Pub Date : 2025-12-11DOI: 10.1016/j.biologicals.2025.101870
Daniela Tendler Leibel Bacellar , Cristiane Santino da Silva , Antonio Alves Pereira-Júnior , Wlamir Correa de Moura , Maria Helena Simões Villas-Boas , Ana Luiza de Mattos-Guaraldi
Diphtheria is an acute infectious disease that can be fatal due to the action of diphtheria toxin (DT). Diphtheria antitoxin (DAT) remains essential for treatment and must be administered within two days of symptom onset to effectively neutralize circulating DT. Immediate availability of DAT is critical, especially during outbreaks. Potency testing is required before lot release, yet current pharmacopeial methods still rely on in vivo assays, such as the subcutaneous toxin neutralization test (TNT-SC) or intradermal TNT (TNT-ID). In response to efforts to reduce animal use, this study aimed to validate an in vitro potency assay for DAT using Vero cells, as an alternative to the in vivo TNT-SC for lot release. Twelve DAT samples were tested using the in vivo method and the alternative in vitro assay. Diagnostic performance (sensitivity, specificity, accuracy), agreement (Lin's CCC, Bland–Altman analysis), linearity, precision, and selectivity were evaluated. The in vitro assay showed high concordance with the in vivo method (CCC >0.90) and correctly classified all samples regarding conformity status. The assay demonstrated acceptable linearity and precision (gCV% ≤ 30 %). These results support the Vero cell assay as a relevant and reliable full replacement for in vivo TNT-SC in DAT potency determination.
{"title":"Diphtheria antitoxin potency assay: an in vitro alternative to the in vivo subcutaneous toxin neutralization test","authors":"Daniela Tendler Leibel Bacellar , Cristiane Santino da Silva , Antonio Alves Pereira-Júnior , Wlamir Correa de Moura , Maria Helena Simões Villas-Boas , Ana Luiza de Mattos-Guaraldi","doi":"10.1016/j.biologicals.2025.101870","DOIUrl":"10.1016/j.biologicals.2025.101870","url":null,"abstract":"<div><div>Diphtheria is an acute infectious disease that can be fatal due to the action of diphtheria toxin (DT). Diphtheria antitoxin (DAT) remains essential for treatment and must be administered within two days of symptom onset to effectively neutralize circulating DT. Immediate availability of DAT is critical, especially during outbreaks. Potency testing is required before lot release, yet current pharmacopeial methods still rely on <em>in vivo</em> assays, such as the subcutaneous toxin neutralization test (TNT-SC) or intradermal TNT (TNT-ID). In response to efforts to reduce animal use, this study aimed to validate an <em>in vitro</em> potency assay for DAT using Vero cells, as an alternative to the <em>in vivo</em> TNT-SC for lot release. Twelve DAT samples were tested using the <em>in vivo</em> method and the alternative <em>in vitro</em> assay. Diagnostic performance (sensitivity, specificity, accuracy), agreement (Lin's CCC, Bland–Altman analysis), linearity, precision, and selectivity were evaluated. The <em>in vitro</em> assay showed high concordance with the <em>in vivo</em> method (CCC >0.90) and correctly classified all samples regarding conformity status. The assay demonstrated acceptable linearity and precision (gCV% ≤ 30 %). These results support the Vero cell assay as a relevant and reliable full replacement for <em>in vivo</em> TNT-SC in DAT potency determination.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"93 ","pages":"Article 101870"},"PeriodicalIF":1.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.biologicals.2025.101850
Bhagwati Khatri , Peggy Riese , Hanna Shkarlet , Daniella Mortier , Helen McShane , Paul W. Bowyer , Edmond Remarque
This study focuses on harmonising the competition ELISA (cELISA) assay for Plasmodium falciparum (P. falciparum), using the 1st WHO reference reagent for anti-malaria (P. falciparum) human reference serum (10/198). Antibody-mediated immune responses against the Apical Membrane Antigen 1 (AMA1) play a significant role in protection against malaria. However, the sequence diversity of AMA1 and cross-reactivity among variants pose challenges in assessing antibody responses. To address this, the cELISA assay was selected to examine cross-reactive antibody responses against different variants.
The harmonisation process for cELISA was performed in three laboratories. The 10/198 served as an internal standard for the calculation of IgG concentrations in the cELISA using ADAMSEL software. Additionally, a novel semi-automated analytical tool was developed in the R-statistics environment. This tool is freely available for download and streamlines generating results while minimising human error.
This study demonstrated the effectiveness of the 1st WHO reference reagent as a standard for cELISA. Additionally, the ADAMSEL software and R-platform tool provide a user-friendly and accessible tool for the analysis of cELISA data. Its automation capabilities improve efficiency and ensure global accessibility at no cost, benefitting laboratories with limited resources.
{"title":"Evaluation of 1st WHO anti-malaria reference reagent for competition ELISA harmonisation and development of ADAMSEL analytical platform","authors":"Bhagwati Khatri , Peggy Riese , Hanna Shkarlet , Daniella Mortier , Helen McShane , Paul W. Bowyer , Edmond Remarque","doi":"10.1016/j.biologicals.2025.101850","DOIUrl":"10.1016/j.biologicals.2025.101850","url":null,"abstract":"<div><div>This study focuses on harmonising the competition ELISA (cELISA) assay for <em>Plasmodium falciparum</em> (<em>P. falciparum</em>), using the 1st WHO reference reagent for anti-malaria (<em>P. falciparum</em>) human reference serum (10/198). Antibody-mediated immune responses against the Apical Membrane Antigen 1 (AMA1) play a significant role in protection against malaria. However, the sequence diversity of AMA1 and cross-reactivity among variants pose challenges in assessing antibody responses. To address this, the cELISA assay was selected to examine cross-reactive antibody responses against different variants.</div><div>The harmonisation process for cELISA was performed in three laboratories. The 10/198 served as an internal standard for the calculation of IgG concentrations in the cELISA using ADAMSEL software. Additionally, a novel semi-automated analytical tool was developed in the R-statistics environment. This tool is freely available for download and streamlines generating results while minimising human error.</div><div>This study demonstrated the effectiveness of the 1st WHO reference reagent as a standard for cELISA. Additionally, the ADAMSEL software and R-platform tool provide a user-friendly and accessible tool for the analysis of cELISA data. Its automation capabilities improve efficiency and ensure global accessibility at no cost, benefitting laboratories with limited resources.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101850"},"PeriodicalIF":1.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.biologicals.2025.101863
Nicolás Berardo Blanch , Diego Ignacio Olivero , Christian Leandro Macoretta , Oscar Pérez , Matías Fingermann
Since their introduction over a century ago, antivenoms have played a central role in Public Health, especially in the world's least developed regions. They are, in most cases, the only effective treatment for envenomation accidents by poisonous animals. A big proportion of currently available antivenoms are based on F(ab’)2 immunoglobulin fragments, produced from hyperimmune equine plasma, following slightly modified protocols developed several decades ago. These protocols show severe limitations for processing starting materials with high lipid contents. In this work, we propose minor modifications to these traditional procedures, based on the addition of octanoic acid, that significantly increase their lipid removal capacities. The method designed for use at the final stages showed reductions of 85–98 % and 64–99 % in cholesterol and phosphatidylcholines, respectively. An alternative, intended for use at the initial stages of the process, improved lipid removal capacity in three out of four independent hyperimmune equine plasmas assayed. Notably, a significant reduction in oligomeric F(ab’)2 species was also observed in all octanoic acid-treated samples. Thus, the methodologies developed and optimised in this work present simple and affordable alternatives to overcome lipid removal limitations of traditional antivenom-producing protocols.
{"title":"Octanoic acid addition: a simple, affordable modification that overcomes lipid removal limitations of traditional antivenom production processes","authors":"Nicolás Berardo Blanch , Diego Ignacio Olivero , Christian Leandro Macoretta , Oscar Pérez , Matías Fingermann","doi":"10.1016/j.biologicals.2025.101863","DOIUrl":"10.1016/j.biologicals.2025.101863","url":null,"abstract":"<div><div>Since their introduction over a century ago, antivenoms have played a central role in Public Health, especially in the world's least developed regions. They are, in most cases, the only effective treatment for envenomation accidents by poisonous animals. A big proportion of currently available antivenoms are based on F(ab’)<sub>2</sub> immunoglobulin fragments, produced from hyperimmune equine plasma, following slightly modified protocols developed several decades ago. These protocols show severe limitations for processing starting materials with high lipid contents. In this work, we propose minor modifications to these traditional procedures, based on the addition of octanoic acid, that significantly increase their lipid removal capacities. The method designed for use at the final stages showed reductions of 85–98 % and 64–99 % in cholesterol and phosphatidylcholines, respectively. An alternative, intended for use at the initial stages of the process, improved lipid removal capacity in three out of four independent hyperimmune equine plasmas assayed. Notably, a significant reduction in oligomeric F(ab’)<sub>2</sub> species was also observed in all octanoic acid-treated samples. Thus, the methodologies developed and optimised in this work present simple and affordable alternatives to overcome lipid removal limitations of traditional antivenom-producing protocols.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101863"},"PeriodicalIF":1.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145410840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alum adjuvants do not induce Th1 responses with killed microorganisms, although Th1 responses are crucial for defending against intracellular microbes. Chlorogenic acid (CGA) can shift immune responses from Th2 toward Th1. This study assessed the benefits of combining CGA with alum on cellular and humoral immunity following immunization with a heat-killed preparation of Salmonella typhimurium (HKST). Male Balb/c mice received two doses of the HKST vaccine, with or without alum, CGA, or both, administered two weeks apart. Immune responses and protection against S. typhimurium were evaluated two weeks after the final dose.The alum and CGA combination enhanced the HKST vaccine's ability to stimulate lymphocyte proliferation, delayed-type hypersensitivity reactions, and antibody titers, and alter the ratio of IgG2a/IgG in favor of IgG2a. These findings correlated with a shift toward a Th1 immune response and improved protective immunity against S. typhimurium. Also, the group receiving the combined adjuvant had a longer survival rate following exposure to the acute dose of S. typhimurium and had a lower bacterial load in the liver when exposed to the subacute dose of S. typhimurium compared to other immunization protocols. Overall,the combined alum and CGA significantly boosted cellular and humoral immunity following HKST immunization.
{"title":"Adjuvant Synergy: Alum and chlorogenic acid enhance Th1 responses and survival in a Salmonella typhimurium challenge model","authors":"Mahtab Pourkamalzadeh, Seyyed Meysam Abtahi Froushani, Abdolgaffar Ownagh","doi":"10.1016/j.biologicals.2025.101864","DOIUrl":"10.1016/j.biologicals.2025.101864","url":null,"abstract":"<div><div>Alum adjuvants do not induce Th1 responses with killed microorganisms, although Th1 responses are crucial for defending against intracellular microbes. Chlorogenic acid (CGA) can shift immune responses from Th2 toward Th1. This study assessed the benefits of combining CGA with alum on cellular and humoral immunity following immunization with a heat-killed preparation of <em>Salmonella typhimurium</em> (HKST). Male Balb/c mice received two doses of the HKST vaccine, with or without alum, CGA, or both, administered two weeks apart. Immune responses and protection against <em>S. typhimurium</em> were evaluated two weeks after the final dose.The alum and CGA combination enhanced the HKST vaccine's ability to stimulate lymphocyte proliferation, delayed-type hypersensitivity reactions, and antibody titers, and alter the ratio of IgG2a/IgG in favor of IgG2a. These findings correlated with a shift toward a Th1 immune response and improved protective immunity against <em>S. typhimurium</em>. Also, the group receiving the combined adjuvant had a longer survival rate following exposure to the acute dose of <em>S. typhimurium</em> and had a lower bacterial load in the liver when exposed to the subacute dose of <em>S. typhimurium</em> compared to other immunization protocols. Overall,the combined alum and CGA significantly boosted cellular and humoral immunity following HKST immunization.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101864"},"PeriodicalIF":1.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/j.biologicals.2025.101861
Silvia M. Becerra-Bayona , Víctor Alfonso Solarte , Juan Dario Alviar Rueda , Claudia L. Sossa , Martha L. Arango-Rodríguez
{"title":"Corrigendum to “Effect of biomolecules derived from human platelet-rich plasma on the ex vivo expansion of human adipose-derived mesenchymal stem cells for clinical applications” [Biologicals 75 (2022) 37–48]","authors":"Silvia M. Becerra-Bayona , Víctor Alfonso Solarte , Juan Dario Alviar Rueda , Claudia L. Sossa\u2028 , Martha L. Arango-Rodríguez","doi":"10.1016/j.biologicals.2025.101861","DOIUrl":"10.1016/j.biologicals.2025.101861","url":null,"abstract":"","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101861"},"PeriodicalIF":1.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.biologicals.2025.101862
Ian Feavers , Dianliang Lei , Catherine Milne , Ivana Knezevic , Tiequn Zhou , Eunkyung Kim
Animal testing has long supported the development and quality control of biotherapeutics and vaccines by ensuring safety and efficacy. However, its variability and time-consuming nature can delay product availability. Advances in non-animal technologies, guided by the 3Rs principles, have led to more efficient and scientifically robust alternatives. Recognizing the limitations of animal assays, WHO encourages their replacement when scientifically justified and has drafted a Guideline on phasing out animal tests in biological product quality control. Following public consultation, an informal meeting at WHO Headquarters brought together regulators, industry representatives, and other stakeholders to review the draft. The Guideline was developed based on ECBS recommendations and a review of existing WHO documents. Participants proposed improvements, including a revised title, to better emphasize the scientific rationale for replacing animal-based tests used in quality control scheme. These updates aim to support finalization of the document for a second public consultation and ECBS adoption.
{"title":"Conference report WHO informal consultation on the draft WHO Guideline on the phasing out of animal tests for the quality control of biological products","authors":"Ian Feavers , Dianliang Lei , Catherine Milne , Ivana Knezevic , Tiequn Zhou , Eunkyung Kim","doi":"10.1016/j.biologicals.2025.101862","DOIUrl":"10.1016/j.biologicals.2025.101862","url":null,"abstract":"<div><div>Animal testing has long supported the development and quality control of biotherapeutics and vaccines by ensuring safety and efficacy. However, its variability and time-consuming nature can delay product availability. Advances in non-animal technologies, guided by the 3Rs principles, have led to more efficient and scientifically robust alternatives. Recognizing the limitations of animal assays, WHO encourages their replacement when scientifically justified and has drafted a Guideline on phasing out animal tests in biological product quality control. Following public consultation, an informal meeting at WHO Headquarters brought together regulators, industry representatives, and other stakeholders to review the draft. The Guideline was developed based on ECBS recommendations and a review of existing WHO documents. Participants proposed improvements, including a revised title, to better emphasize the scientific rationale for replacing animal-based tests used in quality control scheme. These updates aim to support finalization of the document for a second public consultation and ECBS adoption.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101862"},"PeriodicalIF":1.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intravenous immunoglobulin (IVIg) product is a pooled human plasma-derived IgG medicinal product indicated for various immunodeficiency and autoimmune diseases. These indications have essentially been approved in Japan based on clinical evaluations of each product, but a harmonization or standardization of IVIg products would be helpful. We introduce a new Japanese regulatory perspective on the extrapolation of indications for approved IVIg products from a reference product composed of intact IgG (chemically unmodified full-length IgG) based on the consideration of the mode of action (MOA), a quality-comparability analysis, and the post-marketing clinical track record's re-examination regarding the products' efficacy and safety.
{"title":"A new Japanese regulatory perspective regarding the indication extrapolation between approved intravenous immunoglobulins (IVIg) products based on comparability assessments of quality attributes","authors":"Takashi Kameda , Kazuki Nagashima , Shun Masuta , Teruhide Yamaguchi , Michihiro Ogawa","doi":"10.1016/j.biologicals.2025.101860","DOIUrl":"10.1016/j.biologicals.2025.101860","url":null,"abstract":"<div><div>Intravenous immunoglobulin (IVIg) product is a pooled human plasma-derived IgG medicinal product indicated for various immunodeficiency and autoimmune diseases. These indications have essentially been approved in Japan based on clinical evaluations of each product, but a harmonization or standardization of IVIg products would be helpful. We introduce a new Japanese regulatory perspective on the extrapolation of indications for approved IVIg products from a reference product composed of intact IgG (chemically unmodified full-length IgG) based on the consideration of the mode of action (MOA), a quality-comparability analysis, and the post-marketing clinical track record's re-examination regarding the products' efficacy and safety.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101860"},"PeriodicalIF":1.5,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145049270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1016/j.biologicals.2025.101859
Arifa S. Khan , Laurent Mallet , Johannes Blümel , Noémie Deneyer , Sigrid De C.J. Keersmaecker , Blandine de Saint-Vis , Ivana Knezevic , Carine Logvinoff , Marie Murphy , Siemon H.S. Ng , Yoji Sato , Michael Wall , Ana Goios , Pieter Neels
This report is a summary of the 4th Conference on NGS for Adventitious Virus Detection, which took place on December 4–5, 2024, in Frankfurt, Germany, and was sponsored by the International Alliance for Biological Standardization (IABS), and co-chaired by the U.S. Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines & HealthCare (EDQM). The increased interest in using NGS for adventitious virus detection follows its recent introduction in the ICH Q5A (R2) guideline and the new EDQM/European Pharmacopoeia general chapter 2.6.41. Key conference objectives included evaluating NGS validation and implementation, addressing regional challenges, and discussing regulatory acceptance as an alternative method to the conventional assays. The conference fostered networking between early and established NGS users and emphasized the Advanced Virus Detection Technologies Working Group as a key learning hub for NGS applications. Discussions focused on method validation requirements and the need for defining a specific limit of detection. Participants shared updates on scientific developments and regulatory submissions. A general consensus was reached on the readiness of NGS to replace the in vivo adventitious virus detection assays and PCR assays, and to supplement or replace the in vitro cell-based assays, based on a suitable validation package.
{"title":"Report of the fourth conference on next-generation sequencing (NGS) for adventitious virus detection in biologics for humans and animals: Validation and implementation of NGS","authors":"Arifa S. Khan , Laurent Mallet , Johannes Blümel , Noémie Deneyer , Sigrid De C.J. Keersmaecker , Blandine de Saint-Vis , Ivana Knezevic , Carine Logvinoff , Marie Murphy , Siemon H.S. Ng , Yoji Sato , Michael Wall , Ana Goios , Pieter Neels","doi":"10.1016/j.biologicals.2025.101859","DOIUrl":"10.1016/j.biologicals.2025.101859","url":null,"abstract":"<div><div>This report is a summary of the 4th Conference on NGS for Adventitious Virus Detection, which took place on December 4–5, 2024, in Frankfurt, Germany, and was sponsored by the International Alliance for Biological Standardization (IABS), and co-chaired by the U.S. Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines & HealthCare (EDQM). The increased interest in using NGS for adventitious virus detection follows its recent introduction in the ICH Q5A (R2) guideline and the new EDQM/European Pharmacopoeia general chapter 2.6.41. Key conference objectives included evaluating NGS validation and implementation, addressing regional challenges, and discussing regulatory acceptance as an alternative method to the conventional assays. The conference fostered networking between early and established NGS users and emphasized the Advanced Virus Detection Technologies Working Group as a key learning hub for NGS applications. Discussions focused on method validation requirements and the need for defining a specific limit of detection. Participants shared updates on scientific developments and regulatory submissions. A general consensus was reached on the readiness of NGS to replace the <em>in vivo</em> adventitious virus detection assays and PCR assays, and to supplement or replace the <em>in vitro</em> cell-based assays, based on a suitable validation package.</div></div>","PeriodicalId":55369,"journal":{"name":"Biologicals","volume":"92 ","pages":"Article 101859"},"PeriodicalIF":1.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145049269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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