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Hongquan Zheng,1,2 Yan Xia,3 Shengjun Qu,4 Lin Fan,2 Jingjing Zhang,1 Zhixiang Ma,1 Yangsheng Chen,4 Hongwei Fan1,2 1Department of Clinical Pharmacology Lab, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 3Jiangsu Leeway Biological Technology Co., Ltd, Nanjing, Jiangsu, People’s Republic of China; 4CP Pharmaceutical Qingdao Co., Ltd, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Hongwei FanNanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People’s Republic of ChinaTel +86 25 5288 7030Fax +86 25 5288 7031Email fanhongwei178@sina.comYangsheng Chen 3601 Tuanjie Road, Economic and Technological Development Zone, Qingdao, People’s Republic of ChinaTel +86 18766396996Email chenys@cppqd.comPurpose: The present report describes findings from a Phase I clinical study that evaluated the single- and multiple-dose pharmacokinetics of frovatriptan succinate tablet in Chinese healthy subjects.Methods: A total of 24 healthy subjects were enrolled. In single-dose study, 2.5, 5, and 10 mg oral doses of frovatriptan succinate tablet were administrated. A 2.5 mg frovatriptan succinate tablet was administrated 12 times in 7 days in the multiple-dose study. Blood samples were collected at scheduled time points.Results: The results in single-dose study indicated that the blood levels were proportional to the administered dose, with the mean Cmax and AUClast ranging from approximately 6.27 ng/mL– 17.35 ng/mL and 92.52 h⋅ng/mL – 287.40 h⋅ng/mL over the dose range. In the multiple-dose study, moderate drug accumulation was noted, which was attributable to forvatriptan’s long t1/2 of about 26.47 to 30.63 h. Gender differences were noticed in both single- and multiple-dose study; exposure PK parameters were consistently higher in female than in male.Conclusion: These pharmacokinetic evaluations in healthy Chinese subjects found that frovatriptan succinate tablet has an acceptable pharmacokinetic profile in Chinese subjects.Keywords: frovatriptan succinate, pharmacokinetics, single-dose, multiple-dose

The dioxin-like substances polyhalogenated carbazoles (PHCZs) may trigger the aryl hydrocarbon receptor (AhR) signaling pathway. Although the crosstalk between AhR and the hypoxia inducible factor-1 (HIF-1) pathways is generally believed to occur, the exact mechanisms of the HIF-1 pathway in PHCZ toxicity have not been determined. We aimed to elucidate the effect of PHCZs on the HIF-1 pathway and its involvement in the regulation of target genes of HIF-1. Herein, we employed human HepG2 cells transiently transfected with a hypoxia response element (HRE) luciferase reporter to identify PHCZs that could influence HIF-1 pathway. We found that exposure to one of the four selected PHCZs, specifically 1,3,6,8-tetrabromo-9 H-carbazole (1368-BCZ), induced a significant enhancement of the activity of HRE activity. In silico data supported 1368-BCZ-induced HIF-1α activity preferentially. Moreover, 1368-BCZ significantly upregulated the expression of HIF-1 target genes, including endothelial growth factor (VEGF) and erythropoietin. Importantly, the stimulated secretion of VEGF by 1368-BCZ promoted the angiogenesis in human umbilical vein endothelial cells. Therefore, the present experimental and computational studies provide new and direct evidence of 1368-BCZ - HIF-1 interaction, which sheds light on the HIF-mediated cardiovascular toxicity and allows a knowledge-based risk assessment of emerging pollutants.

Emerging data indicate that prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could interfere with myogenic differentiation in vivo. Acetylcholinesterase (EC3.1.1.7; AChE), an enzyme critical for cholinergic neurotransmission, is abundantly expressed in neurons and mature myotubes, and we recently found that muscle AChE expression was suppressed in parallel with the inhibition of myogenic differentiation upon TCDD treatment in mouse C2C12 cells. This TCDD-induced suppression of muscle AChE was proposed to involve an aryl hydrocarbon receptor (AhR)-independent mechanism, but the precise underlying mechanism remains unclear. Considering the widely recognized role of muscular activity in AChE expression and its potential crosstalk with the AhR signaling pathway, we sought to investigate the effect of TCDD on muscle AChE expression in the presence of muscular activity. Therefore, we employed a highly contractile rat primary skeletal muscle culture system in which AChE activity and the expression of genes related to it (AChE T subunit and collagen Q (ColQ)) were increased during the myogenic differentiation process. Although TCDD treatment successfully induced the expression of genes regulated by AhR activation, the treatment exerted no notable effects on myogenic differentiation. Moreover, muscle AChE enzymatic activity and mRNA level remained unchanged following TCDD treatment, and only ColQ mRNA expression was slightly increased after 4-day treatment with TCDD (10−10 M). The compensatory role of muscle-contraction-related signaling pathways in this newly identified unresponsiveness of muscle AChE to TCDD warrants further investigation.

Background: Placing a spinal stimulator for the purpose of restoring paralysed function is a novel procedure; however, paralysis predisposes people to infection. Preventing surgical site infections is critical to benefit this population. Objective: The objective of this study was to review the root cause analysis of postoperative wound infections by a hospital epidemiology team following implantation of epidural spinal cord neurostimulators in patients with chronic spinal cord injury. Methods: A team was assembled to review the case of every individual who had been enrolled to receive a neurostimulator at the facility. A root cause analysis was performed evaluating five categories: the patient; equipment; facility/environment; procedure; and personnel. Findings: The root cause analysis included 11 patients. Two patients became infected. Three others dehisced their wound without becoming infected. All patients were given preoperative antibiotics on time. A mean of 17 personnel were in the operating room during surgery. Vancomycin powder was used in the patients who either dehisced their wound or became infected. Conclusions: The root cause analysis provides guidance for other institutions performing the same novel procedure. This analysis did not reveal a direct association, but did generate several areas for improvement including increasing pre-surgical screening, cleaning transient equipment (e.g., computer screens), limiting traffic in the operating room, using new sterile instruments for each stage of the procedure, not reopening the back incision, not applying vancomycin powder, and using an antimicrobial envelope for the stimulator.

Dioxins and dioxin-like compounds (DLCs) in foodstuffs are closely related to human health. As China is the largest food-consuming country, there is a potentially large demand for screening bioassays that are rapid, cost-effective and capable of determining dioxins and DLCs in foodstuffs. CBG2.8D is a reporter gene-based recombinant cell sensor that was recently developed for determining dioxin and DLCs in ambient and seafood samples. In this study, we established a bioanalytical method with this ready-to-use cell sensor for the bioanalysis of dioxins and DLCs in different types of meat samples. Twenty-nine samples from three typical types of meat (beef, pork and fish) were collected and subjected to both instrumental analysis and a CBG2.8D bioassay. The intra- and inter-lab reproducibility of the bioassay was investigated and the coefficients of variation (CVs) were lower than 25%, suggesting that the cell sensor had a good reproducibility for the meat samples. Based on the correlation equation and coefficient obtained by comparing the data from the instrumental analysis and CBG2.8D bioassay, we found that this method had better performance with pork and fish than with beef. The compliance rate was also determined by comparing the results from the instrumental analysis and there were no false results for the pork and fish samples. Lastly, a complete operation procedure was summarized as a guideline for practical application. In conclusion, the CBG2.8D cell sensor exhibits excellent stability and is capable of screening dioxins and DLCs in meat samples.

Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by organophosphate (OP) and carbamate pesticides. Dioxin is an emerging environmental AChE disruptor and is a typical persistent organic pollutant with multiple toxic effects on the nervous system. Growing evidence has shown that there is a significant link between dioxin exposure and neurodegenerative diseases and neurodevelopmental disorders, most of which involve AChE and cholinergic dysfunctions. Therefore, an in-depth understanding of the effects of dioxin on AChE and the related mechanisms of action might help to shed light on the molecular bases of dioxin impacts on the nervous system. In the past decade, the effects of dioxins on AChE have been revealed in cultured cells of different origins and in rodent animal models. Unlike OP and carbamate pesticides, dioxin-induced AChE disturbance is not due to direct inhibition of enzymatic activity; instead, dioxin causes alterations of AChE expression in certain models. As a widely accepted mechanism for most dioxin effects, the aryl hydrocarbon receptor (AhR)-dependent pathway has become a research focus in studies on the mechanism of action of dioxin-induced AChE dysregulation. In this mini-review, the effects of dioxin on AChE and the diverse roles of the AhR pathway in AChE regulation are summarized. Additionally, the involvement of AhR in AChE regulation during different neurodevelopmental processes is discussed. These AhR-related findings might also provide new insight into AChE regulation triggered by diverse xenobiotics capable of interacting with AhR.

Dechlorane 602 (Dec 602), a chlorinated flame retardant, has been widely detected in different environmental matrices and biota. However, toxicity data for Dec 602 seldom have been reported. A metabolomics study based on ultra-high performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry was employed to study the urine and sera metabolic profiles of mice administered with Dec 602 (0, 0.001, 0.1, and 10 mg/kg body weight per day) for 7 days. A significant difference in metabolic profiling was observed between the Dec 602 treated group and the control group by multivariate analysis, which directly reflected the metabolic perturbations caused by Dec 602. The metabolomics analyses of urine from Dec 602-exposed animals exhibited an increase in the levels of thymidine and tryptophan as well as a decrease in the levels of tyrosine, 12,13-dihydroxy-9Z-octadecenoic acid, 2-hydroxyhexadecanoic acid and cuminaldehyde. The metabolomics analyses of sera showed a decrease in the levels of kynurenic acid, daidzein, adenosine, xanthurenic acid and hypoxanthine from Dec 602-exposed animals. These findings indicated Dec 602 induced disturbance in phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan metabolism, tyrosine metabolism, pyrimidine metabolism, purine metabolism, ubiquinone and other terpenoid-quinone biosynthesis; phenylalanine metabolism and aminoacyl-tRNA biosynthesis. Significant alterations of immune and neurotransmitter-related metabolites (tyrosine, tryptophan, kynurenic acid, and xanthurenic acid) suggest that the toxic effects of Dec 602 may contribute to its interactions with the immune and neuronal systems. This study demonstrated that the UHPLC-ESI-IT-TOF-MS-based metabolomic approach can obtain more specific insights into the potential toxic effects of Dec 602 at molecular level.

Emerging evidence showed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) could induce expression of certain reactivation-associated genes in astrocytes, however, the consequent cellular effects and molecular mechanisms are still unclear. During the process of astrocyte reactivation, migration is a critical cellular event. In the present study, we employed wound-healing assay and Transwell® motility assay to explore the effects of TCDD on cell migration in primary cultured rat cortical astrocytes. We found that upon TCDD treatments at relative low concentrations (10− 10 and/or 10− 9 mol/L), the ability of primary astrocytes to migrate horizontally and vertically was promoted. In line with this cellular effect, the mRNA expression of two pro-migratory genes, including cell division cycle 42 (CDC42) and matrix metalloproteinase 2 (MMP2) was induced by TCDD treatment. Dioxin exerts its toxic effects mainly through aryl hydrocarbon receptor (AhR) pathway. So the role of AhR pathway in the pro-migratory effects of TCDD was examined using an AhR antagonist, CH223191. We found that application of CH223191 significantly reversed the pro-migratory effects of TCDD. Interestingly, the basal ability of horizontal migration as well as basal levels of CDC42 and MMP2 expression were dramatically reduced suggesting a possible physiological role of AhR in maintaining the endogenous migration ability of the primary astrocytes. These findings support the notion that dioxin promotes astrocyte reactivation at molecular and cellular levels.

International audience; In this work, a series of poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) diblock copolymers with relatively short PLGA blocks were synthesized by ring-opening polymerization of D,L-lactide and glycolide in the presence of monomethoxy PEG with Mn of 2000. Spherical micelles were obtained by self-assembly of copolymers using direct dissolution method. The degradation of the micelles was investigated under in vitro conditions at 37 degrees C. The effects of chemical composition on micelle degradation were evaluated from NMR, GPC, DLS and TEM measurements. The molar mass of copolymers constantly decreases during degradation in all cases. The copolymers with longer hydrophobic PLGA blocks exhibit larger molar mass decrease rate since only the PLGA block is degradable. Meanwhile, the molar mass distribution remains almost unchanged, in agreement with random chain cleavage. NMR spectra show that the final degradation products are lactic acid and glycolic acid. A pH decrease is also detected during degradation. The size of the micelle depends on the chemical composition of copolymers. Micelle size is smaller for copolymers with longer hydrophobic PLGA blocks because of more compact core structure. With the hydrolysis of the PLGA blocks, the structure of micelles becomes looser, and the micelle size exhibits a sharp increase after a lag time. At the later stage of degradation, the size of micelles decreases as they become unstable and could collapse. The micelle structure could be clearly distinguished after 45 days degradation for copolymers with longer PLGA blocks, whereas those with shorter PLGA blocks lost the structural integrity. It is also noteworthy that the LA/GA ratio has little effect on the degradation of PLGA-PEG copolymer micelles, which may be related to the amorphous structure of PLGA block and the relatively short block length. These findings should be helpful for the conception of drug delivery systems based on PLGA-PEG micelles.

International audience; A series of poly(e-caprolactone/glycolide)-poly(ethylene glycol) (P(CL/GA)-PEG) diblock copolymers were prepared by ring opening polymerization of a mixture of e-caprolactone and glycolide using mPEG as macro-initiator and stannous octoate as catalyst. Self-assembled micelles were prepared from the copolymers using nanoprecipitation method. The micelles were spherical in shape. The micelle size was larger for copolymers with longer PEG blocks. In contrast, the critical micelle concentration of copolymers increased with decreasing the overall hydrophobic block length. Drug loading and drug release studies were performed under in vitro conditions, using paclitaxel as a hydrophobic model drug. Higher drug loading was obtained for micelles with longer poly(epsilon-caprolactone) blocks. Faster drug release was obtained for micelles of mPEG2000 initiated copolymers than those of mPEG5000 initiated ones. Higher GA content in the copolymers led to faster drug release. Moreover, drug release rate was enhanced in the presence of lipase from Pseudomonas sp., indicating that drug release is facilitated by copolymer degradation. The biocompatibility of copolymers was evaluated from hemolysis, dynamic clotting time, and plasma recalcification time tests, as well as MTT assay and agar diffusion test. Data showed that copolymer micelles present outstanding hemocompatibility and cytocompatibility, thus suggesting that P(CL/GA)-PEG micelles are promising for prolonged release of hydrophobic drugs.

Dioxin can cause a series of neural toxicological effects. MicroRNAs (miRs) play important roles in regulating nervous system function and mediating cellular responses to environmental pollutants, such as dioxin. Hsa-miR-146b-5p appears to be involved in neurodegenerative diseases and brain tumors. However, little is known about effects of dioxin on the expression of hsa-miR-146b-5p. We found that the hsa-miR-146b-5p expression and its promoter activity were significantly increased in dioxin treated SK-N-SH cells, a human-derived neuroblastoma cell line. Potential roles of hsa-miR-146b-5p in mediating neural toxicological effects of dioxin may be due to the regulation of certain target genes. We further confirmed that hsa-miR-146b-5p significantly suppressed acetylcholinesterase (AChE) activity and targeted the 3'-untranslated region of the AChE T subunit, which has been down-regulated in dioxin treated SK-N-SH cells. Functional bioinformatic analysis showed that the known and predicted target genes of hsa-miR-146b-5p were involved in some brain functions or cyto-toxicities related to known dioxin effects, including synapse transmission, in which AChE may serve as a responsive gene for mediating the effect.

Dioxin exposure is reported to affect nervous system development and increase the risk of neurodegenerative diseases. Generally, dioxin exerts its neurotoxicity via aryl hydrocarbon receptor (AhR). Neurofilament (NF) light (NFL) protein is a biomarker for both neuronal differentiation and neurodegeneration and its expression is controlled by the mitogen-activated protein kinase (MAPK) pathway. However, the effects of dioxin on NFL expression and involved mechanisms are incompletely understood. We aimed to investigate the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on NFL expression and elucidate the underlining signaling pathways and their potential crosstalk, specifically between MAPK and AhR pathway. We employed primary cultured rat cortical neurons to evaluate the effect of TCDD exposure on NFL expression. We also used nerve growth factor (NGF)-treated PC12 cells with specific inhibitors to investigate the involvement of and potential crosstalk between the MAPK pathway and the AhR pathway in mediating the effects of TCDD on NFL expression. After TCDD exposure, NFL mRNA and protein levels were upregulated in cultured neurons. NFL protein was preferentially found in the cell body compared with neurites of the cultured neurons. In PC12 cells, TCDD enhanced both NGF-induced NFL expression and phosphorylation of ERK1/2 and p38. The addition of MAPK-pathway inhibitors (PD98059 and SB230580) partially blocked the TCDD-induced NFL upregulation. CH223191, an AhR antagonist, reversed the upregulation of NFL and phosphorylation of ERK1/2 and p38 induced by TCDD. This study demonstrated TCDD-induced upregulation of NFL in cultured neurons, with protein retained in the cell body. TCDD action was dependent on activation of AhR and MAPK, while crosstalk was found between these two signaling pathways.

International audience; A series of poly(2-ethyl-2-oxazoline)-poly(L-lactide) (PEOz-PLA) diblock copolymers were synthesized by ring-opening polymerization of L-lactide using a monohydroxy terminated PEOz-OH macro-initiator in the presence of stannous octoate as catalyst. The resulting diblock copolymers were characterized by H-1 nuclear magnetic resonance and gel permeation chromatography. Self-assembled micelles were prepared using the co-solvent evaporation method in water and in phosphate buffered saline (PBS) at pH 7.4, 6.5 and 5.0. The resulting micelles exhibit different morphologies, such as spherical micelles and worm-like micelles depending on the hydrophilic/hydrophobic balance. Spherical micelles were exclusively observed for PEOz-PLA copolymers with short PLA blocks, whereas co-existence of worm-like and spherical micelles was observed for copolymers with long PLA blocks. The micelle size increases with decreasing pH due to the electrostatic repulsion between PEOz chains resulting from ionization of the tertiary amide groups along PEOz chains. A hydrophobic anti-tumor drug, paclitaxel, was entrapped in PEOz-PLA micelles. High loading efficiency up to 86.7% was obtained for copolymers with long PLA blocks. Drug release was performed in PBS at different pH values. During the 30-day release period, faster release was obtained for copolymers with shorter PLA blocks than for copolymers with longer PLA blocks, at acidic pH than at pH 7.4. It is thus concluded that pH-responsive PEOz-PLA copolymer micellss could be promising as carrier of anti-tumor drugs.

BACKGROUND Cornus officinalis (CO), also known as 'Shanzhuyu', is one of the most common traditional Chinese herbs used against osteoporosis. Although previous studies have found that CO has beneficial effects in alleviating osteoporosis, its mechanisms remain unclear. MATERIAL AND METHODS In this study, we applied system bioinformatic approaches to investigate the possible therapeutic mechanisms of CO against osteoporosis. We collected the active ingredients of CO and their targets from the TCMSP, BATMAN-TCM, and ETCM databases. Next, we obtained the osteoporosis targets from differentially expressed mRNAs from the Gene Expression Omnibus (GEO) gene series (GSE35958). Next, the shared genes of the CO pharmacological targets and osteoporosis-related targets were selected to construct the protein-protein interaction network, based on the results from the STRING database. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out by using the clusterProfiler package in R software. RESULTS In all, there were 58 unique CO compounds and 518 therapeutic targets. Based on the GO and KEGG enrichment results of 98 common genes, we selected the top 25 terms, based on the terms' P values. We found that the anti-osteoporotic effect of CO may mostly involve the regulation of calcium metabolism and reactive oxygen species, and the estrogen signaling pathway and osteoclast differentiation pathway. CONCLUSIONS We found the possible mechanisms of CO in treating osteoporosis may be based on multiple targets and pathways. We also provided a theoretical basis and promising direction for investigating the exact anti-osteoporotic mechanisms of CO.

This paper proposes a hybrid permanent-magnet memory motor. Using finite element method, the utility of AlNiCo and ferrite as low-coercive-force (LCF) magnets in the motor is comparatively analyzed. The results demonstrate that the positive magnetization of the ferrite magnets is difficult, while the field-variation range with the AlNiCo magnets is not sufficient, and the motor-power density and the positive magnetization characteristic of the LCF magnets cannot be improved simultaneously. On the other hand, the q -axis current may cause irreversible demagnetization in the LCF magnets, especially in the AlNiCo magnets. To solve the problems, an improved rotor topology with magnetic barriers is designed and considering that the demagnetization curve of ferrite magnets is mostly linear, ferrite magnets are used as the LCF magnets in the improved motor. Performance of the improved motor is analyzed and compared with that of the original configuration. Simulation results show that the positive magnetization characteristic of the ferrite magnets is significantly improved and the irreversible demagnetization in the ferrite magnets is avoided under load conditions. A prototype is fabricated and tested, verifying the analysis results.

A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry assay method was developed for simultaneous determination of ambroxol and salbutamol in human plasma using citalopram hydrobromide as internal standard (IS). The sample was alkalinized with ammonia water (33:67, v/v) and extracted by single liquid-liquid extraction with ethyl acetate. Separation was achieved on Waters Acquity UPLC BEH C18 column using a gradient program at a flow rate of 0.2 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring mode by monitoring the ion transitions m/z 378.9 → 263.6 (ambroxol), m/z 240.2 → 147.7 (salbutamol) and m/z 325.0 → 261.7 (IS). The total analytical run time was relatively short (3 min). Calibration curves were linear in the concentration range of 0.5-100.0 ng/mL for ambroxol and 0.2-20.0 ng/mL for salbutamol, with intra- and inter-run precision (relative standard deviation)

Emerging evidence suggests that perinatal dioxin exposure affects neurodevelopment and impairs multiple brain functions, including cognitive, language, learning and emotion, in the offspring. However, the impacts of gestational and lactational exposure to dioxin on behavior and related molecular events are still not fully understood. In this study, female C57BL/6J mice were orally administered three doses of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (0.1 or 10 μg/kg body weight (bw)) during the pregnancy and lactation periods. The locomotion, exploration and anxiety-related behaviors were examined by an open field test of the young adult female offspring at postnatal day 68. We found that the maternal TCDD exposure, particularly at a low dose, increased movement ability, novelty-exploration and certain anxiety-related behaviors in the offspring. Such hyperactivity-like behaviors were accompanied by the upregulation of certain genes associated with cholinergic neurotransmission or synaptogenesis in the offspring brain. In accordance with the potential enhancement of cholinergic neurotransmission due to the gene upregulations, the enzymatic activity of acetylcholinesterase was decreased, which might lead to excess acetylcholine and consequent hyper-excitation at the synapses. Thus, we found that gestational and lactational TCDD exposure at low dose caused hyperactivity-like behaviors in young adult female offspring and speculated the enhancement of cholinergic neurotransmission and synaptogenesis as potential molecular events underlying the neurobehavioral effects.

Acetylcholinesterase (EC3.1.1.7; AChE) is a key enzyme in the cholinergic system. Emerging evidence has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a typical persistent organic pollutant, suppressed neuronal AChE activity via dysregulation of different biosynthesis processes in human and rat neuronal cells. In the nervous system, astrocytes protect neurons from environmental pollutants. As a known target cell of TCDD, the astrocyte might be involved in TCDD effects on neuronal AChE. Therefore, in the present study, we found astrocyte-derived conditioned medium (ACM) could induce AChE activity preferentially in mature neurons in the absence of TCDD. The enzymatic activity of AChE was generally decreased in cultured cortical neurons upon direct treatment with TCDD (0.003–0.01 nM). This trend of changes in AChE activity was not significantly altered in immature neurons exposed to ACM produced in the presence of TCDD (TACM group), but reversed in mature neurons. Compared with effects of treatment with ACM plus TCDD (ACMT), a significant differential effect on AChE activity was found in the TACM group in response to TCDD treatment specifically in immature neurons, suggesting the presence of a TCDD-specific active component derived from the astrocyte. Inconsistent alterations in expression and enzymatic activities of the AChE T subunit (AChET) and the proline-rich membrane anchor (PRiMA) were found, suggesting that a mechanism of action beyond the transcriptional level might be involved. These data indicate that the astrocyte might play a protective role in TCDD-induced alterations of neuronal AChE in certain stages of differentiation.

Aryl hydrocarbon receptor (AhR) plays important roles in the interferences of dioxin exposure with the occurrence and development of tumors. Neuroblastoma is a kind of malignant tumor with high mortality and its occurrence is getting higher in dioxin exposed populations. However, there is still a lack of direct evidence of influences of dioxin on neuroblastoma cell migration. SK-N-SH is a human neuroblastoma cell line which has been used to reveal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced dysregulation of certain promigratory gene. Thus, in this study, we employed SK-N-SH cells to investigate the effects of TCDD on the spontaneous movement of neuroblastoma cells, which is a short-range cell migratory behavior related to clone formation and tumor metastasis in vitro. Using unlabeled live cell imaging and high content analysis, we characterized the spontaneous movement under a full-nutrient condition in SK-N-SH cells. We found that the spontaneous movement of SK-N-SH cells was inhibited after 36- or 48-h treatment with TCDD at relative low concentrations (10−10 or 2 × 10−10 M). The TCDD-treated cells were unable to move as freely as that of control cells, resulting in less diffusive trajectories and a decreased displacement of the movement. In line with this cellular effect, the expression of pro-adhesive genes was significantly induced in time- and concentration-dependent manners after TCDD treatment. In addition, with the presence of AhR antagonist, CH223191, the effects of TCDD on the gene expression and the spontaneous cell movement were effectively reversed. Thus, we proposed that AhR-mediated up-regulation of pro-adhesive genes might be involved in the inhibitory effects of dioxin on the spontaneous movement of neuroblastoma cells. To our knowledge, this is the first piece of direct evidence about the influence of dioxin on neuroblastoma cell motility.

Supplemental material, Appendix_B for Root cause analysis of epidural spinal cord stimulator implant infections with resolution after implementation of an improved protocol for surgical placement by Forest W Arnold, Sarah Bishop, David Johnson, LaShawn Scott, Crystal Heishman, Leah Oppy, Tyler Ball, Mayur Sharma, Claudia Angeli, Christie Ferreira, Yangsheng Chen, Susan Harkema and Maxwell Boakye in Journal of Infection Prevention

Acetylcholinesterase (AChE, EC 3.1.1.7) is a classical biomarker for monitoring contamination and intoxication of organophosphate (OP) and carbamate pesticides. In addition to these classical environmental AChE inhibitors, other organic toxic substances have been found to alter AChE activity in various species. These emerging organic AChE disruptors include certain persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs), and wildly used chemicals, most of which have received considerable public health concern in recent years. It is necessary to re-evaluate the environmental significances of AChE in terms of these toxic substances. Therefore, the present review is aiming to summarize correlations of AChE activity of certain organisms with the level of the contaminants in particular habitats, disruptions of AChE activity upon treatment with the emerging disruptors in vivo and in vitro, and action mechanisms underlying the effects on AChE. Over 40 chemicals belonging to six main categories were reviewed, including 12 POPs listed in the Stockholm Convention. AChE activity in certain organisms has been found to be well correlated with the contamination level of certain persistent pesticides and PAHs in particular habitats. Moreover, it has been documented that most of the listed toxic chemicals could inhibit AChE activity in diverse species ranging from invertebrates to mammals. Besides directly inactivating AChE, the mechanisms in terms of interference with the biosynthesis have been recognized for some emerging AChE disruptors, particularly for dioxins. The collected evidence suggests that AChE could serve as a potential biomarker for a diverse spectrum of organic environmental pollutants.

Carboxymethyl chitosan-graft-polylactide (CMCS-PLA) and carboxymethyl chitosan (CMCS) hydrogels were prepared by using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) as crosslinking agent and catalyst at room temperature. The biocompatibility of the hydrogels was evaluated with the aim of assessing their potential as drug carrier. Various aspects of biocompatibility were considered, including MTT assay, agar diffusion test, release of lactate dehydrogenase (LDH), hemolytic test, plasma recalcification time (PRT), and dynamic clotting time. MTT assay showed that the cytotoxicity level of both hydrogels to L-929 cells was 0 or 1. The LDH release of CMCS and CMCS-PLA was 26 and 29%, respectively, which is slightly higher than that of the negative control (21%) and much lower than that of the negative control (87%). The hemolysis ratio of CMCS and CMCS-PLA was 1.4 and 1.7%, respectively, suggesting outstanding anti-hemolysis properties of both materials. The PRT value of CMCS and CMCS-PLA was higher by 77 and 99% than the value of the positive control. All the results revealed that the hydrogels present good cytocompatibility and hemocompatibility in vitro. In vivo degradation and tissue compatibility were evaluated by subcutaneous injection in the dorsal area of rats. CMCS and CMCS-PLA hydrogels were completely degraded and the inflammatory response also completely disappeared around hydrogels after 19 days in vivo. It is thus concluded that hydrogels formed of CMCS and CMCS-PLA with outstanding biocompatibility are promising as potential drug carrier.

Polylactide-poly(ethylene glycol) (PLA-PEG) block copolymers were synthesized by ring opening polymerization of l-lactide using a monomethoxy PEG (mPEG) as macroinitiator and zinc lactate as catalyst. The resulting diblock copolymers were characterized by 1H NMR and GPC. Polymeric micelles were prepared by self-assembly of copolymers in distilled water using co-solvent evaporation or membrane hydration methods. The resulting micelles are worm-like in shape as shown by TEM measurements. A hydrophobic anticancer drug, cycloprotoberberine derivative A35, was successfully loaded in PLA-PEG filomicelles with high encapsulation efficiency (above 88%). Berberine (BBR) was studied for comparison. In both methods, PLA-PEG filomicelles were prepared with a theoretical loading of 5%, 10% and 20%. Physical stability studies indicated that BBR/A35-loaded filomicelles were more stable when stored at 4 °C than at 25 °C. Compared with BBR-loaded filomicelles, A35-loaded filomicelles exhibited higher antitumor activity. Importantly, the in vitro cytotoxicity and stability of A35-loaded filomicelles evidenced the potential of drug-loaded filomicelles in the development of drug delivery systems.

This paper presents an adaptive observer-based approach to improve the speed-tracking control performance in the permanent magnet synchronous motor drive system with unknown load torque and mechanical parameters. An adaptive observer is designed to estimate the load torque and the mechanical parameters. Using the stability analysis result of Popov theory, the proposed observer is restructured. Then, an adaptive torque feed-forward control is introduced to improve the system dynamic performance. The effectiveness of the proposed schemes is illustrated both by simulation and by experimental results.

Permanent magnet synchronous machines (PMSM) have been widely used in a variety of applications. A strong electromagnetic force exists between the rotor magnets and the stator core in a PMSM. The force directly causes mechanical deformation and vibration of the stator. In small PM motors, mechanical vibration comes mainly from the electromagnetic force of the stator. This paper gives the general expression of the frequency and corresponding mode number of radial force harmonics for a PMSM with a three-phase symmetrical double-layer winding. The paper shows that the lowest mode number of radial force harmonics is the greatest common divisor of pole number and slot number. The force harmonics with a low mode number can induce a high mechanical vibration, especially for PMSMs with a fractional slot combination. This is simulated using a weak-coupling electromagnetic-mechanical finite element model. To illustrate the influence of radial force harmonics with a low mode number on vibration, a method to eliminate the lowest mode number force harmonics for the fractional slot combination motor is proposed. A test rig for the 12-slot 8-pole prototype motor is set up. The experimental and simulated results confirm that force harmonics with low mode number have a major impact on vibration.

Several cohort studies have reported that dioxin and dioxin-like polychlorinated biphenyls might impair the nervous system and lead to neurological or neurodegenerative diseases in the elder people, but there is limited research on the involved mechanism. By using microarray analysis, we figured out the differentially expressed genes between brain samples from SD rats after low-dose (0.1μg/(kg▪bw)) dioxin exposure for six months and controls. To investigate the function changes in the course of dioxin exposure, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the differentially expressed genes. And the changes of several picked genes have been verified by real-time PCR. A total of 145 up-regulated and 64 down-regulated genes were identified. The metabolic processes, interleukin-1 secretion and production were significantly associated with the differentially expressed genes. And the genes regulated by dioxin also clustered to cholinergic synapse and long-term potentiation. Candidate biomarker genes such as egr1, gad2, gabrb3, abca1, ccr5 and pycard may be toxicological targets for dioxin. Furthermore, synaptic plasticity and neuro-immune system may be two principal affected areas by dioxin.