Frontiers in drug discovery最新文献

{"title":"Novel and emerging therapies in pulmonary arterial hypertension","authors":"S. Cassady, Danielle Soldin, G. Ramani","doi":"10.3389/fddsv.2022.1022971","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1022971","url":null,"abstract":"Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure exceeding 20 mmHg with a pulmonary vascular resistance of 3 or more Wood units, is an incurable and progressive condition. The cornerstone of PAH treatment is pulmonary vasodilators, which act on the pulmonary vasculature to reduce pulmonary pressures and pulmonary vascular resistance and prevent progression to right heart failure. The number of available pulmonary vasodilator therapies has grown markedly in the last 10 years, alongside a rapidly expanding body of literature establishing strategies for their use. Up-front combination therapy, typically with two pulmonary vasodilator medications, has become the standard of care based on landmark trials showing superior outcomes over single therapies alone. Complex risk stratification matrices have begun to see widespread use as tools with which to guide changes in PAH therapies for individual patients. Strategies for using the pulmonary vasodilators in common use continue to be evaluated in trials exploring concepts such as up-front triple combination therapy and substitution of vasodilators for patients not meeting therapeutic goals. Alongside established pulmonary vasodilator therapies for PAH, there is a broad spectrum of experimental therapies that are being studied for the disease. These include both more conventional medications that act on pathways targeted by existing vasodilator therapies as well as non-vasodilator treatments with novel methods of action, that may act both to vasodilate and to address the detrimental changes of pulmonary arterial and right ventricular remodeling. Many of these emerging medications are the focus of active phase 2 and 3 trials. Finally, there has been significant interest in therapeutic pathways that are well established in left heart failure, with the hope of adapting strategies that may be efficacious in PAH and right heart failure as well. These include explorations of pathways treated by goal-directed medical therapy as well as device therapies such as pacing, resynchronization therapy, and cardiac monitoring devices. Many of these options show promise and may represent a complementary approach to treatment of PAH, allowing for multimodal therapy alongside pulmonary vasodilators to improve patient outcomes.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46595177","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}

{"title":"In silico mapping of the dynamic interactions and structure-activity relationship of flavonoid compounds against the immune checkpoint programmed-cell death 1 pathway","authors":"G. Sartori, Aline Albuquerque, Andrielly Santos-Costa, Luca Milério Andrade, D. Almeida, E. Gaieta, J. Sampaio, V. Albuquerque, João Hermínio Martins da Silva","doi":"10.3389/fddsv.2022.1032587","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1032587","url":null,"abstract":"Flavonoids are a class of natural products widely available in medicinal and dietary plants. Their pharmacological use has shown the potential to reduce the risk of different types of cancer, among other prevalent diseases. Their molecular scaffold inhibits the PD-1/PD-L1 axis, an important pathway related to the adaptive immune resistance of cancer cells already targeted for developing new cancer immunotherapy. However, despite the availability of kinetic and thermodynamic experimental data on the flavonoid–PD-1/PD-L1 interaction, there is still a lack of reliable information about their binding mode at the atomic level. Thus, we aimed to computationally predict the binding mode of flavonoid molecules with PD-1 and/or PD-L1 proteins using unbiased computational methodologies such as blind docking and supervised molecular dynamics simulation. The molecular interactions and dynamics of these predicted poses of protein-flavonoid complexes were further analyzed through multiple molecular dynamics simulations. This information, corroborated with the IC50 and KD values from available literature, was used to perform molecular matched-pair analysis to comprehensively describe the main interactions governing the inhibition of the complex PD-1/PD-L1 by the flavonoid scaffold. By analyzing the effect of substitutions in such a scaffold, we observed a clear correspondence with literature binding assays. Thus, we propose, for dimeric PD-L1, that the 7-O-glucoside forces the molecule displacement in the dimer interface. Furthermore, the 3-OH plays an essential role in stabilizing the buried binding mode by water-bridged hydrogen bonds with Asp122 and Gln66 in both extremities of the pocket. In PD-1, we suggest that flavonoids could bind through the BC loop by inducing a flip of Phe56 after a conformational change of the Asn58 glycosylation. Hence, our results introduced unprecedented information on flavonoid interaction and dynamics when complexed with PD-1 checkpoint pathway proteins and can pave the road for developing new flavonoid derivatives with selective anticancer activity.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45787273","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}

{"title":"Zingiber officinale (Ginger) as a treatment for inflammatory bowel disease: A review of current literature","authors":"Fatemeh Sadeghi Poor Ranjbar, F. Mohammadyari, Atharzahra Omidvar, Farhad Nikzad, Nooria Doozandeh Nargesi, Majid Varmazyar, Soroush Dehghankar, Fatemeh Vosoughian, Sepehr Olangian-Tehrani, Sepehr Nanbakhsh, Tina Mansourian, N. Deravi, Zohreh Tutunchian, Mehrnaz Salahi, Mohadeseh Poudineh, Hani Ghayyem","doi":"10.3389/fddsv.2022.1043617","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1043617","url":null,"abstract":"Inflammatory bowel disease (IBD) is a term used for a variety of conditions involving persistent inflammation of the digestive system. Ulcerative colitis (UC) and Crohn’s disease (CD) are examples of IBD. There were some treatments like Amino salicylates, glucocorticoids, immunosuppressants, antibiotics, and surgery which have been used for treating IBD. However, the short and long-term disabling adverse effects, like nausea, pancreatitis, elevated liver enzymes, allergic reactions, and other life-threatening complications remain a significant clinical problem. On the other hand, herbal medicine, believed to be safer, cheaper, and easily available, has gained popularity for treating IBD. Nowadays, Ginger, the Rizhome of Z. officinale from the Zingiberaceae family, one of the most commonly used fresh spices and herbs, has been proposed as a potential option for IBD treatment. According to upper issues, IBD treatment has become one of the society’s concerns. So, this review aims to summarize the data on the yin and yang of ginger use in IBD treatment.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44737458","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}

{"title":"The landscape of nature-derived antimalarials-potential of marine natural products in countering the evolving Plasmodium","authors":"Cherish Prashar, N. Thakur, Soumyananda Chakraborti, Syed Shah Areeb Hussain, K. Vashisht, K. Pandey","doi":"10.3389/fddsv.2022.1065231","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1065231","url":null,"abstract":"Malaria poses several challenges to the global research community on both diagnostic and therapeutic fronts. Most prominent of them are deletion of target genes (pfhrp2/3) used in rapid diagnostic tests (RDTs) and the emergence of resistance against frontline antimalarials by the evolving parasite. Exploration of novel therapeutics for malaria in view of limited vaccine options is a promising resort for malaria control and elimination. The scope of marine-derived chemotherapeutics is exciting, with a significant number of FDA-approved drugs or therapeutic leads under clinical trials for other diseases. This review article discusses the significant antimalarial potential of marine-derived natural products extracted from diverse biota including sponges, bacteria, sea hare and algae etc. Bioassay-guided fractionation of raw extracts from marine organisms for lead identification and further structural characterization of purified compounds compose a sustainable marine-derived drug discovery pipeline; which can be particularly diverted towards the exploration of antimalarials. It is to be noted that the Indian peninsula is largely unexplored, particularly for antimalarials screening; which has a huge marine biodiversity owing to the three distinct water bodies- Bay of Bengal, Indian Ocean and Arabian sea. This review also envisions a collaborative initiative to explore the potential of marine natural products in an economically feasible manner.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48810955","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}

{"title":"Coumarin-1,2,3-triazole hybrids as leading-edge anticancer agents","authors":"Krishna N. Mishra, Harish C. Upadhyay","doi":"10.3389/fddsv.2022.1072448","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1072448","url":null,"abstract":"Cancer is one of the most feared and dreaded diseases across the world. In clinical practice, a variety of anticancer agents of natural, semi-synthetic and synthetic origin exist, but they suffer from side effects and drug resistance, so they are insufficient to combat the disease. Coumarins are bicyclic benzene-pyrone-fused phytomolecules with a wide range of biological effects, including powerful anticancer activity on numerous cell lines. Additionally, they serve as an adaptable synthetic scaffold and research hub for medicinal chemists. On the other hand, triazoles are nitrogen-containing heterocycles having remarkable pharmacological effects including anticancer activities. Due to a better compatibility with the human metabolic system, the synthesis of nature inspired hybrid compounds as anticancer agents for a wide range of activity and fewer side effects is at the forefront of current research. In the last decade, huge research has been published on coumarin-1,2,3-triazole hybrids showing potent anticancer activities on various types of cancer. This review offers a recent, thorough literature compilation of contemporary research on the development of hybrid compounds based on coumarin-1,2,3-triazoles as potential anticancer leads throughout the previous 10 years. Graphical Abstract","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46604215","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}

{"title":"ASK120067 (limertinib) exerts pre-clinical anti-tumor activity by inhibiting EGFR exon20 insertion","authors":"Zhang Tao, Fang Feng, Lin-jiang Tong, Shingpan Chan, Yi Chen, Yan Li, Peiran Song, Yingqiang Liu, Gang Bai, Mengzhen Lai, Yi Ning, Yanan Wang, Yan-feng Fang, Zi-Xiang Pan, M. Geng, K. Ding, Jian Ding, Hua Xie","doi":"10.3389/fddsv.2022.1050687","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1050687","url":null,"abstract":"Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are classic strategies for the individualized treatment for patients with non-small cell lung cancer (NSCLC). However, EGFR exon20 insertion (EGFR 20ins) mutations, accounting for 6%–12% of all EGFR mutant cases in NSCLC, are generally resistant to the reversible EGFR TKIs (such as gefitinib and erlotinib), which makes them challenging drug-targets in lung cancer. In our previous study, we identified ASK120067 (limertinib) as a novel 3rd-generation EGFR TKI targeting EGFR T790M mutation with promising clinical activities. Here, we accessed the potency of ASK120067 on EGFR 20ins activation and evaluated its in vitro and in vivo anti-tumor activity against EGFR 20ins driven tumor models. We found that ASK120067 showed potent inhibitory activity on TKI-resistant EGFR 20ins kinase. In TKI-resistant EGFR 20ins-dependent BaF3 cells, it dose-dependently suppressed EGFR phosphorylation, impeded cell proliferation, and induced cell apoptosis with much superior efficacy to gefitinib and erlotinib. Moreover, oral administration of ASK120067 decreased the level of phospho-EGFR 20ins and caused significant tumor regression in EGFR 20ins BaF3 xenograft model. These results presented the pre-clinical anti-tumor efficacy of ASK120067 in EGFR 20ins models and highlighted the potential value of ASK120067 for the treatment of NSCLC patients harboring EGFR 20ins mutations.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44508724","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}

{"title":"Oxidized phospholipids are biomarkers, drug targets, and drug leads","authors":"O. Oskolkova, A. Birukova, K. Birukov, V. Bochkov","doi":"10.3389/fddsv.2022.1043708","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1043708","url":null,"abstract":"Enzymatic oxidation or autooxidation of esterified polyunsaturated fatty acids (PUFA) residues within phospholipids in cell membranes or circulating lipoprotein particles leads to the formation of a broad range of oxidized phospholipid (OxPL) species. Chronically elevated OxPL levels present in circulation and atherosclerotic plaques are thought to induce proinflammatory and injurious effects on blood- and vessel wall cells. However, analysis of the structure-activity relationship also identified specific OxPL products exhibiting prominent anti-inflammatory, pro-survival and barrier protective properties. This minireview will briefly summarize rapidly accumulating evidence pointing to the importance of OxPLs in pathology, where they can play multiple roles of biomarkers, drug targets and drug leads.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47728805","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}

{"title":"Artificial intelligence for antiviral drug discovery in low resourced settings: A perspective","authors":"Cyril T. Namba-Nzanguim, Gemma Turon, C. V. Simoben, I. Tietjen, L. Montaner, S. M. Efange, Miquel Duran-Frigola, F. Ntie‐Kang","doi":"10.3389/fddsv.2022.1013285","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1013285","url":null,"abstract":"Current antiviral drug discovery efforts face many challenges, including development of new drugs during an outbreak and coping with drug resistance due to rapidly accumulating viral mutations. Emerging artificial intelligence and machine learning (AI/ML) methods can accelerate anti-infective drug discovery and have the potential to reduce overall development costs in Low and Middle-Income Countries (LMIC), which in turn may help to develop new and/or accessible therapies against communicable diseases within these countries. While the marketplace currently offers a plethora of data-driven AI/ML tools, most to date have been developed within the context of non-communicable diseases like cancer, and several barriers have limited the translation of existing tools to the discovery of drugs against infectious diseases. Here, we provide a perspective on the benefits, limitations, and pitfalls of AI/ML tools in the discovery of novel therapeutics with a focus on antivirals. We also discuss available and emerging data sharing models including intellectual property-preserving AI/ML. In addition, we review available data sources and platforms and provide examples for low-cost and accessible screening methods and other virus-based bioassays suitable for implementation of AI/ML-based programs in LMICs. Finally, we introduce an emerging AI/ML-based Center in Cameroon (Central Africa) which is currently developing methods and tools to promote local, independent drug discovery and represents a model that could be replicated among LMIC globally.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47471427","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}

{"title":"Characterization of KLH-driven immune responses in clinical studies: A systematic review","authors":"Mahdi Saghari, M. A. Jansen, H. Grievink, R. Rissmann, M. Moerland","doi":"10.3389/fddsv.2022.992087","DOIUrl":"https://doi.org/10.3389/fddsv.2022.992087","url":null,"abstract":"The pharmacological activity assessment of novel immunomodulatory drugs in early-stage drug development is challenging as healthy volunteers do not express relevant immune biomarkers. Alternatively, the immune system can be challenged with keyhole limpet hemocyanin (KLH), a suitable antigen for studying adaptive immune responses. This report systemically reviews the KLH challenge in clinical studies focusing on the characterization of the KLH-driven systemic and local immune responses, identification of the KLH-induced biomarkers, and the evaluation of the effect of pharmacological interventions and diseases on the KLH response. A systematic literature review was carried out in PubMed spanning from 1967 to 2022. The systemic humoral KLH responses could be characterized by ELISA after 3 weeks following immunization. For the systemic cellular and molecular immune responses multiple KLH immunizations and the use of novel techniques such as flow cytometry and ELISpot yield optimal results. The objective evaluation of dermal KLH rechallenge allows for more accurate and sensitive quantification of the local response compared to subjective scoring. For the local cellular and molecular assays after KLH dermal rechallenge we also advocate the use of multiple KLH immunizations. Furthermore, oral KLH feeding, age, physical activity, alcohol consumption, stress, as well as certain auto-immune diseases also play a role in the KLH-induced immune response. Importantly, based on the KLH challenges, the effect of (novel) immunomodulatory drugs could be demonstrated in healthy volunteers, providing valuable information for the clinical development of these compounds. This review underlines the value of KLH challenges in clinical studies, but also the need for standardized and well-controlled methodology to induce and evaluate KLH responses. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022335419","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41554473","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}

{"title":"Network pharmacology and molecular docking to explore Siraitia grosvenorii’s potential mechanism in preventing and treating proliferative diabetic retinopathy","authors":"Yehong Zhou, Fuxing Shu, S. Sarsaiya, Hu Jiang, Chengyan Jiang, Ting Qu, Ruixia Wang","doi":"10.3389/fddsv.2022.1038224","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1038224","url":null,"abstract":"Although Siraitia grosvenorii (abbreviated as S.g.) is frequently used to prevent and cure diabetes problems, the precise mechanism underlying its ability to do so remains unknown. Through network pharmacology and molecular docking techniques, we studied the early molecular mechanisms of S.g in the treating of proliferative diabetic retinopathy (PDR) in this study. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen the active compounds and related targets of S.g. Oral bioavailability (OB) 30% and drug likeness (DL) 0.18 were used as screening criteria. The active compounds without knowledge of a probable target were excluded. The Uniprot database included converted symbols for the associated targets. GEO2R was used to explore several genes related to PDR. Using jvenn web service to intersect targets of S.g and PDR. The Xiantao Academic Online website was used to examine the expression patterns of intersect targets in PDR samples. The STRING database was used to create a protein-protein interaction (PPI) network of intersecting targets. Cytoscape software was used to show the PPI network, MCODE software was used to evaluate the network’s core proteins, and CytoHubba software was used to extract the important networks of the top three targets. Omicshare platform carried a functional analysis using the Gene Ontology (GO) and pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Pymol, AutoDock Vina software, Schrödinger Software were used to conduct molecular docking experiments or pockets search on the top three targets. The results showed that 85 targets were matched to six active compounds of S.g. 18 intersect targets were found. Seven DEGs were up-regulated and eleven genes were down-regulated when these targets were divided into two groups. TNF, PTGS2, and CASP3 were the main targets, according to the PPI network. The intersect targets were mostly related to angiogenesis, cell proliferation, oxidative stress, inflammatory response, and metabolism. It was discovered that the core targets TNF, PTGS2, and CASP3 had various levels of affinity for their respective compounds. Interestingly, multiple good drug-forming pockets for CASP3 and PTGS2 targets were identified through Schrödinger software. In particular, six compounds bind to the top three core targets to inhibit IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, Pathways in cancer and 14 other signaling pathways to inhibit inflammation, apoptosis, oxidative stress, arachidonic acid metabolism, and angiogenesis to prevent and treat PDR. The study’s findings, which served as a guide for the widespread use of S.g in PDR clinical practise, included multi-substances and targets of S.g to prevent and cure PDR.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49473467","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}