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Abstract Background CLDN is a core component of tight junctions (TJs). Abnormal expressions of CLDNs are commonly detected in various types of tumors. CLDNs are of interest as a potential therapeutic target. CLDNs are closely associated with most cancers of epithelial origin, especially when CLDN7 promotes cancer cell metastasis, such as in gastric, cervical, and ovarian cancers.Its expression and prognosis in breast cancer (BC) remain unknown.The purpose of this study was to investigate the expression pattern of CLDN7 and related immune factors in BC and shed light on a better therapeutic avenue for BC patients. Method The cBioPortal, GEPIA, and TCGA databases were used to comprehensively assess the expression of CLDN7 in BC. The Kaplan-Meier Plotter (KMP) database was applied to examine the relationship among the CLDN7 overexpression (OE), prognosis, and overall survival (OS) of BC patients. Immunohistochemical staining was performed on 92 BC tissue samples and 20 benign breast tumors to verify the expression level of CLDN-7 protein and its correlation with clinicopathological features and prognosis. TIMER2.0 was used to analyze the correlation between the CLDN7 OE and immune gene activation using BC-related transcriptomic data. Enrichment analyses of CLDN7-related immune pathways were conducted using online databases. The risk of expression of CLDN7-related immune genes was assessed and differentially expressed (DE) genes were included in the construction of the risk prognosis nomogram. Results Both database analysis and clinical sample validation results showed that CLDN7 was significantly overexpressed (OE) in BC, and the OE was correlated with poor DFS in BC patients (p

Abstract Accurate and reliable prediction of porosity forms the foundational basis for evaluating reservoir quality, which is essential for the systematic deployment of oil and gas exploration and development plans. When data quality of samples is low, and critical model parameters are typically determined through subjective experience, resulting in diminished accuracy and reliability of porosity prediction methods utilizing gated recurrent units (GRU), a committee-voting ensemble learning (EL) method, and an enhanced particle swarm optimization (PSO) algorithm are proposed to optimize the GRU-based porosity prediction model. Initially, outliers are eliminated through box plots and the min–max normalization is applied to enhance data quality. To address issues related to model accuracy and high training costs arising from dimensional complexity, substantial noise, and redundant information in logging data, a committee-voting EL strategy based on four feature selection algorithms is introduced. Following data preprocessing, this approach is employed to identify logging parameters highly correlated with porosity, thereby furnishing the most pertinent data samples for the GRU model, mitigating constraints imposed by single-feature selection methods. Second, an improved PSO algorithm is suggested to tackle challenges associated with low convergence accuracy stemming from random population initialization, alongside the absence of global optimal solutions due to overly rapid particle movement during iteration. This algorithm uses a good-point set for population initialization and incorporates a compression factor to devise an adaptive velocity updating strategy, thereby enhancing search efficacy. The enhanced PSO algorithm’s superiority is substantiated through comparison with four alternative swarm intelligent algorithms across 10 benchmark test functions. Ultimately, optimal hyper-parameters for the GRU model are determined using the improved PSO algorithm, thereby minimizing the influence of human factors. Experimental findings based on approximately 15,000 logging data points from well A01 in an operational field validate that, relative to three other deep learning methodologies, the proposed model proficiently extracts spatiotemporal features from logging data, yielding enhanced accuracy in porosity prediction. The mean squared error on the test set was 7.19 × 10–6, the mean absolute error stood at 0.0082, and coefficient of determination reached 0.99, offering novel insights for predicting reservoir porosity.

Abstract Purpose Various complications following hypospadias surgery present distinct manifestations when examined with ultrasound. Utilizing high-frequency ultrasound, clinicians can promptly identify these complications and initiate appropriate treatment. The aim of this study is to catalogue the ultrasonographic presentations of various postoperative complications following hypospadias surgery, thereby providing a reference for ultrasonographic diagnosis. Methods Ultrasonic images of post-hypospadias surgery from October 1, 2015, to June 30, 2023, recorded at the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences, serve as the basis for this investigation. Drawing on patient clinical diagnoses, this study compiles and selects representative ultrasound images of diverse complications. Results The study encompassed a total of 121 subjects; 26 demonstrated urethral stricture on ultrasonic images, two presented local urethral dilation, six showed intraurethral hair-like structures, 17 revealed intraurethral septum, two exhibited intraurethral fold, one had urethral calculus, one displayed urethral calcification, 12 indicated intraurethral urine accumulation, and two showed urethral diverticulum. Conclusion Ultrasound examination is helpful for postoperative diagnosis following hypospadias, detecting complications such as urethral stricture, urethral hair growth, and urethral diverticulum, which can help doctors choose appropriate clinical treatment strategies.

Hydrocarbon production in oil and gas fields generally progresses through stages of production ramp-up, plateau (peak), and decline during field development, with the whole process primarily modeled and forecasted using lifecycle models. SINOPEC's conventional gas reservoirs are dominated by carbonates, low-permeability tight sandstone, condensate, volcanic rocks, and medium-to-high-permeability sandstone. This study identifies the optimal production forecasting models by comparing the fitting coefficients of different models and calculating the relative errors in technically recoverable reserves. To improve forecast precision, it suggests substituting exponential smoothing method-derived predictions for anomalous data caused by subjective influences like market dynamics and maintenance activities. The preferred models for carbonate gas reservoir production forecasts are the generalized Weng's, Beta, Class-I generalized mathematical, and Hu-Chen models. The Vapor pressure and Beta models are optimal for forecasting the annual productivity of wells (APW) from gas-bearing low-permeability tight sandstone reservoirs. The Wang-Li, Beta, and Yu QT tb models are apt for moderate-to-small-reserves, single low-permeability tight sandstone gas reservoirs. The Rayleigh, Hu-Chen, and generalized Weng's models are suitable for condensate gas reservoirs. For medium-to-high-permeability sandstone gas reservoirs, the lognormal, generalized gamma, and Beta models are recommended.

Summary: Background: Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM. Methods: This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18–75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%–11.0% [58.47–96.73 mmol/mol], body mass index (BMI) of 18–40 kg/m2, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%–10.5% [53.0–91.3 mmol/mol] and fasting plasma glucose (FPG)

Moringa oleifera leaves (MOL) are native to India and have high biological activities. To better understand the basic pharmacodynamic materials, the chemical components in MOL and their pharmacokinetic properties were studied and quantitated using UPLC-Q-Exactive Orbitrap-MS. Forty-two compounds were identified, including phenolic acids and their derivatives, flavonoids, isothiocyanates, nucleosides, alkaloids, and other compounds. Two phenolic acids and six flavonoids were studied for their pharmacokinetic properties using UHPLC-MS/MS. Precision, accuracy, stability, matrix effects, and extraction recovery were verified. All substances that were measured reached their maximum within 0.5 h. Vicenin-2 had a high peak concentration and bioavailability. Kaempferol-3-O-rutinoside had a longer biological half-life than other components. The results from this study provide the data basis for subsequent comprehensive qualitative evaluation and potential MOL use in clinical applications.

Introduction Lung isolation is primarily accomplished using a double-lumen tube (DLT) or bronchial blocker. A precise and accurate size of the DLT is a prerequisite for ensuring its accurate placement. Three-dimensional (3D) reconstruction technology can be used to accurately reproduce tracheobronchial structures to improve the accuracy of DLT size selection. Therefore, we have developed automatic comparison software for 3D reconstruction based on CT data (3DRACS). In this study, we aimed to evaluate the efficiency of using 3DRACS to select the DLT size for endobronchial intubation in comparison with using the ‘blind’ DLT intubation method to determine the DLT size, which is based on height and sex.Methods and analysis This is a prospective, single-centre, double-blind randomised controlled trial. In total, 200 patients scheduled for lung resection using a left DLT will be randomly allocated to the 3D group or the control group at a 1:1 ratio. A 3DRACS will be used for the 3D group to determine the size of the DLT, while in the case of the control group, the size of the DLT will be determined according to patient height and sex. The primary outcome is the success rate of placement of the left DLT without fibreoptic bronchoscopy (FOB). The secondary outcomes include the following: successful intubation time, degree of pulmonary atrophy, grade of airway injury, oxygenation during one-lung ventilation, postoperative sore throat and hoarseness, and number of times FOB is used.Ethics and dissemination Ethical approval has been obtained from our local ethics committee (approval number: SCCHEC-02-2022-155). Written informed consent will be obtained from all participants before randomisation, providing them with clear instructions about the purpose of the study. The results will be disseminated through peer-reviewed publications and conferences.Trial registration number NCT06258954.

Abstract Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. Methods We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). Results A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p

Tight gas reservoirs with mobile water exhibit multi-phase flow and high stress sensitivity. Accurately analyzing the reservoir and well parameters using conventional single-phase rate transient analysis methods proves challenging. This study introduces novel rate transient analysis methods incorporating evaluation processes based on the conventional flowing material balance method and the Blasingame type-curve method to examine fractured gas wells producing water. By positing a gas-water two-phase equivalent homogenous phase that considers characteristics of mobile water, gas, and high stress sensitivity, the conventional single-phase rate transient analysis methods can be applied by integrating the phase's characteristics and defining the phase's normalized parameters and material balance pseudo-time. The rate transient analysis methods based on the equivalent homogenous phase can be used to quantitatively assess the parameters of wells and gas reservoirs, such as original gas-in-place, fracture half-length, reservoir permeability, and well drainage radius. This facilitates the analysis of production dynamics of fractured wells and well-controlled areas, subsequently aiding in locating residual gas and guiding the configuration of well patterns. The specific evaluation processes are detailed. Additionally, a numerical simulation mechanism model was constructed to verify the reliability of the developed methods. The methods introduced have been successfully implemented in field water-producing gas wells within tight gas reservoirs containing mobile water.

AbstractObjective To use logistic regression to analyze the attributes underlying patients’ treatment options for low-grade squamous intraepithelial lesion (LSIL) complicated with high-risk human papillomavirus (HR-HPV) infection, and identify the best benefit group of different treatment options.Methods Clinical data of 197 LSIL patients with HR-HPV infection between June 2009 and February 2022 were collected. According to the treatment options chosen by the patients, they were divided into the interferon, photodynamic therapy, follow-up observation, and focused ultrasound (FUS) treatment groups. One-way analysis of variance (ANOVA) and multivariate logistic regression analysis were used to analyze the influencing factors, including age, occupation, education level, maternity history, reason for encounter, route of consultation, annual personal and household income, screening for related risk factors, and identifying the best benefit group of different treatment options.Results One-way ANOVA revealed a statistically significant difference in age, education level, maternity history, reason for encounter, and annual household income (p

Obesity can lead to excessive lipid accumulation in non-adipose tissues, such as the liver and skeletal muscles, leading to ectopic lipid deposition and damaging target organ function through lipotoxicity. FGF-21 is a key factor in regulating lipid metabolism, so we aim to explore whether FGF-21 is involved in improving ectopic lipid deposition. We observed the characteristics of ectopic lipid deposition in the liver and skeletal muscles of obesity-resistant mice, detected the expression of FGF-21 and perilipin, and found that obesity-resistant mice showed a decrease in ectopic lipid deposition in the liver and skeletal muscles and increased expression of FGF-21. After inhibiting the expression of FGF-21, a more severe lipid deposition in liver cells and skeletal muscle cells was found. The results indicate that inhibiting FGF-21 can exacerbate ectopic lipid deposition via regulating lipid droplet synthesis and decomposition, as well as free fatty acid translocation and oxidation. In conclusion, FGF-21 is involved in improving ectopic lipid deposition caused by obesity in the liver and skeletal muscles.

Background:. This study aimed to evaluate the ultrasonic manifestations of diversified corium fillers in the temporal region and to provide clinicians with suggestions for diagnosis and treatment. Methods:. The facial ultrasound images of 116 patients, including 110 women and six men, 20–61years of age, were analyzed at the Chinese Academy Medical Sciences and Peking Union Medical College from November 2014 to November 2021. Results:. We identified 48 cases of polyacrylamide, 31 cases of fat, 27 cases of hyaluronic acid, seven cases of hydroxyapatite, two cases of silicone oil, and one case of prosthesis. Polyacrylamide mainly showed irregular flocculent hypoechoic or fine punctate hypoechoic in ultrasound; it could be aggregated as a cystic hypoechoic area or diffused in the tissue space, and the probe could be pressurized to see the echo floating or dislocation flow. Fat mainly showed lobulated hypoechoic deposition with some hyperechoic linear intervals. Hyaluronic acid mainly showed an anechoic structure with a clear boundary, uniform internal echo, and no obvious blood flow signal. If diffused in the surrounding tissues, it was mainly characterized by anechoic or low-echo areas in the stratified tissues. Hydroxyapatite mainly showed strongly hyperechoic patch areas with posterior acoustic shadowing artifacts. Silicone oil was mostly found under the epidermis, showing a high echo in the form of clouds and causing unclear displays of deep tissue. Prosthesis showed hypoechoic prosthesis structure. Conclusion:. High-frequency ultrasound had a certain significance in the identification of the fillers of the temporal region.

Thangka murals hold significant cultural value in Tibet, but unfortunately, many of these precious murals have sustained damage over time. Therefore, the restoration of Thangka murals is crucial in preserving Tibet’s cultural heritage. The potential of Gated Convolution for Thangka mural restoration is significant due to its impressive performance. However, existing Gated Convolution-based approaches for Thangka restoration face two challenges: 1) restoration results using Gated Convolution still show blurring at the pixel level, and 2) Gated Convolution remains dependent on the perceptual field of the convolution during image inpainting. To address two challenges, we propose a novel Thangka mural inpainting method that incorporates two key components: 1) an Edge-assisted Feature Fusion (EFF) method that leverages edge information to assist in inpainting the texture details of the image and enhance the consistency of textures and edges; and 2) a Self Attention based Local Refine (SALR) network that effectively enhances the perceptual field of the convolution and captures long-distance dependencies. The experimental results demonstrate that our proposed method is effective in repairing broken areas of Thangka murals, even on a small dataset (N = 5605). To validate the effectiveness of our proposed architecture and its components, we conduct a series of ablation experiments. The results demonstrate the necessity of our approach and highlight the contributions of each component. Moreover, the proposed end-to-end approach exhibits broad applicability and can be extended to other profiling tasks based on small datasets.

BackgroundAt present, a large number of reports focus on the bones of limbs and trunk, while there are few studies on the effect of fluorosis on jawbone which is the inevitable structural basis for the development and treatment of oral diseases. ObjectiveTo preliminarily investigate the effect of fluoride exposure on the mechanical properties of jawbone by observing the changes in the intraosseous environment and the maximum load against shearing force (LSFmax) of the jawbone in rats with chronic fluoride treatment. MethodsScreening experiment: 48 SD male rats were randomly divided into a control group and three fluoride exposure groups (50, 150, and 250 mg·L−1 fluoride concentration), 12 rats in each group. The fluoride exposure groups were molded by feeding different concentrations of sodium fluoride solution, and the control group drank tap water from Guizhou area. Each group was further divided into 4 subgroups with 3 animals each according to observation time points after 0, 2, 4, and 6 months. The LSFmax of the jawbone was measured with an electronic universal ergometer, the expression of type I collagen (Col1) was shown by Sirius red staining, and the expression of runt-related transcription factor 2 (Runx2) was determined semi-quantitatively by immunohistochemistry at selected time points. Formal experiment: 12 male SD rats were randomly divided into a fluoride exposure group and a control group. The fluoride exposure group were fed with 150 mg·L−1 sodium fluoride solution, and the control group drank tap water from Guizhou. After feeding with fluoride for 5 months, the ergometer was used to measure the LSFmax of the jawbone. Osteoclasts were counted after tartrate resistant acid phosphatase (TRAP) staining. Col1, Runx2, bone morphogenetic protein 2 (BMP-2), alkaline phosphatase (ALP), and cathepsin K (Cath K) were detected semi-quantitatively by immunohistochemistry expression and Sirius red staining. Micro computed tomography (Micro CT) was used to observe the trabecular bone microstructure. ResultsScreening experiment: The LSFmax of the control group and the 50 mg·L−1 fluoride exposure group reached the peak value at the 2nd month, and the LSFmax of the 50 mg·L−1 fluoride exposure group reached the valley value at the 4th month. The LSFmax of the 150 mg·L−1 fluoride exposure group at the 4th month was higher than that at the 6th month (P

Auricularia auricula-judae (AAJ) has been cultivated for food in China for centuries, and is also used as a folk medicine for the regulation of glucose and lipid metabolism. However, there are few studies on the effects of different processing technologies on the therapeutic efficacy of AAJ to date. This study investigated the effectiveness of the AAJ made by using superfine grinding and enzymatic pre-digestion technologies, respectively, in a high-fat diet obese rat model. It was found that oral administrations of two AAJ products significantly alleviated dyslipidemia by decreasing serum lipid levels and restoring liver functions. AAJ products made by using pre-digestion technology have appreciable potential to ameliorate lipid metabolic disorders over other products, possibly due to the higher levels of dietary fiber, crude polysaccharides, and total flavonoids released from AAJ during processing. By analysis of transcriptome sequencing and protein expression, it was clear that starch and sucrose metabolism and glycerolipid metabolism-related factors involved in fatty acid synthesis and metabolism in the liver of obese rats were significantly improved. This study gives further evidence that AAJ significantly ameliorates the progression of glucose and lipid metabolism in obese rats. Moreover, this study demonstrated for the first time that the pre-digestion method may be a better and more efficient processing approach for the improvement of AAJ bioavailability.

This paper addresses the risk for environmental transmission of pathogenic microorganisms in confined spaces and the serious health hazards for personnel, and research on efficient eradication methods for the pathogenic microorganisms was carried out to provide technical support for ensuring the health of personnel in confined spaces. A series of graphene-MnO2 (G-MnO2) catalytic materials was prepared by hydrothermal and precipitation methods, and processing parameters such as the graphene doping method, the raw material ratio and the plasma action time were optimized. It was shown that G-MnOX-P/HAC prepared by a one-step precipitation method and with a graphene doping ratio of 10% had the best bactericidal effect in a dielectric barrier discharge (DBD) reactor after 4 min of reaction. The eradication rates for Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), coronavirus and Aspergillus niger were all greater than 99.9%. The characterization techniques TEM, SEM, XRD, XPS, BET and FT-IR showed that the G-MnOX-P samples prepared by the one-step precipitation method had larger specific surface areas with more oxygen vacancies and functional groups on the surfaces, which was conducive to decomposition of the ozone generated by the dissociated plasma and formation of reactive oxygen species (ROS) for the microbial eradication process. Finally, by comparing the ozone-decomposition activity with the plasma co-catalytic performance, it was verified that efficient decomposition of the ozone facilitated the eradication of microorganisms. Based on this, an analysis of the mechanism for efficient eradication was carried out.

Background & Aims: Intratumour heterogeneity (ITH) fosters the vulnerability of RNA expression-based biomarkers derived from a single biopsy to tumour sampling bias, and is regarded as an unaddressed confounding factor for patient precision stratification using molecular biomarkers. This study aimed to identify an ITH-free predictive biomarker in hepatocellular carcinoma (HCC). Methods: We interrogated the confounding effect of ITH on performance of molecular biomarkers and quantified transcriptomic heterogeneity utilising three multiregional HCC transcriptome datasets involving 142 tumoural regions from 30 patients. A de novo strategy based on the heterogeneity metrics was devised to develop a surveillant biomarker (a utility gadget using RNA; AUGUR) using three datasets involving 715 liver samples from 509 patients with HCC. The performance of AUGUR was assessed in seven cross-platform HCC cohorts that encompassed 1,206 patients. Results: An average discordance rate of 39.9% at the level of individual patients was observed applying 13 published prognostic signatures to classify tumour regions. We partitioned genes into four heterogeneity quadrants, from which we developed and validated a reproducible robust ITH-free expression signature AUGUR that showed significant positive associations with adverse features of HCC. High AUGUR risk increased the risk of disease progression and mortality independent of established clinicopathological indices, which maintained concordance across seven cohorts. Moreover, AUGUR compared favourably to the discriminative ability, prognostic accuracy, and patient risk concordant rates of 13 published signatures. Finally, a well-calibrated predictive nomogram integrating AUGUR and tumour-node-metastasis (TNM) stage was established, which generated a numerical probability of mortality. Conclusions: We constructed and validated an ITH-free AUGUR and nomogram that overcame sampling bias and provided reliable prognostic information for patients with HCC. Impact and Implications: Intratumour heterogeneity (ITH) is prevalent in hepatocellular carcinoma (HCC), and is regarded as an unaddressed confounding factor for biomarker design and application. We examined the confounding effect of transcriptomic ITH in patient risk classification, and found existing molecular biomarkers of HCC were vulnerable to tumour sampling bias. We then developed an ITH-free expression biomarker (a utility gadget using RNA; AUGUR) that overcame clinical sampling bias and maintained prognostic reproducibility and generalisability across multiple HCC patient cohorts from different commercial platforms. Furthermore, we established and validated a well-calibrated nomogram based on AUGUR and tumour-node-metastasis (TNM) stage that provided an individualised prognostic information for patients with HCC.

Singapore launched a population-based organised mammography screening (MAM) programme in 2002. However, uptake is low. A better understanding of breast cancer (BC) risk factors has generated interest in shifting from a one-size-fits-all to a risk-based screening approach. However, public acceptability of the change is lacking. Focus group discussions (FGD) were conducted with 54 women (median age 37.5 years) with no BC history. Eight online sessions were transcribed, coded, and thematically analysed. Additionally, we surveyed 993 participants in a risk-based MAM study on how they felt in anticipation of receiving their risk profiles. Attitudes towards MAM (e.g., fear, low perceived risk) have remained unchanged for ~25 years. However, FGD participants reported that they would be more likely to attend routine mammography after having their BC risks assessed, despite uncertainty and concerns about risk-based screening. This insight was reinforced by the survey participants reporting more positive than negative feelings before receiving their risk reports. There is enthusiasm in knowing personal disease risk but concerns about the level of support for individuals learning they are at higher risk for breast cancer. Our results support the empowering of Singaporean women with personal health information to improve MAM uptake.

Designing and manufacturing eco/bioresorbable electronic systems remains a challenge. The authors introduce a picosecond-pulsed laser-based scheme that exploits controlled patterning, thinning, and/or cutting to manipulate multilayers of eco/bioresorbable materials for a wide range of advanced electronic systems.

Abstract The systematic investment and rearrangement of the unearthed artefacts of Longtoushan Royal Cemetery of the Bohai Kingdom have provided a bunch of new information for the archaeometallurgy research on non-ferrous metal production. We have synthesised the latest discoveries of several related mining/smelting sites and urban relics for making a direct approach to the chain of copper production in this research. SEM-EDS and p-XRF unveiled the distinction between copper and bronze artefacts. The yield gap between the scale of smelting and the number of artefacts was also discussed based on historical records. The evidence and detail of indigenous copper production could help the researcher comprehend the technology and material exchange and geopolitical relationship development of the Bohai Kingdom.

Abstract Background Immunotherapy has proven to be an emerging treatment for non-small-cell lung cancer in recent years. Notably, smokers show higher programmed cell death ligand-1 (PD-L1) expression and better responses to PD-1/PD-L1 inhibitors than nonsmokers. Genome-wide association studies show that the CHRNΑ5 encoding α5-nicotinic acetylcholine receptor (α5-nAChR) is especially relevant to lung cancer and nicotine dependence. Jab1 is a key regulatory factor and promotes the stabilization of PD-L1. Our previous study reported that α5-nAChR mediates lung adenocarcinoma (LUAD) epithelial-mesenchymal transition (EMT) and metastasis via STAT3/Jab1. However, the link between α5-nAChR and PD-L1 is unclear in LUAD. Methods We used various bioinformatics databases to analyze the expression of related genes and their correlations. Expression and clinicopathologic significance of α5-nAChR and PD-L1 were detected by immunohistochemistry in a tissue microarray. α5-nAChR regulated LUAD cell immune escape by targeting the STAT3/Jab1-PD-L1 signalling by Western-blotting and ChIP in vitro. We used T cell coculture, flow cytometry, ELISA, CCK8 assay and crystal violet staining to detect the expression of regulatory T cell (Tregs), IFN-γ, IL-2 and the ability of T cell-mediated tumour cell killing respectively. IF assays were performed in both cancer cells and tumour xenograft paraffin sections to analyze the protein expression. The in vivo experiments in mouse model were performed to show the α5-nAChR-mediated immune escape via PD-L1 pathway. Results The expression of α5-nAChR was correlated with PD-L1 expression, smoking status and lower survival of LUAD in vivo. In vitro, the expression of α5-nAChR mediated phosphorylated STAT3 (pSTAT3), Jab1 and PD-L1 expression. STAT3 bound to the Jab1 or PD-L1 promoter and mediated PD-L1 expression. Jab1 stabilized PD-L1 expression in LUAD cells. Furthermore, in primary T cell cocultured system, downregulation of α5-nAChR suppressed the function of CD4+CD25+FOXP3+ Tregs, enhanced IFN-γ secretion, and increased T cell-mediated killing of LUAD cells. In the Jurkat T cells and LUAD cells coculture assay, inhibition of α5-nAChR increased IL-2 secretion. In tumour xenograft tissues, α5-nAChR expression was related to PD-L1, Jab1, pSTAT3, CD4 and granzyme B expression (GB). Conclusions Our results suggest that the novel α5-nAChR/STAT3-Jab1-PD-L1 axis is involved in LUAD immune escape, which could lead to potential therapeutic strategies for cancer immunotherapy. Video abstract

Lyme disease is the most common tick-borne disease and is caused by a group of bacteria known as Borrelia burgdorferi sensu lato (s.l.) complex. Sharing the same genus as B. burgdorferi, Borrelia miyamotoi is a distinct genotype that causes relapsing fever disease. This emerging tick-borne disease is increasingly becoming a concern in public health. To investigate the prevalence of B. burgdorferi s.l. and B. miyamotoi in ticks first, we developed a PCR (Bmer-qPCR) that targets the phage terminase large subunit (terL) gene carried by B. miyamotoi. A similar approach had been used successfully in developing Ter-qPCR for detecting B. burgdorferi s.l. The terL protein functions as an enzyme in packaging phage DNA. Analytical validation of the Bmer-qPCR confirmed its specificity, efficiency and sensitivity. Second, we designed a citizen science-based approach to detect 838 ticks collected from numerous sites across Great Britain. Finally, we applied Bmer-qPCR and Ter-qPCR to 153 tick pools and revealed that the prevalence of B. burgdorferi s.l. and B. miyamotoi was dependent on their geographical locations, i.e. Scotland showed a higher rate of B. burgdorferi s.l. and lower rate of B. miyamotoi carriage as compared to those of the England data. A pattern of diminishing rate of B. miyamotoi carriage from southern England to northern Scotland was visible. Together, the citizen science-based approach provided an estimation of the carriage rate of B. burgdorferi s.l. and B. miyamotoi in tick pools and a potential spreading pattern of B. miyamotoi from the south to the north of Great Britain. Our findings underscore the power of combining citizen science with the molecular diagnostic method to reveal hidden pattern of pathogen-host-environment interplay. Our approach can provide a powerful tool to elucidate the ecology of tick-borne diseases and may offer guidance for pathogen control initiatives. In an era of limited resources, monitoring pathogens requires both field and laboratory support. Citizen science approaches provide a method to empower the public for sample collection. Coupling citizen science approaches with laboratory diagnostic tests can make real-time monitoring of pathogen distribution and prevalence possible.

ObjectiveThis study aims to summarize the clinical characteristics of one teenager with autoimmune polyglandular syndrome (APS) type III C + D to improve the understanding of APS III C + D and its effect of thyroid function.MethodsThis article reported the clinical manifestations, laboratory examinations, treatment methods, and outcomes of an adolescent with anemia admitted to the Pediatrics Department of Tianjin Medical University General Hospital in July 2020 and reviewed the literature.ResultsA girl, aged 13 years and 1 month, was admitted to the hospital due to anemia for more than 4 years and episodic abdominal pain for 1 week. Four years ago, the girl went to a local hospital for “vitiligo”, and a routine blood test revealed anemia. The lowest hemoglobin (HGB) was 61 g/L, and the blood test revealed iron deficiency anemia. She had no menstrual cramps for 2 months. Urine routine showed protein 3+∼4+ and 258 red blood cells (RBCs)/high-power field. Urine protein was 3,380 mg/24 h. Free thyroxine was low, thyroid-stimulating hormone was >100 uIU/ml, thyroid peroxidase antibody was >1,000 IU/ml, and thyroglobulin antibody and thyrotropin receptor antibody were negative. Pituitary magnetic resonance imaging showed a mass in the sellar region with a uniform signal and a maximum height of about 15.8 mm. The result of the antinuclear antibody was 1:80 homogeneous type, and anti-dsDNA and anticardiolipin antibodies IgA and IgM were slightly higher. Thyroxine and iron were given for 1 month, menstruation resumed, and urine protein and RBC count decreased. After 5 months of treatment, free thyroid function, HGB, RBCs in urine, and pituitary returned to normal. Later, a renal biopsy showed changes in focal proliferative glomerulonephritis, and the girl was diagnosed with lupus glomerulonephritis type III. After 3 days of shock therapy with methylprednisolone, prednisone, mycophenolate mofetil, and other treatments were administrated for 1 year. At the time of writing, urine protein was 280 mg/24 h.ConclusionCo-occurrence of Hashimoto's thyroiditis, vitiligo, anemia, pituitary hyperplasia, and lupus nephritis is rare. It is very important to pay attention to the screening of thyroid function.

Hemerocallis citrina Baroni (H. citrina) has been commonly utilized in diet and conventional medicine. In this study, 21 compounds were obtained from the flower buds of H. citrina. Compounds 1, 2 and 3 were three novel compounds isolated from Hemerocallis genus. Compounds 4, 6, 7, 9, 10, 13–19 were isolated from Hemerocallis genus for the first time. It indicated that compounds 1, 2, 3, 4, 5, 7 and 13 exhibited a significant NO inhibitory effect in the LPS induced BV2 cells. The analysis result of PPI and molecular docking showed that compound 1 may play an anti-neuroinflammatory role through MAPK signaling pathway. The result of pharmacological experiments proved that compound 1 effectively inhibited the generation of NO and inflammatory cytokines by inhibiting the activation of MAPK and NF-κB pathway. This research provided a basis for further study and utilization of H. citrina in anti-neuroinflammatory effect.

Primary familial brain calcification (PFBC) is a rare neurodegenerative and neuropsychiatric disorder characterized by bilateral symmetric intracranial calcification along the microvessels or inside neuronal cells in the basal ganglia, thalamus, and cerebellum. Slc20a2 homozygous (HO) knockout mice are the most commonly used model to simulate the brain calcification phenotype observed in human patients. However, the cellular and molecular mechanisms related to brain calcification, particularly at the early stage much prior to the emergence of brain calcification, remain largely unknown. In this study, we quantified the central nervous system (CNS)-infiltrating T-cells of different age groups of Slc20a2-HO and matched wild type mice and found CD45+CD3+ T-cells to be significantly increased in the brain parenchyma, even in the pre-calcification stage of 1-month-old -HO mice. The accumulation of the CD3+ T-cells appeared to be associated with the severity of brain calcification. Further immunophenotyping revealed that the two main subtypes that had increased in the brain were CD3+ CD4− CD8– and CD3+ CD4+ T-cells. The expression of endothelial cell (EC) adhesion molecules increased, while that of tight and adherents junction proteins decreased, providing the molecular precondition for T-cell recruitment to ECs and paracellular migration into the brain. The fusion of lymphocytes and EC membranes and transcellular migration of CD3-related gold particles were captured, suggesting enhancement of transcytosis in the brain ECs. Exogenous fluorescent tracers and endogenous IgG and albumin leakage also revealed an impairment of transcellular pathway in the ECs. FTY720 significantly alleviated brain calcification, probably by reducing T-cell infiltration, modulating neuroinflammation and ossification process, and enhancing the autophagy and phagocytosis of CNS-resident immune cells. This study clearly demonstrated CNS-infiltrating T-cells to be associated with the progression of brain calcification. Impairment of blood–brain barrier (BBB) permeability, which was closely related to T-cell invasion into the CNS, could be explained by the BBB alterations of an increase in the paracellular and transcellular pathways of brain ECs. FTY720 was found to be a potential drug to protect patients from PFBC-related lesions in the future.

BackgroundA large number of studies on fluoride-induced systemic bone damage have been reported previously, but there is little understanding of the characteristics of fluoride accumulation in jawbone. Jawbone is homologous to the other bone tissues in the body, and is an indispensable and important frame structure in the oral cavity.ObjectiveTo study fluoride accumulation and its change trends in teeth, jawbone, and femur of SD rats with chronic drinking-water-borne fluorosis.MethodsA total of 144 three-week-old SD rats, half male and half female, were randomly divided into two groups, a normal control group and a fluoride group. The rats in the normal controlgroup drank purified water disinfected and filtered from Guizhou, and the water contained 0.08 mg·kg−1 fluoride which was lower than the national water quality standard at 1 mg·kg−1. The rats in the fluoride group were fed with sodium fluoride (NaF) solution with a concentration of 150 mg·L−1. At 3, 5 and 7 months of the fluoride exposure, the levels of fluoride in urine, blood, teeth, jawbone, and femur were measured by fluoride ion electrode method.ResultsThere was no sex difference in fluoride content in different biological samples of rats in the fluoride group and the normal control group (all P>0.05). After 3 months of fluoride exposure, the rats in the fluoride group showed dental fluorosis of grade II, and higher levels of fluoride ion in blood and urine than the normal control group (all P

In this study, mesoporous TiO2 with various hydrolysis rates were prepared and combined with H2O2 for the photodegradation of unsymmetrical dimethylhydrazine (UDMH) under VUV irradiation. Results showed that the mesoporous TiO2 synthesized by the hydrolysis in water (MT100) exhibited a good mesoporous structure and the largest specific surface area (178.85 m2 g−1). Consequently, MT100 showed the best degradation efficiency, with the rate constant (k) for VUV/MT100 and VUV/MT100/H2O2 of 0.0185 and 0.2595 min−1, respectively, which was 1.4 and 4.0 times of that of P25. The addition of H2O2 significantly enhanced the degradation efficiency by photoactivation of H2O2 and the synergistic effect. The rate constant and the mineralization rate (after a 3-h treatment) increased by 13 and 3.8 times when 40 mM H2O2 was added into VUV/MT100. The weak alkaline condition (pH = 9) would facilitate the degradation of UDMH. The ⋅OH was the key oxidizing species in VUV/MT100/H2O2. Eight intermediates were detected during the degradation and the possible pathways of UDMH degradation in VUV/MT100/H2O2 process were proposed. VUV/MT100/H2O2 provides an efficient method to degrade UDMH.

In this paper, a direct unsymmetrical dimethylhydrazine/H2O2 fuel cell based on a Nafion membrane and Pt/C catalyst is developed, focusing on the effects of different operating parameters on the cell performance, including the cell operating temperature, the concentration of added electrolyte (NaOH, H2SO4), the concentration of oxidant (H2O2), and the volume flow rate of the feed. The experimental results show that the direct unsymmetrical dimethylhydrazine fuel cell reaches a maximum power density of 129 mW.cm−2 at a current density of 234 mA.cm−2, a limiting current density of about 420 mA.cm−2, and an open circuit voltage of up to 1.37 V. The cell performance reaches a good state at a NaOH concentration of 2.0 M and 5.0 M in the low and high current density region, respectively. This study provides a new pathway to the reuse of highly concentrated unsymmetrical dimethylhydrazine waste fluid generated in military and space launch missions.

Rapid and robust detection assays for Salmonella Enteritidis (SE) in shell eggs are essential to enable a quick testing turnaround time (TAT) at the earliest checkpoint and to ensure effective food safety control. Real-time polymerase chain reaction (qPCR) assays provide a workaround for the protracted lead times associated with conventional Salmonella diagnostic testing. However, DNA-based analysis cannot reliably discriminate between signals from viable and dead bacteria. We developed a strategy based on an SE qPCR assay that can be integrated into system testing to accelerate the detection of viable SE in egg-enriched cultures and verify the yielded SE isolates. The specificity of the assay was evaluated against 89 Salmonella strains, and SE was accurately identified in every instance. To define the indicator for a viable bacteria readout, viable or heat-inactivated SE were spiked into shell egg contents to generate post-enriched, artificially contaminated cultures to establish the quantification cycle (Cq) for viable SE. Our study has demonstrated that this technique could potentially be applied to accurately identify viable SE during the screening stage of naturally contaminated shell eggs following enrichment to provide an early alert, and that it consistently identified the serotypes of SE isolates in a shorter time than conventional testing.

Abstract Background This study aimed to investigate the potential role and molecular mechanism of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in cerebral ischemia/reperfusion injury. Results Using an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model, we determined that the expression of MALAT1 was significantly increased during OGD/R. MALAT1 knockdown reversed OGD/R-induced apoptosis and ER stress. Mechanistically, MALAT1 promoted OGD/R-induced neuronal injury through sponging miR-195a-5p to upregulating high mobility group AT-hook1 (HMGA1). Conclusions Collectively, these data demonstrate the mechanism underlying the invovlvement of MALAT1 in cerebral ischemia/reperfusion injury, thus providing translational evidence that MALAT1 may serve as a novel biomarker and therapeutic target for ischemic stroke.

BackgroundOseltamivir resistance in influenza virus (IFV) has been of widespread concern. An increase in the frequency of viruses with reduced inhibition was observed. Whether oseltamivir is effective is uncertain. We conducted this study to understand the real-world situation in northern China and the clinical efficacy for patients with IFV infection after the use of oseltamivir.MethodsThe longitudinal study was performed on influenza-like illness (ILI) cases in a tertiary general hospital in Beijing, China during the flu season of 2018–2019. All ILI cases (≥18 years) were recruited into the study. We analyzed the effect of the oseltamivir therapy on the number of clinic visits, hospitalization frequency, and the duration of fever and cough.ResultsA total of 689 ILI patients were recruited in this study with 355 in the oseltamivir therapy group and 334 in the supportive therapy group. Among the ILI patients, 388 patients were detected for IFV infection (364 IFV-A and 24 IFV-B) and divided into two groups with or without the oseltamivir therapy (302 vs. 86). There were no significant differences in the basic characteristics between the oseltamivir and supportive therapy groups in the ILI patients or in the IFV positive patients (all p

Proteins and peptides are major components of snake venom. Venom protein transcriptomes and proteomes of many snake species have been reported; however, snake venom complexity (i.e., the venom protein-protein interactions, PPIs) remains largely unknown. To detect the venom protein interactions, we used the most common snake venom component, phospholipase A2s (PLA2s) as a “bait” to identify the interactions between PLA2s and 14 of the most common proteins in Western diamondback rattlesnake (Crotalus atrox) venom by using yeast two-hybrid (Y2H) analysis, a technique used to detect PPIs. As a result, we identified PLA2s interacting with themselves, and lysing-49 PLA2 (Lys49 PLA2) interacting with venom cysteine-rich secretory protein (CRISP). To reveal the complex structure of Lys49 PLA2-CRISP interaction at the structural level, we first built the three-dimensional (3D) structures of Lys49 PLA2 and CRISP by a widely used computational program-MODELLER. The binding modes of Lys49 PLA2-CRISP interaction were then predicted through three different docking programs including ClusPro, ZDOCK and HADDOCK. Furthermore, the most likely complex structure of Lys49 PLA2-CRISP was inferred by molecular dynamic (MD) simulations with GROMACS software. The techniques used and results obtained from this study strengthen the understanding of snake venom protein interactions and pave the way for the study of animal venom complexity.

Gas-solid fluidized bed separation is a highly efficient and clean technique for coal separation, and can effectively remove ash and sulfur contained gangue minerals from coal. However, the fine coal plugging distributor often leads to uneven fluidization and affects the separation effect. In this paper, different plugging ways were designed to study their effects on the fluidization characteristics and particle mixing. It was found that when the plugging phenomenon occurs, the minimum fluidization velocity of the fluidized bed gradually decreases as the plugging area enlarges. The difference between the top and the bottom of the bed minimum fluidization velocity increases accordingly, and a “stagnation phenomenon” occurs in the bed. The standard deviation of pressure fluctuations at the top of the bed is smaller than that at the bottom of the bed, which is the opposite of normal conditions. As the area of the plugging increases, the dead zone on the side wall of the fluidized bed significantly increases. The size of the dead zone is rapid reducing at the initial stage. It was noticed that the stratification of the low-density products is particularly affected by plugging, whereas the stratification of high-density products is not obviously influenced by certain conditions.

Routine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore. Advancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit ~3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score. For national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.

rAAVrh74.MCK.GALGT2 is a surrogate gene therapy that inhibits muscular dystrophy in multiple animal models. Here, we report on a dose-response study of functional muscle GALGT2 expression as well as toxicity and biodistribution studies after systemic intravenous (i.v.) delivery of rAAVrh74.MCK.GALGT2. A dose of 4.3 × 1014vg/kg (measured with linear DNA standard) resulted in GALGT2-induced glycosylation in the majority of skeletal myofibers throughout the body and in almost all cardiomyocytes, while several lower doses also showed significant muscle glycosylation. No adverse clinical signs or treatment-dependent changes in tissue or organ pathology were noted at 1 or 3 months post-treatment. Blood cell and serum enzyme chemistry measures in treated mice were all within the normal range except for alkaline phosphatase (ALP) activity, which was elevated in serum but not in tissues. Some anti-rAAVrh74 capsid T cell responses were noted at 4 weeks post-treatment, but all such responses were not present at 12 weeks. Using intramuscular delivery, GALGT2-induced muscle glycosylation was increased in Cmah-deficient mice, which have a humanized sialoglycome, relative to wild-type mice, suggesting that use of mice may underestimate GALGT2 activity in human muscle. These data demonstrate safety and high transduction of muscles throughout the body plan with i.v. delivery of rAAVrh74.MCK.GALGT2. Keywords: Duchenne muscular dystrophy, gene therapy, AAV, GalNAc, dystroglycan

The identification of microorganisms using single-temperatures pyrolysis gas chromatography (ST-PyGC) has limitations, for example, the risk of missing characteristic peaks that are essential to the chemotaxonomic interpretation. In this paper, we proposed a new multi-temperature PyGC (MT-PyGC) method as an alternative to ST-PyGC, without sacrificing its speed and quality. Six bacteria (three Gram-positive and three Gram-negative), one micro-fungus and one archaeon, representing microorganisms from different domains, were analyzed by MT-PyGC. It is found that MT pyrograms cover a more complete range of characteristic peaks than ST. Coupling with thermogravimetric analysis, chemotaxonomic information extracted from pyrograms by MT-PyGC have the potential for the differentiation of microorganisms from environments including deep subterranean reservoirs and biomass conversion/biofuel production.