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The traditional Chinese medicine (TCM) bupleurum-ginger-licorice formula presents significant anti-cancer effects, but its active ingredients and inhibitory mechanism remain unclear. In this work, the core effective ingredient quercetin and its signal transducer and activator of transcription 3 (Stat3) receptor both were identified by network pharmacology. Quercetin is a low-toxicity, non-carcinogenic flavonoid with antioxidant, anti-inflammatory and anticancer activities, which is widely distributed in edible plants. Stat3 can bind to specific DNA response elements and serves as a transcription factor to promote the translation of some invasion/migration-related target genes, considered as a potential anticancer target. Here, molecular docking and molecular dynamics (MD) simulation both were used to explore molecular recognition of quercetin with Stat3. The results show that quercetin impairs DNA transcription efficiency by hindering Stat3 dimerization, partially destroying DNA conformation. Specifically, when the ligand occupies the SH2 cavity of the enzyme, spatial rejection is not conductive to phosphokinase binding. It indirectly prevents the phosphorylation of Y705 and the formation of Stat3 dimer. When the inhibitor binds to the DT1005 position, it obviously shortens the distance between DNA and DBD, enhances their binding capacity, and thereby reduces the degree of freedom required for transcription. This work not only provides the binding modes between Stat3 and quercetin, but also contributes to the optimization and design of such anti-cancer inhibitors.

Accurate monitoring and estimation of heavy metal concentrations is an important process in the prevention and treatment of soil pollution. However, the weak correlation between spectra and heavy metals in soil makes it difficult to use spectroscopy in predicting areas with a risk of heavy metal pollution. In this paper, a method for detection of Ni in soil in eastern China using the fractional-order derivative (FOD) and spectral indices was proposed. The visible-near-infrared (Vis-NIR) spectra were preprocessed using the FOD (range: 0 to 2, interval: 0.1) to solve the problems of baseline drift and overlapping peaks in the original spectra. The product index (PI), ratio index (RI), sum index (SI), difference index (DI), normalized difference index (NDI), and brightness index (BI) were applied and compared. The results showed that the spectral detail increased as the FOD increased, and the interference of the baseline drift and overlapping peaks was eliminated as the spectral reflectance decreased. Furthermore, the FOD extracted the spectral sensitivity information more effectively and improved the correlation between the Vis-NIR spectra and the Ni concentration, and the NDI had a maximum correlation coefficient (r) of 0.803 for order 1.9. The estimation model based on the NDI dataset constructed after FOD processing had the best performance, with a validation accuracy [Formula: see text] of 0.735, RMSE of 3.848, and RPD of 2.423. In addition, this method is easy to carry out and suitable for estimating other heavy metal elements in soil.

The immune checkpoint proteins were reported to involve to host resistance to Mycobacteria tuberculosis (Mtb). Here, we evaluated 11 single nucleotide polymorphisms (SNPs) in PDCD1, CTLA4, and HAVCR2 genes between participants with and without TB infection. Genomic DNA isolated from 285 patients with TB and 270 controls without TB infection were used to perform the genotyping assay. Odds ratios were used to characterize the association of 11 SNPs with TB risk. In this study, the various genotypes of the 11 SNPs did not differ significantly in frequency between the non-TB and TB groups. When patients were stratified by sex, however, men differed significantly from women in genotype frequencies at HAVCR2 rs13170556. Odds ratios indicated that rs2227982, rs13170556, rs231775, and rs231779 were sex-specifically associated with TB risk. In addition, the combinations of rs2227982/rs13170556 GA/TC in men and the A-C-C haplotype of rs231775-rs231777-rs231779 in women were significantly associated with TB risk. Our results indicate that rs2227982 in PDCD1 and rs13170556 in HAVCR2 are associated with increased TB susceptibility in men and that the CTLA4 haplotype appears protective against TB in women.

Spending time outdoors is associated with increased time spent in physical activity, lower chronic disease risk, and wellbeing. Many studies rely on self-reported measures, which are prone to recall bias. Other methods rely on features and functions only available in some GPS devices. Thus, a reliable and versatile method to objectively quantify time spent outdoors is needed. This study sought to develop a versatile method to classify indoor and outdoor (I/O) GPS data that can be widely applied using most types of GPS and accelerometer devices. To develop and test the method, five university students wore an accelerometer (ActiGraph wGT3X-BT) and a GPS device (Canmore GT-730FL-S) on an elastic belt at the right hip for two hours in June 2022 and logged their activity mode, setting, and start time via activity diaries. GPS trackers were set to collect data every 5 seconds. A rule-based point cluster-based method was developed to identify indoor, outdoor, and in-vehicle time. Point clusters were detected using an application called GPSAS_Destinations and classification were done in R using accelerometer lux, building footprint, and park location data. Classification results were compared with the submitted activity diaries for validation. A total of 7,006 points for all participants were used for I/O classification analyses. The overall I/O GPS classification accuracy rate was 89.58% (Kappa = 0.78), indicating good classification accuracy. This method provides reliable I/O clarification results and can be widely applied using most types of GPS and accelerometer devices.

Although PPP(Public-private partnership) mode has been applied for a long time in infrastructural project, the success rate is not very high. The sustainability of PPP projects is still influenced by many factors. In order to examine the evolutionary stable strategies (ESSs) of social capital, government, and paying consumers, a tripartite evolutionary game model is established in this work. In order to further promote consumer participation, it is necessary to make the assumption that customer oversight and review can have an impact on service prices. The results show: i)The strategy choice of consumer depends on the comparison between supervision cost of consumer and price coefficient for consumer to social capital. ii)Consumer supervision can promote the provision of high-quality services by social capital. iii)The difference between high-quality cost and low-quality cost, subsidy coefficient, price coefficient and supervision cost of consumer are critical factors influencing both evolutionary results and trajectories. This paper also puts forward policy implications for the three stakeholders to promote social capital's high-quality strategy so as to maintain the sustainability of PPP projects.

Background and objectiveAcute Kidney Injury (AKI) is a common and severe complication in patients diagnosed with sepsis. It is associated with higher mortality rates, prolonged hospital stays, increased utilization of medical resources, and financial burden on patients' families. This study aimed to establish and validate predictive models using machine learning algorithms to accurately predict the occurrence of AKI in patients diagnosed with sepsis.MethodsThis retrospective study utilized real observational data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. It included patients aged 18 to 90 years diagnosed with sepsis who were admitted to the ICU for the first time and had hospital stays exceeding 48 hours. Predictive models, employing various machine learning algorithms including Light Gradient Boosting Machine (LightGBM), EXtreme Gradient Boosting (XGBoost), Random Forest (RF), Decision Tree (DT), Artificial Neural Network (ANN), Support Vector Machine (SVM), and Logistic Regression (LR), were developed. The dataset was randomly divided into training and test sets at a ratio of 4:1.ResultsA total of 10,575 sepsis patients were included in the analysis, of whom 8,575 (81.1%) developed AKI during hospitalization. A selection of 47 variables was utilized for model construction. The models derived from LightGBM, XGBoost, RF, DT, ANN, SVM, and LR achieved AUCs of 0.801, 0.773, 0.772, 0.737, 0.720, 0.765, and 0.776, respectively. Among these models, LightGBM demonstrated the most superior predictive performance.ConclusionsThese machine learning models offer valuable predictive capabilities for identifying AKI in patients diagnosed with sepsis. The LightGBM model, with its superior predictive capability, could aid clinicians in early identification of high-risk patients.

In the era of rapid product iteration, companies need simple and effective methods to guide the entire process of product innovation design and enhance their product innovation capabilities. Most research focused on improving one or several steps in the product design process. Although some scholars have proposed methods that guided the entire process, they combined more than three different theories, which increased the difficulty of theoretical learning and the complexity of practical implementation. This paper proposed a product innovation design process composed of three theoretical methods: Kano, Axiomatic Design (AD), and Theory of the Solution of Inventive Problems (TRIZ). This new process guided the entire product design process with fewer theoretical methods, reducing the difficulty of learning and implementation. The paper demonstrated the effectiveness of this method through the design practice of a portable two-wheeled self-balancing vehicle. Additionally, the discussion section explored the method's potential from the design management perspective.

Accurate short-term load forecasting is of great significance in improving the dispatching efficiency of power grids, ensuring the safe and reliable operation of power grids, and guiding power systems to formulate reasonable production plans and reduce waste of resources. However, the traditional short-term load forecasting method has limited nonlinear mapping ability and weak generalization ability to unknown data, and it is prone to the loss of time series information, further suggesting that its forecasting accuracy can still be improved. This study presents a short-term power load forecasting method based on Bagging-stochastic configuration networks (SCNs). First, the missing values in the original data are filled with the average values. Second, the influencing factors, such as the weather- and week-type data, are coded. Then, combined with the data of influencing factors after coding, the Bagging-SCNs integration algorithm is used to predict the short-term load. Finally, by taking the daily load data of Quanzhou City, Zhejiang Province as an example, the program of the abovementioned method is compiled in Python language and then compared with the long short-term memory neural network algorithm and the single-SCNs algorithm. Simulation results show that the proposed method for medium- and short-term load forecasting has a high forecasting accuracy and a significant effect on improving the accuracy of load forecasting.

BackgroundWhether the etiology of chronic liver disease (CLD) impacts the overall survival (OS) of patients with hepatocellular carcinoma (HCC) remains unclear. We aim to clarify this issue.Materials and methodsBetween 2011 and 2020, 3941 patients who were newly diagnosed with HCC at our institution were enrolled in this study. In patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related > all negative. All negative was defined as negative for HCV, HBV, and alcohol use disorder.ResultsAmong 3941 patients, 1407 patients were classified with HCV-related HCC, 1677 patients had HBV-related HCC, 145 patients had alcohol-related HCC, and 712 patients had all-negative HCC. Using the all-negative group as the reference group, multivariate analysis showed that HBV is an independent predictor of mortality (hazard ratio: 0.856; 95% confidence interval: 0.745-0.983; p = 0.027). Patients with HBV-related HCC had superior OS compared with patients with other CLD etiologies (p 65 years (pConclusionPatients with HBV-related HCC had superior OS than patients with other HCC etiologies.

Currently, there have been very few reports within the literature which specifically address using fenestrated and branched stent grafts to completely isolate and repair distal entry tears of chronic DeBakey IIIb aortic dissection. This study aimed to evaluate the clinical outcomes of a 3-dimensional (3D) printed aortic model-guided fenestrated stent in the treatment of distal tears of chronic DeBakey IIIb aortic dissection after thoracic endovascular aortic repair (TEVAR). The study was a one-center retrospective study comprising 36 patients who underwent TEVAR and fenestrated endovascular abdominal aortic repair (F-EVAR) between April 2014 and December 2022. Patient data was compiled and analysed for preoperative, intraoperative, and perioperative characteristics. In total, 36 patients (12 females and 24 males) were incorporated into this study. All of the patients included in this study had hypertension, and among them, the leading cause for undergoing II-stage F-EVAR was the progression of a false lumen, accounting for 24 cases (66.7% of the total). The technical success rate was 97.2% and there were no cases of 30-day mortality, myocardial infarction, permanent paraparesis, or organ failure. One year post-F-EVAR treatment, surviving patients showed significant false and true lumen remodelling with 100% complete false-lumen thrombosis. A total of five patients died during the follow-up, two patients died related to aorta complications and three patients died of heart failure, multiple organ failure, or septic shock. II-stage F-EVAR was safe and feasible operation to repair all distal tears of chronic DeBakey IIIb aortic dissection.

Lung adenocarcinoma (LUAD) has a poor prognosis. Circadian genes such as TIMELESS have been associated with several pathologies, including cancer. The expression of TIMELESS and the relationship between TIMELESS, infiltration of tumors and prognosis in LUAD requires further investigation. In this study, we investigated the expression of TIMELESS and its association with survival across several types of human cancer using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Program. Noncoding RNAs (ncRNAs) regulating overexpression of TIMELESS in lung adenocarcinoma (LUAD) were explored with expression, correlation, and survival analyses. Immune cell infiltration and biomarkers were analyzed between different TIMELESS expression levels. The relationship between TIMELESS expression and immunophenoscores, which were used to predict response to immunotherapy, was evaluated. TIMELESS was identified as a potential oncogene in LUAD. NcRNA analysis showed MIR4435-2HG/hsa-miR-1-3p may interact with TIMELESS in a competitive endogenous RNA network in LUAD tumor tissues. Most immune cells were significantly decreased in TCGA LUAD tumor tissues with high TIMELESS expression except for CD4+T cells and Th2 cells. TIMELESS expression in LUAD tumor tissues was significantly negatively correlated with neutrophil biomarkers, dendritic cell biomarkers (HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, CD1C) and an immunophenoscore that predicted outcomes associated with the use of immune checkpoint inhibitors. These findings imply that ncRNAs-mediated TIMELESS overexpression in LUAD tumor tissues correlated with poor prognosis, reduced immune cell infiltration in the tumor microenvironment, and poor response to immune checkpoint inhibitors.

BackgroundTumor necrosis is a significant risk factor affecting patients' prognosis after liver resection (LR) for hepatocellular carcinoma (HCC). We aimed to develop a model with tumor necrosis as a variable to predict early tumor recurrence in HCC patients undergoing LR.Materials and methodsPatients who underwent LR between 2010 and 2018 for newly diagnosed HCC but did not receive neoadjuvant therapy were enrolled in this retrospective study. Six predictive factors based on pathological features-tumor size > 5 cm, multiple tumors, high-grade tumor differentiation, tumor necrosis, microvascular invasion, and cirrhosis-were chosen a priori based on clinical relevance to construct a multivariate logistic regression model. The variables were always retained in the model. The impact of each variable on early tumor recurrence within one year of LR was estimated and visualized using a nomogram. The nomogram's performance was evaluated using calibration plots with bootstrapping.ResultsEarly tumor recurrence was observed in 161 (21.3%) patients. The concordance index of the proposed nomogram was 0.722. The calibration plots showed good agreement between nomogram predictions and actual observations of early recurrence.ConclusionWe developed a nomogram incorporating tumor necrosis to predict early recurrence of HCC after LR. Its predictive accuracy is satisfactory.

IntroductionAccording to several studies, a specific dietary pattern can reduce the risk of dementia and cognitive impairment. However, the robustness of these results has not been tested. The study intends to investigate the association between nutrition intake and cognitive impairment in middle-aged and older adults (≥45-years) and provide reliable, evidence-based references for healthcare decision-makers, researchers, and policymakers.Review questionAre the dietary characteristics of community-dwelling adults (≥45-years) associated with the occurrence of cognitive impairment?ObjectivesThe primary objective of this protocol is to synthesize the longitudinal observational evidence on the relationship between nutrition intake patterns and the incidence of cognitive impairment in middle-aged and older adults (≥45-years), and to provide detailed dietary recommendations for the prevention of cognitive impairment in this population.Methods and analysisCohort studies conducted among adults (≥45-years) will be included. The following electronic databases will be searched for relevant records published by July 2023, with a restriction on language to English: Pubmed, Medline, Embase, Web of science, Cochrane Library. The studies will be selected, the data will be extracted, and the bias risk will be assessed by two independent investigators. The Meta-analysis of Observational Studies in Epidemiology guidelines will be followed to summarize observational studies, and the protocol will adhere to the recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. Endnote X9 will be used to manage data screening. We will use Review Manager 5.4 and Stata 16.0 to conduct data analysis, and a random-effects model will be applied to pool clinically homogenous studies. The results will be presented based on the form of nutrition intake. For assessing publication bias, Egger's test and visual inspection of funnel plots will be utilized.Ethics and disseminationAs this study does not involve primary data, ethical approval is not required. The final report will be published in a peer-reviewed journal.Prospero registration numberA registration number of DOI 10.17605/OSF.IO/NAKC3 was assigned to it on October 15, 2022 on Prospero.

There is a long-standing academic consensus that the higher the absorptive capacity of an organization is, the better its performance. Recently, however, the assumption that absorptive capacity can unconditionally contribute to firm performance has begun to be challenged, and empirical results differentiating absorptive capacity and firm performance have also begun to emerge. Therefore, to effectively integrate the variability of different empirical results and reveal the mechanism by which absorptive capacity acts on firm performance, this paper explores the relationship between absorptive capacity and firm performance from the perspectives of both theoretical exploration and META analysis. Through the process of theoretical combing, this paper finds that the existing core concept of absorptive capacity is based on cognitivism, and the existing process behind absorptive capacity is based on a linear cognitive information processing process that focuses on the internal cognitive structure and process of the subject. However, due to the dynamic and complex nature of social phenomena, the process model cannot effectively reflect the influence of contextual factors on their relationships. Next, based on the results of theoretical sorting, the results of existing empirical studies are synthesized by means of META analysis and different contexts are examined, finding that the role of absorptive capacity on firm performance has significant contextual characteristics, among which the research context, economic context and sample context all have significant but distinct moderating effects on absorptive capacity and firm performance. Overall, by including contextual factors, this paper further deepens the understanding of the relationship between absorptive capacity and firm performance. It also provides a preliminary basis for the role of contextual factors in absorptive capacity.

Background/objectiveTo determine the impact of microvascular invasion (MVI) on outcome in patients with solitary hepatocellular carcinoma (HCC) of ≤ 2 cm undergoing liver resection (LR).MethodsThis retrospective study enrolled consecutive patients between 2007-2019 with newly diagnosed solitary HCC ≤ 2 cm who were undergoing LR at our institution. Overall survival (OS) and recurrent-free survival (RFS) were compared between patients with or without MVI.ResultsOf the 229 patients included in this study, 71 had MVI. The median follow-up period was 28.8 months (interquartile range: 13.5-70.1). Although the 90-day mortality rate was 0, 18 deaths occurred during the study, and the 5-year survival rate was 87.1%. Tumor recurrence occurred in 45 cases, and 5-year RFS was 71.9%. The presence or absence of MVI did not significantly affect the OS and RFS rates (log rank test, p = 0.10 and 0.38, respectively). In univariate and multivariate analysis, the presence of MVI was not associated with OS and RFS.ConclusionThe presence of MVI was not associated with OS and RFS in patients with solitary HCC ≤ 2 cm who underwent LR in this cohort.

Ferroptosis is a cell death form that has been reported to be involved in the progression of gastric cancer (GC). However, the underlying mechanism of ferroptosis in GC still needs to be further explored. This study conducted a survey regarding the biological functions of ferroptosis-related gene AKR1C2 in GC. Multiple bioinformatic platforms were applied to indicate that the expression level of AKR1C2 was downregulated in GC tissues, which displayed good prognostic value. Clinical statistics proved that AKR1C2 expression was correlated with several tumor characteristics of GC patients, such as characteristics of N-stage tumor or residual tumor. Additionally, LinkedOmics was employed to explore the co-expression network and molecular pathways of AKR1C2 in GC. Eventually, AKR1C2 was found to be involved in several immune-related signatures, such as immunostimulators, immunoinhibitors, chemokines and chemokine receptors. To sum up, these results may provide a novel insight into the significance and biological functions of ferroptosis-related gene AKR1C2 in GC tumorigenesis.

Depth image-based rendering (DIBR) is an important technology in the process of 2D-to-3D conversion. It uses texture images and related depth maps to render virtual views. While there are still some challenging problems in the current DIBR systems, such as disocclusion occurrences. Inpainting methods based on deep learning have recently shown significant improvements and generated plausible images. However, most of these methods may not deal well with the disocclusion holes in the synthesized views, because on the one hand they only treat this issue as generative inpainting after 3D warping, rather than following the full DIBR processing procedures. While on the other hand the distributions of holes on the virtual views are always around the transition regions of foreground and background, which makes them more difficult to distinguish without special constraints. Motivated by these observations, this paper proposes a novel learning-based method for stereoscopic view synthesis, in which the disocclusion regions are restored by a progressive structure reconstruction strategy instead of direct texture inpainting. Additionally, some special cues in the synthesized scenes are further exploited as constraints for the network to alleviate hallucinated structure mixtures among different layers. Extensive empirical evaluations and comparisons validate the strengths of the proposed approach and demonstrate that the model is more suitable for stereoscopic synthesis in the 2D-to-3D conversion applications.

To estimate the incidence of foodborne gastroenteritis caused by nontyphoidal Salmonella enterica, Shigella, and Vibrio parahaemolyticus in China, population surveys and sentinel hospital surveillance were implemented in six provinces from July 2010 to July 2011, and a multiplier calculation model for the burden of disease was constructed. The multiplier for salmonellosis and V. parahaemolyticus gastroenteritis was estimated at 4,137 [95% confidence interval (CI) 2,320-5,663], and for shigellosis at 4,356 (95% CI 2,443-5,963). Annual incidence per 100,000 population was estimated as 245 (95% CI 138-336), 67 (95% CI 38-92), and 806 (95% CI 452-1,103) for foodborne salmonellosis, shigellosis, and V. parahaemolyticus gastroenteritis, respectively, indicating that foodborne infection caused by these three pathogens constitutes an important burden to the Chinese healthcare system. Continuous implementation of active surveillance of foodborne diseases, combined with multiplier models to estimate disease burden, makes it possible for us to better understand food safety status in China.

No previous research has examined cognitive-motor interference (CMI) repeatedly in patients with subacute stroke. This pilot study aimed to report on the changes over time in CMI in patients with stroke who have recently learned to walk with a cane. The assessment started as soon as the participants could walk independently with a quad cane, and was repeated up to six sessions as long as the cane was still used. The dual-tasking paradigm required participants to walk and perform continuous subtractions by 3s. Data were analyzed for 9 participants 33–127 days post-stroke. All 9 participants showed CMI in walking velocity at baseline and 8 of these showed improvement over time (Z = -2.547; p = 0.011). The improvement in CMI was associated with baseline dual-tasking performance (ρ = 0.600; p = 0.044), motor control ability (ρ = -0.695; p = 0.019), walking velocity (ρ = -0.767; p = 0.008), and functional mobility (ρ = 0.817; p = 0.004). All participants showed decrements in both tasks (mutual interference) at baseline, 1 evolved to decrements in walking velocity (cognitive-related motor interference), and 3 finally evolved to decrements in cognitive performance but increments in walking velocity (motor-priority tradeoff). In conclusion, during rehabilitation with cane walking in patients with subacute stroke, the dual-tasking paradigm revealed CMI and its improvements in the majority of participants. Greater improvement in CMI was moderately to strongly associated with worse baseline performance of many variables. The evolution of the CMI pattern over time provides novel information relevant to neurological recovery.

The construction of refuge spaces in rapidly urbanizing historic cities is a challenging task owing to their complex urban form, unique urban fabric, and historic preservation requirements. Refuge green space (RGS) is a green space that can serve as an emergency shelter in cities, providing a flexible means to increase the emergency shelter capacity for rapidly urbanized historic cities. After major earthquakes, spatial accessibility to GRSs is a critical planning strategy for disaster prevention and emergency response in historic cities. To match the RGS planning with the emergency service demand, we must examine the spatial disparity in access to existing RGSs. In this study, the urban area of Nanjing was selected as the target region to analyze the spatial disparity in access to RGSs using the Gaussian two-step floating catchment area method at four evacuation times (10, 20, 30, and 60 min). The results showed that the spatial accessibility exhibited clustering characteristics, where high-accessibility spaces were mainly distributed in the northern and southern regions of Nanjing. The increase in the evacuation time improved accessibility to RGSs, but the existing RGSs still could not sufficiently satisfy the emergency shelter needs of citizens. Based on the bivariate local Moran's I analysis of the RGS accessibility and population density, the spatial mismatch regions were dominant in the center of the urban area. These findings not only are expected to assist emergency planners by improving their strategic plans for emergency shelter investment in Nanjing and their ability to respond to catastrophic earthquakes, but also provide a strong reference for the construction of a safe environment in other rapidly developing historic cities that face earthquake threats.

Background Ischemic stroke (IS) is a complex polygenic disease with a strong genetic background. The relationship between the ANRIL (antisense non-coding RNA in the INK4 locus) in chromosome 9p21 region and IS has been reported across populations worldwide; however, these studies have yielded inconsistent results. The aim of this study is to clarify the types of single-nucleotide polymorphisms on the ANRIL locus associated with susceptibility to IS using meta-analysis and comprehensively assess the strength of the association. Methods Relevant studies were identified by comprehensive and systematic literature searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratios with corresponding 95% confidence intervals of combined analyses were calculated under three genetic models (allele frequency comparison, dominant model, and recessive model) using a random-effects or fixed-effects model. Heterogeneity was tested using the chi-square test based on the Cochran Q statistic and I2 metric, and subgroup analyses and a meta-regression model were used to explore sources of heterogeneity. The correction for multiple testing used the false discovery rate method proposed by Benjamini and Hochberg. The assessment of publication bias employed funnel plots and Egger’s test. Results We identified 25 studies (15 SNPs, involving a total of 11,527 cases and 12,216 controls maximum) and performed a meta-analysis. Eight SNPs (rs10757274, rs10757278, rs2383206, rs1333040, rs1333049, rs1537378, rs4977574, and rs1004638) in ANRIL were significantly associated with IS risk. Six of these SNPs (rs10757274, rs10757278, rs2383206, rs1333040, rs1537378, and rs4977574) had a significant relationship to the large artery atherosclerosis subtype of IS. Two SNPs (rs2383206 and rs4977574) were associated with IS mainly in Asians, and three SNPs (rs10757274, rs1333040, and rs1333049) were associated with susceptibility to IS mainly in Caucasians. Sensitivity analyses confirmed the reliability of the original results. Ethnicity and individual studies may be the main sources of heterogeneity in ANRIL. Conclusions Our results suggest that some single-nucleotide polymorphisms on the ANRIL locus may be associated with IS risk. Future studies with larger sample numbers are necessary to confirm this result. Additional functional analyses of causal effects of these polymorphisms on IS subtypes are also essential.

IntroductionHandwriting difficulty (HD) is a widely discussed issue. Previous researchers have revealed many valuable kinematics related to the handwriting performance. However, a clear understanding of the kinetics of handwriting performance in children with HD is still lacking. Therefore, this study investigated the writing performance of children with HD via a force acquisition pen (FAP), which detects the force applied from the digits and pen tip.MethodsData from 64 school-age children were divided into control (36 children without HD; mean age: 7.97 years) and HD (28 children with HD; mean age: 8.67 years) groups. The participants were asked to perform a tracing task using the FAP at their usual writing pace.ResultsCompared with the control group, the HD group had significantly less pen-tip force, an average amount of force (in-air) from all three digits, higher force variations (whole task) in the index finger, less force fluctuations with the index and middle fingers and a smaller force ratio.ConclusionThe findings of this study suggest that an understanding of the handwriting kinetics and the role of digits in handwriting may be crucial for further planning strategies for handwriting training for children with HD.

Path planning plays an essential role in mobile robot navigation, and the A* algorithm is one of the best-known path planning algorithms. However, the traditional A* algorithm has some limitations, such as slow planning speed, close to obstacles. In this paper, we propose an improved A*-based algorithm, called the EBS-A* algorithm, that introduces expansion distance, bidirectional search, and smoothing into path planning. The expansion distance means keeping an extra space from obstacles to improve path reliability by avoiding collisions. Bidirectional search is a strategy searching path from the start node and the goal node simultaneously. Smoothing improves path robustness by reducing the number of right-angle turns. In addition, simulation tests for the EBS-A* algorithm are performed, and the effectiveness of the proposed algorithm is verified by transferring it to a robot operating system (ROS). The experimental results show that compared with the traditional A* algorithm, the proposed algorithm improves the path planning efficiency by 278% and reduces the number of critical nodes by 91.89% and the number of right-angle turns by 100%.

As the rate of percutaneous coronary intervention increases, in-stent restenosis (ISR) has become a burden. Random forest (RF) could be superior to logistic regression (LR) for predicting ISR due to its robustness. We developed an RF model and compared its performance with the LR one for predicting ISR. We retrospectively included 1501 patients (age: 64.0 ± 10.3; male: 76.7%; ISR events: 279) who underwent coronary angiography at 9 to 18 months after implantation of 2nd generation drug-eluting stents. The data were randomly split into a pair of train and test datasets for model development and validation with 50 repeats. The predictive performance was assessed by the area under the curve (AUC) of the receiver operating characteristic (ROC). The RF models predicted ISR with larger AUC-ROCs of 0.829 ± 0.025 compared to 0.784 ± 0.027 of the LR models. The difference was statistically significant in 29 of the 50 repeats. The RF and LR models had similar sensitivity using the same cutoff threshold, but the specificity was significantly higher in the RF models, reducing 25% of the false positives. By removing the high leverage outliers, the LR models had comparable AUC-ROC to the RF models. Compared to the LR, the RF was more robust and significantly improved the performance for predicting ISR. It could cost-effectively identify patients with high ISR risk and help the clinical decision of coronary stenting.

Proper placement of suture anchors is an important step in Bankart repair as improper placement can lead to failure. Concern surrounding suture anchor placement inspired the use navigation systems in shoulder arthroscopy. We aimed to demonstrate the technological advantage of using the O-arm (Medtronic Navigation, Denver, CO, USA) image guidance system to provide real-time images during portal and anchor placements in shoulder arthroscopy. Consecutive patients (from July to October 2014) who were admitted for arthroscopic capsulolabral repair surgeries were included. Ten patients were randomly enrolled in the navigation group and 10 in the traditional group. The glenoid was divided into four zones, and the penetration rates in each zone were compared between the two groups. In zone III, the most inferior region of the glenoid, the penetration rate was 40.9% in the traditional group and 15.7% in the navigation group (P = 0.077), demonstrating a trend toward improved accuracy of anchor placement with the aid of the navigation system; however, this was not statistically significant. Average surgical time in the navigation and traditional groups was 177.6±40.2 and 117.7±17.6 mins, respectively. American Shoulder and Elbow Surgeons Shoulder Scores showed no difference before and 6 months after surgery. This pilot study showed a trend toward decreased penetration rate in O-arm-navigated capsulolabral repair surgeries and decreased risks of implant misplacement; however, possibly due to the small sample size, the difference was not statistically significant. Further large-scale studies are needed to confirm the possible benefit of the navigation system. Even with the use of navigation systems, there were still some penetrations in zone III of the glenoid. This penetration may be attributed to the micro-motion of the acromioclavicular joint. Although the navigation group showed a significant increase in surgical time, with improvements in instrument design, O-arm-navigated arthroscopy will gain popularity in clinical practice.

Feature selection (FS) can eliminate many redundant, irrelevant, and noisy features in high-dimensional data to improve machine learning or data mining models' prediction, classification, and computational performance. We proposed an improved whale optimization algorithm (IWOA) and improved k-nearest neighbors (IKNN) classifier approaches for feature selection (IWOAIKFS). Firstly, WOA is improved by using chaotic elite reverse individual, probability selection of skew distribution, nonlinear adjustment of control parameters and position correction strategy to enhance the search performance of the algorithm for feature subsets. Secondly, the sample similarity measurement criterion and weighted voting criterion based on the simulated annealing algorithm to solve the weight matrix M are proposed to improve the KNN classifier and improve the evaluation performance of the algorithm on feature subsets. The experimental results show: IWOA not only has better optimization performance when solving benchmark functions of different dimensions, but also when used with IKNN for feature selection, IWOAIKFS has better classification and robustness.

For better understanding the genetic diversity and phylogeny of the cultivated Salvia miltiorrhiza populations, four intergenic spacer sequences, ETS, psbA-trnH, trnL-trnF, and ycf1-rps15 of the 40 populations collected from China were Polymerase Chain Reaction (PCR) amplified, analyzed both individually and in combination. Haplotype diversity analysis showed that the cultivated S. miltiorrhiza populations had a very rich genetic diversity and an excellent capacity to resist environmental pressure. The best-fit nucleotide substitution models for ETS, psbA-trnH, trnL-trnF, ycf1-rps15, and their combined sequences were HKY+I, T92, T92, T92+G, and T92+G, respectively; the nucleotide conversion frequency in the combined sequences was lower than the transversion, and the relatively high nucleotide substitution frequencies suggests its high genetic variability. Neutral tests showed that the spacer sequences of the populations conform with the neutral evolution model, and there has been no current expansion events occurred. Phylogeny analyses based on both the individual and the combined sequences showed that the 40 populations were clustered in two clades with a very similar topological structure. The discrimination rate of the combined sequence marker is significantly increased to 52.5% (21 populations) over the highest 35% (13 populations) by the single marker of ETS, though still inadequate but a big step forward. Further exploration of more DNA markers is needed. This study for the first time revealed the rich genetic diversity and phylogeny of the currently cultivated S. miltiorrhiza populations in China and provides novel alternative molecular markers for the genetic identification and resources evaluation of the cultivated S. miltiorrhiza populations.

A service can be an intangible commodity in which no physical goods are transferred from the seller to the buyer. However, traditional trading platforms have many limitations in trading services due to dishonest buyers and brokers. In this paper, we propose a service trading ecosystem based on blockchain, named STEB, which combines blockchain, smart contract, encryption, and digital authentication techniques for service trading. In addition, a dual-chain architecture, which contains two types of blockchains, namely TraChain and SerChain, and a hierarchical encryption scheme of the data on the chain, are proposed to ensure the integrity of transaction data and fine-grained privacy protection of users. Furthermore, we describe a new set of smart contracts to ensure safe transactions for the entire service trading. Security analysis and simulation results confirm that the proposed STEB can achieve more efficient contract execution and enhance service transaction privacy.

Based on the modified gravity model, a spatial correlation network of innovation was constructed among cities in Guangdong, China. Social network analysis was employed to explore their evolution characteristics during 2009-2017. The results indicate that the innovation output of prefecture-level cities in Guangdong Province shows both spatial correlations and differences. Their network shows lower density, higher efficiency, and rigid stratification properties. Based on small cluster analysis, these cities are classified into four blocks, the members of which changed. In 2017, four well-defined subgroups formed, which are "bidirectional spillover plate", "main spillover plate", "net beneficial plate", and "agent plate". With this network, the geographical characteristics of the innovation capabilities and differences among the cities in Guangdong, as well as the different positions and roles of each city in the associated network, can be properly understood. Consequently, the transmission mechanisms and development strategies of innovation in Guangdong Province can be better explored.

In recent years, machine learning methods have been applied to various prediction scenarios in time-series data. However, some processing procedures such as cross-validation (CV) that rearrange the order of the longitudinal data might ruin the seriality and lead to a potentially biased outcome. Regarding this issue, a recent study investigated how different types of CV methods influence the predictive errors in conventional time-series data. Here, we examine a more complex distributed lag nonlinear model (DLNM), which has been widely used to assess the cumulative impacts of past exposures on the current health outcome. This research extends the DLNM into an artificial neural network (ANN) and investigates how the ANN model reacts to various CV schemes that result in different predictive biases. We also propose a newly designed permutation ratio to evaluate the performance of the CV in the ANN. This ratio mimics the concept of the R-square in conventional statistical regression models. The results show that as the complexity of the ANN increases, the predicted outcome becomes more stable, and the bias shows a decreasing trend. Among the different settings of hyperparameters, the novel strategy, Leave One Block Out Cross-Validation (LOBO-CV), demonstrated much better results, and the lowest mean square error was observed. The hyperparameters of the ANN trained by the LOBO-CV yielded the minimum number of prediction errors. The newly proposed permutation ratio indicates that LOBO-CV can contribute up to 34% of the prediction accuracy.

Currently, safety of laparoscopic pancreaticoduodenectomy (LPD) in patients with liver cirrhosis is unknown. The aim of this study was to explore postoperative morbidity and mortality and long-term outcomes of cirrhotic patients after LPD. The study was a one-center retrospective study comprising 353 patients who underwent LPD between October 2010 and December 2019. A total of 28 patients had liver cirrhosis and were paired with 56 non-cirrhotic counterparts through propensity score matching (PSM). Baseline data, intra-operative data, postoperative data, and survival data were collected. Postoperative morbidity was considered as primary outcome whereas postoperative mortality, surgical parameters (operative durations, intraoperative blood loss), and long-term overall survival were secondary outcomes. Cirrhotic patients showed postoperative complication rates of 82% compared with rates of patients in the control group (48%) (P = 0.003). Further, Clavien-Dindo ≥III complication rates of 14% and 11% (P = 0.634), Clavien-Dindo I-II complication rates of 68% and 38% (P = 0.009), hospital mortality of 4% and 2% (P = 0.613) were observed for cirrhotic patients and non-cirrhotic patients, respectively. In addition, an overall survival rate of 32 months and 34.5 months (P = 0.991), intraoperative blood loss of 300 (200-400) ml and 150 (100-250) ml (P

Background/aimsUndetectable HCV RNA 12 weeks after the end of treatment (SVR12) has been the valid efficacy endpoint in the era of direct-acting antivirals (DAAs). Its concordance with SVR4 and SVR24 and long-term durability is unknown in Taiwanese chronic hepatitis C (CHC) patients.MethodsA total of 1080 CHC patients who received all-oral DAAs and an achieved end-of-treatment virological response (EOTVR), defined as undetectable HCV RNA at the end of therapy, were consecutively enrolled. HCV RNA was monitored 4, 12, and 24 weeks after EOT. Patients who achieved SVR24, defined as undetectable HCV RNA 24 weeks after EOT, were followed annually for assessing SVR durability.ResultsEleven (1.02%) patients experienced HCV RNA reappearance after EOT. The most frequent timing of RNA reappearance was observed at SVR4 (n = 7), followed by SVR12 (n = 3) and SVR 24 (n = 1). The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 in predicting SVR12 were 99.7% and 100%, respectively, whereas the PPV and NPV of SVR12 in predicting SVR24 were 99.9% and 100%, respectively. Pyrosequencing confirmed delayed relapse rather than reinfection for the patient who had detectable HCV RNA at SVR24. Among 978 patients who achieved SVR24, after a median follow-up period of 17.3±8.2 months, the SVR durability is 100% up to a 4-year follow-up.ConclusionAchievement of SVR12 provides excellent durability of HCV seroclearance after DAA therapy. On-demand HCV RNA beyond SVR12 should be recommended for patients with unexplainable abnormal liver function or high-risk behaviors.

BackgroundMetformin is proposed to have chemopreventive effect of various cancer currently. However, the anti-cancer effect of metformin for diabetic patients with hepatocellular carcinoma (HCC) undergoing liver resection remains unclear. The aim of our cohort study was to assess whether metformin influence the recurrence of HCC.MethodsWe retrospectively enrolled 857 HCC patients who received primary resection from April 2001 to June 2016. 222 patients were diagnosed with diabetes mellitus (DM) from medical record. Factors influence the overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis.ResultsDuring the follow-up period (mean, 75 months), 471 (54.9%) patients experienced recurrence, and 158 (18.4%) patients died. Multivariate analysis revealed that DM (p = 0.015), elevated AST (p = 0.006), hypoalbuminemia (p = 0.003), tumor number (p = 0.001), tumor size (p < 0.001), vascular invasion (p 9% (p = 0.033), hypoalbuminemia (p = 0.030) and vascular invasion (p = 0.001) were independent risk factors for HCC recurrence; but the metformin use revealed no significance on recurrence. DM is a risk factor of HCC recurrence after resection. Adequate DM control can reduce the recurrence of HCC. However, the use of metformin does not reduce the risk of HCC recurrence in diabetic patient after initial resection. Hence, metformin may not have protective influences on HCC recurrence in diabetic patients who undergo initial liver resection.

The small LOV/F-box/Kelch family of E3 ubiquitin ligases plays an essential role in the regulation of plant circadian clocks and flowering time by sensing dusk. The family consists of three members, ZEITLUPE (ZTL), LOV KELCH PROTEIN 2 (LKP2), and FLAVIN-BINDING KELCH REPEAT F-BOX PROTEIN 1 (FKF1), which share a unique protein domain architecture allowing them to act as photoreceptors that transduce light signals via altering stability of target proteins. Despite intensive study of this protein family we still lack important knowledge about the biochemical and functional roles of the protein domains that comprise these unique photoreceptors. Here, we perform comparative analyses of transgenic lines constitutively expressing the photoreceptor LOV domain or the Kelch repeat protein-protein interaction domains of ZTL, FKF1, and LKP2. Expression of each domain alone is sufficient to disrupt circadian rhythms and flowering time, but each domain differs in the magnitude of effect. Immunoprecipitation followed by mass spectrometry with the ZTL Kelch repeat domain identified a suite of potential interacting partners. Furthermore, the ZTL Kelch repeat domain can interact with the ZTL homologs, LKP2 and FKF1, and the LOV domain of ZTL itself. This suggests a hypothesis that the Kelch repeat domain of ZTL may mediate inter- and intra-molecular interactions of the three LOV/F-box/Kelch proteins and provides added insight into the composition of the protein complexes and an additional role for the Kelch repeat domain.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that reduces lung and respiratory function, with a high mortality rate. Severe and acute deterioration of COPD can easily lead to respiratory failure, resulting in personal, social, and medical burden. Recent studies have shown a high correlation between the gut microbiota and lung inflammation. In this study, we investigated the relationship between gut microbiota and COPD severity. A total of 60 COPD patients with varying severity according to GOLD guidelines were enrolled in this study. DNA was extracted from patients' stool and 16S rRNA data analysis conducted using high-throughput sequencing followed by bioinformatics analysis. The richness of the gut microbiota was not associated with COPD severity. The gut microbiome is more similar in stage 1 and 2 COPD than stage 3+4 COPD. Fusobacterium and Aerococcus were more abundant in stage 3+4 COPD. Ruminococcaceae NK4A214 group and Lachnoclostridium were less abundant in stage 2-4, and Tyzzerella 4 and Dialister were less abundant in stage 1. However, the abundance of a Bacteroides was associated with blood eosinophils and lung function. This study suggests that no distinctive gut microbiota pattern is associated with the severity of COPD. The gut microbiome could affect COPD by gut inflammation shaping the host immune system.

Background and objectiveStroke is a major contributor to the global burden of disease. Although numerous modifiable risk factors (RF) for stroke have been identified, some remain unexplained. Increasing studies have investigated stroke risk in arthritis, but their results are inconsistent. We aimed to synthesize, quantify, and compare the risk of stroke for the major types of arthritis in cohort studies by using a systematic review and meta-analysis approach.MethodsWe searched Chinese and English databases to identify relevant studies from inception to April 30, 2020. Only studies adjusting at least for age and sex were included. We calculated pooled effect estimates for relative risk (RR) and 95% confidence interval (CI) and identified potential sources of heterogeneity and publication bias.ResultsA total of 1,348 articles were retrieved, and after an preliminary screening of titles and abstracts, 69 were reviewed for full text, and finally, 32 met the criteria for meta-analysis. Stroke risk in arthritis was significantly increased in studies adjusting for age and sex (RR = 1.36, 95% CI: 1.27-1.46) and for at least one traditional risk factor (RR = 1.40, 95% CI: 1.28-1.54). The results of studies stratified by stroke subtype were consistent with the main finding (ischemic stroke: RR = 1.53, 95% CI: 1.32-1.78; hemorrhagic stroke: RR = 1.45, 95% CI: 1.15-1.84). In subgroup analysis by arthritis type, stroke risk was significantly increased in rheumatoid arthritis (RR = 1.38, 95% CI: 1.29-1.48), ankylosing spondylitis (RR = 1.49, 95% CI: 1.25-1.77), psoriatic arthritis (RR = 1.33, 95% CI: 1.22-1.45), and gout (RR = 1.40, 95% CI: 1.13-1.73) but not osteoarthritis (RR = 1.03, 95% CI: 0.91-1.16). Age and sex subgroup analyses indicated that stroke risk was similar by sex (women: RR = 1.47, 95% CI: 1.31-1.66; men: RR = 1.44, 95% CI: 1.28-1.61); risk was higher with younger age (ConclusionsStroke risk was increased in multiple arthritis and similar between ischemic and hemorrhagic stroke. Young patients with arthritis had the highest risk.

Since the financial system has illustrated an increasingly prominent characteristic of inextricable connections, information theory is gradually utilized to study the financial system. By collecting the daily data of industry index (2005-2020) and region index (2012-2020) listed in China as samples, this paper applies an innovative measure named partial mutual information on mixed embedding to generate directed networks. Based on the analysis of nonlinear relationships among sectors, this paper realizes the accurate construction of "time-varying" financial network from the perspective of risk spillover. The results are presented as follow: (1) interactions can be better understood through the nonlinear networks among distinct sectors, and sectors in the networks could be classified into different types according to their topological properties connected to risk spillover; (2) in the rising stage, information is transmitted rapidly in the network, so the risk is fast diffused and absorbed; (3) in the declining stage, the network topology is more complex and panic sentiments have long term impact leading to more connections; (4) The US market, Japan market and Hongkong market have significant affect on China's market. The results suggest that this nonlinear measure is an effective approach to develop financial networks and explore the mechanism of risk spillover.

PurposeTo investigate any associations between cigarette smoking and retinal microvascular changes in diabetic patients without visible retinopathy.DesignRetrospective, cross-sectional study.Participants1099 eyes from 1099 diabetic patients with no clinical evidence of diabetic retinopathy (DR) were included in this study.MethodsDiabetic patients underwent optical coherence tomography angiography (OCTA) scanning at Zuckerberg San Francisco General Hospital and Trauma Center between April 2018 and September 2019. Patient demographic and clinical information was collected. Standard bivariate statistics and multivariate linear regression were performed.Main outcome measuresOCTA parameters included metrics related to the foveal avascular zone (FAZ; area, perimeter, circularity), perfusion density (PD; full, center, inner), and vessel length density (VLD; full, center, inner).ResultsThe study population included 750 non-smokers and 349 smokers. FAZ perimeter was the only OCTA parameter that was significantly different between the two groups on uncontrolled analysis (P = 0.033). Multivariate regression analyses revealed significant associations between lower VLD full (β = -0.31, P = 0.048), lower VLD inner (β = -0.35, P = 0.046) and a history of smoking. No significant associations between cigarette smoking and either FAZ or PD were detected.ConclusionsOur results suggest that smoking is likely associated with deleterious changes in the retinal microvasculature of patients with a history of diabetes and no visible DR. Based on these findings, diabetic patients with a history of smoking may benefit from higher prioritization in terms of ophthalmic screening.

PurposeAssociation of the neutrophil-to-lymphocyte ratio (NLR) with mortality has not been comprehensively explored in critical limb ischemia (CLI) patients. We investigated the association between the NLR and clinical outcomes in CLI.Materials and methodsWe retrospectively enrolled consecutive CLI patients between 1/1/2013 and 12/31/2018. Receiver operating characteristic curve analysis determined NLR cutoffs for 1-year in-hospital, all-cause and cardiac-related mortality; major adverse cardiovascular events (MACEs); and major adverse limb events (MALEs).ResultsAmong 195 patients (age, 74.0 years, SD: 11.5; 51.8% male; body mass index, 23.4 kg/m2, SD: 4.2), 14.4% exhibited acute limb ischemia. After 1 year, patients with NLR>8 had higher in-hospital mortality (21.1% vs. 3.6%, PConclusionCLI patients with high NLRs had significantly higher risks of 1-year all-cause and cardiac-related mortality and MALEs. The NLR can be used for prognostic prediction in these patients.

Developing countries need a large number of social infrastructure projects (e.g. schools, medical care, nursing homes). But the government's finance to invest in these projects is limited. By using the public-private partnership (PPP) mode to attract social capital to invest in PPP projects, it can relieve the financial pressure and improve the operation efficiency. The cooperation between government and consumer can ensure the sustainable development of the project operation. A system dynamics model of tripartite evolutionary game is developed to analyze the interaction of participant's strategies and simulate the corresponding evolution process. We employ the scenario analysis method to investigate the impact of the key parameters in relation with PPP projects based on realistic scenario assumptions. The results reveal the effect of some policies including reverse effect, blocking effect and over-reliance effect. Specifically, the results show that high penalty can prevent social capital from providing low-quality services, the low cost of government regulation can promote social capital to provide high-quality services, compensation to consumer can increase the enthusiasm of consumer participating in supervision, appropriate difference between price and cost of high-quality service as social capital's profit can encourage social capital to provide high-quality service. These policy suggestions will contribute to the sustainable development of social infrastructures in PPP mode.

For staged multi-cluster fracturing, methods for controlling perforation friction to adjust the flow distribution of each cluster can effectively promote the uniform extension of multiple fractures but lacks a fast and quantitative optimization method for different perforation parameters of each cluster. By establishing a numerical model of single-stage three-cluster flow-limited fracturing under stress-seepage coupling, and based on the response surface optimization method, fully considering the impact of perforation parameters interaction among three perforation clusters, according to the regression equation fitted under the global response, the rapid optimization of perforation parameters of segmented multi-cluster fracturing model is realized. The results show that: in determining the three factors of the study, it is found that there is an obvious interaction between the number of intermediate cluster perforations and the number of cluster perforations on both sides, the number of cluster perforations on both sides and the diameter of intermediate cluster perforations, the response surface optimization method gives the optimal perforation parameter combination of three clusters of fractures under global response; When the perforation parameters were combined before optimization, the fracture length difference was 32.550m, and the intermediate perforation cluster evolved into invalid perforation cluster, when the perforation parameters were combined after optimization, the fracture length difference was 0.528m, the three perforation clusters spread uniformly, and there are no invalid clusters. At the same time, the regression equation under the response is optimized before and after the comparison between the predicted value of the equation and the actual simulation value. It is found that the estimated deviation rate of the equation before optimization is 1.2%, and the estimated deviation rate after optimization is 0.4%. The estimated deviation rates are all less, and the response regression equation based on the response surface optimization method can quickly optimize the perforation parameters. The response surface optimization method is suitable for the multi parameter optimization research of formation fracturing which is often affected by many geological and engineering factors. Combining with the engineering practice and integrating more factors to optimize the hydraulic fracturing parameters, it is of great significance to improve the success rate of hydraulic fracturing application.

MicroRNAs (miRNAs) are important molecules that mediate virus-host interactions, mainly by regulating gene expression via gene silencing. Here, we demonstrated that HIV-1 infection upregulated miR-210-5p in HIV-1-inoculated cell lines and in the serum of HIV-1-infected individuals. Luciferase reporter assays and western blotting confirmed that a target protein of miR-210-5p, TGIF2, is regulated by HIV-1 infection. Furthermore, HIV-1 Vpr protein induced miR-210-5p expression. The use of a miR-210-5p inhibitor and TGIF2 overexpression showed that Vpr upregulated miR-210-5p and thereby downregulated TGIF2, which might be one of the mechanisms used by Vpr to induce G2 arrest. Moreover, we identified a transcription factor, NF-κB p50, which upregulated miR-210-5p in response to Vpr protein. In conclusion, we identified a mechanism whereby miR-210-5p, which is induced upon HIV-1 infection, targets TGIF2. This pathway was initiated by Vpr protein activating NF-κB p50, which promoted G2 arrest. These alterations orchestrated by miRNA provide new evidence on how HIV-1 interacts with its host during infection and increase our understanding of the mechanism by which Vpr regulates the cell cycle.