{"title":"Isocoumarins from <i>Spegazzinia</i> sp. MDCW-573 with Antibacterial and Proangiogenic Activities.","authors":"Cong Wang, Hui Xu, Jianjian Wang, Caixia Wei, Shengyan Zheng, Rui Xu, Shiyi Wang, Zilin Li, Peihai Li, Fandong Kong","doi":"10.1021/acs.jnatprod.4c01437","DOIUrl":"10.1021/acs.jnatprod.4c01437","url":null,"abstract":"<p><p>Twelve new isocoumarins, spegazmarins A-L (<b>1</b>-<b>12</b>), including nine novel dimeric derivatives (<b>1</b>-<b>9</b>), three monomeric derivatives (<b>10</b>-<b>12</b>), as well as eight known ones (<b>13</b>-<b>20</b>), were isolated from the endophytic fungus <i>Spegazzinia</i> sp. MDCW-573. Their structures were elucidated by analysis of NMR, X-ray crystallography, and ECD data. Notably, the dimeric isocoumarins (<b>1</b>-<b>9</b>) possess a unique linkage, where the phenyl of one monomer is connected to the lactone of another. The methods for determining the configurations of both the monomeric and dimeric isocoumarins within this class were proposed, leading to the correction of the configurations of two previously reported isocoumarins. The isolated compounds inhibited <i>Staphylococcus aureus</i>, <i>Escherichia coli</i>, and <i>Pseudomonas aeruginosa</i>, with MIC values of 1 to 64 μg/mL. Compounds <b>5</b>, <b>6</b>, and <b>12</b> significantly promoted the growth of zebrafish intersegmental vessels at concentrations of 10, 20, and 40 μM, respectively.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"757-767"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ângela Brito, Teresa Martins, Sara Freitas, Raquel Castelo Branco, Adriana Rego, Vitor M Vasconcelos, William H Gerwick, Paula Tamagnini, Pedro N Leão
{"title":"Isolation and Biosynthesis of Hyellamide, a Glycosylated N-Acyltyrosine Derivative, from the Cyanobacterium <i>Hyella patelloides</i> LEGE 07179.","authors":"Ângela Brito, Teresa Martins, Sara Freitas, Raquel Castelo Branco, Adriana Rego, Vitor M Vasconcelos, William H Gerwick, Paula Tamagnini, Pedro N Leão","doi":"10.1021/acs.jnatprod.4c00968","DOIUrl":"10.1021/acs.jnatprod.4c00968","url":null,"abstract":"<p><p>Recent analyses of genome data indicate that members of the cyanobacterial order Pleurocapsales show tremendous potential for natural product discovery. However, only a few compounds have been reported from this order. Here, we report the isolation of hyellamide (<b>1</b>), a glycosylated N-acyl tyrosine-derived eneamide, from the pleurocapsalean cyanobacterium <i>Hyella patelloides</i> LEGE 07179. The putative biosynthetic gene cluster for <b>1</b> was identified in the genome of the producing organism and a biosynthetic proposal is presented. This work sheds light on the chemistry of the Pleurocapsales and expands the chemical repertoire of cyanobacterial natural products to include N-acyl tyrosine-derived molecules.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"850-856"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lydia J Davis, Aleksej Krunić, Kelsey Alexander, Manead Khin, Jared S Wood, Cody Earp, Manuel Rangel-Grimaldo, Alessandra S Eustáquio, Joanna E Burdette, R Thomas Williamson, Nicholas H Oberlies, Jimmy Orjala
{"title":"Menominin A and B: Cytotoxic Cyclodepsipeptides from the Freshwater Sponge-Associated Cyanobacterium <i>Nostoc</i> sp. UIC 10607.","authors":"Lydia J Davis, Aleksej Krunić, Kelsey Alexander, Manead Khin, Jared S Wood, Cody Earp, Manuel Rangel-Grimaldo, Alessandra S Eustáquio, Joanna E Burdette, R Thomas Williamson, Nicholas H Oberlies, Jimmy Orjala","doi":"10.1021/acs.jnatprod.4c01445","DOIUrl":"10.1021/acs.jnatprod.4c01445","url":null,"abstract":"<p><p>Menominin A (<b>1</b>) and B (<b>2</b>), two cyclodepsipeptides containing a 3,8-dihydroxy-2-methyltetradecanoic acid residue, were isolated from the freshwater sponge-associated cyanobacterium, <i>Nostoc</i> sp. UIC 10607, using bioactivity-guided and spectroscopic approaches. The planar structures of <b>1</b> and <b>2</b> were established using HRESIMS and one- and two-dimensional NMR experiments. Comparative genomic analysis revealed unique differences in the putative menominin biosynthetic gene cluster compared to that of the closely related cyanobacterial cyclic lipodepsipeptide, hapalosin, assisting in structure elucidation and highlighting the structural diversity of this class of compounds. Configuration assignments were determined using a combination of <i>J</i>-based configuration analysis, chiral HPLC, modified Mosher's ester analysis, and DFT calculations. Menominin A and B demonstrate antiproliferative bioactivity against the high-grade serous ovarian cancer cell line OVCAR3 (IC<sub>50</sub> = 3.1 (<b>1</b>) and 2.4 μM (<b>2</b>)). Menominin A and B are the first reported secondary metabolites from a freshwater sponge-associated cyanobacterium, underscoring the potential of freshwater sponges as a microbial culture source in natural product discovery.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"732-746"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"<i>laeA</i> Gene Introduction Strategy Enabling the Construction of a Prolific Fungal Secondary Metabolite Library.","authors":"Aoi Kimishima, Sota Honma, Satoshi Kato, Masako Honsho, Hiroki Kojima, Toshiyuki Tokiwa, Akihiro Sugawara, Kenichi Nonaka, Yasuko Araki, Tadashi Takahashi, Kotaro Ito, Yukihiro Asami","doi":"10.1021/acs.jnatprod.4c01317","DOIUrl":"10.1021/acs.jnatprod.4c01317","url":null,"abstract":"<p><p>LaeA is a putative nuclear methyltransferase protein that epigenetically influences secondary metabolite production in fungi. LaeA has drawn attention as one of the promising approaches to activate fungal chemical production, and the <i>laeA</i> gene has been introduced into some fungal strains with the aim of producing secondary metabolic changes mainly based on the evaluation of mycotoxicity. However, these studies were applied for limited fungal species, and its utility and versatility for broad fungal species remained unclear. In this study, 47 strains were selected composed of three different genera, <i>Pochonia</i> spp., <i>Gamszarea kalimantanensis</i>, and <i>Lecanicillium</i> spp., which have never been modified with the <i>laeA</i> gene. We obtained a total of 125 mutants with <i>laeA</i> genes for our fungal strain library. The chemical productivity and the biological activity of the library were analyzed, and two natural products, radicicol (<b>1</b>) and sch210972 (<b>2</b>), were isolated in more than 10-fold the yield of the parent strains.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"682-687"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xingxiang Chen, Ping Yi, Hang Lv, Mimi Zhang, Junwei Yang, Zengguang Zhang, Zhilong Zhao, Yu Mu, Li Han, Xueshi Huang
{"title":"Phenolics and Phenolic Glycosides from <i>Wrightia pubescens</i> and Their Hepatoprotective Activities.","authors":"Xingxiang Chen, Ping Yi, Hang Lv, Mimi Zhang, Junwei Yang, Zengguang Zhang, Zhilong Zhao, Yu Mu, Li Han, Xueshi Huang","doi":"10.1021/acs.jnatprod.4c01040","DOIUrl":"10.1021/acs.jnatprod.4c01040","url":null,"abstract":"<p><p>Thirty compounds including 13 new phenolic glycosides (<b>1</b>-<b>6</b>, <b>9</b>-<b>15</b>) and 17 known aromatic compounds and aromatic glycosides (<b>7</b>-<b>8</b>, <b>16</b>-<b>30</b>) were isolated from the roots of <i>Wrightia pubescens</i>. The structures of the new phenolic glycosides were established by extensive NMR spectroscopic data analysis as well as chemical derivatization method. The isolated compounds were evaluated for their hepatoprotective activities using cell model of acetaminophen (APAP)-induced HepG2 cells. The results indicated that phenolic glycosides (<b>2</b>, <b>4</b>, <b>5</b>, <b>7</b>, <b>8</b>, <b>11</b>, <b>13</b>) pretreatment enhanced the cells viability and reduced the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT). The hepatoprotective mechanism of a representative new compound, wrightioside D (<b>4</b>), was further investigated. Compound <b>4</b> exhibited hepatoprotective effects via reducing oxidative stress by attenuating ROS formation and inhibiting apoptosis in APAP-treated HepG2 cells.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"631-643"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"(±)-Feionemycin A and Chromonemycins A-D, Rearranged Aromatic Polyketides Uncovered by Type II Polyketide Gene Cluster Expression.","authors":"Xiaofei Huang, Xiao Xu, Luning Zhou, Jiayi Li, Chuanteng Ma, Wenxue Wang, Qian Che, Dehai Li, Tianjiao Zhu, Guojian Zhang","doi":"10.1021/acs.jnatprod.4c01433","DOIUrl":"10.1021/acs.jnatprod.4c01433","url":null,"abstract":"<p><p>Two novel spiro aromatic polyketides, (+)- and (-)-feionemycin A (<b>1</b>), along with four atypical angucyclinones named as chromonemycins A-D (<b>2</b>-<b>5</b>), were discovered through heterologous expression of a type II polyketide gene cluster, within which one previously characterized flavoprotein monooxygenase was deactivated. Among those structures, compound <b>1</b> features an unprecedented oxaspiro[5.4]undecane architecture, and compounds <b>2</b>-<b>5</b> represent novel atypical angucyclinone variants derived from unusual cyclization of the polyketide chains. The structures and absolute configurations were elucidated by NMR, MS, single-crystal X-ray diffraction, theoretical NMR calculations, DP4+ probability analysis, and ECD analyses. (+)-<b>1</b> showed cytotoxic activity against NCI-H446, with an IC<sub>50</sub> value of 2.26 μM.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"768-776"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Total Syntheses, Absolute Configuration, and Cytotoxicity Evaluation of Ugonins L, S, U, and Z from the Rhizomes of <i>Helminthostachys zeylanica</i>.","authors":"Cheng-Tin Lin, Jing-Jy Cheng, Huei-Ling You, Cheng-Hsun Hsieh, Chiao-Jou Pan, Ming-Jaw Don","doi":"10.1021/acs.jnatprod.4c01487","DOIUrl":"10.1021/acs.jnatprod.4c01487","url":null,"abstract":"<p><p>This study describes the first and efficient syntheses of naturally occurring ugonins L (<b>1a</b>), S (<b>2a</b>, <b>2b</b>), U (<b>3</b>), and Z (<b>4</b>). Naturally occurring ugonin S has two stereoisomers. On the basis of their NMR and specific rotation data, the absolute configuration of <i>trans</i>-ugonin L (<b>1a</b>) was determined as 10<i>R</i>,11<i>R</i>, while the absolute configurations of <i>trans</i>-ugonin S (<b>2a</b>) and <i>cis</i>-ugonin S (<b>2b</b>) were determined to be 10<i>R</i>,11<i>R</i> and 10<i>R</i>,11<i>S</i>, respectively. The naturally occurring <i>cis</i>-ugonin U (<b>3</b>) presented the 10<i>S</i>,11<i>R</i> configuration. The naturally occurring <i>cis</i>-ugonin Z (<b>4</b>) was suggested to have a 10<i>S</i>,11<i>R</i> configuration. Four isomers of compound <b>2</b> and two isomers of compound <b>3</b> showed moderate cytotoxic activities against the CEM and H460 human cancer cell lines.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"785-796"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Somporn Palasarn, Prattana Tanyapanyachon, Vanicha Vichai, Phongeun Sysouphanthong, Kevin D Hyde, Nattika Saengkrit, Masahiko Isaka
{"title":"Chromene Dimers from Cultures of Basidiomycete <i>Panus similis</i>.","authors":"Somporn Palasarn, Prattana Tanyapanyachon, Vanicha Vichai, Phongeun Sysouphanthong, Kevin D Hyde, Nattika Saengkrit, Masahiko Isaka","doi":"10.1021/acs.jnatprod.4c01475","DOIUrl":"10.1021/acs.jnatprod.4c01475","url":null,"abstract":"<p><p>Four chromene dimers, panusimilins A-D (<b>1</b>-<b>4</b>) (racemic mixtures), and two previously undescribed chromanes (<b>5a</b>/<b>5b</b> and <b>6a</b>/<b>6b</b>) were isolated from cultures of basidiomycete <i>Panus similis</i> TBRC-BCC 52578. Interestingly, synthetic compounds closely related to panusimilins A-C (<b>1</b>-<b>3</b>) were previously reported, which were produced by Lewis acid promoted dimerization of a plant-derived chromene, precocene II. In the present study, panusimilins were isolated from the culture broth extract of the fungus <i>P. similis</i>. The chromane monomers were shown to be a non-racemic mixture of enantiomers, and their absolute configurations were elucidated by conversion to Mosher ester derivatives. The isolated compounds were evaluated for their cytotoxic activities. Among them, 2,2-dimethyl-3,4,6-trihydroxychromane (<b>6a</b>/<b>6b</b>) showed selective activity to NCI-H187 cells (IC<sub>50</sub> 9.1 μM). On the other hand, panusimilin B (<b>2</b>) exhibited antioxidant activity in the DPPH radical scavenging assay (IC<sub>50</sub> 66 μM).</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"777-784"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dušan Goranovič, Branko Jenko, Barbara Ramšak, Ajda Podgoršek Berke, Leon Bedrač, Jaka Horvat, Martin Šala, Damjan Makuc, Guilhermina M Carriche, Luana Silva, Aleksandra Lopez Krol, Alen Pšeničnik, María Beatriz Durán Alonso, Martina Avbelj, Stojan Stavber, Janez Plavec, Tim Sparwasser, Rolf Müller, Gregor Kosec, Štefan Fujs, Hrvoje Petković
{"title":"Efficient and Selective Biosynthesis of a Precursor-Directed FK506 Analogue: Paving the Way for Click Chemistry.","authors":"Dušan Goranovič, Branko Jenko, Barbara Ramšak, Ajda Podgoršek Berke, Leon Bedrač, Jaka Horvat, Martin Šala, Damjan Makuc, Guilhermina M Carriche, Luana Silva, Aleksandra Lopez Krol, Alen Pšeničnik, María Beatriz Durán Alonso, Martina Avbelj, Stojan Stavber, Janez Plavec, Tim Sparwasser, Rolf Müller, Gregor Kosec, Štefan Fujs, Hrvoje Petković","doi":"10.1021/acs.jnatprod.4c00394","DOIUrl":"10.1021/acs.jnatprod.4c00394","url":null,"abstract":"<p><p>The medically important immunosuppressant FK506 is a structurally complex macrolactone biosynthesized by a combined polyketide synthase and a nonribosomal peptide synthetase enzyme complex. Its acyltransferase domain 4 (AT4) selects an unusual extender unit, resulting in an allyl moiety on carbon 21 of the macrolactone backbone. Based on the AT4 domain, chemobiosynthetic processes have been developed that enable the introduction of diverse moieties at the carbon 21 position. However, the novel moieties that were introduced into the polyketide backbone are chemically inert. Reported here is a novel and efficient chemobiosynthetic approach that ensures high titer of an FK506 analogue containing a propargyl moiety. The novel FK506 analogue displays lower immunosuppression activity than FK506 with significantly reduced cytotoxicity. More importantly, the propargyl moiety contains a terminal alkyl group, which makes click chemistry reactions possible; this approach may potentially be translated to other medically important drugs of polyketide origin.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"619-630"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Characterization of an Iterative Halogenase Acting on Ribosomal Peptides Underlies the Combinatorial Biosynthesis Logic of Lasso Peptides.","authors":"Jin-Long Lu, Jiao-Jiao Cui, Zhe-Yang Hu, Jin-Ming Di, Yuan-Yuan Li, Jiang Xiong, Yu-Meng Jiao, Kun Gao, Jian Min, Shangwen Luo, Shi-Hui Dong","doi":"10.1021/acs.jnatprod.4c01199","DOIUrl":"10.1021/acs.jnatprod.4c01199","url":null,"abstract":"<p><p>Halogenation is commonly utilized in medicinal chemistry for the improvement of drug leads. Flavin-dependent halogenases (FDHs) are ubiquitous across all domains of life, yet iterative FDHs are rare in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Herein, we characterize a novel iterative FDH, ChlH, which orchestrates nonsequential chlorination of two specific Trp within the core peptide of a lasso precursor containing three Trp. Biochemical and computational studies enable the characterization of ChlH, which employs unique protein-peptide interactions (PPIs) between its distinct N- and C-terminal motifs and a crucial recognition sequence (RS-II) downstream of RS-I in the leader peptide. Previous studies have demonstrated the indispensability of RS-I for lasso peptide biosynthesis, while RS-II was considered to be replaceable. Furthermore, we find that the core peptide substantially contributes to the PPI. Bioinformatic analysis reveals the prevalence of homologous FDHs in the biosynthetic gene clusters (BGCs) of various RiPP classes. Heterologous expression of the <i>chl</i> BGC yields non-, mono-, and dichlorinated lasso peptides, with chlorination, particularly dichlorination, enhancing their antibacterial activity. This study expands the FDH activity spectrum to include iterative catalysis on ribosomal peptides and underscores the significance of RS-II in tailoring enzymes for the combinatorial biosynthesis of lasso peptides.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"650-661"},"PeriodicalIF":3.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}