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Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available. In this study, we reported the enhanced expression of mesenchymal homobox 1 (MEOX1) in pulmonary fibrosis patients, especially in their fibroblasts and endothelial cells, and confirmed MEOX1 as a central orchestrator in the activation of profibrotic genes. By high-throughput screening, we identified Ailanthone (AIL) from a natural compound library as the first small molecule capable of directly targeting and suppressing MEOX1. AIL demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-β1 (TGF-β1). In an animal model of bleomycin-induced pulmonary fibrosis, AIL effectively mitigated the fibrotic process and restored respiratory functions. Mechanistically, AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1, thereby inhibiting MEOX1 expression and activity. In summary, our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in fibrosis. Moreover, we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis, specifically through the suppression of JUN-dependent MEOX1 activation.

Abstract Background Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. Results We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. Conclusions We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.

Background Whole brain radiotherapy (WBRT) is the mainstay of treatment for patients with non-small cell lung cancer (NSCLC) with multiple brain metastases (BMs); however, the BRAIN study showed that the efficacy of WBRT is unsatisfactory. This prospective phase II study aimed to evaluate the efficacy and safety of WBRT combined with anlotinib, a novel anti-angiogenic multi-target tyrosine kinase inhibitor (TKI), in patients with multiple BMs (>3) from advanced NSCLC.Methods Patients with advanced NSCLC with multiple BMs who had received two or more lines of treatment were eligible for enrolment into this study. All patients were treated with anlotinib (8–12 mg, QD, on days 1–14 of a 21-day cycle) combined with WBRT (DT 30 Gy/12 F), followed by maintenance therapy with anlotinib until disease progression or treatment intolerance. The primary endpoint of this study was the intracranial progression-free survival (iPFS). The secondary endpoints were intracranial objective response rate (iORR), intracranial disease control rate (iDCR), overall survival (OS) and treatment safety.Results Between May 2019 and January 2021, 28 patients were enrolled, all of whom were evaluable for efficacy and safety. The median age was 57.7 years, and 46.4% were male. Twenty-five patients had adenocarcinoma (89.3%), six had EGFR mutations (21.4%) and two had ALK mutations (7.1%). The median iPFS was 11.1 months (95% confidence interval (CI): 5.4–16.8 months) and the median OS was 13.4 months (95% CI: 5.2–21.6 months). The iORR was 71.4% (six complete responses + 14 partial responses). The most frequently observed adverse events (AEs) were hypertension (71.4%), fatigue (64.3%), anorexia (46.4%), and foot and hand skin reactions (25.0%). No patients developed ≥ grade 4 AEs. No intracranial haemorrhages occurred during treatment. Dose adjustment due to AEs occurred in 17.9% of patients.Conclusions Anlotinib combined with WBRT is effective and well-tolerated in patients with NSCLC with multiple BMs.

AbstractPurpose To evaluate the efficacy and safety of high-intensity focused ultrasound (HIFU) ablation in the treatment of uterine arteriovenous fistula (UAVF).Materials and methods This case series included three patients diagnosed with acquired UAVF. All patients underwent routine laboratory tests, electrocardiography (ECG), chest X-ray, ultrasound, and pelvic contrast-enhanced magnetic resonance imaging (MRI). HIFU treatment was performed under sedation and analgesia using a Model JC Focused Ultrasound Tumor Therapeutic System (made by Chongqing Haifu Medical Technology Co. Ltd., China) with a B mode ultrasound device for treatment guidance. The treatment time, sonication power, sonication time, and complications were recorded. Follow-up evaluations were scheduled at 1-, 3-, 6-, and 12-month to assess symptom improvement and evaluate the post-treatment imaging.Results All patients completed HIFU treatment in a single session without any major complication. All patients complained of mild lower abdominal and sacrococcygeal pain. Typically, no special treatment is required. Following HIFU treatment, there was a significant relief in clinical symptoms, particularly abnormal uterine bleeding. Ultrasound examinations conducted one month after the treatment revealed a notable reduction in the volume of the lesion, ranging from 57% to 100%. Moreover, the efficacy and safety of HIFU treatment remained consistent during the 12-month follow-up period.Conclusion HIFU ablation appears to be an effective and safe treatment modality for UAVF. It provides a noninvasive approach with favorable clinical outcomes.

Abstract Background The rising burden of thyroid cancer (TC) is a public health problem in Asia. Predicting the future burden of TC in Asian countries is essential for disease prevention. Methods Data were obtained from the Global Burden of Disease 2019 for five Asian countries. We applied Bayesian age‐period‐cohort models to predict morbidity and mortality to 2035 and calculated age‐standardized incidence rate (ASIR) and age‐standardized mortality rate (ASMR). Furthermore, the estimated annual percentage change was calculated to evaluate the variation of ASIR and ASMR. Results By 2035, predictions suggest that cases of TC will reach 75.56 × 103 in China, 70.22 × 103 in India, 15.78 × 103 in the Republic of Korea, 9.01 × 103 in Japan and 5.55 × 103 in Thailand, respectively. Except Japan, a significant upward trend of ASIR of TC will be observed in five Asian countries. The deaths from TC will increase in five countries and India will become the highest reaching 14.07 × 103. The ASMR will rise to 0.83/100 000 in India and 1.06/100 000 in the Republic of Korea, while it will drop to 0.35/100 000 in China, 0.43/100 000 in Japan and 0.50/100 000 in Thailand. In further predictions projected by sex, the growth rate of ASIR is reported higher in males than in females among most countries. ASMR of male will exceed that of females in China and Thailand by 2035. Conclusion The disease burden caused by TC will further increase in five Asian countries, especially for men. It is necessary to develop more rational and timely disease prevention and manage strategies facing this disease trend.

Background: The solute carrier (SLC) superfamily, which transports solutes across biological membranes, includes four members (SLC2A1, SLC6A1, SLC9A64, and SLC35A2) that have been linked to epilepsy. This study sought to examine the DNA methylation patterns near the promoters of these genes in temporal lobe epilepsy (TLE), as DNA methylation is a crucial epigenetic modification that can impact gene expression. Methods: The study comprised 38 individuals with TLE and 38 healthy controls. Methylation experiments were performed using peripheral blood, while demethylation experiments were carried out using SH-SY5Y cells with the DNA methylation inhibitor decitabine. Results: A significant difference was observed in the DNA methylation rate of SLC6A1 between TLE patients and controls, with TLE patients showing a lower rate (4.81% vs. 5.77%, p = 0.0000), which remained significant even after Bonferroni correction (p = 0.0000). Based on the hypomethylated SLC6A1 in TLE, a predictive model was established that showed promise in distinguishing and calibrating TLE. In the TLE group, there were differences in DNA methylation rates of SLC6A1 between the young patients and the older controls (4.42% vs. 5.22%, p = 0.0004). A similar trend (p = 0.0436) was noted after adjusting for sex, age at onset, and drug response. In addition, the study found that DNA methylation had a silencing impact on the expression of the SLC6A1 gene in SH-SY5Y cells, which were treated with decitabine at a set dose gradient. Conclusions: The evidence suggests that lower methylation of SLC6A1 may stimulate transcription in TLE, however, further investigation is necessary to confirm the exact mechanism.

The marine carbonates in the Ordovician Majiagou Formation in the Ordos Basin have significant exploration potential. Research has focused on their thermal history and hydrocarbon accumulation stages, as these are essential for guiding the exploration and development of hydrocarbons. In this paper, we study the thermal evolution history of the carbonate reservoirs of the Ordovician Majiagou Formation in the east-central Ordos Basin. Furthermore, petrographic and homogenization temperature studies of fluid inclusions were carried out to further reveal the hydrocarbon accumulation stages. The results demonstrate that the degree of thermal evolution of the Ordovician carbonate reservoirs is predominantly influenced by the deep thermal structure, exhibiting a trend of high to low values from south to north in the central region of the basin. The Fuxian area is located in the center of the Early Cretaceous thermal anomalies, with the maturity degree of the organic matter ranging from 1 to 3.2%, with a maximum value of 3.2%. The present geothermal gradient of the Ordovician Formation exhibits the characteristics of east–high and west–low, with an average of 28.6 °C/km. The average paleo-geotemperature gradient is 54.2 °C/km, the paleoheat flux is 55 mW/m2, and the maximum paleo-geotemperature reaches up to 270 °C. The thermal history recovery indicates that the Ordovician in the central part of the basin underwent three thermal evolution stages: (i) a slow warming stage before the Late Permian; (ii) a rapid warming stage from the end of the Late Permian to the end of the Early Cretaceous; (iii) a cooling stage after the Early Cretaceous, with the hydrocarbon production of hydrocarbon source rocks weakening. In the central part of the basin, the carbonate rock strata of the Majiagou Formation mainly developed asphalt inclusions, natural gas inclusions, and aqueous inclusions. The fluid inclusions can be classified into two stages. The early-stage fluid inclusions are mainly present in dissolution holes. The homogenization temperature is 110–130 °C; this coincides with the hydrocarbon charging period of 210–165 Ma, which corresponds to the end of the Triassic to the end of the Middle Jurassic. The late-stage fluid inclusions are in the dolomite vein or late calcite that filled the gypsum-model pores. The homogenization temperature is 160–170 °C; this coincides with the hydrocarbon charging period of 123–97 Ma, which corresponds to the late Early Cretaceous. Both hydrocarbon charging periods are in the rapid stratigraphic warming stage.

Given the friction and drag reduction effects observed in various biological hexagonal structures in nature, a new design was implemented on the rubber surface of the stator of a submersible screw pump. This design featured a multilayer concentric hexagonal groove structure. Furthermore, a composite multilayer hexagonal structure integrating grooves and pits was also developed and applied. This study investigated the influence of groove layer number, groove depth, pit depth, and multilayer hexagonal groove texture arrangement on the rubber surface flow characteristics. Additionally, the pressure field state, the degree of influence on the oil film-bearing capacity, and the biomimetic and hydrodynamic lubrication theories were tested using the finite element analysis method. Tribological experiments were conducted on nanosecond laser-processed rubber textures under simulated liquid lubrication conditions, reflecting actual shale oil well experiments. These experiments aimed to investigate the influence of multilayer hexagonal shape parameters on the tribological characteristics of the stator-rotor friction pair of a submersible screw pump. The results indicated that with a constant overall size, a multilayer hexagonal structure with ~0.1 mm groove depth enhanced the oil film-bearing capacity, providing significant friction and drag reduction. For composite textures, a deeper pit depth within the study area enhanced the oil film-bearing capacity. Furthermore, a gradient arrangement of groove textures featuring wider outer grooves and shallower depth exhibited superior performance in terms of bearing capacity.

AbstractObjective This study assessed the improvement of symptoms and pregnancy outcomes in infertile patients with various types of adenomyosis who were treated with high-intensity focused ultrasound (HIFU).Materials and methods Between October 2017 and January 2022, 129 infertile patients with adenomyosis who wished to conceive were treated with HIFU. Based on the relationship between the adenomyotic lesion, the endometrium, and the subserosa of the uterus on magnetic resonance imaging, the adenomyotic lesions were divided into internal, external, intramural, and full-thickness types. Menstruation pain score, menstruation blood volume score, anti-Müllerian hormone (AMH) levels, reproductive results, pregnancy and delivery complications, and other clinical variables were compared among these four groups.Results Patients with external adenomyosis had the greatest menstrual distress, whereas patients with internal adenomyosis had the greatest menstrual blood volume. Dysmenorrhea and heavy menstruation were significantly improved after HIFU treatment in all groups. AMH levels were not significantly different before and six months after HIFU. Of the 129 patients, 50 (38.7%) became pregnant after HIFU, and patients with internal adenomyosis had the highest pregnancy rate. Patients with adenomyotic lesions located in the posterior wall of the uterus had a higher pregnancy rate than those with lesions located in the fundus of the uterus.Conclusions The classification of adenomyosis is closely related to distinctions in clinical symptoms and pregnancy outcomes. Infertile patients with different types of adenomyosis could be effectively treated with HIFU. HIFU can be considered as an option for infertile patients with adenomyosis who want to maintain their fertility.

AbstractObjectives To investigate changes in vaginal microecology in women with high-risk human papillomavirus (HR-HPV) infection after focused ultrasound (FU) treatment.Materials and methods We collected vaginal secretions at the time of admission and 3 months after FU treatment from 169 women who received FU treatment for cervical HR-HPV infection between July 2020 and September 2022. Among them, there were 101 patients with cute vaginitis, we also collected their vaginal secretions after one week of drug treatment. These samples were evaluated for vaginal microecology and HPV-DNA examination.Results Of the 169 patients, 101 (59.7%) suffered from acute vaginitis at the time of admission. After one week of targeted antibiotics drug treatment, there were no pathogens or pus cells on the field of microscopic vision, but there was no significant difference(p > 0.05) in the diversity and density of vaginal flora, the proportion and function of Lactobacillus (H2O2 negative rate) between one week after treatment and at the time of admission. At the time of admission of the 169 patients, the normal flora rate was 40.3%, which increased to 93.5% three months after FU treatment. The differences in vaginal secretion parameters at the time of admission and 3 months after FU treatment were as follows: H2O2 negative rate (37.3% vs. 3.6%), leukocyte esterase positive rate (54.4% vs. 5.9%), sialidase positive rate (38.5% vs. 4.1%), bacterial vaginitis positive rate (55% vs. 4.7%), fungal vaginitis positive rate (44.4% vs. 5.9%), and trichomonal vaginitis positive rate (7.1% vs. 0). The difference was statistically significant (p

AbstractObjectives To compare pregnancy outcomes after high-intensity focused ultrasound ablation (HIFU), myomectomy and uterine artery embolization (UAE) for fertility-sparing patients with uterine fibroids and to investigate the possible mechanism of improving pregnancy by HIFU.Materials and methods A meta-analysis of 54 studies containing 12,367 patients was conducted to compare the pregnancy outcomes of three fertility-sparing therapies. And a retrospective self-control study of 26 patients with uterine fibroids from May 2019 to December 2020 was performed to assess the blood flow impedance of bilateral uterine arteries before and after HIFU.Results In the analysis by treatment option, the pregnancy rate after myomectomy was 0.43 (95% CI 0.36–0.49), which was higher than 0.18 (95% CI 0.10–0.26) after HIFU, the latter was significantly higher than that after UAE (ratio 0.08, 95% CI 0.06–0.10). The miscarriage rate after HIFU was 0.08 (95% CI 0.04–0.12), which was similar to 0.15 (95% CI 0.09–0.21) after myomectomy and also similar to 0.16 after UAE (95% CI 0.01–0.30). In the subgroup analysis, women who received ultrasound guided HIFU (USgHIFU) were more likely to have ideal pregnancy outcomes than that after magnetic resonance imaging-guided HIFU. The pulsatility index and resistance index on the right side were significantly higher 3 months after HIFU than before (1.637 ± 0.435 vs. 1.845 ± 0.469; p = 0.033; 0.729 ± 0.141 vs. 0.784 ± 0.081, p = 0.039).Conclusions HIFU, especially USgHIFU, may be an alternative fertility-sparing modality for patients with uterine fibroids over 40 years old. HIFU may contribute to improving pregnancy rates by elevating uterine blood flow impedance.

The oral cavity is the second most microbially rich region of the human body, and many studies have shown that there is a strong association between microorganisms and oral health. Some pathogenic bacteria produce biofilms and harmful metabolites in the mouth that may cause oral problems such as oral malodor, periodontitis, and dental caries. Altering the oral microbiota by using probiotics may alleviate oral health problems. Thus, using multi-function screening, we aimed to identify probiotics that can significantly improve oral health. The main parameters were the inhibition of pathogenic bacteria growth, inhibition of biofilm formation, reduction in the production of indole, H2S, and NH3 metabolites that cause halitosis, increase in the production of H2O2 to combat harmful bacteria, and co-aggregation with pathogens to prevent their adhesion and colonization in the oral cavity. Tolerance to cholic acid and choline was also assessed. Bifidobacterium animalis ZK-77, Lactobacillus salivarius ZK-88, and Streptococcus salivarius ZK-102 had antibacterial activity and inhibited biofilm production to prevent caries. They also improved the oral malodor parameter, H2S, NH3, and indole production. The selected probiotics (especially L. salivarius ZK-88) alleviated the inflammation in the oral cavity of rats with periodontitis. The analysis of the gingival crevicular fluid microbiome after probiotic intervention showed that B. animalis ZK-77 likely helped to restore the oral microbiota and maintain the oral microecology. Next, we determined the best prebiotics for each candidate probiotic in order to obtain a formulation with improved effects. We then verified that a probiotics/prebiotic combination (B. animalis ZK-77, L. salivarius ZK-88, and fructooligosaccharides) significantly improved halitosis and teeth color in cats. Using whole-genome sequencing and acute toxicity mouse experiments involving the two probiotics, we found that neither probiotic had virulence genes and they had no significant effects on the growth or development of mice, indicating their safety. Taking the results together, B. animalis ZK-77 and L. salivarius ZK-88 can improve oral health, as verified by in vivo and in vitro experiments. This study provides a reference for clinical research and also provides new evidence for the oral health benefits of probiotics.

Abstract To examine the feasibility of quantitative dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) in the early assessment of the therapeutic response to concurrent chemoradiotherapy (CRT) in esophageal cancer (EC) patients and to determine its value in predicting HIF‐1α expression. EC patients underwent DCE‐MRI 1 week pre‐CRT and 3 weeks post‐CRT (3w‐CRT). According to tumor regression post‐treatment, patients were divided into sensitive group (SG) and resistant group (RG). HIF‐1α expression was assessed by immunohistochemistry (IHC). Quantitative parameters (ktrans, kep, and ve) were compared between the SG and RG groups, as well as between the HIF‐1α(+) and HIF‐1α(−) groups. Receiver operating characteristic (ROC) curve analysis was performed to detect the best predictor of the above parameters in the therapeutic response and in predicting HIF‐1α expression. Totally 34 and 5 patients were included in the SG and RG, respectively. Pre‐ktrans and pre‐kep were decreased significantly in the SG at 3w‐CRT (p

A linear model for coherent diffractive imaging (CDI) is proposed herein. In this model, CDI is expressed as a system of linear equations in the frequency domain of an object and illumination. The linear system can be directly determined to provide a unique solution for complex samples. The method is analytical and straightforward and does not require any approximation. The simulation results demonstrate that the proposed method is valid for all CDI-related imaging methods, such as traditional CDI, ptychography, coherent modulation imaging, and multiple-plane phase retrieval. The relationship between the method and the convergence of iterative phase retrieval is discussed. This mathematical model provides a direct method for analyzing the underlying physics of CDI and can be used to predict the accuracy and error in CDI applications, such as measurement and metrology.

The coordinated control method of Unmanned Electric Formula Racing (UEFC) was studied to improve the handling stability of UEFC. The UEFC’s mechanical structure, which is based on the driving system and transmission system, was designed. In accordance with mechanical structure of the designed racing car, a seven-degree of freedom mathematical model of the UEFC was established. In accordance with the built mathematical model of racing car, the lateral controller of racing car was designed by using a fuzzy neural network method. The longitudinal controller of the racing car was designed by using the method of incremental PID control, and the coordination controller of the racing car was designed by combining the lateral controller and the longitudinal controller so as to realize the lateral and longitudinal coordination control of the UEFC. The experimental results showed that the output parameters such as yaw rate, vehicle speed and heading angle were slightly different from the expected output. It was confirmed that the research method can enhance the handling stability of the UEFC.

Epilepsy is characterized by highly abnormal synchronous discharge of brain neurons, and ion channels are fundamental in the generation and modulation of neural excitability. Considering that abnormal methylation can either activate or repress genes, this study was designed to explore the DNA methylation signature of pathogenic genes encoding ion channels in temporal lobe epilepsy (TLE). In total, 38 TLE patients and 38 healthy controls were enrolled in the study, and genomic DNA and total protein of the lymphocytes were extracted from peripheral blood samples to assess methylation and protein levels. The DNA methylation levels of all 12 genes examined were significantly lower in the TLE group than in the control group. After false-positive correction, 83.3% (10/12) of these genes, namely, gamma-aminobutyric acid type A receptor subunit beta1 (GABRB1), gamma-aminobutyric acid type A receptor subunit beta2 (GABRB2), gamma-aminobutyric acid type A receptor subunit beta1 (GABRB3), glutamate ionotropic receptor NMDA type subunit 1 (GRIN1), glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B), hyperpolarization activated cyclic nucleotide gated potassium channel 1 (HCN1), potassium voltage-gated channel subfamily A member 2 (KCNA2), potassium voltage-gated channel subfamily B member 1 (KCNB1), and potassium sodium-activated channel subfamily T member 1 (KCNT1), were still differentially expressed. Among these ion channels, HCN1 and KCNA2 were selected to evaluate the effects of DNA methylation, and the levels of these proteins were inversely upregulated in the TLE group compared to the control group. As the genes identified as having differential methylation levels are involved in both excitatory and inhibitory ion channels, this study observed by binary logistic regression that hypermethylated GARAB1 was an independent risk factor for TLE, indicating that the overwhelming effect of ion channels on TLE is probably inhibitory from the perspective of DNA methylation. All these findings support the involvement of DNA methylation in TLE pathologies, but the mechanisms need to be further investigated.

A new method for optical multiple-image encryption based on polarization-resolved diffraction imaging is proposed in this study. A linearly polarized beam is split into two beams of orthogonal polarization to illuminate different images to be encrypted, and these images are then encrypted into a single white-noise-like intensity image in a single shot. A multi-mode iterative phase-retrieval algorithm is used in the decryption to reconstruct the amplitudes and phases of the secret images simultaneously. Both computer simulations and optical experiments are performed to demonstrate the feasibility and effectiveness of the proposed method.

Gas reservoirs with high CO2 have been found in several wells in the Hailar Basin. In this paper, a composition analysis, stable carbon isotope analysis, and a rare gas helium isotope 3He/4He and argon isotope 40Ar/36Ar analysis were carried out. These comprehensive analyses show that the CO2 in the Hailar Basin is inorganic-origin gas, which generally has the characteristics of crust–mantle-mixed CO2, and the fraction of helium of mantle source can reach 15.12~18.76%. There are various types of CO2 gas reservoirs. CO2 gas mainly comes from deep crust. The distribution of gas reservoirs is mainly controlled by deep faults and volcanic rocks, as well as by reservoir properties and preservation conditions. Magmatic rocks provide gas source conditions for the formation of inorganic CO2 reservoirs. Deep–large faults provide the main migration channels for CO2 gas. The sandy conglomerate and bedrock weathering crust of the Nantun Formation and the Tongbomiao Formation provide favorable reservoir spaces for the formation of CO2 gas reservoirs. The combination of volcanic rock mass and deep–large faults creates a favorable area for CO2 gas accumulation. The age of magmatic intrusion and the homogenization temperature of oil–gas inclusions in Dawsonite-bearing sandstone indicate that 120 Ma in the Early Cretaceous was the initial gas generation period of the CO2 reservoir and that oil and gas were injected into the reservoir in large quantities in 122~88 Ma. This period is the peak period of magmatic activity in Northeast China, as well as when the crust of Northeast China greatly changed. A large-scale CO2 injection period occurred in 100~80 Ma, slightly later than the large-scale injection period of the oil and gas. Since the Cenozoic, the structure has been reversed, and the gas reservoir has been adjusted.

Recent studies have reported patients who concurrently exhibit conditions of epilepsy and schizophrenia, indicating certain shared pathologies between them. This study aimed to investigate the genetic effects of the schizophrenia-related gene DTNBP1 in temporal lobe epilepsy (TLE). A total of 496 TLE patients and 528 healthy individuals were successfully genotyped for six DTNBP1 polymorphisms (rs760665, rs1011313, rs2619528, rs2619522, rs909706, and rs2619538), including 335 TLE patients and 325 healthy controls in cohort 1, and 161 TLE patients and 203 healthy controls in cohort 2. The frequency of the TT genotype at rs909706 T > C was lower in TLE patients than in normal controls in the initial cohort (cohort 1), which was confirmed in an independent cohort (cohort 2). However, the intronic T allele failed to be in linkage disequilibrium (LD) with any functional variations nearby; thus, together with the CCAC and TCAT haplotypes (rs1011313-rs2619528-rs2619522-rs909706) observed in the study, this allele acts only as a protective factor against susceptibility to TLE. Meanwhile, a novo mutant allele rs2619538 T > A was exclusively observed in TLE patients, and a dual-luciferase assay revealed that the mutant allele was increased by approximately 22% in the DTNBP2 promoter compared with the wild-type allele. Together with the trend of increasing DTNBP1 expression in epilepsy patients and animal models in this study, these are the first findings to demonstrate the genetic association of DTNBP1 with TLE. Homozygous mutation of rs2619538 T > A likely promotes DTNBP1 expression and facilitates subsequent processes in epilepsy pathologies. Thus, the role of DTNBP1 in TLE deserves further exploration in the future.

Abstract Background Atherosclerosis is the primary cause of coronary artery disease (CAD), and stearoyl‐CoA desaturase (SCD) is associated with atherosclerosis. However, the associations between variants of SCD and CAD have not yet been decided. Methods This study analyzed SCD rs41290540 single‐nucleotide polymorphism (SNP) in the 3′‐untranslated region for an association with a risk of CAD among the Chinese Han population. CAD patients and controls were genotyped for SNP rs41290540 in SCD by SNaPshot. The binding affinity of miR‐498 to rs41290540 was determined by a luciferase assay, and SCD expression was assessed using Western blot. Results A total of 969 CAD patients and 1,095 control subjects were involved in this study. The SCD rs41290540CC genotype is associated with a decreased risk of CAD compared with the AA genotype. Furthermore, the CC genotype is associated with lower serum total cholesterol (TC). Western blot analysis demonstrated that miR‐498 suppressed the expression of SCD. A luciferase assay confirmed that rs41290540 A>C variation in the SCD 3′UTR inhibits miR‐498 binding. Conclusion This study demonstrates that the SCD rs41290540 may be associated with a decreased risk of CAD, lower serum TC, and decreased miR‐498 binding.

This study was conducted to explore the composition of the fecal microflora of Chinese Parkinson's disease (PD) patients, as well as to explore links between PD clinical features and antiparkinsonian medications on the gut microflora. Seventy-two PD cases [59 patients suffering from PD for >1 year (OPD) and 13 new PD (NPD) patients] were studied. Microflora communities in the feces of the patients and corresponding healthy controls (HCs) were examined using high-throughput Illumina MiSeq sequencing targeting the 16S rRNA gene. The gut microflora of OPD patients contained high levels of Rikenellaceae compared to corresponding HCs. In addition, significantly higher levels of Turicibacteraceae were found in the NPD group compared to the corresponding HCs. The genera Turicibacter and Prevotella were significantly correlated with the PD severity scores. Our findings that some fecal microflora were closely related to PD clinical characteristics may enhance our understanding of the pathogenesis and treatment of PD.

Background: A disintegrin and metalloproteinase 17 (ADAM17) has been confirmed to play a significant role in the pathogenesis of sepsis. However, little is known about the clinical relevance of ADAM17 polymorphisms to sepsis onset and development. Methods: This study analyzed the associations of five ADAM17 promoter polymorphisms (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) with sepsis (370 sepsis cases and 400 controls). Genotyping was performed using pyrosequencing and polymerase chain reaction-length polymorphism method. The ADAM17 expression was measured using the real-time PCR method and the concentrations of related cytokines were detected using enzyme-linked immunosorbent assay. Results: No associations were observed between these polymorphisms and sepsis susceptibility, while the rs12692386GA/GG genotypes were overrepresented among the patients with severe sepsis (P=0.002) or septic shock (P=0.0147) compared to those with sepsis subtype, suggesting a susceptible role of rs12692386A>G in the progression of sepsis. Moreover, ADAM17 expression was increased in the sepsis patients with the rs12692386GA/GG genotypes, accompanied by up-regulation of expression of the ADAM17 substrates (TNF-α, IL-6R and CX3CL1) and pro-inflammatory cytokines (IL-1β and IL-6). Conclusion: The present study has provided potentially valuable clinical evidence that the ADAM17 rs12692386 polymorphism is a functional variant that might be used as a relevant risk estimate for the progression of sepsis.

The coarse granularity vehicle mobility information is extracted from the vehicle trace data.Then a fine granularity mobility model was presented based on the coarse-grained mobility information.Based on the mobility model,a VANET routing algorithm,RPT-D,was proposed to quickly deliver the packets to the destination according to the mobility attributes.The RPT-GA algorithm,which was integrated with the QoS demands in the path selection objective,was designed.Finally,through the extensive simulations,the proposed algorithms are compared with other typical VANET routing algorithms,IGRP and GPSR,in terms of the transmission latency,the delivery ratio,the hop count and the extra package number.The simulation results verify the performance of the proposed algorithms.

According to an update from the World Health Organization, approximately 50 million people worldwide suffer from epilepsy, and nearly one-third of these individuals are resistant to the currently available antiepileptic drugs, which has resulted in an insistent pursuit of novel strategies for seizure treatment. Recently, methylglyoxal (MG) was demonstrated to serve as a partial agonist of the gamma-aminobutyric acid type A (GABAA) receptor and to play an inhibitory role in epileptic activities. However, MG is also a substrate in the generation of advanced glycation end products (AGEs) that function by activating the receptor of AGEs (RAGE). The AGE/RAGE axis is responsible for the transduction of inflammatory cascades and appears to be an adverse pathway in epilepsy. This study systematically reviewed the significance of GABAergic MG, glyoxalase I (GLO1; responsible for enzymatic catalysis of MG cleavage) and downstream RAGE signaling in epilepsy. This work also discussed the potential of miRNAs that target multiple mRNAs and introduced a preliminary scheme for screening and validating miRNA candidates with the goal of reconciling the conflicting effects of MG for the future development of seizure treatments.

Background: miR-146a polymorphisms have been involved in susceptibility to multiple diseases. The aim of the present study was to analyze the potential association between two functional miR-146a polymorphisms (rs2910164 and rs57095329) and multiple sclerosis (MS) in the Han Chinese population. Methods: A cohort of 525 patients and 568 healthy controls were genotyped to detect the two polymorphisms by SNaPshot. Results: No significant differences were detected in the distribution of the two miR-146a polymorphisms between the patients and controls (P > 0.05). However, stratification by gender showed a statistically significant difference in the frequency of the genotype rs2910164 between MS patients and control females (P=0.009). Further stratification analysis by subgroup revealed that the miR-146a rs2910164 C allele conferred a higher risk of developing relapsing-remitting MS (RRMS) (P=0.018). In addition, the rs2910164 C allele was significantly associated with increased expression of miR-146a in patients with RRMS (P=0.025). Moreover, patients with the rs2910164 C allele released more TNF-α and IFN-γ, but not IL-1β, compared with individuals carrying the homozygous GG genotype (P Conclusions: Our results provide evidence that rs2910164 may play a role in MS susceptibility in females. The rs2910164 G>C variation may affect the expression of miR-146a and the release of proinflammatory cytokines.

Objective: To study the distribution and patterns of resistance to antimicrobial agents of normal conjunctival bacteria.Materials and Methods: Conjunctival specimens were collected from 8,224 patients and then cultured, which underwent antimicrobial susceptibility test following standard methods. Patients with infectious symptoms such as erythema or oedema and those using systemic or topical antibiotics within 1 month were excluded.Results: In this study, the incidence of isolated bacteria was 24.2%. The middle aged group of 41–65 years presented the lowest rate of bacterial isolation which was 19.4%, while the highest isolation rate (83.1%) was found in patients in the age range of 0–6 years. In every age group, the incidence of bacterial isolation in men was higher than that in women. The top 3 most commonly isolated micro-organisms were Staphylococcus epidermidis (39.7%), Streptococcus pneumoniae (4.5%), and Staphylococcus aureus (2.7%), of which about 83.1% S. aureus were isolated in the group of 0-6 years. We found that coagulase-negative Staphylococcus (CONS) were more resistant to penicillin, macrolides, clindamycin and sulfonamides with the rate ranging from 57.9 to 90.8%, which were highly susceptible to vancomycin, linezolid, rifampin, tetracyclines, and aminoglycosides. Contrasting to CONS, the general resistance rate of S. aureus was significantly lower. Additionally, Streptococcus was susceptible well to the majority of antimicrobial agents, while highly resistant to macrolides and tetracyclines with the rate >80%.Conclusions: In conclusion, our study revealed the incidence and antimicrobial sensitivity profiles of normal conjunctiva bacterial flora in the central area of China, which could be useful in the prevention of ocular infections. Importantly, our data could be used to guide the selection of appropriate prophylactic agents.

Unveiling the key mechanism of temporal lobe epilepsy (TLE) for the development of novel treatments is of increasing interest, and anti-inflammatory miR-146a is now considered a promising molecular target for TLE. In the current study, a C57BL/6 TLE mouse model was established using the lithium-pilocarpine protocol. The seizure degree was evaluated according to the Racine scale, and level 5 was considered the threshold for generalized convulsions. Animals were sacrificed to analyze the hippocampus at three time points (2 h and 4 and 8 weeks after pilocarpine administration to evaluate the acute, latent, and chronic phases, resp.). After intranasal delivery of miR-146a mimics (30 min before pilocarpine injection), the percent of animals with no induced seizures increased by 6.7%, the latency to generalized convulsions was extended, and seizure severity was reduced. Additionally, hippocampal damage was alleviated. While the relative miR-146a levels significantly increased, the expression of its target mRNAs (IRAK-1 and TRAF-6) and typical inflammatory modulators (NF-κB, TNF-α, IL-1β, and IL-6) decreased, supporting an anti-inflammatory role of miR-146a via the TLR pathway. This study is the first to demonstrate that intranasal delivery of miR-146a mimics can improve seizure onset and hippocampal damage in the acute phase of lithium-pilocarpine-induced seizures, which provides inflammation-based clues for the development of novel TLE treatments.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P=0.622 for genotype; P=0.629 for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P=0.014 for allele and P=0.012, for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P=0.002). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P

Our previous in vitro studies suggested that cyclic AMP (cAMP) signaling prevents adriamycin (ADR) and puromycin aminonucleoside (PAN)-induced apoptosis in podocytes. As cAMP is an important second messenger and plays a key role in cell proliferation, differentiation and cytoskeleton formation via protein kinase A (PKA) or exchange protein directly activated by cAMP (Epac) pathways, we sought to determine the role of PKA or Epac signaling in cAMP-mediated protection of podocytes. In the ADR nephrosis model, we found that forskolin, a selective activator of adenylate cyclase, attenuated albuminuria and improved the expression of podocyte marker WT-1. When podocytes were treated with pCPT-cAMP (a selective cAMP/PKA activator), PKA activation was increased in a time-dependent manner and prevented PAN-induced podocyte loss and caspase 3 activation, as well as a reduction in mitochondrial membrane potential. We found that PAN and ADR resulted in a decrease in Mfn1 expression and mitochondrial fission in podocytes. pCPT-cAMP restored Mfn1 expression in puromycin or ADR-treated podocytes and induced Drp1 phosphorylation, as well as mitochondrial fusion. Treating podocytes with arachidonic acid resulted in mitochondrial fission, podocyte loss and cleaved caspase 3 production. Arachidonic acid abolished the protective effects of pCPT-cAMP on PAN-treated podocytes. Mdivi, a mitochondrial division inhibitor, prevented PAN-induced cleaved caspase 3 production in podocytes. We conclude that activation of cAMP alleviated murine podocyte caused by ADR. PKA signaling resulted in mitochondrial fusion in podocytes, which at least partially mediated the effects of cAMP.

Anti-HER2/neu antibody therapy has been reported to mediate tumor regression of HER2/ neu(+) tumors. Here we demonstrated the expression of HER2 in a wide range of human melanoma cells including a primary culture and seven cell lines, and we further investigated whether HER2 could be served as a target for T cell mediated immunotherapy of human melanoma. Specific cytolytic activity of activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2Bi-Ab) against Malme-3M-luc cells was evaluated by bioluminescent signal generated by luciferase reporter which did not alter HER2 expression or proliferation ability of Malme-3M cells. Contrast with unarmed ATC, increased cytotoxic activity of HER2Bi-armed ATC against Malme-3M-luc cells was observed at effector/target (E/T) ratios of 1:1, 5:1, and 20:1. Moreover, HER2Bi-armed ATC expressed higher level of activation marker CD69 and secreted significantly higher level of IFN-γ than unarmed ATC counterpart at the E/T ratio of 20:1. In addition, compared with anti-HER2 mAb (Herceptin®) or unarmed ATC, HER2Bi-armed ATC showed remarkable suppression effect on Malme-3M-luc tumor cells. Furthermore, in melanoma tumor cell xenograft mice, infusion of HER2Bi-armed ATC successfully inhibited the growth of melanoma tumors. The anti-tumor effect of HER2Bi-armed ATC may provide a promising immunotherapy for melanoma in the future.