Metabolic engineering最新文献

{"title":"Network for Knowledge Organization (NEKO): an AI knowledge mining workflow for synthetic biology research.","authors":"Zhengyang Xiao, Himadri B Pakrasi, Yixin Chen, Yinjie J Tang","doi":"10.1016/j.ymben.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.ymben.2024.11.006","url":null,"abstract":"<p><p>Large language models (LLMs) can complete general scientific question-and-answer, yet they are constrained by their pretraining cut-off dates and lack the ability to provide specific, cited scientific knowledge. Here, we introduce Network for Knowledge Organization (NEKO), a workflow that uses LLM Qwen to extract knowledge through scientific literature text mining. When user inputs a keyword of interest, NEKO can generate knowledge graphs to link bioinformation entities and perform comprehensive summaries from PubMed search. NEKO significantly enhance LLM ability and has immediate applications in daily academic tasks such as education of young scientists, literature review, paper writing, experiment planning/troubleshooting, and new ideas/hypothesis generation. We exemplified this workflow's applicability through several case studies on yeast fermentation and cyanobacterial biorefinery. NEKO's output is more informative, specific, and actionable than GPT-4's zero-shot Q&A. NEKO offers flexible, lightweight local deployment options. NEKO democratizes artificial intelligence (AI) tools, making scientific foundation model more accessible to researchers without excessive computational power.</p>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flux balance analysis and peptide mapping elucidate the impact of bioreactor pH on Chinese Hamster Ovary (CHO) cell metabolism and N-linked glycosylation in the Fab and Fc regions of the produced IgG.","authors":"Jayanth Venkatarama Reddy, Sumit Kumar Singh, Thomas Leibiger, Kelvin H Lee, Marianthi Ierapetritou, Eleftherios Terry Papoutsakis","doi":"10.1016/j.ymben.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.ymben.2024.11.005","url":null,"abstract":"<p><p>Culture conditions have a profound impact on therapeutic protein production and glycosylation, a critical therapeutic-quality attribute, especially for monoclonal antibodies (mAbs). While the critical culture parameter of pH has been known since the early 1990s to affect protein glycosylation and production, detailed glycan and metabolic characterization and mechanistic understanding are critically lacking. Here, Chinese Hamster Ovary (CHO) cells were grown in bioreactors at pH 6.75, 7 and 7.25 to examine how pH affects cell metabolism and site-specific N-linked glycosylation of the produced broadly neutralizing anti-HIV IgG1 mAb. VRC01 has N-linked glycosylation sites in both the Fc region and the Fab region, a situation not previously examined with respect to mAb glycosylation as affected by culture conditions. Using Parsimonious Flux Balance Analysis (pFBA) and Flux Variability Analysis (FVA), we dissect and quantitate the impact of pH on cell growth, glucose/lactate metabolism, accumulation of the toxic metabolite ammonia, IgG production rates, and nonessential amino acid metabolism. pFBA revealed thar that beyond the established mechanism of glutamine conversion to glutamate, ammonia is also produced by the reaction converting serine to pyruvate, especially in the later phases of culture. pFBA also provided insights into the switch from ammonia production to consumption, notably due to depletion of glutamine, and consumption of glutamate and aspartate. We document that culture duration and pH alter the complex bimodal patterns (production/uptake) of several essential and non-essential amino acids. Site-specific N-linked glycan analysis using glycopeptide mapping demonstrated that pH significantly affects the glycosylation profiles of the two IgG1 sites. Fc region glycans were completely fucosylated but did not contain any sialylation. The Fab region glycans were not completely fucosylated but contained sialylated glycans. Bioreactor pH affected both the fucosylation and sialylation indexes in the Fab region and the galactosylation index of the Fc region. However, fucosylation in the Fc region was unaffected thus demonstrating that the effect of pH on site-specific N-linked glycosylation is complex.</p>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling productivity-enhancing genes in Chinese hamster ovary cells via CRISPR activation screening using recombinase-mediated cassette exchange system.","authors":"Minhye Baek, Che Lin Kim, Su Hyun Kim, Karen Julie la Cour Karottki, Hooman Hefzi, Lise Marie Grav, Lasse Ebdrup Pedersen, Nathan E Lewis, Jae Seong Lee, Gyun Min Lee","doi":"10.1016/j.ymben.2024.11.009","DOIUrl":"10.1016/j.ymben.2024.11.009","url":null,"abstract":"<p><p>Chinese hamster ovary (CHO) cells, which are widely used for therapeutic protein production, have been genetically manipulated to enhance productivity. Nearly half of the genes in CHO cells are silenced, which are promising targets for CHO cell engineering. To identify novel gene targets among the silenced genes that can enhance productivity, we established a genome-wide clustered regularly interspaced short palindromic repeats activation (CRISPRa) screening platform for bispecific antibody (bsAb)-producing CHO (CHO-bsAb) cells with 110,979 guide RNAs (gRNAs) targeting 13,812 silenced genes using a virus-free recombinase-mediated cassette exchange-based gRNA integration method. Using this platform, we performed a fluorescence-activated cell sorting-based cold-capture assay to isolate cells with high fluorescence intensity, which is indicative of high specific bsAb productivity (q_bsAb), and identified 90 significantly enriched genes. To verify the screening results, 14 high-scoring candidate genes were individually activated in CHO-bsAb cells via CRISPRa. Among these, 10 genes demonstrated enhanced fluorescence intensity of CHO-bsAb cells in the cold-capture assay when activated. Furthermore, the overexpression of the identified novel gene target Syce3 in CHO-bsAb cells resulted in a 1.4- to 1.9-fold increase in the maximum bsAb concentration, owing to improved q_bsAb and specific growth rate. Thus, this virus-free CRISPRa screening platform is a potent tool for identifying novel engineering targets in CHO cells to improve bsAb production.</p>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":" ","pages":"11-20"},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning for NAD/NADP cofactor prediction and engineering using transformer attention analysis in enzymes.","authors":"Jaehyung Kim, Jihoon Woo, Joon Young Park, Kyung-Jin Kim, Donghyuk Kim","doi":"10.1016/j.ymben.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.ymben.2024.11.007","url":null,"abstract":"<p><p>Understanding and manipulating the cofactor preferences of NAD(P)-dependent oxidoreductases, the most widely distributed enzyme group in nature, is increasingly crucial in bioengineering. However, large-scale identification of the cofactor preferences and the design of mutants to switch cofactor specificity remain as complex tasks. Here, we introduce DISCODE (Deep learning-based iterative pipeline to analyze Specificity of Cofactors and to Design Enzyme), a novel transformer-based deep learning model to predict NAD(P) cofactor preferences. For model training, a total of 7,132 NAD(P)-dependent enzyme sequences were collected. Leveraging whole-length sequence information, DISCODE classifies the cofactor preferences of NAD(P)-dependent oxidoreductase protein sequences without structural or taxonomic limitation. The model showed 97.4% and 97.3% of accuracy and F1 score, respectively. A notable feature of DISCODE is the interpretability of its transformer layers. Analysis of attention layers in the model enables identification of several residues that showed significantly higher attention weights. They were well aligned with structurally important residues that closely interact with NAD(P), facilitating the identification of key residues for determining cofactor specificities. These key residues showed high consistency with verified cofactor switching mutants. Integrated into an enzyme design pipeline, DISCODE coupled with attention analysis, enables a fully automated approach to redesign cofactor specificity.</p>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The faucet knob effect of DptE crotonylation on the initial flow of daptomycin biosynthesis.","authors":"Wen-Li Gao, Lie Ma, Meng-Han Li, Wei-Feng Xu, Chen-Fan Sun, Qing-Wei Zhao, Xin-Ai Chen, Zhong-Yuan Lyu, Yong-Quan Li","doi":"10.1016/j.ymben.2024.11.003","DOIUrl":"10.1016/j.ymben.2024.11.003","url":null,"abstract":"<p><p>We propose here that acylation modification of actinomycete proteins is a restrictive system that limits the excessive synthesis of secondary metabolites, its mechanism has not been clearly elucidated before. We used crotonylation as an example to investigate the acylation effect in the daptomycin biosynthesis by Streptomyces roseosporus. Our experiments revealed abundant crotonylation of numerous secondary metabolic enzymes in Streptomyces roseosporus, a daptomycin producer. DptE, which initiates daptomycin biosynthesis, is crotonylated at K454. We experimentally identified the corresponding DptE crotonyltransferase Kct1 and decrotonylase CobB. Further studies consistently confirmed that decrotonylation increases DptE activity. Decrotonylation functions like loosening a faucet knob, increasing substrate channel throughput and the initial flow of daptomycin biosynthesis. Moreover, DptE catalytic activity was enhanced via K454 and neighboring residues K184 and Q420 mutation, increasing daptomycin yield by 132%; daptomycin biosynthesis related metabolism activities also increased. Substrate channel prediction revealed 38% higher throughput for mutant DptE (K454I/K184Q/Q420N) than crotonylated DptE. Molecular dynamics (MD) simulations revealed significant increases in flexibility and substrate affinity of the mutant. In summary, we elucidated the faucet knob effect of DptE crotonylation on the initial flow of daptomycin biosynthesis and adopted decrotonylation to generate high-yield industrial strains.</p>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":" ","pages":"1-10"},"PeriodicalIF":6.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Versatile Xylose and Arabinose Genetic Switches development for Yeasts.","authors":"Shuhui Guo, Juhua Du, Donghan Li, Jinghui Xiong, Ye Chen","doi":"10.1016/j.ymben.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.ymben.2024.11.004","url":null,"abstract":"<p><p>Inducible transcription systems are essential tools in genetic engineering, where tight control, strong inducibility and fast response with cost-effective inducers are highly desired. However, existing systems in yeasts are rarely used in large-scale fermentations due to either cost-prohibitive inducers or incompatible performance. Here, we developed powerful xylose and arabinose induction systems in Saccharomyces cerevisiae, utilizing eukaryotic activators XlnR and AraR^A from Aspergillus species and bacterial repressors XylR and AraR^R. By integrating these signals into a highly-structured synthetic promoter, we created dual-mode systems with strong outputs and minimal leakiness. These systems demonstrated over 4000- and 300-fold regulation with strong activation and rapid response. The dual-mode xylose system was fully activated by xylose-rich agricultural residues like corncob hydrolysate, outperforming existing systems in terms of leakiness, inducibility, dynamic range, induction rate, and growth impact on host. We validated their utility in metabolic engineering with high-titer linalool production and demonstrated the transferability of the XlnR-based xylose induction system to Pichia pastoris, Candida glabrata and Candida albicans. This work provides robust genetic switches for yeasts and a general strategy for integrating activation-repression signals into synthetic promoters to achieve optimal performance.</p>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterologous biosynthesis of betanin triggers metabolic reprogramming in tobacco","authors":"Xun Jiang ,&nbsp;Zhuoxiang Zhang ,&nbsp;Xiuming Wu ,&nbsp;Changmei Li,&nbsp;Xuan Sun,&nbsp;Fengyan Wu,&nbsp;Aiguo Yang,&nbsp;Changqing Yang","doi":"10.1016/j.ymben.2024.11.002","DOIUrl":"10.1016/j.ymben.2024.11.002","url":null,"abstract":"<div><div>Engineering of a specialized metabolic pathway in plants is a promising approach to produce high-value bioactive compounds to address the challenges of climate change and population growth. Understanding the interaction between the heterologous pathway and the native metabolic network of the host plant is crucial for optimizing the engineered system and maximizing the yield of the target compound. In this study, we performed transcriptomic, metabolomic and metagenomic analysis of tobacco (<em>Nicotiana tabacum</em>) plants engineered to produce betanin, an alkaloid pigment that is found in <em>Caryophyllaceae</em> plants. Our data reveals that, in a dose-dependent manor, the biosynthesis of betanin promotes carbohydrate metabolism and represses nitrogen metabolism in the leaf, but enhances nitrogen assimilation and metabolism in the root. By supplying nitrate or ammonium, the accumulation of betanin increased by 1.5–3.8-fold in leaves and roots of the transgenic plants, confirming the pivotal role of nitrogen in betanin production. In addition, the rhizosphere microbial community is reshaped to reduce denitrification and increase respiration and oxidation, assistant to suppress nitrogen loss. Our analysis not only provides a framework for evaluating the pleiotropic effects of an engineered metabolic pathway on the host plant, but also facilitates the development of novel strategies to balance the heterologous process and the native metabolic network for the high-yield and nutrient-efficient production of bioactive compounds in plants.</div></div>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":"86 ","pages":"Pages 308-325"},"PeriodicalIF":6.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying metabolic control strategies to engineered T cell cancer therapies","authors":"Andrea C. Fox,&nbsp;John Blazeck","doi":"10.1016/j.ymben.2024.10.009","DOIUrl":"10.1016/j.ymben.2024.10.009","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise in improving CAR T cells for the treatment of solid tumors.</div></div>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":"86 ","pages":"Pages 250-261"},"PeriodicalIF":6.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multiscale hybrid modelling methodology for cell cultures enabled by enzyme-constrained dynamic metabolic flux analysis under uncertainty","authors":"Oliver Pennington ,&nbsp;Sebastián Espinel Ríos ,&nbsp;Mauro Torres Sebastian ,&nbsp;Alan Dickson ,&nbsp;Dongda Zhang","doi":"10.1016/j.ymben.2024.10.013","DOIUrl":"10.1016/j.ymben.2024.10.013","url":null,"abstract":"<div><div>Mammalian cell cultures make a significant contribution to the pharmaceutical industry. They produce many of the biopharmaceuticals obtaining FDA-approval each year. Motivated by quality-by-design principles, various modelling methodologies are frequently trialled to gain insight into these bioprocesses. However, these systems are highly complex and uncertain, involving dynamics at different scales, both in time and space, making them challenging to model in a comprehensive and fully mechanistic manner. This study develops a machine-learning-supported multiscale modelling framework of cell cultures, linking the macroscale bioprocess dynamics to the microscale metabolic flux distribution. As a relevant biopharmaceutical case study, we consider the production of Trastuzumab by Chinese Hamster Ovary (CHO) cells in batch. A macroscale hybrid model is constructed by integrating macro-kinetic and machine-learning approaches. Enzyme-constrained Dynamic Metabolic Flux Analysis (ecDMFA) is adopted to calculate flux distributions based on the dynamic predictions of the hybrid model. Uncertainty estimation of the multiscale model is conducted through bootstrapping. Judging from experimental data, our hybrid model can reduce the modelling error of the macroscale dynamics to 8.0%; a 70% reduction from the purely mechanistic model. In addition, the predicted dynamic flux distribution aligns with observations seen in literature, highlighting important metabolic changes throughout the process. Model uncertainty is maintained at a low level, demonstrating the trustworthiness of the predictions. Overall, our comprehensive modelling framework has the potential to facilitate the development of digital twins in the biopharmaceutical industry.</div></div>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":"86 ","pages":"Pages 274-287"},"PeriodicalIF":6.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering peroxisomal surface display for enhanced biosynthesis in the emerging yeast Kluyveromyces marxianus","authors":"Shane Bassett,&nbsp;Jonathan C. Suganda,&nbsp;Nancy A. Da Silva","doi":"10.1016/j.ymben.2024.10.014","DOIUrl":"10.1016/j.ymben.2024.10.014","url":null,"abstract":"<div><div>The non-conventional yeast <em>Kluyveromyces marxianus</em> is a promising microbial host for industrial biomanufacturing. With the recent development of Cas9-based genome editing systems and other novel synthetic biology tools for <em>K. marxianus</em>, engineering of this yeast has become far more accessible. Enzyme colocalization is a proven approach to increase pathway flux and the synthesis of non-native products. Here, we engineer <em>K. marxianus</em> to enable peroxisomal surface display, an enzyme colocalization technique for displaying enzymes on the peroxisome membrane via an anchoring motif from the peroxin Pex15. The native <em>Km</em>Pex15 anchoring motif was identified and fused to GFP, resulting in successful localization to the surface of the peroxisomes. To demonstrate the advantages for pathway localization, the <em>Pseudomonas savastanoi</em> IaaM and IaaH enzymes were co-displayed on the peroxisome surface; this increased production of indole-3-acetic acid 7.9-fold via substrate channeling effects. We then redirected pathway flux by displaying the violacein pathway enzymes VioE and VioD from <em>Chromobacterium violaceum</em>, increasing selectivity of proviolacein to prodeoxyviolacein by 2.5-fold. Finally, we improved direct access to peroxisomal acetyl-CoA and increased titers of the polyketide triacetic acid lactone (TAL) by 2-fold through concurrent display of the proteins Cat2, Acc1, and the type III PKS 2-pyrone synthase from <em>Gerbera hybrida</em> relative to the same three enzymes diffusing in the cytosol. We further improved TAL production by up to 2.1-fold through engineering peroxisome morphology and lifespan. Our findings demonstrate that peroxisomal surface display is an efficient enzyme colocalization strategy in <em>K. marxianus</em> and applicable for improving production of a wide range of non-native products.</div></div>","PeriodicalId":18483,"journal":{"name":"Metabolic engineering","volume":"86 ","pages":"Pages 326-336"},"PeriodicalIF":6.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}