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Meng-Meng Zheng,1,&ast; Ming-Xing Guo,2,&ast; Li-Min Shang,1,&ast; Jian Zhang,1 Jun Lin,1 Ye Tian,1 Xiang-Li Cui,2,&ast; Yi-Chen Zhu1,&ast; 1Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang-Li Cui, Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email xianglicui@ccmu.edu.cn Yi-Chen Zhu, Department of Urology, Capital Medical University, Beijing Friendship Hospital, No. 95 Yong’an Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email zhuyc@ccmu.edu.cnBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has proven to be difficult to control and typically presents with devastating effects.Methods: This retrospective study was conducted on the renal recipients at our institution between January 2021 to January 2022. Clinical data was collected to identify factors associated with CRKP infection and clinical outcomes.Results: There were 104 cases out of 186 total renal recipients who presented with at least one infection within 3 months after KT, and 14 cases developed unfavorable clinical outcomes. We identified 16 confirmed CRKP infected cases with the incidence of 8.60%. Possible donor derived infection (DDI) (OR = 6.743; 95% CI: 1.477– 30.786; P = 0.014) were independent risk factors for the occurrence of CRKP infection of renal recipients in our analysis, CRKP infection (OR = 20.723; 95% CI: 3.448– 124.547; P = 0.001) and pneumonia (OR = 28.458; 95% CI: 1.956– 413.984 P = 0.014) were independent risk factors for the occurrence of unfavorable clinical outcomes following KT, and the occurrence of unfavorable clinical outcomes following KT were significantly associated with CRKP infection (r = 0.535; P < 0.001) and antibiotic regimen containing ceftazidime/avibactam (CZA) (r = − 0.655; P = 0.006). The use of CZA was significantly different in the comparison of antibiotic regimens between the CRKP infected renal recipients with unfavorable outcomes and CRKP infected patients with favorable outcomes.Conclusion: It is possible that DDI can lead to CRKP infection, and CRKP infection and pneumonia were closely correlated with poor prognosis. The use of CZA may play a role in avoiding the unfavorable outcomes of CRKP infected recipients.Keywords: kidney transplant, carbapenem-resistant Klebsiella pneumoniae, early infections, risk factors, clinical outcomes

Dietary-derived substances possess significant potential as anthropogenic markers owing to the large consumption and different intake habit. To investigate and evaluate such markers, wastewater samples from 35 wastewater treatment plants across 29 Chinese cities were collected to analyze artificial sweeteners (acesulfame and cyclamate) and natural spicy compounds (capsaicin and dihydrocapsaicin). Acesulfame (mean: 14.6 μg/L), cyclamate (mean: 24.3 μg/L), and capsaicin (mean: 101 ng/L) can be further investigated as anthropogenic markers due to their high detection frequency at high concentrations. Spatial use patterns revealed that acesulfame (5.31 g/d/1000 inhabitants (inh)) and cyclamate (8.16 g/d/1000 inh) use in northern China notably surpassed that in southern China (1.79 g/d/1000 inh and 3.23 g/d/1000 inh, p < 0.05). Conversely, chili pepper use was significantly higher (p < 0.05) in southern China (6702 g/d/1000 inh) than in northern China (2751 g/d/1000 inh), signifying a preference for sweetness in the northern regions and a predilection for spiciness in the southern regions. The total annual use of acesulfame (1842 t), cyclamate (3110 t), and chili (18.4 million tonnes) in China was estimated by this study, which was close to the national statistical production. In addition, sweetener use was negatively associated with the elderly population ratio, suggesting that the elderly population might not consume sweet foods. This study reveals the dietary sources of anthropogenic markers, highlighting the need for further research on the environmental implications of such markers., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Based on the existing statistical data of the Lingang Special Area in Shanghai and considering its future socio-economic development， industrial structure， and technological development， a LEAP-Lingang model was developed to analyze the evolution trends of energy demand and carbon emissions under the baseline scenario， low-carbon scenario， and enhanced low-carbon scenario. To enhance the prediction accuracy of the model， the Logistic population growth model was used to predict future population data， and the learning curve model was used to simulate the cost evolution trend of related carbon reduction technologies. In addition， an economic evaluation model for carbon reduction technologies was developed， and the economic costs and emission reduction potential of typical carbon reduction technologies were evaluated by drawing a marginal emission reduction cost curve. The results showed that under the enhanced low-carbon scenario， the renewable energy accounted for 69% of the primary energy consumption， and the electric energy accounted for 91% of the terminal energy demand in 2060. The Lingang Special Area could achieve carbon peak by 2030， and the carbon emissions in 2060 were predicted to decrease by 94% compared to that in the baseline scenario. In terms of contribution to emission reduction， clean energy substitution， industrial structure optimization， and terminal energy efficiency improvement played a key role in reducing carbon emissions near the port. In the medium term （until 2035）， they were predicted to contribute 35.1%， 27.3%， and 16.2% of carbon emissions， respectively， and in the long term （until 2060）， they should contribute 50.6%， 8.75%， and 7.7% of carbon emissions， respectively. Regarding specific carbon reduction technologies， hydrogen power generation； water electrolysis for hydrogen； and carbon capture， utilization， and storage （CCUS） technology were of great significance for achieving net-zero emissions， but the costs of emission reduction were relatively high. The research results can provide ideas and references for the low-carbon and green development of the Lingang Special Area and related areas.

Ethnopharmacological Relevance Lagotis Brachystachya: Maxim is a traditional ethnic medicine commonly used in Tibet. In Tibetan medicine theory, Lagotis brachystachya is mainly used for the treatment of inflammatory related diseases. However, the active components and mechanism of the anti-inflammatory activity of Lagotis brachystachya are not clear., Aim of the Study: The putative anti-inflammatory active compounds from Lagotis brachystachya Maxim and its anti-inflammation related mechanism involving in the TLR4/MyD88/NF-κB and NLRP3 signaling pathways were investigated., Materials and Methods: In this study, we investigated the anti-inflammatory activity and mechanism of 32 compounds extracted from Lagotis brachystachya in HepG2 and THP-1 cells using the alcohol-induced HepG2 cell injury model and the monosodium urate (MSU) combined with lipopolysaccharide (LPS)-induced THP-1 cell inflammation model., Results: The results found that six compounds, including Echinacoside, Quercetin, Homoplantaginin, Tricin-7-O-glucoside, Apigenin and Luteolin-7-O-beta-d-glucopyranoside, were shown to exhibit significant anti-inflammatory effects in both cell models. Furthermore, these compounds were shown to inhibit the TLR4/MyD88/NF-κB and NLRP3 signaling pathways and reduce the release of pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 in both cell models., Conclusion: These findings suggest that Echinacoside, Quercetin, Homoplantaginin, Tricin-7-O-glucoside, Apigenin and Luteolin-7-O-beta-d-glucopyranoside from Lagotis brachystachya have promising potential as natural anti-inflammatory agents for the treatment of inflammatory-related diseases. The discovery of bioactive compounds from this plant opens up possibilities for the development of novel treatments for inflammatory-related diseases, potentially providing alternative or adjunctive options to conventional therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper titled “Anti-inflammatory activity and mechanism of six active compounds from Lagotis brachystachya Maxim in HepG2 and THP-1 cells via TLR4/MyD88/NF-κB and NLRP3 pathways”., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Follicle dysplasia can cause polycystic ovary syndrome, which can lead to anovulatory infertility. This study explored gene(s) that may contribute to polycystic ovary syndrome., Methods: Three animal models of polycystic ovary syndrome were created by treating 3-week-old rats respectively with estradiol valerate, testosterone propionate, or constant illumination for 8 weeks. Granulosa cells from the three disease groups and from healthy controls were transcriptionally profiled to identify differentially expressed genes. The phosphodiesterase-4d (Pde4d) was screened as the most promising candidate pathogenic gene. The Pde4d was overexpressed in rats via intrabursal infection with recombinant lentivirus to see the effect of Pde4d on ovarian morphology. The potential roles of the candidate gene and interactors of the encoded protein were explored using polymerase chain reaction, western blotting, transfection and co-immunoprecipitation., Results: All three rat models of polycystic ovary syndrome showed polycystic ovary phenotype. Seven promising candidate genes were obtained by transcriptomics and verifications. Pde4d was further investigated because it could trigger downstream signaling pathways. The Pde4d overexpression in rat ovary induced cystic follicles. It inhibited follicle maturation through a mechanism involving inhibition of cAMP-PKA-CREB signaling. The Pde4d also inhibited phosphorylation of c-Jun N-terminal kinase to reduce apoptosis in the ovary, through a mechanism involving interaction of its poly-proline domain with the protein POSH., Conclusion: Upregulation of Pde4d may contribute to polycystic ovary syndrome by impeding follicle maturation and preventing apoptotic atresia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Linaridins are a family of underexplored ribosomally synthesized and post-translationally modified peptides despite the prevalence of their biosynthetic gene clusters (BGCs) in microbial genomes, as shown by bioinformatic studies. Our genome mining efforts reveal that 96 putative oxidoreductase genes, namely, LinC, are encoded in linaridin BGCs. We heterologously expressed two such LinC-containing linaridin BGCs, yan and ydn , from Streptomyces yunnanensis and obtained three new linaridins, named yunnanaridins A-C ( 1 - 3 ). Their structures are characterized by Z -configurations of the dehydrobutyrines and the presence of a variety of epimerized amino acid residues. Yunnanaridin A ( 1 ) is the sixth member of the family of type-B linaridins, whereas yunnanaridins B ( 2 ) and C ( 3 ) represent the first examples of expressed type-C linaridins. Interestingly, heterologous expression of the same BGCs with LinC in-frame knockouts produced the same compounds. This work expands the structural diversity of linaridins and provides evidence for the notion that the widespread LinCs may not be involved in linaridin biosynthesis.

Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1β signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1β signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1β expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lagotis brachystachya Maxim, a common herb in Tibetan medicine, is mainly used to treat pneumonia, hepatitis, yellow water disease (gouty arthritis). Since long-term heavy drinking is also a risk factor for gouty arthritis, the present study aimed to evaluate the underlying protective role and mechanism of extracts of Lagotis brachystachya (ELB) in chronic alcoholic liver injury combined with gouty arthritis. The rat chronic alcoholic liver injury combined with gouty arthritis model was established by long-term alcohol consumption and monosodium urate (MSU) injection. The therapeutical action of ELB was then evaluated by biochemical measurement, histopathological examination, ankle swelling assessment, and protein detection. According to biochemical measurements and histopathological evaluation, ELB could alleviate the symptoms of alcoholic liver injury combined with gouty arthritis. In addition, chronic alcohol consumption and MSU activated inflammatory-related signaling such as TLR4/MyD88/NF-κB, NLRP3, and JAK2/STAT3 pathways in the liver and synovial tissues, while ELB significantly inhibited the activation of the inflammatory signaling pathway. In conclusion, ELB is protective in rats with chronic alcoholic liver injury and gouty arthritis, possibly mediated by the inhibition of TLR4/MyD88/NF-κB, NLRP3, and JAK2-STAT3 signaling pathways in both the hepatic and synovial tissues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Zhang, Yang, Zhang, Cheng, Li, Yi and Zhu.)

The objective of this study was to investigate the expression of SVEP1 in hepatocellular carcinoma (HCC) and to evaluate the association among SVEP1, cancer stem cell-like phenotype, and the prognosis of patients to provide new possibilities for the accurate diagnosis and stratification of HCC. Two hundred HCC and paired adjacent tissues were analyzed by immunohistochemistry and scored, and their relationships with clinicopathological parameters and survival rates were analyzed. We found that compared with adjacent tissues, the expression of SVEP1 in HCC was relatively low and was closely related to tumor size, satellite nodule formation, and histological grade (p<0.05). Statistical analysis showed that the survival rate of patients with low expression of SVEP1 decreased significantly (p<0.05). Our results showed that the expression of SVEP1 was negatively correlated with the expression of the cancer stem cell markers CD44 and CD133 (p<0.05). Moreover, multivariate Cox regression analysis showed that SVEP1 was an independent prognostic factor for the survival of HCC patients. In conclusion, our results suggest that decreased SVEP1 expression may promote HCC acquisition of a cancer stem cell-like phenotype, ultimately leading to heterogeneity and poor prognosis of HCC. This work may provide new insight into the development of HCC and suggests a potential marker for predicting the prognosis of patients.

Introduction: Conventional intracytoplasmic sperm injection (ICSI) is a widely used treatment for couples with severe male infertility. However, there are controversies regarding the selection and the damage to gametes during the ICSI procedure. Although preimplantation genetic testing for aneuploidies (PGT-A) can give genetic information about embryos for transfer and improve fertility rate, and it is widely used in women with recurrent spontaneous abortion or advanced age, PGT-A is not only more expensive but also has unclear effectiveness with respect to the improvement of fertility rate among couples with severe male infertility. High-quality, well-powered randomised clinical trials (RCTs) comparing ICSI+PGT-A and ICSI are lacking., Methods and Analysis: This is a protocol for a multicenter, open-label RCT in four reproductive medical centers qualified for PGT technique in China. We will study couples with severe male infertility scheduled for their fertility treatment. After the blastocyst culture, eligible participants are randomised to the ICSI+PGT-A group or the conventional ICSI group in a 1:1 ratio. Other assisted reproductive procedures are similar and parallel between the two groups. The primary outcome will be live birth rate and cumulative live-birth rate . Secondary outcomes will be embryo implantation rate, biochemical pregnancy rate, clinical pregnancy rate, spontaneous abortion rate, ongoing pregnancy rate, preterm birth rate, fetal chromosomal abnormality rate, birth defect rate and treatment complications. To demonstrate or refute a difference between the two groups, we plan to include 188 participants in each group; taking consideration of 20% of dropout, the total target sample size is 450., Ethics and Dissemination: Ethical approval was obtained from International Peace Maternity and Child Health Hospital of Shanghai Jiao Tong University Medical Science Research Ethics Committee (GKLW2016-16). Informed consent will be obtained from each participant. The findings will be disseminated to the public through conference presentations and publication in peer-reviewed scientific journals., Trial Registration Number: ClinicalTrials.gov, NCT02941965., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Major depressive disorder is characterized by not only monoamine neurotransmitters deficiencies but also persistent neuroinflammation. The complement system is an attractive therapeutic target for various inflammation-related diseases due to its early activation in inflammatory processes., Results: In the present study, the dynamic alteration of complement C3 and its receptor C3aR during the occurrence of depression and the mechanism of astrocyte-microglia IL-1R/C3/C3aR on synaptic pruning were investigated. The proteomic analysis firstly showed that chronic stress caused an elevation of C3. GO analysis indicated that complement system-mediated synaptic pruning signaling was involved in depression. The dynamic observation indicated that C3/C3aR was activated in the early onset and throughout the course of depression induced by lipopolysaccharide (LPS) and chronic stress. In contrast, C3aR blockade inhibited the hyperactivation of microglial APT2/DHHC7 palmitoylation cycle, which mediated the translocation of STAT3 and the expression of proinflammatory cytokines. Meanwhile, C3aR blockade also attenuated the synaptic pruning and enhanced the synaptogenesis in the prefrontal cortex of mice. Moreover, the blockade of IL-1R/NF-κB signaling pathway reduced the release of C3 from astrocyte., Conclusions: The current study demonstrates that astrocyte-microglia IL-1R/C3/C3aR activation causes the abnormal synaptic pruning in depression, and suggests that the activation of complement C3/C3aR may be particularly helpful in predicting the onset stage of depression., (© 2022. The Author(s).)

Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.

Purpose: This study aimed to investigate the association of Demodex infestation with pediatric chalazia., Methods: In a prospective study, 446 children with chalazia and 50 children with non-inflammatory eye disease (controls) who underwent surgical treatment were enrolled from December 2018 to December 2019. Patient ages ranged from 7 months to 13 years old. All patients underwent eyelash sampling for light microscope examination, and statistical correlation analysis between Demodex infestation and chalazia, including the occurrence, recurrence, and course of disease, morphological characteristics, and meibomian gland dysfunction (MGD) in chalazia patients was performed., Results: Demodex was found in 236 (52.91%) patients with chalazia and zero control patients. Demodicosis was significantly more prevalent in chalazia patients than the control group (P < 1 × 10 - 14 ). Recurrent chalazia (P = 0.006) and skin surface involvement (P = 0.029) were highly correlated with Demodex infestation. Demodicosis was also associated with multiple chalazia (P = .023) and MGD(P = .024). However, Demodex infestation was comparable in the course of disease (P = 0.15), seasonal change (P = 0.68) and blepharitis subgroups (P = 0.15). Within the group of chalazia patients who underwent surgical removal of cysts, 4 (0.9%) patients with concurrent demodicosis experienced recurrence., Conclusions: Demodex infestation was more prevalent in pediatric chalazia patients than healthy children, and was associated with recurrent and multiple chalazia. Demodicosis should be considered as a risk factor of chalazia. In children with chalazia, Demodex examination and comprehensive treatment of Demodex mites should be applied to potentially prevent recurrence., (© 2022. The Author(s).)

Thioamitides are apoptosis-inducing ribosomally synthesized and post-translationally modified peptides (RiPPs) with substantial post-translational modifications (PTMs), whose biosynthetic details remain elusive. We reconstituted their key PTMs through in vitro enzymatic reactions and gene coexpressions in E. coli and rigorously demonstrated the order of those modifications. Notably, thioamitide biosynthesis involves N- to C-terminal thioamidations and employs both leader-dependent and leader-independent reactions followed by leader removal by successive degradation. Our study provides a comprehensive overview of thioamitide biosynthesis and lays the foundation for thioamitide engineering in E. coli .

To realize the quantum anomalous Hall effect (QAHE) at elevated temperatures, the approach of magnetic proximity effect (MPE) was adopted to break the time-reversal symmetry in the topological insulator (Bi 0.3 Sb 0.7 ) 2 Te 3 (BST) based heterostructures with a ferrimagnetic insulator europium iron garnet (EuIG) of perpendicular magnetic anisotropy. Here we demonstrate large anomalous Hall resistance ( R AHE ) exceeding 8 Ω ( ρ AHE of 3.2 μΩ·cm) at 300 K and sustaining to 400 K in 35 BST/EuIG samples, surpassing the past record of 0.28 Ω ( ρ AHE of 0.14 μΩ·cm) at 300 K. The large R AHE is attributed to an atomically abrupt, Fe-rich interface between BST and EuIG. Importantly, the gate dependence of the AHE loops shows no sign change with varying chemical potential. This observation is supported by our first-principles calculations via applying a gradient Zeeman field plus a contact potential on BST. Our calculations further demonstrate that the AHE in this heterostructure is attributed to the intrinsic Berry curvature. Furthermore, for gate-biased 4 nm BST on EuIG, a pronounced topological Hall effect-like (THE-like) feature coexisting with AHE is observed at the negative top-gate voltage up to 15 K. Interface tuning with theoretical calculations has realized topologically distinct phenomena in tailored magnetic TI-based heterostructures.

Lagotis brachystachya Maxim is a characteristic herb commonly used in Tibetan medicine. Tibetan medicine records it as an important medicine for the clinical treatment of "Yellow Water Disease," the symptoms of which are similar to that of arthritis. Our previous study showed that the flavonoid fraction extracted from L. brachystachya could attenuate hyperuricemia. However, the effects of the active flavonoids on gouty arthritis remain elusive, and the underlying mechanism is not understood. In the present study, the effects of the active flavonoids were evaluated in rats or Raw264.7 cells with gouty arthritis induced by monosodium urate (MSU) crystal, followed by the detection of TLR4, MyD88, pNF-κB, and NLR family pyrin domain-containing 3 (NLRP3) expression. The swelling of the ankle joint induced by MSU crystal began to be relieved 6 h post the administration with the active flavonoids. In addition, the active flavonoids not only alleviated MSU crystal-induced inflammation in synovial tissues by histopathological examination but also reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the joint tissue fluid of MSU crystal-induced rats. Furthermore, Western blot analysis indicated that the active flavonoids reduced the production of these cytokines by inhibiting the TLR4/MyD88/NF-κB pathway and decreasing NLRP3 expression in synovial tissues of rats. More importantly, the inhibition of TLR4/MyD88/NF-κB pathway and NLRP3 expression was also confirmed in MSU-induced Raw264.7 cells. In conclusion, these results indicated that the active flavonoids from L. brachystachya could effectively attenuate gouty arthritis induced by MSU crystal through the TLR4/MyD88/NF-κB pathway and NLRP3 expression in vivo and in vitro , suggesting several potential candidates for the treatment of gouty arthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ouyang, Li, Guo, Zhang, Cheng, Yi and Zhu.)

Background: The current study analyzed resected stage I-IIIA pulmonary lymphoepithelioma-like carcinoma (LELC) cases to define the clinical characteristics, prognosis and long-term outcomes of resected LELC, with the purpose of guiding clinical management for this rare tumor. Methods: Resected stage I-IIIA LELC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cases from our center were enrolled. Propensity score matching (PSM) was applied to minimize the selection bias. Overall survival (OS) and disease-free survival (DFS) were compared between groups. Multivariate analyses were performed to identify the prognostic factors, and a nomogram was developed. Results: A total of 159 LELCs, 2,757 ADCs, and 1,331 SCCs were included. LELC, dominated among younger patients and non-smokers. LELC was a poorly differentiated disease that lacked driver gene mutations and was positive for immunohistochemistry indicators of squamous cell lineage. Survival analyses revealed that OS was significantly better for LELC than for other common non-small cell lung cancers (NSCLCs) both before PSM (all P < 0.001) and after PSM (all P < 0.05). Further analyses revealed that early pathological node stage and preoperative albumin level ≥35 were identified as independent prognostic factors favoring OS and DFS. Conclusions: LELC, dominated among younger and non-smoking populations, lacked driver gene mutations and was positive for immunohistochemistry indicators of squamous cell lineage. The survival outcome of LELC was better than other common NSCLCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiang, Feng, Zhu, Guo, Tan, Jiang, Dou and Liu.)

Severe acute pancreatitis (SAP) is a common acute abdominal disease accompanied by systemic inflammatory response syndrome, which may be complicated by acute kidney injury (AKI). Isoacteoside (ISO) is the active ingredient of Monochasma savatieri Franch. ex Maxim and has been reported to have anti‑inflammatory activities. The present study detected the effects of ISO on AKI induced by SAP in rat models, and the underlying mechanism. The optimum dose of ISO for treatment of AKI induced by SAP was determined. The serum levels of TNF‑α and IL‑6 were estimated using an ELISA. Kidney injury was evaluated by histopathological examination, and the expression levels of nitric oxide were also detected. The expression levels of Toll‑like receptor 4 (TLR4) and NF‑κB p65 were measured by immunohistochemistry and western blotting. The results revealed that ISO may serve a critical role in ameliorating AKI induced by SAP. These effects may be associated with the TLR4/NF‑κB signaling pathway.

Maternal metabolism dysregulation during pregnancy predisposes offspring to major diseases, including hypertension, in later life, but the mechanism involved remains to be fully elucidated. A high-fat-diet (HFD) pregnant rat model was used to investigate whether excessive intrauterine lipid exposure was associated with elevated blood pressure in offspring and increased levels of leptin, an important biomarker and mediator of vascular dysfunction and hypertension. We found that gestational hyperlipidemia predisposed offspring to blood pressure elevation and sustained increases in leptin levels with no difference in body weight in the rat model. Increased leptin expression and leptin promoter hypomethylation were found in adipose tissues of HFD-exposed offspring. The treatment of mesenchymal stem cells with free fatty acids during adipogenic differentiation resulted in increased leptin expression, accompanied by leptin promoter hypomethylation. In addition, we also followed up 121 children to evaluate the association between maternal triglyceride levels and offspring blood pressure. Consistent with the animal study results, we observed elevated serum leptin levels and blood pressure in the offspring born to women with gestational hypertriglyceridemia. Our findings provide new insights that maternal hyperlipidemia is associated with elevated blood pressure in offspring and is associated with increases in leptin levels through epigenetic memory.

Purpose: Higher serum estradiol levels occur in women undergoing assisted reproductive technology (ART) owing to ovarian stimulation. Here, we investigated the association between maternal serum estradiol levels and the intellectual development of offspring conceived with ART., Methods: A total of 204 singletons born after fresh embryo transfer were recruited for this cohort study. Among them, 102 children were born from mothers with high serum estradiol levels (> 12,000 pmol/L) on the day that human chorionic gonadotropin was administered. Another 102 children, matched by gestational age and age of the children, were recruited as controls from mothers with low serum estradiol (≤ 12,000 pmol/L). The Wechsler Preschool and Primary Scale of Intelligence was used to evaluate the intellectual development of the children., Results: Children from mothers with higher serum estradiol levels scored lower in the verbal intelligence quotient (IQ) tests and verbal comprehension than children whose mothers had lower estradiol levels. The main difference between the two groups was in verbal subtests including information, vocabulary, and sorting. Partial correlation analysis revealed that the logarithm of maternal serum estradiol level negatively correlated with verbal IQ, performance IQ, and full scale IQ., Conclusion: Our data demonstrate that a high maternal serum estradiol level may negatively associate the verbal ability of children conceived via ART.

The recommendations for the diagnosis of stage 1 hypertension were recently revised by the American Heart Association primarily based on its impact on cardiovascular disease risks. Whether the newly diagnosed stage 1 hypertension impacts pregnancy complications remain poorly defined. We designed a retrospective cohort study to investigate the associations of stage 1 hypertension detected in early gestation (<20 weeks) with risks of adverse pregnancy outcomes stratified by prepregnancy body mass index. A total of 47 874 women with singleton live births and blood pressure (BP) <140/90 mm Hg were included, with 5781 identified as stage 1a (systolic BP, 130-134 mm Hg; diastolic BP, 80-84 mm Hg; or both) and 3267 as stage 1b hypertension (systolic BP, 135-139 mm Hg; diastolic BP, 85-90 mm Hg; or both). Slightly higher, yet significant, rates and risks of gestational diabetes mellitus, preterm delivery, and low birth weight (<2500 g) were observed in both groups compared with normotensive controls. Importantly, women with stage 1a and stage 1b hypertension had significantly increased incidences of hypertensive disorders in pregnancy compared with normotensive women (adjusted odds ratio, 2.34 [95% CI, 2.16-2.53]; 3.05 [2.78-3.34], respectively). After stratifying by body mass index, stage 1a and 1b hypertension were associated with increased hypertensive disorders in pregnancy risks in both normal weight (body mass index, 18.5-24.9; adjusted odds ratio, 2.44 [2.23-2.67]; 3.26 [2.93-3.63]) and the overweight/obese (body mass index, ≥25; adjusted odds ratio, 1.90 [1.56-2.31]; 2.36 [1.92-2.90]). Current findings suggested significantly increased adverse pregnancy outcomes associated with stage 1 hypertension based on the revised American Heart Association guidelines, especially in women with prepregnancy normal weight.

Cu (II)-based metal-organic gels (Cu-MOGs), which are formed by 4-[2,2':6',2″-terpyridine]-4'-ylbenzoic acid (Hcptpy) and Cu (II) through ionic interactions, π-π stacking, van der Waals and hydrogen bonding, have been simply synthesized and used for the preparation of Cu (II)-based metal-organic xerogels (Cu-MOXs). Owing to the metal active sites in Cu-MOXs, Cu-MOXs were successfully applied to chromogenic experiment. The peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB), which could be catalyzed by Cu-MOXs from TMB to the oxidation state of TMB (oxTMB) and the color of TMB could be changed from colorless to blue with maximum absorbance at 657 nm, was selected as chromogenic agent. Thus, the Cu-MOXs-TMB-H 2 O 2 system based on MOXs was established. Due to the inhibitory effect of dopamine (DA) on oxidation process of TMB, the characteristic absorption peak intensity of oxTMB decreased when the DA was added into the mixed solution. Subsequently, the Cu-MOXs-TMB- H 2 O 2 system was used for DA detection. The linear range for DA was 0.5 μM-20 μM and the detection limit was 85.76 nM. Our work has helped to develop the promising application of Cu-MOGs material in the field of nanozymes property., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: This study aimed to determine the effects of diet-induced paternal obesity on cognitive function in mice offspring., Methods: Male mice (F0) were randomized to receive either a control diet (10 kcal% fat) or a high-fat diet (HFD; 60 kcal% fat) for 10 weeks before being mated with normal females to generate F1 offspring. Male F1 offspring were mated with normal females to generate F2 offspring. Behavioral tests were used to assess cognitive functions in F1 and F2 offspring. Reduced representation bisulfite sequencing was used to the explore mechanisms of epigenetic inheritance., Results: HFD-induced paternal obesity resulted in cognitive impairments in F1 offspring, potentially due, at least in part, to increased methylation of the BDNF gene promoter, which was inherited from F0 spermatozoa. BDNF/tyrosine receptor kinase B signaling was associated with cognitive impairments in HFD-fed F1 offspring. However, there were no significant changes in F2 offspring., Conclusions: The findings provide evidence of intergenerational effects of paternal obesity on cognitive function in offspring occurring via epigenetic spermatozoan modifications., (© 2018 The Obesity Society.)

Objective: To investigate the effect of silencing NSD2 gene by RNA interference on the proliferation, apoptosis and the alteration of Akt /mTOR signaling pathway in diffuse large B cell lymphoma OCI-Ly3 cells., Methods: The shRNA targeting NSD2 gene was transfected into OCI-Ly3 cells by lentivirus infection. The NSD2 mRNA and protein were detected by real time Q-PCR and Western blot, respectively. The cell proliferation was detected by CCK-8 and apoptosis was measured by flow cytometry. The expressions of BCL-2, BAX, caspase-3, Akt, p-Akt, p-mTOR, p-P70S6K, H3K36me2 were detected by Western blot., Results: After transfecting the OCI-Ly3 cells by NSD2-shRNA for 72 h, the expressions of NSD2 mRNA and protein both were down-regulated(P<0.05), the proliferation rate of cells in NSD2 shRNA group was significantly lower than that in control and Neg shRNA groups (P<0.05); the apoptosis rate of cells in NSD2 shRNA group was significantly higher than that in control and neg-shRNA group (30.37±4.22)% vs 1.36±0.52 % and 2.17±1.43)%(P<0.05); the expressions of BAX and caspase-3 were up-regulated, while the expression of BCL-2 was down-regulated; the H3K36me2 level significantly decreased as compared with control group, no obvious decrease of the total protein level of AKT was found, but the expressions of p-Akt, p-mTOR and p-70S6K were down-regulated., Conclusion: The silencing NSD2 gene can inhibit the proliferation and induce the apoptosis of OCI-Ly3 cells, their mechanisms may relate with regulating the H3K36me2 level, specifically inhibiting the activivty of AKT/mTOR signal pathway.

High androgen level impairs endometrial receptivity in women experiences the recurrent miscarriage. The mechanism of androgen actions on endometrium is still uncertain. We hypothesized that androgen has a direct effect on the endometrium in women with recurrent miscarriage. In the present study, we assess the impact of androgen (A 2 ) at high concentration (10 -7 M) on Ishikawa cells compared with the physiological concentration of androgen (10 -9 M). To go into deeper analysis, we use global stable isotopes labeled profiling tactic using iTRAQ reagents, followed by 2D LC-MS/MS. We determine 175 non-redundant proteins, and 18 of these were quantified. The analysis of differentially expressed proteins (DEPs) identified 8 up-regulated proteins and 10 down-regulated in the high androgen group. These DEPs were examined by ingenuity pathway (IPA) analysis and established that these proteins might play vital roles in recurrent miscarriage and endometrium receptivity. In addition, proteins cyclin-dependent kinase inhibitor 2a (CDKN2a), endothelial protein C receptor (EPCR), armadillo repeat for velocardiofacial (ARVCF) were independently confirmed using western blot. Knockdown of CDKN2a significantly decreased the expression level of CDKN2a protein in ishikawa cells, and decreased migration ( p < 0.01), invasion ( p < 0.05), proliferation ( p < 0.05), and the rate of Jar spheroid attachment ( p < 0.05) to Ishikawa cell monolayer. The present results suggest that androgen at high concentration could alter the expression levels of proteins related to endometrium development and embryo implantation, which might be a cause of the impaired endometrial receptivity and miscarriage., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

A three-dimensional (3D) electrode material was successfully synthesized through a facile ZnO-assisted hydrothermal process in which vertical MnO 2 nanotube arrays were in situ grown on the conductive graphene/polyester composite fabric. The morphology and structure of MnO 2 nanotubes/graphene/polyester textile electrode were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The 3D electrode structure facilitates to achieve the maximum number of active sites for the pesudocapacitance redox reaction, fast electrolyte ion transportation and short ion diffusion path. The electrochemical measurements showed that the electrode possesses good capacitance capacity which reached 498F/g at a scan rate of 2mV/s in Na 2 SO 4 electrolyte solution. The electrode also showed stable electrochemical performances under the conditions of long-term cycling, and mechanical bending and twisting., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The novel class of luminescent Al 3+ -based metal-organic gels (Al-MOGs) have been developed by mix 4-[2,2':6',2″-terpyridine]-4'-ylbenzoic acid (Hcptpy) with Al 3+ under mild condition. The as-prepared Al-MOGs have not only multiple stimuli-responsive properties, but selective recognition of hydroxyl nitro aromatic compounds, which can quench the fluorescence of the Al-MOGs, while other nitro aromatic analogues without hydroxyl substitutes cannot. The fluorescence of Al-MOGs at 467nm was seriously quenched by picric acid (PA) whose lowest unoccupied molecular orbital (LUMO) energy levels are lower than those of three other hydroxyl nitro aromatic compounds including 4-nitrophenol (4-NP), 3,5-dinitrosalicylic acid (3,5-DNTSA) and 2,4-dinitrophenol (2,4-DNP). Thus, PA was chosen as a model compound under optimal conditions and the relative fluorescence intensity of Al-MOGs was proportional to the concentration of PA in the range of 5.0-320.0μM with a detection limit of 4.64μM. Furthermore, the fluorescence quenching mechanism has also been investigated and revealed that the quenching was attributed to inner filter effects (IFEs), as well as electron transfer (ET) between Al-MOGs and PA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Drug product assay is one of several tests required for new drug products to ensure the quality of the product at release and throughout the life cycle of the product. Drug product assay testing is typically performed by preparing a composite sample of multiple dosage units to obtain an assay value representative of the batch. In some cases replicate composite samples may be prepared and the reportable assay value is the average value of all the replicates. In previously published work by Harrington et al. (2014) [5], a sample preparation composite and replicate strategy for assay was developed to provide a systematic approach which accounts for variability due to the analytical method and dosage form with a standard error of the potency assay criteria based on compendia and regulatory requirements. In this work, this sample preparation composite and replicate strategy for assay is applied to several case studies to demonstrate the utility of this approach and its application at various stages of pharmaceutical drug product development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The aims of this study were to determine the effects of ω-3 fatty acids (ω-3FAs) on the Toll-like receptor 4 (TLR4)/nuclear factor κB p56 (NF-κBp56) signaling pathway in the pancreas of rats with severe acute pancreatitis (SAP)., Methods: Sixty-four Sprague-Dawley rats were randomly divided into 4 groups: the control, SAP-saline, SAP-soybean oil, and SAP-ω-FA groups. Severe acute pancreatitis was induced by the retrograde infusion of sodium taurocholate into the pancreatic duct. The expression of TLR4 and NF-κBp56 in the pancreas was evaluated by immunohistochemistry and Western blot analysis. The levels of the proinflammatory cytokines interleukin 6 and tumor necrosis factor α in the pancreas were measured by enzyme-linked immunosorbent assays., Results: Toll-like receptor 4, NF-κBp56, and inflammatory cytokine expression in the pancreas was increased significantly in the SAP group compared with that in the control group (P < 0.05), but was significantly decreased in the ω-3FA group compared with that in the soybean oil group at 24 and 48 hours (P < 0.05)., Conclusions: Our results suggest that during the initial stage of SAP ω-3FAs could efficiently lower the inflammatory response by activating the TLR4/NF-κBp56 signaling pathway.

Previous studies have shown that increasing estradiol concentrations had a toxic effect on the embryo and were deleterious to embryo adhesion. In this study, we evaluated the physiological impact of estradiol concentrations on endometrial cells to reveal that serum estradiol levels probably targeted the endometrium in controlled ovarian hyperstimulation (COH) protocols. An attachment model of human choriocarcinoma (JAr) cell spheroids to receptive-phase endometrial epithelial cells and Ishikawa cells treated with different estradiol (10 -9  M or 10 -7  M) concentrations was developed. Differentially expressed protein profiling of the Ishikawa cells was performed by proteomic analysis. Estradiol at 10 -7  M demonstrated a high attachment rate of JAr spheroids to the endometrial cell monolayers. Using iTRAQ coupled with LC-MS/MS, we identified 45 differentially expressed proteins containing 43 significantly upregulated and 2 downregulated proteins in Ishikawa cells treated with 10 -7  M estradiol. Differential expression of C 3 , plasminogen and kininogen-1 by Western blot confirmed the proteomic results. C 3 , plasminogen and kininogen-1 localization in human receptive endometrial luminal epithelium highlighted the key proteins as possible targets for endometrial receptivity and interception. Ingenuity pathway analysis of differentially expressed proteins exhibited a variety of signaling pathways, including LXR/RXR activation pathway and acute-phase response signaling and upstream regulators (TNF, IL6, Hmgn3 and miR-140-3p) associated with endometrial receptivity. The observed estrogenic effect on differential proteome dynamics in Ishikawa cells indicates that the human endometrium is the probable target for serum estradiol levels in COH cycles. The findings are also important for future functional studies with the identified proteins that may influence embryo implantation., (© 2017 The authors.)

Sewage epidemiology is a real-time tool used to monitor tobacco consumption. In this study, we investigated the tobacco consumption in eight cities in Jilin province using sewage epidemiology. We collected influent wastewater samples from ten wastewater treatment plants (WWTPs) that serve nearly four million people. Mean nicotine (NIC) loads ranged from 1.42 to 14.2mg/d/capita, whereas mean cotinine (COT) loads showed lower levels with 0.33 to 2.15mg/d/capita. Population size was estimated to provide an accurate and real-time population based on ammonia nitrogen (NH 4 -N) concentration in influent. To verify the NH 4 -N equivalent population, we compared these results with the corresponding population estimated based on the expert knowledge of the local WWTPs operators. Daily consumption of NIC was estimated to be approximately 2.39±1.47mg/d/capita. Monte Carlo simulation was used to analyze uncertainty and variability in the number of cigarettes consumed by smokers in the range of 9.8 to 31.4 per day with a median of 16.9. The data of tobacco consumption in this study coordinated strongly with a traditional survey on the consumption of tobacco in China, indicating sewage epidemiology with NH 4 -N equivalent population estimation may provide a suitable and useful tool for tobacco use monitoring., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Maternal obesity influence the child's long-term development and health. Though, the mechanism concerned in this process is still uncertain. In the present study, we explored whether overfeeding of a high-fat diet during pregnancy in female rats altered metabolic phenotypes in an F1 generation and authenticated the contribution of hypothalamic leptin signaling. Leptin responsiveness and the number of immunopositive neurons for phosphorylated signal transducer and activator transcription 3 (pSTAT3) were analyzed. Neuropeptide Y in the arcuate nucleus of the hypothalamus and in nucleus tractus solitaries was examined. Triglycerides and leptin levels were increased in the high-fat diet mother. The number of neuropeptide Y positive cell bodies and neurons was significantly increased in the high-fat diet-F1 offspring (HDF-F1) as compared to Chow-F1. Leptin administration significantly decreased the food intake and increased the pSTAT3 expression levels in neurons in the arcuate nucleus of Chow-F1. However, leptin did not show any effect on food intake and had a reduced effect on pSTAT3 expression levels in neurons in the arcuate nucleus of HDF-F1. From the present domino effect, we conclude that mothers exposed to high-fat diet during pregnancy may pass the obese phenotype to the succeeding generation via altering hypothalamic leptin signaling., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Iron is essential for growth and development of rice, which is able to take up Fe 3+ -phytosiderophore, Fe 2+ -nicotianamine and free Fe 2+ . Researchers have uncovered key molecular components including transporters, enzymes, and chelators involved in iron uptake and translocation, as well as factors regulating the expression of these genes in rice. Manipulation of these molecular components has produced transgenic rice with enhanced tolerance to alkaline stress on calcareous soils with low-Fe availability due to high soil pH. In this review, we mainly summarize the molecular mechanisms of iron uptake, translocation, and regulation in rice, and discuss some perspectives of this field.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease and is often accompanied by a variety of genetic abnormalities. Hence, our study aims to investigate the relationship between MMP-2 -1306C>T and MMP-9 -1562C>T polymorphisms and the risk and prognosis of T-ALL., Methods: From April 2009 to February 2011, a total of 376 T-ALL patients were chosen as the case group. Meanwhile, 352 healthy people who passed routine health examinations were selected as the control group. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the frequency of MMP-2 -1306C>T (rs243865) and MMP-9 -1562C>T (rs3918242) polymorphisms in the study subjects. The serum levels of MMP-2 and MMP-9 were detected using enzyme-linked immunosorbent assay (ELISA). A Kaplan-Meier analysis was employed to analyze the event-free survival (EFS) rates of the T-All patients with different MMP-2 and MMP-9 genotypes. A multivariate COX model was applied to analyze the relationship between MMP-2 and MMP-9 polymorphisms and the prognosis of T-ALL patients. A C-statistic and net reclassification index (NRI) was carried out to evaluate the predictive value of MMP-2 and MMP-9 gene polymorphisms using the Cox model., Results: Compared to the control group, the genotypic frequency of MMP-2 -1306C>T (CT + TT) and MMP-9 -1562C>T (CT + TT) in the case group was significantly higher. The serum level of MMP-9 was markedly elevated in T-ALL patients with the CT + TT genotype compared to patients with the CC genotype. The results of the Kaplan-Meier analysis showed that the median EFS was lower in T-ALL patients with the CT + TT genotype of MMP-9 -1562C>T compared to patients with the CC genotype. The results of a multivariate analysis using the Cox proportional hazard model indicated that the MMP-9 -1562C>T polymorphism was associated with the prognosis of T-ALL patients., Conclusion: These results indicated that MMP-2 -1306C/T and MMP-9 -1562C/T polymorphisms might be associated with an increased risk of T-ALL. The MMP-9 -1562C>T polymorphism may also be related to the prognosis of T-ALL patients., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Objective: The study aimed to explore the effects of blood purification (BP) on serum levels of inflammatory cytokines and cardiac function in a rat model of sepsis., Methods: A rat model of sepsis was established by cecal ligation and puncture. All rats were divided into the normal control, sham operation, model, sham treatment, and BP treatment groups. Cardiac functions, inflammatory cytokines, myocardial enzymes, pathological score of cardiac muscle tissue, and myocardial apoptosis of rats in each group were compared., Results: Sepsis rats had higher serum levels of inflammatory cytokines and lower cardiac function than those in the normal control and sham operation groups. Compared with the model and sham treatment groups, improved cardiac functions, decreased inflammatory cytokines, myocardial enzymes, pathological score, and myocardial apoptosis and mortality were observed in the BP treatment group., Conclusion: BP may reduce serum levels of inflammatory cytokines and improve cardiac function of sepsis rats., (© 2017 S. Karger AG, Basel.)

Background: Infants being born Large-for-gestational-age (LGA) are prone to developing cardiometabolic disease. However, the underlying mechanisms remain unclear., Results: Clinical investigation showed that children born LGA had significantly higher serum level of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and insulin, ratio of TC/high-density lipoprotein-cholesterol (HDL-c) compared to children born appropriate for gestational age (AGA). Birth weight (BW) was positively correlated to TC, LDL-c, and the ratio of TC/HDL in serum. Genome-wide DNA methylation analyzed in umbilical cord blood of controls and macrosomia cases. We identified 3459 methylation variable positions (MVPs) achieving genome-wide significance (adjusted P-value < 0.05) with methylation differences of ≥ 5%. A total of 327 MVPs were filtered by methylation differences of ≥ 7% located within an island, which mapped to 213 genes. Function analysis using Ingenuity Pathway Analysis showed 16 genes enriched in "cardiovascular disease". Four genes included contributed to hyperlipidemia., Materials and Methods: Fifty-eight children aged 3-6 years born LGA and 123 subjects born AGA were enrolled. Anthropometric parameters and blood pressure (BP) were measured, and metabolic assessment was performed in all subjects. Genome-wide DNA methylation in umbilical blood was assayed by the 450K BeadChip in six AGA and six macrosomia newborns., Conclusions: Our data indicate that excess birth weight may increase the risk of lipid dysfunction in children aged 3-6 years. It might through reprogramming a group of genes correlated to cardiovascular disease. The genes identified in this study might be potential biomarker for cardiometabolic disease.

Aim: To determine the effects of ω-3 fatty acids (ω-3FA) on the toll-like receptor 4 (TLR4)/nuclear factor κB p56 (NF-κBp56) signal pathway in the lungs of rats with severe acute pancreatitis (SAP)., Methods: A total of 56 Sprague-Dawley rats were randomly divided into 4 groups: control group, SAP-saline group, SAP-soybean oil group and SAP-ω-3FA group. SAP was induced by the retrograde infusion of sodium taurocholate into the pancreatic duct. The expression of TLR4 and NF-κBp56 in the lungs was evaluated by immunohistochemistry and Western blot analysis. The levels of inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in the lungs were measured by enzyme-linked immunosorbent assay., Results: The expression of TLR4 and NF-κBp56 in lungs and of inflammatory cytokines in serum significantly increased in the SAP group compared with the control group ( P < 0.05), but was significantly decreased in the ω-3FA group compared with the soybean oil group at 12 and 24 h ( P < 0.05)., Conclusion: During the initial stage of SAP, ω-3FA can efficiently lower the inflammatory response and reduce lung injury by triggering the TLR4/NF-κBp56 signal pathway., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.

Vertical polyaniline (PANI) nanowire arrays on graphene-sheet-coated polyester cloth (RGO/PETC) were fabricated by the in situ chemical polymerization of aniline. The 3D conductive network that was formed by the graphene sheets greatly enhanced the conductivity of PANI/RGO/PETC and improved its mechanical stability. PANI nanowire arrays increased the active surface area of PANI, whilst the hierarchically porous structure of the PANI/RGO/PETC electrode facilitated the diffusion of the electrolyte ions. Electrochemical measurements showed that the composite electrode exhibited a maximum specific capacitance of 1293 F g(-1) at a current density of 1 A g(-1) . Capacitance retention was greater than 95 %, even after 3000 cycles, which indicated that the electrode material has excellent cycling stability. Moreover, the electrode structure endowed the PANI/RGO/PETC electrode with a stable electrochemical performance under mechanical bending and stretching., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.

Objective: To investigate the effect of extracellular regulating kinase (ERK) signaling pathway on the secretion of gamma-aminobutyric acid (GABA) in cultured rat hippocampal neurons induced by stromal cell derived factor-1 (SDF-1)., Methods: The hippocampal neurons of newborn SD rats were cultured and identified in vitro; the phosphorylation level of ERK1/2 was examined by Western blot; ELISA was used to detect the effect of PD98059, a ERK1/2 specific blocker on GABA secretion of cultured hippocampal neurons and Western blot were adopted to measure the protein expression levels of glutamate decarboxylase (GAD65/67) and gamma aminobutyric acid transporter (GAT); after blocking ERK1/2 signaling pathway with PD98059; RT-PCR was used to detect the mRNA expression levels of GAT-1 and GAD65 after treated with PD98059., Results: The levels of ERKl/2 phosphorylation were increased significantly by SDF1 acting on hippocampal neurons, and CX-CR4 receptor blocker AMD3100, could inhibit SDF-1 induced ERK1/2 activation; SDF-1 could inhibit the secretion of GABA in cultured hippocampal neurons, and ERK1/2 specific inhibitor PD98059, could partly reverse the inhibition of GABA secretion by SDF-1. The effects of SDF-1 on cultured hippocampal neurons was to decrease the mRNA genesis of glutamic acid decarboxylase GAD65 and GABA transporter GAT-1, besides, ERK inhibitor PD98059 could effectively flip the effect of SDF-1. The results of Western blot showed that SDF-1 could inhibit the protein expression of GAT-1 and GAD65/67 in hippocampal neurons and the inhibition of GAT-1 and GAD65/67 protein expression could be partially restored by ERK1/2 blocker., Conclusion: SDF-1 acts on the CXCR4 of hippocampal neurons in vitro, and inhibits the expression of GAD by activating the ERK1/2 signaling pathway, and this may represent one possible pathway of GABA secretion inhibition.

Unlabelled: While the intrauterine environment is essential for the health of offspring, the impact of high maternal serum estradiol (E2) on lipid metabolism in offspring and the mechanisms are unknown. We found that ovarian stimulation (OS) could result in high E2 levels in women throughout pregnancy. Strikingly, their newborns showed elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels that were positively related with E2 in newborns. In vitro, E2 dose-dependently stimulated TC and LDL-C secretion, and increased expression of the cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) in HepG2 cells and mouse fetal hepatocytes. In vivo, high maternal E2 was detected and fetal livers also showed significantly higher HMGCR expression in an OS mouse model. Notably, an estrogen response element (ERE) was identified in the HMGCR promoter, indicating that high maternal serum E2 could up-regulate HMGCR expression in fetal hepatocytes via an ERE that in turn induces elevated levels of TC and LDL-C in offspring., Conclusion: OS can induce a high maternal E2 environment, which up-regulates HMGCR expression in fetal hepatocytes via an ERE in the promoter, and induces elevated levels of TC and LDL-C in newborns that may be related to increased risk of metabolic disease in adulthood.

Chlorinated flame retardants, particularly dechlorane plus (DP), were widely used in commercial applications and are ubiquitous in the environment. A total of seven species of aquatic organisms were collected concurrently from the region of a chemical production facility in Huai’an, China. DP and structurally related compounds including mirex, dechloranes 602, 603, 604, chlordene plus (CP), DP monoadduct (DPMA), and two dechlorinated breakdown products of DP, decachloropentacyclooctadecadiene (anti-Cl(10)-DP) and undecachloropentacyclooctadecadiene (anti-Cl(11)-DP), were detected in these aquatic organisms. Nitrogen stable isotope ratios were also measured to determine the trophic levels of the organisms. Trophic magnification factors (TMFs) for these chemicals were calculated with values ranging from 1.0 to 3.1. TMFs for CP, mirex, anti-DP, and ∑DP were statistically greater than 1, showing evidence of biomagnification in the food web. Concentration ratios of anti-Cl(11)-DP to anti-DP showed a significant relationship with trophic level, implying that anti-Cl(11)-DP had a higher food-web magnification potential than its precursor. The biota-sediment accumulation factors and TMFs for DP demonstrated stereoselectivity, with syn-DP having a greater bioaccumulation potential than anti-DP in the aquatic environment.

Epidemiological studies suggest that the impact of preeclampsia does not only affect the mother but also the children. We know that adverse events in utero may predispose individuals to premature cardiovascular disease in adulthood, but we do not know the mechanisms. To gain insights into the mechanisms of cardiovascular dysfunction in the offspring of preeclampsia, we employed a global stable isotope labeled profiling strategy using iTRAQ reagents, followed by 2D-LC-MS/MS. We identified 1521 non-redundant proteins, and 1496 of these were quantified. Further analysis identified 53 differentially expressed proteins in umbilical artery; 22 proteins were up-regulated and 31 proteins were down-regulated. K-means clustering analysis showed that there was a specific protein expression profile in the umbilical artery which could distinguish between normal and preeclampsia patients. These 53 proteins were analyzed by Ingenuity Pathway Analysis (IPA) and were found to play important roles in the angiogenesis, vasculogenesis, and development of the cardiovascular system. In addition, the differential expression of three cardiovascular relative proteins (aldose reductase, fibronectin-1, fibrillin-1) was independently verified using western blot. These results may supply new insights into the mechanisms of vascular dysfunction in the offspring of preeclampsia patients., Biological Significance: Increasing evidence suggests that the children who were exposed to preeclampsia in utero have an increased cardiovascular risk, and vascular dysfunction has been found in some children born of preeclampsia. However, the mechanism remains largely unknown. In this study, we identified 1521 non-redundant proteins, and 1496 of these were quantified. Further analysis identified 53 differentially expressed proteins in the umbilical artery from preeclampsia patients; 22 proteins were up-regulated and 31 proteins were down-regulated. Some of these differentially expressed proteins have been shown to play important roles in cardiovascular system development. Our results provide new insights into the potential mechanisms underlying the changed blood pressure of offspring of mothers with preeclampsia, and, the elevation of their risk of cardiovascular abnormality in later life., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In pharmaceutical analysis, the results of drug product assay testing are used to make decisions regarding the quality, efficacy, and stability of the drug product. In order to make sound risk-based decisions concerning drug product potency, an understanding of the uncertainty of the reportable assay value is required. Utilizing the most restrictive criteria in current regulatory documentation, a maximum variability attributed to method repeatability is defined for a drug product potency assay. A sampling strategy that reduces the repeatability component of the assay variability below this predefined maximum is demonstrated. The sampling strategy consists of determining the number of dosage units (k) to be prepared in a composite sample of which there may be a number of equivalent replicate (r) sample preparations. The variability, as measured by the standard error (SE), of a potency assay consists of several sources such as sample preparation and dosage unit variability. A sampling scheme that increases the number of sample preparations (r) and/or number of dosage units (k) per sample preparation will reduce the assay variability and thus decrease the uncertainty around decisions made concerning the potency of the drug product. A maximum allowable repeatability component of the standard error (SE) for the potency assay is derived using material in current regulatory documents. A table of solutions for the number of dosage units per sample preparation (r) and number of replicate sample preparations (k) is presented for any ratio of sample preparation and dosage unit variability.

This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD 50 ) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215-4640 mg/kg BW, given orally) showed lowest LD 50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75-300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.

To demonstrate rhizospheric effect on the mechanism of (polycyclic aromatic hydrocarbon) PAH degradation, and to establish a proper joint phyto-microbial remediation mode, microcosms containing microorganisms and PAHs (pyrene and benzo[a]Pyrene) were added with clover (Trifolium repens) root exudates to study their effects on PAH degradation. Dioxygenase gene and 16S rDNA gene copy number changes during the biodegradation process were analyzed, and the microorganism with a good ability for degrading PAHs was identified. The results showed that Mycobacterium M1 had the capability to degrade PAHs. When total organic carbon (TOC) concentration of clover root exudates was 35.5 mg · L(-1), pyrene and benzo[a]pyrene degradation rates increased significantly, and the proportion of dioxygenase gene to 16S rDNA of Mycobacterium M1 increased. In the biodegradation process, dioxygenase gene copy number increased significantly, whereas 16S rDNA copy number increase was not so obvious, showing that the former was related to degradation process, but the latter was related to microbial numbers. It was concluded that the clover root exudates promoted the dioxygenase gene copy number of Mycobacterium M1, which contributed to the degradation of PAHs.

Endosulfan concentrations and its distribution in air, soil, sediment and foodstuffs in the area surrounding a production facility in Huai'an, China were investigated because of its threats to the environment and human health. Air concentrations for endosulfan Ι, endosulfan II and endosulfan sulfate measured in this study were several orders of magnitude higher than those reported previously for this region. Surface soil concentration ranges of endosulfan I, endosulfan II, and endosulfan sulfate were greater than in sediment. Endosulfan II was the greatest contributor to total endosulfan concentrations in both surface sediment and soil followed by endosulfan sulfate and endosulfan Ι. However, a different concentration profile was observed in fish and crop samples, with endosulfan sulfate having the highest concentration followed by endosulfan I and endosulfan II. The concentration of Σendosulfans (endosulfans Ι and II) in soil decreased rapidly with increasing distance from the plant by a factor of 10 within 45 km. Trace amounts of Σendosulfans were observed in deep soil layers which implied that these compounds are transported through the leaching of pore water in soil. This demonstrated that emissions from the manufacturing facility can lead to ground water contamination in the area near the plant. A screening level human health risk assessment of Σendosulfans based on the worst-case scenario was performed for people living in the vicinity of the manufacturing facility. The hazard indices were at least 2 orders of magnitude of <1, indicating no adverse health effects are likely to occur at current exposure levels, and the risk to human health is generally acceptable., (Copyright © 2014 Elsevier B.V. All rights reserved.)