IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-06-23 DOI: 10.14573/altex.2003182

Stefanie Klima, Ilinca Suciu, Lisa Hoelting, Simon Gutbier, Tanja Waldmann, Daniel R Dietrich, Marcel Leist

{"title":"Examination of microcystin neurotoxicity using central and peripheral human neurons.","authors":"Stefanie Klima, Ilinca Suciu, Lisa Hoelting, Simon Gutbier, Tanja Waldmann, Daniel R Dietrich, Marcel Leist","doi":"10.14573/altex.2003182","DOIUrl":"https://doi.org/10.14573/altex.2003182","url":null,"abstract":"Microcystins (MC) are a group of cyanobacterial toxins that comprises MC-LF and other cyclic heptapeptides, best known as potent hepatotoxicants. Cell culture and epidemiological studies suggest that MC might also affect the nervous system when there is systemic exposure, e.g., via drinking water or food. We asked whether in vitro studies with human neurons could provide estimates on the neurotoxicity hazard of MC-LF. First, we used LUHMES neurons, a well-established test system for neurotoxicants and neuropathological processes. These central nervous system cells express OATP1A2, a presumed carrier of MC-LF, and we observed selective neurite toxicity in the μM range (EC20 = 3.3 μM ≈ 3.3 μg/mL). Transcriptome changes pointed towards attenuated cell maintenance and biosynthetic processes. Prolonged exposure for up to four days did not increase toxicity. As a second model, we used human dorsal root ganglia-like neurons. These peripheral nervous system cells represent parts of the nervous system not protected by the blood-brain barrier in humans. Toxicity was observed in a similar concentration range (EC20 = 7.4 μM). We conclude that MC-LF poses a potential neurotoxic hazard in humans. The adverse effect concentrations observed here were orders of magnitude higher than those presumed to be encountered after normal nutritional or environmental exposure. However, the low μM concentrations found to be toxic are close to levels that may be reached after very excessive algae supplement intake.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"73-81"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38090499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database. 测量实验室小鼠体内的内源性皮质酮——一个图谱回顾、荟萃分析和开源数据库。

IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-10-06 DOI: 10.14573/altex.2004221

Stevie Van der Mierden, Cathalijn H C Leenaars, Erin C Boyle, Florenza L Ripoli, Peter Gass, Mattea Durst, Vivian C Goerlich-Jansson, Paulin Jirkof, Lydia M Keubler, Steven R Talbot, Anne Habedank, Lars Lewejohann, Rene H Tolba, André Bleich

{"title":"Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database.","authors":"Stevie Van der Mierden, Cathalijn H C Leenaars, Erin C Boyle, Florenza L Ripoli, Peter Gass, Mattea Durst, Vivian C Goerlich-Jansson, Paulin Jirkof, Lydia M Keubler, Steven R Talbot, Anne Habedank, Lars Lewejohann, Rene H Tolba, André Bleich","doi":"10.14573/altex.2004221","DOIUrl":"https://doi.org/10.14573/altex.2004221","url":null,"abstract":"Evaluating stress in laboratory animals is a key principle in animal welfare. Measuring corticosterone is a common method to assess stress in laboratory mice. There are, however, numerous methods to measure glucocorticoids with differences in sample matrix (e.g., plasma, urine) and quantification techniques (e.g., enzyme immunoassay or radioimmunoassay). Here, the authors present a mapping review and a searchable database, giving a complete overview of all studies measuring endogenous corticosterone in mice up to February 2018. For each study, information was recorded regarding mouse strain and sex; corticosterone sample matrix and quantification technique; and whether the study covered the research theme animal welfare, neuroscience, stress, inflammation, or pain (the themes of specific interest in our consortium). Using all database entries for the year 2012, an exploratory meta-regression was performed to determine the effect of predictors on basal corticosterone concentrations. Seventy-five studies were included using the predictors sex, time-since-lights-on, sample matrix, quantification technique, age of the mice, and type of control. Sex, time-since-lights-on, and type of control significantly affected basal corticosterone concentrations. The resulting database can be used, inter alia, for preventing unnecessary duplication of experiments, identifying knowledge gaps, and standardizing or heterogenizing methodologies. These results will help plan more efficient and valid experiments in the future and can answer new questions in silico using meta-analyses.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"111-122"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38610091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Bottom-up physiologically-based biokinetic modelling as an alternative to animal testing. 自下而上的基于生理的生物动力学建模作为动物试验的替代方法。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2019-05-10 DOI: 10.14573/altex.1812051

James C Y Chan, Shawn P F Tan, Zee Upton, Eric C Y Chan

{"title":"Bottom-up physiologically-based biokinetic modelling as an alternative to animal testing.","authors":"James C Y Chan, Shawn P F Tan, Zee Upton, Eric C Y Chan","doi":"10.14573/altex.1812051","DOIUrl":"https://doi.org/10.14573/altex.1812051","url":null,"abstract":"There is a growing need for alternatives to animal testing to derive biokinetic data for evaluating both efficacy and safety of chemicals. One such alternative is bottom-up physiologically-based biokinetic (PBK) modeling which requires only in vitro data. The primary objective of this study is to develop and validate bottom-up PBK models of 3 HMG-CoA reductase inhibitors: rosuvastatin, fluvastatin and pitavastatin. Bottom-up PBK models were built using the Simcyp® Simulator by incorporating in vitro transporter and metabolism data (Vmax, Jmax, Km, CLint) obtained from the literature and proteomics-based scaling factors to account for differences in transporters expression between in vitro systems and in vivo organs. Simulations were performed for single intravenous, single oral and multiple oral dose of these chemicals. The results showed that our bottom-up models predicted systemic exposure (AUC0h-t), maximum plasma concentration (Cmax), plasma clearance and time to reach Cmax (Tmax) within two-fold of the observed data, with the exception of parameters associated with multiple oral pitavastatin dosing and single oral fluvastatin dosing. Additional middle-out simulations were performed using animal distribution data to inform tissue-to-plasma equilibrium distribution ratios for rosuvastatin and pitavastatin. This improved the predicted plasma-concentration time profiles but did not significantly alter the predicted biokinetic parameters. Our study demonstrates that quantitative proteomics-based mechanistic in vitro-to-in vivo extrapolation (IVIVE) could account for downregulation of transporters in culture and predict whole organ clearances without empirical scaling. Hence, bottom-up PBK modeling incorporating mechanistic IVIVE could be a viable alternative to animal testing in predicting human biokinetics.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"597-612"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37230375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Retrospective review of anesthetic and analgesic regimens used in animal research proposals. 动物研究方案中使用的麻醉和镇痛方案的回顾性回顾。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-09-14 DOI: 10.14573/altex.1804011

Kathrin Herrmann, Paul Flecknell

{"title":"Retrospective review of anesthetic and analgesic regimens used in animal research proposals.","authors":"Kathrin Herrmann, Paul Flecknell","doi":"10.14573/altex.1804011","DOIUrl":"https://doi.org/10.14573/altex.1804011","url":null,"abstract":"Pain has a profound effect on an animal's wellbeing. In Germany, researchers using animals have been legally required since 1972 to reduce any possible pain, suffering, distress or lasting harm to an absolute minimum. To evaluate how these provisions have been implemented in practice, an assessment of refinements to experimental techniques was conducted by retrospectively reviewing 684 surgical interventions described in 506 animal research applications that were sent to the German competent authorities for approval in 2010. This paper focuses on the efficacy of proposed anesthesia and peri- and postoperative analgesia. Postoperative analgesia was not proposed for 30 % of surgeries. Following 10 % of procedures, animals were to be given pain relieving medication if the investigators decided this was necessary; however, structured assessments to detect pain were absent. Consequences of unalleviated pain and omission of pain assessment techniques are discussed, and some recommendations to improve anesthesia and analgesia are given. The findings of this review highlight the need for improvement, both to fulfil legal requirements and to improve animal welfare. To monitor compliance with animal welfare regulations, and ensure good veterinary and scientific practices, education and training needs to be intensified. Adherence to the items listed in the PREPARE and ARRIVE guidelines and the Gold Standard Publication checklist (GSPC) should become legally binding.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"65-80"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36495038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 32

A three-dimensional model to study human synovial pathology. 研究人类滑膜病理的三维模型。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-10-09 DOI: 10.14573/altex.1804161

Mathijs G A Broeren, Claire E J Waterborg, Renske Wiegertjes, Rogier M Thurlings, Marije I Koenders, Peter L E M Van Lent, Peter M Van der Kraan, Fons A J Van de Loo

{"title":"A three-dimensional model to study human synovial pathology.","authors":"Mathijs G A Broeren, Claire E J Waterborg, Renske Wiegertjes, Rogier M Thurlings, Marije I Koenders, Peter L E M Van Lent, Peter M Van der Kraan, Fons A J Van de Loo","doi":"10.14573/altex.1804161","DOIUrl":"https://doi.org/10.14573/altex.1804161","url":null,"abstract":"Therapeutic agents that are used by patients with rheumatic and musculoskeletal diseases were originally developed and tested in animal models, and although retrospective studies show a limited predictive value, it could be explained by the fact that there are no good in vitro alternatives. In this study, we developed a 3-dimensional synovial membrane model made of either human primary synovial cell suspensions or a mix of primary fibroblast-like synoviocytes and CD14+ mononuclear cells. We analyzed the composition of the mature micromasses by immunohistochemical staining and flow cytometry and show that the outer surface forms a lining layer consisting out of fibroblast-like and macrophage-like cells, reflecting the in vivo naïve synovial membrane. To recreate the affected synovial membrane in rheumatoid arthritis (RA), the micromasses were exposed to the pro-inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α). This led to increased pro-inflammatory cytokine expression and production and to hyperplasia of the membrane. To recreate the synovial membrane in osteoarthritis (OA), the micromasses were exposed to Transforming Growth Factor Beta (TGF-β). This led to fibrosis-like changes of the membrane, including increased Alpha Smooth Muscle Actin and increased expression of fibrosis-related genes PLOD2 and COL1A1. Interestingly, the macrophages in the micromass showed phenotypic plasticity as prolonged TNF-α or TGF-β stimulation strongly reduced the occurrence of Cluster of Differentiation 163-positive M2-like macrophages. We showed the plasticity of the micromasses as a synovial model for studying RA and OA pathology and propose that the synovial lining micromass system can be a good alternative for testing drugs.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"18-28"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36571791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 25

Zebrafish embryo and acute fish toxicity test show similar sensitivity for narcotic compounds. 斑马鱼胚胎毒性试验和急性鱼类毒性试验显示对麻醉性化合物具有相似的敏感性。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-10-29 DOI: 10.14573/altex.1808101

Anita Birke, Stefan Scholz

引用次数: 8

Activation of TRPA1 by volatile organic chemicals leading to sensory irritation. 挥发性有机化学物质激活TRPA1导致感觉刺激。

ALTEX Pub Date : 2019-01-01 Epub Date: 2019-04-18 DOI: 10.14573/altex.1811012

Jeanelle M Martinez, Thomas E Eling

{"title":"Activation of TRPA1 by volatile organic chemicals leading to sensory irritation.","authors":"Jeanelle M Martinez, Thomas E Eling","doi":"10.14573/altex.1811012","DOIUrl":"10.14573/altex.1811012","url":null,"abstract":"Many volatile organic chemicals (VOCs) have not been tested for sensory pulmonary irritation. Development of in vitro non-animal sensory irritation assay suitable for a large number of chemicals is needed to replace the mouse assay. An adverse outcome pathway (AOP) is designed to provide a clear description of the biochemical and cellular processes leading to toxicological effects or an adverse outcome. The AOP for chemical sensory pulmonary irritation was developed according to the Organization for Economic Co-operation and Development guidance including the Bradford Hill criteria for a weight of evidence to determine the confidence of the AOP. The proposed AOP is based on an in-depth review of the relevant scientific literature to identify the initial molecular event for respiratory irritation. The activation of TRPA1 receptor (transient receptor potential cation channel, subfamily A, member 1) is the molecular initial event (MIE) leading to sensory irritation. A direct measure of TRPA1 activation in vitro should identify chemical sensory irritants and provide an estimate of potency. Fibroblasts expressing TRPA1 are used to determine TRPA1 activation and irritant potency. We report a linear relationship between the in vivo RD₅₀ and the in vitro pEC₅₀ values (R=0.81) to support this hypothesis. We propose that this in vitro assay after additional analysis and validation could serve as a suitable candidate to replace the mouse sensory irritation assay.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"572-582"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829608/pdf/nihms-1529994.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37188660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemical concentrations in cell culture compartments (C5) - concentration definitions. 细胞培养室中的化学浓度(C5) .浓度定义

IF 5.6

ALTEX Pub Date : 2019-01-01 DOI: 10.14573/altex.1901031

Jaffar Kisitu, Susanne Hougaard Bennekou, Marcel Leist

{"title":"Chemical concentrations in cell culture compartments (C5) - concentration definitions.","authors":"Jaffar Kisitu, Susanne Hougaard Bennekou, Marcel Leist","doi":"10.14573/altex.1901031","DOIUrl":"https://doi.org/10.14573/altex.1901031","url":null,"abstract":"Some laboratory issues are taken for granted as they seem to be simple and not worth much thought. This applies to \"concentrations of a chemical tested for bioactivity/toxicity\". Can there be any issue about weighing a compound, diluting it in culture medium and calculating the final mass (or particle number)-to-volume ratio? We discuss here some basic concepts about concentrations and their units, addressing also differences between \"dose\" and \"concentration\". The problem of calculated nominal concentrations not necessarily corresponding to local concentrations (relevant for biological effects of a chemical) is highlighted. We present and exemplify different concentration measures, for instance those relying on weight, volume, or particle number of the test compound in a given volume; we also include normalizations to the mass, protein content, or cell number of the reference system. Interconversion is discussed as a major, often unresolved, issue. We put this into the context of the overall objective of defining concentrations, i.e., the determination of threshold values of bioactivity (e.g., an EC50). As standard approach for data display, the negative decadic logarithm of the molar concentrations (-log(M)) is recommended here, but arguments are also presented for exceptions from such a rule. These basic definitions are meant as a foundation for follow-up articles that examine the concepts of nominal, free, and intracellular concentrations to provide guidance on how to relate in vitro concentrations to in vivo doses by in vitro-to-in vivo extrapolation (IVIVE) in order to advance the use of new approach methods (NAM) in regulatory decision making.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"154-160"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36854879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

The HaCaT/THP-1 Cocultured Activation Test (COCAT) for skin sensitization: a study of intra-lab reproducibility and predictivity. HaCaT/THP-1共培养激活试验(COCAT)用于皮肤致敏:实验室内可重复性和预测性的研究

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2019-05-27 DOI: 10.14573/altex.1905031

Chantra Eskes, Jennifer Hennen, Mario T Schellenberger, Sebastian Hoffmann, Sabine Frey, Daniela Goldinger-Oggier, Niklas Peter, Erwin Van Vliet, Brunhilde Blömeke

{"title":"The HaCaT/THP-1 Cocultured Activation Test (COCAT) for skin sensitization: a study of intra-lab reproducibility and predictivity.","authors":"Chantra Eskes, Jennifer Hennen, Mario T Schellenberger, Sebastian Hoffmann, Sabine Frey, Daniela Goldinger-Oggier, Niklas Peter, Erwin Van Vliet, Brunhilde Blömeke","doi":"10.14573/altex.1905031","DOIUrl":"https://doi.org/10.14573/altex.1905031","url":null,"abstract":"The Cocultured Activation Test (COCAT) consists of cocultured HaCaT (human keratinocyte cell line) and THP-1 cells (surrogate of antigen presenting cells). Individually, these cell lines are used to address key event 2 and 3 of the skin sensitization Adverse Outcome Pathway (AOP). Their exposure in coculture was found to have the potential to increase their response to sensitizing chemicals, enable the detection of pro-haptens and support the identification of skin sensitization potency. The present study was undertaken to assess the predictive capacity of COCAT to both skin sensitization hazard and potency and to assess the intra-laboratory reproducibility of COCAT based on the blind testing of chemicals. Results showed a reproducibility between runs of 80 % for 15 coded chemicals. 100 % sensitivity (9/9), 75 % specificity (3/4) and 92.3 % accuracy (12/13) was found for skin sensitization hazard prediction, while the tests of two chemicals were inconclusive. Including additional chemicals tested during the optimization phase in addition to the blind tested chemicals, the skin sensitization UN GHS sub-categories were correctly predicted for 85.7 % (12/14) Sub-category 1A chemicals, 83.3 % (10/12) Sub-category 1B chemicals and 92.3 % (12/13) 'No Category' chemicals, resulting in an overall accuracy of 87.4 % (34/39). The present study shows the COCAT to be a promising method for the identification of skin sensitization hazard and potency sub-categorization according to the UN GHS classification.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"613-622"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37276269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Botulinum toxin testing on animals is still a Europe-wide issue. 对动物进行肉毒杆菌毒素检测仍然是一个欧洲范围内的问题。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-10-10 DOI: 10.14573/altex.1807101

Katy Taylor, Corina Gericke, Laura Rego Alvarez

{"title":"Botulinum toxin testing on animals is still a Europe-wide issue.","authors":"Katy Taylor, Corina Gericke, Laura Rego Alvarez","doi":"10.14573/altex.1807101","DOIUrl":"https://doi.org/10.14573/altex.1807101","url":null,"abstract":"There have been significant developments in the use of animals to test Botulinum toxin products in Europe in recent years. This paper summarises and discusses these from the perspective of the animal protection organisation. A cell-based assay has been validated by Allergan and is now being used for the replacement of the mouse bioassay for the batch testing of their Botulinum toxin A products. Two further companies (Merz and Ipsen) have recently validated similar cell-based assays to replace animals in their batch testing. However, the number of animals being used in batch tests across Europe remains at record levels; an estimated 400,000 animals per year, based on official statistics and non-technical summaries. There are concerns from animal protection organisations about the authorisation of animal testing for Botulinum toxin products that are to be used for aesthetic purposes. Furthermore, should testing for companies that have not yet implemented the alternative method continue to be permitted under the EU Directive 2010/63 on the use of animals for scientific purposes? Whilst we are on the cusp of an era where the mouse bioassay has been replaced for the potency testing of Botulinum toxin A for injection, it is important that Europe sees a reduction of animal testing in real terms.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"81-90"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36571792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

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