Transporters are the main determinant for pharmacokinetics characteristics of drugs, such as absorption, distribution, and excretion of drugs in humans. However, it is difficult to perform drug ...transporter validation and structure analysis of membrane transporter proteins by experimental methods. Many studies have demonstrated that knowledge graphs (KG) could effectively excavate potential association information between different entities. To improve the effectiveness of drug discovery, a transporter-related KG was constructed in this study. Meanwhile, a predictive frame (AutoInt_KG) and a generative frame (MolGPT_KG) were established based on the heterogeneity information obtained from the transporter-related KG by the RESCAL model. Natural product Luteolin with known transporters was selected to verify the reliability of the AutoInt_KG frame, its ROC-AUC (1:1), ROC-AUC (1:10), PR-AUC (1:1), PR-AUC (1:10) are 0.91, 0.94, 0.91 and 0.78, respectively. Subsequently, the MolGPT_KG frame was constructed to implement efficient drug design based on transporter structure. The evaluation results showed that the MolGPT_KG could generate novel and valid molecules and that these molecules were further confirmed by molecular docking analysis. The docking results showed that they could bind to important amino acids at the active site of the target transporter. Our findings will provide rich information resources and guidance for the further development of the transporter-related drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Association of nasopharyngeal carcinoma (NPC) with lifelong residential exposures.•A population-based study of 2533 incident NPC cases and 2597 population controls.•Poorer residential conditions ...were associated with an increased risk of NPC.•Risk of NPC was stronger for residential exposures at an earlier age.•Risk of NPC increased with increasing duration of residential exposures.
Given the role of exposures related to residence in the development of nasopharyngeal carcinoma (NPC) has not been well explored, present study aims to investigate the magnitude and pattern of associations for NPC with lifelong residential exposures.
We carried out a multi-center, population-based case-control study with 2533 incident NPC cases and 2597 randomly selected population controls in southern China between 2010 and 2014. We performed multivariate logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of NPC associated with residential exposures.
Compared with those living in a building over lifetime, risk of NPC was higher for individuals living in a cottage (OR: 1.56; 95% CI: 1.34–1.81) or in a boat (3.87; 2.07–7.21). NPC risk was also increased in individuals using wood (1.34; 1.03–1.75), coal (1.70; 1.17–2.47), or kerosene (3.58; 1.75–7.36) vs. using gas/electricity as cooking fuel; using well water (1.57; 1.34–1.83), river water (1.80; 1.47–2.21), or spring/pond/stream water (2.03; 1.70–2.41) vs. tap water for source of drinking water; living in houses with smaller-sized vs. larger windows in the bedroom (3.08; 2.46–3.86), hall (1.89; 1.55–2.31) or kitchen (1.67; 1.34–2.08); and increasing exposure to cooking smoke (1.53; 1.20–1.94) for high exposure) or burned incense (1.59; 1.31–1.95) for daily use). Weighted Cox regression analysis corroborated these results.
Poorer residential conditions and household air pollution are associated with an increased risk of NPC. Large-scale studies in other populations or longitudinal studies are warranted to further corroborate these findings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
AbstractObjectiveTo evaluate the diagnostic accuracy and safety of using magnetically guided capsule endoscopy with a detachable string (ds-MCE) for detecting and grading oesophagogastric varices in ...adults with cirrhosis.DesignProspective multicentre diagnostic accuracy study.Setting14 medical centres in China.Participants607 adults (>18 years) with cirrhosis recruited between 7 January 2021 and 25 August 2022. Participants underwent ds-MCE (index test), followed by oesophagogastroduodenoscopy (OGD, reference test) within 48 hours. The participants were divided into development and validation cohorts in a ratio of 2:1.Main outcome measuresThe primary outcomes were the sensitivity and specificity of ds-MCE in detecting oesophagogastric varices compared with OGD. Secondary outcomes included the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices and the diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices.Resultsds-MCE and OGD examinations were completed in 582 (95.9%) of the 607 participants. Using OGD as the reference standard, ds-MCE had a sensitivity of 97.5% (95% confidence interval 95.5% to 98.7%) and specificity of 97.8% (94.4% to 99.1%) for detecting oesophagogastric varices (both P<0.001 compared with a prespecified 85% threshold). When using the optimal 18% threshold for luminal circumference of the oesophagus derived from the development cohort (n=393), the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices in the validation cohort (n=189) were 95.8% (89.7% to 98.4%) and 94.7% (88.2% to 97.7%), respectively. The diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices was 96.3% (92.6% to 98.2%), 96.9% (95.2% to 98.0%), and 96.7% (95.0% to 97.9%), respectively. Two serious adverse events occurred with OGD but none with ds-MCE.ConclusionThe findings of this study suggest that ds-MCE is a highly accurate and safe diagnostic tool for detecting and grading oesophagogastric varices and is a promising alternative to OGD for screening and surveillance of oesophagogastric varices in patients with cirrhosis.Trial registrationClinicalTrials.gov NCT03748563.
Challenged by the detection of trace amounts of mutants and disturbance from endogenous substances in clinical samples, herein, we present a novel electrochemical biosensor based on ligase chain ...reaction (eLCR) via the thermostable ligase with high mutation recognizing ability. The lengthened double-stranded DNAs exponentially generated via LCR were uniformly distributed on a bovine serum albumin-modified gold electrode, in which the phosphate buffer was tactfully added to remove adsorbed uninterested-probes, and thereafter the amperometry current was collected for the specific binding of streptavidin-poly-HRP and subsequent catalysis in the 3, 3′, 5, 5′-tetramethylbenzidine substrate that contained hydrogen peroxide. It found that, under optimized conditions, the proposed biosensor exhibited a high selectivity of mutant targets from the 104-fold excess of co-existent wild targets within a detection limit of 0.5 fM. Impressively, without the involvement of pre-PCR, the homozygous mutants were specifically distinguished from the wild genotype of CYP2C19*2 allele in human whole blood samples. Therefore, the proposed eLCR, due to its advantages in simple primer design, operational ease and ease of miniaturization, has demonstrated its considerable potential for point-of-care testing in the diagnosis of point mutation-related diseases and personalized medicine.
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•A new eLCR coupling the dsDNA-bovine serum albumin platform and HRP-H2O2-TMB system.•Effective removal of unwanted DNA probes' adsorption via phosphate buffer regulation.•High selectivity of mutants from the co-existent excessive wild targets (104-fold).•Successful discrimination of CYP2C19*2 allele in clinical samples without pre-PCR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNAs (miRNAs) have been found to play important regulatory roles in various physiological and pathological processes. MiRNAs also exhibit high stability and are present at high concentrations in ...human bodily fluids. Consequently, miRNAs may represent attractive and novel diagnostic biomarkers for certain clinical conditions. Recently, the capacity for extracellular vesicles, including microvesicles and exosomes, to carry miRNAs that participate in cell-to-cell communication has been described. In the present study, the miRNA expression patterns for three kinds of pleural effusions that were obtained from patients with pneumonia (group A), pulmonary tuberculosis (group B), and lung cancer (group C) were detected with high-throughput sequencing. When the expression levels of these miRNAs were compared among the three groups, three differentially expressed miRNAs were detected between groups A and B, while 27 differentially expressed miRNAs were detected between groups A and C. Notably, miR-378i was significantly elevated only in group B, while miR-205-5p and miR-200b were markedly increased only in group C (
p
< 0.01). Further studies are needed to confirm whether these differentially expressed miRNAs may serve as prospective diagnostic markers for pulmonary diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
The bonding ability of emulsified asphalt residue-aggregate interface is crucial for improving the pavement performance of emulsified asphalt mixtures. The aim of the study was to explore the ...adhesion mechanism and characteristics of emulsified asphalt residue-aggregate interface under the different emulsifier contents using molecular dynamics (MD) simulation. Firstly, the emulsified asphalt residue-aggregate interface model was established, and its validity was validated through the related thermodynamic properties. Secondly, the performance-related parameters were employed to discuss the molecular arrangement features of emulsified asphalt residue components on the aggregate surface, and investigate the interfacial adhesion mechanism. Thirdly, the adhesion strength of emulsified asphalt residue-aggregate interface was calculated and evaluated by the adhesion energy. Lastly, the influence of temperature and moisture on the interfacial adhesion strength was further examined through the molecular orientation theory and the electrostatic interaction theory. The results indicate that the addition of emulsifiers could affect the aggregation behaviors and distribution characteristics of asphalt components as observed from performance-related parameters. When compared to relatively high emulsifier content (4–6 %), the molecular arrangement of emulsified asphalt residue components with relatively low emulsifier content (1–3 %) is more similar to that of the base asphalt and exhibits greater interfacial adhesion strength with aggregates. The polar components and emulsifiers in emulsified asphalt residue with relatively low emulsifier content are minor affected by the increase of temperature, which further proving that interfacial adhesion strength is higher at this condition. Meanwhile, emulsified asphalt residue with relatively low emulsifier content is confirmed to have better moisture damage resistance due to the existence of the certain number of Silica-Water(S-W) and Asphalt-Water(A-W) hydrogen bonds near interface. Moisture exhibits more significant influence on the interfacial adhesion strength between emulsified asphalt residue and aggregates according to the results of the average adhesion energy. It is advisable to apply emulsified asphalt with moderate emulsifier content during the actual production process considering the influence of moisture and temperature on the pavement performance of emulsified asphalt mixtures.
•Double-layer model can be used to explore interfacial adhesion behaviors.•Performance-related parameters are effective to reflect interfacial adhesion mechanism.•Emulsifier content dramatically affects interfacial adhesion properties.•Emulsified asphalt-aggregate interface is more sensitive to moisture damage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Histone methylation is an epigenetic change mediated by histone methyltransferase, and has been connected to the beginning and progression of several diseases. The most common ailments that affect ...the elderly are cardiovascular and cerebrovascular disorders. They are the leading causes of death, and their incidence is linked to vascular calcification (VC). The key mechanism of VC is the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes, which is a highly adjustable process involving a variety of complex pathophysiological processes, such as metabolic abnormalities, apoptosis, oxidative stress and signalling pathways. Many researchers have investigated the mechanism of VC and related targets for the prevention and treatment of cardiovascular and cerebrovascular diseases. Their findings revealed that histone lysine methylation modification may play a key role in the various stages of VC. As a result, a thorough examination of the role and mechanism of lysine methylation modification in physiological and pathological states is critical, not only for identifying specific molecular markers of VC and new therapeutic targets, but also for directing the development of new related drugs. Finally, we provide this review to discover the association between histone methylation modification and VC, as well as diverse approaches with which to investigate the pathophysiology of VC and prospective treatment possibilities.
Background and Aim
Single‐nucleotide polymorphisms (SNPs) in long non‐coding RNAs (lncRNAs) are potential biomarkers for cancer risk, but their association with hepatocellular carcinoma (HCC) is ...unclear. We examined the association of lncRNA‐related SNPs with HCC susceptibility and explored the optimal genetic models for SNPs.
Methods
Five candidate SNPs linked with digestive tumors were first genotyped in a screening population of 700 HCC and 2800 control cases. The association between each SNP and HCC risk was estimated by multivariate logistic regression adjusted by sex and age and recorded as odds ratio (OR) with 95% confidence interval. Significant associations were further tested in a validation population with 1140 HCC and 5115 control cases. Finally, the most appropriate genetic models for HCC‐associated SNPs were identified using pairwise allele differences; the overall gene effects of each SNP were further evaluated based on optimal genetic models.
Results
Three candidate SNPs, rs7315438, rs6983267, and rs10795668, showed statistical connections with HCC risk in the discovery stage. Among these, rs7315438 remained steadily significant in the validation stage; rs7315438 and rs10795668 both reached statistical threshold in the combined analysis of both stages. SNP rs7315438 (TC vs TT/CC, OR = 1.410, P < 0.001) was associated with increased risk of HCC in a complete overdominant model, whereas rs10795668 (AG vs AA/GG, OR = 0.892, P = 0.035) exerted a protective effect on HCC risk in a complete overdominant model.
Conclusions
Long non‐coding RNA‐related SNPs rs7315438 and rs10795668 are potential biomarkers for HCC susceptibility, especially when evaluated based on their optimal genetic models.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In the ocean environment, the riserless mud recovery (RMR) system uses the return line as the return channel, resulting in the injection and return channels for the drilling fluid becoming two ...independent structures. Consequently, the RMR system exhibits different characteristics of circulating fluid temperature than conventional offshore drilling technology. To investigate this, a RMR system was divided into four simulation areas based on its structural characteristics, and a new transient simulation model was developed to simulate the circulating fluid temperature in each area. This study also explored the changing characteristics of the circulating fluid temperature under various sensitive factors, such as operating time, drilling fluid density, seawater depth, and pump rate, in both the time and space dimensions. Our results reveal that the transient simulation model developed is more suitable for simulating actual drilling situations than analytical solution models, and the simulation results are accurate. Furthermore, the distribution characteristics of circulating fluid temperature in the space dimension change with the operating time and drilling fluid density, but the trends and reasons for change vary between the two sensitive factors. Additionally, seawater depth mainly affects the circulating fluid temperature in each structure of the ocean environment when the RMR system is used for drilling in different sea areas, while its effect on the circulating fluid temperature in the formation environment structures is weak. Finally, pump rate mainly affects the circulating fluid temperature by changing its heat transfer time at a single space node, which is more remarkable than the frictional heat.
•The heat transfer characteristics of the circulating fluid in the RMR system are analyzed.•A new model for simulating the circulating fluid temperature in the RMR system is built.•The reliability of the new model has been verified through comparative analysis.•The changing characteristics of the circulating fluid temperature in RMR system are simulated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ovarian cancer (OC) is a severe malignancy featuring a poor prognosis due to rapid metastasis and chemotherapy resistance. In this study, we extensively investigated the upstream and downstream ...mechanisms of miR-548e in regulating OC progression and cisplatin resistance. Our results indicated that ZFAS1 was highly expressed and promoted OC cell proliferation, migration, invasion, and cisplatin resistance by directly suppressing miR-548e expression. ZFAS1 co-localized with miR-548e in the cytosols of OC cells. miR-548e repressed CXCR4 expression, and elevated CXCR4 expression promoted OC cell proliferation, migration, invasion, and cisplatin resistance. Cisplatin resistance induced by ZFAS1 and CXCR4 overexpression in OC cells was mediated by their suppression on let-7a and elevation of BCL-XL/S expression. ZFAS1 knockdown and miR-548e and let-7a overexpression impaired cisplatin resistance and suppressed lung metastatic nodule formation in nude mice. In conclusion, ZFAS1 binds with miR-548e to enhance CXCR4 expression to promote OC cell proliferation and metastasis, which also enhances cisplatin resistance by suppressing let-7a and elevating BCL-XL/S protein expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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