RSC Chemical Biology最新文献

{"title":"Efficient synthesis of O-glycosylated amino acids†","authors":"Felicity J. Frank, Rebecca A. Lawson and Tom E. McAllister","doi":"10.1039/D5CB00076A","DOIUrl":"10.1039/D5CB00076A","url":null,"abstract":"<p >Protein glycosylation is one of the most abundant and complex post-translational modifications, necessitating many different approaches to fully understand the biological effects. Investigation using synthetic glycopeptides is limited by the high cost of building blocks; typically &gt;100<em>x</em> more than other modified amino acids <em>e.g.</em> phosphorylation. We report a simple, low cost route to <em>O</em>-glycosylated amino acids suitable for Fmoc-SPPS in two or three steps starting from peracetylated sugars. One set of reagents can furnish either the α- or β-anomer through adjusting the equivalents and reaction time. Depending on the derivative, the cost of our route is 25–60× less than commercial alternatives and offers scope for producing modified analogues. Overall, this is a convenient and user-friendly approach to access <em>O</em>-glycosylated amino acids, urgently required for continued investigation of the manifold roles of glycosylation in biology.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 851-856"},"PeriodicalIF":4.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081243","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}

{"title":"Exploring substitution effects on the potential dominant conformations of NBF derivatives leading to functional conversion at the mu opioid receptor†","authors":"Ennian Li, Ahmed Reda, Hongguang Ma, Samuel Woodard, James C. Gillespie, Dana E. Selley, William L. Dewey, Piyusha P. Pagare and Yan Zhang","doi":"10.1039/D5CB00036J","DOIUrl":"10.1039/D5CB00036J","url":null,"abstract":"<p >We previously identified NBF (β-configuration at C6) and its 6α-counterpart as mu opioid receptor (MOR) antagonists. To explore the effect of C6 conformation of the epoxymorphinan ring on their MOR function, five pairs of NBF derivatives bearing both 6α and 6β configurations with substitutions on the 3′-position of the benzofuran ring were synthesized. <em>In vitro</em> and <em>in vivo</em> studies demonstrated that compounds carrying phenyl and 4-pyridine substituents retained their antagonistic properties independent of the C6 configuration. Halogen and methyl substituents with the 6α-configuration remained as MOR antagonists, while their 6β-counterparts switched to MOR agonists. Molecular modeling studies indicated that the C6 configuration and structural modification may collectively decide the orientation of the benzofuran ring, leading to conformation retention or a switch within the MOR binding pocket. These results together aid the understanding of the NBF structure–activity relationship (SAR) and provide insights for functional conversion at the MOR, supporting future endeavors to develop novel MOR ligands.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 7","pages":" 1115-1125"},"PeriodicalIF":4.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143920","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}

{"title":"Exploring sequence- and structure-based fitness landscapes to enhance thermal resistance and activity of endoglucanase II with minimal experimental effort†","authors":"Atul Kumar, Alexander-Maurice Illig, Nicolas de la Vega Guerra, Francisca Contreras, Mehdi D. Davari and Ulrich Schwaneberg","doi":"10.1039/D5CB00013K","DOIUrl":"10.1039/D5CB00013K","url":null,"abstract":"<p >Enhancing the performance of cellulases at high temperatures is crucial for efficient biomass hydrolysis—a fundamental process in biorefineries. Traditional protein engineering methods, while effective, are time-consuming and labour-intensive, limiting rapid advancements. To streamline the engineering process, we tested two distinct <em>in silico</em> methods for predicting thermally resistant and highly active variants of <em>Penicillium verruculosum</em> endoglucanase II. Specifically, we used FoldX to pinpoint structure-stabilizing substitutions (ΔΔ<em>G</em> &lt; 0) and applied the sequence-based method EVmutation to identify evolutionarily favorable substitutions (Δ<em>E</em> &gt; 0). Experimental validation of the top 20 ranked single-substituted variants from both methods showed that EVmutation outperformed FoldX, identifying variants with enhanced enzyme activity after one-hour incubation at 75 °C (up to 3.6-fold increase), increased melting temperature (Δ<em>T</em><small>_m</small> of 2.8 °C), and longer half-lives at 75 °C (up to 104 minutes <em>vs.</em> 40 minutes for the wild type). Building upon these results, EVmutation was used to predict variants with two amino acid substitutions. These double-substituted endoglucanase variants showed further improvements—up to a 4.4-fold increase in activity, Δ<em>T</em><small>_m</small> gains of 3.7 °C, and half-life extensions up to 82 minutes. This study highlights EVmutation's potential for accelerating protein engineering campaigns and enhancing enzyme properties while reducing experimental efforts, thereby contributing to more efficient and sustainable bioprocesses.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 975-986"},"PeriodicalIF":4.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095224","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}

{"title":"Co-delivery of antigen and adjuvant by site-specific conjugation to dendritic cell-targeted Fab fragments potentiates T cell responses†","authors":"Zacharias Wijfjes, Iván Ramos Tomillero, Camille M. Le Gall, Eric A. W. van Dinther, Frederique Turlings, René Classens, Saikat Manna, Duco van Dalen, Ruud J. R. W. Peters, Kayleigh Schouren, Felix L. Fennemann, Iris M. Hagemans, Floris J. van Dalen, Johan M. S. van der Schoot, Carl G. Figdor, Aaron Esser-Kahn, Ferenc A. Scheeren and Martijn Verdoes","doi":"10.1039/D5CB00014A","DOIUrl":"10.1039/D5CB00014A","url":null,"abstract":"<p >The aim of therapeutic cancer vaccines is to induce tumor-specific cellular immune responses. This requires tumor antigens to be efficiently processed and presented by antigen-presenting cells, in particular dendritic cells (DCs). In addition, DCs require maturation to upregulate the surface expression and secretion of T cell costimulatory molecules, which is achieved by co-administration of adjuvants in vaccines. Peptide-based antigen vaccination is an attractive strategy due to the established biocompatibility of peptides as well as the dosing control. To enhance the efficacy of peptide-based vaccines, antigens can be targeted to DCs. Antigen–adjuvant conjugates are known to enhance T cell activation by ensuring DC maturation upon antigen delivery. In this study, we aim to combine these two approaches in a single molecule, and present a DC-targeted antibody fragment–antigen–adjuvant (AAA)-conjugate. We generate the AAA-conjugate through a combination of site-specific sortase-mediated chemoenzymatic ligation and click chemistry. <em>Ex vivo</em> T cell activation assays show enhanced efficacy of the AAA-conjugate compared to non-adjuvanted control conjugates. The <em>in vivo</em> performance of the AAA-conjugate was suboptimal, which we hypothesize to be a consequence of the hydrophobic character of the conjugate. <em>In vivo</em> efficacy was rescued by co-administration of antibody fragment–antigen conjugates and antibody fragment-adjuvant conjugates, in which the antigen and adjuvant were separatedly delivered using two different DC-targeting molecules. In conclusion, this study provides a proof-of-concept for effective <em>in vivo</em> antigen-specific T cell activation by targeted delivery of both antigen and adjuvant to DCs in a single or separate molecule using site-specific protein engineering.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 948-962"},"PeriodicalIF":4.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988840","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}

{"title":"A state-of-the-art view: G-quadruplex-targeting for platinum complexes’ treatment of tumors","authors":"Jinrong Yang, Yu Chen and Hui Chao","doi":"10.1039/D5CB00024F","DOIUrl":"10.1039/D5CB00024F","url":null,"abstract":"<p >Cisplatin and its analogs are extensively utilized as metal-based anticancer agents in clinical settings due to their mechanism of action, which involves targeting genomic double-stranded DNA to induce cytotoxicity in cancer cells. However, the associated severe side effects and DNA damage repair-inducing drug resistance present significant challenges. In recent years, G-quadruplex nucleic acids, formed through the self-assembly of guanine-rich nucleic acid sequences, have emerged as a compelling target for the design of novel anticancer therapeutics. The strategic design of platinum complexes that selectively interact with, stabilize, or cleave G-quadruplex structures represents a promising approach for developing effective anticancer agents to overcome cisplatin resistance. This review will emphasize the advancements made over the past decade in interacting G-quadruplexes with platinum complexes as potential anticancer therapeutics. The ongoing development of platinum complexes spans from targeting nuclear DNA G-quadruplexes to mitochondrial DNA and cytoplasmic RNA G-quadruplexes, evolving from monotherapy approaches, such as chemotherapy and photodynamic therapy, to a combination of radiotherapy, immunotherapy, and more, highlighting the dynamic progress of platinum complexes. At the end, we have summarized 4 points of pending issues in this fast-growing field, which we hope can provide some help to the development of this field.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 7","pages":" 1034-1047"},"PeriodicalIF":4.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200272","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}

{"title":"Design of a stapled peptide that binds to the Ebola virus matrix protein dimer interface†","authors":"Roopashi Saxena, Madison M. Wright, Benjamin M. Rathman, Ukesh Karki, Prem P. Chapagain, Juan R. Del Valle and Robert V. Stahelin","doi":"10.1039/D5CB00048C","DOIUrl":"10.1039/D5CB00048C","url":null,"abstract":"<p >The Ebola virus (EBOV) is a filamentous lipid-enveloped RNA virus that can cause viral hemmorhagic fever and has a high fatility rate. EBOV encodes seven genes including the lipid-binding matrix protein, VP40, which lies beneath the lipid-envelope. VP40 is a 326 amino acid protein with a N-terminal domain (NTD) harboring a high affinity dimer interface and a C-terminal domain (CTD) critical to plasma membrane lipid interactions. Disruption of VP40 dimer formation <em>via</em> mutagenesis inhibits assembly and budding of VP40. A series of conformationally constrained mimics of the VP40 α2 helix were designed based on the crystal structures of the VP40 dimer. A thermal shift assay was used to screen constrained and native peptides for significant alterations in VP40 stability. The most meritorious peptides were then confirmed to directly bind VP40 using microscale thermophoresis and isothermal titration calorimetry. A constrained VP40 peptide mimetic with a di-cysteine staple emerged with micromolar affinity for the VP40 dimer. This peptide was able to shift the VP40 dimer–monomer equilibrium as evidenced by size exclusion chromatography and bound near the NTD α-helix dimer interface. This study provides the first evidence of a designed small molecule induced disruption of VP40 dimer–monomer equilibrium.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 963-974"},"PeriodicalIF":4.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990209","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}

{"title":"Proximity-induced SuFEx increases the potency of cytosolic nucleotidase inhibitors and reveals a rare example of covalently targeted histidine†","authors":"Mikolaj Chrominski, Marcin Warminski, Mateusz Kozarski, Dorota Kubacka, Joanna Panecka-Hofman, Tomasz Spiewla, Mikolaj Zmudzinski, Jacek Jemeility and Joanna Kowalska","doi":"10.1039/D5CB00005J","DOIUrl":"10.1039/D5CB00005J","url":null,"abstract":"<p >Structure-guided design is one of the most validated solutions for targeting proteins with specific ligands for therapeutic purposes. Nevertheless, it remains challenging to target enzymes with low affinity for their natural ligands and specificities that overlap with those of other proteins. Cytosolic 5′-nucleotidases – involved in the metabolism of nucleic acid derivatives – are an example of such a family. Here we illustrate how precisely designed covalent inhibitors represent a potential solution for selective nucleotidase targeting. We employed the sulfur–fluoride exchange (SuFEx) to develop a covalent inhibitor of cytosolic nucleotidase IIIB (cNIIIB). Using the known inhibitor (7-benzylguanosine monophosphate, Bn<small>⁷</small>GMP) and computational methods, we designed and synthesized a series of SuFExable inhibitors. One compound indeed covalently bound cNIIIB, which increased the inhibition potency by over 100-fold. The formation of a covalent S–N bond with a non-catalytic His110 residue was confirmed through MS and <small>¹⁵</small>N NMR. The selectivity of the compound in the context of other protein that recognises similar ligands was also confirmed. The study expands the principle of covalent inhibition of nucleotide processing enzymes. It also represents a rare example of histidine tagging by SuFEx. This may facilitate the broader application of SuFEx chemistry in biochemistry and medicinal chemistry.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 942-947"},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055983","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}

{"title":"Monitoring SARS-CoV-2 Nsp13 helicase binding activity using expanded genetic code techniques†","authors":"Eryn Lundrigan, Christine Hum, Nadine Ahmed and John Paul Pezacki","doi":"10.1039/D4CB00230J","DOIUrl":"10.1039/D4CB00230J","url":null,"abstract":"<p >The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 13 (Nsp13) helicase is a multi-functional protein that can unwind dsDNA and dsRNA in an NTP-dependent manner. Given that this viral helicase is essential for viral replication and highly conserved among coronaviruses, a thorough understanding of the helicase's unwinding and binding activity may allow for the development of more effective pan-coronavirus therapeutics. Herein, we describe the use of genetic code expansion techniques to site-specifically incorporate the non-canonical amino acid (ncAA) <em>p</em>-azido-<small>L</small>-phenylalanine (AzF) into Nsp13 for fluorescent labelling of the enzyme with a conjugated Cy5 fluorophore. This Cy5-labelled Nsp13-AzF can then be used in Förster resonance energy transfer (FRET) experiments to investigate the dynamics of enzyme translocation on its substrate during binding and unwinding. Five sites (F81, F90, Y205, Y246, and Y253) were identified for AzF incorporation in Nsp13 and assessed for fluorescent labelling efficiency. The incorporation of AzF was confirmed to not interfere with the unwinding activity of the helicase. Subsequently, FRET-based binding assays were conducted to monitor the binding of Cy5-labelled Nsp13-AzF constructs to a series of fluorescently-labelled nucleic acid substrates in a distance-dependent manner. Overall, this approach not only allows for the direct monitoring of Nsp13's binding activity on its substrate, it may also introduce a novel method to screen for compounds that can inhibit this essential enzymatic activity during viral replication.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 860-868"},"PeriodicalIF":4.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003355","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}

{"title":"Synthesis of 4-azido sialic acid for testing against Siglec-7 and in metabolic oligosaccharide engineering†","authors":"Taylor E. Gray, Kristin B. Labasan, Gour C. Daskhan, Duong T. Bui, Maju Joe, Dhanraj Kumawat, Edward N. Schmidt, John S. Klassen and Matthew S. Macauley","doi":"10.1039/D5CB00030K","DOIUrl":"10.1039/D5CB00030K","url":null,"abstract":"<p >An important approach for tracking and visualizing sialic acid-containing glycans involves using sialic acid reporters functionalized with bioorthogonal handles. More specifically, metabolic oligosaccharide engineering (MOE) commonly employs monosaccharides with an alkyne or azide handle for incorporation into cellular glycans, followed by a subsequent click reaction to elaborate with a biotin or fluorophore handle. For sialic acid, this has been carried out extensively, with an azide or alkyne appended to the C5 <em>N</em>-acetamido group being the most common location for the handle. However, circumstances may require the handle to be at different positions and, to date, the C7 and C9 positions have been shown to work to varying degrees. Herein, we synthesized protected 4AzNeu5Ac that could be incorporated into cellular glycans nearly as efficiently as Neu5Az and targeted with DBCO-biotin through strain promoted azide–alkyne cycloaddition. Owing to the good incorporation of 4AzNeu5Ac into cellular glycans, we followed up this ability by first synthesizing the deprotected form of 4AzNeu5Ac, using a thioglycoside to lock the anomeric center during deprotection of the acetyl groups. Activation of 4AzNeu5Ac to CMP-4AzNeu5Ac then enabled the use of this donor by human sialyltransferase ST3GAL1 to transfer CMP-4AzNeu5Ac to β-Gal<em>p</em>-(1→3)-α-Gal<em>p</em>NAc. With purified α-4AzNeu<em>p</em>5Ac-(2→3)-β-Gal<em>p</em>-(1→3)-α-Gal<em>p</em>NAc in hand, we tested it as a ligand for Siglec-7 and found that the C4-Az modification is tolerated, opening future possibilities to exploit this position to generate high affinity and selective ligands. These findings expand the repertoire of metabolic oligosaccharide engineering agents and show that azide modifications are tolerated at the C4 position of sialic acid.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 869-881"},"PeriodicalIF":4.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057161","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}

{"title":"Structural and mechanistic insights into KslB, a bacterial Pictet–Spenglerase in kitasetaline biosynthesis†","authors":"Wantae Kim, Ziyang Zheng, Kangsan Kim, Yu-Hsuan Lee, Hung-wen Liu and Y. Jessie Zhang","doi":"10.1039/D5CB00070J","DOIUrl":"10.1039/D5CB00070J","url":null,"abstract":"<p >KslB is one of the few bacterial Pictet–Spenglerases recently identified in the biosynthesis of the β-carboline compound kitasetaline. While previous <em>in vitro</em> studies established that KslB catalyzes the condensation between <small>L</small>-tryptophan and α-ketoglutarate, the reaction mechanism, particularly its stereochemistry, remains poorly understood. This study presents five crystal structures of KslB, capturing key stages of reaction, shedding light on its catalytic dynamics. Among these, alternative binding poses of substrate and reaction product highlighted two significant features: (1) an additional pocket that accommodates <small>L</small>-tryptophan, and (2) two positively charged residues, Lys264 and Arg256, which form salt bridges with the product C1′ and C5′ carboxylate groups derived from α-ketoglutarate, ensuring a stereoselective process. These structural insights elucidate how KslB governs the stereochemistry of the cyclization process. Accordingly, we propose the configurations for the cyclized intermediate that align with the reaction's stereochemical outcome. Together, these findings offer valuable structural and mechanistic insights into KslB, paving the way for its potential engineering as a Pictet–Spengler biocatalyst.</p>","PeriodicalId":40691,"journal":{"name":"RSC Chemical Biology","volume":" 6","pages":" 933-941"},"PeriodicalIF":4.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003356","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}