Province (ts201511106) and the National Natural Science Foundation of China (Nos. 61603218). Keywords: Oral squamous cell carcinoma, Receiver operating characteristic curve, Biomarker, Weighted gene co-expression network analysis, Survival analysis, AUNIP

Abstract Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp)‐induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes‐associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor‐promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL‐1β in gastric cells infected with Hp. As IL‐1ß accounts for inflammation‐associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP‐5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1‐TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.

Duchenne muscular dystrophy (DMD), an inherited disease caused by the dystrophin gene mutation, is the most common muscular dystrophy in children and is clinically characterized by progressive muscle degeneration and severe cardiomyopathy. In this study, renal epithelial cells were obtained from urine samples of a DMD patient (4 years old) and his recessive carrier parent (35 years old). The cells were reprogrammed with non-integrating Sendai virus to generate three induced pluripotent stem cell (iPSC) clones for the patient and two clones for non-manifesting mutation carrier parent. The iPSC lines had normal karyotypes, iPSC morphology, pluripotency expression markers, and were capable of differentiating into the three germ layers.

Wilson’s disease (WD) is an inherited autosomal recessive disease, which is caused by the mutation of ATP7B gene encoding copper-transporting ATPase protein. The WD patients always suffer from the excessive copper deposition in the liver and other tissues because of the dysfunction of the copper-transporting ATPase protein. In this study, we generated a patient-specific induced pluripotent stem cell (iPSC) line (ZJUi003-A), which showed normal karyotype, expressed pluripotency markers and was capable to differentiate into three germ layers.

Background: Rhythm abnormalities are crucial for diverse diseases. However, their role in disease progression induced by Helicobacter pylori (H. pylori) remains elusive. Methods: H. pylori infection was used in in vivo and in vitro experiments to examine its effect on rhythmic genes. The GEO database was used to screen H. pylori affecting rhythm genes, and the effect of rhythm genes on inflammatory factors. Chromatin immunoprecipitation and dual luciferase assays were used to further find out the regulation between molecules. Animal models were used to confirm the relationship between rhythm genes and H. pylori-induced inflammation. Findings: BMAL1 disorders aggravate inflammation induced by H. pylori. Specifically, H. pylori induce BMAL1 expression in vitro and in vivo through transcriptional activation of LIN28A, breaking the circadian rhythm. Mechanistically, LIN28A binds to the promoter region of BMAL1 and directly activates its transcription under H. pylori infection. BMAL1 in turn functions as a transcription factor and enhances the expression of proinflammatory cytokine TNF-α, thereby promoting inflammation. Of note, BMAL1 dysfunction in the rhythm disorder animal model aggravates inflammatory response induced by H. pylori infection in vivo. Interpretation: These findings in this study imply the pathogenic relationship between BMAL1 and H. pylori. BMAL1 may serve as a potential diagnostic marker and therapeutic target for the early diagnosis and treatment of diseases related to H. pylori infection. Fund: National Natural Science Foundation of China. Keywords: BMAL1, H. pylori, Circadian rhythm, TNF-α, LIN28A

Background: Abnormal expression of the orphan nuclear receptor Nurr1 is a critical factor in the etiology of multiple cancers. However, its potential role in gastric cancer (GC) remains elusive. In this study, we have demonstrated that the expression of Nurr1 was elevated and had an oncogenic function in GC. Methods: Nurr1 expression was analyzed in clinical specimens and the GEO database. Functions of Nurr1 in GC cells were analyzed using Nurr1 knockdown and overexpression. Various cell and molecular biological methods were used to explore the potential mechanisms of Nurr1 upregulation and its role in promoting GC. Findings: Overexpression of Nurr1 was directly related to the poor prognosis of GC patients. What's more, Nurr1 was induced by Helicobacter pylori (H. pylori) via the PI3K/AKT-Sp1 pathway. Sp1 enhanced Nurr1 expression by binding to its promoter to activate the transcription. Upregulated Nurr1 then directly targeted CDK4 by binding to its promoter region to increase its expression, thereby facilitated GC cells proliferation both in vitro and in vivo. Interpretation: We identified Nurr1 as a driving oncogenic factor in GC. In addition, Nurr1 could be used as a potential therapeutic target for the diagnosis and treatment of H. pylori-associated GC. Funding: This work was supported by the National Natural Science Foundation of China (Nos 81801983, 81871620, 81971901, 81772151 and 81571960), and the Department of Science and Technology of Shandong Province (2018CXGC1208). Keywords: Gastric cancer, PI3K/AKT/Sp1, Proliferation, CDK4, Helicobacter pylori

Background: Histones chaperones have been found to play critical roles in tumor development and progression. However, the role of histone chaperone CHAF1A in gastric carcinogenesis and its underlying mechanisms remain elusive. Methods: CHAF1A expression in gastric cancer (GC) was analyzed in GEO datasets and clinical specimens. CHAF1A knockdown and overexpression were used to explore its functions in gastric cancer cells. The regulation and potential molecular mechanism of CHAF1A expression in gastric cancer cells were studied by using cell and molecular biological methods. Findings: CHAF1A was upregulated in GC tissues and its high expression predicted poor prognosis in GC patients. Overexpression of CHAF1A promoted gastric cancer cell proliferation both in vitro and in vivo, whereas CHAF1A suppression exhibited the opposite effects. Mechanistically, CHAF1A acted as a co-activator in the Wnt pathway. CHAF1A directly interacted with TCF4 to enhance the expression of c-MYC and CCND1 through binding to their promoter regions. In addition, the overexpression of CHAF1A was modulated by specificity protein 1 (Sp1) in GC. Sp1 transcriptionally enhanced the expression of CHAF1A in GC. Furthermore, CHAF1A expression induced by Helicobacter pylori was Sp1 dependent. Interpretation: CHAF1A is a potential oncogene in GC, and may serve as a novel therapeutic target for GC treatment. Keywords: Histone chaperone, CHAF1A, Gastric cancer, Carcinogenesis

Nile tilapia Oreochromis niloticus is a freshwater fish but can tolerate a wide range of salinities. The mechanism of salinity adaptation at the molecular level was studied using RNA-Seq to explore the molecular pathways in fish exposed to 0, 8, or 16 (practical salinity unit, psu). Based on the change of gene expressions, the differential genes unions from freshwater to saline water were classified into three categories. In the constant change category (1), steroid biosynthesis, steroid hormone biosynthesis, fat digestion and absorption, complement and coagulation cascades were significantly affected by salinity indicating the pivotal roles of sterol-related pathways in response to salinity stress. In the change-then-stable category (2), ribosomes, oxidative phosphorylation, signaling pathways for peroxisome proliferator activated receptors, and fat digestion and absorption changed significantly with increasing salinity, showing sensitivity to salinity variation in the environment and a responding threshold to salinity change. In the stable-then-change category (3), protein export, protein processing in endoplasmic reticulum, tight junction, thyroid hormone synthesis, antigen processing and presentation, glycolysis/gluconeogenesis and glycosaminoglycan biosynthesis-keratan sulfate were the significantly changed pathways, suggesting that these pathways were less sensitive to salinity variation. This study reveals fundamental mechanism of the molecular response to salinity adaptation in O. niloticus, and provides a general guidance to understand saline acclimation in O. niloticus.

RNA-seq was used to compare the transcriptomic response of hepatopancreas in juvenile Litopenaeus vannamei fed three diets with different lipid sources, including beef tallow (BT), fish oil (FO), and an equal combination of soybean oil + BT + linseed oil (SBL) for 8 weeks at 3 practical salinity unit (psu). A total of 9622 isogenes were annotated in 316 KEGG pathways and 39, 42 and 32 pathways significantly changed in the paired comparisons of FO vs SBL, BT vs SBL, or FO vs BT, respectively. The pathways of glycerolipid metabolism, linoleic acid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, fatty acid biosynthesis, fatty acid elongation, fatty acid degradation, and biosynthesis of unsaturated fatty acid were significantly changed in all paired comparisons between dietary lipid sources, and the pathways of glycerolipid metabolism, linoleic acid metabolism, arachidonic acid metabolism and glycerophospholipid metabolism significantly changed in the FO vs SBL and BT vs SBL comparisons. These pathways are associated with energy metabolism and cell membrane structure. The results indicate that lipids sources affect the adaptation of L. vannamei to low salinity by providing extra energy or specific fatty acids to change gill membrane structure and control iron balance. The results of this study lay a foundation for further understanding lipid or fatty acid metabolism in L. vannamei at low salinity.

The Pacific white shrimp Litopenaeus vannamei is a euryhaline penaeid species that shows ontogenetic adaptations to salinity, with its larvae inhabiting oceanic environments and postlarvae and juveniles inhabiting estuaries and lagoons. Ontogenetic adaptations to salinity manifest in L. vannamei through strong hyper-osmoregulatory and hypo-osmoregulatory patterns and an ability to tolerate extremely low salinity levels. To understand this adaptive mechanism to salinity stress, RNA-seq was used to compare the transcriptomic response of L. vannamei to changes in salinity from 30 (control) to 3 practical salinity units (psu) for 8 weeks. In total, 26,034 genes were obtained from the hepatopancreas tissue of L. vannamei using the Illumina HiSeq 2000 system, and 855 genes showed significant changes in expression under salinity stress. Eighteen top Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly involved in physiological responses, particularly in lipid metabolism, including fatty-acid biosynthesis, arachidonic acid metabolism and glycosphingolipid and glycosaminoglycan metabolism. Lipids or fatty acids can reduce osmotic stress in L. vannamei by providing additional energy or changing the membrane structure to allow osmoregulation in relevant organs, such as the gills. Steroid hormone biosynthesis and the phosphonate and phosphinate metabolism pathways were also involved in the adaptation of L. vannamei to low salinity, and the differential expression patterns of 20 randomly selected genes were validated by quantitative real-time PCR (qPCR). This study is the first report on the long-term adaptive transcriptomic response of L. vannamei to low salinity, and the results will further our understanding of the mechanisms underlying osmoregulation in euryhaline crustaceans.