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Dysregulation of adenosine-to-inosine (A-to-I) RNA editing has been implicated in cancer progression. However, a comprehensive understanding of how A-to-I RNA editing is incorporated into miRNA regulation to modulate gene expression in cancer remains unclear, given the lack of effective identification methods. To this end, we introduced an information theory-based algorithm named REMR to systematically identify 12,006 A-to-I RNA editing-mediated miRNA regulatory triplets (RNA editing sites, miRNAs, and genes) across ten major cancer types based on multi-omics profiling data from The Cancer Genome Atlas (TCGA). Through analyses of functional enrichment, transcriptional regulatory networks, and protein-protein interaction (PPI) networks, we showed that RNA editing-mediated miRNA regulation potentially affects critical cancer-related functions, such as apoptosis, cell cycle, drug resistance, and immunity. Furthermore, triplets can serve as biomarkers for classifying cancer subtypes with distinct prognoses or drug responses, highlighting the clinical relevance of such regulation. In addition, an online resource (http://www.jianglab.cn/REMR/) was constructed to support the convenient retrieval of our findings. In summary, our study systematically dissected the RNA editing-mediated miRNA regulations, thereby providing a valuable resource for understanding the mechanism of RNA editing as an epitranscriptomic regulator in cancer.

Abstract Background Gestational diabetes mellitus (GDM) significantly impacts maternal and infant health both immediately and over the long term, yet effective early diagnostic biomarkers are currently lacking. Thus, it is essential to identify early diagnostic biomarkers for GDM risk screening. Extrachromosomal circular DNA (eccDNA), being more stable than linear DNA and involved in disease pathologies, is a viable biomarker candidate for diverse conditions. In this study, eccDNA biomarkers identified for early diagnosis and assessment of GDM risk were explored. Methods Using Circle-seq, we identified plasma eccDNA profiles in five pregnant women who later developed GDM and five matched healthy controls at 11–13 weeks of gestation. These profiles were subsequently analyzed through bioinformatics and validated through outward PCR combined with Sanger sequencing. Furthermore, candidate eccDNA was validated by quantitative PCR (qPCR) in a larger cohort of 70 women who developed GDM and 70 normal glucose-tolerant (NGT) subjects. A ROC curve assessed the eccDNA’s diagnostic potential for GDM. Results 2217 eccDNAs were differentially detected between future GDM patients and controls, with 1289 increased and 928 decreased in abundance. KEGG analysis linked eccDNA genes mainly to GDM-related pathways such as Rap1, MAPK, and PI3K-Akt, and Insulin resistance, among others. Validation confirmed a significant decrease in eccDNA PRDM16circle in the plasma of 70 women who developed GDM compared to 70 NGT women, consistent with the eccDNA-seq results. PRDM16circle showed significant diagnostic value in 11–13 weeks of gestation (AUC = 0.941, p

Summary: Background: The survival rate of patients with distant metastasis (DM) of papillary thyroid carcinoma (PTC) is significantly reduced. It is of great significance to find an effective method for early prediction of the risk of DM for formulating individualized diagnosis and treatment plans and improving prognosis. Previous studies have significant limitations, and it is still necessary to develop new models for predicting the risk of DM of PTC. We aimed to develop and validate interpretable machine learning (ML) models for early prediction of DM in patients with PTC using a multicenter cohort. Methods: We collected data on patients with PTC who were admitted between June 2013 and May 2023. Data from 1430 patients at Yunnan Cancer Hospital (YCH) served as the training and internal validation set, while data from 434 patients at the First Affiliated Hospital of Kunming Medical University (KMU 1st AH) was used as the external test set. Nine ML methods such as random forest (RF) were used to construct the model. Model prediction performance was compared using evaluation indicators such as the area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanation (SHAP) method was used to rank the feature importance and explain the final model. Findings: Among the nine ML models, the RF model performed the best. The RF model accurately predicted the risk of DM in patients with PTC in both the internal validation of the training set [AUC: 0.913, 95% confidence interval (CI) (0.9075–0.9185)] and the external test set [AUC: 0.8996, 95% CI (0.8483–0.9509)]. The calibration curve showed high agreement between the predicted and observed risks. In the sensitivity analysis focusing on DM sites of PTC, the RF model exhibited outstanding performance in predicting “lung-only metastasis” showing high AUC, specificity, sensitivity, F1 score, and a low Brier score. SHAP analysis identified variables that contributed to the model predictions. An online calculator based on the RF model was developed and made available for clinicians at https://predictingdistantmetastasis.shinyapps.io/shiny1/. 11 variables were included in the final RF model: age of the patient with PTC, whether the tumor size is > 2 cm, whether the tumor size is ≤ 1 cm, lymphocyte (LYM) count, monocyte (MONO) count, monocyte/lymphocyte ratio (MLR), thyroglobulin (TG) level, thyroid peroxidase antibody (TPOAb) level, whether the T stage is T1/2, whether the T stage is T3/4, and whether the N stage is N0. Interpretation: On the basis of large-sample and multicenter data, we developed and validated an explainable ML model for predicting the risk of DM in patients with PTC. The model helps clinicians to identify high-risk patients early and provides a basis for individualized patient treatment plans. Funding: This work was supported by the National Natural Science Foundation of China (No. 81960426, 82360345 and 82001986), the Outstanding Youth Science Foundation of Yunnan Basic Research Project (No. 202401AY070001-316), Yunnan Province Applied and Basic Research Foundation (No. 202401AT070008), and Ten Thousand Talent Plans for Young Top-notch Talents of Yunnan Province.

This article studies the correlation between ground surface deformation of transmission lines in mining affected areas and various geological and human factors, and it constructs the corresponding numerical models. By analyzing the distribution of goaf areas, geological structures, slope structures, and other factors that affect transmission lines, the tower foundations’ deformation characteristics and disaster mechanisms under mining conditions have been clarified. On this basis, research on ground surface deformation risk prediction technology was carried out using monitoring data, and a safety operation risk assessment model was established to achieve rapid identification and accurate prediction and warning of hidden dangers. At the same time, a monitoring, early warning, and risk assessment system has been constructed and demonstrated to be highly accurate and practical in pilot verification. In addition, through the comprehensive application of physical models and numerical simulations, the influence of different ground surface settlements on the deformation of transmission line towers was explored, providing important references for improving the safety of transmission lines.

Air pollution significantly impacts lung cancer progression, but there is a lack of a comprehensive molecular characterization of clinical samples associated with air pollution. Here, we performed a proteogenomic analysis of lung adenocarcinoma (LUAD) in 169 female never-smokers from the Xuanwei area (XWLC cohort), where coal smoke is the primary contributor to the high lung cancer incidence. Genomic mutation analysis revealed XWLC as a distinct subtype of LUAD separate from cases associated with smoking or endogenous factors. Mutational signature analysis suggested that Benzo[a]pyrene (BaP) is the major risk factor in XWLC. The BaP-induced mutation hotspot, EGFR-G719X, was present in 20% of XWLC which endowed XWLC with elevated MAPK pathway activations and worse outcomes compared to common EGFR mutations. Multi-omics clustering of XWLC identified four clinically relevant subtypes. These subgroups exhibited distinct features in biological processes, genetic alterations, metabolism demands, immune landscape, and radiomic features. Finally, MAD1 and TPRN were identified as novel potential therapeutic targets in XWLC. Our study provides a valuable resource for researchers and clinicians to explore prevention and treatment strategies for air-pollution-associated lung cancers.

BackgroundThe clinical phenotypes of 16p13.11 microduplication syndrome have been extensively reported in previous studies, mostly about adults and children, with limited information available on fetal cases. This study aims to explore the genotype-phenotype correlation of fetuses with 16p13.11 microduplication syndrome and analyze the characteristics of prenatal diagnosis indications and provide clinical information for prenatal and postnatal genetic counseling.MethodsWe conducted a retrospective analysis of 3,451 pregnant women who underwent invasive prenatal diagnosis for SNP array between January 2018 and December 2022 at the Jinan Maternal and Child Health Hospital. Descriptive statistical analysis was performed on the prenatal diagnosis indications, pedigree analysis, pregnancy outcomes and postnatal follow-up of 15 fetuses with 16p13.11 microduplication syndrome.ResultsSNP array revealed that 15 fetuses had duplications in the 16p13.11 region with varying prenatal diagnosis indications. Among the cases, 6/15 exhibited ultrasound abnormalities, 5/15 had abnormal chromosomal copy number variations as indicated by non-invasive prenatal testing (NIPT), one case involved advanced maternal age, and 3/15 had other abnormalities. 16p13.11 microduplication syndrome was closely related to ultrasound abnormalities, especially structural abnormalities and soft marker anomalies (abnormal ultrasonic soft indicators), while the indication of NIPT could improve the detection rate of copy number variations (CNVs) in this region. Only 7/15 fetuses underwent pedigree verification, with one case of de novo 16p13.11 microduplication, and the others inherited from one parent. Pregnancy was terminated in 2/15 cases and the outcome of one case is unknown due to loss to follow-up. Among the remaining cases, only one case exhibited a ventricular septal defect, while another presented with omphalocele. No other obvious abnormalities were reported postnatally.ConclusionThe prenatal phenotypes of fetuses with 16p13.11 microduplication were highly associated with ultrasound abnormalities but lacked specificity. Comprehensive genetic tracing, outcome analysis, and follow-up are essential for providing accurate prenatal and postnatal genetic counseling.

Abstract Objectives This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. Methods We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. Results Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. Conclusion Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.

Abstract This study proposes an image-based three-dimensional (3D) vector reconstruction of industrial parts that can generate non-uniform rational B-splines (NURBS) surfaces with high fidelity and flexibility. The contributions of this study include three parts: first, a dataset of two-dimensional images is constructed for typical industrial parts, including hexagonal head bolts, cylindrical gears, shoulder rings, hexagonal nuts, and cylindrical roller bearings; second, a deep learning algorithm is developed for parameter extraction of 3D industrial parts, which can determine the final 3D parameters and pose information of the reconstructed model using two new nets, CAD-ClassNet and CAD-ReconNet; and finally, a 3D vector shape reconstruction of mechanical parts is presented to generate NURBS from the obtained shape parameters. The final reconstructed models show that the proposed approach is highly accurate, efficient, and practical.

ABSTRACT: Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P

Abstract Learning and inferring underlying motion patterns of captured 2D scenes and then re-creating dynamic evolution consistent with the real-world natural phenomena have high appeal for graphics and animation. To bridge the technical gap between virtual and real environments, we focus on the inverse modeling and reconstruction of visually consistent and property-verifiable oceans, taking advantage of deep learning and differentiable physics to learn geometry and constitute waves in a self-supervised manner. First, we infer hierarchical geometry using two networks, which are optimized via the differentiable renderer. We extract wave components from the sequence of inferred geometry through a network equipped with a differentiable ocean model. Then, ocean dynamics can be evolved using the reconstructed wave components. Through extensive experiments, we verify that our new method yields satisfactory results for both geometry reconstruction and wave estimation. Moreover, the new framework has the inverse modeling potential to facilitate a host of graphics applications, such as the rapid production of physically accurate scene animation and editing guided by real ocean scenes.

Abstract The explosive growth of social media means portrait editing and retouching are in high demand. While portraits are commonly captured and stored as raster images, editing raster images is non-trivial and requires the user to be highly skilled. Aiming at developing intuitive and easy-to-use portrait editing tools, we propose a novel vectorization method that can automatically convert raster images into a 3-tier hierarchical representation. The base layer consists of a set of sparse diffusion curves (DCs) which characterize salient geometric features and low-frequency colors, providing a means for semantic color transfer and facial expression editing. The middle level encodes specular highlights and shadows as large, editable Poisson regions (PRs) and allows the user to directly adjust illumination by tuning the strength and changing the shapes of PRs. The top level contains two types of pixel-sized PRs for high-frequency residuals and fine details such as pimples and pigmentation. We train a deep generative model that can produce high-frequency residuals automatically. Thanks to the inherent meaning in vector primitives, editing portraits becomes easy and intuitive. In particular, our method supports color transfer, facial expression editing, highlight and shadow editing, and automatic retouching. To quantitatively evaluate the results, we extend the commonly used FLIP metric (which measures color and feature differences between two images) to consider illumination. The new metric, illumination-sensitive FLIP, can effectively capture salient changes in color transfer results, and is more consistent with human perception than FLIP and other quality measures for portrait images. We evaluate our method on the FFHQR dataset and show it to be effective for common portrait editing tasks, such as retouching, light editing, color transfer, and expression editing.

We investigate the triple correlation sums of coefficients of $ \theta $-series and prove an asymptotic formula with power-saving error term. As a result, we present that this type of sum is non-trivial in the regime $ H\ge X^{2/3+\varepsilon} $.

Abstract Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.

Abstract Gears play an important role in virtual manufacturing systems for digital twins; however, the image of gear tooth defects is difficult to acquire owing to its non-convex shape. In this study, a deep learning network is proposed to detect gear defects based on their point cloud representation. This approach mainly consists of three steps: (1) Various types of gear defects are classified into four cases (fracture, pitting, glue, and wear); A 3D gear dataset was constructed with 10000 instances following the aforementioned classification. (2) Gear-PCNet+ + introduces a novel Combinational Convolution Block, proposed based on the gear dataset for gear defect detection to effectively extract the local gear information and identify its complex topology; (3) Compared with other methods, experiments show that this method can achieve better recognition results for gear defects with higher efficiency and practicability.

The therapeutic efficacy of umbilical cord mesenchymal stem cells (UCMSCs) in acute respiratory distress syndrome (ARDS) is mainly limited by the efficiency of homing of UCMSCs toward tissue damage. C-X-C chemokine receptor type 7 (CXCR7), which is involved in the mobilization of UCMSCs, is only expressed on the surface of a small proportion of UCMSCs. This study examined whether overexpression of CXCR7 in UCMSCs (UCMSCsOE-CXCR7) could improve their homing efficiency, and therefore, improve their effectiveness in fibrosis repair at the site of lung injury caused by ARDS. A lentiviral vector expressing CXCR7 was built and then transfect into UCMSCs. The impacts of CXCR7 expression of the proliferationand homing of UCMSCs were examined in a lipopolysaccharide-induced ARDS mouse model. The potential role and underlying mechanism of CXCR7 were examined by performing scratch assays, transwell assays, and immunoassays. The therapeutic dose and treatment time of UCMSCsOE-CXCR7 were directly proportional to their therapeutic effect on lung injury. In addition, overexpression of CXCR7 increased SDF-1-induced proliferation and migration of lung epithelial cells (Base-2b cells), and upregulation of CXCR7 inhibited α-SMA expression, suggesting that CXCR7 may have a role in alleviating pulmonary fibrosis caused by ARDS. Overexpression of CXCR7 in UCMSCs may improve their therapeutic effect of acute lung injury mouse, The mechanism of fibrosis repair by CXCR7 is inhibition of Jag1 via suppression of the Wnt/β-catenin pathway under the chemotaxis of SDF-1.

Let $ F $ be a normlized Hecke-Maaß form for the congruent subgroup $ \Gamma_0(N) $ with trivial nebentypus. In this paper, we study the problem of the level aspect estimates for the exponential sum $ \mathscr{L}_F(\alpha) = \sum\limits_{n\le X} A_F(n, 1)e(n \alpha). $ As a result, we present an explicit non-trivial bound for the sum $ \mathscr{L}_F(\alpha) $ in the case of $ N = P $. In addition, we investigate the magnitude for the non-linear exponential sums with the level being explicitly determined from the sup-norm's point of view as well.

Abstract Background Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated. Methods To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with >440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in GPCM, we assign a risk score to genes in the GPCM and identify risk pathways enriched with the risk genes. Results Analysis of >8300 expression profiles covering ten cancer tissues and blood samples indicates that CTpathway outperforms the current state-of-the-art methods in identifying risk pathways with higher accuracy, reproducibility, and speed. CTpathway recapitulates known risk pathways and exclusively identifies several previously unreported critical pathways for individual cancer types. CTpathway also outperforms other methods in identifying risk pathways across all cancer stages, including early-stage cancer with a small number of differentially expressed genes. Moreover, the robust design of CTpathway enables researchers to analyze both bulk and single-cell RNA-seq profiles to predict both cancer tissue and cell type-specific risk pathways with higher accuracy. Conclusions Collectively, CTpathway is a fast, accurate, and stable pathway enrichment analysis method for cancer research that can be used to identify cancer risk pathways. The CTpathway interactive web server can be accessed here http://www.jianglab.cn/CTpathway/ . The stand-alone program can be accessed here https://github.com/Bioccjw/CTpathway .

Let $ p $ be a prime. In this paper, we study the sum $ \sum\limits_{m\ge 1} \sum\limits_{n\ge 1} a_n \lambda_g(m)\lambda_{f}(m+pn) \,U{ \left( \frac{m}{X} \right) }V{ \left ( \frac{n}{H} \right)} $ for any newforms $ g\in \mathcal{B}_k(1) $ (or $ \mathcal{B}_\lambda^\ast(1) $) and $ f\in \mathcal{B}_k(p) $ (or $ \mathcal{B}_\lambda^\ast(p) $), with the aim of determining the explicit dependence on the level, where $ {\bf{a}} = \{a_n\in\mathbb{C}\} $ is an arbitrary complex sequence. As a result, we prove a uniform bound with respect to the level parameter $ p $, and present that this type of sum is non-trivial for any given $ H, X\ge 2 $.

Background Patients with non-small cell lung cancer (NSCLC) who develop brain metastases (BM) have a poor prognosis. This study aimed to construct a clinical prediction model to determine the overall survival (OS) of NSCLC patients with BM. Methods A total of 300 NSCLC patients with BM at the Yunnan Cancer Centre were retrospectively analysed. The prediction model was constructed using the least absolute shrinkage and selection operator-Cox regression. The bootstrap sampling method was employed for internal validation. The performance of our prediction model was compared using recursive partitioning analysis (RPA), graded prognostic assessment (GPA), the update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molGPA), the basic score for BM (BSBM), and tumour-lymph node-metastasis (TNM) staging. Results The prediction models comprising 15 predictors were constructed. The area under the curve (AUC) values for the 1-year, 3-year, and 5-year time-dependent receiver operating characteristic (curves) were 0.746 (0.678–0.814), 0.819 (0.761–0.877), and 0.865 (0.774–0.957), respectively. The bootstrap-corrected AUC values and Brier scores for the prediction model were 0.811 (0.638–0.950) and 0.123 (0.066-0.188), respectively. The time-dependent C-index indicated that our model exhibited significantly greater discrimination compared with RPA, GPA, Lung-molGPA, BSBM, and TNM staging. Similarly, the decision curve analysis demonstrated that our model displayed the widest range of thresholds and yielded the highest net benefit. Furthermore, the net reclassification improvement and integrated discrimination improvement analyses confirmed the enhanced predictive power of our prediction model. Finally, the risk subgroups identified by our prognostic model exhibited superior differentiation of patients’ OS. Conclusion The clinical prediction model constructed by us shows promise in predicting OS for NSCLC patients with BM. Its predictability is superior compared with RPA, GPA, Lung-molGPA, BSBM, and TNM staging.

Abstract Adenosine‐to‐inosine RNA editing critically affects the response of cancer therapies. However, comprehensive identification of drug resistance‐related RNA editing events and systematic understanding of how RNA editing mediates anticancer drug resistance remain unclear. Here, 7157 differential editing sites (DESs) are identified from 98 127 informative RNA editing sites in tumor tissues, many of which are validated in cancer cell lines. Diverse editing patterns of DESs are discovered in resistant samples, which could not be fully explained by adenosine deaminase acting on RNA enzymes. Some RNA‐binding proteins are identified that potentially regulate these editing events. Notably, the DESs are significantly enriched in 3’‐untranslated regions (3’‐UTRs). The impact of DESs in 3’‐UTR on the microRNA (miRNA) regulations is explored, and some triplets (DES, miRNA, and gene) that may contribute to drug resistance are identified. In addition, it is determined that the functions of genes enriched with DESs are associated with drug resistance, such as apoptosis, drug metabolism, and DNA synthesis involved in DNA repair. An online resource (http://www.jianglab.cn/REDR/) to support convenient retrieval of DESs is also built. The findings reveal the landscape and potential regulatory mechanism of RNA editing in drug resistance, providing new therapeutic targets for reversing drug resistance.

Mobile Earthquake Recording in Marine Areas by Independent Divers (MERMAID) provides a possibility for long-term and large-scale observation of natural seismic P waves, but it does not have mobility and can only drift with ocean currents, resulting in observation equipment locations that are too sparse or too dense, both of which are not suitable for network observation. Therefore, this paper developed a new type of Autonomous Glide Marine Seismometer (AGMS) with mobility and the ability to adjust the observation position. The AGMS adopts a flying saucer shape, which has better hydrodynamic characteristics and better motion stability. This paper focused on the material, shape, and structure of the pressure-resistant shell for the selection of design and strength checking research. Using the finite element analysis method and introducing the initial defect, the results showed that the yield strength of the pressure-resistant shell decreases with the initial defect value. The calculation results were compared and analyzed with the relevant theoretical formulas and specification calculation results, and all the results met the design requirements. The results of this design could also provide reference for the design of related deep-sea pressure chambers.

Abstract This paper presents a novel algorithm for planar G1 interpolation using typical curves with monotonic curvature. The G1 interpolation problem is converted into a system of nonlinear equations and sufficient conditions are provided to check whether there is a solution. The proposed algorithm was applied to a curve completion task. The main advantages of the proposed method are its simple construction, compatibility with NURBS, and monotonic curvature.

Long-term isolation is one of the risk factors that astronauts will encounter in spaceflight. At present, few researches have explored DNA methylation dynamics during long-term isolation. In this study, using time series DNA methylation data from “Mars-500” mission, we conducted a multi-step analysis to investigate the characteristics and dynamic patterns of DNA methylation as well as their functional insights during long-term isolation. The results showed that genome-wide methylation changes were minimal. In the six identified DNA methylation dynamic patterns, most of significantly fluctuating CpG sites could be returned to the baseline in post-isolation, and the remaining sites persistently decreased during isolation. Next, functional enrichment analysis of genes with each pattern revealed strong functional specificity. Some patterns were also significantly associated with nervous system diseases, digestive system diseases and cancers. In conclusion, the DNA methylation dynamics during long-term isolation have great functional significance, and might be helpful for protection of astronaut health.

Abstract. Background:. Recently, T-helper 17 (Th17) cells have been proved to play an important role in promoting cervical cancer. But, till now, few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments. This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer (LACC) patients before and after concurrent chemoradiotherapy (cCRT) and to analyze the correlations between the alterations in Th17 cells and treatment efficacy. Methods:. A prospective study with 49 LACC (International federation of gynecology and obstetrics [FIGO] stage IIB–IIIB) patients and 23 controls was conducted. Patients received the same cCRT schedule and were followed up for 3 years. Circulating Th17 cells (CD3+CD8– interleukin [IL]-17+ T cells) and related cytokines IL-17, transforming growth factor-β (TGF-β), IL-10, IL-23, IL-6, and IL-22 were detected before and after cCRT. Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). Results:. We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study. The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls, and it significantly decreased after cCRT (P < 0.05). After cCRT, patients were divided into two groups based on the average of the Th17 cells declined. The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times. Compared with the control patients, LACC patients had higher IL-6, IL-10, IL-22, TGF-β levels and a lower IL-23 level (P < 0.05). After cCRT, IL-6, IL-10, IL-17, IL-23 level significantly increased and TGF-β level significantly decreased compared with the levels before cCRT (P < 0.05). Conclusion:. Circulating Th17 cells in the LACC patients (FIGO stage IIB–IIIB) were higher than those in the controls, but they generally decreased after cCRT. A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high intratumoral heterogeneity. Recent studies revealed that TNBC patients might comprise cells with distinct molecular subtypes. In addition, gene regulatory networks (GRNs) constructed based on single-cell RNA sequencing (scRNA-seq) data have demonstrated the significance for decoding the key regulators. We performed a comprehensive analysis of the GRNs for the intrinsic subtypes of TNBC patients using scRNA-seq. The copy number variations (CNVs) were inferred from scRNA-seq data and identified 545 malignant cells. The subtypes of the malignant cells were assigned based on the PAM50 model. The cell-cell communication analysis revealed that the macrophage plays a dominant role in the tumor microenvironment. Next, the GRN for each subtype was constructed through integrating gene co-expression and enrichment of transcription-binding motifs. Then, we identified the critical genes based on the centrality metrics of genes. Importantly, the critical gene ETV6 was ubiquitously upregulated in all subtypes, but it exerted diverse roles in each subtype through regulating different target genes. In conclusion, the construction of GRNs based on scRNA-seq data could help us to dissect the intratumoral heterogeneity and identify the critical genes of TNBC.

In this work, a new low voltage-triggered silicon-controlled rectifier named MTSCR is realized in a 65 nm CMOS process for low voltage-integrated circuits electrostatic discharge (ESD) protections. The MTSCR incorporates an external NMOSs-string, which drives the internal NMOS (INMOS) of MTSCR to turn on, and then the INMOS drive SCR structure to turn on. Compared with the existing low trigger voltage (Vt1) ESD component named diodes-string-triggered SCR (DTSCR), the MTSCR can realize the same low Vt1 characteristic but less area penalty of ~44.3% reduction. The results of the transmission line pulsing (TLP) measurement shows that the MTSCR possesses above 2.42 V holding voltage (Vh) and a low Vt1 of ~5.03 V, making it very suitable for the ESD protections for 1.8 V input/output (I/O) ports in CMOS technologies.

Abstract Acute respiratory distress syndrome (ARDS) develops rapidly and has a high mortality rate. Survivors usually have low quality of life. Current clinical management strategies are respiratory support and restricted fluid input, and there is no suggested pharmacological treatment. Mesenchymal stromal cells (MSCs) have been reported to be promising treatments for lung diseases. MSCs have been shown to have a number of protective effects in some animal models of ARDS by releasing soluble, biologically active factors. In this review, we will focus on clinical progress in the use of MSCs as a cell therapy for ARDS, which may have clinical implications during the coronavirus disease 2019 (COVID-19) pandemic.

Macrophages are highly heterogeneous immune cells that fulfill tissue-specific functions. Tissue-derived signals play a critical role in determining macrophage heterogeneity. However, these signals remain largely unknown. The BMP receptor activin receptor–like kinase 1 (ALK1) is well known for its role in blood vessel formation; however, its role within the immune system has never been revealed to our knowledge. Here, we found that BMP9/BMP10/ALK1 signaling controlled the identity and self-renewal of Kupffer cells (KCs) through a Smad4-dependent pathway. In contrast, ALK1 was dispensable for the maintenance of macrophages located in the lung, kidney, spleen, and brain. Following ALK1 deletion, KCs were lost over time and were replaced by monocyte-derived macrophages. These hepatic macrophages showed significantly reduced expression of the complement receptor VSIG4 and alterations in immune zonation and morphology, which is important for the tissue-specialized function of KCs. Furthermore, we found that this signaling pathway was important for KC-mediated Listeria monocytogenes capture, as the loss of ALK1 and Smad4 led to a failure of bacterial capture and overwhelming disseminated infections. Thus, ALK1 signaling instructs a tissue-specific phenotype that allows KCs to protect the host from systemic bacterial dissemination.

Although most existing studies have considered entrepreneurial bricolage as a means to overcome resource constraints in new ventures, few have explored the direct effects of entrepreneurial bricolage on employee creativity, particularly in the context of entrepreneurial internet firms. Drawing from multiple theories (i.e., social learning theory and social cognitive theory), this study proposes a cross-level mediation model for the trickle-down effects of entrepreneurial bricolage and business model innovation on employee creativity. By using a 2-wave longitudinal design, survey data were collected from multiple sources, including 49 leaders and 336 employees from entrepreneurial internet firms in China. Multilevel structural equation modeling (MSEM) was applied to analyze the cross-level mediation model. The results show that both entrepreneurial bricolage and business model innovation failed to significantly and positively direct employee creativity. Furthermore, entrepreneurial bricolage exerted a cross-level influence on employee creativity that was sequentially transmitted through between-level business model innovation and within-level creative self-efficacy. The theoretical and managerial implications of these findings are also discussed.

Highlighting the implications of entrepreneurship education, this study examines the effects of entrepreneurship education in predicting the entrepreneurial intention of university students. The study also explores the mediating role of opportunity recognition and the moderating role of entrepreneurial learning in this process. To test our multilevel-moderated mediation model, based on a dataset containing 1,150 university students from 55 universities in the Guangdong-Hong Kong-Macao Greater Bay Area of China, hierarchical linear modeling is utilized to test the research hypotheses. The findings reveal that entrepreneurship education can promote the entrepreneurial intention of students through opportunity recognition. Furthermore, entrepreneurial learning plays a moderating role in the link between entrepreneurship education and opportunity recognition. Implications for the design and delivery of entrepreneurship education are discussed.

Background: Cholangiocytes are primary targets in chronic cholestatic liver diseases. Myocyte enhancer factor 2A (MEF2A) is a transcription factor with a crucial role in some fibrogenic diseases. However, whether it contributes to cholestatic liver fibrosis is still obscure. Methods: A bile duct–ligated (BDL) mouse model was established to detect MEF2A expression during cholestatic liver fibrosis. In addition, human intrahepatic biliary epithelial cells (HIBECs) were transfected with lentivirus-expressing shMEF2A (LV-shMEF2A) to regulate the expression of MEF2A in vitro. Biomarkers of epithelial to mesenchymal transition (EMT), senescence, and fibrogenesis were evaluated using various assays: Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, senescence-associated β-galactosidase (SA-β-gal), and immunofluorescence. Furthermore, MEF2A expression and cytoplasm translocation induced by transforming growth factor β1 (TGF-β1) in HIBECs were determined by qRT-PCR, western blotting, and immunofluorescence. The expression of TGF-β1-induced MEF2A, EMT, senescence, and fibrosis markers inhibited by p38 MAPK signaling were evaluated by western blotting. Finally, the peripheral blood from primary biliary cholangitis (PBC) patients and healthy controls (HCs) was collected to analyze expression of MEF2A using Enzyme-linked immunosorbent assay (ELISA). Results: We found that MEF2A expression increased in liver tissues of BDL mice, and positively related to the extent of fibrosis. Silencing MEF2A in HIBECs restrained TGF-β1-induced EMT, senescence, and fibrotic reaction. Moreover, TGF-β1 enhanced the expression of MEF2A and induced its cytoplasm translocation in a concentration- and time-dependent manner, partially through interacting with p38 MAPK. The expression of MEF2A was also higher in the serum of PBC patients than in HCs, and positively correlated with fibrosis degree. Conclusions: Our study demonstrates that MEF2A is a central mediator linking TGF-β1-induced EMT and senescence in HIBECs. We propose it as a novel biomarker of fibrogenesis in cholestatic liver fibrosis. We also suggest inhibiting MEF2A as a potential strategy in treating cholestatic liver fibrosis.

Although the academic community has consistent with the key role of entrepreneurial team knowledge diversity (ETKD), which serves as a critical catalyst of creativity in organizations, the extant research on the link between knowledge diversity and creativity is mainly concerned with individual creativity in single-level analyses. With emerging entrepreneurial ventures increasingly relying on innovation enhancement in the form of teams, there is research motivation to explore how team-level creativity develops. In this sense, this study attempts to investigate the underlying mechanism through which ETKD is associated with team-level creativity. Through a multilevel mediation model, this study proposes that ETKD can facilitate team creativity (TC) sequentially transmitted through individual-level team members' knowledge sharing (KS) and creativity. Based on a survey of 252 team members from 42 entrepreneurial teams in China, multilevel structural equation modeling (MSEM) is applied to test the top–down relationship between ETKD and KS, as well as the bottom-up link between individual creativity and TC. The findings show that our hypotheses are supported. Our findings provide some of the first empirical evidence to examine how knowledge-based diversity of entrepreneurial teams facilitates TC potential by multilevel approach. Theoretical contributions and practical implications are also offered.

Lung macrophages play important roles in the maintenance of homeostasis, pathogen clearance and immune regulation. The different types of pulmonary macrophages and their roles in lung diseases have attracted attention in recent years. Alveolar macrophages (AMs), including tissue-resident alveolar macrophages (TR-AMs) and monocyte-derived alveolar macrophages (Mo-AMs), as well as interstitial macrophages (IMs) are the major macrophage populations in the lung and have unique characteristics in both steady-state conditions and disease states. The different characteristics of these three types of macrophages determine the different roles they play in the development of disease. Therefore, it is important to fully understand the similarities and differences among these three types of macrophages for the study of lung diseases. In this review, we will discuss the physiological characteristics and unique functions of these three types of macrophages in acute and chronic lung diseases. We will also discuss possible methods to target macrophages in lung diseases.

The development, survivorship, fecundity, and cannibalism of the predatory phytoseiid mite, Amblyseius herbicolus (Chant), fed six different alternative foods (Oulenziella bakeri, Tyrophagus putrescentiae, Aleuroglyphus ovatus, almond pollen (Prunus armeniaca), apple pollen (Malus pumila), maize pollen (Zea mays)), and natural prey (Tetranychus urticae) were determined in the laboratory. Our findings indicated that A. herbicolus that fed on all six alternative foods could normally complete its developmental and reproductive cycles. The shortest pre-adult developmental duration was observed when A. herbicolus fed on almond pollen (4.91 d) as well as T. urticae (4.90 d), and the longest when it fed on maize pollen (6.24 d). Pre-adult survival rates were higher when the predator fed on almond pollen (0.99), maize pollen (0.96), and O. bakeri (0.93). The highest fecundity was observed when A. herbicolus fed on apple pollen (28.55 eggs/female), almond pollen (26.06 eggs/female), and O. bakeri (26.02 eggs/female) in addition to T. urticae (48.95 eggs/female), and the lowest when it fed on maize pollen (7.84 eggs/female). The highest value of the intrinsic rate of increase (r) was obtained when A. herbicolus fed on O. bakeri (0.202 d−1) in addition to T. urticae (0.210 d−1), followed by almond pollen (0.163 d−1), and the lowest was when it fed on maize pollen (0.064 d−1). Cannibalism of conspecific eggs by adults of A. herbicolus did not occur when O. bakeri and T. urticae were provided. The cannibalism rate of the predatory mite was the lowest when fed on almond pollen, T. putrescentiae, and A. ovatus and the highest on apple pollen. Above all, when fed on O. bakeri and almond pollen, and with no or low cannibalism rate, A. herbicolus had the best development, survivorship, fecundity, and population parameters. Therefore, O. bakeri and almond pollen could be potential alternative foods for mass rearing programs of A. herbicolus or to support its population in the fields.

In order to meet the requirements of mobile marine seismometers to observe and record seismic signals, a study of fast and accurate seismic signal recognition was carried out. This paper introduces the use of the wavelet analysis method for seismic signal processing and recognition, and compares and analyzes the abilities of different wavelet basis functions to detect the seismic signal. By denoising and reconstructing the signal, the distribution law of the wavelet coefficients of seismic signal at different scales was obtained. On this basis, this paper proposes an identification model of seismic signals based on wavelet analysis and thereby solves the conflict between high speed and high accuracy of seismic signal recognition methods. In this study, the simulation was carried out in the Matlab2020b environment, and the feasibility of wavelet recognition algorithm was proven by applying this algorithm to the seismic signal database for experimental verification.

In this study, we examine whether education, as an important component of the human capital of auditors, is related to the occurrence of financial misstatement, and investigate the moderating effect of professional experience. Using a sample of 16,651 firm-year observations from the Chinese stock market from 2003 to 2014, we find that the education level of signing auditors is significantly negatively associated with the likelihood of financial misstatement, which suggests that higher education can enhance the ethics and independence of auditors and mitigate the risk of financial misstatement. In addition, professional experience attenuates the negative relation between the education level of signing auditors and financial misstatement. Our findings are also robust to a variety of sensitivity tests, and our conclusions still hold after using a two-stage OLS-logistic regression to address the endogeneity problem. Lastly, the negative effect of education level on financial misstatement holds only for 985 Project universities, low individual-level (audit-firm-level) client importance, and state-owned enterprises. Keywords: Auditor human capital, Financial misstatement, Education level, Professional experience, Signing auditors, JEL classification: M42, J41, P36

Summary: Controlling intraocular pressure (IOP) remains the mainstay of glaucoma therapy. The trabecular meshwork (TM), the key tissue responsible for aqueous humor (AH) outflow and IOP maintenance, is very sensitive to mechanical forces. However, it is not understood whether Piezo channels, very sensitive mechanosensors, functionally influence AH outflow. Here, we characterize the role of Piezo1 in conventional AH outflow. Immunostaining and western blot analysis showed that Piezo1 is widely expressed by TM. Patch-clamp recordings in TM cells confirmed the activation of Piezo1-derived mechanosensitive currents. Importantly, the antagonist GsMTx4 for mechanosensitive channels significantly decreased steady-state facility, yet activation of Piezo1 by the specific agonist Yoda1 did not lead to a facility change. Furthermore, GsMTx4, but not Yoda1, caused a significant increase in ocular compliance, a measure of the eye's transient response to IOP perturbation. Our findings demonstrate a potential role for Piezo1 in conventional outflow, likely under pathological and rapid transient conditions.

Background and methods Stroke has become a major public health problem worldwide. In this article, we carried out statistical analysis, correlation analysis and principal component analysis (PCA) to evaluate the clinical value of routine hematological indicators in early diagnosis of ischemic stroke using R language. Results For the full blood count comparisons, stroke patients had obvious differences in the distribution width of red blood cells (RDW-CV), average distribution width of red blood cells (RDW-SD), mean hemoglobin concentrations, platelet large cell ratio, mean platelet volume and lymphocytes. Patients with ischemic stroke also exhibited different degrees of abnormalities in liver function test. With respect to renal function, stroke patients had obvious changes in uric acid and urea levels. Finally, when comparing the lipid profile, triglyceride concentrations were increased and high-density lipoprotein cholesterol concentrations were reduced in stroke patients. In addition, correlation analysis among these clinical indicators indicated that there were both common characteristics and differences between patients and health controls. Furthermore, the results of PCA indicated that these clinical indicators could distinguish patients from the healthy controls. Conclusion Conventional hematological clinical indicators, such as liver function, renal function, full blood count and lipid concentration profiles highly correlated with the occurrence of ischemic stroke. Therefore, the detection and analyzation of these clinical indicators are of great significance for the prediction of ischemic stroke.

Abstract Background This study was to evaluate the effects of herbal compound 861 (Cpd861) on ski-related novel protein N (SnoN) and transforming growth factor-β1 (TGF-β1) /Smad signaling in rats with bile duct ligation (BDL)-induced hepatic fibrosis, and to explore the mechanisms of Cpd861 on hepatic fibrosis. Methods Thirty Wistar male rats were randomly divided into three groups: sham operation, BDL, and Cpd861. To induce hepatic fibrosis, BDL and Cpd861 group rats underwent bile duct ligation. Cpd861 at 9 g/kg/d or an equal volume of normal saline was administered intragastrically for 28 days. Liver injury was assessed biochemically and histologically. Protein and mRNA changes for SnoN and TGF-β1/Smad signaling (TGF-β1, Smad2, phosphorylated Smad2 [p-Smad2], phosphorylated Smad3 [p-Smad3], fibronectin, and collagen III) were determined by Western blotting and quantitative real-time PCR. Results BDL rats treated with Cpd861 had significantly alleviated hepatic fibrosis compared to BDL rats not receiving Cpd861 treatment. Moreover, Cpd861 decreased the expression of fibrosis-associated proteins fibronectin and collagen III in liver tissue. Cpd861 administration increased the expression of SnoN protein, did not change SnoN mRNA level, and decreased TGF-β1, p-Smad2, and p-Smad3 protein expression compared to BDL without Cpd861 treatment. Conclusions Cpd861 attenuates hepatic fibrosis by increasing SnoN protein expression and inhibiting the TGF-β1/Smad signaling pathway.

Although the entrepreneurial intention of university students has been studied from different perspectives, the results are still not convergent, and the mechanism and outcomes related to how entrepreneurial intention could be affected by different factors lacking integrated investigation and comparative research. Based on emotional theory, the theory of planned behavior (TPB), and entrepreneurial cognitive theory, as well as the perception of specific situations encountered by university students, this paper attempts to explore entrepreneurial intention from three perspectives, including individual, family and school; and constructs an integrated model that includes entrepreneurial passion, role models, entrepreneurial education, entrepreneurial self-efficacy, and entrepreneurial intention. Based on a survey of university students in the Pearl River Delta of China, this paper attempts to explore the intrinsic mechanism of the development of entrepreneurial intention from these three perspectives. The results show that entrepreneurial passion, role models, and entrepreneurial education could have different effects on entrepreneurial intention; additionally, entrepreneurial self-efficacy plays an important mediating role. The research findings contribute to the literatures regarding the factors influencing entrepreneurial intention, providing empirical evidence to formulate policies to encourage university students’ entrepreneurship practices and help to enhance effectiveness of entrepreneurship education.

Previous studies have demonstrated that microgravity could lead to health risks. The investigation of the molecular mechanisms from the aspect of systems biology has not been performed yet. Here, we integratively analyzed transcriptional and post-transcriptional regulations based on gene and miRNA expression profiles in human peripheral blood lymphocytes cultured in modeled microgravity. Two hundred and thirty dysregulated TF-miRNA (transcription factor and microRNA) feed-forward loops (FFLs) were identified in microgravity. The immune, cardiovascular, endocrine, nervous and skeletal system subnetworks were constructed according to the functions of dysregulated FFLs. Taking the skeletal system as an example, most of genes and miRNAs in the subnetwork were involved in bone loss. In addition, several drugs have been predicted to have potential to reduce bone loss, such as traditional Chinese medicines Emodin and Ginsenoside Rh2. Furthermore, we investigated the relationships between microgravity and 20 cancer types, and found that most of cancers might be promoted by microgravity. For example, rectum adenocarcinoma (READ) might be induced by microgravity through reducing antigen presentation and suppressing IgA-antibody-secreting cells’ migration. Collectively, TF-miRNA FFL might provide a novel mechanism to elucidate the changes induced by microgravity, serve as drug targets to relieve microgravity effects, and give new insights to explore the relationships between microgravity and cancers.

The changing climatic conditions are causing erratic rains and frequent episodes of moisture stress; these impose a great challenge to cotton productivity by negatively affecting plant physiological, biochemical and molecular processes. This situation requires an efficient management of water-nutrient to achieve optimal crop production. Wise use of water-nutrient in cotton production and improved water use-efficiency may help to produce more crop per drop. We hypothesized that the application of nitrogen into deep soil layers can improve water-nitrogen productivity by promoting root growth and functional attributes of cotton crop. To test this hypothesis, a two-year pot experiment under field conditions was conducted to explore the effects of two irrigation levels (i.e., pre-sowing irrigation (W80) and no pre-sowing irrigation (W0)) combined with different fertilization methods (i.e., surface application (F10) and deep application (F30)) on soil water content, soil available nitrogen, roots morpho-physiological attributes, dry mass and water-nitrogen productivity of cotton. W80 treatment increased root length by 3.1%−17.5% in the 0−40 cm soil layer compared with W0. W80 had 11.3%−52.9% higher root nitrate reductase activity in the 10−30 cm soil layer and 18.8%−67.9% in the 60−80 cm soil layer compared with W0. The W80F10 resulted in 4.3%−44.1% greater root nitrate reductase activity compared with other treatments in the 0−30 cm soil layer at 54−84 days after emergence. Water-nitrogen productivity was positively associated with dry mass, water consumption, root length and root nitrate reductase activity. Our data highlighted that pre-sowing irrigation coupled with basal surface fertilization is a promising option in terms of improved cotton root growth. Functioning in the surface soil profile led to a higher reproductive organ biomass production and water-nitrogen productivity.

Histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are involved in both physiological and pathological conditions by regulating the status of histone acetylation. Although histone deacetylase 4 (HDAC4), a member of the HDAC family, may lack histone deacetylase activity, it is actively involved in regulating the transcription of genes involved in synaptic plasticity, neuronal survival and neurodevelopment by interacting with transcription factors, signal transduction molecules and HDAC3, another member of the HDAC family. HDAC4 is highly expressed in brain and its homeostasis is crucial for the maintenance of cognitive function. Accumulated evidence shows that HDAC4 expression is dysregulated in several brain disorders, including neurodegenerative diseases and mental disorders. Moreover, cognitive impairment is a characteristic feature of these diseases. It indicates that aberrant HDAC4 expression plays a pivotal role in cognitive impairment of these disorders. This review aims to describe the current understanding of HDAC4’s role in the maintenance of cognitive function and its dysregulation in neurodegenerative diseases and mental disorders, discuss underlying molecular mechanisms, and provide an outlook into targeting HDAC4 as a potential therapeutic approach to rescue cognitive impairment in these diseases.

The modeling of free-form engineering complex curves is an important subject in product modeling, graphics, and computer aided design/computer aided manufacturing (CAD/CAM). In this paper, we propose a novel method to construct free-form complex curves using shape-adjustable generalized Bézier (or SG-Bézier, for short) curves with constraints of geometric continuities. In order to overcome the difficulty that most of the composite curves in engineering cannot often be constructed by using only a single curve, we propose the necessary and sufficient conditions for G1 and G2 continuity between two adjacent SG-Bézier curves. Furthermore, the detailed steps of smooth continuity for two SG-Bézier curves, and the influence rules of shape parameters on the composite curves, are studied. We also give some important applications of SG-Bézier curves. The modeling examples show that our methods in this paper are very effective, can easily be performed, and can provide an alternative powerful strategy for the design of complex curves.

BACKGROUND: The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated. METHODS: The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining. RESULTS: Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues. CONCLUSIONS: This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis.