Biotechnology Progress最新文献_第5页

Mechanistic model of minute virus of mice elution behavior in anion exchange chromatography purification. 阴离子交换色谱纯化过程中小鼠微小病毒洗脱行为的机理模型。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-10-23 DOI: 10.1002/btpr.3516

Ryunosuke Kitamura, Lena Enghauser, Riku Miyamoto, Takahiro Ichikawa, Takaki Aiso, Yumiko Masuda, Daisuke Kajihara, Hirofumi Kakihara, Koichi Nonaka

{"title":"Mechanistic model of minute virus of mice elution behavior in anion exchange chromatography purification.","authors":"Ryunosuke Kitamura, Lena Enghauser, Riku Miyamoto, Takahiro Ichikawa, Takaki Aiso, Yumiko Masuda, Daisuke Kajihara, Hirofumi Kakihara, Koichi Nonaka","doi":"10.1002/btpr.3516","DOIUrl":"https://doi.org/10.1002/btpr.3516","url":null,"abstract":"This study aimed to propose a methodology for developing a mechanistic model for viral clearance of the minute virus of mice (MVM) on flow-through anion exchange (AEX) chromatography. Protein surface analysis was applied to investigate the possibility of molecular interaction between the recombinant biotherapeutic and MVM. The protein product-free Tris buffers were spiked with MVM, and the MVM elution profile from AEX chromatography was quantitatively analyzed using quantitative polymerase chain reaction (qPCR) for pooled fractions. GoSilico™ Chromatography Modeling Software was applied to develop the mechanistic models for MVM species. For evaluating the visual fit of the developed model, the R2 of intact MVM virions and uncoated capsids between the simulated and measured amount in each fraction are 0.880 and 0.948, respectively. Response surface plots of logarithmic reduction values (LRV) against pH and conductivity in loaded sample were generated to show the range for suitable loaded sample conditions for achieving a good LRV. To evaluate the applicability of the developed MVM elution model to a recombinant biotherapeutic, two demonstrations of AEX chromatography purification were performed with a loaded sample of a model monoclonal antibody. The peaks of the MVM species in the elution step of both runs were accurately simulated by the developed model. In addition, to assess the possibility of molecular interaction between the virus and the target protein significantly affecting the MVM elution behavior, the antibody's surface was evaluated in terms of hydrophobicity/hydrophilicity using surface analysis.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":" ","pages":"e3516"},"PeriodicalIF":2.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493972","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

Comparing in silico flowsheet optimization strategies in biopharmaceutical downstream processes. 比较生物制药下游工艺中的硅学流程优化策略。

IF 2.5 3区生物学

Biotechnology Progress Pub Date : 2024-10-18 DOI: 10.1002/btpr.3514

Daphne Keulen, Myrto Apostolidi, Geoffroy Geldhof, Olivier Le Bussy, Martin Pabst, Marcel Ottens

{"title":"Comparing in silico flowsheet optimization strategies in biopharmaceutical downstream processes.","authors":"Daphne Keulen, Myrto Apostolidi, Geoffroy Geldhof, Olivier Le Bussy, Martin Pabst, Marcel Ottens","doi":"10.1002/btpr.3514","DOIUrl":"https://doi.org/10.1002/btpr.3514","url":null,"abstract":"The challenging task of designing biopharmaceutical downstream processes is initially to select the type of unit operations, followed by optimizing their operating conditions. For complex flowsheet optimizations, the strategy becomes crucial in terms of duration and outcome. In this study, we compared three optimization strategies, namely, simultaneous, top-to-bottom, and superstructure decomposition. Moreover, all strategies were evaluated by either using chromatographic Mechanistic Models (MMs) or Artificial Neural Networks (ANNs). An overall evaluation of 39 flowsheets was performed, including a buffer-exchange step between the chromatography operations. All strategies identified orthogonal structures to be optimal, and the weighted overall performance values were generally consistent between the MMs and ANNs. In terms of time-efficiency, the decomposition method with MMs stands out when utilizing multiple cores on a multiprocessing system for simulations. This study analyses the influence of different optimization strategies on flowsheet optimization and advices on suitable strategies and modeling techniques for specific scenarios.","PeriodicalId":8856,"journal":{"name":"Biotechnology Progress","volume":" ","pages":"e3514"},"PeriodicalIF":2.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457093","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

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