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Background: Huangkui Lianchang Decoction (HLD) is a traditional Chinese herbal formula for treating ulcerative colitis (UC). However, its mechanism of action remains poorly understood. The Study aims to validate the therapeutic effect of HLD on UC and its mechanism by integrating network pharmacology, bioinformatics, and experimental validation., Methods: UC targets were collected by databases and GSE19101. The active ingredients in HLD were detected by ultra-performance liquid chromatography-tandem mass spectrometry. PubChem collected targets of active ingredients. Protein-protein interaction (PPI) networks were established with UC-related targets. Gene Ontology and Kyoto Encyclopedia (KEGG) of Genes and Genomes enrichment were analyzed for the mechanism of HLD treatment of UC and validated by the signaling pathways of HLD. Effects of HLD on UC were verified using dextran sulfate sodium (DDS)-induced UC mice experiments., Results: A total of 1883 UC-related targets were obtained from the GSE10191 dataset, 1589 from the database, and 1313 matching HLD-related targets, for a total of 94 key targets. Combined with PPI, GO, and KEGG network analyses, the signaling pathways were enriched to obtain IL-17, Toll-like receptor, NF-κB, and tumor necrosis factor signaling pathways. In animal experiments, HLD improved the inflammatory response of UC and reduced UC-induced pro-inflammatory factors such as Tumor Necrosis Factor Alpha (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6). HLD suppressed proteins TLR4, MyD88, and NF-κB expression., Conclusions: This study systematically dissected the molecular mechanism of HLD for the treatment of UC using a network pharmacology approach. Further animal verification experiments revealed that HLD inhibited inflammatory responses and improved intestinal barrier function through the TLR4/MyD88/NF-κB pathway., (© 2024. The Author(s).)

Background: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by persistent colonic inflammation. Here, we performed a systematic analysis to gain better insights into UC pathogenesis., Methods: We analyzed two UC-related datasets extracted from the gene expression omnibus database using several bioinformatics tools. The primary cell types and key subgroups of primary cells associated with UC and differentially expressed genes (DEGs) between UC and control samples were identified. The molecular regulation of the key genes was also predicted. The gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses of marker genes of key cell subgroups and model genes were performed. The expression of key enriched genes was validated in 10 clinical samples using real-time quantitative polymerase chain reaction (RT-qPCR)., Results: Monocytes were identified as the major cell type. Ten differentially expressed marker genes were obtained by intersecting the 3121 DEGs, 38 marker genes in major cell types, and 104 marker genes in key cell subgroups. Four essential genes, associated with immune response, were obtained using support vector machine recursive feature elimination and least absolute shrinkage and selection operator analyses. The four essential genes were highly expressed in Cluster 0 during differentiation. Validation of the four key genes in colonic mucosal biopsy specimens from 10 normal and 10 UC patients revealed that CREM was highly expressed in both the lesion-free sites and lesion sites colonic mucosa of UC patients compared with normal adults., Conclusions: We identified CREM involved in UC pathogenesis, which is expected to provide a new therapeutic target for UC., Competing Interests: 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., (© 2024 The Authors.)

Background: Chronic Kidney Disease (CKD) leads to structural and functional abnormalities of the kidneys and seriously jeopardizes human health. Shenyan Oral Liquid (SOLI), a Chinese medicinal preparation, has been reported to protect podocytes in patients with chronic kidney disease (CKD)., Objective: The objective of this study is to investigate the mechanism of action of the Chinese medicinal preparation Senyan Oral Liquid (SOLI) in the treatment of CKD by protecting podocytes through network pharmacology technology and experimental validation., Methods: Compounds of SOLI and targets of CKD disease were collected and screened. The SOLI network of bioactive compounds targeting CKD and the protein-protein interaction (PPI) network were constructed using Cytoscape software and the STRING online database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R software Cluster Profiler package. Molecular docking was performed using Autodock software to verify the binding ability of bioactive compounds and target genes. Subsequently, the potential mechanism of SOLI on CKD predicted by network pharmacological analysis was experimentally studied and verified in an adriamycin-induced nephropathy rat model., Results: A total of 81 targets of SOLI components acting on CKD were identified. The results of the PPI analysis clarified that five key target genes (TNF, AKT1, IL6, VEGFA, and TP53) play a critical role in the treatment of CKD by SOLI. The GO analysis and KEGG enrichment analysis indicated that SOLI acts through multiple pathways, including the PI3K/AKT signaling pathway against CKD. Molecular docking showed that the main compounds of SOLI and five key genes had strong binding affinity. In a rat model of adriamycin-induced nephropathy, SOLI significantly ameliorated disease symptoms and improved renal histopathology. Mechanistic studies showed that SOLI upregulated the expression level of Nephrin, inhibited the PI3K/AKT pathway in renal tissues, and ultimately suppressed the activation of autophagy-related proteins in CKD., Conclusion: SOLI exerted a renoprotective effect by regulating the Nephrin-PI3K/AKT autophagy signaling pathway, and these findings provide new ideas for the development of SOLI-based therapeutic approaches for CKD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Arsenic oxidation plays a crucial role in its removal, which has been identified in numerous studies. However, the mechanisms, especially reaction pathways of arsenic oxidation on sorbent surfaces remain inadequately explored. In this work, the effects of Mn doping on arsenic adsorption and oxidation were first verified by adsorption experiments. Subsequently, DFT calculations were carried out to identify alterations in the adsorption energies, active sites, and oxidation pathways. By integrating the experimental and simulation results, a dual-functional framework encompassing adsorption and catalysis of Mn-modified Fe-based material was distinctly established. For adsorption, the introduction of manganese into iron-based sorbent considerably enhanced As 2 O 3 adsorption owing to the increased active sites available for As 2 O 3 chemisorption and the promotion of surface nucleophilicity. Concerning oxidative catalysis, the incorporation of MnO 2 augmented surface catalytic oxidation and provided a substantial amount of active O load . Consequently, the arsenic oxidation occurring on the Mn-modified sorbent surfaces possessed a lower oxidation RDS energy barrier and a shorter oxidation pathway than those on the bare sorbent surfaces. These experimental and simulation results provide a theoretical basis for the design and application of efficient gaseous arsenic adsorbents., 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 B.V. All rights reserved.)

Background: This study aimed to investigate a causal relationship between IBD and multiple kidney diseases using two-sample Mendelian randomization (MR) analyses., Methods: We selected a group of single nucleotide polymorphisms (SNPs) specific to IBD as instrumental variables from a published genome-wide association study (GWAS) with 86,640 individuals of European ancestry. Summary statistics for multiple kidney diseases were obtained from the publicly available GWAS. Genetic data from one GWAS involving 210 extensive T-cell traits was used to estimate the mediating effect on specific kidney disease. Inverse-variance weighted method were used to evaluate the MR estimates for primary analysis., Results: Genetic predisposition to IBD was associated with higher risk of IgA nephropathy (IgAN) (OR, 1.78; 95% CI, 1.45-2.19), but not membranous nephropathy, diabetic nephropathy, glomerulonephritis, nephrotic syndrome, chronic kidney disease, and urolithiasis. CD4 expression on CD4 + T cell had a significant genetic association with the risk of IgAN (OR, 2.72; 95% CI, 1.10-6.72). Additionally, consistent results were also observed when IBD was subclassified as ulcerative colitis (OR, 1.38; 95% CI, 1.10-1.71) and Crohn's disease (OR, 1.37; 95% CI, 1.12-1.68). MR-PRESSO and the MR-Egger intercept did not identify pleiotropic SNPs., Conclusions: This study provides genetic evidence supporting a positive casual association between IBD, including its subclassification as ulcerative colitis and Crohn's disease, and the risk of IgAN. However, no casual association was found between IBD and other types of kidney diseases. Further exploration of IBD interventions as potential preventive measures for IgAN is warranted., (© 2023. The Author(s).)

Introduction: We implemented a two-sample multivariable Mendelian randomisation (MR) analyses to estimate the causal effect of socioeconomic status and leisure sedentary behaviours on gastro-oesophageal reflux disease (GERD)., Methods: Independent single-nucleotide polymorphisms associated with socioeconomic status and leisure sedentary behaviours at the genome-wide significance level from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) UK Biobank were selected as instrumental variables. Summary-level data for GERD were obtained from a recent publicly available genome-wide association involving 78 707 GERD cases and 288 734 controls of European descent. Univariable and multivariable two-sample MR analyses, using inverse variance weighted method for primary analyses, were performed to jointly evaluate the effect of socioeconomic status and leisure sedentary behaviours on GERD risk., Results: Three socioeconomic status, including educational attainment (OR 0.46; 95% CI 0.30 to 0.69; p<0.001), average total household income before tax (OR 0.65; 95% CI 0.47 to 0.90; p=0.009) and Townsend Deprivation Index at recruitment (OR 1.60; 95% CI 1.06 to 2.41; p=0.026), were independently and predominately responsible for the genetic causal effect on GERD. In addition, one leisure sedentary behaviour, such as time spent watching television, was independently and predominately responsible for genetic causal effect on GERD (OR 3.74; 95% CI 2.89 to 4.84; p<0.001). No causal effects of social activities and driving on GERD were observed., Conclusions: Genetically predicted Townsend Deprivation Index at recruitment and leisure watching television were causally associated with increased risk of GERD, and age at completion of full-time education and average total household income before tax were causally associated with decreased risk of GERD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

A novel fourth-generation nickel-based single crystal superalloy was brazed with Co-based filler alloy. The effects of post-weld heat treatment (PWHT) on the microstructure and mechanical properties of brazed joints were investigated. The experimental and CALPHAD simulation results show that the non-isothermal solidification zone was composed of M 3 B 2 , MB-type boride and MC carbide, and the isothermal solidification zone was composed of γ and γ' phases. After the PWHT, the distribution of borides and the morphology of the γ' phase were changed. The change of the γ' phase was mainly attributed to the effect of borides on the diffusion behavior of Al and Ta atoms. In the process of PWHT, stress concentration leads to the nucleation and growth of grains during recrystallization, thus forming high angle grain boundaries in the joint. The microhardness was slightly increased compared to the joint before PWHT. The relationship between microstructure and microhardness during the PWHT of the joint was discussed. In addition, the tensile strength and stress fracture life of the joints were significantly increased after the PWHT. The reasons for the improved mechanical properties of the joints were analyzed and the fracture mechanism of the joints was elucidated. These research results can provide important guidance for the brazing work of fourth-generation nickel-based single crystal superalloy.

In this study, a modified coagulation sludge (MCS) from a real landfill leachate coagulation pretreatment was first prepared with polymerized ferric sulfate (PFS) as the activator for PMS to degrade bisphenol A (BPA). The results showed that 43.34% of BPA was adsorbed by MCS when [BPA] 0  = 20 mg/L, [MCS] 0  = 0.8 g/L, and time = 80 min. Thereafter, by adding 3000 mg/L PMS to initiate the oxidation process, complete BPA removal, i.e. 100%, was achieved in 60 min. In addition, in tap water and municipal wastewater scenarios, 100% and 90.07% removal of BPA were obtained, respectively, and MCS exhibited outstanding performance after repeated use. MCS displayed an excellent adsorption capacity in which chemical adsorption was the main effect, and hydroxyl radicals were the major contributor to BPA degradation. Characterizations of fresh and reacted MCS were conducted, and the results showed that the MCS structure was stable after repeated use, and the surface functional groups, surface defect sites, and iron oxides participated in PMS activation. Overall, this study demonstrated successful recycling of coagulation sludge from landfill leachate pretreatment to activate PMS for environmental pollution control, which is in accordance with the goal of using waste to control waste.

Tumor angiogenesis, which may be affected by microenvironmental inflammation and promotes tumor development and metastasis, is one of the key reasons contributing to increased mortality. The goal of this study is to investigate how lignin analogs, specifically honokiol (HNK), block angiogenesis induced by the inflammatory milieu of lung cancer. The human lung cancer cell lines A549 and H460 were treated with HNK. Interleukin-1 was employed to mimic an inflammatory tumor microenvironment. Findings demonstrated that HNK drastically decreased the cell viability of A549 and H460 cells. In A549 and H460 cells, HNK also reduced the production of vascular endothelial growth factor (VEGF), the most important marker of tumor angiogenesis. Signal pathway studies revealed that HNK blocked the NF-κB signaling pathway. This effect, in turn, prevented the expression of VEGF by inhibiting the NF-κB signaling pathway. Human umbilical vein endothelial cells (HUVECs) from A549-conditioned medium cultures were subjected to HNK treatment, which decreased tubulogenesis, horizontal and vertical migration, and cell proliferation in HUVECs. Overall, HNK inhibited the NF-κB pathway. This effect resulted in the downregulation of VEGF, thus reducing the viability and angiogenesis of human lung cancer cell lines. In A549 cell xenografts, HNK decreased VEGF expression, tumor angiogenesis, and tumor development. Our research shows that HNK is a potential antiangiogenic molecule for the treatment of lung cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Minggang Wei reports financial support was provided by National Natural Science Foundation of China. Fei Wang reports was provided by National Natural Science Foundation of China. Xudong Cheng reports financial support was provided by Jiangsu Province Science and Technology Bureau. Xudong Cheng reports financial support was provided by Jiangsu Provincial Commission of Health and Family Planning. Xudong Cheng reports financial support was provided by Suzhou City Science and Technology Bureau. Xudong Cheng reports financial support was provided by Nanjing University of Chinese Medicine., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

N6-methyladenosine (m6A) has been recognized as a common type of post-transcriptional epigenetic modification. m6A modification and YTHDF1, one of its reader proteins, have been documented to play a pivotal role in numerous human diseases via regulating mRNA splicing, translation, stability, and subcellular localization. The chemotherapeutic drug cisplatin (CDP) can damage sensory hair cells (HCs) and result in permanent sensorineural hearing loss. However, whether YTHDF1-mediated modification of mRNA is potentially involved in CDP-induced injury in sensory hair cells was not fully clarified. This study investigated the potential mechanisms for the modification of YTHDF1 in CDP-induced damage in HCs. Here, we discovered that YTHDF1's expression level statistically increased significantly after treating with CDP. Apoptosis and cell death of HCs induced by CDP were exacerbated after the knockdown of YTHDF1, while overexpression of YTHDF1 in HCs alleviated their injury induced by CDP. Moreover, YTHDF1 expression correlated with cisplatin-induced autophagy with statistical significance in HCs; namely, YTHDF1's overexpression enhanced the activation of autophagy, while its deficiency suppressed autophagy and, at the same time, increased the loss of HCs after CDP damage. WB analysis and qRT-PCR results of autophagy-related genes indicated that YTHDF1 promoted the translation of autophagy-related genes ATG14, thus boosting autophagy. Therefore, CDP-induced YTHDF1 expression protected HCs against CDP-induced apoptosis by upregulating the translation of autophagy-related genes ATG14, along with enhancing autophagy. Based on these findings, it can be inferred that YTHDF1 is potentially a target for ameliorating drug-induced HCs damage through m6A modification., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hearing loss affecting about 2/1000 newborns is the most common congenital disease. Genetic defects caused approximately 70% of patients who have non-syndromic hearing loss. We recruited 13 Chinese Han deafness families who tested negative for GJB2, SLC26A4 , and mitochondrial 12S rRNA. The probands of each family were performed whole-exome sequencing (WES) or targeted next-generation sequencing (NGS) for known deafness genes to study for pathogenic causes. We found four novel mutations of CDH23 , one novel mutation of MYO15A , one novel mutation of TMC1 , one novel mutation of PAX3 , and one novel mutation of ADGRV1 , one novel CNV of ADGRV1 , and one novel CNV of STRC . Hearing loss is a highly hereditary and heterogeneous disease. The results in the limited samples of this study show that Usher and Waardenburg syndrome-related genes account for a major proportion are strongly associated with Chinese Han hearing loss patients negative for GJB2, SLC26A4 , and mitochondrial 12S rRNA, followed by STRC resulting in mild to moderate deafness., 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 Sun, Lin, Wang, Shen, Li, Huang and Yang.)

Purpose of Review: Auditory neuropathy is a disorder of auditory dysfunction characterized by the normal function of the outer hair cells and malfunction of the inner hair cells, synapses, postsynapses and/or auditory afferent nervous system. This review summarizes the process of discovery and naming of auditory neuropathy and describes the acquired, associated genetic disorders and management available., Recent Findings: In the last 40 years, auditory neuropathy has undergone a process of discovery, naming and progressive elucidation of its complex pathological mechanisms. Recent studies have revealed numerous acquired and inherited causative factors associated with auditory neuropathy. Studies have analyzed the pathogenic mechanisms of various genes and the outcomes of cochlear implantation. New therapeutic approaches, such as stem cell therapy and gene therapy are the future trends in the treatment of auditory neuropathy., Summary: A comprehensive understanding of the pathogenic mechanisms is crucial in illustrating auditory neuropathy and assist in developing future management strategies., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In this study, the transformation and degradation mechanisms of refractory organic matter in biologically treated leachate from a semi-aerobic aged refuse biofilter (SAARB) in a nano-Fe 3 O 4 enhanced ozonation process (nFe 3 O 4 -O 3 ) were investigated in batch experiments. A continuous experiment then confirmed the effectiveness of the process for SAARB effluent treatment. In a batch experiment, the effects of influencing factors, including nFe 3 O 4 dosage, O 3 dosage and initial pH on the treatment performance of nFe 3 O 4 -O 3 process, were comprehensively investigated. The results showed that when the nFe 3 O 4 dosage = 6 g L -1 , O 3 dosage = 0.15 L minute -1 and initial pH = 7, the total organic carbon, absorbance at 254 nm and colour number removal efficiencies were 40.58%, 62.55% and 89.80%, respectively. In addition, most of the humic- and fulvic-like substances in the SAARB effluent were removed, and the condensation degree, aromaticity and humification degree of the organics were substantially reduced. The morphology and elemental valence state analysis showed that the nFe 3 O 4 in the process was relatively stable and could form an nFe 3 O 4 -organic complex. Therefore, the probability of organics reacting with hydroxyl radical increased and the oxidation efficiency was enhanced. In the continuous experiment, both the O 3 dosage and hydraulic retention time (HRT) were the key influencing factors. The treatment efficiency of the nFe 3 O 4 -O 3 process was enhanced at a higher O 3 dosage and longer HRT. The electrical energy consumption of the continuous nFe 3 O 3 -O 3 process was calculated to be 17.72 kW h m -3 in SAARB effluent treatment. This study proved the feasibility of biologically treated landfill leachate treatment by the nFe 3 O 3 -O 3 process.

Myelin undergoes various changes after nerve injury, and c-Jun has a close relationship with Schwann cells (SCs). However, it remains unclear whether c-Jun can be involved in nerve repair by regulating ferroptosis. To explore this, we first set up a facial nerve injury model and detected the changes of ferroptosis-related proteins and c-Jun by immunofluorescence and Western blot. Then, we cultured RSC 96 and pSCs, and studied the potential regulatory relationships by a combination of experimental methods such as CCK-8, ELISA, immunofluorescence, qRT-PCR, Western blot and viral transfection. Finally, we corroborated the role of c-Jun through animal experiments. Our experiments revealed that ferroptosis occurs after facial nerve injury. Erastin decreased GPX4, c-Jun proteins and GSH content, while PTGS2, NRF2, HO-1 proteins, MDA, Fe 2+ and ROS contents increased. This effect was inhibited after c-Jun overexpression but was reversed after the addition of c-Jun siRNA. Besides, we proved in vivo that c-Jun could inhibit ferroptosis and promote the recovery of facial nerve function. In conclusion, our study identified the relationship between c-Jun and ferroptosis during peripheral nerve injury repair, which provides new ideas for studying peripheral nerve injury and repair., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Mutations in the GJB2 gene that encodes connexin 26 (Cx26) are the predominant cause of prelingual hereditary deafness, and the most frequently encountered variants cause complete loss of protein function. To investigate how Cx26 deficiency induces deafness, we examined the levels of apoptosis and autophagy in Gjb2 loxP/loxP ; ROSA26 CreER mice injected with tamoxifen on the day of birth. After weaning, these mice exhibited severe hearing impairment and reduced Cx26 expression in the cochlear duct. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells were observed in apical, middle, and basal turns of Kölliker's organ at postnatal (P) day 1 (P1), associated with increased expression levels of cleaved caspase 3, but decreased levels of autophagy-related proteins LC3-II, P62, and Beclin1. In Kölliker's organ cells with decreased Cx26 expression, we also found significantly reduced levels of intracellular ATP and hampered Ca 2+ responses evoked by extracellular ATP application. These results offer novel insight into the mechanisms that prevent hearing acquisition in mouse models of non-syndromic hearing impairment due to Cx26 loss of function., 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 Sun, Gao, Chen, Hou, Li, Huang, Mammano, Chen and Yang.)

Objectives: We attempted to improve the accuracy of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) (FFR CT ) by expanding the coronary tree in the computational fluid dynamics (CFD) domain. An observational study was performed to evaluate the effects of extending the coronary tree analysis for FFR CT from a minimal diameter of 1.2 to 0.8 mm., Methods: Patients who underwent CCTA and interventional FFR were enrolled retrospectively. Seventy-six patients qualified based on the inclusion criteria. The three-dimensional (3D) coronary artery tree was reconstructed to generate a finite element mesh for each subject with different lower limits of luminal diameter (1.2 mm and 0.8 mm). Outlet boundary conditions were defined according to Murray's law. The Newton-Krylov-Schwarz (NKS) method was applied to solve the governing equations of CFD to derive FFR CT ., Results: At the individual patient level, extending the minimal diameter of the coronary tree from 1.2 to 0.8 mm improved the sensitivity of FFR CT by 16.7% (p = 0.022). This led to the conversion of four false-negative cases into true-positive cases. The AUC value of the ROC curve increased from 0.74 to 0.83. Moreover, the NKS method can solve the computational problem of extending the coronary tree to an 0.8-mm luminal diameter in 10.5 min with 2160 processor cores., Conclusions: Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFR CT . The NKS method can achieve favorable computational times for future clinical applications., Key Points: • Extending the reconstructed coronary tree to a smaller luminal diameter can considerably improve the sensitivity of FFR CT . • The NKS method applied in our study can effectively reduce the computational time of this process for future clinical applications., (© 2021. European Society of Radiology.)

Objective: To investigate the hearing protection outcomes of different drug-eluting analog electrode arrays implanted into guinea pig cochleae., Methods: Sixty guinea pigs were randomly divided into a negative control group and five experimental groups implanted separately with blank (drug carrier), dexamethasone (DXM), aracytine (Ara-C), Ara-C+DXM, and nicotinamide adenine dinucleotide (NAD+) eluting analog electrode arrays. Micro CT was used to supervise the surgical procedure. Auditory brainstem response (ABR) thresholds of the guinea pigs were measured and analyzed., Results and Conclusions: Compared with the negative control, all other groups showed a significant increase in ABR threshold (p<0.001) after surgery. Among them, there was no obvious difference between the blank (0 vs 90 days: 59.70±10.57 vs 64.60±9.47 dB SPL) and the NAD+ group (0 vs 90 days: 59.90±9.87 vs 64.70±8.65 dB SPL). On the other hand, the ABR thresholds in the DXM (0 days: 58.10±10.73 dB SPL; 90 days: 51.70±9.07 dB SPL) and the Ara-C group (0 days: 59.00±10.05 dB SPL; 90 days: 51.60±8.48 dB SPL) decreased significantly compared with the former two groups (p<0.001). However, the Ara-C+DXM group showed no further benefit (p>0.05). In addition, a significantly higher survival rate of spiral ganglion neurons in cochleae was observed in the Ara-C and/or DXM groups., Competing Interests: The authors declare that they have no competing interests., (© 2021 Huang et al.)

Objective . A previous study has shown that a data-driven approach can significantly improve the discriminative power of transfer function analysis (TFA) used to differentiate between normal and impaired cerebral autoregulation (CA) in two groups of data. The data was collected from both healthy subjects (assumed to have normal CA) and symptomatic patients with severe stenosis (assumed to have impaired CA). However, the sample size of the labeled data was relatively small, owing to the difficulty in data collection. Therefore, in this proof-of-concept study, we investigate the feasibility of using an unsupervised learning model to differentiate between normal and impaired CA on TFA variables without requiring labeled data for learning. Approach . Continuous arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV), which were recorded simultaneously for approximately 10 min, were included from 148 subjects (41 healthy subjects, 31 with mild stenosis, 13 with moderate stenosis, 22 asymptomatic patients with severe stenosis, and 41 symptomatic patients with severe stenosis). Tiecks' model was used to generate surrogate data with normal and impaired CA. A recently proposed unsupervised learning model was optimized and applied to separate the normal and impaired CA for both the surrogate data and real data. Main results . It achieved 98.9% and 74.1% accuracy for the surrogate and real data, respectively. Significance . To our knowledge, this is the first attempt to employ an unsupervised data-driven approach to assess CA using TFA. This method enables the development of a classifier to determine the status of CA, which is currently lacking., (© 2021 Institute of Physics and Engineering in Medicine.)

Cocaine abuse is a serious global public health and social problem, and cocaine detoxification remains a challenge. Benzoylecgonine (BE) is the main toxic metabolite after cocaine consumption, with a longer retention time in the body and environment than cocaine itself. According to many studies, the toxicity of BE to humans is as significant as cocaine itself. Moreover, BE is recognized as an addictive drug contaminant in the environment, especially the freshwater system, leading to worries of its ecotoxicity. Extensive studies on the adverse effects of BE on both humans and ecology have been conducted, showing a marked sub-lethal toxicity of BE to diverse organisms. To eliminate BE in vivo and in vitro, various elimination methods have been developed and their BE removal capacity were evaluated. In this review, we aimed to summarize information in the literature to understand better BE toxicity and elimination that may facilitate the clinical treatment of cocaine abuse. By studying the critical role of BE in cocaine abuse, we propose that the ideal treatment for cocaine abuse should not only detoxify cocaine itself but also remove or degrade BE. Emphasizing the necessity of developing effective BE elimination methods is significant for the development of potential clinical treatments and environmental protections.

An Fe 0 -participated O 3 /H 2 O 2 (Fe 0 -O 3 /H 2 O 2 ) process was applied to remove refractory organic matter (OM) in semi-aerobic aged refuse biofilter (SAARB) leachate arising from treating mature landfill leachate. The degradation and transformation characteristics of refractory OM were revealed at molecular level. Removal efficiencies of aromatic substances were 63.55% by the Fe 0 -O 3 /H 2 O 2 process (much higher than in other single or binary processes), and fulvic- and humic-like substances were more effectively degraded by this process than by other treatments. According to Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS), 6645 categories of OM in SAARB leachate were identified. Although there was little difference in number of OM categories after treatment using the single-O 3 and Fe 0 -O 3 /H 2 O 2 processes, Fe 0 -O 3 /H 2 O 2 process can better reduce OM relative abundance. It is noteworthy that the Fe 0 -O 3 /H 2 O 2 process more effectively degraded CHONS compounds than the single-O 3 process, while also producing more CHO compounds having higher bio-availability. The enhanced degradation efficiency of the Fe 0 -O 3 /H 2 O 2 process were attributed to the formation of the Fenton process initiated by leached Fe 2+ and H 2 O 2 . The heterogeneous catalytic effect from iron (hydro) oxides for O 3 /H 2 O 2 also increased the treatment capacity of the Fe 0 -O 3 /H 2 O 2 process, resulting in better total organic carbon removal. The Fe 0 -O 3 /H 2 O 2 process is an efficient method for removing refractory OM in SAARB leachate., 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 © 2020 Elsevier Ltd. All rights reserved.)

In this research, for the first time, three kinds of landfill leachate (young (YL), mature (ML) and mixed (MYL) leachate) were treated in a semi-aerobic aged refuse biofilter (SAARB) to compare the effectiveness of, and microbial changes in, this biofilter when treating leachates that have significantly different characteristics. The SAARB achieved stable removal of organic matter from all three leachates and reduced the concentrations of aromatic substances. The best treatment was achieved with YL, followed in order by MYL and ML. The removal of nitrogen from all three leachates by the SAARB was particularly significant. The microbial abundance and diversity in the media of the SAARB changed after treatment of the three leachates, and the order of change from small to large was ML# < MYL# < YL#. The microbial communities were mainly affected by (and negatively correlated to) the relative content of refractory organics in leachate. Proteobacteria was the dominant microorganism. Deinococcus-thermus responded most to the quality of leachate being treated, increasing in relative abundance as the content of refractory organics increased. This was opposite to the response of Chloroflexi. In YL# the dominant species at the genus level was Thauera, and in ML# the dominant species were Truepera and Iodidimonas. The microbial activity and metabolic intensity were enhanced after treatment of the different leachates. The expression of nitrification-related genes was the strongest and the total abundance was the highest when YL was treated. This study promotes the optimization and application of SAARB., 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 © 2020 Elsevier Ltd. All rights reserved.)

Macromolecular refractory organics in landfill leachate are extremely complex compounds. This study examined the molecular-level transformation characteristics of refractory organics in biologically-treated landfill leachate (i.e., membrane bioreactor (MBR) leachate) during ozonation treatment. Results indicated that higher ozone dosage and longer reaction time enhanced organics removal. When ozone dosage was 32.16 mg/min and reaction time was 30 min, the efficiencies of removing color number, chemical oxygen demand (COD), and dissolved organic carbon (DOC) were 95.16%, 51.13%, and 26.40%, respectively. Furthermore COD / DOC decreased from 3.38 to 2.24, and the content of aromatic substances and macromolecular humic substances (e.g., humic- and fulvic-like substances) substantially decreased. The MBR-treated leachate mainly contained phenolic compounds (82%, aromatic index ≤ 0.50 and H/C < 1.5), and the major elements within the dissolved organic matter in the MBR-treated leachate were C, H, O, N, and S. The CHOS and CHONS compounds in the leachate indicated that it would have a much greater biorefractory property than the natural organic matter (i.e., technical grade humic acid). After the MBR-treated leachate was treated by ozonation for 10 min, the CHO, CHON, CHOS and CHONS compounds were greatly degraded and removed, and the oxidation degree of dissolved organic matter was significantly increased owing to the strong oxidation ability of ozone. At 30 min of ozonation, CHON, CHOS and CHONS compounds were further degraded, and CHOS and CHONS compounds (as the biorefractory substances) were almost completely removed. It was noteworthy that some CHO compounds that mainly contained phenolic compounds (m/z = 250-300, carbon number > 20, and double bond equivalent < 6) with a higher bioavailability and higher saturation degree accumulated. This study provides beneficial references for practical application of landfill leachate treatment using the ozonation process., 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 © 2020 Elsevier B.V. All rights reserved.)

The fruit flies Bactrocera tau (Walker) and B. cucurbitae (Coquillett) are economically important invasive pests on numerous vegetable and fruit species in China. Due to the instability of the early spring climate, temperatures often deviate far below the normal temperature for short periods of time. Such a sudden short-term low temperature may impact the reproduction and development of the two fruit fly species. In this study, the effects of low temperatures (8, 6, 4, 2, 0, -2, and -4°С) on the development and reproduction of these two closely related fruit fly species were studied under laboratory condition. The results showed that their survival rates decreased gradually with corresponding decreases in the tested temperatures. On the other hand, their pre-oviposition periods and their adult female to male sex ratios increased, while the average number of eggs per female of each species and longevity of male adult of B. cucurbitae initially increased and later decreased after exposure to the low-temperature treatments. Overall, low temperatures promoted reproduction in B. cucurbitae and B. tau at temperatures ranging from 24°С to as low as 8°С. Development and reproduction of the two species were negatively affected when temperatures were between 8 to -4°С. The cold resistance of each developmental stage was higher in B. tau than in corresponding stages of B. cucurbitae., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

FoxM1 is a transcriptional regulator involved in tumor development, pulmonary fibrosis, and cardiac fibrosis. However, its role in renal interstitial fibrosis (RIF) has yet to be elucidated. We established a TGF-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro and a unilateral ureteral obstruction (UUO)-induced rat RIF model in vivo. FoxM1 inhibition was achieved by siRNA interference in vitro and by injecting thiostrepton into UUO-induced RIF rats in vivo. The degree of renal damage and fibrosis were determined by histological assessment via hematoxylin and eosin (H&E) staining. Immunohistochemistry, western blots, and qPCR were used to determine the expression levels of FoxM1, Collagen I, E-cadherin, α-SMA, and Snail1. Our results showed that FoxM1 inhibition could ameliorate RIF and reduce the deposition of Collagen I. H&E staining revealed that renal structural damage, inflammatory cell infiltration, and ECM deposition were significantly attenuated by thiostrepton treatment in the UUO rats. Furthermore, FoxM1 downregulation significantly suppressed epithelial-to-mesenchymal transition, as evidenced by decreased protein and mRNA expression levels of α-SMA and Snail1 and a significant increase in protein and mRNA expression levels of E-cadherin. Collectively, these results suggested that FoxM1 inhibition could be a novel therapeutic strategy for the treatment of RIF., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Radiotherapy is an effective treatment for pancreatic cancer. However, radio-resistance often resulted in poor prognostic. Ibrutinib is an orally small molecule drug in B cell malignancies. Here, we investigated for the first time the effect of ibrutinib on radio-sensitivity of human pancreatic cancer cells in vitro and the potential mechanism involved in it. Human BXPC3 and Capan2 cell lines were treated with ibrutinib, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed after treated with ibrutinib and (or) radiation by clone formation assay. The cell cycle and cell apoptosis were measured by flow cytometry. Protein levels was analyzed by western blot. The results revealed that ibrutinib inhibited the proliferation of pancreatic cancer cells. Ibrutinib enhanced the effect of radiation with a sensitization enhancement ratio (SER) of 1.34, 1.68 in BXPC3 and Capan2 cells respectively. Ibrutinib combined with radiation induced G2/M arrest and cell apoptosis. Further investigations revealed that ibrutinib decreased the phosphorylation of EGFR, then reversed the upregulation of p-AKT and downstream genes by radiation. In conclusion, these results suggested that ibrutinib might be an excellent radiosensitizer in pancreatic cancer., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To develop a drug-eluting polymer film which can be easily personalized and rapidly made on the electrode array of a cochlear implant during surgery., Methods: A precursor solution was prepared with poly lactic-co-glycolic acid (PLGA) and trichloromethane. Using a dip-coating method, the silicone electrode array (HiFocus 1J, Advanced Bionics) was coated in polymer film produced from the precursor solution containing one of three drugs: dexamethasone sodium phosphate (DSP), cytosine arabinoside hydrochloride (Ara-C), or nicotinamide adenine dinucleotide (NAD), and the release of these drugs from the polymer film was studied. The drug-eluting film on the electrode array was analyzed by environmental scanning electron microscopy (ESEM). The water contact angle and the impedance of the electrode array were measured before and after coating. Drug release kinetics was evaluated in a quasi-stationary release model, using high performance liquid chromatography every 24 h for 15 days., Results: Five electrode arrays were tested with each of the three drugs in the polymer film coating. Before and after coating, ESEM studies revealed that the drug-loaded PLGA coating yielded a smooth covering with an average thickness of 1.02 ± 0.05 μm. The mass of the coated electrode increased by 1.00 ± 0.03 mg. The water contact angle decreased after coating (102 ± 0.6° vs 77 ± 1.6°, p < 0.01) but there was no significant change in the average impedance of the electrodes after coating (0.9 ± 0.22 kΩ vs 1.0 ± 0.18 kΩ, p > 0.05). An in vitro drug kinetics study revealed a faster release in the first 24 h (63.4 ± 0.6%) and a sustained release over the following 15 days (78.3 ± 1.7% in 2 days, 95.6 ± 1.0% in 7 days and 99.1 ± 0.4% in 14 days). The release rate was not affected by the drug, dose or the thickness of the coating., Conclusion: The dip-coating method is feasible for rapid casting of a drug-eluting PLGA film on an electrode array during CI surgery. The coated electrode array maintained its original morphology and became more hydrophilic. The loaded drug is released in a sustained manner and is easily regulated, and so the method might represent a potential application for clinical use in cochlear 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 © 2020 Elsevier Inc. All rights reserved.)

The expansion and harvest of stem cells at clinically relevant scales is critical for cell-based therapies. These approaches need to be robust and cost-effective, support the functional maintenance of desired cell behaviors, and allow for simple harvest. Here, we introduce a real-time monitoring 3D printing approach to fabricate scaffolds with quadruple hierarchical structure that meet these design goals for stem cell expansion. Specifically, a versatile strategy was developed to produce scaffolds from alginate and gelatin with approximately 102 μm interconnected macropores, 300 μm microfilaments, 1.3 mm hollow channels, and centimeter-scale overall dimensions. The scaffolds exhibited good pattern fidelity and stable mechanical properties (compressive modulus value was 22-fold that of hydrogels from the same materials), facilitating uniform and efficient cell seeding with high viability (98.9%). The utility of the scaffold was shown with the 3D culture of HepaRG cells and embryonic stem cells (ESCs) with aggregated morphology, and significantly enhanced cell proliferation was observed compared to those of cultures on flat surfaces, obtaining approximately 2 × 10 8 cells within a single culture. Interestingly, the functional behavior of the cells was dependent on the cell type, as ESCs maintained their pluripotency, while HepaRG cells improved their hepatic differentiation. Cells were harmlessly harvested through chelating the calcium ions in the cross-linked alginate and de-cross-linking the scaffolds, indicating the potential of this study for scalable stem cell culture for numerous downstream applications.

Bactrocera tau (Walker) (Diptera: Tephritidae) is an economically important invasive pest, that is capable of seriously reducing the quality and yield of vegetables and fruits, it was first recorded from Fujian province in 1849 and later introduced to Yunnan province in 1912 as a result in trade fruits and vegetables of China. In recent years, with the onset of global climate change and the accompanying increase in the greenhouse effect, elevated climatic temperatures have become one of the main environmental factors affecting growth and reproduction in insects, and the optimal developmental temperature of B. tau was found to be from 25 °C to 31 °C, the growth, development and reproduction of B. tau are normal under the optimal temperature conditions. In order to determine the repercussions that elevated temperature have on B. tau, we assessed the effects that short-term (12 h) high-temperature exposures (34 °C, 36 °C, 38 °C, 40 °C, 42 °C, 44 °C, 46 °C, and 48 °C) had on the growth, development and reproduction of B. tau at different developmental stages of the fly. The results showed that the survival rate of B. tau gradually decreased in all stages following exposure to short-term high-temperatures. The pupal stage was the least sensitive to increased temperatures. The pupae withstood the highest lethal temperature, having an LT 50 of 42.060 °C, followed by female adults (40.447 °C), male adults (40.013 °C), and larvae (36.740 °C). The egg stage, which was the most susceptible to heat increases, had the lowest LT 50 (38.310 °C). No significant effects were observed in the developmental stages of B. tau at temperatures from 24 °C to 38 °C. The development duration was significantly prolonged at 40 °C (P < 0.05) in the eggs (2.830d), larvae (7.330d), and pupae (8.170d) (P < 0.05). B. tau was unable to survive at temperatures above 42 °C. The pre-oviposition of female adults was extended, the average egg number per female showed a downward trend, the longevity of adults gradually shortened, and the ratio of female to male offspring increased as temperature increments were increased. In summary, short-term high-temperatures over 42 °C were not suitable for successful development of B. tau, while short-term high-temperatures over 40 °C were not suitable for successful reproduction in B. tau.

Objective: To investigate the effect of otitis media with effusion（OME） on vestibular function in children. Method: A total of 57 patients diagnosed with OME were collected and treated with grommet insertion and returned to our hospital 2 weeks later. Sixty children were also included as control group. Bone conducted vestibular evoked myogenic potentials（VEMP） and video head impulse（vHIT） were performed with OME patients both preoperatively and postoperatively. Control group received the same examination. The N1 latency, P1 latency, N1-P1 amplitude, N1-P1 latency were recorded with 60 dB nHL bone conducted stimulus, also bone conducted VEMP threshold. Single factor analysis of variance and paired t -test were used for statistical analysis. Result: In OME group, threshold value of oVEMP was higher and amplitude of N1-P1 in OME group was lower after grommet insertion. In cVEMP, amplitude of N1-P1 in the normal group and OME preoperative group was larger than that in postoperative group. In oVEMP, there was no significant difference in N1-P1 amplitude between control group and OME preoperative group, N1 latency, P1 latercy and N1-P1 latency showed no significant difference as well. In cVEMP, there was no significant difference in N1-P1 amplitude between control group and OME group. There were no significant differences in threshold, N1 latency, P1 latency and N1-P1 latency. In vHIT, there was no significant difference between OME group, postoperative group and control group. After grommet insertion, instantaneous gain of the horizontal semicircular canal at 60 ms was lower than that before surgery. Conclusion: Vestibular test results of children with OME are different from those of normal children, and the corresponding changes also occur after grommet insertion, which deserves further clinical attention., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Bruceine D (BD) is the quassinoids isolated from the traditional Chinese herbal medicine Brucea javanica's fruit, which exhibits anti-cancer activity. Here, we demonstrated that BD inhibited human non-small cell lung cancer (NSCLC) cell lines in vitro that were attributed to the induction of cell apoptosis. Human NSCLC H460 and A549 cell lines were treated with BD, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed by clone formation assay. Cell apoptosis was measured using DAPI staining and flow cytometry. Protein levels was analyzed by western blot. The results showed BD inhibited the cell viability of H460 and A549 cells in a dose-dependent manner with IC50 values of 0.5 and 0.6 μmol/L, respectively, at 48 h of treatment. Treatment with BD (0.125-1.0 μmol/L) dose-dependently promoted chromatin condensation, Annexin V-positive cell population and caspase-dependent apoptosis in H460 and A549 cells. Mechanistically, BD stimulated the phosphorylation of JNK. Furthermore, the anti-cancer effects of BD were alleviated effectively by a specific JNK inhibitor SP600125 in NSCLC cells. In conclusion, the results demonstrated that BD exerted anti-cancer activity against NSCLC cells through JNK activation, which suggests its potent usefulness for prevention and treatment of NSCLC., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Rupture of lysosome is a major cellular stress condition leading to cell death in PD. We have previously shown that environmental oxidative toxins could impair autophagic flux and lysosomal functions in PD. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in traumatic brain injury and stroke. But whether Dyrk1A could rescue lysosome malfunction-mediated DA neuron death and α-synuclein aggregation in PD is still unknown. In the present study, MPTP mice models and MPP + -treated SH-SY5Y cells were used for study, and we found that P188 rescued MPP + -induced lysosomal dysfunction and impaired autophagy flux in mild MPP + -treated SH-SY5Y cells. P188 administration significantly restored lysosomal membrane integrity and prevented cathepsins leakage from the lysosomes into the cytoplasm, which triggered caspase-dependent apoptotic cell death in sub-acute MPTP mouse model and MPP + -treated SH-SY5Y cells. Furthermore, P188 ameliorated α-synuclein accumulation and behavioral impairment in chronic MPTP mouse model with MPTP and probenecid treatment. P188 could alleviate MPTP-induced DA neurons damage by restoring lysosome function., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: MicroRNAs (miRs) are endogenous substances that act as important diagnostic and treatment targets in renal diseases. miR-146 plays an important role in the development of endotoxin tolerance through NF-κB pathway, but the underlying mechanism is not clearly understood. The aim of this study was to determine the molecular regulation and function of miR-146 and also the expression of miR-146 in an experimental model of renal ischemia reperfusion injury (IRI)., Methods: IRI was induced in mouse by bilateral IRI for 45 min followed by reperfusion. The male mice were randomized as: sham, I/R, I/R+miR-146, and I/R+antago-miR-146 groups. Renal function, histological damage, and cell apoptosis were evaluated at 24 h after reperfusion., Results: Overexpression of miR-146 protected renal function. Renal cells with upregulated miR-146 had lower plasma levels of blood urea nitrogen (BUN) and creatinine, decreased apoptosis and active caspase-3 protein expressions. miR-146 was shown to have a role in renal IR injury. miR-146 has a protective effect on renal function and plays a significant role in apoptosis. IGSF1 acts as a target of miR-146. IGSF1 rescued the effects of miR-146 on renal IRI. miR-146 protected renal function by activation of PI3K/AKT., Conclusion: These findings suggest that miR-146 might regulate apoptosis and can cause injury in I/R via targeting IGSF1 and also exert renal protection property.