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RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case–control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10–14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.

Opioid use disorder is a chronic brain disease influenced by genetic and epigenetic factors, accounting for approximately 50% of the liability. Adrenergic signaling is involved in opioid use disorder. To demonstrate the associations between methylation alterations in the alpha-1-adrenergic receptor (ADRA1A) gene and opioid use disorder, in the present study, we first examined and compared the methylation levels of 97 CpG sites in the promoter region of the ADRA1A gene in the peripheral blood in 120 patients with heroin use disorder and 111 healthy controls. Correlations between methylation levels and duration of heroin/methadone use were then analyzed. Finally, the predicted binding transcription factors (TFs) and their target sequences in the promoter region of the ADRA1A gene, which include the selected CpG sites, were screened in the JASPAR database. Our results demonstrated that hypermethylation in the promoter region of the ADRA1A gene in the blood was associated with opioid use disorder. Correlations between methylation levels of several CpG sites and duration of heroin/methadone use were observed. TFs TFAP2A and RUNX1 were predicted to bind to the target sequences, which include the CpG sites selected in the current study, in the promoter region of the ADRA1A gene. Our findings further extend the associations between methylation alterations in the ADRA1A gene and opioid use disorder potentially through mechanisms of gene expression regulations in the ADRA1A gene.

We incorporated intergenerational digital communication (frequency of texting, video call, and social media interaction) into the intergenerational solidarity paradigm and identified new types of intergenerational and digital solidarity with adult children among older parents during the COVID-19 pandemic. In addition, we examined whether those types are associated with older parents’ mental health (depressive symptoms, psychological well-being, and self-esteem). We used the 2021/2022 wave of the Longitudinal Study of Generations (LSOG), and a sample of 519 older parents (mean age = 69 years). Latent class analysis identified four classes describing intergenerational and digital solidarity with adult children (distant-but-digitally connected, tight-knit-traditional, detached, and ambivalent). We found that older parents who had distant-but-digitally connected and tight-knit-traditional relationships with their adult children reported better mental health, compared to those who had detached and ambivalent relationships with their adult children during the COVID-19 pandemic. Our findings suggest that intergenerational digital communication should be considered as a digital solidarity in intergenerational solidarity paradigm, which is useful for measuring multidimension of intergenerational relationships within family members during and after the pandemic.

Several recent publications have revealed that obsessive-compulsive disorder (OCD) patients were adversely affected during coronavirus disease 2019 (COVID-19); however, how long this negative impact will last is unclear. Our study aimed to investigate the impact of the COVID-19 pandemic on OCD patients after one year. Online questionnaires were administered, and clinical interviews were conducted to assess OCD symptoms, depression, anxiety, information about COVID-19 and mental resilience at baseline (1 December 2019-1 January 2020), during early COVID-19 (26 February-25 March 2020) and at the one-year follow-up (26 February-25 March 2021). A total of 110 OCD patients were enrolled. Our findings showed that OCD, depressive and anxiety symptoms worsened during early COVID-19, and the negative impact persisted at the one-year follow-up. Multivariate analysis showed that female gender, concern about COVID-19 and OCD symptom severity at baseline were risk factors for exacerbation of OCD symptoms during early COVID-19, while optimism, as one composite factor of resilience, was a protective factor against exacerbation of OCD symptoms both during early COVID-19 and at follow-up. Our study showed that COVID-19 had immediate and long-term impacts on the exacerbation of OCD symptoms, and interventions targeted at improving resilience are recommended.

Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Results In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder and in non-smoking controls. We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. To investigate the function of cannabis use-associated microbiome, mice were orally exposured to Actinomyces. meyeri, Actinomyces. odontolyticus, or Neisseria. elongate through oral gavage twice per week for six months which mimics human conditions. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bactreria, decreased global activity and increased β-amyloid 42 protein production in the mouse brains. Conclusions This is the first study to reveal that cannabis-associated enrichment of Actinomyces meyeri may contribute to a hallmark of neuropathology.

In this paper, we prove an optimal three-ball inequality for bi-Laplace equation in some open, connected set. The derivation of such estimate relies on a delicate Carleman estimate for the bi-Laplace equation and some Caccioppoli inequalities to estimate the lower-ters. Based on three -ball inequality, we then derive the vanishing order of solutions, which is a quantitative version of the strong unique continuation property.

People infected with chronic hepatitis B virus (HBV) might progress to acute-on-chronic liver failure (ACLF) with a high fatality rate. Long noncoding RNAs (lncRNAs) are involved in human diseases, but it is unknown whether lncRNAs are involved in the progression of chronic HBV infection to ACLF. Hence, this study is aimed at systemically identifying and characterizing the landscape and the molecular mechanism of lncRNAs in the pathogenesis of chronic HBV infection progress to ACLF. RNA sequencing (RNA-Seq) of peripheral blood samples from 5 ACLF and 5 HBV infection patients was performed. We detected 9733 lncRNAs, including 406 annotated lncRNAs and 9327 novel lncRNAs. A total of 407 lncRNAs were found to be significantly dysregulated in the patients with ACLF as compared with those in the chronic HBV infection patients. The flanking protein-coding genes of differentially expressed lncRNAs were enriched with pathways that might contribute to the pathogenesis of ACLF, such as the WNT signaling pathway. Furthermore, 9 selected differentially expressed lncRNAs validated by the qRT-PCR, showing that the expression patterns of these 9 lncRNAs were consistent with the RNA-Seq data. Four selected differentially expressed lncRNAs were also validated in another patient cohort comprising 80 patients with ACLF and 65 patients with chronic HBV infection. Aberrant lncRNAs might be used to develop novel diagnostic biomarkers or drug targets for ACLF.

Cardiac ischemia–reperfusion (I/R) injury is a pathological process resulting in cardiomyocyte death. The present study aims to evaluate the role of the long noncoding RNA Cardiac Injury-Related Bclaf1-Inhibiting LncRNA (lncCIRBIL) on cardiac I/R injury and delineate its mechanism of action. The level of lncCIRBIL is reduced in I/R hearts. Cardiomyocyte-specific transgenic overexpression of lncCIRBIL reduces infarct area following I/R injury. Knockout of lncCIRBIL in mice exacerbates cardiac I/R injury. Qualitatively, the same results are observed in vitro. LncCIRBIL directly binds to BCL2-associated transcription factor 1 (Bclaf1), to inhibit its nuclear translocation. Cardiomyocyte-specific transgenic overexpression of Bclaf1 worsens, while partial knockout of Bclaf1 mitigates cardiac I/R injury. Meanwhile, partial knockout of Bclaf1 abrogates the detrimental effects of lncCIRBIL knockout on cardiac I/R injury. Collectively, the protective effect of lncCIRBIL on I/R injury is accomplished by inhibiting the nuclear translocation of Bclaf1. LncCIRBIL and Bclaf1 are potential therapeutic targets for ischemic cardiac disease., Cardiac ischemia–reperfusion (I/R) injury represents a key threat to human health. This study reveals that the long noncoding RNA lncRNA-CIRBIL is protective against I/R injury by inhibiting the nuclear translocation of Bclaf1.

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has progressed to a pandemic associated with substantial morbidity and mortality. The WHO and the United States Center for Disease Control and Prevention (CDC) have issued interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19), but there is limited data on the virologic and clinical characteristics for prognosis of severe COVID-19.MethodsA total of 50 patients with severe COVID-19 were divided into good and poor recovery groups. The dynamic viral shedding and serological characteristics of SARS-CoV-2 were explored. The risk factors associated with poor recovery and lung lesion resolutions were identified. In addition, the potential relationships among the viral shedding, the pro-inflammatory response, and lung lesion evolutions were characterized.ResultsA total of 58% of the patients had poor recovery and were more likely to have a prolonged interval of viral shedding. The longest viral shedding was 57 days after symptom onset. Older age, hyperlipemia, hypoproteinemia, corticosteroid therapy, consolidation on chest computed-tomography (CT), and prolonged SARS-CoV-2 IgM positive were all associated with poor recovery. Additionally, the odds of impaired lung lesion resolutions were higher in patients with hypoproteinemia, hyperlipemia, and elevated levels of IL-4 and ferritin. Finally, viral shedding and proinflammatory responses were closely correlated with lung lesion evolutions on chest CT.ConclusionsPatients with severe COVID-19 have prolonged SARS-CoV-2 infection and delayed intermittent viral shedding. Older age, hyperlipemia, hypoproteinemia, corticosteroid usage, and prolonged SARS-CoV-2 IgM positive might be utilized as predicative factors for the patients with poor recovery.

Objectives The current study aimed to investigate the mechanism by which exosomes secreted by CHB patients with PNALT and liver inflammation grade (≥A2) affected the development of liver cancer. Materials and methods Gene expression was assessed by RT‐PCR, Western blotting and immunohistochemistry. CCK‐8, colony formation, transwell, scratch‐wound and flow cytometry assays were used to detect cell viability, proliferation, apoptosis and metastasis. The interaction of TCF21 and HHIP was assessed by co‐immunoprecipitation assay. Luciferase reporter was used to detect the combination of TCF21/HHIP and miR‐25‐3p. Xenograft studies in nude mice manifested tumour growth ability of miR‐25‐3p. Bioinformatics analyses were conducted using TargetScan, EVmiRNA, TCGA, GEO, DAVID, COEXPEDIA, UALCAN, UCSC and the Human Protein Atlas databases. Results CHB‐PNALT‐Exo (≥A2) promoted the proliferation and metastasis of HepG2.2.15 cells. miR‐25‐3p was upregulated in CHB‐PNALT‐Exo (≥A2). miR‐25‐3p overexpression promoted cell proliferation and metastasis and was related to poor survival in patients with CHB‐PNALT (≥A2). The cell proliferation‐ and metastasis‐promoting functions of CHB‐PNALT‐Exo (≥A2) were abolished by miR‐25‐3p inhibitors. TCF21 directly interacted with HHIP. Inhibition of TCF21 or HHIP promoted cell proliferation and metastasis. Knockdown of TCF21 or HHIP counteracted the effects of CHB‐PNALT‐Exo (≥A2) containing miR‐25‐3p inhibitor on cell proliferation, metastasis and the expression of Ki67, E‐cadherin and caspase‐3/‐9. Conclusions Transfer of miR‐25‐3p by CHB‐PNALT‐Exo promoted the development of liver cancer by inhibiting the co‐expression of TCF21 and HHIP.

Background. Kudiezi injection is a traditional Chinese medicine for acute cerebral infarction, but the exact mechanisms are poorly understood. Objective. To investigate the mechanisms of Kudiezi injection on the inflammatory response in the treatment of acute cerebral infarction. Methods. This was a prospective study of patients with acute cerebral infarction within 48 h of onset and treated between July 2012 and July 2016 at three hospitals in China. The patients were randomized to routine treatments (control group) versus routine treatments and Kudiezi injection (Kudiezi group). The National Institutes of Health Stroke Score was assessed on days 1, 3, 5, 7, and 14. The patients were tested for serum levels of pro- and anti-inflammatory cytokines (S100 calcium-binding protein B, neuron-specific enolase, interleukin-6, interleukin-10, interleukin-18, and matrix metaloproteinase-9; by enzyme-linked immunosorbent assay) immediately after admission and on days 3, 5, and 14. Results. Stroke scores were improved in both groups from days 1 to 14. On days 5 and 7, stroke scores in the Kudiezi group were lower than in the control group (P<0.05). Compared with controls, the Kudiezi group had lower serum S100 calcium-binding protein B on day 14; higher interleukin-6 and interleukin-10 on day 3; lower interleukin-6 and interleukin-18 on day 5; and lower interleukin-18 and matrix metaloproteinase-9 on day 14. Conclusion. Kudiezi injection could lead to early reduction of interleukin-6, interleukin-18, matrix metaloproteinase-9, neuron-specific enolase, and S100 calcium-binding protein B levels and increases of interleukin-10 levels in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov NCT01636154.

Due to the strong nonlinear perturbations near the libration points, the continuous low-thrust technique has many potential applications in stationkeeping relative motions. The Hamiltonian structure-preserving (HSP) control is employed in this paper to stabilize formation flying on quasi-periodic orbits near L L 1 of the restricted Sun–Earth–Moon–spacecraft system. In the bi-circular model (BCM), a multiple shooting corrector is developed to refine quasi-periodic orbits as the chief spacecraft's reference trajectories. The linearized variation equation in BCM is used to design the stationkeeping control. A HSP controller is constructed to change the topology of the equilibrium from hyperbolic to elliptic using only relative position feedbacks consisting of stable, unstable and center manifolds. The critical control gains for transient and long-term stabilities are presented to guide the selection of control gains.

Currently, a tremendous amount of space debris in Earth’s orbit imperils operational spacecraft. It is essential to undertake risk assessments of collisions and predict dangerous encounters in space. However, collision predictions for an enormous amount of space debris give rise to large-scale computations. In this paper, a parallel algorithm is established on the Compute Unified Device Architecture (CUDA) platform of NVIDIA Corporation for collision prediction. According to the parallel structure of NVIDIA graphics processors, a block decomposition strategy is adopted in the algorithm. Space debris is divided into batches, and the computation and data transfer operations of adjacent batches overlap. As a consequence, the latency to access shared memory during the entire computing process is significantly reduced, and a higher computing speed is reached. Theoretically, a simulation of collision prediction for space debris of any amount and for any time span can be executed. To verify this algorithm, a simulation example including 1382 pieces of debris, whose operational time scales vary from 1 min to 3 days, is conducted on Tesla C2075 of NVIDIA. The simulation results demonstrate that with the same computational accuracy as that of a CPU, the computing speed of the parallel algorithm on a GPU is 30 times that on a CPU. Based on this algorithm, collision prediction of over 150 Chinese spacecraft for a time span of 3 days can be completed in less than 3 h on a single computer, which meets the timeliness requirement of the initial screening task. Furthermore, the algorithm can be adapted for multiple tasks, including particle filtration, constellation design, and Monte-Carlo simulation of an orbital computation.

Accumulating studies assessing the impacts of hot spot mutations on conventional interferon (IFN) efficacy come to discrepant conclusions; studies regarding the mutations in S and RT regions are also unclear. The present study aimed to evaluate the impacts of HBV mutations on the efficacy of conventional IFN.A total of 126 patients who received conventional IFN treatment for 48 weeks were enrolled. Biochemical and serological parameters were routinely tested. The sequences of HBV from 78 serum samples were amplified by nested-PCR; mutations were identified with sequence scanner V1.0 after ABI 3730xl direct sequencing, HBV genotypes were determined according to RT gene sequences utilizing NCBI Genotyping Tool which was based on phylogenetic analysis.The baseline DNA levels of virological response (VR) group were significantly lower than those of no VR group [7.13+/-0.76 vs 7.69+/-0.56 lg (copies/mL), P=0.001]. The baseline ALT levels were significantly higher in the HBeAg clearance group (204.72+/-88.65 vs 162.80+/-85.81 IU/L, P0.05) and HBeAg seroconversion group (204.89+/-95.68 vs 166.75+/-84.43 IU/L, P0.05). Females and lower BMI levels (20.01+/-2.33 vs 21.65+/-3.66 kg/m2, P0.05) were prone to acquired biochemical response (BR). PC-W28STOP (ntG1896A) was significantly higher in the combined response (CR) group than that in the no CR group (91.7% vs 39.7%, P=0.001). Multivariate logistic regression analysis showed that baseline DNA, PC-P159T (ntC2288A), BCP-N118T (ntA1726C) and BCP-L134L (ntA1775C/G/T) influenced VR independently. PC-G182C (ntG2357T), PC-S64A/T (ntT2003G/A) and BMI were independent influence factors for HBeAg clearance, HBeAg seroconversion and BR, respectively. The new predicting model concluded that baseline DNA and new mutations for VR were established successfully, and ROC analysis showed that AUC was 0.842 (P0.001) with a sensitivity of 0.652 and a specificity of 0.933.PC-P159T (ntC2288A), BCP-N118T (ntA1726C), BCP-L134L (ntA1775C/G/T), PC-G182C (ntG2357T) and PC-S64A/T (ntT2003G/A) were novel identified mutations that impacted IFN therapeutic efficacy. These novel mutations could serve as important predictors before conventional IFN treatment.

In living organisms, daily light/dark cycles profoundly affect cellular processes. In plants, optimal growth and development, and adaptation to daily light-dark cycles, require starch synthesis and turnover. However, the underlying molecular mechanisms coordinating daily starch metabolism remain poorly understood. To explore the roles of Arabidopsis thaliana light signal transduction proteins FAR-RED ELONGATED HYPOCOTYLS3 (FHY3) and FAR-RED-IMPAIRED RESPONSE1 (FAR1) in starch metabolism, the contents of starch and water-soluble polysaccharides, and the structure of starch granules were investigated in fhy3, far1 and fhy3 far1 mutant plants. Disruption of FHY3 or FAR1 reduced starch accumulation and altered starch granule structure in the fhy3-4, far1-2, and fhy3-4 far1-2 mutant plants. Furthermore, molecular and genetic evidence revealed that the gene encoding the starch-debranching enzyme ISOAMYLASE2 (ISA2) is a direct target of FHY3 and FAR1, and functions in light-induced starch synthesis. Our data establish the first molecular link between light signal transduction and starch synthesis, suggesting that the light-signaling proteins FHY3 and FAR1 influence starch synthesis and starch granule formation through transcriptional activation of ISA2.

To detect the levels of miR-146a and miR-155 in different samples from chronic hepatitis B (CHB), reveal whether there is a correlation between the 2 miRNAs in different samples, and to provide a theoretical basis for sample choice of miRNA research in liver. Methods: Real-time PCR was conducted to examine the expression of miR-146a and miR-155 in the plasma, peripheral blood mononuclear cell (PBMC), and liver tissues from 41 CHB patients who underwent nucleoside analogues antiviral therapy for 104 weeks. Correlations between the levels of miR-146a and miR-155 among the 3 samples were analyzed. Results: The expressions of miR-146a and miR-155 in the plasma, PBMC and liver tissues were significantly down-regulated at the 104th week than those at the baseline (all P0.05). There was a correlation in the expression of miR-146a between plasma and liver tissues (r=0.560, P=0.007), PBMC and liver tissues (r=0.428, P=0.047) at baseline. There was a correlation in the expression of miR-155 between plasma and liver tissue (r=0.587, P=0.004), PBMC and liver tissue (r=0.483, P=0.023) at baseline. The expressions of miR-146a and miR-155 between the plasma and PBMC were not correlated (P0.05). Conclusion: Compared with PBMC, miR-146a and miR-155 from plasma can better reflect the expression in the liver tissues, suggesting that plasma can be applied in the mechanism research on miR-146a and miR-155 in the liver diseases instead of liver tissues.目的：通过检测慢性乙型肝炎(chronic hepatitis B，CHB)患者不同来源标本中miR-146a和miR-155的表达，了解不同来源标本中2种miRNAs表达的相关性，为研究miRNA在肝病中的作用机制提供标本选择的理论依据。方法：采用real-time PCR对41例CHB患者核苷(酸)类似物抗病毒治疗基线期和第104周血浆、外周血单个核细胞和肝组织中miR-146a和miR-155的表达进行检测，分析3种来源标本中这2种miRNAs表达的相关性。结果：治疗第104周时血浆、外周血单个核细胞和肝组织miR-146a和miR-155的表达水平均较基线期显著下调(P0.05)。基线期血浆和肝组织(r=0.560，P=0.007)、外周血单个核细胞和肝组织(r=0.428，P=0.047)miR-146a的表达均相关。基线期血浆和肝组织(r=0.587，P=0.004)、外周血单个核细胞和肝组织(r=0.483，P=0.023)miR-155的表达相关，miR-146a和miR-155在血浆中的表达与外周血单个核细胞中的表达不相关(P0.05)。结论：与外周血单个核细胞相比，血浆中miR-146a和miR-155的表达能更好地反映和预测肝组织miR-146a和miR-155的表达，血浆可作为研究miR-146a和miR-155在肝病中作用机制的标本来源。.

Mesenchymal stem cells (MSCs) have potential ability to differentiate into osteocytes in response to in vitro specific induction. However, the molecular basis underlying this biological process remains largely unclear. In this study, we identify lncRNA HOTAIRM1 as a critical regulator to promote osteogenesis of MSCs. Loss of HOTAIRM1 significantly inhibits the calcium deposition and alkaline phosphatase activity of MSCs. Mechanistically, we find that HOTAIRM1 positively modulates the activity of JNK and c‐Jun, both of which are widely accepted as crucial regulators of osteogenic differentiation. More importantly, c‐Jun is found to be functionally involved in the regulation of RUNX2 expression, a master transcription factor of osteogenesis. In detail, c‐Jun can help recruit the acetyltransferase p300 to RUNX2 promoter, facilitating acetylation of histone 3 at K27 site, therefore epigenetically activating RUNX2 gene transcription. In summary, this study highlights the functional importance of HOTAIRM1 in regulation of osteogenesis, and we characterize HOTAIRM1 as a promising molecular target for bone tissue repair and regeneration.

An integrated algorithm to design the optimal ascent trajectory of a target Sun-synchronous orbit (SSO) for small-lift launch vehicles is studied in this paper. A general problem description is provided, including the specific pitch law designed for an ascent trajectory to SSO and the definitions of design variables and equality/inequality constraints. Then an integrated optimization scheme is introduced to solve this problem. In order to improve its efficiency, a preliminary determination method is to analytically generate two sensitive design variables related with the coast arc. With the help of the two design variables, an initial combination of design variables can be obtained by solving separately the optimization problems of two powered phases. Based on the predetermination method, an efficient integrated algorithm using hierarchical optimization is proposed. A simulation based on a type of small-lift Electron Rocket and Rutherford engine is performed using this hierarchical optimization algorithm and the feasibility and efficiency of this algorithm is evaluated. These systematic investigations on all the possible injected orbits give a full detail of launching capability for Electron Rocket.

Introduction: As the most reliable means of diagnosing hepatitis (HBV) infection and predicting the prognosis of HBV-related chronic liver disease, the COBAS AmpliPrep/COBAS TaqMan real-time polymerase chain reaction (PCR) (CAP/CTM) assay provides a highly sensitive and accurate method for quantifying HBV DNA. However, the high cost of the COBAS reagents is prohibitive in many developing countries. Thus, we compared the Sansure magnetic bead (Magb) assay, a novel technology developed by a Chinese company, with the CAP/CTM assay. Methodology: The reproducibility and sensitivity of the Sansure Magb assay were first validated using HBV DNA reference samples. Next, the quantitative results for the two assays using 635 blood samples collected from chronic hepatitis B patients and 10 healthy controls were compared. Results: The Sansure Magb assay showed high reproducibility and was at least as sensitive and specific as the CAP/CTM assay. Among the patient samples, 407 tested positive by both methods, with 386 (94.84%) showing quantitative differences of less than 1 log unit and 21 (5.16%) showing quantitative differences of between 1 and 2 log units. The results from the assays were closely correlated. Bland-Altman plot analysis showed that only 6.6% of the data points fell outside the 95% limits of agreement, which suggests that the differences between methods are clinically acceptable. Conclusions: This study demonstrates that the Sansure Magb assay is highly sensitive and reproducible. Based on its reduced cost, the Sansure Magb assay may be more applicable than the CAP/CTM assay for HBV diagnosis in developing countries such as China.

Current hepatitis C virus (HCV) genotyping techniques are often highly technical, costly, or need improvements in sensitivity and specificity. These limitations indicate the need of novel methods for HCV genotyping. The present study aimed to develop a novel genotyping method combining high-resolution melting (HRM) analysis with Bayes discriminant analysis (BDA). Target gene fragment including 5'-untranslated and core region was selected. Four or five inner amplicons for every serum were amplified using nested PCR, HRM was used to determine the melting temperature of the amplicons, and HCV genotypes were then analyzed utilizing BDA. In initial genotyping (HCV genotypes were classified into 1b, 2a, 3a, 3b, and 6a), both the overall accuracy rate and the cross-validation accuracy rate were 92.6 %, external validation accuracy rate was 95.0 %. To enhance the accuracy rate of genotyping, HCV genotypes were firstly classified into 1b, 3a, 3b, and 2a-6a, followed by a supplementary genotyping for 2a-6a. Both the overall accuracy rate and the cross-validation accuracy rate reached 97.5 %, and external validation accuracy rate was 100 %. Comparing adjusted HRM genotyping with type-specific probe technique, the difference in accuracy rates was not significant. However, the limit of detection and cost were lower for HRM. Comparing with sequencing, the limit detection of HRM was the same as the former, but the cost of HRM was lower. Hence, HRM combined with BDA was a novel method that equipped with superior accuracy, high sensitivity, and lower cost and therefore could be a better technique for HCV genotyping.

Objects The present study sought to analyze the long-time clinical outcomes of the stage IB1 cervical cancer patients who had received the radical vaginal trachelectomy (RVT) and laparoscopic lymphadenectomy after neoadjuvant chemotherapy (NACT). Method This is a prospective study of 60 patients potentially selected for RVT for a clinical and radiologic cervical cancer (stages IB 1) less than 2 cm. These patients were treated with surgery combined with preoperative NACT in the Department of Obstetrics and Gynecology, PLA General Hospital. We collected the patients' general clinical information, surgical characteristics and obstetric data, and then assessed their long-term oncological outcomes. Results The average operative time of the enrolled cases was 204 min and the average blood loss was 443 mL. The average postoperative hospitalization time was 10.6 days. The postoperative pathologic results indicated that the average parametrical width was 1.99 cm; the average length of removed of cervical was 2.6 cm; the average number of excised pelvic lymph node was 20. The median of the follow-up was 43 months (range between 13month and 12 years). Only one case of recurrence was found. Thus far, totally 42 women had tried to conceive, and 36 of them had live births. The live birth pregnancy rate was 86% (36/42). Conclusion The radical vaginal trachelectomy in combination with the laparoscopic lymphadenectomy surgical is a safe and effective therapeutic strategy for the for IB 1 cervical cancer.

The aim of the present study was to establish an ovarian cancer (OC) cell line from ascites of an ovarian serous cystadenocarcinoma patient and investigate the biological characteristics of its side population (SP) cells. The OC cell line was established by isolating, purifying and subculturing primary cells from ascites of an ovarian serous cystadenocarcinoma patient (stage IIIc; grade 3). SP and non-SP (NSP) cells were isolated by fluorescence-activated cell sorting and cultured in serum-free medium and soft agar to compare the tumorsphere and colony formation capacities. Furthermore, SP and NSP cell tumorigenesis was examined by subcutaneous and intraperitoneal injection of the cells to non-obese diabetic/severe combined immune deficiency (NOD/SCID) mice. Drug resistance to cisplatin was examined by cell counting kit-8. The OC cell line was successfully established from ascites of an ovarian serous cystadenocarcinoma patient, which exhibited properties similar to primary tumors subsequent to >50 passages and >2 years of culture. The SP cell ratio was 0.38% in the OC cell line, and a similar SP cell ratio (0.39%) was observed when sorted SP cells were cultured for 3 weeks. Compared with NSP cells, SP cells exhibited increased abilities in differentiation and tumorsphere and colony formation, in addition to the formation of xenografted tumors and ascites and metastasis of the tumors in NOD/SCID mice, even at low cell numbers (3.0×103 cells). The xenografted tumors demonstrated histological features similar to primary tumors and expressed the ovarian serous cystadenocarcinoma marker CA125. In addition, SP cells demonstrated a significantly stronger drug resistance to cisplatin compared with NSP and unsorted cells, while treatment with verapamil, an inhibitor of ATP-binding cassette transporters, potently abrogated SP cell drug resistance. In conclusion, the present study verified SP cells from an established OC cell line and characterized the cells with self-renewal, differentiation, proliferation, tumorigenesis and stronger drug resistance capacities.

In order to evaluate the highway maintenance enterprise synthetically and quantificationally, a safety evaluation indicator is established according to the impact conservation production safety factors in this paper. It can help the conservation and management departments to keep abreast of the conservation highway enterprise safety production dynamic and make the targeted safety measures. Lee scale is designed for expert scoring. Analytic hierarchy process (AHP) is adopted to select it. The indicator weights are ensured by AHP so as to establish highway maintenance safety production comprehensive evaluation system. By verifying the evaluated cases, this method can effectively improve the effectiveness and accuracy of the highway safety production. It has great significance for accelerating highway maintenance safety management system.

Close-proximity Coulomb formation flying offers attractive prospects in multiple astronautical missions. To achieve a deeper understanding of the dynamical structures of Coulomb formations, in this paper, an eight-charge symmetric configuration of Coulomb formation is presented and its dynamics is analyzed by center manifold reduction and Poincare maps. The Hamiltonian equations of motion for the Coulomb formation are derived on the basis of Clohessy–Wiltshire equations. Equilibrium configurations of the Coulomb formation and their corresponding linearized vector fields in different charging scenarios are studied. Nonlinear dynamics near the equilibrium points is investigated with center manifold reduction based on Lie series method. Poincare maps are employed to describe the bounded motions of the reduced Hamiltonian system. Numerical results indicate that there exist two families of Lyapunov periodic orbits, 1:1 and 1:2 resonance halo orbits, chaotic orbits, and two-dimensional invariant tori and the center manifold is capable of capturing all the dynamics in different charging scenarios.

To investigate expression profiles of the plasma exosomal miRNAs of the chronic hepatitis B (CHB) patients with persistently normal alamine aminotransferase (PNALT) for the first time and try to find exosomal miRNAs which could reflect liver inflammation better. Methods: Five CHB patients with liver tissue inflammation grade ≥A2 of PNALT and 5 CHB patients with liver tissue inflammation gradeA2 of PNALT were enrolled and their blood samples were collected. The exosomes were extracted from these blood samples and measured by electron microscope to determine the extraction effect. The exosomal miRNAs were extracted and sent for high throughput sequencing, and the expression of exosomal miRNAs in the 2 groups of patients was analyzed. Results: Under the electron microscope, exosomes were small membranous vesicles with 30-100 nm in diameter. The peak value of particle size ranged from 10 to 100 nm. High throughput sequencing showed that there were 591 differentially expressed exosomal miRNAs between the 2 groups. Compared with the control group, 18 exosomal miRNAs were up-regulated and 6 exosomal miRNAs were down-regulated in PNALT patients with the liver tissue inflammation grade≥A2. Conclusion: Exosomal miRNAs in the CHB patients with PNALT who have the different grades of liver inflammation are differently expressed. Some of the differently expressed exosomal miRNAs are expected to be sensitive biomarkers for timely assessment of liver inflammation in the CHB patients with PNALT.目的：通过分析持续丙氨酸氨基转移酶(alanine aminotransferase，ALT)正常的慢性乙型肝炎(以下简称慢乙肝)患者外泌体miRNAs的表达情况，试图找出更好反映肝组织炎症的外泌体miRNAs。方法：收集持续ALT正常并行肝活检的慢乙肝患者，选取肝组织炎症分级≥A2和A2的患者各5例，提取血浆外泌体并鉴定；提取外泌体miRNAs行高通量测序，比较两组患者的外泌体miRNAs表达情况。结果：扫描电镜示外泌体呈囊泡状，直径30~100 nm；粒径检测示其体积峰度集中在10~100 nm之间。高通量测序共筛出591个表达有差异的外泌体miRNAs，与对照组相比，肝组织炎症分级≥A2组有18个显著上调；6个显著下调。结论：对于肝组织炎症分级不同的持续ALT正常的慢乙肝患者，其外泌体miRNAs的表达有差异，某些外泌体miRNAs有望成为判断肝组织炎症的敏感生物学标志物。.

This paper is addressed to a stabilization problem of a system coupled by a wave and a Euler-Bernoulli plate equation. Only one equation is supposed to be damped. Under some assumption about the damping and the coupling terms, it is shown that sufficiently smooth solutions of the system decay logarithmically at infinity without any geometric conditions on the effective damping domain. The proofs of these decay results rely on the interpolation inequalities for the coupled elliptic-parabolic systems and make use of the estimate of the resolvent operator for the coupled system. The main tools to derive the desired interpolation inequalities are global Carleman estimates.

Objective Hepatitis B Virus (HBV) DNA integration and HBV X (HBx) deletion mutation occurs in HBV-positive liver cancer patients, and C-terminal deletion in HBx gene mutants are highly associated with hepatocarcinogenesis. Our previous study found that the HBx-d382 deletion mutant (deleted at nt 382–400) can down-regulate miR-338-3p expression in HBx-expressing cells. The aim of the present study is to examine the role of miR-338-3p in the HBx-d382-mediated liver-cell proliferation. Methods We established HBx-expressing LO2 cells by Lipofectamine 2000 transfection. A miR-338-3p mimics or inhibitor was transfected into LO2/HBx-d382 and LO2/HBx cells using miR-NC as a control miRNA. In silico analysis of potential miR-338-3p targets revealed that miR-338-3p could target the cell cycle regulatory protein CyclinD1. To confirm that CyclinD1 is negatively regulated by miR-338-3p, we constructed luciferase reporters with wild-type and mutated CyclinD1-3′UTR target sites for miR-338-3p binding. We examined the CyclinD1 expression by real-time PCR and western blot, and proliferation activity by flow cytometric cell cycle analysis, Edu incorporation, and soft agar colony. Results HBx-d382 exhibited enhanced proliferation and CyclinD1 expression in LO2 cells. miR-338-3p expression inhibited cell proliferation in LO2/HBx-d382 cells (and LO2/HBx cells), and also negatively regulated CyclinD1 protein expression. Of the two putative miR-338-3p binding sites in the CyclinD1-3′UTR region, the effect of miR-338-3p on the second binding site (nt 2397–2403) was required for the inhibition. Conclusion miR-338-3p can directly regulate CyclinD1 expression through binding to the CyclinD1-3′UTR region, mainly at nt 2397–2403. Down-regulation of miR-338-3p expression is required for liver cell proliferation in both LO2/HBx and LO2/HBx-d382 mutant cells, although the effect is more pronounced in LO2/HBx-d382 cells. Our study elucidated a novel mechanism, from a new miRNA-regulation perspective, underlying the propensity of HBx deletion mutants to induce hepatocarcinogenesis at a faster rate than HBx.

Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.

This paper investigates the Cauchy problem for an isentropic magnetogasdynamic system. Under certain reasonable hypotheses on the initial data, we obtain the global existence and uniqueness of the C 1 solution to the system. Meanwhile, when the hypotheses on the initial data do not hold, we obtain the blow-up phenomena of the C 1 solution to the system. The bounds of the solution are shown to depend on the parameter ν, which characterizes a one-dimensional plane flow ( ν = 0 ) or a three-dimensional cylindrically symmetric flow ( ν = 1 ); it is shown that the existence of the finite time singularity is significantly influenced by the magnetic field strength present in the flow along with the initial data.

This paper is devoted to study decay properties of solutions to hyperbolic equations in a bounded domain with two types of dissipative mechanisms, i.e. either with a small boundary or an internal damping. Both of the equations are equipped with the mixed boundary conditions. When the Geometric Control Condition on the dissipative region is not satisfied, we show that sufficiently smooth solutions to the equations decay logarithmically, under sharp regularity assumptions on the coefficients, the damping and the boundary of the domain involved in the equations. Our decay results rely on an analysis of the size of resolvent operators for hyperbolic equations on the imaginary axis. To derive this kind of resolvent estimates, we employ global Carleman estimates for elliptic equations with mixed boundary conditions.

Increasing evidence supports the significance of long non-coding RNA in cancer development. Several recent studies suggest the oncogenic activity of long non-coding RNA metastasis–associated lung adenocarcinoma transcript 1 (MALAT1) in hepatocellular carcinoma. In this study, we explored the molecular mechanisms by which MALAT1 modulates hepatocellular carcinoma biological behaviors. We found that microRNA-204 was significantly downregulated in sh-MALAT1 HepG2 cell and 15 hepatocellular carcinoma tissues by quantitative real-time polymerase chain reaction analysis. Through bioinformatic screening, luciferase reporter assay, RNA-binding protein immunoprecipitation, and RNA pull-down assay, we identified microRNA-204 as a potential interacting partner for MALAT1. Functionally, wound-healing and transwell assays revealed that microRNA-204 significantly inhibited the migration and invasion of hepatocellular carcinoma cells. Notably, sirtuin 1 was recognized as a direct downstream target of microRNA-204 in HepG2 cells. Moreover, si-SIRT1 significantly inhibited cell invasion and migration process. These data elucidated, by sponging and competitive binding to microRNA-204, MALAT1 releases the suppression on sirtuin 1, which in turn promotes hepatocellular carcinoma migration and invasion. This study reveals a novel mechanism by which MALAT1 stimulates hepatocellular carcinoma progression and justifies targeting metastasis–associated lung adenocarcinoma transcript 1 as a potential therapy for hepatocellular carcinoma.

With the rapid development of economy, early expressway in our country is facing with reconstruction and extension. The expressway alignment, as the skeleton of expressway, is an important guarantee for the safety of the vehicle driving. Therefore, road alignment evaluation is a major content in the extension of the expressway. In this paper, on the basis of evaluation method of expressway alignment, with the combination of domestic and foreign research experience, the expressway alignment is evaluated from three aspects: continuity, comfort and safety, and the alignment adaptability evaluation system is established through principal component analysis (PCA). At last, the applicability of the adaptability model is tested and verified for the alignment adaptability evaluation of Beijing Shijiazhuang expressway.

Background Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum miRNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF. Methods Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to 30 chronic asymptomatic HBV carriers as controls. The miRNAs expressions were measured by real-time quantitative PCR (q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed miRNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model. Results Real-time q-PCR indicated that serum miR-146a-5p, miR-122-3p and miR-328-3p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and miR-122-3p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+ − 1.72 × INR − 4.963 × gastrointestinal bleeding (Yes = 0; No = 1)−0.278 × (miR-122-3p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve (AUROC) was 0.847. Conclusions Expression levels of these miRNAs (miR-146a-5p, miR-122-3p and miR-328-3p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.

Based on a well-established theoretical foundation, Lagrangian Coherent Structures (LCSs) have elicited widespread research on the intrinsic structures of dynamical systems in many fields, including the field of astrodynamics. Although the application of LCSs in dynamical problems seems straightforward theoretically, its associated computational cost is prohibitive. We propose a block decomposition algorithm developed on Compute Unified Device Architecture (CUDA) platform for the computation of the LCSs of multi-body gravitational regimes. In order to take advantage of GPU’s outstanding computing properties, such as Shared Memory, Constant Memory, and Zero-Copy, the algorithm utilizes a block decomposition strategy to facilitate computation of finite-time Lyapunov exponent (FTLE) fields of arbitrary size and timespan. Simulation results demonstrate that this GPU-based algorithm can satisfy double-precision accuracy requirements and greatly decrease the time needed to calculate final results, increasing speed by approximately 13 times. Additionally, this algorithm can be generalized to various large-scale computing problems, such as particle filters, constellation design, and Monte-Carlo simulation.

Though it is widely known that hepatitis B virus X protein (HBx) is involved in the progression of hepatocellular carcinoma (HCC), the underlying mechanisms are not entirely clear. In recent years, metastasis associated with lung adenocarcinoma transcript 1 (MALAT1), which is an oncogenic long non-coding RNA (lncRNA), has been proved to be associated with many kinds of tumors, including liver cancer. In this study, we demonstrated that MALAT1 was involved in the HBx-mediated hepatocarcinogenesis. Firstly, we found that expression of MALAT1 was strongly up-regulated in HCC tissues and was directly proportional to the expression of HBx. Moreover, in HBx transfected LO2 and HepG2 cells, MALAT1 was also up-regulated compared with non-transfected cells. Then, we observed up-regulated MALAT1 in HepG2 cells could promote cell invasion and migration, whereas knockdown of MALAT1 in HBx-expressing hepatic cells (HepG2-HBx) resulted in a markedly inhibition of cell invasion and migration both in vitro and in vivo. To further obtain a deeper understanding of the effect of MALAT1, we took latent transforming growth factor β-binding protein 3 (LTBP3) into account by using several assays such as RNA interference, luciferase, transwell and wound healing. Results showed that MALAT1 could promote tumor growth and metastasis by activating LTBP3, which could also be up-regulated by HBx. Meanwhile, the similar results were detected in nude mice. These findings could demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-MALAT1/LTBP3 axis, and may give a potential target for treatment of HCC.

Improving the cell penetration and enhancing the cell selectivity of drugs have been approved for overcoming the major drawbacks of chemotherapeutic agents: the toxicity to normal cells and the drug resistance in tumors. In this paper, lysine dendrimers (G1-G3) were chosen as novel cell-penetrating carriers for anti-cancer drugs based on the internalization mechanism of cell-penetrating peptides and the characteristics of dendritic peptides. After labeling with fluorescein isothiocyanate (FITC), the cell-penetrable capacity of lysine dendrimers was certified by flow cytometric analysis. In a preliminary biological evaluation, the conjugates of lysine dendrimers and 5-fluorouracil showed the expected advantages: stable drug release, low toxicity to normal cells, and moderate inhibition of tumor cells. These results imply that cell-penetrable lysine dendrimers could be potential carriers in drug delivery of anti-cancer medicine.

AIM To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B. METHODS A total of 172 hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B patients who received initial treatment at 16 tertiary hospitals in Hunan Province, China were enrolled in this study. All patients received conventional doses of lamivudine and adefovir dipivoxil, telbivudine, entecavir dispersible tablets, or entecavir tablets for 96 wk. Patients who used other antiviral drugs or antitumor and immune regulation therapy were excluded. Patients were stratified into three groups according to their viral DNA load at 24 wk: < 10 IU/mL (group 1), 10-103 IU/mL (group 2), and > 103 IU/mL (group 3). Correlations of 24-wk DNA load with HBeAg negative status and HBeAg seroconversion at 96 wk were analyzed. Receiver operating characteristic curve analysis was used to test the predictive value of the HBV DNA load at 24 wk for long-term response. RESULTS The rates of conversion to HBeAg negative status and HBeAg seroconversion rates were 53.7% and 51.9%, respectively, in group 1; 35.21% and 32.39% in group 2; and 6.38% and 6.38% in group 3. The receiver operating characteristic curves for the three subgroups revealed that the lowest DNA load (< 10 IU/mL) was better correlated with response at 96 wk than a higher DNA load (10-103 IU/mL). Nested PCR was used for amplifying and sequencing viral DNA in patients with a viral DNA load > 200 IU/mL at 96 wk; resistance mutations involving different loci were present in 26 patients, and three of these patients had a viral DNA load 10-103 IU/mL at 96 wk. CONCLUSION Hepatitis B viral DNA load at 24 wk of antiviral treatment in patients with chronic hepatitis B is a predictor of the viral load and response rate at 96 wk.