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• Isolation, identification and characterization of potential impurities in doramectin. • Structural conformation of these impurities has been confirmed by 1D (1H, 13C, H-D, DEPT 90 and 135), 2D (COSY, HSQC, HMBC, and NOESY) NMR, IR, and ESI-HRMS data. • The possible pathway for the formation of the impurities has been discussed. • The insecticidal activity of impurities was also tested and discussed. Seven impurities were detected in doramectin bulk drug by HPLC analysis. These impurities were named as Imp-I, Imp-II, Imp-III, Imp-IV, Imp-V, Imp-VI, and Imp-VII. All impurities were isolated from doramectin bulk drug by means of preparative HPLC. Among impurities, Imp-IV and Imp-V were unknown and have not been reported previously. Based on the complete spectral analysis, including 1D (1H, 13C, H-D, DEPT 90 and 135), 2D (COSY, HSQC, HMBC, and NOESY) NMR, IR, and ESI-HRMS, the structure of Imp-IV and Imp-V were elucidated. Imp-IV was found to be a furan ring-opening product, while Imp-V lacked a methyl group at the C-14 in doramectin. Identification, isolation, structural characterization, probable formation mechanism, and insecticidal activity of impurities of doramectin were also discussed. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3 dioxygenase (IDO) is upregulated in many tumor types, including breast cancer, and plays a reputable role in promoting tumor immune tolerance. The importance of the immunosuppressive mechanism of IDO by suppressing T-cell function has garnered profound interest in the development of clinical IDO inhibitors. Herein, we established a screening method with cervical HeLa cells to induce IDO expression using interferon-γ (IFN-γ). After screening our chemical library, we found that salinomycin potently inhibited IFN-γ-stimulated kynurenine synthesis with IC 50 values of 3.36–4.66 μM in both human cervical and breast cancer cells. Salinomycin lowered the IDO1 and IDO2 expression with no impact on the expression of tryptophan-2,3-dioxygenase. Interestingly, salinomycin potently repressed the IDO1 enzymatic activity by directly targeting the proteins in cells. Molecular docking revealed an alignment that favors nucleophilic attack of salinomycin in the catalytic domain of IDO1. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway by IFN-γ was significantly suppressed by salinomycin, via inhibiting the Jak1, Jak2, and STAT1/3 phosphorylation. Moreover, it inhibited IFN-γ-induced activation of the nuclear factor (NF)-κB pathway by inhibiting IκB degradation and NF-κB phosphorylation without affecting BIN1 expression. Furthermore, salinomycin significantly restored the proliferation of T cells co-cultured with IFN-γ-treated breast cancer cells and potentiated antitumor activity of cisplatin in vivo. These findings suggest that salinomycin suppresses kynurenine synthesis by inhibiting the catalytic activity of IDO1 and its expression by inhibiting the JAK/STAT and NF-κB pathways. Salinomycin warrants further investigation as a novel dual-functional IDO inhibitor for cancer immunotherapy. • Salinomycin decreases IFN-γ stimulated IDO1 and IDO2 expression. • Salinomycin inhibits the enzymatic activity of the IDO1 protein. • Salinomycin suppresses the IFN-γ induced JAK/STAT and NF-κB pathways. • Salinomycin enhances the proliferation of T cells. • Salinomycin potentiates the antitumor activity of cisplatin in vivo. [ABSTRACT FROM AUTHOR]

A series of novel chalcone- O -alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC 50 = 1.3 ± 0.01 μM) and butyrylcholinesterase (IC 50 = 1.2 ± 0.09 μM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC 50 value of 0.57 ± 0.01 μM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced A β 1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu2+-induced A β 1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro , and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, A β 1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD. Image 1 • Novel chalcone- O -alkylamine derivatives was rationally designed. • Compound 23c was the best dual AChE/BuChE inhibitor and selective MAO-B inhibitor. • Compound 23c showed good antioxidant activity and neuroprotective effect. • Compound 23c could inhibit and disaggregate A β 1-42 aggregation. • Compound 23c could improve scopolamine-induced memory impairment. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study is to describe the season of RSV prevalence in China during the COVID-19 pandemic., Methods: This multicenter retrospective study analyzed the epidemiology of pediatric RSV infections and the possible factors contributing to its variations in China from January 1, 2019, to October 31, 2022., Results: A total of 872,565 children were included. During the pandemic, RSV detection rate increased across various regions, including South China, East China, Central China, and Northeast China. From 2019 to 2021, the detection rates of RSV showed an increasing trend among children aged <1 year, 1-2 years, and 3-5 years, but decreased in 2022. Among those tested positive for RSV, the proportion of children under 1 year old significantly decreased during the pandemic. The spring season of RSV in China in 2020 was shortened, and most regions experienced a summer season of RSV in 2021. This shift led to a year-round RSV outbreak throughout 2021. After April 2022, RSV positive rate significantly decreased, and no clear seasonal pattern was observed., Conclusion: Our study found that the COVID-19 pandemic has disrupted the seasonal pattern of RSV outbreaks in China, leading to increased RSV positive rate and off-season outbreaks., Competing Interests: Declaration of competing interest This project is supported in part by MSD R&D (CHINA) CO., LTD. We declare that we have no conflicts of interest related to this research work., (Copyright © 2024. Published by Elsevier Ltd.)

Sestrin2 is a highly conserved protein that can be induced under various stress conditions. Researches have revealed that the signaling pathway of the mammalian target of rapamycin (mTOR) is essential in modulating both glucose and lipid metabolism. However, the precise involvement of Sestrin2 in the hypothalamus, particularly in pro-opiomelanocortin (POMC) neurons, in control of energy homeostasis remains uncertain. In this study, we aimed to investigate the functional role of Sestrin2 in hypothalamic POMC neurons in regulation of energy balance, as well as revealing the underlying mechanisms. Therefore, cre-dependent AAV virus encoding or silencing Sestrin2 was injected into the hypothalamic ARC of pomc-cre transgenic mice. The results demonstrated that Sestrin2 overexpression in POMC neurons ameliorated high-fat diet (HFD)-induced obesity and increased energy expenditure. Conversely, Sestrin2 deficiency in POMC neurons predisposed mice to HFD induced obesity. Additionally, the thermogenesis of brown adipose tissue and lipolysis of inguinal white adipose tissue were both enhanced by the increased sympathetic nerve innervation in Sestrin2 overexpressed mice. Further exploration revealed that Sestrin2 overexpression inhibited the mTOR signaling pathway in hypothalamic POMC neurons, which may account for the alleviation of systematic metabolic disturbance induced by HFD in these mice. Collectively, our findings demonstrate that Sestrin2 in POMC neurons plays a pivotal role in maintaining energy balance in a context of HFD-induced obesity by inhibiting the mTOR pathway, providing new insights into how hypothalamic neurons respond to nutritional signals to protect against obesity-associated metabolic dysfunction., Competing Interests: Declaration of competing interest We declare there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To investigate the epidemiological and clinical characteristics of children with Mycoplasma pneumoniae pneumonia (MPP) in Hubei, China., Methods: We retrospectively analyzed inpatients with MPP from 20 hospitals in Hubei, China from January 2021 to December 2022. The co-detected pathogens of Mycoplasma pneumoniae ( M. pneumoniae ) were investigated using targeted next-generation sequencing (tNGS), and 23S rRNA gene mutations were analyzed to assess the macrolide resistance., Results: M. pneumoniae infected 20.7% of patients with CAP, with cough (96.59%) and fever (80.28%) being the most prevalent symptoms. The infection rates in children younger than 1, 1-2, 3-6, 7-12, and older than 12 years were 6.17%, 19.98%, 26.97%, 43.93%, and 2.95%, respectively. Among 1,349 patients undergoing tNGS, the overall co-detection rate was 59.45%, with Streptococcus pneumoniae (29.30%), Haemophilus influenzae (23.57%), and Human rhinovirus (17.21%) being the most commonly co-detected pathogens. In 635 patients undergoing the 23S rRNA gene mutation test, 86.30% exhibited positive mutations (A2063G, 98.00%; A2064G, 1.50%; A2067G, 0.50%). Despite a significant age difference ( P  = 0.037) between macrolide-resistant M. pneumoniae and macrolide-sensitive M. pneumoniae groups, there were no significant differences in symptoms, lab data, or disease severity., Conclusions: In Hubei Province, the prevalence of exhibited consistent changes during the COVID-19 pandemic. MPP was prevalent year-round, particularly in summer and autumn, with school-age children being more susceptible. Co-detections of viruses and bacteria were frequent in MPP cases, and macrolide resistance exceeded 85%. Ongoing surveillance of M. pneumoniae in children is crucial for understanding the healthcare impact of MPP., 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., (© 2024 Du, Li, Li, Zhao, Lu, Zhang, Liu, Luo, Lu, Hu, Ma, He, Sha, Zhang, Wu, Yang, Li, Chen, Li, Li, Lin, Liu, Wu, Liu, Li and Lu.)

Background: Respiratory syncytial virus (RSV) is a leading cause of severe illness in infants, with no effective treatment. Results of a phase 2 trial suggested that ziresovir may have efficacy in the treatment of infants hospitalized with RSV infection., Methods: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted in China, we enrolled participants 1 to 24 months of age who were hospitalized with RSV infection. Participants were randomly assigned, in a 2:1 ratio, to receive ziresovir (at a dose of 10 to 40 mg, according to body weight) or placebo, administered twice daily, for 5 days. The primary end point was the change from baseline to day 3 (defined as 48 hours after the first administration) in the Wang bronchiolitis clinical score (total scores range from 0 to 12, with higher scores indicating greater severity of signs and symptoms). The intention-to-treat population included all the participants with RSV-confirmed infection who received at least one dose of ziresovir or placebo; the safety population included all the participants who received at least one dose of ziresovir or placebo., Results: The intention-to-treat population included 244 participants, and the safety population included 302. The reduction from baseline in the Wang bronchiolitis clinical score at day 3 was significantly greater with ziresovir than with placebo (-3.4 points [95% confidence interval {CI}, -3.7 to -3.1] vs. -2.7 points [95% CI, -3.1 to -2.2]; difference, -0.8 points [95% CI, -1.3 to -0.3]; P = 0.002). The reduction in the RSV viral load at day 5 was greater in the ziresovir group than in the placebo group (-2.5 vs. -1.9 log 10 copies per milliliter; difference, -0.6 log 10 copies per milliliter [95% CI, -1.1 to -0.2]). Improvements were observed in prespecified subgroups, including in participants with a baseline bronchiolitis score of at least 8 and in those 6 months of age or younger. The incidence of adverse events related to the drug or placebo was 16% with ziresovir and 13% with placebo. The most common adverse events that were assessed by the investigator as being related to the drug or placebo were diarrhea (in 4% and 2% of the participants, respectively), an elevated liver-enzyme level (in 3% and 3%, respectively), and rash (in 2% and 1%). Resistance-associated mutations were identified in 15 participants (9%) in the ziresovir group., Conclusions: Ziresovir treatment reduced signs and symptoms of bronchiolitis in infants and young children hospitalized with RSV infection. No safety concerns were identified. (Funded by Shanghai Ark Biopharmaceutical; AIRFLO ClinicalTrials.gov number, NCT04231968.)., (Copyright © 2024 Massachusetts Medical Society.)

In the study, a novel surface-enhanced Raman scattering (SERS)-lateral flow assay (LFA) tray for the real-time detection of pyroptosis-associated miR-155-5p in breast cancer cells was established and validated. The SERS probe modified with monoclonal antibodies and functionalized HP1@5-FAM was first synthesized. When miR-155-5p was present, HP1@5-FAM on the SERS probe specifically recognized target miRNAs and hybridized with them, resulting in HP2 on the T line only capturing some SERS probes that were not bound to miR-155-5p. The T line appeared as a light orange band or there was no color change, and the corresponding Raman detection result showed a weak or insignificant Raman signal. The SERS probe showed high selectivity, satisfactory stability, and excellent reproducibility, and the limit of detection (LOD) for miR-155-5p was 7.26 aM. Finally, the proposed SERS-LFA tray was applied to detect miR-155-5p in MBA-MD-468 cells that underwent varying degrees of pyroptosis, and the detection results of SERS were consistent with those of the conventional real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. The study demonstrated that the SERS-LFA tray was a convenient and ultrasensitive method for miR-155-5p real-time detection, which could provide more detailed information for pyroptosis and be of potential value in guiding the treatment of breast cancer.

Background: An important first step in enhancing professional palliative care training is to investigate the educational needs of pediatric clinicians in this field. The aims of this research were to analyze the extent of end-of-life care experience of Chinese pediatric clinicians and identify the differing educational needs of physicians and nurses as well as associated impact factors., Methods: A cross-sectional descriptive survey via a structural questionnaire was used in this research., Results: In total, 187 clinicians, comprising 52 physicians and 135 nurses, participated in this study. The topics "pain management", "symptom management", and "discussing the prognosis with family members" were the most expressed educational needs among both physicians and nurses. Compared to nurses, physicians placed greater emphasis on the importance of "communication" and "pain and symptom management" ( p < 0.05). Clinicians with more extensive end-of-life care experience more strongly felt the importance of learning about pain management and communication regarding end-of-life care ( p < 0.05)., Conclusions: Research showed that the education currently provided to pediatric clinicians does not meet their distinctive needs. Future palliative care education must be a continuing multi-level, interdisciplinary program and different education should be provided to physicians and nurses based on their respective needs.

Close relationships exist between metal(loid)s exposure and embryo implantation failure (EIF) from animal and epidemiological studies. However, there are still inconsistent results and lacking of sensitive metal(loid) exposure biomarkers associated with EIF risk. We aimed to ascertain sensitive metal(loid) biomarkers to EIF and provide potential biological explanations. Candidate metal(loid) biomarkers were measured in the female hair (FH), female serum (FS), and follicular fluid (FF) with various exposure time periods. An analytical framework was established by integrating epidemiological association results, comprehensive literature searching, and knowledge-based adverse outcome pathway (AOP) networks. The sensitive biomarkers of metal(loid)s along with potential biological pathways to EIF were identified in this framework. Among the concerned 272 candidates, 45 metal(loid)s biomarkers across six time periods and three biomatrix were initially identified by single-metal(loid) analyses. Two biomarkers with counterfactual results according to literature summary results were excluded, and a total of five biomarkers were further determined from 43 remained candidates in mixture models. Finally, four sensitive metal(loid) biomarkers were eventually assessed by overlapping AOP networks information, including Se and Co in FH, and Fe and Zn in FS. AOP networks also identified key GO pathways and proteins involved in regulation of oxygen species biosynthetic, cell proliferation, and inflammatory response. Partial dependence results revealed Fe in FS and Co in FH at their low levels might be potential sensitive exposure levels for EIF. Our study provided a typical framework to screen the crucial metal(loid) biomarkers and ascertain that Se and Co in FH, and Fe and Zn in FS played an important role in embryo implantation., 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 © 2024 Elsevier Ltd. All rights reserved.)

Polycyclic aromatic hydrocarbons (PAHs) and arsenic (As) are common pollutants co-existing in the environment, causing potential hazards to the ecosystem and human health. How their behaviors are affected by micro/nano particles in the environment are still not very clear. Through a series of static adsorption experiments, this study investigated the adsorption of pyrene and arsenite (As (III)) using micro/nano carbon black and iron oxide under different conditions. The objectives were to determine the kinetics and isotherms of the adsorption of pyrene and As (III) using micro/nano carbon black and iron oxide and evaluate the impact of co-existing conditions on the adsorption. The microstructure of micro/nano carbon black (C 94.03%) is spherical-like, with a diameter of 100-200 nm. The micro/nano iron oxide (hematite) has irregular rod-shaped structures, mostly about 1 µm long and 100-200 nm wide. The results show that the micro/nano black carbon easily adsorbed the pyrene, with a pseudo-second-order rate constant of 0.016 mg/(g·h) and an adsorption capacity of 283.23 μg/g at 24 h. The micro/nano iron oxide easily adsorbed As (III), with a pseudo-second-order rate constant of 0.814 mg/(g·h) and an adsorption capacity of 3.45 mg/g at 24 h. The mechanisms of adsorption were mainly chemical reactions. Micro/nano carbon black hardly adsorbed As (III), but its adsorption capability for pyrene was reduced by the presence of As (III), and this effect increased with an increase in the As (III) concentration. The adsorbed pyrene on the micro/nano black carbon could hardly be desorbed. On the other hand, the micro/nano iron oxide could hardly adsorb the pyrene, but its adsorption capability for As (III) was increased by the presence of pyrene, and this effect increased with an increase in the pyrene concentration. The results of this study provide guidance for the risk management and remediation of the environment when there is combined pollution of PAHs and As.

This study investigated the interaction between the co-pollutants of Benzo[a]pyrene (BaP) and decabromodiphenyl ether (BDE-209) and the bacterial community in soil under flooding anaerobic condition. Three levels of combined pollution (at nominal concentrations of 1, 5, and 25 mg/kg, respectively, for each pollutant), their corresponding sterilized controls, and a blank control (CK) were set up. During the incubation time of 270 days, BaP attenuated more easily than BDE-209. The second-order rate constant of BaP attenuation was negatively correlated with the Ln value of initial BaP concentration. Maximal difference in bacterial community occurred between the CK soil and the highly polluted soil. Desulfomonilaceae, Parcubacteria and Rhodanobacter were probably involved in BaP and BDE-209 degradation, while Nitrosomonadaceae, Phenylobacterium and Mitochondria were significantly suppressed by BaP and BDE-209 or their degrading products. Genes narI, bcrC, fadJ, had, dmpC, narG and CfrA were involved in the degradation of BaP and BDE-209. Impacts of BaP and BDE-209 on metabolisms of carbon, nitrogen and sulfur were not significant. The results provide guidance for the management and remediation of the contaminated soil., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

What Is Already Known About This Topic?: Acute respiratory infections (ARIs) are a significant contributor to illness and death in children. There has been a notable rise in the occurrence of ARIs and the associated pathogens in China, which has garnered worldwide attention., What Is Added by This Report?: This study conducted a retrospective analysis of the clinical characteristics of children with ARIs in Wuhan City from September to November 2023. The study evaluated the epidemiological patterns of common respiratory viruses and Mycoplasma pneumoniae (MP), revealing a continued prevalence of MP and a growing trend of influenza. Our findings emphasize that the circulation of respiratory viruses and MP has not returned to pre-pandemic levels, underscoring the importance of enhancing surveillance for respiratory pathogens., What Are the Implications for Public Health Practice?: The epidemiology of ARIs and the pathogens involved need to be emphasized. This highlights the importance of developing policies to protect children from respiratory pathogens such as MP, influenza, and respiratory syncytial virus., Competing Interests: No conflicts of interest., (Copyright and License information: Editorial Office of CCDCW, Chinese Center for Disease Control and Prevention 2024.)

Benzo[a]pyrene (BaP) and 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) are common contaminants in the environment, posing a threat to the ecosystems and human health. Currently, information on the microbial metabolism of BaP and BDE-47 as well as the correlated bacteria is still limited. This research aimed to study the degradation of BaP and BDE-47 by enriched cultures originated from an agricultural soil in Tianjin (North China) and characterize the bacteria involved in the degradation. Two sets of experiments were set up with BaP and BDE-47 (2 mg/L) as the sole carbon source, respectively. The degradation of BaP and BDE-47 occurred at rate constants of 0.030 /d and 0.026 /d, respectively. For BaP, the degradation products included benzo[a]pyrene-9,10-dihydrodiol or its isomers, ben-zo(a)pyrene-7,8-dihydrodiol-9,10-epoxide, and cis-4 (8-hydroxypyrenyl-7)-2-oxo-3-butenoic acid. For BDE-47, the degradation products included 2,2',4-tribrominated diphenyl ether (BDE-17), 2,4-dibrominated diphenyl ether (BDE-7), and hydroxylated dibromodiphenyl ether. The bacterial community structures in the original soil, the BaP culture, and the BDE-47 culture were quite different. The richness and diversity of bacteria in the two cultures were much lower than that in the original soil, and the BaP culture had higher richness and diversity than the BDE-47 culture. In the BaP culture, multiple species such as Niabella (23.4%), Burkholderia-Caballeronia-Paraburkholderia (13.7%), Cupriavidus (8.3%), and Allorhizobi-um-Neorhizobium-Pararhizobium-Rhizobium (8.0%) were dominant. In the BDE-47 culture, an unassigned species in the Rhizobiaceae was dominant (82.3%). The results from this study provide a scientific basis for the risk assessment and bioremediation of BaP and/or BDE-47 in a contaminated environment.

Competing Interests: Conflicts of interest: 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.

Recent studies have shown that the epigenetic protein histone deacetylase 11 (HDAC11) is highly expressed in the brain and critically modulates neuroimmune functions, making it a potential therapeutic target for neurological disorders. Herein, we report the development of PB94, which is a novel HDAC11 inhibitor. PB94 exhibited potency and selectivity against HDAC11 with IC 50 = 108 nM and >40-fold selectivity over other HDAC isoforms. Pharmacokinetic/pharmacodynamic evaluation indicated that PB94 possesses promising drug-like properties. Additionally, PB94 was radiolabeled with carbon-11 as [ 11 C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for drug development in live animals. Furthermore, we demonstrated that neuropathic pain was associated with brain upregulation of HDAC11 and that pharmacological inhibition of HDAC11 by PB94 ameliorated neuropathic pain in a mouse model. Collectively, our findings support further development of PB94 as a selective HDAC11 inhibitor for neurological indications, including pain.

Increasing pollution of microplastics (MPs) and nanoplastics (NPs) has caused widespread concern worldwide. Extracellular polymeric substances (EPS) are natural organic polymers mainly produced by microorganisms, the major components of which are polysaccharides and proteins. This review focuses on the interactions that occur between EPS and MPs/NPs in the water environment and evaluates the effects of these interactions on the behaviors of MPs/NPs. EPS-driven formation of eco-corona, biofilm, and "marine snow" can incorporate MPs and NPs into sinking aggregates, resulting in the export of MPs/NPs from the upper water column. EPS coating greatly enhances the adsorption of metals and organic pollutants by MPs due to the larger specific surface area and the abundance of functional groups such as carboxyl, hydroxyl and amide groups. EPS can weaken the physical properties of MPs. Through the synergistic action of different extracellular enzymes, MPs may be decomposed into oligomers and monomers that can enter microbial cells for further mineralization. This review contributes to a comprehensive understanding of the dynamics of MPs and NPs in the water environment and the associated ecological risks., 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 Elsevier Ltd. All rights reserved.)

A series of novel erianin analogues were designed and synthesized based on the bioisosterism principle by altering the two aromatic rings of erianin, the substituents on the rings and the linker between them. The analogues were evaluated as pyruvate carboxylase (PC) inhibitors in hepatocellular carcinoma cells. It was found that compounds 35 and 36, where fluorine replaces a hydroxyl group, exhibited higher activity than erianin (IC 50 value of 17.30 nM) in liver cancer cells with IC 50 values of 15.15 nM and 10.05 nM, respectively. Additionally, at a concentration of 10 nM, compounds 35 and 36 inhibited PC with inhibitory rates of 39.10% and 40.15%, respectively, exhibiting nearly identical inhibitory activity to erianin (inhibitory rate of 40.07%). Additionally, a computer simulation docking study demonstrated the basis for better interactions between the receptors and ligands. The fluorine atom of 35 can not only form hydrogen bonds with Lys-1043 (NH⋯F, 2.04 Å), but also form fluorine bonds with the carbonyl groups of Lys-1043 (3.67 Å) and Glu-1046 (3.70 Å), due to the different orientations of the halogens on the B ring warhead. Conversely, the chlorine atom of 34 can only form alkyl hydrophobic interactions with the alkane chain in Lys-1043. Fluorinated compounds 35 and 36 also show better chemical stability and higher log  P (clog  P = 3.89 for 35 and 36) values than that of erianin (clog  P = 3.07), and may be used as candidate compounds for further drug development.

Purpose: Circulating tumor DNA (ctDNA) is more representative and accurate than biopsy and is also conducive to dynamic monitoring, facilitating accurate diagnosis and prognosis of glioma. Therefore, the present study aimed to establish and validate a novel amplified method for the detection of IDH1 R132H and BRAF V600E, which were associated with the genetic diagnosis of glioma., Patients and Methods: A dual-signal amplification method based on magnetic aggregation and catalytic hairpin assembly (CHA) was constructed for the simultaneous detection of ctDNAs. When target ctDNAs are present, the CHA reaction is initiated and leads to the assembly of Au-Ag nanoshuttles (Au-Ag NSs) onto magnetic beads (MBs). Further enrichment of MBs under an external magnetic field facilitated the dual-signal amplification of SERS., Results: The limit of detection (LOD) for IDH1 R132H and BRAF V600E in serum was as low as 6.01 aM and 5.48 aM. The reproducibility and selectivity of the proposed SERS analysis platform was satisfactory. Finally, the platform was applied to quantify IDH1 R132H and BRAF V600E in the serum of subcutaneous-tumor‑bearing nude mice, and the results obtained by SERS were consistent with those from quantitative real-time polymerase chain reaction (qRT-PCR)., Conclusion: The present study showed that the dual-signal amplification method is a simple and ultrasensitive strategy for gliomas-associated ctDNAs detection, which is crucial for early diagnosis and dynamic monitoring., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Wang et al.)

Human respiratory syncytial virus (RSV) is a severe threat to children and a main cause of acute lower respiratory tract infections. Nevertheless, the intra-host evolution and inter-regional diffusion of RSV are little known. In this study, we performed a systematic surveillance in hospitalized children in Hubei during 2020-2021, in which 106 RSV-positive samples were detected both clinically and by metagenomic next generation sequencing (mNGS). RSV-A and RSV-B groups co-circulated during surveillance with RSV-B being predominant. About 46 high-quality genomes were used for further analyses. A total of 163 intra-host nucleotide variation (iSNV) sites distributed in 34 samples were detected, and glycoprotein (G) gene was the most enriched gene for iSNVs, with non-synonymous substitutions more than synonymous substitutions. Evolutionary dynamic analysis showed that the evolutionary rates of G and NS2 genes were higher, and the population size of RSV groups changed over time. We also found evidences of inter-regional diffusion from Europe and Oceania to Hubei for RSV-A and RSV-B, respectively. This study highlighted the intra-host and inter-host evolution of RSV, and provided some evidences for understanding the evolution of RSV., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Microglia are resident immune cells in the brain and are closely associated with central nervous system inflammation and neurodegenerative diseases. It is known that mammalian target of rapamycin (mTOR) pathway plays an important role in the polarization of microglia. Castor1 has been identified as the cytosolic arginine sensor for the mTOR complex 1 (mTORC1) pathway, but the role of Castor1 in microglial polarization is still unknown. The purpose of this study was to explore the regulatory effect of Castor1 on microglial polarization and the underlying mechanism. The results demonstrated that Castor1 expression was significantly decreased in lipopolysaccharides (LPS) and interferon (IFN)-γ treated microglia. Castor1 overexpression inhibited the microglia M1 polarization by reducing the expression of M1 related markers. However, the expression of M2-related genes was promoted when Castor1 was overexpressed in IL-4 treated microglia. Mechanistically, Castor1 overexpression inhibited the activation of mTOR signaling pathway. In addition, after treatment with the mTOR activator MHY1485, the inhibitory effect of Castor1 overexpression on M1 polarization was attenuated, indicating that the regulation effects of Castor1 on M1 polarization was dependent on its inhibition of mTOR pathway. We propose that Castor1-mTOR signaling pathway could be considered as a potential target for treatment and intervention of central nervous system-related diseases by regulating microglia polarization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The contamination of soil and groundwater with BTEX (benzene, toluene, ethyl benzene, and xylenes) is a common issue at petrochemical sites, posing a threat to the ecosystems and human health. The goal of this study was to evaluate the biodegradation of BTEX in the subsurface of a petrochemical site near the Yangtze River, thus providing scientific basis for bioremediation of the contaminated site. Both molecular analysis of field samples and microcosm study in the laboratory were performed for the evaluation. Soil and groundwater samples were collected from the site. Microcosms were constructed with inoculum from the soil and incubated anaerobically in the presence of nitrate, ferric oxide, manganese oxide, sulfate, and sodium bicarbonate, respectively. The initial concentration of each component of BTEX (benzene, toluene, ethyl benzene, o-xylene) was 4-5 mg/L. Actinobacteria was dominant in the highly contaminated soil, while Proteobacteria was dominant in the slightly contaminated soil and the groundwater. The relative abundances of Firmicutes, Spirochaetes, and Caldiserica were higher in the highly contaminated soil and groundwater samples compared to those in the corresponding slightly contaminated samples. The relative abundances of predicted functions, such as carbohydrate transport and metabolism, nucleotide transport and metabolism, coenzyme transport and metabolism, amino acid transport and metabolism, etc., in the highly contaminated soil and groundwater samples were higher than those in the corresponding slightly contaminated samples. In microcosms, biodegradations of BTEX occurred, and the first-order rate constants in the presence of various electron acceptors had the following order: sulfate (0.08-0.10/d) > sodium bicarbonate (0.07-0.09/d) > ferric oxide (0.04-0.06/d) > nitrate (0.03-0.05/d) > manganese oxide (0.01-0.04/d).

In this work, a highly specific and sensitive method for the detection of dual miRNAs was successfully developed by a hybridization chain reaction (HCR) amplification coupled with surface-enhanced Raman scattering (SERS) on Au-Ag hollow nanoparticles (Au-Ag HNPs) and a gold nanohexagon (AuNH) array. Two Raman reporter-labelled and hairpin DNA-modified Au-Ag HNPs acted as SERS probes (Au-Ag HNPs@4-MBA@HP 1-1 , Au-Ag HNPs@4-MBA@HP 2-1 , Au-Ag HNPs@DTNB@HP 1-2 , and Au-Ag HNPs@DTNB@HP 2-2 ), and the hairpin DNA-modified AuNH array acted as the capture substrate. The HCR process could be triggered by the presence of target miRNAs, and long DNA hybridization chains on the substrate were formed by self-assembly rapidly, causing significant signal enhancement. Using the mentioned strategy, a low detection limit (LOD) of 6.51 aM for miR-31 and 6.52 aM for miR-21 in human saliva were obtained, showing the biosensor's remarkable sensitivity. The proposed biosensor also displays a significant specificity in detecting target miRNAs by introducing different interfering factors. This method has been successfully applied to detect and identify miR-21 and miR-31 in saliva from oral squamous cell carcinoma (OSCC) patients and healthy subjects. The results were consistent with those of the traditional test method in detecting target miRNAs, which confirmed the good accuracy of our method. Hence, the new assay method has great potential to be a valuable platform for detecting miRNAs in the early diagnosis of OSCC.

Previous studies have demonstrated that promyelocytic leukemia zinc finger protein (PLZF) promotes the expression of gluconeogenic genes and hepatic glucose output, which leads to hyperglycemia. However, the role played by PLZF in regulating lipid metabolism is not known. In this study, we aimed to examine the function of PLZF in regulating hepatic lipid and glucose homeostasis and the underlying mechanisms. The expression of PLZF was determined in different mouse models with regard to non-alcoholic fatty liver disease (NAFLD). In the next step, adenoviruses that express PLZF (Ad-PLZF) or PLZF-specific shRNA (Ad-shPLZF) were utilized to alter PLZF expression in mouse livers and in primary hepatocytes. For the phenotype of the fatty liver, histologic and biochemical analyses of hepatic triglyceride (TG), serum TG and cholesterol levels were carried out. The underlying molecular mechanism for the regulation of lipid metabolism by PLZF was further explored using luciferase reporter gene assay and ChIP analysis. The results demonstrated that PLZF expression was upregulated in livers derived from ob/ob, db/db and diet-induced obesity (DIO) mice. Liver PLZF-overexpressing C57BL/6J mice showed fatty liver phenotype, liver inflammation, impaired glucose tolerance and insulin sensitivity. On the other hand, hepatic PLZF knockdown in db/db and DIO mice alleviated hepatic steatosis. Of note, we found that PLZF activates SREBP-1c gene transcription through binding directly to the promoter fragment of this gene, which would induce a repressor-to-activator conversion depending on its interaction with SIRT1 in the role played by PLZF in the transcription process through deacetylation. Thus, PLZF is identified as an essential regulator of hepatic lipid and glucose metabolism, where the modulation of its liver expression could open up a therapeutic path for treating NAFLD., 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. The handling editor XC declared a shared parent affiliation with several of the authors HH, KP, XLL, XXL, and CD at the time of review., (Copyright © 2022 Hu, Sun, Du, He, Pan, Liu, Lu, Wei, Liao and Duan.)

Transforming growth factor-beta (TGF- β ) is a double-edged sword in cancer treatment because of its pivotal yet complex and roles played during cancer initiation/development. Current anti-cancer strategies involving TGF- β largely view TGF- β as an onco-therapeutic target that not only substantially hinders its full utilisation for cancer control, but also considerably restricts innovations in this field. Thereby, how to take advantages of therapeutically favourable properties of TGF- β for cancer management represents an interesting and less investigated problem. Here, by categorising cancer hallmarks into four critical transition events and one enabling characteristic controlling cancer initiation and progression, and delineating TGF- β complexities according to these cancer traits, we identify the suppressive role of TGF- β in tumour initiation and early-stage progression and its promotive functionalities in cancer metastasis as well as other cancer hallmarks. We also propose the feasibility and possible scenarios of combining cold atmospheric plasma (CAP) with onco-therapeutics utilising TGF- β for cancer control given the intrinsic properties of CAP against cancer hallmarks.

Background: Rapid Advice Guidelines (RAG) provide decision makers with guidance to respond to public health emergencies by developing evidence-based recommendations in a short period of time with a scientific and standardized approach. However, the experience from the development process of a RAG has so far not been systematically summarized. Therefore, our working group will take the experience of the development of the RAG for children with COVID-19 as an example to systematically explore the methodology, advantages, and challenges in the development of the RAG. We shall propose suggestions and reflections for future research, in order to provide a more detailed reference for future development of RAGs., Result: The development of the RAG by a group of 67 researchers from 11 countries took 50 days from the official commencement of the work (January 28, 2020) to submission (March 17, 2020). A total of 21 meetings were held with a total duration of 48 h (average 2.3 h per meeting) and an average of 16.5 participants attending. Only two of the ten recommendations were fully supported by direct evidence for COVID-19, three recommendations were supported by indirect evidence only, and the proportion of COVID-19 studies among the body of evidence in the remaining five recommendations ranged between 10 and 83%. Six of the ten recommendations used COVID-19 preprints as evidence support, and up to 50% of the studies with direct evidence on COVID-19 were preprints., Conclusions: In order to respond to public health emergencies, the development of RAG also requires a clear and transparent formulation process, usually using a large amount of indirect and non-peer-reviewed evidence to support the formation of recommendations. Strict following of the WHO RAG handbook does not only enhance the transparency and clarity of the guideline, but also can speed up the guideline development process, thereby saving time and labor costs., (© 2022. The Author(s).)

The prenylation of phenolic substrates promoted by magnesium dicarboxylates was developed. An investigation of the scope demonstrated that substrates with electron-donating group(s) gave better yields than those with electron-withdrawing group(s). Although the conversions of all substrates were higher in MeCN than in DMF, DMF was still the favorable solvent for polyphenolic substrates since MeCN would cause the generation of cyclized by-products (6) and reduce the yield of 3. The regio-selectivity of ortho - vs. para -prenylation (3' vs. 3'') for those para -unoccupied substrates was also solvent dependant. DMF produced mainly ortho -products but with poor conversions. On the other hand, MeCN generated mainly para -products, along with minor ortho -products. Mechanistic study of the prenylation provided evidence for the nucleophilic addition/substitution of the phenolic substrate to the alkyl halide in the presence of the magnesium dicarboxylates. The proto application of this method in the total synthesis of icaritin through the prenylation of 2,4,6-trihydroxyacetophenone, followed by the reaction with benzaldehyde to afford the flavonol, was successful, with a total yield of 33%.

Human adenoviruses (HAdVs) type 7 can cause severe respiratory disease. During the period between December 2018 and August 2019, HAdV-7 infection was identified in 129 patients in Wuhan Children's Hospital, Hubei Province, China. Samples were collected from hospitalized children and metagenomic sequencing was applied to detect the HAdV infections. Hemophagocytic lymphohistiocystosis (HLH) related to HAdV infections was observed in some patients clinically and patients were divided into two groups based on this to test the differences among clinical indicators. Genome variation, in silico restriction endonuclease analysis (REA), and phylogenetic analyses were carried out to show the genome characterization of HAdV-7 in this study. It was found that many indicators, such as all blood routine indicators, in patients of the HLH group showed significant levels. In this study, REA revealed that HAdV-7 might belong to genome 7d and genome variation analysis displayed the stable genome of HAdV. HAdV-7 is an ongoing threat to the public, and global surveillance should be established., 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 Li, Wang, Zhang, Huang, Du, Xu, Chen, Yan, Chen, Lu and Liu.)

Colchicine poisoning is complicated and has a high mortality rate. The aim of this study was to identify the pathogenic characteristics of colchicine poisoning cases and to propose a comprehensive treatment procedure. A total of 43 patients were divided into survival ( n  = 32) and death groups ( n  = 11) according to prognosis. The clinical data (basic information, clinical manifestations, laboratory tests, examination results, therapeutic schedule, response evaluation, and prognosis) were analyzed, and the comprehensive treatment was proposed. The ingestion doses were ≤0.5, 0.5-0.8, and ≥0.8 mg/kg, and the survival rates were 100, 83.33, and 28.60%. The causes of death were cardiovascular and bone marrow hematopoietic failures. We found that the order of organ damage was digestive tract, coagulation, muscle, heart, hematopoietic, lung, liver, and kidney, while the recovery order was digestive tract, coagulation, heart, hematopoietic, lung, muscle, kidney, and liver. Different doses of recombinant human granulocyte colony-stimulating factor and recombinant human thrombopoietin can shorten the severity and duration of neutropenia and thrombocytopenia. Plasma exchange combined with continuous veno-venous hemodialysis filtration treatment can increase survival time. The prognosis is positively correlated with the dose. Early removal of toxicants from the digestive tract and blood is essential. It is vital to give comprehensive treatment of multiple organ injuries， include the use of recombinant human granulocyte colony-stimulating factor, recombinant human thrombopoietin, plasma exchange, and continuous veno-venous hemodialysis filtration., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Abstract: Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, considerable attention has been paid on its epidemiology and clinical characteristics in children patients. However, it is also crucial for clinicians to summarize and investigate the co-infection of SARS-CoV-2 in children.We retrospectively reviewed the clinical manifestations, laboratory findings, and imaging characteristics of COVID-19 patients in co-infection group (CI, n = 27) and single infection group (SI, n = 54). Samples were tested for multiple pathogens.A high incidence (27/81, 33%) of co-infection in children with COVID-19 was revealed. The most frequent co-infected pathogen was mycoplasma pneumoniae (MP, 20/81, 25%), followed by virus (6/81, 7%), and bacteria (4/81, 5%). No significant difference in clinical characteristics, laboratory examinations, or hospital stay was observed between the patients with co-infections and those with monomicrobial, only lower in white blood cell counts (CI: 5.54 ± 0.36 vs SI: 7.38 ± 0.37, P = .002), neutrophil counts (CI: 2.20 ± 0.20 vs SI: 2.92 ± 0.23, P = .024) and lymphocyte counts (CI: 2.72 ± 0.024 vs SI: 3.87 ± 0.28, P = .006). Compared with the patients with monomicrobial, chest imaging of those with co-infections showed consolidation in more cases (CI: 29.6% vs SI: 11.1%, P = .038) and duration of positive in nucleic acid was shorter (CI: 6.69 ± 0.82 vs SI: 9.69 ± 0.74, P = .015).Co-infection was relatively common in children with COVID-19, almost 1/3 had co-infection, most commonly caused by MP. Co-infection did not cause a significant exacerbation in clinical manifestations., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD1 bromodomains of the PET radiotracer [ 18 F]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 ( K d = 100 nM and 29-fold selectively for BD1 over BD2) in an in vitro binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [ 18 F]PB006 in vivo . A biodistribution study of [ 18 F]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20-30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [ 18 F]PB006. Our study indicated that [ 18 F]PB006 is a potent PET probe selectively targeting BET BD1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Introduction: An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow. Methods: We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 15, 2020. We systematically examined the expression and distribution of ACE2 in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and ex vivo SARS-CoV-2 pseudoviral infections. Results: It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury. The expression levels of ACE2 however do not vary by age in children's lung. ACE2 is notably expressed not only in Alveolar Type II (AT II) cells, but also in SOX9 positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs. The ACE2 + SOX9 + cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children. Conclusions: Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries. ACE2 expression in multiple types of lung cells including SOX9 positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Bromodomain and extra-terminal domain (BET) family proteins have become a hot research area because of their close relationship with a variety of human diseases. The non-invasive imaging technique, such as positron emission tomography (PET), provides a powerful tool to visualize and quantify the BET family proteins that accelerating the investigation of this domain. Herein, we describe the development of a promising PET probe, [ 11 C]1 , specifically targeting BET family proteins based on the potent BET inhibitor CF53. [ 11 C]1 was successfully radio-synthesized with good yield and high purity after the optimization of radiolabeling conditions. The in vivo bio-activities evaluation of [ 11 C]1 was performed using PET imaging in rodents. The results demonstrated that [ 11 C]1 has favorable uptake in peripheral organs and moderate uptake in the brain. Further blocking studies indicated the high binding specificity and selectivity for BET proteins of this probe. Our findings suggest that [ 11 C]1 is a promising BET PET probe for BET proteins as well as epigenetic imaging., (Copyright © 2020 Bai, Lan, Wang, Chen, Fiedler, Striar, Lu and Wang.)

Background: Novel coronavirus disease (COVID-19) is spreading globally. Little is known about the risk factors for the clinical outcomes of COVID-19 in children., Methods: A retrospective case-control study was taken in children with severe acute respiratory syndrome coronary virus-2 infection in Wuhan Children's Hospital. Risk factors associated with the development of COVID-19 and progression were collected and analyzed., Results: Eight of 260 children diagnosed with severe COVID-19 pneumonia were included in the study. Thirty-five children with COVID-19 infection matched for age, sex and date of admission, and who classified as non-severe type, were randomly selected from the hospital admissions. For cases with severe pneumonia caused by COVID-19, the most common symptoms were dyspnea (87.5%), fever (62.5%) and cough (62.5%). In laboratory, white blood cells count was significantly higher in severe children than non-severe children. Levels of inflammation bio-makers such as hsCRP, IL-6, IL-10 and D-dimer elevated in severe children compared with non-severe children on admission. The level of total bilirubin and uric acid clearly elevated in severe children compared with non-severe children on admission. All of severe children displayed the lesions on chest CT, more lung segments were involved in severe children than in non-severe children, which was only risk factor associated with severe COVID-19 pneumonia in multivariable analysis., Conclusions: More than 3 lung segments involved were associated with greater risk of development of severe COVID-19 in children. Moreover, the possible risk of the elevation of IL-6, high total bilirubin and D-dimer with univariable analysis could identify patients to be severe earlier.

Introduction: Bromodomain and extra-terminal domain (BET) family proteins play a vital role in the epigenetic regulation process by interacting with acetylated lysine (Ac-K) residues in histones. BET inhibitors have become promising candidates to treat various diseases through the inhibition of the interaction between BET bromodomains and Ac-K of histone tails. With a molecular imaging probe, noninvasive imaging such as positron emission tomography (PET) can visualize the distribution and roles of BET family proteins in vivo and enlighten our understanding of BET protein function in both healthy and diseased tissue., Methods: We radiolabeled the potent BET inhibitor INCB054329 by N-methylation to make [ 11 C]PB003 as a BET PET radiotracer. The bioactivity evaluation of unlabeled PB003 in vitro was performed to confirm its binding affinity for BRDs, then the PET/CT imaging in rodents was performed to evaluate the bioactivity of [ 11 C]PB003 in vivo., Results: In our in vitro evaluation, PB003 showed a high BET binding affinity for BRDs (K d  = 2 nM, 1.2 nM, and 1.2 nM for BRD2, BRD3, and BRD4, respectively). In vivo PET/CT imaging demonstrated that [ 11 C]PB003 has favorable uptake with appropriate kinetics and distributions in main peripheral organs. Besides, the blockade of [ 11 C]PB003 binding was found in our blocking study which indicated the specificity of [ 11 C]PB003. However, the BBB penetration and brain uptake of [ 11 C]PB003 was limited, with only a maximum 0.2% injected dose/g at ~2 min post-injection., Conclusion: The imaging results in rodents in vivo demonstrate that [ 11 C]PB003 binds to BET with high selectivity and specificity and has favorable uptake in peripheral organs. However, the low brain uptake of [ 11 C]PB003 limits the visualization of brain regions indicating the efforts are still needed to discover the new BET imaging probes for brain visualization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A method for simultaneous measure of nine neonicotinoid insecticide residues in soil was developed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with a quick pretreatment procedure. The soil was extracted with a mixture of acetonitrile and dichloromethane (1:2, v:v) and cleaned up with Primary Secondary Amine (PSA). Matrix-matched standards were prepared to eliminate the interference of the matrix. The LC-MS/MS conditions were optimized to separate the nine neonicotinoids within 6.7 min, and the obtained limits of detection (LODs) and limits of quantification (LOQs) ranged from 0.01 to 0.84 ng g -1 and 0.05-2.79 ng g -1 , respectively. Recoveries of the studied neonicotinoids (except for nitenpyram) ranged from 79.41 to 100.20% with relative standard deviations (RSDs) less than 10% at spiked levels of 5 ng mL -1 , 100 ng mL -1 and 500 ng mL -1 , and RSDs for the interday and intraday method repeatability were less than 9%. The method was applied to measure neonicotinoid residues in soil samples collected from parks (n = 35) and residential areas (n = 33) in Tianjin, China. Seven neonicotinoids were detected, with imidacloprid being the most frequently detected one, followed by acetamiprid and thiamethoxam. The total concentrations of neonicotinoids in soil ranged from 0.27 to 230.76 ng g -1 in parks and 0.23-132.66 ng g -1 in residential areas., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is common in people with hypertension and cardiac rhythm disorder. The objectives of this study were to determine the effect of short-term continuous positive airway pressure (CPAP) on blood pressure (BP) and cardiac rhythm in Chinese patients with moderate to severe OSAHS., Patients and Methods: Eligible patients in the two hospitals were consecutively enrolled into the prospective study. Ambulatory BP monitoring and Holter monitoring were both performed for 24 h in 214 patients who previously encountered a full night polysomnography. Ambulatory BP was measured again in the follow-up of 59 patients with OSAHS who underwent home CPAP for 30 days, whereas Holter was repeated within 2-3 days after institution of CPAP therapy in 15 patients with OSAHS., Results: Fifty-one patients with OSAHS with hypertension who used CPAP for at least 4 h/night received 30 days of CPAP treatment. Added CPAP on usual antihypertension treatment showed that systolic BP, diastolic BP, and mean arterial BP were significantly reduced at night (5.08, 3.05, and 3.73 mmHg, respectively), in the morning (6.31, 4.83, and 5.32 mmHg, respectively), and during the whole a day (3.09, 2.60, and 2.76 mmHg, respectively). There were no significant changes in daytime BP values but did reduce daytime BP by 2.09, 2.37, and 2.28 mmHg, respectively. In addition, CPAP therapy resulted in abolition of most sinus pauses and atrioventricular block in the 15 patients with OSAHS having coexisting pathologically rhythm disturbances, whereas the effect on other types of arrhythmia was not effective enough., Conclusion: Short-term CPAP reduced BP modestly in patients with OSAHS with hypertension, especially in the morning and at night-time.

Objective: To explore the therapeutic effect of honokiol on particulate matter 2.5 (PM2.5)-induced lung injury in asthmatic mice and the possible mechanisms.
 Methods: A total of 32 BALB/C mice were randomly divided into four groups: a normal saline group, a model group, a PM2.5 group and a honokiol group (n=8 in each group). The asthma mouse model was established by ovalbumin treatment. The mice were treated with physiological saline, ovalbumin, PM2.5 and honokiol, respectively. Lung tissues and serum were collected. The pathological changes of lung tissues were evaluated. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were measured and the expressions of Toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), retinoid-related orphan receptor gamma-t (RORγt) and forkhead box protein 3 (Foxp3) in lung tissues were detected.
 Results: 1) The lung tissues of mice in the asthma group showed obvious pathological changes and inflammatory state, suggesting that the asthma model was established successfully. PM2.5 could aggravate the pathological condition of inflammatory injury in lung tissues in asthmatic mice. 2) Compared to the PM2.5 group, the pathological symptoms in the lung tissues were alleviated in the honokiol group and the percentage of inflammatory cells in BALF and the levels of inflammatory cytokines in BALF and serum were significantly reduced (all P<0.05). 3) Compared to the PM2.5 group, the expressions of TLR4, NF-κB (p-p65) and RORγt in lung tissues were significantly decreased, while the expression of Foxp3 was increased; the ratio of RORγt/Foxp3 was also decreased in the honokiol group (all P<0.05).
 Conclusion: Honokiol can resist lung injury induced by PM2.5 in asthmatic mice. These effects are through inhibiting TLR4-NF-κB pathway-mediated inflammatory response or regulating the balance of Th17/Treg cells.

Objective: To investigate the efficacy of prussian blue (PB) or its combination with hemoperfusion (HP) in the treatment of acute thallium poisoning., Methods: Forty-seven patients with acute thallium poisoning with complete data hospitalized in the 307th Hospital of PLA from September 2002 to December 2017 were enrolled, and they were divided into mild poisoning group (blood thallium < 150 μg/L, urinary thallium < 1 000 μg/L) and moderate-severe poisoning group (blood thallium ≥ 150 μg/L, urinary thallium ≥ 1 000 μg/L) according to the toxic degrees. All patients were given symptomatic supportive treatments such as potassium supplementation, catharsis, vital organ protections, neurotrophic drugs, and circulation support. The mild poisoning patients were given PB with an oral dose of 250 mg×kg -1 ×d -1 , while moderate-severe poisoning patients were given PB combined HP continued 2-4 hours each time. The PB dose or frequency of HP application was adjusted according to the monitoring results of blood and urine thallium. Data of gender, age, pain grading (numeric rating scale NRS), clinical manifestations, blood and urine thallium before and after treatment, length of hospitalization and prognosis were collected., Results: Of the 47 patients, patients with incomplete blood and urine test results, and used non-single HP treatment such as plasmapheresis and hemodialysis for treatment were excluded, and a total of 29 patients were enrolled in the analysis. (1) Among 29 patients, there were 20 males and 9 females, median age of 40.0 (34.0, 49.0) years old; the main clinical manifestations were nervous system and alopecia, some patients had digestive system symptoms. There were 13 patients (44.8%) in the mild poisoning group with painless (grade 0) or mild pain (grade 1-3) with mild clinical symptoms, the length of hospitalization was 17.0 (14.2, 21.5) days. There were 16 patients (55.2%) in the moderate-severe poisoning group with moderate pain (grade 4-6) or severe pain (grade 7-10) with severe clinical symptoms, the length of hospitalization was 24.0 (18.0, 29.0) days. (2) After treatment, the thallium concentrations in blood and urine in the mild poisoning group were significantly lower than those before treatment [μg/L: blood thallium was 0.80 (0, 8.83) vs. 60.00 (40.00, 120.00), urine thallium was 11.30 (0, 70.10) vs. 370.00 (168.30, 610.00), both P < 0.01], the thallium concentrations in blood and urine in the moderate-severe poisoning group were also significantly lower than those before treatment [μg/L: blood thallium was 6.95 (0, 50.50) vs. 614.50 (245.00, 922.00), urinary thallium was 20.70 (1.95, 283.00) vs. 5 434.00 (4 077.20, 10 273.00), both P < 0.01]. None of the 29 patients died, and their clinical symptoms were improved significantly. All the 27 patients had good prognosis without sequela in half a year follow-up, and 2 patients with severe acute thallium poisoning suffered from nervous system injury., Conclusions: In the acute thallium poisoning patients, on the basis of general treatment, additional PB in mild poisoning group and PB combined with HP in moderate-severe poisoning group can obtain satisfactory curative effects.

Purpose: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common breathing disorder during sleep characterized by multiple disease roots, including disorders of complement and glycometabolism. And the main purpose of the present study is to make clear the effect of complement C3 on glucose metabolism abnormalities in patients with OSAHS., Methods: This was a cross-sectional study. Two hundred six patients, mean age 44.58 ± 11.84 years and 26 female patients (26/206), had been suspected with OSAHS and underwent overnight polysomnography. The assessment of complement levels included complement 3 (C3), complement 4 (C4), and serum total complement (TC). The measured indicators of glucose metabolism were fasting blood glucose (FPG), fasting insulin (FINS), and 75 g oral glucose tolerance test-derived glucose. A multivariate linear regression was used to determine relevant factors with 2-h postprandial blood glucose (2hPG) and C3., Results: The patients were classified according to apnea-hypopnea index (AHI) into four groups: simple snore (n = 21), mild OSAHS (n = 43), moderate OSAHS (n = 35), and severe OSAHS (n = 107). The level of C3 in the severe OSAHS was higher than other groups (simple snore: 1.16 ± 0.18 g/L VS 1.00 ± 0.18 g/L, p < 0.001; mild OSAHS: 1.16 ± 0.18 g/L VS 1.04 ± 0.17 g/L, p < 0.001; moderate OSAHS: 1.16 ± 0.18 g/L VS 1.06 ± 0.14 g/L, p = 0.003) and no-severe OSAHS group (1.16 ± 0.18 g/L VS 1.04 ± 0.16 g/L, p < 0.001). And C3 was associated with AHI, average pulse oxygen saturation (A-spo2), homeostasis model assessment-insulin resistance (HOMA-IR), 2hPG, age, sleep stage (I + II)/TST, and sleep stage (III)/TST, respectively. HOMA-IR was correlated to AHI after adjustment with age and BMI. OSAHS was an independent risk of C3 regardless of obesity and sleep parameters (p = 0.002). After adjustment with neck circumference (NC), BMI, AHI, sleep stage (I + II)/TST, and sleep stage (III)/TST,C3 level was associated with 2hPG (p < 0.001)., Conclusions: A high level in C3 is correlated with the occurrence of OSAHS and C3 alterations in OSAHS patients seem to contribute to disorders of glucose metabolism. And targeting OSAHS to improve glucose metabolism and immune function could be useful.

Objective: To analyze the clinical manifestation and therapeutic method in patients with acute mushroom poisoning., Methods: A retrospective study was conducted. The clinical data of 48 patients with acute mushroom poisoning admitted to Department of Poisoning Treatment of the 307th Hospital of PLA from January 2016 to May 2017 were analyzed. The clinical data including gender, age, clinical symptoms, onset season, initial symptoms, incubation time, the length of hospital stay, treatment, and prognosis. In addition to the conventional treatment, the patients with severe liver damage were treated with continuous blood purification (CBP). The changes in routine blood test, biochemical parameters, blood ammonia and coagulation function before and 1, 3 and 7 days after CBP were observed., Results: There were 29 of male (60.4%) and 19 of female (39.6%) in 48 patients with acute mushroom poisoning, with an average age of (48.10±13.14) years. There were 9 patients suffering from gastroenteritis type, 26 suffering from liver damage type, 8 suffering from neuro-psychosis type, 2 suffering from hemolytic type, and 3 suffering from renal damage type. All of the poisoned patients had evident seasonal characteristic, mainly concentrated in the autumn, especially in August, according for 66.7% (32/48). The initial symptoms of poisoning patients were mainly manifested as nausea and vomiting (50.0%). In five kinds of poisoned patients, the incubation time [(1.44±1.15) hours] and the length of hospital stay [(3.50±2.33) days] of neuro-psychosis type was the shortest, and the incubation time of liver-damaged type [(10.63±3.50) hours] and the length of hospital stay of renal damage type [(20.67±0.58) days] was the longest. Patients received symptomatic treatment according to different types, among whom 12 patients with severe liver damage received additional treatment for CBP. After the treatment, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), and prothrombin activity (PTA) were significantly improved as compared with those before CBP treatment, with significant differences between 7 days after CBP and before CBP [ALT (U/L): 213.08±127.30 vs. 2 766.83±1 909.66, AST (U/L): 50.00 (41.00, 85.00) vs. 2 142.00 (1 225.00, 3 126.00), CK-MB (U/L): 24.09±8.87 vs. 44.75±22.09, LDH (μmol×s -1 ×L -1 ): 3.70±1.46 vs. 13.03±12.77, PTA: (79.08±24.29)% vs. (35.25±19.85)%, all P < 0.01]. Among 48 patients, 47 were cured and discharged, and 1 patient with liver failure died due to aggravation of liver dysfunction, abnormal coagulation and bleeding, and massive hemorrhage of gastrointestinal tract., Conclusions: Acute mushroom poisoning patients demonstrated obvious seasonal characteristics, mostly liver-damaged type, and its initial symptoms were mainly presented as nausea, vomiting and other gastrointestinal manifestations. Early clarification of diagnosis, timely treatment, as well as providence with CBP treatment in severe patients should be carried out as soon as possible. In such a way the curative effect can be enhanced, the mortality can be reduced, and the prognosis of the patients could be improved.

Spinel Li 4 Ti 5 O 12 , known as a zero-strain material, is capable to be a competent anode material for promising applications in state-of-art electrochemical energy storage devices (EESDs). Compared with commercial graphite, spinel Li 4 Ti 5 O 12 offers a high operating potential of ∼1.55 V vs Li/Li + , negligible volume expansion during Li + intercalation process and excellent thermal stability, leading to high safety and favorable cyclability. Despite the merits of Li 4 Ti 5 O 12 been presented, there still remains the issue of Li 4 Ti 5 O 12 suffering from poor electronic conductivity, manifesting disadvantageous rate performance. Typically, a material modification process of Li 4 Ti 5 O 12 will be proposed to overcome such an issue. However, the previous reports have made few investigations and achievements to analyze the subsequent processes after a material modification process. In this review, we attempt to put considerable interest in complete device design and assembly process with its material structure design (or modification process), electrode structure design and device construction design. Moreover, we have systematically concluded a series of representative design schemes, which can be divided into three major categories involving: (1) nanostructures design, conductive material coating process and doping process on material level; (2) self-supporting or flexible electrode structure design on electrode level; (3) rational assembling of lithium ion full cell or lithium ion capacitor on device level. We believe that these rational designs can give an advanced performance for Li 4 Ti 5 O 12 -based energy storage device and deliver a deep inspiration., (© 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Adenocarcinoma of esophagogastric junction (AEG) is a lethal malignancy featured with early metastasis, poor prognosis, and few treatment options. Matrix metalloproteinase (MMP) and metalloproteinase suppressor (TIMP) have been considered to be associated with cancer invasion and metastasis. In our study, we evaluated expressions of MMP-9, MMP-2, TIMP-1, and TIMP-2 in AEG and their correlation with clinicopathological parameters and the overall survival rate., Methods: Expressions of MMP-9, MMP-2, TIMP-1, and TIMP-2 in specimens from 120 AEGs were detected by immunohistochemistry. The correlations between expressions of these four proteins and clinicopathological characters were analyzed by chi-square test. Moreover, the prognostic value of these four biomarkers was evaluated by univariate analysis with Kaplan-Meier method and multivariate analysis with Cox regression model., Results: The positive expression rate of MMP-9, MMP-2, TIMP-1, and TIMP-2 was 65%, 53%, 70%, and 49%, respectively, in the detected 120 AEG samples. MMP-9 was significantly associated with poorly histological differentiation (P=0.001), lymph node metastasis (P=0.007), and UICC stage (P=0.008). TIMP-1 showed significantly reversed correlations with histological differentiation (P=0.001), lymph node metastasis (P=0.007), and Union for International Cancer Control stage (P=0.008). Univariate analysis revealed that lymph node metastasis (P=0.002), depth of invasion (P=0.050), and MMP-9+/TIMP-1 phonotype (P<0.001) were significantly associated with the overall survival rate. Multivariate analyses demonstrated that MMP-9+/TIMP-1-phenotype was an independent prognostic factor in AEGs., Conclusion: Detection of MMP-9 and TIMP-1 expression allows stratification of AEG patients into different survival categories and can be useful for precise individual evaluation and survival prediction.

A Pd-catalyzed cascade oxidation/sp(2) C-H bond acylation of azoarenes was developed in which readily available aryl methanes were used as the in situ generated acyl sources. This reaction provides a convenient access to ortho-acyl azoarenes under mild conditions.

Sediments were sampled from different surface water bodies in Tianjin coastal area, China, and persistent organic pollutants (POPs) including polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) were measured using GC/MS or GC/ECD. The purposes were to investigate the concentration levels of the POPs and to assess their ecological risks. The results showed that all the 16 priority PAHs were detected from the 10 sediments sampled with the total concentrations of the 16 PAHs ranging from 274.06 μg/kg to 2656.65 μg/kg, while the concentrations of the halogenated POPs were generally low except in the Dagu waste discharging river where the total concentrations of 24 OCPs, 35 PCBs, and 14 PBDEs were 3103.36 μg/kg, 87.31 μg/kg, and 13.88 μg/kg, respectively. In the studied sediments, PAHs exhibited risks to benthonic organisms; particularly the concentrations of naphthalene and/or acenaphthene exceeded their probable effect concentrations in several locations. In comparison, only in the Dagu waste discharging river, OCPs exhibited risks with the concentrations of heptachlor epoxide and lindane exceeding their probable effect concentrations. PCBs and PBDEs posed rare risks in the studied area.

A previous study on mobilization of organochlorine pesticides (OCPs) in contaminated soils from the field revealed that the total amount of OCPs measured in digestive fluid and chyme of an in vitro gastrointestinal model was higher than the quantity directly extracted using a solvent extraction without digestion, providing a clue that the bound residue of OCPs might be mobilized. This hypothesis was tested in this study for both OCPs and polycyclic aromatic hydrocarbons (PAHs). Three contaminated surface soil samples with different organic carbon (OC) contents were collected from the field, and extracted with a solvent with and without digestion in an in vitro gastrointestinal model. It was found that bound residues of OCPs and PAHs were mobilized to a certain extent during digestion. The ratios of the mobilized bound residues over the total quantities extracted after digestion (R(b)) varied from 0 to 0.96 for individual compounds. The R(b) was positively correlated with OC content. Among the five constitutes of digestive juice, bile salt was the only one that served to mobilize the bound residues and the extractability of bile salt was constant over a concentration range from 2 to 20 mg/mL. The mobilization process followed typical first-order kinetics. The calculated rate constants suggest that mobilization was fast and 90% of extracted bound residues of OCPs and PAHs were mobilized within 2.4 and 4.8 h, respectively.

Background: Beta-defensin-2 (BD-2) plays an important role in host defense against pathogenic microbe challenge by its direct antimicrobial activity and immunomodulatory functions. The present study aimed to determine whether genetic up-regulation of rat BD-2 (rBD-2) could ameliorate chronic Pseudomonas aeruginosa lung infection in rats., Methods: Plasmid-encoding rBD-2 was delivered to lungs in vivo using linear polyethylenimine at 48 h before challenging with seaweed alginate beads containing P. aeruginosa. Macroscopic and histopathological changes of the lungs, bacterial loads, inflammatory infiltration, and the levels of cytokines/chemokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, kertinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2)] were measured at 3 and 7 days post-infection (p.i.)., Results: The overexpression of rBD-2 resulted in a significant increase in animal survival rate (at 3 days p.i.), a significant decrease in bacterial loads in the lungs (at 3 and 7 days p.i.), and significantly milder lung pathology. In addition, the overexpression of rBD-2 led to increased infiltration of polymorphonuclear neutrophils (PMN), and elevated protein expression of cytokines/chemokines (IL-1beta, TNF-alpha, KC and MIP-2) at the early stage of infection (at 3 days p.i.), at the same time as being dramatically decreased at the later stage of infection (at 7 days p.i.)., Conclusions: Genetic up-regulation of rBD-2 increased animal survival rate, and reduced bacterial loads in lungs after bacterial infection. The overexpression of rBD-2 also modulated the production of several cytokines/chemokines and increased PMN recruitment at the early stage of infection. Our findings indicate that the enhancement of BD-2 may be an efficacious intervention for chronic P. aeruginosa lung infection.