Biotechnology Progress最新文献_第6页

General strategies for IgG-like bispecific antibody purification. IgG 样双特异性抗体纯化的一般策略。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-10-15 DOI: 10.1002/btpr.3515

Yifeng Li

{"title":"General strategies for IgG-like bispecific antibody purification.","authors":"Yifeng Li","doi":"10.1002/btpr.3515","DOIUrl":"https://doi.org/10.1002/btpr.3515","url":null,"abstract":"Bispecific antibodies (bsAbs) can simultaneously bind two different antigens or epitopes. Their dual-targeting capability enables novel mechanisms of action, gaining therapeutic advantages over conventional monospecific mAbs. In recent years, the number of bsAbs grows rapidly and bsAbs under development are available in diverse formats. In particular, Fc-containing IgG-like bsAbs, which represent the major group, can be constructed in asymmetric or symmetric format. For asymmetric ones, whose assembly requires multiple distinct chains, although numerous strategies have been developed to promote desired chain pairing, product-related variants such as free chains, half molecules and mispaired species are usually present at various levels. For symmetric ones, increased level of aggregates and truncating variants is often associated with their production. In general, bsAbs pose greater challenges to the downstream team than regular mAbs. In the past few years, our team successfully developed the downstream process for over 70 bsAbs in greater than 30 different formats and accumulated substantial experience. This review introduces general strategies that we have used while purifying these challenging molecules.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":" ","pages":"e3515"},"PeriodicalIF":2.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the biocatalysis of psilocybin and other tryptamines: Enzymatic pathways, synthetic strategies, and industrial implications. 探索迷幻药和其他色胺的生物催化：酶途径、合成策略和工业影响。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-10-04 DOI: 10.1002/btpr.3513

Lucas Henrique Junges, Marcelo Müller-Santos

引用次数: 0

From protein structure to an optimized chromatographic capture step using multiscale modeling 利用多尺度建模从蛋白质结构到优化色谱捕获步骤。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-29 DOI: 10.1002/btpr.3505

Daphne Keulen, Tim Neijenhuis, Adamantia Lazopoulou, Roxana Disela, Geoffroy Geldhof, Olivier Le Bussy, Marieke E. Klijn, Marcel Ottens

{"title":"From protein structure to an optimized chromatographic capture step using multiscale modeling","authors":"Daphne Keulen, Tim Neijenhuis, Adamantia Lazopoulou, Roxana Disela, Geoffroy Geldhof, Olivier Le Bussy, Marieke E. Klijn, Marcel Ottens","doi":"10.1002/btpr.3505","DOIUrl":"10.1002/btpr.3505","url":null,"abstract":"Optimizing a biopharmaceutical chromatographic purification process is currently the greatest challenge during process development. A lack of process understanding calls for extensive experimental efforts in pursuit of an optimal process. In silico techniques, such as mechanistic or data driven modeling, enhance the understanding, allowing more cost-effective and time efficient process optimization. This work presents a modeling strategy integrating quantitative structure property relationship (QSPR) models and chromatographic mechanistic models (MM) to optimize a cation exchange (CEX) capture step, limiting experiments. In QSPR, structural characteristics obtained from the protein structure are used to describe physicochemical behavior. This QSPR information can be applied in MM to predict the chromatogram and optimize the entire process. To validate this approach, retention profiles of six proteins were determined experimentally from mixtures, at different pH (3.5, 4.3, 5.0, and 7.0). Four proteins at different pH's were used to train QSPR models predicting the retention volumes and characteristic charge, subsequently the equilibrium constant was determined. For an unseen protein knowing only the protein structure, the retention peak difference between the modeled and experimental peaks was 0.2% relative to the gradient length (60 column volume). Next, the CEX capture step was optimized, demonstrating a consistent result in both the experimental and QSPR-based methods. The impact of model parameter confidence on the final optimization revealed two viable process conditions, one of which is similar to the optimization achieved using experimentally obtained parameters. The multiscale modeling approach reduces the required experimental effort by identification of initial process conditions, which can be optimized.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btpr.3505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CHO stable pool fed-batch process development of SARS-CoV-2 spike protein production: Impact of aeration conditions and feeding strategies 生产 SARS-CoV-2 穗状病毒蛋白的 CHO 稳定池喂料批次工艺开发：通气条件和喂料策略的影响。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-27 DOI: 10.1002/btpr.3507

Sebastian-Juan Reyes, Phuong Lan Pham, Yves Durocher, Olivier Henry

{"title":"CHO stable pool fed-batch process development of SARS-CoV-2 spike protein production: Impact of aeration conditions and feeding strategies","authors":"Sebastian-Juan Reyes, Phuong Lan Pham, Yves Durocher, Olivier Henry","doi":"10.1002/btpr.3507","DOIUrl":"10.1002/btpr.3507","url":null,"abstract":"Technology scale-up and transfer are a fundamental and critical part of process development in biomanufacturing. Important bioreactor hydrodynamic characteristics such as working volume, overhead gas flow rate, volumetric power input (P/V), impeller type, agitation regimen, sparging aeration strategy, sparger type, and kLa must be selected based on key performance indicators (KPI) to ensure a smooth and seamless process scale-up and transfer. Finding suitable operational setpoints and developing an efficient feeding regimen to ensure process efficacy and consistency are instrumental. In this investigation, process development of a cumate inducible Chinese hamster ovary (CHO) stable pool expressing trimeric SARS-CoV-2 spike protein in 1.8 L benchtop stirred-tank bioreactors is detailed. Various dissolved oxygen levels and aeration air caps were studied to determine their impact on cell growth and metabolism, culture longevity, and endpoint product titers. Once hydrodynamic conditions were tuned to an optimal zone, various feeding strategies were explored to increase culture performance. Dynamic feedings such as feeding based on current culture volume, viable cell density (VCD), oxygen uptake rate (OUR), and bio-capacitance signals were tested and compared to standard bolus addition. Increases in integral of viable cell concentration (IVCC) (1.25-fold) and protein yield (2.52-fold), as well as greater culture longevity (extension of 5 days) were observed in dynamic feeding strategies when compared to periodic bolus feeding. Our study emphasizes the benefits of designing feeding strategies around metabolically relevant signals such as OUR and bio-capacitance signals.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btpr.3507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanosensor based on HP-MAP1 and carbon nanotubes for bacteria detection 基于 HP-MAP1 和碳纳米管的细菌检测纳米传感器

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-26 DOI: 10.1002/btpr.3510

Winne F. S. M. Silva, Ludovico Migliolo, Patrícia S. Silva, Glaucia M. S. Lima, Maria D. L. Oliveira, Cesar A. S. Andrade

{"title":"Nanosensor based on HP-MAP1 and carbon nanotubes for bacteria detection","authors":"Winne F. S. M. Silva, Ludovico Migliolo, Patrícia S. Silva, Glaucia M. S. Lima, Maria D. L. Oliveira, Cesar A. S. Andrade","doi":"10.1002/btpr.3510","DOIUrl":"10.1002/btpr.3510","url":null,"abstract":"Healthcare-associated infections (HAIs) pose significant challenges to global health due to pathogen complexity and antimicrobial resistance. Biosensors utilizing antimicrobial peptides offer innovative solutions. Hylarana picturata Multiple Active Peptide 1 (Hp-MAP1), derived from Temporin-PTA, exhibits antibacterial properties sourced from the skin secretions of the Malaysian fire-bellied frog. An innovative sensing layer was developed for the electrochemical biorecognition of diverse pathogens: Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. Electrochemical impedance spectroscopy differentiated microorganisms based on distinct electrochemical responses. The sensor layer, composed of functionalized multi-walled carbon nanotubes (MWCNTs) associated with Hp-MAP1, exhibited varying levels of charge transfer resistance (RCT) for different microorganisms. Gram-negative species, especially P. aeruginosa, displayed higher RCT values, indicating better impedimetric responses. Excellent LODs were observed for P. aeruginosa (0.60), K. pneumoniae (0.42), E. coli (0.67), and S. aureus (0.59), highlighting the efficacy of the MWCNTs/Hp-MAP1 biosensor in microbial identification. The MWCNTs/Hp-MAP1 biosensor platform presents a promising and effective microbial identification strategy with potential healthcare applications to mitigate HAIs and enhance patient care.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hybrid modeling for in silico optimization of a dynamic perfusion cell culture process 用于动态灌流细胞培养过程硅优化的混合模型

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-18 DOI: 10.1002/btpr.3503

Piyush Agarwal, Chris McCready, Say Kong Ng, Jake Chng Ng, Jeroen van de Laar, Maarten Pennings, Gerben Zijlstra

{"title":"Hybrid modeling for in silico optimization of a dynamic perfusion cell culture process","authors":"Piyush Agarwal, Chris McCready, Say Kong Ng, Jake Chng Ng, Jeroen van de Laar, Maarten Pennings, Gerben Zijlstra","doi":"10.1002/btpr.3503","DOIUrl":"10.1002/btpr.3503","url":null,"abstract":"The bio-pharmaceutical industry heavily relies on mammalian cells for the production of bio-therapeutic proteins. The complexity of implementing and high cost-of-goods of these processes are currently limiting more widespread patient access. This is driving efforts to enhance cell culture productivity and cost reduction. Upstream process intensification (PI), using perfusion approaches in the seed train and/or the main bioreactor, has shown substantial promise to enhance productivity. However, developing optimal process conditions for perfusion-based processes remain challenging due to resource and time constraints. Model-based optimization offers a solution by systematically screening process parameters like temperature, pH, and culture media to find the optimum conditions in silico. To our knowledge, this is the first experimentally validated model to explain the perfusion dynamics under different operating conditions and scales for process optimization. The hybrid model accurately describes Chinese hamster ovary (CHO) cell culture growth dynamics and a neural network model explains the production of mAb, allowing for optimization of media exchange rates. Results from six perfusion runs in Ambr® 250 demonstrated high accuracy, confirming the model's utility. Further, the implementation of dynamic media exchange rate schedule determined through model-based optimization resulted in 50% increase in volumetric productivity. Additionally, two 5 L-scale experiments validated the model's reliable extrapolation capabilities to large bioreactors. This approach could reduce the number of wet lab experiments needed for culture process optimization, offering a promising avenue for improving productivity, cost-of-goods in bio-pharmaceutical manufacturing, in turn improving patient access to pivotal medicine.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btpr.3503","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fed-batch strategies for intensified rVSV vector production in high cell density cultures of suspension HEK293 cells 在悬浮 HEK293 细胞的高细胞密度培养液中强化 rVSV 载体生产的联批策略

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-17 DOI: 10.1002/btpr.3506

Cristina A. T. Silva, Amine A. Kamen, Olivier Henry

{"title":"Fed-batch strategies for intensified rVSV vector production in high cell density cultures of suspension HEK293 cells","authors":"Cristina A. T. Silva, Amine A. Kamen, Olivier Henry","doi":"10.1002/btpr.3506","DOIUrl":"10.1002/btpr.3506","url":null,"abstract":"Vesicular stomatitis virus (VSV) has been increasingly demonstrated as a promising viral vector platform. As the interest over this modality for vaccine and gene therapy applications increases, the need for intensified processes to produce these vectors emerge. In this study, we develop fed-batch-based operations to intensify the production of a recombinant VSV-based vaccine candidate (rVSV-SARS-CoV-2) in suspension cultures of HEK293 cells. A feeding strategy, in which a commercial concentrated medium was added to cultures based on cell growth through a fixed cell specific feeding rate (CSFR), was applied for the development of two different processes using Ambr250 modular bioreactors. Cultures operated in hybrid fed-batch/perfusion (FB/P) or fed-batch (FB) were able to sustain infections performed at 8.0 × 106 cells/mL, respectively resulting in 3.9 and 5.0-fold increase in total yield (YT) and 1.7 and 5.6-fold increase in volumetric productivity (VP) when compared with a batch reference. A maximum viral titer of 4.5 × 1010 TCID50/mL was reached, which is comparable or higher than other processes for VSV production in different cell lines. Overall, our study reports efficient fed-batch options to intensify the production of a rVSV-based vaccine candidate in suspension HEK293 cells.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btpr.3506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Assessment of membrane-based downstream purification processes as a replacement to traditional resin bead for monoclonal antibody purification 评估以膜为基础的下游纯化工艺，以取代传统的树脂珠单克隆抗体纯化工艺。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-16 DOI: 10.1002/btpr.3508

Victor Pasquier, Kevin Botelho Ferreira, Morgane Lergenmuller, Alexis Tottoli, Arnaud Perilleux, Jonathan Souquet, Jean-Marc Bielser

{"title":"Assessment of membrane-based downstream purification processes as a replacement to traditional resin bead for monoclonal antibody purification","authors":"Victor Pasquier, Kevin Botelho Ferreira, Morgane Lergenmuller, Alexis Tottoli, Arnaud Perilleux, Jonathan Souquet, Jean-Marc Bielser","doi":"10.1002/btpr.3508","DOIUrl":"10.1002/btpr.3508","url":null,"abstract":"Membrane chromatography devices are a viable alternative to packed-bed resins and enable highly productive purification cascades for monoclonal antibodies and Fc-fusion proteins. In this study, ion exchange and protein A membrane chromatography performances were assessed and compared with their resin counterparts. Protein A dynamic binding capacities were higher than 50 g/L for two of the tested membranes and with a residence time of 0.2 min. For polishing, it was observed that aggregate clearance was generally less performant with membrane separation when compared to resins with similar ligands. However, the comparable yield and increased productivity of membranes could be enough to consider their implementation. In addition, lifetime studies demonstrated that the performance of membranes remained robust over cycles. One hundred cycles were reached for most of the tested membranes with no impact on the process performance nor product quality. Finally, purification cascades were fully operated with membranes, from capture to polishing, reaching good levels of host cells proteins (less than 50 ppm) and aggregates (equal to or less than 1%). The outcome of this study demonstrated that resin chromatography could be fully replaced by membranes for monoclonal antibody and Fc-fusion protein purification processes.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic engineering of rapidly growing Synechococcus elongatus strains for phototrophic production of alkanes 对快速生长的细长 Synechococcus 菌株进行代谢工程改造，以实现光营养生产烷烃。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-15 DOI: 10.1002/btpr.3509

Vaibhav Srivastava, Aditya P. Sarnaik, Pramod P. Wangikar

{"title":"Metabolic engineering of rapidly growing Synechococcus elongatus strains for phototrophic production of alkanes","authors":"Vaibhav Srivastava, Aditya P. Sarnaik, Pramod P. Wangikar","doi":"10.1002/btpr.3509","DOIUrl":"10.1002/btpr.3509","url":null,"abstract":"Alkanes are high-energy hydrocarbons that are foreseen as next generation biofuels. Cyanobacteria are known to naturally synthesize C15–C19 alkanes; however, the titers are too low to make this a commercially viable process. Therefore, to leverage these photosynthetic platforms for improved alkane production, here we engineered three novel isolates of Synechococcus elongatus PCC 11801, PCC 11802, and IITB6. The two gene AAR-ADO alkane biosynthesis pathway was constructed by cloning the genes for acyl-ACP reductase (aar) and aldehyde deformylating oxygenase (ado) from S. elongatus PCC 7942 under the regulation of PrbcL promoter from PCC 7942 and native promoters from PCC 11801 such as PcpcB300, PpsbAI, and PpsbAIII. The genes were separately cloned under two different promoters, creating a library of the engineered strains. The results indicated that the engineered strains of novel S. elongatus isolates produced significantly higher amounts of alkanes than the model strain PCC 7942. The highest alkane yield achieved was 4.1 mg/gDCW in BG-11, while the highest titer was 31.5 mg/L in 5X BG-11, with an engineered IITB6 strain (PcpcB300:aar:TrrnB::PrbcL:ado:TLac). Overall, the study highlights the potential of newly isolated S. elongatus strains as efficient alkane production platforms.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"41 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimizing cryopreservation strategies for scalable cell therapies: A comprehensive review with insights from iPSC-derived therapies 为可扩展的细胞疗法优化低温保存策略：全面回顾 iPSC 衍生疗法的启示

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-09-13 DOI: 10.1002/btpr.3504

Michael Dobruskin, Geoffrey Toner, Ronald Kander

{"title":"Optimizing cryopreservation strategies for scalable cell therapies: A comprehensive review with insights from iPSC-derived therapies","authors":"Michael Dobruskin, Geoffrey Toner, Ronald Kander","doi":"10.1002/btpr.3504","DOIUrl":"10.1002/btpr.3504","url":null,"abstract":"Off-the-shelf cell therapies hold significant curative potential for conditions, such as Parkinson's disease and heart failure. However, these therapies face unique cryopreservation challenges, especially when novel routes of administration, such as intracerebral or epicardial injection, require cryopreservation media that are safe for direct post-thaw administration. Current practices often involve post-thaw washing to remove dimethyl sulfoxide (Me2SO), a cytotoxic cryoprotective agent, which complicates the development and clinical translation of off-the-shelf therapies. To overcome these obstacles, there is a critical need to explore Me2SO-free cryopreservation methods. While such methods typically yield suboptimal post-thaw viability with conventional slow-freeze protocols, optimizing freezing profiles offers a promising strategy to enhance their performance. This comprehensive review examines the latest advancements in cryopreservation techniques across various cell therapy platforms, with a specific case study of iPSC-derived therapies used to illustrate the scalability challenges. By identifying key thermodynamic and biochemical phenomena that occur during freezing, this review aims to identify cell-type independent approaches to improve the efficiency and efficacy of cryopreservation strategies, thereby supporting the widespread adoption and clinical success of off-the-shelf cell therapies.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":"40 6","pages":""},"PeriodicalIF":2.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/btpr.3504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0