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Abstract Lactate leads to the imbalance of mitochondria homeostasis, which then promotes vascular calcification. PARP1 can upregulate osteogenic genes and accelerate vascular calcification. However, the relationship among lactate, PARP1, and mitochondrial homeostasis is unclear. The present study aimed to explore the new molecular mechanism of lactate to promote VSMC calcification by evaluating PARP1 as a breakthrough molecule. A coculture model of VECs and VSMCs was established, and the model revealed that the glycolysis ability and lactate production of VECs were significantly enhanced after incubation in DOM. Osteogenic marker expression, calcium deposition, and apoptosis in VSMCs were decreased after lactate dehydrogenase A knockdown in VECs. Mechanistically, exogenous lactate increased the overall level of PARP and PARylation in VSMCs. PARP1 knockdown inhibited Drp1-mediated mitochondrial fission and partially restored PINK1/Parkin-mediated mitophagy, thereby reducing mitochondrial oxidative stress. Moreover, lactate induced the translocation of PARP1 from the nucleus to the mitochondria, which then combined with POLG and inhibited POLG-mediated mitochondrial DNA synthesis. This process led to the downregulation of mitochondria-encoded genes, disturbance of mitochondrial respiration, and inhibition of oxidative phosphorylation. The knockdown of PARP1 could partially reverse the damage of mitochondrial gene expression and function caused by lactate. Furthermore, UCP2 was upregulated by the PARP1/POLG signal, and UCP2 knockdown inhibited Drp1-mediated mitochondrial fission and partially recovered PINK1/Parkin-mediated mitophagy. Finally, UCP2 knockdown in VSMCs alleviated DOM-caused VSMC calcification in the coculture model. The study results thus suggest that upregulated PARP1 is involved in the mechanism through which lactate accelerates VSMC calcification partly via POLG/UCP2-caused unbalanced mitochondrial homeostasis.

Abstract Background Hepatocellular carcinoma (HCC) has a high incidence and mortality worldwide, which seriously threatens people's physical and mental health. Coagulation is closely related to the occurrence and development of HCC. Whether coagulation-related genes (CRGs) can be used as prognostic markers for HCC remains to be investigated. Methods Firstly, we identified differentially expressed coagulation-related genes of HCC and control samples in the datasets GSE54236, GSE102079, TCGA-LIHC, and Genecards database. Then, univariate Cox regression analysis, LASSO regression analysis, and multivariate Cox regression analysis were used to determine the key CRGs and establish the coagulation-related risk score (CRRS) prognostic model in the TCGA-LIHC dataset. The predictive capability of the CRRS model was evaluated by Kaplan–Meier survival analysis and ROC analysis. External validation was performed in the ICGC-LIRI-JP dataset. Besides, combining risk score and age, gender, grade, and stage, a nomogram was constructed to quantify the survival probability. We further analyzed the correlation between risk score and functional enrichment, pathway, and tumor immune microenvironment. Results We identified 5 key CRGs (FLVCR1, CENPE, LCAT, CYP2C9, and NQO1) and constructed the CRRS prognostic model. The overall survival (OS) of the high-risk group was shorter than that of the low-risk group. The AUC values for 1 -, 3 -, and 5-year OS in the TCGA dataset were 0.769, 0.691, and 0.674, respectively. The Cox analysis showed that CRRS was an independent prognostic factor for HCC. A nomogram established with risk score, age, gender, grade, and stage, has a better prognostic value for HCC patients. In the high-risk group, CD4+T cells memory resting, NK cells activated, and B cells naive were significantly lower. The expression levels of immune checkpoint genes in the high-risk group were generally higher than that in the low-risk group. Conclusions The CRRS model has reliable predictive value for the prognosis of HCC patients.

BackgroundThis study was to probe into the relationship between the neutrophil-to-lymphocyte ratio (NLR) and both in-hospital and long-term heart failure risk in patients with acute myocardial infarction (AMI).Methods990 patients with AMI, including 386 with non-ST-segment elevation myocardial infarction (NSTEMI) and 604 with segment elevation myocardial infarction (STEMI) were recruited between January 2019 and March 2022. The in-hospital acute heart failure (AHF) and arrhythmia events were recorded.ResultsThe NLR was significantly greater in the AHF group in STEMI and NSTEMI patients, with a higher frequency of arrhythmia in comparison to the non-AHF group. A high NLR was related to a high level of myocardial injury markers, accompanied with more AHF and arrhythmia events. Multivariate logistic regression analyses revealed that high NLR is independently linked with increased in-hospital AHF and arrhythmia risk. Receiver operating characteristic curve analyses revealed that the prognostic value of NLR for in-hospital AHF was 0.704 in STEMI patients and 0.766 in NSTEMI patients. However, during a median follow-up of 28 months with 32 heart failure patients, there was no significant difference between the low NLR group (n = 18) and the high NLR group (n = 14). Further analysis showed that the two groups did not significantly differ in the occurrence of heart failure within 12 months of discharge.ConclusionOur results indicate that NLR is an independent risk factor of in-hospital AHF in AMI patients. However, NLR has no value in predicting long-term heart failure.

Abstract Background and aims The effect of dapagliflozin (DAPA) on the prognosis of patients with acute myocardial infarction (AMI) is unclear. The present study was conducted to evaluate the association between DAPA administration and adverse events in patients with AMI undergoing percutaneous coronary intervention (PCI). Methods This single-center retrospective analysis study included a total of 786 patients with AMI from January 2019 to August 2021 who were or were not administered DAPA at discharge. The primary endpoint was the composite of major adverse cardiovascular events (MACE), including overall deaths, heart failure, nonfatal MI, nonfatal stroke, and unplanned repeat revascularization (URR). Differences in the triglyceride glucose (TyG) index and the atherogenic index of plasma (AIP) both during hospitalization and 12 months after discharge (if achievable) were also compared. Results During a median follow-up of 23 months, 130 patients had MACE (118 in the DAPA-free group and 12 in the DAPA group). Kaplan–Meier survival analyses revealed that the cumulative incidence of MACE (log-rank test, p = 0.009), heart failure (p = 0.003), nonfatal MI (p = 0.005), and URR (p = 0.031) was higher in the DAPA-free group. In addition, the multivariate Cox analysis showed that DAPA was significantly associated with the reduced risk of MACE (hazard ratio = 0.170, 95% confidence interval = 0.078–0.373, p

Background and aimsThe roles of sodium-glucose cotransporter 2 inhibitor (SGLT2i) in acute heart failure (AHF) risk after acute myocardial infarction (AMI) remain unclear. In this study, we explored the correlation between SGLT2i administration and short-term in-hospital AHF risk in AMI patients.MethodsThis single-center, retrospective, and observational study included 990 AMI patients comprising 386 non-ST-segment elevation myocardial infarction (NSTEMI) and 604 segment elevation myocardial infarction (STEMI) patients enrolled from January 2019 to March 2022. Demographic information, clinical characteristics, medical treatment, and laboratory examination results during hospitalization were extracted from an electronic medical record system. The primary outcome was defined as all-cause AHF during hospitalization.ResultsIn NSTEMI patients, a significantly lower proportion received SGLT2i treatment in the AHF group compared with the non-AHF group. During hospitalization, SGLT2i significantly reduced brain natriuretic peptide levels both in STEMI and NSTEMI patients. Multivariate logistic regression and stratification analyses suggested that SGLT2i is associated with reduced in-hospital AHF risk, and has a strong protective effect against AHF in NSTEMI patients with hypertension. Furthermore, SGLT2i significantly reduced the risk of in-hospital AHF for both patients with diabetes and non-diabetes.ConclusionsSGLT2i can reduce the risk of AHF in AMI patients during hospitalization.

Abstract With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008–2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.

Abstract Background Altered metabolic pathways have recently been considered as potential drivers of idiopathic pulmonary fibrosis (IPF) for the study of drug therapeutic targets. However, our understanding of the metabolite profile during IPF formation is lacking. Methods To comprehensively characterize the metabolic disorders of IPF, a mouse IPF model was constructed by intratracheal injection of bleomycin into C57BL/6J male mice, and lung tissues from IPF mice at 7 days, 14 days, and controls were analyzed by pathology, immunohistochemistry, and Western Blots. Meanwhile, serum metabolite detections were conducted in IPF mice using LC–ESI–MS/MS, KEGG metabolic pathway analysis was applied to the differential metabolites, and biomarkers were screened using machine learning algorithms. Results We analyzed the levels of 1465 metabolites and found that more than one-third of the metabolites were altered during IPF formation. There were 504 and 565 metabolites that differed between M7 and M14 and controls, respectively, while 201 differential metabolites were found between M7 and M14. In IPF mouse sera, about 80% of differential metabolite expression was downregulated. Lipids accounted for more than 80% of the differential metabolite species with down-regulated expression. The KEGG pathway enrichment analysis of differential metabolites was mainly enriched to pathways such as the metabolism of glycerolipids and glycerophospholipids. Eight metabolites were screened by a machine learning random forest model, and receiver operating characteristic curves (ROC) assessed them as ideal diagnostic tools. Conclusions In conclusion, we have identified disturbances in serum lipid metabolism associated with the formation of pulmonary fibrosis, contributing to the understanding of the pathogenesis of pulmonary fibrosis.

Abstract Background Metal(loid)s can promote the spread and enrichment of antibiotic resistance genes (ARGs) in the environment through a co-selection effect. However, it remains unclear whether exposure of microorganisms to varying concentrations of selenium (Se), an essential but potentially deleterious metal(loid) to living organisms, can influence the migration and distribution of ARGs in forest soils. Results Precisely 235 ARGs conferring resistance to seven classes of antibiotics were detected along a Se gradient (0.06–20.65 mg kg−1) across 24 forest soils. (flor)/(chlor)/(am)phenicol resistance genes were the most abundant in all samples. The total abundance of ARGs first increased and then decreased with an elevated available Se content threshold of 0.034 mg kg−1 (P = 2E−05). A structural equation model revealed that the dominant mechanism through which Se indirectly influences the vertical migration of ARGs is by regulating the abundance of the bacterial community. In addition, the methylation of Se (mediated by tehB) and the repairing of DNA damages (mediated by ruvB and recG) were the dominant mechanisms involved in Se resistance in the forest soils. The co-occurrence network analysis revealed a significant correlated cluster between Se-resistance genes, MGEs and ARGs, suggesting the co-transfer potential. Lelliottia amnigena YTB01 isolated from the soil was able to tolerate 50 μg mL−1 ampicillin and 1000 mg kg−1 sodium selenite, and harbored both Se resistant genes and ARGs in the genome. Conclusions Our study demonstrated that the spread and enrichment of ARGs are enhanced under moderate Se pressure but inhibited under severe Se pressure in the forest soil (threshold at 0.034 mg kg−1 available Se content). The data generated in this pilot study points to the potential health risk associated with Se contamination and its associated influence on ARGs distribution in soil.

BackgroundThe incidence, prevalence, and mortality of ischemic stroke (IS) continue to rise, resulting in a serious global disease burden. The prediction models have a great value in the early prediction and diagnosis of IS.MethodsThe R software was used to screen the differentially expressed genes (DEGs) of IS and control samples in the datasets GSE16561, GSE58294, and GSE37587 and analyze DEGs for enrichment analysis. The feature genes of IS were obtained by several machine learning algorithms, including the least absolute shrinkage and selector operation (LASSO) logistic regression, the support vector machine-recursive feature elimination (SVM-RFE), and the Random Forest (RF). The IS diagnostic models were constructed based on transcriptomics by machine learning and artificial neural network (ANN).ResultsA total of 69 DEGs, mainly involved in immune and inflammatory responses, were identified. The pathways enriched in the IS group were complement and coagulation cascades, lysosome, PPAR signaling pathway, regulation of autophagy, and toll-like receptor signaling pathway. The feature genes selected by LASSO, SVM-RFE, and RF were 17, 10, and 12, respectively. The area under the curve (AUC) of the LASSO model in the training dataset, GSE22255, and GSE195442 was 0.969, 0.890, and 1.000. The AUC of the SVM-RFE model was 0.957, 0.805, and 1.000, respectively. The AUC of the RF model was 0.947, 0.935, and 1.000, respectively. The models have good sensitivity, specificity, and accuracy. The AUC of the LASSO+ANN, SVM-RFE+ANN, and RF+ANN models was 1.000, 0.995, and 0.997, respectively, in the training dataset. However, the AUC of LASSO+ANN, SVM-RFE+ANN, and RF+ANN models was 0.688, 0.605, and 0.619, respectively, in the GSE22255 dataset. The AUC of the LASSO+ANN and RF+ANN models was 0.740 and 0.630, respectively, in the GSE195442 dataset. In the training dataset, the sensitivity, specificity, and accuracy of the LASSO+ANN model were 1.000, 1.000, and 1.000, respectively; of the SVM-RFE+ANN model were 0.946, 0.982, and 0.964, respectively; and of the RF+ANN model were 0.964, 1.000, and 0.982, respectively. In the test datasets, the sensitivity was very satisfactory; however, the specificity and accuracy were not good.ConclusionThe LASSO, SVM-RFE, and RF models have good prediction abilities. However, the ANN model is efficient at classifying positive samples and is unsuitable at classifying negative samples.

ABSTRACT Bacterial motility has great medical and ecological significance because of its essential role in bacterial survival and pathogenesis. Cyclic dimeric GMP (c-di-GMP), a second messenger in bacteria, is the predominant regulator of flagellar synthesis and motility and possesses turnover mechanisms that have been thoroughly investigated. Therefore, much attention has been focused on identifying the upstream stimulatory signals and downstream modules that respond to altered c-di-GMP levels. Here, we systematically analyzed c-di-GMP cyclases and phosphodiesterases in Stenotrophomonas maltophilia to screen for motility regulators. Of these enzymes, we identified and characterized a new phosphodiesterase named SisP, which was found to facilitate bacterial swimming upon stimulation with ferrous iron. SisP-mediated degradation of c-di-GMP leads to FsnR-dependent transcription of flagellar genes. Remarkably, c-di-GMP controls FsnR via two independent mechanisms: by direct binding and indirectly by modulating its phosphorylation state. In this study, we deciphered a novel “one stone, two birds” regulatory strategy of c-di-GMP and uncovered the signal that stimulates c-di-GMP hydrolysis. Facilitation of bacterial swimming motility by ferrous iron might contribute to the higher risk of bacterial infection in acutely ill patients. IMPORTANCE Stenotrophomonas maltophilia has become a great threat to human health because of the high mortality of infected patients. Swimming motility plays a crucial role in regulating bacterial virulence and adaptation. However, limited progress has been made in cyclic dimeric GMP (c-di-GMP) controlling swimming motility of S. maltophilia. Here, we characterized c-di-GMP turnover enzymes encoded by S. maltophilia and dissected the regulatory details of a phosphodiesterase named SisP. We demonstrated that SisP degrades c-di-GMP to fully activate FsnR through directly releasing FsnR from the FsnR-c-di-GMP complex and indirectly increasing its phosphorylation level. This finding uncovered a quantitative, rather than an on-off, regulatory manner employed by c-di-GMP to regulate activities of its effectors. Identification of the specific activation of SisP by ferrous iron proposes SisP as a putative drug-target for controlling bacterial infection and ferrous iron at the wounds or cuts as a putative factor contributing to the higher risk of bacterial infection.

The stability of geogrid-reinforced soil structure is closely related to the interface characteristics between geogrid and soil. However, the creep behavior of the soil–geogrid interface is still unrevealed. In this study, using a modified stress-controlled pullout device, influence of the normal pressure, dry density, and water content on creep behavior of interface of compacted loess and high-density polyethylene (HDPE) geogrid is investigated. A three-parameter empirical model and a Merchant element model were established through fitting analysis. Analysis results show that the normal pressure, dry density, and water content have significant effects on the creep shear displacement of the reinforced soil interface. Under the same pullout level, creep displacement of the interface increases with the increase of water content and decreases with the increase of dry density and normal pressure. Both the three-parameter empirical model and Merchant element model can describe the creep characteristics of the reinforced soil interface. The Merchant model is more accurate in the early stage, while the three-parameter empirical model is more suitable for predicting the long-term creep deformation of the interface of compacted loess and geogrid.

Property of geotechnical materials has inherent uncertainty due to the complex formation process and inevitable test error. However, existing long-term deformation prediction methods for geotechnical structure such as a filling embankment are deterministic, which ignores the uncertainty of soil property. In this study, the uncertainty of creep behavior of compacted loess was investigated through repetitive creep tests and statistical analysis. Five different loading levels and two loading modes were considered in the tests. The creep test was repeated 45 times for each condition. Through a statistical analysis for the test results, a modified Merchant creep model was established to improve the accuracy of long-term deformation prediction. An empirical transformation equation between staged loading and separated loading mode of the creep test results was also introduced to improve applicability of the method. On this basis, a non-deterministic predication method for post-construction settlement of loess fill embankment was proposed. Furthermore, the proposed method was applied to the prediction of the post-construction of a 61.5 m loess filling embankment. The measured on-site post-construction settlement value falls within the 95% confidence interval of the predicted range which proves the efficiency and practicability of the proposed non-deterministic predication method. Compared to deterministic methods, the proposed method can describe the predicted deformation in a probabilistic way in the form of contour plot. The proposed method provides a basic approach for the probabilistic design and reliability assessment of filling engineering.

Abstract Background Emerging data has suggested that Tregs, Th17, Th1 and Th2 are correlated with early immune mechanisms by controlling Plasmodium infection. Plasmodium infection appeared to impair the antigen presentation and maturation of DCs, leading to attenuation of specific cellular immune response ultimately. Hence, in this study, we aim to evaluate the relevance between DCs and Tregs/Th17 populations in the process and outcomes of infection with Plasmodium yoelii 17XL (P.y17XL). Methods DCs detection/analysis dynamically was performed by Tregs depletion or Th17 neutralization in P.y17XL infected BALB/c mice via flow cytometry. Then the levels of cytokines production were detected using enzyme-linked mmunosorbent assay (ELISA). Results Our results indicated that Tregs depletion or Th17 neutralization in BALB/c mice infected with P.y17XL significantly up-regulated the percentages of mDC and pDC, increased the expressions of major histocompatibility complex (MHC) class II, CD80, CD86 on DCs and the levels of IL-10/IL-12 secreted by DCs, indicating that abnormal amplification of Tregs or Th17 may damage the maturation and function of DCs during the early stage of malaria infection. Interestingly, we also found that the abnormal amplification of Th17, as well as Tregs, could inhibit the maturation of DCs. Conclusions Tregs skewing or Th17 amplification during the early stage of malaria infection may inhibit the maturation and function of DCs by modifying the subsets of DCs, expressions of surface molecules on DCs and secretion mode of cytokines.

Large eddy simulation (LES) explicitly calculates the large-scale vortex field and parameterizes the small-scale vortices. In this study, LES and κ-ε models were developed for a specific geometrical configuration of backward-facing step (BFS). The simulation results were validated with particle image velocimetry (PIV) measurements and direct numerical simulation (DNS). This LES simulation was carried out with a Reynolds number of 9000 in a pressurized water tunnel with an expansion ratio of 2.00. The results indicate that the LES model can reveal large-scale vortex motion although with a larger grid-cell size. However, the LES model tends to overestimate the top wall separation and the Reynolds stress components for the BFS flow simulation without a sufficiently fine grid. Overall, LES is a potential tool for simulating separated flow controlled by large-scale vortices. Keywords: Large eddy simulation, κ-ε model, Backward-facing step, Direct numerical simulation, Large-scale vortices, Particle image velocimetry

Recently, a growing body of evidence has suggested that abnormal ovarian angiogenesis, secondary to the imbalance between various angiogenic markers, is involved in the pathogenesis of PCOS, and this has led to the use of various interventions (such as Diane-35) to restore the normal ovarian angiogenesis. Therefore, we conducted the current investigation to determine the role of such markers (endothelial growth factor (VEGF), endostatin (ES), and thrombospondin-1 (TSP-1)) in the pathogenesis of PCOS along with the associated changes in ovarian blood flow in patients with PCOS compared to healthy controls, both before and after a course of oral contraception. A total of 381 patients with PCOS and 98 healthy females of childbearing age were recruited from July 2014 to June 2017 at the Reproductive Center of the Second Affiliated Hospital of Harbin Medical University. The serum levels of VEGF, ES, and TSP-1 were determined by enzyme-linked immunosorbent assay, while ovarian perfusion was measured by the pulsatility index (PI) and resistance index (RI) by using transvaginal color Doppler ultrasound. Repeated analyses were carried out after 3 months of Diane-35 treatment. Post-treatment serum levels of luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio of patients with PCOS decreased significantly (P

Background: During the COVID-19 epidemic period, Traditional Chinese Medicine (TCM) course for international students of Medical Bachelor, Bachelor of Surgery (MBBS) program in Zhejiang University has shifted from traditional classroom to online environment. This study aimed to investigate MBBS international students’ perception on online TCM course, and to assess the online learning efficacy. Methods: A total of 84 MBBS international students attending course of “Basic Traditional Chinese Medicine” during 2020 academic years at Zhejiang University were enrolled in this study. A quantitative questionnaire was respectively completed before and after the TCM course using a pretest–post-test design. By means of two online learning platforms, Learning in ZJU and DingTalk, TCM course was broadcast in both live and archived format to students. Results: A total of 48 participants completed both baseline and follow-up questionnaires. The majority of participants preferred face-to-face classroom learning (26, 54.17% of total) when compared with online learning. Students felt that the course had brought in much benefits (mean 3.88, SD 0.87), and they were satisfied with the course content (mean 3.83, SD 0.95). Students’ TCM related knowledge and their behaviors of discussion and consulting were significantly improved by online TCM course (all P

Precipitation behavior and growth kinetics of Ti-bearing inclusions in SWRH 92A tire cord steel were analyzed in the present work. The calculated results showed that higher cooling rate would lead to a higher precipitation ratio of solution elements and make the precipitation time of inclusions earlier. However, both TiCyN1−y (a continuous solid solution between TiC and TiN, y denotes the molar ratio of TiC in TiCyN1−y) and TiN could only precipitate in the two-phase region at the very late stage during the solidification processes, with the solid fraction exceeds 0.99. The precipitation time of TiCyN1−y was a little earlier than that of TiN as well as the value of y in the range of 0.1577–0.1617 (cooling rate: 0.5–2 K/s) was also obtained. Particle size of Ti-bearing inclusions decreased with the increasing cooling rate and were within the range of 1.5–6.5 μm under the calculated conditions, which accorded well with the size observed by the FE-SEM (field emission scanning electronic microscope). Increasing the contents of both N and Ti could lead to an earlier precipitation time of Ti-bearing inclusions and make the particle size bigger, while the effect of N is much larger than that of Ti. The results obtained by the adopted model were in well consistent with those of the statistical analysis. This work may give an important guidance on the understanding of the precipitation and growth processes of Ti-bearing inclusions in tire cord steel.

Objectives Di(2-ethylhexyl) phthalate (DEHP) is a common endocrine-disrupting chemical, which has potential reproductive toxicity. This study aimed to explore the effects of DEHP exposure in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization. Methods In this case-control study, DEHP levels in follicular fluid (FF) of women with PCOS (n = 56) and controls (n = 51) were measured. The in vitro effects of DEHP exposure on primary-cultured human granulosa cells (GCs) and a steroidogenic human granulosa-like tumor cell line (KGN cells) were analyzed. Results Concentrations of DEHP in FF were significantly higher in women with PCOS than in controls. The clinical pregnancy rate was significantly lower in women with PCOS with high levels of DEHP than in controls. The levels of androgens produced by human GCs were significantly increased following DEHP exposure. Compared with controls, DEHP-treated human GCs and KGN cells showed significantly lower viability, cell cycle arrest, higher apoptosis, and altered expression of apoptosis-related genes. Conclusion Women with PCOS are exposed to increased levels of DEHP in follicles, which may be associated with pregnancy loss following in vitro fertilization. DEHP may disrupt steroid production, balance in cellular proliferation, and apoptosis in human granulosa cells.

Abstract Background Polycystic ovary syndrome (PCOS), whose etiology remains uncertain, is a highly heterogenous and genetically complex endocrine disorder. The aim of this study was to identify differentially expressed genes (DEGs) in granulosa cells (GCs) from PCOS patients and make epigenetic insights into the pathogenesis of PCOS. Results Included in this study were 110 women with PCOS and 119 women with normal ovulatory cycles undergoing in vitro fertilization acting as the control group. RNA-seq identified 92 DEGs unique to PCOS GCs in comparison with the control group. Bioinformatic analysis indicated that synthesis of lipids and steroids was activated in PCOS GCs. 5-Methylcytosine analysis demonstrated that there was an approximate 25% reduction in global DNA methylation of GCs in PCOS women (4.44 ± 0.65%) compared with the controls (6.07 ± 0.72%; P

Summary: Recognition of the host plant is a prerequisite for infection by pathogenic bacteria. However, how bacterial cells sense plant-derived stimuli, especially chemicals that function in regulating plant development, remains completely unknown. Here, we have identified a membrane-bound histidine kinase of the phytopathogenic bacterium Xanthomonas campestris, PcrK, as a bacterial receptor that specifically detects the plant cytokinin 2-isopentenyladenine (2iP). 2iP binds to the extracytoplasmic region of PcrK to decrease its autokinase activity. Through a four-step phosphorelay, 2iP stimulation decreased the phosphorylation level of PcrR, the cognate response regulator of PcrK, to activate the phosphodiesterase activity of PcrR in degrading the second messenger 3′,5′-cyclic diguanylic acid. 2iP perception by the PcrK-PcrR remarkably improves bacterial tolerance to oxidative stress by regulating the transcription of 56 genes, including the virulence-associated TonB-dependent receptor gene ctrA. Our results reveal an evolutionarily conserved, inter-kingdom signaling by which phytopathogenic bacteria intercept a plant hormone signal to promote adaptation to oxidative stress. : How pathogenic bacteria use receptors to recognize the signals of the host plant is unknown. Wang et al. have identified a bacterial receptor histidine kinase that specifically senses the plant hormone cytokinin. Through a four-step phosphorelay, cytokinin perception triggers degradation of a second messenger, c-di-GMP, to activate the bacterial response to oxidative stress. Keywords: histidine kinase, ligand, cytokinin, autokinase activity, phosphorelay, response regulator, two-component signal transduction system, Xanthomonas campestris pv. campestris, virulence, oxidative stress

Abstract: Dissecting the genetic relationships among gluten-related traits is important for high quality wheat breeding. Quantitative trait loci (QTLs) analysis for gluten strength, as measured by sedimentation volume (SV) and gluten index (GI), was performed using the QTLNetwork 2.0 software. Recombinant inbred lines (RILs) derived from the winter wheat varieties Shannong 01-35×Gaocheng 9411 were used for the study. A total of seven additive QTLs for gluten strength were identified using an unconditional analysis. QGi1D-13 and QSv1D-14 were detected through unconditional and conditional QTLs mapping, which explained 9.15–45.08% of the phenotypic variation. QTLs only identified under conditional QTL mapping were located in three marker intervals: WPT-3743–GLU-D1 (1D), WPT-7001–WMC258 (1B), and WPT-8682–WPT-5562 (1B). Six pairs of epistatic QTLs distributed nine chromosomes were identified. Of these, two main effect QTLs (QGi1D-13 and QSv1D-14) and 12 pairs of epistatic QTLs were involved in interactions with the environment. The results indicated that chromosomes 1B and 1D are important for the improvement of gluten strength in common wheat. The combination of conditional and unconditional QTLs mapping could be useful for a better understanding of the interdependence of different traits at the QTL molecular level.

Abstract c-di-GMP is a cellular second messenger that regulates diverse bacterial processes, including swimming, biofilm formation and virulence. However, in Stenotrophomonas maltophilia, a nosocomial pathogen that frequently infects immunodeficient or immunoincompetent patients, the regulatory function of c-di-GMP remains unclear. Here we show that BsmR is a negative regulator of biofilm development that degrades c-di-GMP through its EAL domain. Increasing BsmR expression resulted in significant increase in bacterial swimming and decrease in cell aggregation. BsmR regulates the expression of at least 349 genes. Among them, 34 involved in flagellar assembly and a flagellar-assembly-related transcription factor (fsnR) are positively regulated. Although BsmR is a response regulator of the two-component signaling system, its role in biofilm formation depends on the expression level of its respective gene (bsmR), not on the protein’s phosphorylation level. A transcription factor, BsmT, whose coding gene is located in the same tetra-cistronic operon as bsmR, was shown to directly bind to the promoter region of the operon and, through a positive regulatory loop, modulate bsmR transcription. Thus, our results revealed that the c-di-GMP signaling pathway controls biofilm formation and swimming in S. maltophilia, suggesting c-di-GMP signaling as a target in the development of novel antibacterial agents to resist this pathogen.

Abstract This systematic review and meta-analysis was designed to investigate whether maternal psychological stress and recent life events are associated with an increased risk of miscarriage. A literature search was conducted to identify studies reporting miscarriage in women with and without history of exposure to psychological stress (the only exposure considered). The search produced 1978 studies; 8 studies were suitable for analysis. A meta-analysis was performed using a random-effects model with effect sizes weighted by the sampling variance. The risk of miscarriage was significantly higher in women with a history of exposure to psychological stress (OR 1.42, 95% CI 1.19–1.70). These findings remained after controlling for study type (cohort and nested case-control study OR 1.33 95% CI 1.14–1.54), exposure types (work stress OR 1.27, 95% CI 1.10–1.47), types of controls included (live birth OR 2.82 95% CI: 1.64–4.86). We found no evidence that publication bias or study heterogeneity significantly influenced the results. Our finding provides the most robust evidence to date, that prior psychological stress is harmful to women in early pregnancy.

The two-component signalling system (TCS) comprising a histidine kinase (HK) and a response regulator (RR) is the predominant bacterial sense-and-response machinery. Because bacterial cells usually encode a number of TCSs to adapt to various ecological niches, the specificity of a TCS is in the centre of regulation. Specificity of TCS is defined by the capability and velocity of phosphoryl transfer between a cognate HK and a RR. Here, we provide genetic, enzymology and structural data demonstrating that the second messenger cyclic-di-GMP physically and specifically binds to RavS, a HK of the phytopathogenic, gram-negative bacterium Xanthomonas campestris pv. campestris. The [c-di-GMP]-RavS interaction substantially promotes specificity between RavS and RavR, a GGDEF-EAL domain-containing RR, by reinforcing the kinetic preference of RavS to phosphorylate RavR. [c-di-GMP]-RavS binding effectively decreases the phosphorylation level of RavS and negatively regulates bacterial swimming. Intriguingly, the EAL domain of RavR counteracts the above regulation by degrading c-di-GMP and then increasing the level of phosphorylated RavS. Therefore, RavR acts as a bifunctional phosphate sink that finely controls the level of phosphorylated RavS. These biochemical processes interactively modulate the phosphoryl flux between RavS-RavR and bacterial lifestyle transition. Our results revealed that c-di-GMP acts as an allosteric effector to dynamically modulate specificity between HK and RR.

Nitric oxide (NO) production via NO synthase (NOS) plays a vital role in plant tolerance to salt stress. However, the factor(s) regulating NOS-like activity in plant salt stress tolerance remains elusive. Here, we show that Arabidopsis SORTING NEXIN 1 (SNX1), which can restore H2O2-induced NO accumulation in yeast Δsnx4 mutant, functions in plant salt stress tolerance. Salt stress induced NO accumulation through promoted NOS-like activity in the wild type, but this induction was repressed in salt-stressed snx1-2 mutant with the mutation of SNX1 because NOS-like activity was inhibited in the mutant. Consistently, snx1-2 displayed reduced tolerance to high salinity with decreased survival rate compared with the wild type, and exogenous treatment with NO donor significantly rescued the hypersensitivity of the mutant to salt stress. In addition, the snx1-2 mutant with reduced NOS-like activity repressed the expression of stress-responsive genes, decreased proline accumulation and anti-oxidant ability compared with wild-type plants when subjected to salt stress. Taken together with our finding that salt induces the expression of SNX1, our results reveal that SNX1 plays a crucial role in plant salt stress tolerance by regulating NOS-like activity and thus NO accumulation.

Tunable photoluminescent-functionalized carbon quantum dots CQDs@Ln (TFA)3 (Ln = Eu, Tb; TFA: trifluoroacetylacetone) were designed and synthesized by introducing lanthanide complexes into the modified CQDs surface through the carboxyl group. The as-prepared CQDs@Ln (TFA)3 emit strong blue–green light with the peak at 435 nm and simultaneously show the characteristic emission of Ln3+ under irradiation of 365 nm light in aqueous solution. Moreover, these functionalized CQDs exhibit excellent photoluminescence properties. In addition, a white luminescent solution CQDs@Eu/Tb (TFA)3 was obtained by adjusting the ratio of Eu3+/Tb3+ and the excitation wavelengths. Moreover, CQDs@Tb (TFA)3 can be utilized as a fluorescent probe for the sensitive and selective detection of MnO4− without interference from other ions in aqueous solution. These results provide the meaningful data for the multicomponent assembly and the photoluminescent-functionalized materials based on the modified CQDs and lanthanide, which can be expected to have potential application in photocatalytic or sensors.

As well as their importance to nutrition, fatty acids (FA) represent a unique group of quorum sensing chemicals that modulate the behavior of bacterial population in virulence. However, the way in which full-length, membrane-bound receptors biochemically detect FA remains unclear. Here, we provide genetic, enzymological and biophysical evidences to demonstrate that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, a medium-chain FA diffusible signal factor (DSF) binds directly to the N-terminal, 22 amino acid-length sensor region of a receptor histidine kinase (HK), RpfC. The binding event remarkably activates RpfC autokinase activity by causing an allosteric change associated with the dimerization and histidine phosphotransfer (DHp) and catalytic ATP-binding (CA) domains. Six residues were found essential for sensing DSF, especially those located in the region adjoining to the inner membrane of cells. Disrupting direct DSF-RpfC interaction caused deficiency in bacterial virulence and biofilm development. In addition, two amino acids within the juxtamembrane domain of RpfC, Leu172 and Ala178, are involved in the autoinhibition of the RpfC kinase activity. Replacements of them caused constitutive activation of RpfC-mediated signaling regardless of DSF stimulation. Therefore, our results revealed a biochemical mechanism whereby FA activates bacterial HK in an allosteric manner, which will assist in future studies on the specificity of FA-HK recognition during bacterial virulence regulation and cell-cell communication.

Objectives. To explore the relationship between insulin levels and nonpsychotic dementia. Methods. Six electronic databases (PubMed, Cochrane, SCI, CNKI, VIP, and Wanfang) were searched from January 1, 2007, to March 1, 2017. Experimental or observational studies that enrolled people with nonpsychotic dementia or abnormal insulin levels in which insulin levels or MMSE scores (events in nonpsychotic dementia) were the outcome measures. Random-effects models were chosen for this meta-analysis. Sample size, mean, s.d., and events were primarily used to generate effect sizes (with the PRIMA registration number CRD42017069860). Results. 50 articles met the final inclusion criteria. Insulin levels in cerebrospinal fluid were lower (Hedges’ g = 1.196, 95% CI = 0.238 to 2.514, and P=0.014), while the levels in peripheral blood were higher in nonpsychotic dementia patients (Hedges’ g = 0.853 and 95% CI = 0.579 to 1.127), and MMSE scores were significantly lower in the high insulin group than in the healthy control group (Hedges’ g = 0.334, 95% CI = 0.249 to 0.419, and P=0.000). Conclusions. Our comprehensive results indicate that blood insulin levels may increase in patients with nonpsychotic dementia.

A novel dimer of piceatannol glycoside, named rheumaustralin (1) was isolated from the underground parts of the ethnomedicinal plant Rheum austral (Polygonaceae) collected from Tibet together with 17 known compounds, including rheumin (2), 2,5-dimethyl-7-hydroxychromone (3), 2,5-dimethylchromone-7-O-β-d-glucopyranoside (4), 7-hydroxy-2-(2'-hydroxypropyl)-5-methylchromone (5), torachrysone (6) torachrysone-8-O-β-d-glucopyranoside (7), 4-(4'-hydroxyphenyl)-2-butanone-4'-O-β-d-glucopyranoside (8), amabiloside (9), N-trans-feruloyl tyramine (10), chrysophanol (11), aloe-emodin (12), emodin (13), physcion (14), physcion-1-O-β-d-glucopyranoside (15), emodin-8-O-β-d-glucopyranoside (16), d-catechin (17) and gallic acid (18). Their structures were determined by combined spectroscopic methods and by comparison of their spectral data with those reported in literature. Compounds 1–10 were tested for their ability to scavenge 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical.

AIM: To establish a reference range of retinal nerve fiber layer(RNFL)thickness by optical coherence tomography(OCT)in Chinese teenagers aged from 13 to 18 years old, and investigate its relationship with age, eye side, gender, and ethnic group.METHODS: A total of 402 eyes from 201 normal Chinese aged from 13 to 18 years old were recruited for this study. Optic disk with 3.4mm diameter circle in different global average, quadrant and part-time bit retinal nerve fiber layer thickness(RNFLT)was measured by RNFL thickness average analysis program. Their RNFLT at different part-time bit, quadrant and global average RNFLT around the disc were measured by OCT with 3.4mm diameter circle, using the RNFL thickness average analysis program. The data was analyzed with SPSS statistical 19.0. The influences of several factors(such as age, eye side, gender, and ethnic group)on RNFLT were also analyzed.RESULTS: The global average RNFLT at 13, 14, 15, 16, 17, 18 years old was 108.32±9.42μm, 109.23±9.67μm, 110.36±11.14μm, 111.27±10.21μm, 109.23±9.67μm, 112.11±8.83μm respectively. RNFLT of right eyes was 109.82±8.93μm and of left eyes was 110.33±9.89μm. All of the male's average RNFLT was 110.14±10.02μm, and all of the female's average RNFLT was 109.96±11.22μm. The average RNFLT of Han nationality was 110.22±9.31μm and of non-Han nationality was 109.87±8.65μm. The average RNFLT of all was 110.02±9.87μm, the RNFLT at the superior, nasal, inferior and temporal quadrant was 146.56 ±18.88μm, 76.49±13.28μm, 136.64±16.29μm, 82.01±12.55μm respectively. There was no significant difference in gender, eye side, and ethnic group(all PCONCLUSION: This study has established a normal standard reference of RNFLT and its related indexes by OCT in Chinese teenagers aged 13-18 years old. Gender, age, eye side, and ethnic group have no effect on their RNFLT, which has significant difference with adult's data. And for the diagnosis and follow-up of diseases involving in RNFL changes, the adult's data can not be used.

Both iron starvation and excess are detrimental to cellular life, especially for animal and plant pathogens since they always live in iron-limited environments produced by host immune responses. However, how organisms sense and respond to iron is incompletely understood. Herein, we reveal that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, VgrS (also named ColS) is a membrane-bound receptor histidine kinase that senses extracytoplasmic iron limitation in the periplasm, while its cognate response regulator, VgrR (ColR), detects intracellular iron excess. Under iron-depleted conditions, dissociation of Fe3+ from the periplasmic sensor region of VgrS activates the VgrS autophosphorylation and subsequent phosphotransfer to VgrR, an OmpR-family transcription factor that regulates bacterial responses to take up iron. VgrR-VgrS regulon and the consensus DNA binding motif of the transcription factor VgrR were dissected by comparative proteomic and ChIP-seq analyses, which revealed that in reacting to iron-depleted environments, VgrR directly or indirectly controls the expressions of hundreds of genes that are involved in various physiological cascades, especially those associated with iron-uptake. Among them, we demonstrated that the phosphorylated VgrR tightly represses the transcription of a special TonB-dependent receptor gene, tdvA. This regulation is a critical prerequisite for efficient iron uptake and bacterial virulence since activation of tdvA transcription is detrimental to these processes. When the intracellular iron accumulates, the VgrR-Fe2+ interaction dissociates not only the binding between VgrR and the tdvA promoter, but also the interaction between VgrR and VgrS. This relieves the repression in tdvA transcription to impede continuous iron uptake and avoids possible toxic effects of excessive iron accumulation. Our results revealed a signaling system that directly senses both extracytoplasmic and intracellular iron to modulate bacterial iron homeostasis.

Two new resveratrol trimer derivatives, named rheumlhasol A (1) and rheumlhasol B (2) were isolated from the methanolic extract of roots of Rheum lhasaense A. J. Li et P. K. Hsiao together with four known resveratrol dimer derivatives, including maximol A (3), gnetin C (4), e-viniferin (5), and pallidol (6). The structures were determined by combined spectroscopic methods and by comparison of their spectral data with those reported in the literature. All the compounds isolated from R. lhasaense were tested for their ability to scavenge1,1-diphenyl-2-picrylhydrazyl (DPPH) radical.

In through-wall radar imaging (TWRI), ambiguities in wall characteristics including the thickness and the relative permittivity will distort the image and shift the imaged target position. To quickly and accurately estimate the wall parameters, an approach based on a support vector machine (SVM) is proposed. In TWRI problem, the nonlinearity is embodied in the relationship between backscatter data and the wall parameters, which can be obtained through the SVM training process. Measurement results reveal that once the training phase is completed, the technique only needs no more than one second to estimate wall parameters with acceptable errors. Then through-wall images are reconstructed using a back-projection (BP) algorithm by a finite-difference time-domain (FDTD) simulation. Noiseless and noisy measurements are discussed; the simulation results demonstrate that noisy contamination has little influence on the imaging quality. Furthermore, the feasibility and the validity are tested by a more realistic situation. The results show that high-quality and focused images are obtained regardless of the errors in the wall parameter estimates.

AIM: To observe the effect of cataract extraction and intraocular lens implantation with manual small incision cataract surgery under surface anesthesia in the Primary Hospitals.METHODS: Totally, 372 eyes of 358 cataract cases, in our hospital from January 2010 to March 2013, underwent cataract extraction and intraocular lens implantation with manual small incision cataract surgery under surface anesthesia. Intraoperative pain, postoperative complications and visual acuity were observed.RESULTS: In the process of surgery, patients without pain and being-cooperated were recorded in 342 eyes(91.9%), that occasionally felt slight pain, but within endure and the operation was completed successfully were recorded in 17 eyes(4.6%). There were 13 eyes quit, 8 eyes(2.2%)of them because of the intolerable pain, the other 5 eyes(1.3%)of the ceaseless movement of the eye. The best corrected visual acuity on the 3rd day after operation of 4.0～4.5 were observed in 57 eyes(15.9%), 4.5～4.8 in 213 eyes(59.3%), above 4.8 in 89 eyes(24.8%).CONCLUSION: The cataract extraction and intraocular lens implantation with manual small incision cataract surgery under surface anesthesia can avoid corresponding complications, reduce the operation time obviously and ensure better quality of operation. It's suitable to carry out the prevention and treatment of blindness at the Primary Hospitals.

PurposeTo investigate the mechanism of the anti-epileptic effect of Ganoderma lucidum polysaccharides (GLP), the changes of intracellular calcium and CaMK II α expression in a model of epileptic neurons were investigated.MethodPrimary hippocampal neurons were divided into: 1) Control group, neurons were cultured with Neurobasal medium, for 3 hours; 2) Model group I: neurons were incubated with Mg(2+) free medium for 3 hours; 3) Model group II: neurons were incubated with Mg(2+) free medium for 3 hours then cultured with the normal medium for a further 3 hours; 4) GLP group I: neurons were incubated with Mg(2+) free medium containing GLP (0.375 mg/ml) for 3 hours; 5) GLP group II: neurons were incubated with Mg(2+) free medium for 3 hours then cultured with a normal culture medium containing GLP for a further 3 hours. The CaMK II α protein expression was assessed by Western-blot. Ca(2+) turnover in neurons was assessed using Fluo-3/AM which was added into the replacement medium and Ca(2+) turnover was observed under a laser scanning confocal microscope.ResultsThe CaMK II α expression in the model groups was less than in the control groups, however, in the GLP groups, it was higher than that observed in the model group. Ca(2+) fluorescence intensity in GLP group I was significantly lower than that in model group I after 30 seconds, while in GLP group II, it was reduced significantly compared to model group II after 5 minutes.ConclusionGLP may inhibit calcium overload and promote CaMK II α expression to protect epileptic neurons.

Epilepsy can cause cerebral transient dysfunctions. Ganoderma lucidum spores (GLS), a traditional Chinese medicinal herb, has shown some antiepileptic effects in our previous studies. This was the first study of the effects of GLS on cultured primary hippocampal neurons, treated with Mg(2+) free medium. This in vitro model of epileptiform discharge hippocampal neurons allowed us to investigate the anti-epileptic effects and mechanism of GLS activity. Primary hippocampal neurons from

Piroplasmosis is a serious debilitating and sometimes fatal disease. Phylogenetic relationships within piroplasmida are complex and remain unclear. We compared the intron-exon structure and DNA sequences of the RPS8 gene from Babesia and Theileria spp. isolates in China. Similar to 18S rDNA, the 40S ribosomal protein S8 gene, RPS8, including both coding and non-coding regions is a useful and novel genetic marker for defining species boundaries and for inferring phylogenies because it tends to have little intra-specific variation but considerable inter-specific difference. However, more samples are needed to verify the usefulness of the RPS8 (coding and non-coding regions) gene as a marker for the phylogenetic position and detection of most Babesia and Theileria species, particularly for some closely related species.

BACKGROUND: To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure-quality-adjusted life years (QALYs)-was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis. CONCLUSIONS/SIGNIFICANCE: tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China, infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA.