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Background Oesophageal squamous cell carcinoma (OSCC) poses a considerable health burden, particularly in regions such as East Asia. This study aims to investigate the long-term outcomes of OSCC patients who are smokers and drinkers.Materials and methods In this retrospective analysis, data from Sichuan Cancer Hospital and Institute Esophageal Cancer Case Management Database between January 2010 and December 2017 were examined. Patients were categorised into different groups based on their smoking and alcohol consumption history: None, Smoker, Non-Smoker, Smoke-Only, Drinker, Non-Drinker, Drinker-Only, and Both. Survival outcomes were compared between the groups using Kaplan-Meier analysis and propensity score matching (PSM). The primary outcome was overall survival (OS), measured from surgery to death or last follow-up in April 2022.Results The OS median was 45.4 months for all patients after oesophagectomy. Smokers had a significantly lower median OS of 36.6 months compared with Non-Smokers with 66.2 months (p

Pulmonary fibrosis is a severe and progressive lung disease characterized by the abnormal accumulation of extracellular matrix, leading to scarring and loss of normal lung function. Recent bioinformatics analysis through the Gene Expression Omnibus (GEO) database identified a significant downregulation of Transmembrane Protein 176B (TMEM176B), previously unexplored in the context of fibrotic lung tissues. To investigate the functional role of TMEM176B, we induced pulmonary fibrosis in mice using bleomycin, TGFβ1, and silica, which consistently resulted in a marked decrease in TMEM176B expression. Intriguingly, overexpression of TMEM176B via adenoviral vectors prior to the induction of fibrosis led to significant improvements in fibrotic manifestations and lung function. Mechanistically, TMEM176B appears to mitigate pulmonary fibrosis by inhibiting the TGFβ1-SMAD signaling pathway, which is a critical mediator of fibroblast proliferation and differentiation and promotes extracellular matrix production. These findings suggest that TMEM176B plays an inhibitory role in the pathophysiological processes of pulmonary fibrosis, highlighting its potential as a therapeutic target.

Abstract Background Marfan syndrome (MFS) is a hereditary connective tissue disorder involving multiple systems, including ophthalmologic abnormalities. Most cases are due to heterozygous mutations in the fibrillin‐1 gene (FBN1). Other associated genes include LTBP2, MYH11, MYLK, and SLC2A10. There is significant clinical overlap between MFS and other Marfan‐like disorders. Purpose To expand the mutation spectrum of FBN1 gene and validate the pathogenicity of Marfan‐related genes in patients with MFS and ocular manifestations. Methods We recruited 318 participants (195 cases, 123 controls), including 59 sporadic cases and 88 families. All patients had comprehensive ophthalmic examinations showing ocular features of MFS and met Ghent criteria. Additionally, 754 cases with other eye diseases were recruited. Panel‐based next‐generation sequencing (NGS) screened mutations in 792 genes related to inherited eye diseases. Results We detected 181 mutations with an 84.7% detection rate in sporadic cases and 87.5% in familial cases. The overall detection rate was 86.4%, with FBN1 accounting for 74.8%. In cases without FBN1 mutations, 23 mutations from seven Marfan‐related genes were identified, including four pathogenic or likely pathogenic mutations in LTBP2. The 181 mutations included 165 missenses, 10 splicings, three frameshifts, and three nonsenses. FBN1 accounted for 53.0% of mutations. The most prevalent pathogenic mutation was FBN1 c.4096G>A. Additionally, 94 novel mutations were detected, with 13 de novo mutations in 14 families. Conclusion We expanded the mutation spectrum of the FBN1 gene and provided evidence for the pathogenicity of other Marfan‐related genes. Variants in LTBP2 may contribute to the ocular manifestations in MFS, underscoring its role in phenotypic diversity.

Depression is a prevalent mental health problem across the globe, presenting significant social and economic challenges. Early detection and treatment are pivotal in reducing these impacts and improving patient outcomes. Traditional diagnostic methods largely rely on subjective assessments by psychiatrists, underscoring the importance of developing automated and objective diagnostic tools. This paper presents IntervoxNet, a novel computeraided detection system designed specifically for analyzing interview audio. IntervoxNet incorporates a dual-modal approach, utilizing both the Audio Mel-Spectrogram Transformer (AMST) for audio processing and a hybrid model combining Bidirectional Encoder Representations from Transformers with a Convolutional Neural Network (BERT-CNN) for text analysis. Evaluated on the DAIC-WOZ database, IntervoxNet demonstrates excellent performance, achieving F1 score, recall, precision, and accuracy of 0.90, 0.92, 0.88, and 0.86 respectively, thereby surpassing existing state of the art methods. These results demonstrate IntervoxNet’s potential as a highly effective and efficient tool for rapid depression screening in interview settings.

The spatially continuous mapping of vegetation structure parameters in forested areas serves as a crucial foundation for research in various fields, including ecosystem ecology, climate change, hydrology, and forest management and protection. However, there is a notable scarcity of regional scale data regarding vegetation structure parameters. Therefore, our objective was to fill this data gap by providing a methodology for mapping vegetation structure parameters in forested areas at regional-scale. Global Ecosystem Dynamics Investigation (GEDI) provides precise observational data on vegetation structure parameters across the world. Using GEDI vegetation structure parameter point data, we developed a vegetation state coefficient based on the ratio of plant area index (PAI) and vegetation coverage (COVER). Subsequently, we proposed a method for decomposing vegetation coverage to simulate layered vegetation coverage. Taking Jiangxi Province as a case study, we integrated machine learning models to generate a spatially continuous map of vegetation structure parameters in forested areas, including layered coverage and layered leaf area index, in 2020. The map has a spatial resolution of 30 m and a vertical resolution of 5 m. The model exhibits excellent performance. Among the 140 sets of models, approximately 63 % of them achieved an R2 surpassing 0.6, while 89 % of the models achieved a root mean square error (RMSE) below 0.3. This study can serve as a valuable reference for the decomposition of vegetation structure parameters at the regional scale and provide a more precise depiction of the spatial characteristics of vertical vegetation structure at the regional scale. It contributes by providing data support and methodological guidance for research related to forest structure analysis, resource management, and ecological process simulation at the regional scale.

Abstract Objective We have developed explainable machine learning models to predict the overall survival (OS) of retroperitoneal liposarcoma (RLPS) patients. This approach aims to enhance the explainability and transparency of our modeling results. Methods We collected clinicopathological information of RLPS patients from The Surveillance, Epidemiology, and End Results (SEER) database and allocated them into training and validation sets with a 7:3 ratio. Simultaneously, we obtained an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). We performed LASSO regression and multivariate Cox proportional hazards analysis to identify relevant risk factors, which were then combined to develop six machine learning (ML) models: Cox proportional hazards model (Coxph), random survival forest (RSF), ranger, gradient boosting with component‐wise linear models (GBM), decision trees, and boosting trees. The predictive performance of these ML models was evaluated using the concordance index (C‐index), the integrated cumulative/dynamic area under the curve (AUC), and the integrated Brier score, as well as the Cox–Snell residual plot. We also used time‐dependent variable importance, analysis of partial dependence survival plots, and the generation of aggregated survival SHapley Additive exPlanations (SurvSHAP) plots to provide a global explanation of the optimal model. Additionally, SurvSHAP (t) and survival local interpretable model‐agnostic explanations (SurvLIME) plots were used to provide a local explanation of the optimal model. Results The final ML models are consisted of six factors: patient's age, gender, marital status, surgical history, as well as tumor's histopathological classification, histological grade, and SEER stage. Our prognostic model exhibits significant discriminative ability, particularly with the ranger model performing optimally. In the training set, validation set, and external validation set, the AUC for 1, 3, and 5 year OS are all above 0.83, and the integrated Brier scores are consistently below 0.15. The explainability analysis of the ranger model also indicates that histological grade, histopathological classification, and age are the most influential factors in predicting OS. Conclusions The ranger ML prognostic model exhibits optimal performance and can be utilized to predict the OS of RLPS patients, offering valuable and crucial references for clinical physicians to make informed decisions in advance.

Influenced by the exploitation of natural resources and industrialization, ecological and environmental problems have become increasingly severe worldwide, particularly in rapidly developing countries such as China. This study utilizes Earth observation satellite data to monitor changes in ecological environment quality of the Wuhan Urban Development Zone (WUDZ) from 2000 to 2020, employing the remote sensing ecological index considering full elements. By incorporating water bodies into the calculation through the entropy weight method and moving window, this approach takes into account the benefits of water elements on the overall ecological environment (EE). The results indicate the following: 1) from 2000 to 2020, the overall EE of WUDZ exhibited an initial improvement followed by a subsequent decline, with minor fluctuations. 2) The EE of WUDZ is dominated by greenness and dryness. The central and main urban areas have poorer ecological environment quality compared to the urban development area, while remote suburban areas experience gradual deterioration as progression of urbanization. 3) The primary driving factors for ecological environment quality changes in WUDZ are increased urbanization and lake resource erosion. This study provides a quantitative method for the temporal monitoring of wetland urban EE, and provides a scientific basis for the rational formulation of policies and planning for the development of lake ecological space and the restriction of urban construction space.

Poplar line NL895 can potentially become a model plant for poplar study as it is a widely cultivated elite line. However, the lack of genome resources hindered the use of NL895 as the major plant material in poplar. In this study, we provided a high-quality genome assembly for poplar line NL895 with PacBio single molecule real-time (SMRT) sequencing and High-throughput chromosome conformation capture (Hi-C) technology. The raw assembly of NL895 for the diploid genome included 606 contigs with a total size of ~815 Mb, and the monoploid genome included 246 contigs with a total size of ~412 Mb. The haplotype-resolved chromosomes in the diploid genomes were also generated. All the monoploid, diploid, and haplotype-resolved genomes showed more than 97% completeness and they can largely improve the mapping efficiency in RNA-Seq analysis. By comprehensively comparing the two haplotype genomes we found the heterozygosity of NL895 is much higher than other poplar lines. We also found that NL895 harbors more genomic variants and more gene diversity. The haplotype-specific genes showed higher variable gene expression patterns. These characters would be attributed to the high heterosis of poplar line NL895. The allele-specific expression (ASE) was also investigated and lots of alleles showed biased expressions in different tissues or environmental conditions. Taken together, the genome sequence for NL895 is a valuable tree genomic resource and it would greatly facilitate studies in poplar.

Machine learning has achieved great success in electroencephalogram (EEG) based brain-computer interfaces (BCIs). Most existing BCI studies focused on improving the decoding accuracy, with only a few considering the adversarial security. Although many adversarial defense approaches have been proposed in other application domains such as computer vision, previous research showed that their direct extensions to BCIs degrade the classification accuracy on benign samples. This phenomenon greatly affects the applicability of adversarial defense approaches to EEG-based BCIs. To mitigate this problem, we propose alignment-based adversarial training (ABAT), which performs EEG data alignment before adversarial training. Data alignment aligns EEG trials from different domains to reduce their distribution discrepancies, and adversarial training further robustifies the classification boundary. The integration of data alignment and adversarial training can make the trained EEG classifiers simultaneously more accurate and more robust. Experiments on five EEG datasets from two different BCI paradigms (motor imagery classification, and event related potential recognition), three convolutional neural network classifiers (EEGNet, ShallowCNN and DeepCNN) and three different experimental settings (offline within-subject cross-block/-session classification, online cross-session classification, and pre-trained classifiers) demonstrated its effectiveness. It is very intriguing that adversarial attacks, which are usually used to damage BCI systems, can be used in ABAT to simultaneously improve the model accuracy and robustness.

Abstract Background To compare the expression levels of long non-coding RNA (lncRNA) and messenger RNA (mRNA) in pre-receptive endometrium between patients with Polycystic Ovary Syndrome (PCOS)and normal ovulation undergoing in vitro fertilization-embryo transfer (IVF-ET). Methods Endometrial tissues were collected with endometrial vacuum curette in pre-receptive phase (3 days after oocytes retrieval) from PCOS and control groups. LncRNAs and mRNAs of endometrium were identified via RNA sequencing and alignments. A subset of 9 differentially expressed lncRNAs and 11 mRNAs were validated by quantitative reverse transcription polymerase chain reaction(qRT-PCR)in 22 PCOS patients and 18 ovulation patients. The function of mRNAs with differential expression patterns were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results We found out 687 up-regulated and 680 down-regulated mRNAs, as well as 345 up-regulated and 63 down-regulated lncRNAs in the PCOS patients in contrast to normal ovulation patients. qRT-PCR was used to detect the expression of 11 mRNAs, and validated that the expression of these 6 mRNAs CXCR4, RABL6, OPN3, SYBU, IDH1, NOP10 were significantly elevated among PCOS patients, and the expression of ZEB1 was significantly decreased. qRT-PCR was performed to detect the expression of 9 lncRNAs, and validated that the expression of these 7 lncRNAs IDH1-AS1, PCAT14, FTX, DANCR, PRKCQ-AS1, SNHG8, TPT1-AS1 were significantly enhanced among PCOS patients. Bioinformatics analysis showed that differentially expressed genes (DEGs) involved KEGG pathway were tyrosine metabolism, PI3K-Akt pathway, metabolic pathway, Jak-STAT pathway, pyruvate metabolism, protein processing in endoplasmic reticulum, oxidative phosphorylation and proteasome. The up-regulation of GO classification was involved in ATP metabolic process, oxidative phosphorylation, RNA catabolic process, and down-regulation of GO classification was response to corticosteroid, steroid hormone, and T cell activation. Conclusion Our results determined the characteristics and expression profile of endometrial lncRNAs and mRNAs in PCOS patients in pre-receptive phase, which is the day 3 after oocytes retrival. The possible pathways and related genes of endometrial receptivity disorders were found, and those lncRNAs may be developed as a predictive biomarker of endometrium in pre-receptive phase.

The reinjection exploitation of hydrothermal resources is a recognized method of sustainable exploitation. The well space between the production and reinjection well is an essential issue because the thermal breakthrough in production well is the main negative impact during reinjection. The migration of reinjection water in the geothermal reservoir depends on the permeability of the reservoir, constrained by the geothermal reservoir characteristics. In this study, A numerical model using the Petrasim software with Tough2, as the core as well as reservoir data of each typical geothermal field in Jiyang depression, was established. The impact of the reservoir porosity and permeability and the thickness of a single sand layer on the migration of reinjection water and temperature field in the geothermal reservoir were analyzed systematically. The simulation results revealed that the reservoir porosity had a minor impact on the reinjection of the geothermal reservoir, including the reinjection pressure and the spacing of production and reinjection wells. The reservoir permeability affected the reinjection pressure, and then controlled the reinjection performance of the geothermal reservoir, while it had no impact on the spacing of production and reinjection wells. The sand layer superposition combination had a minor impact on the reinjection pressure of the geothermal reservoir. The distance of the horizontal migration of reinjection water in the multilayer stacked thin sand layers was longer, and the range of temperature influence was larger. Thus, it is necessary to expand the well space between production and reinjection well. This study is of significance for the stable operation of geothermal development projects.

Abstract Aims Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. Methods and results We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B−/− mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. Conclusions These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

Adopting the yield of the epicatechin gallate (EGCG)–Cu complex as an indicator, the impact of four conditions, such as pH, reaction time, temperature and reactant ratio, on the synthesis of the target complex was analyzed to identify the optimal conditions on synthesizing the compound. The reactant ratio between EGCG and Cu2+ was explored, and the characteristic peaks and functional groups of the EGCG–Cu complex were scrutinized by UV–Visible and Fourier-Transform Infrared spectrophotometers. Finally, the efficacy difference of bactericidal properties against Escherichia coli suspensions between EGCG and its complex was evaluated as the criteria. Furthermore, comparative studies were performed to gauge the antimicrobial activity of EGCG and its complex at equivalent concentrations. The results demonstrated that the optimal experimental conditions for the complex reaction were a pH of 7, at 40 °C, in a reaction time of 60 min and a reactant ratio of 1:2. By the molar ratio method, the reactant ratio was determined as n(EGCG):n(Cu2+) = 1:2, and the complex reaction was at the phenolic hydroxyl group on the benzene ring of EGCG. Compared to EGCG, the complex demonstrated significant enhancement in bactericidal properties against E. coli and has lower chromaticity. HIGHLIGHTS The optimal parameters for complexation were determined.; The absorbance curve showed that the complex ratio of EGCG and Cu2+ was 1:2.; The changes in absorption peaks of functional groups indicated that EGCG's phenolic hydroxyl groups on the benzene ring formed complexes.; Complexing Cu2+ to EGCG enhances its antibacterial properties.; The EGCG–Cu complex solution has lower chromaticity than EGCG during disinfection.;

Abstract Background The BOP (Bambusoideae, Oryzoideae, and Pooideae) clade of the Poaceae has a common ancestor, with similarities to the genomes of rice, Oryza sativa (2n = 24; genome size 389 Mb) and Brachypodium, Brachypodium distachyon (2n = 10; 271 Mb). We exploit chromosome-scale genome assemblies to show the nature of genomic expansion, structural variation, and chromosomal rearrangements from rice and Brachypodium, to diploids in the tribe Aveneae (e.g., Avena longiglumis, 2n = 2x = 14; 3,961 Mb assembled to 3,850 Mb in chromosomes). Results Most of the Avena chromosome arms show relatively uniform expansion over the 10-fold to 15-fold genome-size increase. Apart from non-coding sequence diversification and accumulation around the centromeres, blocks of genes are not interspersed with blocks of repeats, even in subterminal regions. As in the tribe Triticeae, blocks of conserved synteny are seen between the analyzed species with chromosome fusion, fission, and nesting (insertion) events showing deep evolutionary conservation of chromosome structure during genomic expansion. Unexpectedly, the terminal gene-rich chromosomal segments (representing about 50 Mb) show translocations between chromosomes during speciation, with homogenization of genome-specific repetitive elements within the tribe Aveneae. Newly-formed intergenomic translocations of similar extent are found in the hexaploid A. sativa. Conclusions The study provides insight into evolutionary mechanisms and speciation in the BOP clade, which is valuable for measurement of biodiversity, development of a clade-wide pangenome, and exploitation of genomic diversity through breeding programs in Poaceae.

ObjectivePrevious observational studies revealed the potential correlation between psychiatric disorders (PDs) and non-tumor gastrointestinal diseases (NTGDs). However, their causation remains unclear.MethodsWe explored the causal relationship between PDs and NTGDs through bidirectional two-sample Mendelian randomization (MR) study. Large-scale genome-wide association study (GWAS) summary statistics and bidirectional two-sample MR study were used to assess the causality between PDs and NTGDs. Multiple sensitivity analyses were used to identify the robustness of our results.ResultsWe found that major depression was causally associated with increased risk of gastric ulcer (OR: 1.812, 95% CI: 1.320–2.487, p < 0.001) and irritable bowel syndrome (OR: 1.645, 95% CI: 1.291–2.097, p < 0.001). Meanwhile, genetically predicted gastroesophageal reflux disease contributed to the increased risk of anxiety disorders (OR: 1.425, 95% CI: 1.295–1.568, p < 0.001), and ulcerative colitis was related to increased risk of attention deficit/hyperactivity disorder (OR: 1.042, 95% CI: 1.008–1.078, p = 0.0157).ConclusionOur study provided MR evidence to support the close causality and identify the specific direction between eight PDs and eight common NTGDs. Experimental studies to further examine the causality, underlying mechanism, and therapeutic potential of PDs and NTGDs are required.

BackgroundHepatic steatosis is a significant pathological feature of fatty liver disease (FLD) which is widely spread with no effective treatment available. Previous studies suggest that chromium (Cr) intake reduces lipid deposition in the liver in animals. However, the connection between blood Cr and hepatic steatosis among humans remains inconclusive.MethodsUsing the data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020, we performed a cross-sectional analysis, including 4,926 participants. The controlled attenuation parameter (CAP) measured by the vibration controlled transient elastography (VCTE) was used to evaluate the degree of liver steatosis. Weighted univariate regression, multivariate linear regression, smooth fitting curves and subgroup analysis were used. In addition, we carried out trend tests, multiple interpolations, and interaction analyses to conduct sensitivity analyses.ResultsAfter adjusting with various covariables, multivariate linear regression analysis demonstrated a significant negative correlation between blood Cr and CAP [β (95% CI) = −5.62 (−11.02, −0.21)]. The negative correlation between blood Cr and CAP was more significant in the males, 50–59 years, overweight, hypercholesterolemia, HDL-C ≥ 65 mg/dL, HbA1c (5.70–6.10 %), HOMA-IR (0.12–2.76), total bilirubin (0.30–0.40 mg/dL), ever alcohol consumption subjects. Of note, the relationships between blood Cr and CAP followed a U-shaped curve in the smokers and non-smokers, with blood Cr thresholds of 0.48, 0.69 μg/L, respectively.ConclusionsThere is an independently negative correlation between blood Cr and hepatic steatosis in American. Our study provides clinical researchers with a new insight into the prospective prevention of hepatic steatosis.

Abstract Cisplatin‐containing combination chemotherapy has been used as the standard treatment for bladder cancer patients at advanced stage. However, nearly 50% of patients are nonresponders. To guide the selection of more effective chemotherapeutic agents, a bladder cancer spheroids microfluidic drug sensitivity analysis system was established in this study. Bladder cancer spheroids were established and successfully cultured in a customized microfluidic device to assess their response to different chemotherapeutic agents. The in vitro drug sensitivity results were also compared to patient‐derived xenograft (PDX) models and clinical responses of patients. As a result, bladder cancer spheroids faithfully recapitulate the histopathological and genetic features of their corresponding parental tumors. Furthermore, the in vitro drug sensitivity outcomes of spheroids (n = 8) demonstrated a high level of correlation with the PDX (n = 2) and clinical response in patients (n = 2). Our study highlights the potential of combining bladder cancer spheroids and microfluidic devices as an efficient and accurate platform for personalized selection of chemotherapeutic agents.

Abstract Objective Previous observational studies have explored the correlation between testosterone and cancer risk. However, the causal association between testosterone and various cancer types in women remains inconclusive. The objective of this Mendelian randomization study is to evaluate the causal links between total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in females. Methods Initially, a rigorous quality control process was employed to identify suitable instrumental single nucleotide polymorphisms (SNPs) associated with the exposure under investigation that exhibited a significant association. The genetic causal relationship between female testosterone levels and the risk of developing cancers was examined through a two-sample Mendelian randomization. Various analytical methods, including inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode, were applied in the investigation. Key findings were primarily based on the results obtained via IVW (random effects), and sensitivity analyses were conducted to assess the reliability of the obtained results. Furthermore, maximum likelihood, penalized weighted median, and IVW (fixed effects) methods were utilized to further validate the robustness of the results. Results Based on the results of IVW analysis, our study indicated a positive causal relationship between BT and breast cancer (OR = 1.1407, 95%CI: 1.0627–1.2244, P = 0.0015) and endometrial cancer (OR = 1.4610, 95%CI: 1.2695–1.6813, P = 1.22E-06). Moreover, our findings also showed a positive causal association between TT and breast cancer (OR = 1.1764, 95%CI: 1.0846–1.2761, P = 0.0005), cervical cancer(OR = 1.0020, 95%CI: 1.0007–1.0032, P = 0.0077), and endometrial cancer(OR = 1.4124, 95%CI: 1.2083–1.6511, P = 0.0001). Additionally, our results demonstrated a negative causal relationship between BT and ovarian cancer (OR = 0.8649, 95%CI: 0.7750–0.9653, P = 0.0320). However, no causal relationship was found between BT, TT and other types of cancer (corrected P > 0.05). Conclusions This study elucidates the role of testosterone on the development of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer. It also hints at a potential but fragile link between testosterone and bladder cancer, as well as thyroid cancer. Nonetheless, it's worth noting that no statistically significant relationship between testosterone and various other types of cancer in females was identified.

Gastric carcinoma (GC) progression is mainly caused by local aggression and lymph node metastasis. However, some patients with early T-stage disease have lymph node metastasis, whereas some patients with late T-stage disease do not have lymph node metastasis, which indicates that invasion and metastasis are not always sequential in some GC patients. In the present study, the data of 101 GC cases were acquired from TCGA and divided into T-late-N-negative and T-early-N-positive groups according to pathological stages. A total of 338 genes were identified as differential genes between the T-late-N-negative and T-early-N-positive groups. GSEA showed that epithelial cell signaling in the Helicobacter pylori (HP) infection pathway was enriched in the T-early-N-positive group. MB staining indicated that the HP infection rate was 63% (39/62) in N-positive patients compared to 42% (16/38) in N-negative patients. To investigate the potential mechanism, we focused on the gene chemokine (C-X-C motif) receptor 2 (CXCR2), which was not only clustered in the gene set of epithelial cells signaling in the HP infection pathway but also significantly upregulated in T-early-N-positive GC by the analysis of the different genes based on the TCGA dataset. A meta-analysis showed that CXCR2 expression was positively correlated with N-stage but not with T-stage in GC. This study indicated that invasion and metastasis could be independent processes driven by different molecular mechanisms in some GC patients. HP infection was a potential factor that promoted lymph node metastasis by upregulating CXCR2 expression.

Abstract Multi-key membership testing plays a crucial role in computing systems and networking applications, encompassing web search, mail systems, distributed databases, firewalls, and network routing. Traditional approaches, such as the Bloom filter, encounter limitations within this specific context. Addressing these challenges, we propose the Multi-key Learned Bloom Filter (MLBF), a hybrid method that combines machine learning techniques with the Bloom filter. The MLBF introduces a value-interaction-based multi-key classifier and a multi-key Bloom filter. Furthermore, we introduce an Interval-based MLBF approach, which categorizes keys into specific intervals based on data distribution to minimize the False Positive Rate (FPR). Additionally, MLBF incorporates an out-of-distribution (OOD) detection component to identify data shifts. Through extensive experimental evaluations on three authentic datasets, we demonstrate the superiority of the proposed MLBF in terms of FPR and query efficiency.

Abstract The persuasive function of topoi—the conclusion rules connecting the arguments and claims—in national image construction through news discourse has been relatively under-researched. This article presents findings from a corpus-based discourse analysis of 21 China-related environmental news stories in The New York Times to address this gap. The corpus analysis of frequency was utilized to find out recurrent and characteristic topics in the news discourse, while the concordance analysis revealed the discourse prosody in the news stories. Topoi in the reported speech was scrutinized to uncover the persuasive intentions in the coverage and the press’s opinion of China’s pro-environmental actions. The findings demonstrate that China is constructed as a country pursuing economic growth at the expense of the environment and a country that is good at showing resolution of governance but with poor governance capacity. The paper suggests that China should spread environmental-related information more transparently using a vigorous international discourse system and diversify means of communication to offer the world more ways to see China’s pro-environmental actions.

This paper proposes a new hybrid hierarchical roadside unit (RSU) deployment algorithm that combines traditional RSU deployment strategies with temporary RSUs (t-RSUs) selected from many parked vehicles. The driving vehicles in the corresponding RSU coverage section are divided into clusters and the demand is thus summarized. We first solve the problem of how to choose the appropriate cars serving as t-RSUs and then optimize the RSU deployment with the dynamic existing t-RSUs. We simulate the deployment application in a downtown area of Shanghai, China, using the simulation of urban mobility (SUMO), version 1.11.0, an open-source traffic simulation package, and its traffic-control interface (TraCI) with Python. The simulation results show that, within a given economic cost, the proposed hybrid hierarchical RSU deployment algorithm outperforms the maximum vehicle coverage deployment algorithm (MVCD) and the random deployment algorithm (RandDeploy) in terms of overall vehicle coverage and point-to-point vehicle connectivity ratio. Our scheme provides new solutions and ideas for the deployment of RSUs in future urban traffic environments.

This study investigates the impact of corn straw return and nitrogen application rates on ammonia volatilization and yield enhancement under field conditions, in order to reduce emissions while increasing crop yield. During the winter wheat season, a fissure area design was implemented, comprising three levels of straw return in the main area and three distinct nitrogen fertilizer levels in the subsidiary area, for a total of nine treatments. The results can be summarized as follows: (1) The ammonia emissions flux initially increased followed by a decrease, and was primarily concentrated within the first 14 days after fertilization, with a peak observed at 4–5 days before decreasing. Notably, nitrogen fertilizer significantly affected the cumulative ammonia emissions, ranging from 0.019 to 1.786 kg·hm−2·d−1 and 0.013 to 1.693 kg·hm−2·d−1 across the two seasons. (2) The soil with a higher nitrogen application rate exhibited elevated levels of inorganic nitrogen content and urease activity under the same straw return level. Maintaining a consistent nitrogen application level, the return of straw to the field increased the cumulative ammonia discharge, inorganic nitrogen content, and urease activity. (3) The interaction between straw return and nitrogen fertilizer substantially affected crop yield. Specifically, during the winter wheat season, the optimal combination for reducing ammonia emissions and enhancing yield was observed under straw return (both half or full) combined with 180 kg·hm−2 nitrogen application. Notably, the reduction of soil emissions and winter wheat yield augmentation were feasible through appropriate corn straw return in the preceding season.

While Portland cement produces large amounts of carbon dioxide, low-calcium high-strength cements effectively reduce carbon emissions by decreasing the proportion of high-calcium minerals. In order to enhance the practical application value of low-calcium high-strength cement, the effects of mineral admixtures on the chloride binding capacity and pore structure characteristics of low-calcium high-strength cement pastes were investigated by equilibrium method and mercury intrusion method. The results showed that the chloride binding capacity of low-calcium high-strength cement pastes is superior to that of Portland cement. Fly ash and slag enhance this capacity by promoting monosulfoaluminate and C-S-H gel formation, with fly ash being more effective. Ground limestone also boosts chloride binding when incorporated at less than 10 wt%. However, sulfates have a more significant negative impact on chloride binding capacity in low-calcium high-strength cement pastes compared to Portland cement. The porosity of low-calcium high-strength cement pastes exhibits contrasting trends with the addition of fly ash, ground limestone, and slag. Fly ash and limestone initially coarsen the pore structure but later facilitate the transition of larger pores to smaller ones. In contrast, slag initially has little impact but later promotes the conversion of large capillary pores to medium ones, optimizing the pore structure. Notably, above 10 wt% fly ash, the critical pore diameter decreases with additional fly ash except at 10% where it increases for 3 days. Ground limestone enlarges the critical pore diameter, and this effect intensifies with higher content. During early hydration, slag decreases the critical pore diameter, but its impact diminishes in later stages.

Bambusa arundinacea (Retz.) Willd. is a large and thorny bamboo species used for construction and scaffolding purposes. Bamboo fibers, which are an important part of bamboo, give bamboo its excellent mechanical properties. The goal of this work was to get more information about fiber in order to learn more about bamboo material. It was tested for different ages, heights, and radial positions using the nanoindentation method. The results showed that the mean values of indentation modulus of elasticity and hardness of this species were 20.79 GPa and 497.01 MPa, respectively, and that the mechanical properties of the fiber cell walls were less affected by the three factors and were generally consistent. In regards to the age factor, it had little effect on the indentation modulus of elasticity, while the hardness increased slightly with age. The indentation modulus of elasticity and hardness tended to increase with increasing height. The fiber strength was relatively stable in different parts of the radial direction.

Rice husk-based activated carbon was prepared with the help of zinc chloride using microwave and electrical dual-mode heating. The pore characteristics and chemical properties of rice husk-based activated carbon (RH-AC) were characterized by BET, XRD, Raman spectra, FTIR and pHIEP (pH of isoelectric point). The specific surface area of RH-AC is 1719.32 m2/g with a total pore volume of 1.05 cm3/g. The performance of RH-AC for removing Cr(VI) from aqueous solution was examined considering the variation of the contact time (0–120 min), pH value (2.0–9.0), adsorbent dose (0.5–3.0 g/L), initial concentration (28–145 mg/L) and solvent temperature (15–45 °C). The ideal pH for Cr(VI) removal is between 2.0 and 3.0 with the equilibrium time of 90 min, achieving the maximum adsorption capacity of 56.82 mg/g with the pH of 3.0. Comparable study on the established kinetic models and isotherms to simulate the removal of Cr(VI) by RH-AC was carried out to sort out the inherent mechanism of the absorption. Reasonable agreements could be obtained by the pseudo-second-order kinetic model and Langmuir, Freundlich and Tempkin isothermal models. Results from Body model simulation suggest that external mass transfer was the essential cause for rate-controlling in the adsorption process of Cr(VI).

The space of production well plays a crucial role in the heat extraction performance of the Enhanced Geothermal System (EGS), which have the potential to meet the growing global energy demand as a reliable energy source. Nonetheless, there has been insufficient research and attention focused on comprehending the impact of the space of production well on the efficiency and effectiveness of EGS. In this work, a series of numerical simulations were conducted to assess the impact of the space of production well on heat extraction efficiency in EGS. Three different cases were considered: Case 50 with 50 m production well spacing, Case 100 with 100 m production well spacing, and Case 150 with 150 m production well spacing. At the X-Y plane and Y-Z plane, the simulation results indicated that there were slight differences in temperature variation among the Case 50, Case 100 and Case 150. And the cooling area decreasing as the spacing of production wells decreased. Moreover, the delivery of cooling water via the injection well and its subsequent distribution to various reference points lead to a decline in temperature at each point, albeit with varying degrees of variation. Besides, the established efficiency (ef) for Case 50 is smaller than the Case 100 and Case 150 during the last 15 years. These findings contribute valuable insights to the exploration and exploitation of EGS systems and can serve as a guide for further research in this field.

Summary: Various synthetic substances were utilized in large quantities during the recent coronavirus pandemic, COVID-19. Some of these chemicals could potentially enter drinking water sources. Persistent, mobile, and toxic (PMT) substances have been recognized as a threat to drinking water resources. It has not yet been assessed how many COVID-19 related substances could be considered PMT substances. One reason is the lack of high-quality experimental data for the identification of PMT substances. To solve this problem, we applied a machine learning model to identify the PMT substances among COVID-19 related chemicals. The optimal model achieved an accuracy of 90.6% based on external test data. The model interpretation and causal inference indicated that our approach understood causation between PMT properties and molecular descriptors. Notably, the screening results showed that over 60% of the COVID-19 chemicals considered are candidate PMT substances, which should be prioritized to prevent undue pollution of water resources.

Summary: Transposable elements (TEs) can provide ectopic promoters to drive the expression of oncogenes in cancer, a mechanism known as onco-exaptation. Onco-exaptation events have been extensively identified in various cancers, with bladder cancer showing a high frequency of onco-exaptation events (77%). However, the effect of most of these events in bladder cancer remains unclear. This study identified 44 onco-exaptation events in 44 bladder cancer cell lines in 137 RNA-seq datasets from six publicly available cohorts, with L1PA2 contributing the most events. L1PA2-SYT1, L1PA2-MET, and L1PA2-XCL1 had the highest frequency not only in cell lines but also in TCGA-BLCA samples. L1PA2-SYT1 showed significant tumor specificity and was found to be activated by CpG island demethylation in its promoter. The upregulation of L1PA2-SYT1 enhances the in vitro invasion of bladder cancer and is an independent risk factor for patient’s overall survival, suggesting L1PA2-SYT1 being an important event that promotes the development of bladder cancer.

Abstract Background As one of the most aggressive neuroendocrine tumors, small cell lung cancer (SCLC) has the most disappointing prognosis of all lung cancers. Although SCLC responds well to initial chemotherapy, the majority of patients experience disease recurrence within one year, and patient survival is poor. It is still necessary to explore the application of ICIs in SCLC since the beginning of the road to immunotherapy, which broke the 30‐year treatment deadlock of SCLC. Methods We searched PubMed, Web of Science, and Embase with search terms such as "SCLC", "ES‐SCLC", "ICIs", and "ICBs", and categorized and summarized the relevant literature obtained, and we compiled the latest progress about the application of ICIs in SCLC. Results We listed 14 clinical trials on ICIs, including 8 clinical trials on first‐line SCLC treatment, 2 clinical trials on second‐line SCLC treatment, 3 clinical trials on third‐line SCLC treatment, and 1 clinical trial on SCLC maintenance treatment. Conclusion ICIs in combination with chemotherapy can improve OS in SCLC patients, but the extent to which SCLC patients can benefit from ICIs is limited, and ICIs' combination treatment strategies still need to be continuously explored.

Abstract Background Mutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice. Methods We generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r +/− microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r +/− mice and wild-type control littermates. Results We found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r +/− mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r +/− microglia. Treatment with minocycline could suppress the activation of Csf1r +/− microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r +/− mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r +/− mice. Conclusions Our study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.

Abstract Background Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated. Results Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM2.5 concentration of 95.77 µg/m3. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice. Conclusions These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

Colorectal carcinoma (CRC) is a major global health concern, with cancer metastasis being the main cause of patient mortality, and current CRC treatments are challenged by drug resistance. Although natural compounds, especially in foods like hawthorn proanthocyanidin extract (HPOE), have good anticancer activity, their effects on CRC metastasis remain unknown. Therefore, our objective was to investigate the impact and potential mechanisms of HPOE on the movement and infiltration of cells in the HCT116 CRC cells. Firstly, scratch-healing experiments confirmed the anti-migratory and anti-invasive capabilities of HPOE. Then, network pharmacology identified 16 possible targets, including MMP-9. Subsequently, RT-qPCR and Western blotting experiments confirmed that HPOE downregulated epithelial-mesenchymal transition-related factors (N-cadherin and MMP-9) and inhibited Wnt/β-catenin pathway activation. Finally, these results were experimentally validated using the Wnt pathway activator Licl and inhibitor XAV939. It was confirmed that HPOE had a certain inhibitory effect on the activation of the Wnt signaling pathway caused by the activator Licl and could enhance the inhibitory effect of the inhibitor XAV939. Our findings provide a basis for developing functional foods or dietary supplements, especially positioning HPOE as a functional food raw material for adjuvant treatment of CRC, given its ability to inhibit metastasis through the Wnt/β-catenin pathway.

Soil fungal communities play a critical role in the promotion of nutrient cycling and the stabilization of ecosystem functions in subtropical forests. Yet, clarifying the relationships between soil fungal diversity and microclimate variability along an elevational gradient, as well as understanding the driving mechanisms of their variations in subtropical forests, remains insufficiently understood. In this study, we recorded the composition and soil fungal diversity along an elevational gradient in Daiyun Mountain of China, aiming to elucidate the primary factors influencing the structure of the dominant soil fungal along an elevational gradient in subtropical forests. The results showed that (1) the dominant phylum of soil fungi at different elevations were Basidiomycota, Ascomycota (relative abundance > 10%) and Zygomycota (relative abundance > 1%). The Simpson index of soil fungi showed a clear upward trend along the elevational gradient, while no significant difference was observed in the other indices, and both overall reached their maximum value at the elevation of 1200 m. (2) The mean annual soil temperature and moisture, soil pH and available phosphorus were the main factors driving the dominant soil fungal along the elevational gradient. (3) Co–occurrence network analyses revealed a distinct modular structure of dominant soil fungal communities at different elevations, with Ascomycetes identified as the key taxa in fungi network relationships. Our research holds ecological significance in understanding the pivotal role of soil environmental factors in shaping the complex composition and interactions within soil fungal communities.

Phycocyanobilin (PCB) is a natural blue tetrapyrrole chromophore that is found in phycocyanin and plays an essential role in photosynthesis. Due to PCB’s antioxidation, anti-inflammatory and anti-cancer properties, it has been utilized in the food, pharmaceutical and cosmetic industries. Currently, the extraction of PCB from Spirulina involves complex processes, which has led to increasing interest in the biosynthesis of PCB in Escherichia coli. However, the PCB titer remains low because of the poor activity of key enzymes and the insufficient precursor supply. Here, the synthesis of PCB was firstly improved by screening the optimal heme oxygenase (HO) from Thermosynechococcus elongatus BP-1(HOT) and PCB: ferredoxin oxidoreductase from Synechocystis sp. PCC6803 (PcyAS). In addition, based on a rational design and the infrared fluorescence method for high-throughput screening, the mutants of HOT(F29W/K166D) and PcyAS(D220G/H74M) with significantly higher activities were obtained. Furthermore, a DNA scaffold was applied in the assembly of HOT and PcyAS mutants to reduce the spatial barriers, and the heme supply was enhanced via the moderate overexpression of hemB and hemH, resulting in the highest PCB titer (184.20 mg/L) obtained in a 5 L fermenter. The strategies applied in this study lay the foundation for the industrial production of PCB and its heme derivatives.

Background: N6-methyladenosine (m6A) modification is one of the most common RNA modifications in mammals. m6A modification, and associated abnormal gene expression, occur during various biological processes, most notably tumorigenesis. YTH domain-containing family protein 1 (YTHDF1), a m6A reader, bind to messenger RNAs (mRNAs) containing a m6A modification and this enhances its interaction with the ribosome and promotes translation. The function of YTHDF1 in gastric cancer (GC) has been the subject of earlier studies; however, the precise mechanism underlying YTHDF1’s role in GC has not been fully elucidated. Methods: The expression of YTHDF1 was evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry and western blotting. CCK-8, 5-Ethynyl-2′-deoxyuridine (EdU) and flow cytometry assays were utilized to explore the effect of YTHDF1 on GC cell viability and proliferation. Transcriptome sequencing and RNA immunoprecipitation assays were utilized to explore the underlying mechanisms mediated by YTHDF1. Results: We observed that YTHDF1 is upregulated in GC cancer tissues. Knockdown of YTHDF1 in GC cells significantly inhibited proliferation and promoted apoptosis, suggesting that YTHDF1 increases proliferation and blocks apoptosis in GC cells. Mechanistically, data gathered suggest that YTHDF1 promotes the translation of the transcription factor TCF7 and this results in activation of the WNT signaling axis. Conclusions: We found that YTHDF1 was upregulated in GC and that YTHDF1 could promote GC progression through modulating the translational efficiency of TCF7. Taken together, these findings may provide a novel therapeutic target for GC.

Objective: According to the 2020 data from the World Health Organization (WHO), cancers stand as one of the foremost contributors to global mortality. Revealing novel cancer risk factors and protective factors is of paramount importance in the prevention of disease occurrence. Studies on the relationship between chemokines and cancer are ongoing; however, due to the coordination of multiple potential mechanisms, the specific causal association remains unclear.Methods: We performed a bidirectional Mendelian randomization analysis to explore the causal association between serum chemokines and pan-carcinoma. All data is from the GWAS catalog and IEU Open GWAS database. The inverse-variance weighted (IVW) method is primarily employed for assessing the statistical significance of the findings. In addition, the significance threshold after the multiple hypothesis test (Bonferroni) was 0.0013, and the evidence of a potential association was considered if the p-value < 0.05, but remained greater than Bonferroni’s threshold.Results: The results indicate that CCL1 (odds ratio, OR = 1.18), CCL2 (OR = 1.04), CCL8 (OR = 1.36), CCL14 (Colorectal, OR = 1.08, Small intestine, OR = 0.77, Lung, OR = 1.11), CCL15 (OR = 0.85), CCL18 (Breast, OR = 0.95, Prostate, OR = 0.96), CCL19 (Lung, OR = 0.66, Prostate, OR = 0.92), CCL20 (Lung, OR = 0.53, Thyroid, OR = 0.76), CCL21 (OR = 0.62), CCL22 (OR = 2.05), CCL23 (OR = 1.31), CCL24 (OR = 1.06), CCL27 (OR = 1.49), CCL28 (OR = 0.74), CXCL5 (OR = 0.95), CXCL9 (OR = 3.60), CXCL12 (Breast, OR = 0.87, Small intestine, OR = 0.58), CXCL13 (Breast, OR = 0.93, Lung, OR = 1.29), CXCL14 (Colon, OR = 1.40) and CXCL17 (OR = 1.07) are potential risk factors for cancers. In addition, there was a reverse causal association between CCL1 (OR = 0.94) and CCL18 (OR = 0.94) and breast cancer. Sensitivity analysis results were similar. The results of the other four MR Methods were consistent with the main results, and the leave-one-out method showed that the results were not driven by a Single nucleotide polymorphism (SNP). Moreover, there was no heterogeneity and pleiotropy in our analysis.Conclusion: Based on the two-sample MR Analysis method, we found that chemokines might be upstream factors of cancer pathogenesis. These results might provide new insights into the future use of chemokines as potential targets for cancer prevention and treatment. Our results also provide important clues for tumor prevention, and changes of serum chemokine concentration may be recognized as one of the features of precancerous lesions in future clinical trials.

BackgroundTraumatic brain injury (TBI) increases the risk of mental disorders and neurodegenerative diseases in the chronic phase. However, there is limited neuropathological or molecular data on the long-term neural dysfunction and its potential mechanism following adolescent TBI.MethodsA total of 160 male mice aged 8 weeks were used to mimic moderate TBI by controlled cortical impact. At 1, 3, 6 and 12 months post-injury (mpi), different neurological functions were evaluated by elevated plus maze, forced swimming test, sucrose preference test and Morris water maze. The levels of oxidative stress, antioxidant response, reactive astrocytes and microglia, and expression of inflammatory cytokines were subsequently assessed in the ipsilateral hippocampus, followed by neuronal apoptosis detection. Additionally, the morphological complexity of hippocampal astrocytes was evaluated by Sholl analysis.ResultsThe adolescent mice exhibited persistent and incremental deficits in memory and anxiety-like behavior after TBI, which were sharply exacerbated at 12 mpi. Depression-like behaviors were observed in TBI mice at 6 mpi and 12 mpi. Compared with the age-matched control mice, apoptotic neurons were observed in the ipsilateral hippocampus during the chronic phase of TBI, which were accompanied by enhanced oxidative stress, and expression of inflammatory cytokines (IL-1β and TNF-α). Moreover, the reactive astrogliosis and microgliosis in the ipsilateral hippocampus were observed in the late phase of TBI, especially at 12 mpi.ConclusionAdolescent TBI leads to incremental cognitive dysfunction, and depression- and anxiety-like behaviors in middle-aged mice. The chronic persistent neuroinflammation and oxidative stress account for the neuronal loss and neural dysfunction in the ipsilateral hippocampus. Our results provide evidence for the pathogenesis of chronic neural damage following TBI and shed new light on the treatment of TBI-induced late-phase neurological dysfunction.