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Two new two-dimensional (2D) coordination polymers, [Fe II (L) 2 {Pd II (SCN) 4 }] (L 1 = 2-methoxypyrazine, 1; and L 2 = ( E )-3-(phenyldiazenyl)pyridine, 2), were successfully constructed by using square-planar [Pd(SCN) 4 ] 2- building blocks. Complex 1 exhibits complete and one-step spin-crossover (SCO) behavior, while 2 exhibits incomplete and two-step SCO behavior. Further structural insight into this synergy reveals that the flat/flexing [Fe{Pd(SCN) 4 }] ∞ sheets in 1 and 2 are stabilized by interlayered/intralayered supramolecular interactions.

Landfills in developing countries are typically characterized by high waste water content and elevated leachate levels. Despite the ongoing biodegradation of waste in the highly saturated regions of these landfills, which leads to gas accumulation and bubble formation, the associated gas pressure that poses a risk to landfill stability is often overlooked. This paper introduces a landfill gas (LFG) bubble generation model and a two-fluid model that considers bubble buoyancy and porous medium resistance. The entire process can be divided into two stages based on the force balance and velocity of bubbles: Bubble Development Stage and the Two-Fluid Flow Stage. The models were validated using a one-dimensional analytical solution of hydraulic distribution that considers bubble generation, as well as an experiment involving air injection into a saturated medium. The mechanisms of LFG accumulation and ascent, leachate level rise, and discontinuous leachate-gas flow were then investigated in conjunction with continuous flow in the unsaturated region. The results indicate that the generation of LFG bubbles below the leachate level can cause a rise in the level height of more than 20%. During the Bubble Development Stage, there is a critical height for bubble ascent, above which the buoyancy exceeds the combined forces of gravity and resistance, resulting in less than 10% of bubbles continuously flowing into the unsaturated zone for recovery. The developed model effectively captures the accumulation and flow of LFG bubbles below the leachate level and could be further utilized to study leachate-gas pumping in the future., 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.)

Objective: The aim of the present study was to assess the therapeutic impact of diosgenin derivative ML5 on Parkinson's disease (PD) and explore the mechanism underlying mitochondrial biogenesis and fusion/fission., Methods: We established 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models and N-methyl-4-phenylpyridinium iodide (MPP + )-induced cell models of PD. The pole test and forced swimming test were used to detect the motor coordination and depressive symptoms in mice. The influence of ML5 on dopaminergic neuronal injury was investigated. Meanwhile, adenosine triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) production were measured to evaluate mitochondrial function. Confocal and transmission electron microscopy were used to detect mitochondrial morphology of cell. The expression of mitochondrial biogenesis-related proteins was measured by Western blotting., Results: The administration of ML5 showed the neuroprotection against MPTP-induced damage in vivo and in vitro . The levels of ATP, MMP, and ROS were restored after ML5 administration. In addition, we observed that ML5 preserved the mitochondrial network morphology and inhibited mitochondrial fission. Furthermore, the amelioration of mitochondrial dysfunction was mediated by enhancing 5'-monophosphate-activated protein kinase (AMPK) and peroxisome proliferators-activated receptor γ coactivator-l alpha (PGC-1α) expression, which activated its downstream modulators leading to the enhancing of mitochondrial biogenesis and the balance of mitochondrial fusion/fission., Conclusion: ML5 can protect the PD models against MPTP/MPP + -induced mitochondrial dysfunction and neuronal injury via promoting AMPK/PGC-1α signaling activation and be used as a therapeutic drug for PD treatment., Competing Interests: None., (AJTR Copyright © 2024.)

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer., (© 2024. The Author(s).)

Objective: The aim of this study was to investigate the effects of sodium hydrosulfide (NaHS) on Lipopolysaccharide (LPS)-induced cardiomyocyte injury in H9c2 cells., Methods: H9c2 cardiomyocytes cultivated with medium containing 10  μ g/mL LPS were used to recapitulate the phenotypes of those in sepsis. Two sequential experiments were performed. The first contained a control group, a LPS group, and a LPS + NaHS group, with the aim to assure the protective effects of NaHS on LPS-treated cardiomyocytes. The second experiment added a fourth group, the LPS + NaHS + miR-133a-3p inhibition group, with the aim to preliminarily explore whether miR-133-3p exerts a protective function downstream of NaHS. The adenosine triphosphate (ATP) kit was used to detect ATP content; real-time quantitative polynucleotide chain reaction (qPCR) was used to measure the levels of mammalian targets of rapamycin (mTOR), AMP-dependent protein kinase (AMPK), and miR-133a-3p, and Western blot (WB) was used to detect protein levels of mTOR, AMPK, myosin-like Bcl2 interacting protein (Beclin-1), microtubule-associated protein 1 light chain 3 (LC3I/II), and P62 (sequestosome-1, sqstm-1/P62)., Results: Compared with the control group, the expressions of miR-133a-3p ( P  < 0.001), P62 ( P  < 0.001), and the content of ATP ( P  < 0.001) decreased, while the expressions of Beclin-1 ( P  = 0.023) and LC3I/II ( P  = 0.048) increased in the LPS group. Compared with the LPS group, the expressions of miR-133a-3p ( P  < 0.001), P62 ( P  < 0.001), and the content of ATP ( P  < 0.001) in the NaHS + LPS group increased, while the expressions of Beclin-1 ( P  = 0.023) and LC3I/II ( P  = 0.022) decreased. Compared with the NaHS + LPS group, the expression levels of miR-133a-3p ( P  < 0.001), P62 ( P  = 0.001), and the content of ATP ( P  < 0.001) in the LPS + NaHS + miR-133a-3p inhibition group were downregulated, and the expression levels of Beclin-1 ( P  = 0.012) and LC3I/II ( P  = 0.010) were upregulated. The difference was statistically significant. There was no significant difference in the expression of AMPK and mTOR between groups., Conclusion: Our research demonstrated that NaHS relieved LPS-induced myocardial injury in H9c2 by promoting the expression of miR-133a-3p, inhibiting autophagy in cardiomyocytes, and restoring cellular ATP levels., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Yi-Mei Jin et al.)

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background/aim: Acute exogenous lipoid pneumonia (AELP) is a rare disorder caused by intake of lipid formulations and is often underdiagnosed. Meanwhile, the mechanism of AELP is still underlying. MCC950, was previously found to significantly suppress the release of inflammatory cytokines IL-18 and IL-1β. However, the effect of MCC950 on AELP induced by sewing machine oil has not been reported., Materials and Methods: The NLRP3, NF-[Formula: see text]B p65, caspase-1 and IL-1β expression in lung tissues were compared between a rat model of AELP and control rats using western blotting and real-time quantitative assay. Moreover, haematoxylin and eosin (H&E) staining was performed to elucidate the mechanisms by which MCC950 ameliorates sewing machine oil-induced AELP in vivo., Results: MCC950 reduced the expression of NF-[Formula: see text]B p65 in the lung samples of the treatment group and further down-regulated the NLRP3 and caspase-1 levels while inhibited the production of IL-1β. Besides, decreases in inflammatory cell infiltration in the lung were shown using H&E staining., Conclusion: MCC950 ameliorates sewing machine oil-induced acute exogenous lipoid pneumonia in rats through inhibition of the NF-[Formula: see text]B/NLRP3 inflammasome pathway., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Intrinsic drug resistance mechanisms of tumor cells often reduce intracellular drug concentration to suboptimal levels. Epithelial-to-mesenchymal transition (EMT) is a pivotal process in tumor progression and metastasis that confers an aggressive phenotype as well as resistance to chemotherapeutics. Therefore, it is imperative to develop novel strategies and identify new targets to improve the overall efficacy of cancer treatment. We developed SN38 (active metabolite of irinotecan)-assembled glycol chitosan nanoparticles (cSN38) for the treatment of pancreatic ductal adenocarcinoma (PDAC). Furthermore, cSN38 and the TGF-β1 inhibitor LY364947 formed composite nanoparticles upon self-assembly (cSN38 + LY), which obviated the poor aqueous solubility of LY364947 and enhanced drug sensitivity. The therapeutic efficacy of cSN38 + LY nanotherapeutics was studied in vitro and in vivo using suitable models. The cSN38 nanoparticles exhibited an antitumor effect that was significantly attenuated by TGF-β-induced EMT. The cellular uptake of SN38 was impeded during EMT, which affected the therapeutic efficacy. The combination of LY364947 and cSN38 markedly enhanced the cellular uptake of SN38, increased cytotoxic effects, and inhibited EMT in PDAC cells in vitro. Furthermore, cSN38 + LY significantly inhibited PDAC xenograft growth in vivo. The cSN38 + LY nanoparticles increased the therapeutic efficacy of cSN38 via repressing the EMT of PDAC cells. Our findings provide a rationale for designing nanoscale therapeutics to combat PDAC., (© 2023 Federation of European Biochemical Societies.)

Paeoniflorin, a representative pinane monoterpene glycoside, is the main active component and quality index of Paeoniae Radix Alba and Paeoniae Radix Rubra.The possible biosynthesis of paeoniflorin is as follows: GPP is derived from mevalonate(MVA) and/or 2-C-methyl-D-erythritol 4-phosphate(MEP) pathway(s) followed by the catalysis with terpene synthase, cytochrome P450(CYP450), UDP-glucuronosyltransferase(UGT), and acyltransferase(AT), respectively.This study aims to explore the genes rela-ted to the biosynthesis of paeoniflorin.To be specific, the cDNA libraries for flowers, leaves, and roots of Paeonia lactiflora were established and sequenced.A total of 30 609 open reading frames(ORFs) were yielded.Through functional annotation and expression analysis of all CYP450 genes in the transcriptome, 11 CYP450 genes belonging to CYP71 A and CYP71 D subfamilies and showing expression trend consistent with monoterpene synthase PlPIN that may be involved in paeoniflorin biosynthesis were screened out.Subsequently, 7 UGT genes and 9 AT genes demonstrating the expression trend consistent with PlPIN which were possibly involved in paeoniflorin biosynthesis were further screened by functional annotation analysis, full-length sequence analysis, expression analysis, and phylogeny analysis.This study provided a systematic screening method with smaller number of candidate genes, thus reducing the workload of functional gene verification.The result laid a foundation for analyzing the biosynthesis pathway of paeoniflorin and the formation mechanism.

Ichthyophthirius multifiliis, a global distributed protozoan parasite, causes "White spot disease" and leads to serious mortality of freshwater fish in aquaculture. The present study was conducted to assess the anti-I. multifiliis efficacy of active compound isolated from Sophora flavescens. The isolated active compound was identified as sophoraflavanone G (SG) with ESI-MS and NMR. In vitro tests, SG at concentrations of 0.5 mg/L and 2 mg/L resulted in death of all theronts and tomonts, respectively; SG at concentrations of 0.125 mg/L and 0.25 mg/L notably decreased theronts infectivity (p < 0.05). Additionally, the in vivo test results showed that a cumulative delivery of SG at concentration of 2 mg/L for 7 days protected fish from I. multifiliis infection. The 96-h LC 50 (median lethal concentration) and safety concentration of SG to grass carp were 46.6 mg/L and 11.3 mg/L, respectively. The present work indicated that SG was a potential safe and effectively therapeutic agent in treating I. multifiliis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neuropeptides act mostly on a class of G-protein coupled receptors, and play a fundamental role in the functions of neural circuits underlying behaviors. However, physiological functions of some neuropeptide receptors are poorly understood. Here, we used the molluscan model system Aplysia and microinjected the exogenous neuropeptide receptor apATRPR (Aplysia allatotropin-related peptide receptor) with an expression vector (pNEX3) into Aplysia neurons that did not express the receptor endogenously. Physiological experiments demonstrated that apATRPR could mediate the excitability increase induced by its ligand, apATRP (Aplysia allatotropin-related peptide), in the Aplysia neurons that now express the receptor. This study provides a definitive evidence for a physiological function of a neuropeptide receptor in molluscan animals., (© 2022. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) usually presents infrequent infiltration of T lymphocytes. The known immune-checkpoint inhibitors to date focus on activating T cells and manifest limited effectiveness in PDAC. SIGLEC15 was identified as a novel tumor-associated macrophage (TAM)-related immune-checkpoint in other cancer types, while its immunosuppressive role and clinical significance remained unclear in PDAC. In our study, SIGLEC15 presented immunosuppressive relevance in PDAC via bioinformatic analysis and expressed on TAM and PDAC cells. SIGLEC15 + TAM, rather than SIGLEC15 + PDAC cells or SIGLEC15 - TAM, correlated with poor prognosis and immunosuppressive microenvironment in the PDAC microarray cohort. Compared with SIGLEC15 - TAM, SIGLEC15 + TAM presented an M2-like phenotype that could be modulated by SIGLEC15 in a tumor cell-dependent manner. In mechanism, SIGLEC15 interacted with PDAC-expressed sialic acid, preferentially α-2, 3 sialic acids, to stimulate SYK phosphorylation in TAM, which further promoted its immunoregulatory cytokines and chemokines production. In vivo, SIGLEC15 + TAM also presented an M2-like phenotype, accelerated tumor growth, and facilitated immunosuppressive microenvironment, which was greatly abolished by SYK inhibitor. Our study highlighted a novel M2-promoting function of SIGLEC15 and strongly suggested SIGLEC15 as a potential immunotherapeutic target for PDAC., (Copyright © 2022. Published by Elsevier B.V.)

Background: Prenatal exposure to metals has been linked with adverse pregnancy outcomes. Oxidative stress and epigenetic changes are potential mechanisms of action., Objectives: We aimed to examine the associations of individual and mixtures of metal exposures with oxidative stress and DNA methylation among pregnant women., Methods: We measured a panel of 16 metals and 3 oxidative stress biomarkers including 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-isoprostaglandin F2α (8-isoPGF2α) in urine from 113 pregnant women in a Chinese cohort. Biomarkers of global DNA methylation including Alu and long interspersed nucleotide element-1 (LINE-1) in cord blood were measured. Multivariable linear regression and Bayesian kernel machine regression (BKMR) models were separately applied to estimate the associations between individual and mixtures of metal exposures and biomarkers of oxidative stress and global DNA methylation., Results: In single-metal analyses, we observed positive associations between 11 metals [arsenic (As), cadmium (Cd), thallium (Tl), barium (Ba), nickel (Ni), vanadium (V), cobalt (Co), zinc (Zn), copper (Cu), selenium (Se) and molybdenum (Mo)] and at least one of oxidative stress biomarkers (all FDR-adjusted P-values < 0.05). In mixture analyses, we found positive overall associations of metal mixtures with 8-OHdG and 8-isoPGF2α, and Se was the most important predictor. There was no evidence on associations of urinary metals as individual chemicals and mixtures with Alu and LINE-1 methylation., Conclusion: Urinary metals as individual chemicals and mixtures were associated with increased oxidative stress, especially Se., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Based on network pharmacology, the mechanism of Polygoni Cuspidati Rhizoma et Radix-Ligustri Lucidi Fructus(PL) combination against acute gouty arthritis(AGA) was explored and preliminarily verified by animal experiment. The chemical components and corresponding targets of PL were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The active components with oral bioavailability(OB)≥30% and drug-likeness(DL)≥0.18 were screened based on literature, and the related protein targets were collected. Then the protein targets were standardized with the help of UniProt database. The AGA-related targets were searched from GeneCards, NCBI, and DrugBank. The common targets of the disease and the medicinals were yielded by FunRich V3, and the protein-protein interaction(PPI) network was constructed to screen the key targets, followed by Gene Ontology(GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis of the key targets. Afterwards, some of the key targets were verified by sodium urate crystal-induced AGA mouse model. A total of 25 active components and 287 targets of PL, 811 targets of AGA, and 88 common targets were screened out. PPI network analysis showed that tumor necrosis factor(TNF), interleukin-6(IL-6), and interleukin-1β(IL-1β) may be the core targets of PL in the treatment of AGA. The key targets were mainly involved in 566 GO terms(P&lt;0.05), including multiple biological processes such as inflammatory response and immune response. Moreover, they were related to 116 KEGG pathways and these pathways were involved in inflammation and immunity, mainly including NOD-like receptor signaling pathway and TNF signaling pathway. Animal experiment confirmed that PL can alleviate ankle swelling, improve abnormal gait, and down-regulate the protein expression of TNF-α, IL-6, and IL-1β in AGA mice, indicating that PL can treat AGA through TNF-α, IL-6, and IL-1β and the feasibility of network pharmacology to predict drug targets. This study preliminarily discussed the key targets and biological signaling pathways involved in the treatment of AGA with PL combination, which reflected the multi-pathway and multi-target action characteristics of Chinese medicine. Moreover, this study laid a scientific basis for research on the treatment of AGA with PL combination, as well as the mechanism of action.

Intensive aquaculture often results in immunosuppression in fish, which may cause a series of diseases. In this study, to investigate the immunosuppressive mechanisms in fish, tilapia were intrapleural injected cyclophosphamide (CTX) at the doses of 10, 25, 50, 75 and 100 mg·kg -1 to induce immunosuppression. We determined the viability of immune cells, the content of lysozyme (LZM) and immunoglobulin M (IgM), the levels of nitric oxide (NO) and antioxidant parameters. Meanwhile, the mRNA levels of complement C3 (c3), igm and the genes associated with the TLR-NF-κB signaling pathway in the head kidney (HK) and spleen were also determined. The results showed that CTX had a significant cytotoxic effect on peripheral blood leukocytes, HK macrophages and spleen cells in a dose-dependent manner. The protein and mRNA levels of C3 and IgM were down-regulated with the increase of CTX concentrations in serum, HK and/or spleen. The NO and LZM contents decreased significantly in HK and spleen after CTX treatments with 75 and 100 mg·kg -1 . CTX treatments with 50, 75 and/or 100 mg·kg -1 markedly decreased the antioxidant ability and enhanced lipid peroxidation in HK and spleen. Furthermore, qPCR data showed that CTX treatments with 50-100 mg·kg -1 clearly down-regulated the mRNA levels of tlr2, myd88, irak1, traf6, nfκb1, nfκb2, il-6, il-10 and tnf-α in the HK and/or spleen. Overall results suggested that CTX treatment had a cytotoxic effect on immune cells, induced lipid peroxidation, decreased the antioxidant capacity and inhibited immune function. The immunosuppressive mechanisms of CTX may be associated with the TLR-NF-κB signaling pathway., (Copyright © 2021. Published by Elsevier B.V.)

Background: Periprocedural myocardial infarction is a common complication following percutaneous coronary intervention. The present study was conducted with an aim to compare the safety and efficacy of loading doses of ticagrelor versus clopidogrel in preventing periprocedural myocardial infarction in Asian patients with acute coronary syndrome undergoing elective percutaneous coronary intervention., Methods: A total of 114 patients with acute coronary syndrome undergoing elective percutaneous coronary intervention were assigned to clopidogrel group (n = 57, the loading and maintenance doses were 300 and 75 mg qd for clopidogrel, and 300 and 100 mg qd for aspirin), or ticagrelor group (n = 57, the loading and maintenance doses were 180 and 90 mg bid for ticagrelor, and 300 and 100 mg qd for aspirin). Cardiac biomarkers were measured before, 8 hours, and 24 hours after percutaneous coronary intervention. The percutaneous coronary intervention-related periprocedural myocardial infarction was defined according to the fourth universal definition of myocardial infarction (2018)., Results: The overall incidence of percutaneous coronary intervention-related periprocedural myocardial infarction was 21.1%. The ticagrelor group showed a significantly lower incidence of periprocedural myocardial infarction (12.3% vs 29.8%, p = 0.022) and numerically lower bleeding events (3.5% vs 8.8%, p = 0.242) as compared with clopidogrel group. No patient had major adverse cardiovascular events during the 1-month follow-up. The levels of high-sensitivity C-reactive protein did not differ significantly between the two groups (p > 0.05), indicating that the benefits of ticagrelor were not from its anti-inflammatory effects. Multivariable analysis showed that the use of ticagrelor (odds ratio: 0.50; 95% confidence interval: 0.29-0.87; p = 0.014) and number of stents (odds ratio: 2.75; 95% confidence interval: 1.25-6.06; p = 0.012) were independent predictors of periprocedural myocardial infarction., Conclusion: Pretreatment with a loading dose of ticagrelor seems to be superior in reducing the incidence of percutaneous coronary intervention-related periprocedural myocardial infarction in Asian patients with acute coronary syndrome as compared with clopidogrel.

Echinococcus multilocularis larvae, predominantly located in the liver, cause a tumor-like parasitic disease, alveolar echinococcosis (AE), that is characterized by increased infiltration of various immune cells, including macrophages, around the lesion that produces an "immunosuppressive" microenvironment, favoring its persistent infection. However, the role of hepatic macrophages in the host defense against E. multilocularis infection remains poorly defined. Using human liver tissues from patients with AE and a hepatic experimental mouse model of E. multilocularis , we investigated the phenotype and function of hepatic macrophages during the parasite infection. In the present study, we found that a large number of CD68 + macrophages accumulated around the metacestode lesion in the liver of human AE samples and that both S100A9 + proinflammatory (M1 phenotype) and CD163 + anti-inflammatory (M2 phenotype) macrophages were significantly higher in close liver tissue (CLT) than in distant liver tissue (DLT), whereas M2 macrophages represent the dominant macrophage population. Furthermore, E. multilocularis -infected mice exhibited a massive increase in macrophage (F4/80 + ) infiltration in the liver as early as day 5, and the infiltrated macrophages were mainly monocyte-derived macrophages (CD11b hi F4/80 int MoMFs) that preferentially differentiated into the M1 phenotype (iNOS + ) at the early stage of E. multilocularis infection and then polarized to anti-inflammatory macrophages of the M2 phenotype (CD206 + ) at the chronic stage of infection. We further showed that elimination of macrophages by treatment of mice with clodronate-liposomes before E. multilocularis infection impaired worm expulsion and was accompanied by a reduction in liver fibrosis, yielding a high parasite burden. These results suggest that hepatic macrophages may play a dual role in the establishment and development of E. multilocularis metacestodes in which early larvae clearance is promoted by M1 macrophages while persistent metacestode infection is favored by M2 macrophages., 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 Wang, Zhang, Fang, Hou, Li, Li, Li, Bi, Li, Abulizi, Shao, Lin and Wen.)

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Behavioral variability often arises from variable activity in the behavior-generating neural network. The synaptic mechanisms underlying this variability are poorly understood. We show that synaptic noise, in conjunction with weak feedforward excitation, generates variable motor output in the Aplysia feeding system. A command-like neuron (CBI-10) triggers rhythmic motor programs more variable than programs triggered by CBI-2. CBI-10 weakly excites a pivotal pattern-generating interneuron (B34) strongly activated by CBI-2. The activation properties of B34 substantially account for the degree of program variability. CBI-10- and CBI-2-induced EPSPs in B34 vary in amplitude across trials, suggesting that there is synaptic noise. Computational studies show that synaptic noise is required for program variability. Further, at network state transition points when synaptic conductance is low, maximum program variability is promoted by moderate noise levels. Thus, synaptic strength and noise act together in a nonlinear manner to determine the degree of variability within a feedforward network., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: The present study was designed to explore the underlying role of hypoxia-inducible factor 1α (HIF-1α) in reactive oxygen species (ROS) formation and apoptosis in osteosarcoma (OS) cells induced by hypoxia., Methods: In OS cells, ROS accumulated and apoptosis increased within 24 h after exposure to low HIF-1α expression levels. A co-expression analysis showed that HIF was positively correlated with Forkhead box class O1 (FoxO1) expression and negatively correlated with CYP-related genes from the National Center for Biotechnology Information's Gene Expression Omnibus (NCBI GEO) datasets. Hypoxia also considerably increased HIF-1α and FoxO1 expression. Moreover, the promoter region of FoxO1 was directly regulated by HIF-1α. We inhibited HIF-1α via siRNA and found that the ROS accumulation and apoptosis induced by hypoxia in OS cells decreased. In this study, a murine xenograft model of BALB-c nude mice was adopted to test tumour growth and measure the efficacy of 2-ME + As 2 O 3 treatment., Results: Ad interim knockdown of HIF-1α also inhibited manganese-dependent superoxide dismutase (MnSOD), catalase and sestrin 3 (Sesn3) expression in OS cells. Furthermore, hypoxia-induced ROS formation and apoptosis in OS cells were associated with CYP450 protein interference and were ablated by HIF-1α silencing via siRNA., Conclusions: Our data reveal that HIF-1α inhibits ROS accumulation by directly regulating FoxO1 in OS cells, which induces MnSOD, catalase and Sesn3 interference, thus resulting in anti-oxidation effects. The combination of an HIF-1α inhibitor (2-mercaptoethanol,2-ME) and ROS inducer (arsenous oxide, As 2 O 3 ) can prohibit proliferation and migration and promote apoptosis in MG63 cells in vitro while inhibiting tumour growth in vivo.

Background: Larvae of Echinococcus granulosus (sensu lato) dwell in host organs for a long time but elicit only a mild inflammatory response, which indicates that the resolution of host inflammation is necessary for parasite survival. The recruitment of alternatively activated macrophages (AAMs) has been observed in a variety of helminth infections, and emerging evidence indicates that AAMs are critical for the resolution of inflammation. However, whether AAMs can be induced by E. granulosus (s.l.) infection or thioredoxin peroxidase (TPx), one of the important molecules secreted by the parasite, remains unclear., Methods: The activation status of peritoneal macrophages (PMs) derived from mice infected with E. granulosus (sensu stricto) was analyzed by evaluating the expression of phenotypic markers. PMs were then treated in vivo and in vitro with recombinant EgTPx (rEgTPx) and its variant (rvEgTPx) in combination with parasite excretory-secretory (ES) products, and the resulting activation of the PMs was evaluated by flow cytometry and real-time PCR. The phosphorylation levels of various molecules in the PI3K/AKT/mTOR pathway after parasite infection and antigen stimulation were also detected., Results: The expression of AAM-related genes in PMs was preferentially induced after E. granulosus (s.s.) infection, and phenotypic differences in cell morphology were detected between PMs isolated from E. granulosus (s.s.)-infected mice and control mice. The administration of parasite ES products or rEgTPx induced the recruitment of AAMs to the peritoneum and a notable skewing of the ratio of PM subsets, and these effects are consistent with those obtained after E. granulosus (s.s.) infection. ES products or rEgTPx also induced PMs toward an AAM phenotype in vitro. Interestingly, this immunomodulatory property of rEgTPx was dependent on its antioxidant activity. In addition, the PI3K/AKT/mTOR pathway was activated after parasite infection and antigen stimulation, and the activation of this pathway was suppressed by pre-treatment with an AKT/mTOR inhibitor., Conclusions: This study demonstrates that E. granulosus (s.s.) infection and ES products, including EgTPx, can induce PM recruitment and alternative activation, at least in part, via the PI3K/AKT/mTOR pathway. These results suggest that EgTPx-induced AAMs might play a key role in the resolution of inflammation and thereby favour the establishment of hydatid cysts in the host.

Introduction: Keloids are a prevalent chronic skin disorder with significant psychosocial morbidity. Intralesional corticosteroid injections are the first-line treatment but are painful and require repeated injections by medical professionals. Dissolving microneedles are a novel method of cutaneous drug delivery that induces minimal/no pain and can be self-administered. The objective of the study was to evaluate the efficacy and safety of triamcinolone-embedded dissolving microneedles in treatment of keloids., Methods: This was a single-blind, intra-individual controlled two-phase clinical trial of 8-week duration each. Two keloids per subject were selected for (1) once-daily 2-min application with microneedles for 4 weeks, followed by no treatment for the next 4 weeks, or (2) non-intervention as control. Primary outcome was change in keloid volume as assessed by a high-resolution 3D scanner., Results: There was significant reduction in keloid volume compared with controls after 4 weeks of treatment. This reduction was greater with a higher dosage of triamcinolone used., Conclusions: Once-daily application of dissolving triamcinolone-embedded microneedles significantly reduced the volume of keloids. The treatment was safe, can be self-administered and can serve as an alternative for patients unsuitable for conventional treatments., Trial Registration: Trial Registry: Health Science Authority (Singapore) Clinical Trials Register Registration number: 2015/00440.

Cholangiocarcinoma (CCA) is a malignant cancer that is associated with high mortality rates. The relationship between laminin γ 2 chain gene (LAMC2) and epidermal growth factor receptor (EGFR) has been previously documented in gastric cancer and oral squamous cell carcinoma. This study investigates the role of LAMC2 in epithelial-mesenchymal transition (EMT) and angiogenesis in CCA and explores the underlying mechanism(s). Differentially expressed genes related to CCA were initially screened using a microarray analysis, and the interaction between LAMC2 and the EGFR signaling pathway was identified. To determine the regulatory effects of LAMC2 on CCA progression, LAMC2 was silenced or overexpressed and the EGFR signaling pathway was activated or blocked. Subsequently, the regulation effects of LAMC2 were evaluated on the expression of EMT markers, invasion and migration of CCA cells, as well as microvessel density in nude mice. Microarray analysis demonstrated that highly expressed LAMC2 is linked to CCA development, which involves the EGFR signaling pathway. When LAMC2 expression was increased, the EGFR signaling pathway and EMT were activated in CCA tissues. Silencing of LAMC2 as well as EGFR signaling pathway inhibition led to suppression of EMT, cell invasion, and migration abilities in vitro, as well as angiogenesis in vivo. This study demonstrates that LAMC2 silencing suppresses the activity of the EGFR signaling pathway, thus functioning as a tumor suppressor in CCA., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Hospital admission rate for the patients with chest pain has already been increased worldwide but no existing risk score has been designed to stratify non-ST-elevation myocardial infarction (NSTEMI) from non-cardiogenic chest pain. Clinical diagnosis of chest pain in the emergency department is always highly subjective and variable. We, therefore, aimed to develop an artificial intelligence approach to predict stable NSTEMI that would give valuable insight to reduce misdiagnosis in the real clinical setting., Methods: A standard protocol was developed to collect data from chest pain patients who had visited the emergency department between December 2016 and February 2017. All the chest pain patients with aged <20 years were primarily included in this study. However, STEMI, previous history of ACS, and out-of-hospital cardiac arrest were excluded from our study. An artificial neural network (ANN) model was then developed to predict NSTEMI patients. The accuracy, sensitivity, specificity, and receiver operating characteristic curve was used to measure the performance of this model., Results: A total of 268 chest pain patients were included in this study; of those, 47 (17.5%) was stable NSTEMI, and 221 (82.5%) was unstable angina patients. Serval risk factors such as cardiac risk factor, systolic blood pressure, hemoglobin, corrected QT interval (QTc), PR interval, glutamic-oxaloacetic transaminase, glutamic pyruvic transaminase and troponin were independently associated with stable NSTEMI. The area under the receiver operating characteristic (AUROC) and accuracy of ANN were 98.4, and 92.86. Additionally, the sensitivity, specificity, positive predictive value, and negative predictive value of the ANN model was 90.91, 93.33, 76.92, and 97.67 respectively., Conclusion: Our prediction model showed a higher accuracy to predict NSTEMI patients. This model has a potential application in disease detection, monitoring, and prognosis of chest pain at risk of AMI., (Copyright © 2019. Published by Elsevier B.V.)

It has been reported that disorders of epigenetic modulation play a critical role in carcinogenesis. Methyl-CpG binding domain protein 2 (MBD2) is known to act as an epigenetic modulator in various types of tumors; however, the role of MBD2 in lung adenocarcinoma (LUAD) remains unclear. Herein, we demonstrated the down-regulation of MBD2 in LUAD compared with adjacent nontumor tissues. The down-regulation of MBD2 in LUAD was correlated with metastasis and poor survival. In addition, MBD2 inhibited tumor metastasis by maintaining the expression of the miR-200s, which suppressed the invasive properties of tumors. Also, MBD2 positively correlated with 5-hydroxymethylcytosine content in the promoter of miR-200s. The conventional view is that MBD2 acts as a transcriptional suppressor. However, the data revealed that MBD2 may act as a transcriptional activator by recruiting 10 to 11 translocation 1 (TET1) and forming a chromatin-remodeling complex. The MBD2-TET1 complex locates to the TET1 promoter and removes the methyl residues in this region, thereby activating TET1 transcription. TET1 also acted as a tumor suppressor in LUAD. Taken together, the data demonstrate the correlation between MBD2, miR-200s, and TET1, and tumor suppressive effect of MBD2 through up-regulation of TET1 and the miR-200s., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Fatty liver disease (FLD) is a common clinical complication; it is associated with high morbidity and mortality. However, an early prediction of FLD patients provides an opportunity to make an appropriate strategy for prevention, early diagnosis and treatment. We aimed to develop a machine learning model to predict FLD that could assist physicians in classifying high-risk patients and make a novel diagnosis, prevent and manage FLD., Methods: We included all patients who had an initial fatty liver screening at the New Taipei City Hospital between 1st and 31st December 2009. Classification models such as random forest (RF), Naïve Bayes (NB), artificial neural networks (ANN), and logistic regression (LR) were developed to predict FLD. The area under the receiver operating characteristic curve (ROC) was used to evaluate performances among the four models., Results: A total of 577 patients were included in this study; of those 377 patients had fatty liver. The area under the receiver operating characteristic (AUROC) of RF, NB, ANN, and LR with 10 fold-cross validation was 0.925, 0.888, 0.895, and 0.854 respectively. Additionally, The accuracy of RF, NB, ANN, and LR 87.48, 82.65, 81.85, and 76.96%., Conclusion: In this study, we developed and compared the four classification models to predict fatty liver disease accurately. However, the random forest model showed higher performance than other classification models. Implementation of a random forest model in the clinical setting could help physicians to stratify fatty liver patients for primary prevention, surveillance, early treatment, and management., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Pancreatic cancer (PC) represents one of the most aggressive forms of cancer. The role of long non-coding RNAs (lncRNAs) has been highlighted in various malignancies including PC. The aim of the present study was to investigate the effects associated with actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) on the progression of PC and the underlying mechanism., Methods: Microarray-based gene expression profiling of PC was performed to identify PC-related lncRNAs, after which the expression of AFAP1-AS1 and cancer stem cell (CSC) markers in PC tissues and cells were determined accordingly. The potential microRNA-384 (miR-384) capable of binding to AFAP1-AS1, in addition to its ability to regulate activin receptor A type I (ACVR1) were analyzed. In order to investigate the effect of the AFAP1-AS1/miR-384/ACVR1 axis on self-renewal ability, tumorigenicity, invasion, migration and stemness of PC cells, shRNA-AFAP1-AS1, miR-384 mimic and inhibitor were cloned into cells., Results: High expression of AFAP1-AS1 and ACVR1 with low expression of miR-384 were detected in PC tissues. ACVR1 was determined to be down-regulated when miR-384 was overexpressed, while the inhibition of AFAP1-AS1 decreased its ability to binding competitively to miR-384, resulting in the down-regulation of ACVR1 and enhancing miR-384 expression, ultimately inhibiting the progression of PC. The knockdown of AFAP1-AS1 or overexpression of miR-384 was confirmed to impair PC cell self-renewal ability, tumorigenicity, invasion, migration and stemness., Conclusions: Taken together, AFAP1-AS1 functions as an endogenous RNA by competitively binding to miR-384 to regulate ACVR1, thus conferring inhibitory effects on PC cell stemness and tumorigenicity.

l- to d-residue isomerization is a post-translational modification (PTM) present in neuropeptides, peptide hormones, and peptide toxins from several animals. In most cases, the d-residue is critical for the biological function of the resulting d-amino acid-containing peptide (DAACP). Here, we provide an example in native neuropeptides in which the DAACP and its all-l-amino acid epimer are both active at their newly identified receptor in vitro and at a neuronal target associated with feeding behavior. On the basis of sequence similarity to a known DAACP from cone snail venom, we hypothesized that allatotropin-related peptide (ATRP), a neuropeptide from the neuroscience model organism Aplysia californica , may form multiple diastereomers in the Aplysia central nervous system. We determined that ATRP exists as a d-amino acid-containing peptide (d2-ATRP) and identified a specific G protein-coupled receptor as an ATRP receptor. Interestingly, unlike many previously reported DAACPs and their all-l-residue analogs, both l-ATRP and d2-ATRP were potent agonists of this receptor and active in electrophysiological experiments. Finally, d2-ATRP was much more stable than its all-l-residue counterpart in Aplysia plasma, suggesting that in the case of ATRP, the primary role of the l- to d-residue isomerization may be to protect this peptide from aminopeptidase activity in the extracellular space. Our results indicate that l- to d-residue isomerization can occur even in an all-l-residue peptide with a known biological activity and that in some cases, this PTM may help modulate peptide signal lifetime in the extracellular space rather than activity at the cognate receptor., (© 2018 Checco et al.)

When individual neurons in a circuit contain multiple neuropeptides, these peptides can target different sets of follower neurons. This endows the circuit with a certain degree of flexibility. Here we identified a novel family of peptides, the Aplysia SPTR-Gene Family-Derived peptides (apSPTR-GF-DPs). We demonstrated apSPTR-GF-DPs, particularly apSPTR-GF-DP2, are expressed in the Aplysia CNS using immunohistochemistry and MALDI-TOF MS. Furthermore, apSPTR-GF-DP2 is present in single projection neurons, e.g., in the cerebral-buccal interneuron-12 (CBI-12). Previous studies have demonstrated that CBI-12 contains two other peptides, FCAP/CP2. In addition, CBI-12 and CP2 promote shortening of the protraction phase of motor programs. Here, we demonstrate that FCAP shortens protraction. Moreover, we show that apSPTR-GF-DP2 also shortens protraction. Surprisingly, apSPTR-GF-DP2 does not increase the excitability of retraction interneuron B64. B64 terminates protraction and is modulated by FCAP/CP2 and CBI-12. Instead, we show that apSPTR-GF-DP2 and CBI-12 increase B20 excitability and B20 activity can shorten protraction. Taken together, these data indicate that different CBI-12 peptides target different sets of pattern-generating interneurons to exert similar modulatory actions. These findings provide the first definitive evidence for SPTR-GF's role in modulation of feeding, and a form of molecular degeneracy by multiple peptide cotransmitters in single identified neurons.

Neuropeptides in several animals undergo an unusual post-translational modification, the isomerization of an amino acid residue from the l-stereoisomer to the d-stereoisomer. The resulting d-amino acid-containing peptide (DAACP) often displays biological activity higher than that of its all-l-residue analogue, with the d-residue being critical for function in many cases. However, little is known about the full physiological roles played by DAACPs, and few studies have examined the interaction of DAACPs with their cognate receptors. Here, we characterized the signaling of several DAACPs derived from a single neuropeptide prohormone, the Aplysia californica achatin-like neuropeptide precursor (apALNP), at their putative receptor, the achatin-like neuropeptide receptor (apALNR). We first used quantitative polymerase chain reaction and in situ hybridization experiments to demonstrate receptor ( apALNR) expression throughout the central nervous system; on the basis of the expression pattern, we identified novel physiological functions that may be mediated by apALNR. To gain insight into ligand signaling through apALNR, we created a library of native and non-native neuropeptide analogues derived from apALNP (the neuropeptide prohormone) and evaluated them for activity in cells co-transfected with apALNR and the promiscuous Gα subunit Gα-16. Several of these neuropeptide analogues were also evaluated for their ability to induce circuit activity in a well-defined neural network associated with feeding behavior in intact ganglia from Aplysia. Our results reveal the specificity of apALNR and provide strong evidence that this receptor mediates diverse physiological functions throughout the central nervous system. Finally, we show that some native apALNP-derived DAACPs exhibit enhanced stability toward endogenous proteases, suggesting that the d-residues in these DAACPs may increase the peptide lifetime, in addition to influencing receptor specificity, in the nervous system. Ultimately, these studies provide insight into signaling at one of the few known DAACP-specific receptors and advance our understanding of the roles that l- to d-residue isomerization play in neuropeptide signaling.

Here, the mesoporous silica (Sylysia 350) was selected as mesoporous material, hydroxypropyl methylcellulose (HPMC) was selected as crystallization inhibitor, and febuxostat (FBT) was selected as model drug, respectively. The FBT-Sylysia-HPMC nanomatrix (FBT@SHN) was prepared. The characteristics of FBT@SHN were investigated in vitro and in vivo. Our results indicated that the FBT in FBT@SHN was in amorphous form. The solubility and dissolution of FBT in FBT@SHN were significantly increased. The oral bioavailability of FBT in FBT@SHN was greatly improved 5.8-fold compared with that in FBT suspension. This nanomatrix could be used as a drug delivery platform for improving the oral bioavailability.

Background: Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer., Methods: In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis., Results: Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis., Conclusions: Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.

Bio-stability is a key feature for the utilization and final disposal of biowaste-derived residues, such as aerobic compost or vermicompost of food waste, bio-dried waste, anaerobic digestate or landfilled waste. The present paper reviews conventional methods and advanced techniques used for the assessment of bio-stability. The conventional methods are reclassified into two categories. Advanced techniques, including spectroscopic (fluorescent, ultraviolet-visible, infrared, Raman, nuclear magnetic resonance), thermogravimetric and thermochemolysis analysis, are emphasized for their application in bio-stability assessment in recent years. Their principles, pros and cons are critically discussed. These advanced techniques are found to be convenient in sample preparation and to supply diversified information. However, the viability of these techniques as potential indicators for bio-stability assessment ultimately lies in the establishment of the relationship of advanced ones with the conventional methods, especially with the methods based on biotic response. Furthermore, some misuses in data explanation should be noted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Itch is frequently associated with dermatoses characterized by a defective skin barrier. We formulated an itch-relieving moisturizing cream containing 3% menthol and ceramides. Our aim was to evaluate the safety and antipruritic efficacy of application of this cream in volunteers with and without skin diseases. Volunteers were asked to apply the cream for 1 month on a minimum body surface area of 6%. Safety was assessed by the absence of contact dermatitis or other side effects, using a self-administered questionnaire completed at 5 minutes, 1 week, and 1 month after application. To determine efficacy, volunteers with pruritic dermatoses were asked to grade their average itch intensity at baseline, 1 week, and 1 month after application. Sixty volunteers were recruited, of whom 41 had no skin disease; no adverse events were reported in the latter. Of the 19 volunteers with dermatoses, 18 reportedly had atopic dermatitis. One of the 60 volunteers stopped application due to stinging sensations induced by menthol. Itch scores of volunteers with dermatitis improved from baseline at 1 week ( P =.01) and 1 month ( P <.01) after application. Application of a 3% menthol-containing moisturizing cream was safe in healthy individuals and participants with dermatitis. In the latter, itch scores were significantly reduced during follow-up.

A better understanding of neuromodulation in a behavioral system requires identification of active modulatory transmitters. Here, we used identifiable neurons in a neurobiological model system, the mollusc Aplysia , to study neuropeptides, a diverse class of neuromodulators. We took advantage of two types of feeding neurons, B48 and B1/B2, in the Aplysia buccal ganglion that might contain different neuropeptides. We performed a representational difference analysis (RDA) by subtraction of mRNAs in B48 versus mRNAs in B1/B2. The RDA identified an unusually long (2025 amino acids) peptide precursor encoding Aplysia leucokinin-like peptides (ALKs; e.g. ALK-1 and ALK-2). Northern blot analysis revealed that, compared with other ganglia ( e.g. the pedal-pleural ganglion), ALK mRNA is predominantly present in the buccal ganglion, which controls feeding behavior. We then used in situ hybridization and immunohistochemistry to localize ALKs to specific neurons, including B48. MALDI-TOF MS on single buccal neurons revealed expression of 40 ALK precursor-derived peptides. Among these, ALK-1 and ALK-2 are active in the feeding network; they shortened the radula protraction phase of feeding motor programs triggered by a command-like neuron. We also found that this effect may be mediated by the ALK-stimulated enhancement of activity of an interneuron, which has previously been shown to terminate protraction. We conclude that our multipronged approach is effective for determining the structure and defining the diverse functions of leucokinin-like peptides. Notably, the ALK precursor is the first verified nonarthropod precursor for leucokinin-like peptides with a novel, marked modulatory effect on a specific parameter (protraction duration) of feeding motor programs., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Circular RNAs (circRNAs) as a novel type of noncoding RNAs (ncRNAs) are widely studied in the development of human various diseases, including cancer. Here, we found circular RNA hsa&#95;circ&#95;000984 encoded by the CDK6 gene was remarkably upregulated in the tissues of colorectal cancer (CRC) patients and in the CRC cell lines. Moreover, high expression level of hsa&#95;circ&#95;000984 was significantly associated with advanced colorectal cancer. Further analysis revealed that hsa&#95;circ&#95;000984 knockdown could inhibit cell proliferation, migration, invasion in vitro and tumor formation in vivo in CRC cell lines. Mechanically, we found that hsa&#95;circ&#95;000984 may act as a competing endogenous RNA (ceRNA) by competitively binding miR-106b and effectively upregulate the expression of CDK6 , thereby inducing a series of malignant phenotypes of tumor cells. Taken together, these observations suggest that the hsa&#95;circ&#95;000984 could mediate the expression of gene CDK6 by acting as a ceRNA, which may contribute to a better understanding of between the regulatory miRNA network and CRC pathogenesis., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

CHRDL1 (Chordin-like 1) is a secreted protein that acts as an antagonist of bone morphogenetic protein (BMP). BMP plays a role as an activator of BMP receptor II (BMPR II), which mediates extracellular to intracellular signal transmission and is involved in carcinogenesis and metastasis. Herein, we report that CHRDL1 expression was significantly down-regulated in gastric cancer tissues and associated with poor survival. Clinic-pathological parameters demonstrated a close relationship between low CHRDL1 expression and metastasis. In vitro, CHRDL1 knockdown promoted tumor cell proliferation and migration through BMPR II by activating Akt, Erk and β-catenin. Furthermore, we observed the hypermethylation of the CHRDL1 promoter in gastric cancer, which induced low expression of CHRDL1 and decreased its secretion to the supernatant. Finally, in vivo experiments confirmed that CHRDL1 acted as a tumor suppressor gene in suppressing tumor growth and metastasis.

The present study investigates the pathogenesis of periprosthetic cysts after total hip replacement, and explores appropriate treatment appoaches. Six patients with periprosthetic cysts after total hip arthroplasty were treated at the First Affiliated Hospital of Nanjing Medical University between 2009 and 2014. During surgery, it was found that all cysts communicated with the hip and the hip prosthesis could be seen after cyst excision. Four patients simply underwent cyst excision, and light red liquid was found in the cyst. Among them, radiological examination revealed that a part of the hip prosthesis projected from the bone bed in one case. Postoperative pathology revealed a synovial cyst with inflammatory cell infiltration. Prostheses were loosened in two cases, so cystectomy and revision of the prosthesis were performed at the same time. Among the six patients, polyethylene wear particles could be seen in five patients through a pathological polarizing microscope. Out of the four patients who underwent simple cyst excision, two patients experienced cyst recurrence within 1 year after surgery; however, there was no cyst recurrence in the two patients who underwent cyst excision and revision of the prosthesis. The formation of a periprosthetic cyst after hip replacement is likely to be related to polyethylene wear and undesirable prosthesis position; in addition, when treated by simple cyst excision, the rate of recurrence was higher., (© 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Background: Noncultured cellular grafting is a known surgical technique for vitiligo., Objective: This study evaluated our center's 12-month repigmentation outcome and its maintenance up to 60 months, factors influencing repigmentation and safety data., Methods: Clinicoepidemiologic and repigmentation data were reviewed for patients with vitiligo who had undergone noncultured cellular grafting from March 2006 to December 2012 at the National Skin Center, Singapore., Results: All 177 patients who received noncultured cellular grafting during the study period were included. For those with available data, good to excellent repigmentation was present in 83% at 60 months. At 12 months, 88% of patients (n = 52) with segmental vitiligo achieved good to excellent repigmentation compared with 71% (n = 55) with nonsegmental vitiligo (P < .05). More patients on collagen dressings (82%) achieved good to excellent repigmentation compared with those who received hyaluronic acid (63%) (P < .05). Sites of lesions and postgrafting phototherapy did not significantly affect repigmentation outcome. Adverse reactions were uncommon and mild., Limitations: The study is limited by its retrospective nature, the progressive loss to follow-up of patients, the absence of blinding, and the lack of use of standardized assessment tools., Conclusion: Noncultured cellular grafting was successful in allowing more than 80% of patients to achieve good to excellent repigmentation for at least 60 months., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: Acute kidney injury (AKI) carries an increasing incidence rate worldwide and increases the risk of developing end-stage renal disease (ESRD) as well as the medical expenses during the post-AKI course. The Taiwan Consortium for Acute Kidney Injury and Renal Diseases (CAKs) has thus launched a nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study, which prospectively enrols critically ill patients with AKI. Through thoroughly evaluating the risk and prognostic factors of AKI, we hope to lower the incidence of AKI and ESRD from the perspective of AKI-ESRD interaction., Methods: The CAKs includes 30 hospitals which distribute widely through the four geographical regions (north, middle, south, and east) of Taiwan, and have a 1:1 ratio of medical centres to regional hospitals in each region. The NEP-AKI-D study enrols intensive care unit-based AKI patients who receive dialysis in the four seasonal sampled months (October 2014, along with January, April, and July 2015) in the included hospitals. The collected data include demographic information, pertaining laboratory results, dialysis settings and patient outcomes. The data are uploaded in a centre website and will be audited by on-site principal investigators, computer logic gates, and the CAKs staffs. The outcomes of interest are in-hospital mortality, dialysis-dependency and readmission rate within 90 days after discharge., Conclusion: The NEP-AKI-D study enrols a large number of representative AKI patients throughout Taiwan. The results of the current study are expected to provide more insight into the risk and prognostic factors of AKI and further attenuated further chronic kidney disease transition., (© 2015 Asian Pacific Society of Nephrology.)

Background: Splenectomy and pericardial devascularization (SPD) is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes (ICGR15) was reported to offer better sensitivity and specificity than the Child-Pugh classification in hepatectomy, but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD., Methods: From January 2012 to January 2015, 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15, Child-Pugh classification, model for end-stage liver disease (MELD) score, and perioperative characteristics were analyzed retrospectively., Results: Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20; 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17; 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%, which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15, MELD score, surgical procedure, intraoperative blood loss, and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery (P=0.020)., Conclusions: ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD.

In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose-lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To investigate the feasibility and safety of en bloc resection of cervical primary malignant bone tumors by a combined anterior and posterior approach based on a three-dimensional (3-D) printing model., Methods: Five patients with primary malignant bone tumors of the cervical spine underwent en bloc resection via a one-stage combined anteroposterior approach in our hospital from March 2013 to June 2014. They comprised three men and two women of mean age 47.2 years (range, 26-67 years). Three of the tumors were chondrosarcomas and two chordomas. Preoperative 3-D printing models were created by 3-D printing technology. Sagittal en bloc resections were planned based on these models and successfully performed. A 360° reconstruction was performed by spinal instrumentation in all cases. Surgical margins, perioperative complications, local control rate and survival rate were assessed., Results: All patients underwent en bloc excision via a combined posterior and anterior approach in one stage. Mean operative time and estimated blood loss were 465 minutes and 1290 mL, respectively. Mean follow-up was 21 months. Wide surgical margins were achieved in two patients and marginal resection in three; these three patients underwent postoperative adjuvant radiation therapy. One vertebral artery was ligated and sacrificed in each of three patients. Nerve root involved by tumor was sacrificed in three patients with preoperative upper extremity weakness. One patient (Case 3) had significant transient radiculopathy with paresis postoperatively. Another (Case 4) with C 4 and C 5 chordoma had respiratory difficulties and pneumonia after surgery postoperatively. He recovered completely after 2 weeks' management with a tracheotomy tube and antibiotics in the intensive care unit. No cerebrovascular complications and wound infection were observed. No local recurrence or instrumentation failure were detected during follow-up., Conclusion: Though technically challenging, it is feasible and safe to perform en bloc resection of cervical primary bone tumors. This is the most effective means of managing cervical spine tumors. Preoperative 3-D printing modelling enables better anatomical understanding of the relationship between the tumor and cervical spine and can assist in planning the surgical procedure., (© 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

The knee joint is extremely susceptible to injury, which is usually identified by magnetic resonance imaging (MRI). In the present study, MRI was applied to quantitatively detect the association between anterior cruciate ligament (ACL) rupture and anatomic morphologic changes of the intercondylar notch. Forty patients with unilateral ACL rupture who were treated between July, 2013 and October, 2014 were enrolled in the present study. The patients were divided into the observation (affected side) and control (healthy side) groups. MRI measurements were undertaken based on parameters associated with intercondylar notch of double knee joints. The results showed that intercondylar notch width (ICW) in the observation group was significantly smaller than that in the control group, and differences were statistically significant (P<0.05). Differences on the intercondylar notch height and femoral condyle width [epicondylar width (EW)] between the two groups were not statistically significant (P>0.05). Notch width index (NWI) and notch shape index (NSI) in the observation group were significantly less than those in the control group and differences were statistically significant (P<0.05). Differences of Lysholm and Tegner scoring between the two groups were not statistically significant (P>0.05). The differential value of ICW in the observation group was 2.6±1.3 mm and the ACL rupture time of the affected knee was 20.4±1.3 months on average. The correlation was statistically significant (P<0.05). The correlation of Lysholm scoring, Tegner scoring and intercondylar notch stenosis degree on the affected knee was not statistically significant (P>0.05). In conclusion, after ACL rupture, ICW on the affected knee had significant stenosis, NSI and NWI were significantly reduced and the stenosis degree was aggravated with the prolongation of course. By contrast, Lysholm and Tegner scoring of patients with different degrees of stenosis had no correlation.

The purpose of this study was to examine the establishment of a model concerned with osteoarthritis resulting from the anterior cruciate ligament rupture of rats and investigate the associated mechanism, as well as provide a theoretical basis for clinical treatment of the disease. Forty Sprague-Dawley male rats were randomly divided into two groups of 20 rats each and the anterior cruciate ligament transaction model and knee joint brake model were successfully established. Two rats in the anterior cruciate ligament transection group (10%) and 3 rats in the knee joint brake group (15.0%) died. The survival rate of the two groups was not statistically significant (χ 2 <0.001, P=1.000). Swelling of the knee joint and synovium of rats in the two experimental groups was aggravated. The Mankin score was significantly higher in the anterior cruciate ligament transection group than that in the experimental group and the difference was statistically significant (P<0.05). By contrast, no significant difference was observed for osteoarthritis severity for the two experimental groups (P>0.05). Analysis of the subgroups showed that the proportion of the anterior cruciate ligament in the experimental group was significantly higher than that of the knee joint brake group, and the difference was statistically significant (P<0.05). By contrast, the difference was not statistically significant in the comparison of the medium and early proportion (P>0.05). The content of protein polysaccharide and II collagen fiber in the experimental group of the anterior cruciate ligament transection was lower than that of the knee joint brake group, and this difference was statistically significant (P<0.05). Thus the mechanism of osteoarthritis may be associated with the decrease in the content of protein and II collagen fibers.

Rhizoma Dioscoreae polysaccharides (RDPS) are the primary active ingredient of Rhizoma Dioscoreae , which is a traditional Chinese medicine. RDPS have previously been shown to scavenge reactive oxygen species, and protect against D-galactose-induced mimetic aging. The present study aimed to investigate the neuroprotective effects of RDPS against hypoxia-induced neuronal cell apoptosis. Neuronal cells harvested from pregnant Sprague-Dawley rats were divided into groups, as follows: i) Normal control group; ii) hypoxia-induced apoptosis neuronal cell model; iii) 0.025 g/l RDPS-treated group; iv) 0.05 g/l RDPS-treated group; v) 0.1 g/l RDPS-treated group; and vi) 0.25 g/l RDPS treated group. Neuronal cell viability was investigated using an MTT assay, and neuronal cell apoptosis was analyzed using Annexin V-fluorescein isothiocyanate/propidium iodide double-staining, Hoechst 33342 fluorescent staining, Rhodamine 123 staining, polymerase chain reaction and immunocytochemical staining. The RDPS-treated neuronal cells exhibited improved viability, and decreased hypoxia-induced mitochondrial injury and apoptosis. In addition, the mRNA and protein expression levels of caspase-3 and B-cell lymphoma (Bcl)-2-associated X protein (Bax) were significantly downregulated, whereas the mRNA and protein expression levels of Bcl-2 were significantly upregulated, in the RDPS-treated hypoxic neurons, as compared with the apoptosis model (P<0.05). Furthermore, the ratio of Bcl-2 expression:Bax expression significantly increased following RDPS treatment, as compared with the apoptosis model (P<0.05). The results of the present study suggested that RDPS may attenuate hypoxia-induced neuronal cell apoptosis by altering the expression levels of key apoptosis-regulating proteins in hypoxic neurons.