{"title":"Usefulness of antibody-drug conjugate as preconditioning for hematopoietic stem cell-targeted gene therapy in wild-type and Fabry disease mouse models","authors":"Jin Ogata , Yohta Shimada , Toya Ohashi , Hiroshi Kobayashi","doi":"10.1016/j.ymgme.2024.108494","DOIUrl":"10.1016/j.ymgme.2024.108494","url":null,"abstract":"<div><h3>Background</h3><p>Fabry disease (FD) is characterized by deficient activity of α-galactosidase A (GLA). Consequently, globotriaosylceramide (Gb3) accumulates in various organs, causing cardiac, renal, and cerebrovascular damage. Gene therapies for FD have been investigated in humans. Strong conditioning is required for hematopoietic stem cell-targeted gene therapy (HSC-GT). However, strong conditioning leads to various side effects and should be avoided. In this study, we tested antibody-based conditioning for HSC-GT in wild-type and FD model mice.</p></div><div><h3>Methods</h3><p>After preconditioning with an antibody-drug conjugate, HSC-GT using a lentiviral vector was performed in wild-type and Fabry model mice. In the wild-type experiment, the <em>EGFP</em> gene was introduced into HSCs and transplanted into preconditioned mice, and donor chimerism and EGFP expression were analyzed. In the FD mouse model, the <em>GLA</em> gene was introduced into HSCs and transplanted into preconditioned Fabry mice. GLA activity and Gb3 accumulation in the organs were analyzed.</p></div><div><h3>Results</h3><p>In the wild-type mouse experiment, when anti-CD45 antibody-drug conjugate was used, the percentage of donor cells at 6 months was 64.5%, and 69.6% of engrafted donor peripheral blood expressed EGFP. When anti-CD117 antibody-drug conjugate and ATG were used, the percentage of donor cells at 6 months was 80.7%, and 73.4% of engrafted donor peripheral blood expressed EGFP. Although large variations in GLA activity among mice were observed in the FD mouse experiment for both preconditioning regimens, Gb3 was significantly reduced in many organs.</p></div><div><h3>Conclusions</h3><p>Antibody-based preconditioning may be an alternative preconditioning strategy for HSC-GT for treating FD.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141037183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yu Leng Phua , Olivia M. D'Annibale , Anuradha Karunanidhi , Al-Walid Mohsen , Brian Kirmse , Steven F. Dobrowolski , Jerry Vockley
{"title":"A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria","authors":"Yu Leng Phua , Olivia M. D'Annibale , Anuradha Karunanidhi , Al-Walid Mohsen , Brian Kirmse , Steven F. Dobrowolski , Jerry Vockley","doi":"10.1016/j.ymgme.2024.108495","DOIUrl":"10.1016/j.ymgme.2024.108495","url":null,"abstract":"<div><h3>Purpose</h3><p>To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the <em>SLC25A1</em> gene.</p></div><div><h3>Methods</h3><p>Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing.</p></div><div><h3>Results</h3><p>In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink.</p></div><div><h3>Conclusion</h3><p>Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141046704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Promyelinating drugs ameliorate oligodendrocyte pathologies in a mouse model of Krabbe disease","authors":"Naoko Inamura , Taeko Kawai , Takashi Watanabe , Hiromasa Aoki , Mineyoshi Aoyama , Atsuo Nakayama , Junko Matsuda , Yasushi Enokido","doi":"10.1016/j.ymgme.2024.108497","DOIUrl":"10.1016/j.ymgme.2024.108497","url":null,"abstract":"<div><p>Krabbe disease (KD) is a rare inherited demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramide (GalCer) β-galactosidase. Most patients with KD exhibit fatal cerebral demyelination with apoptotic oligodendrocyte (OL) death and die before the age of 2–4 years. We have previously reported that primary OLs isolated from the brains of twitcher (twi) mice, an authentic mouse model of KD, have cell-autonomous developmental defects and undergo apoptotic death accompanied by abnormal accumulation of psychosine, an endogenous cytotoxic lyso-derivative of GalCer. In this study, we aimed to investigate the effects of the preclinical promyelinating drugs clemastine and Sob-AM2 on KD OL pathologies using primary OLs isolated from the brains of twi mice. Both agents specifically prevented the apoptotic death observed in twi OLs. However, while Sob-AM2 showed higher efficacy in restoring the impaired differentiation and maturation of twi OLs, clemastine more potently reduced the endogenous psychosine levels. These results present the first preclinical <em>in vitro</em> data, suggesting that clemastine and Sob-AM2 can act directly and distinctly on OLs in KD and ameliorate their cellular pathologies associated with myelin degeneration.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141061361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals","authors":"Tanyel Zubarioglu , Ertuğrul Kıykım , Engin Köse , Fatma Tuba Eminoğlu , Pelin Teke Kısa , Mehmet Cihan Balcı , Işıl Özer , Aslı İnci , Kübra Çilesiz , Ebru Canda , Havva Yazıcı , Burcu Öztürk-Hişmi , Fatma Derya Bulut , Sevil Dorum , Abdurrahman Akgun , Gül Yalçın-Çakmaklı , Gonca Kılıç-Yıldırım , Erdoğan Soyuçen , Aylin Akçalı , Dilek Güneş , Çiğdem Aktuğlu-Zeybek","doi":"10.1016/j.ymgme.2024.108493","DOIUrl":"10.1016/j.ymgme.2024.108493","url":null,"abstract":"<div><h3>Objective</h3><p>Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey.</p></div><div><h3>Methods</h3><p>The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed.</p></div><div><h3>Results</h3><p>100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (<em>p</em> = 0.069), peripheral neuropathy (<em>p</em> = 0.234) and psychiatric manifestations (<em>p</em> = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the <em>CYP27A1</em> gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature.</p></div><div><h3>Conclusion</h3><p>Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141040956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rodrigo Tzovenos Starosta , Angela J. Lee , Elizabeth R. Toolan , Miao He , Parith Wongkittichote , Earnest James Paul Daniel , Silvia Radenkovic , Rohit Budhraja , Akhilesh Pandey , Jaiprakash Sharma , Eva Morava , Hoanh Nguyen , Patricia I. Dickson
{"title":"D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG)","authors":"Rodrigo Tzovenos Starosta , Angela J. Lee , Elizabeth R. Toolan , Miao He , Parith Wongkittichote , Earnest James Paul Daniel , Silvia Radenkovic , Rohit Budhraja , Akhilesh Pandey , Jaiprakash Sharma , Eva Morava , Hoanh Nguyen , Patricia I. Dickson","doi":"10.1016/j.ymgme.2024.108488","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108488","url":null,"abstract":"<div><h3>Introduction</h3><p>Fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG) is a rare autosomal recessive inborn error of metabolism characterized by a decreased flux through the salvage pathway of GDP-fucose biosynthesis due to a block in the recycling of L-fucose that exits the lysosome. FCSK-CDG has been described in 5 individuals to date in the medical literature, with a phenotype comprising global developmental delays/intellectual disability, hypotonia, abnormal myelination, posterior ocular disease, growth and feeding failure, immune deficiency, and chronic diarrhea, without clear therapeutic recommendations.</p></div><div><h3>Patient and methods</h3><p>In a so far unreported FCSK-CDG patient, we studied proteomics and glycoproteomics <em>in vitro</em> in patient-derived fibroblasts and also performed <em>in vivo</em> glycomics, before and after treatment with either D-Mannose or L-Fucose.</p></div><div><h3>Results</h3><p>We observed a marked increase in fucosylation after D-mannose supplementation in fibroblasts compared to treatment with L-Fucose. The patient was then treated with D-mannose at 850 mg/kg/d, with resolution of the chronic diarrhea, resolution of oral aversion, improved weight gain, and observed developmental gains. Serum N-glycan profiles showed an improvement in the abundance of fucosylated glycans after treatment. No treatment-attributed adverse effects were observed.</p></div><div><h3>Conclusion</h3><p>D-mannose is a promising new treatment for FCSK-CDG.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140910194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marta Murray , Lindsay Davidson , Andrew T. Ferenbach , Dirk Lefeber , Daan M.F. van Aalten
{"title":"Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability","authors":"Marta Murray , Lindsay Davidson , Andrew T. Ferenbach , Dirk Lefeber , Daan M.F. van Aalten","doi":"10.1016/j.ymgme.2024.108492","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108492","url":null,"abstract":"<div><p>Pathogenic variants in the O-GlcNAc transferase gene (<em>OGT</em>) have been associated with a congenital disorder of glycosylation (OGT-CDG), presenting with intellectual disability which may be of neuroectodermal origin. To test the hypothesis that pathology is linked to defects in differentiation during early embryogenesis, we developed an OGT-CDG induced pluripotent stem cell line together with isogenic control generated by CRISPR/Cas9 gene-editing. Although the OGT-CDG variant leads to a significant decrease in OGT and O-GlcNAcase protein levels, there were no changes in differentiation potential or stemness. However, differentiation into ectoderm resulted in significant differences in O-GlcNAc homeostasis. Further differentiation to neuronal stem cells revealed differences in morphology between patient and control lines, accompanied by disruption of the O-GlcNAc pathway. This suggests a critical role for O-GlcNAcylation in early neuroectoderm architecture, with robust compensatory mechanisms in the earliest stages of stem cell differentiation.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003767/pdfft?md5=d52608713fac9ecbebb266e4897a3884&pid=1-s2.0-S1096719224003767-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140951291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rohit Budhraja , Silvia Radenkovic , Anu Jain , Irena J.J. Muffels , Moulay Hicham Alaoui Ismaili , Tamas Kozicz , Akhilesh Pandey , Eva Morava
{"title":"Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation","authors":"Rohit Budhraja , Silvia Radenkovic , Anu Jain , Irena J.J. Muffels , Moulay Hicham Alaoui Ismaili , Tamas Kozicz , Akhilesh Pandey , Eva Morava","doi":"10.1016/j.ymgme.2024.108487","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108487","url":null,"abstract":"<div><p>Phosphomannomutase 2 (PMM2) converts mannose-6-phospahate to mannose-1-phosphate; the substrate for GDP-mannose, a building block of the glycosylation biosynthetic pathway. Pathogenic variants in the <em>PMM2</em> gene have been shown to be associated with protein hypoglycosylation causing PMM2-congenital disorder of glycosylation (PMM2-CDG). While mannose supplementation improves glycosylation in vitro, but not in vivo, we hypothesized that liposomal delivery of mannose-1-phosphate could increase the stability and delivery of the activated sugar to enter the targeted compartments of cells. Thus, we studied the effect of liposome-encapsulated mannose-1-P (GLM101) on global protein glycosylation and on the cellular proteome in skin fibroblasts from individuals with PMM2-CDG, as well as in individuals with two N-glycosylation defects early in the pathway, namely ALG2-CDG and ALG11-CDG. We leveraged multiplexed proteomics and N-glycoproteomics in fibroblasts derived from different individuals with various pathogenic variants in <em>PMM2, ALG2</em> and <em>ALG11</em> genes. Proteomics data revealed a moderate but significant change in the abundance of some of the proteins in all CDG fibroblasts upon GLM101 treatment. On the other hand, N-glycoproteomics revealed the GLM101 treatment enhanced the expression levels of several high-mannose and complex/hybrid glycopeptides from numerous cellular proteins in individuals with defects in <em>PMM2</em> and <em>ALG2</em> genes. Both PMM2-CDG and ALG2-CDG exhibited several-fold increase in glycopeptides bearing Man<sub>6</sub> and higher glycans and a decrease in Man<sub>5</sub> and smaller glycan moieties, suggesting that GLM101 helps in the formation of mature glycoforms. These changes in protein glycosylation were observed in all individuals irrespective of their genetic variants. ALG11-CDG fibroblasts also showed increase in high mannose glycopeptides upon treatment; however, the improvement was not as dramatic as the other two CDG. Overall, our findings suggest that treatment with GLM101 overcomes the genetic block in the glycosylation pathway and can be used as a potential therapy for CDG with enzymatic defects in early steps in protein N-glycosylation.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Posern , Benjamin Dreyer , Sarah L. Maier , Florian Eichler , Michael H. Gelb , René Santer , Annette Bley , Simona Murko
{"title":"Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease","authors":"Christian Posern , Benjamin Dreyer , Sarah L. Maier , Florian Eichler , Michael H. Gelb , René Santer , Annette Bley , Simona Murko","doi":"10.1016/j.ymgme.2024.108489","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108489","url":null,"abstract":"<div><h3>Background</h3><p>Canavan disease is a devastating neurometabolic disorder caused by accumulation of <em>N</em> acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (<em>ASPA</em>). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective.</p></div><div><h3>Methods</h3><p>We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of <em>N</em>-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample.</p></div><div><h3>Results</h3><p>Measuring <em>N</em>-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6–13.6 μmol/L [<em>n</em> = 45] <em>vs</em> 0.44; 0.24–0.99 μmol/L [<em>n</em> = 59] (<em>p</em> < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1–9.9 μmol/L [<em>n</em> = 8]) and neonatal controls (0.93; 0.4–1.8 μmol/L [<em>n</em> = 784]) (p < 0.05).</p></div><div><h3>Conclusions</h3><p>We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224003731/pdfft?md5=1dea0f8fc69b0aeaadc13dc8e0e625fa&pid=1-s2.0-S1096719224003731-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140879429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael H. Gelb , Dietrich Matern , Matthew Ellinwood , Amy Gaviglio
{"title":"It's time to reconsider the newborn screening RUSP prospective pilot study “N of 1” rule","authors":"Michael H. Gelb , Dietrich Matern , Matthew Ellinwood , Amy Gaviglio","doi":"10.1016/j.ymgme.2024.108352","DOIUrl":"10.1016/j.ymgme.2024.108352","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}