ACS Pharmacology and Translational Science最新文献

{"title":"Correction to “Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy”","authors":"Tianyi Wang, Kaiqi Long, Yang Zhou, Xiaoding Jiang, Jinzhao Liu, John H.C. Fong, Alan S.L. Wong, Wai-Lung Ng and Weiping Wang*, ","doi":"10.1021/acsptsci.4c0071410.1021/acsptsci.4c00714","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00714https://doi.org/10.1021/acsptsci.4c00714","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"270 270"},"PeriodicalIF":4.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detailed Structural Elucidation of Antibody-Drug Conjugate Biotransformation Species Using High Resolution Multiple Reaction Monitoring Mass Spectrometry with Orthogonal Dissociation Methods.","authors":"Junyan Yang, Hui Yin Tan, Jiaqi Yuan, Yue Huang, Anton I Rosenbaum","doi":"10.1021/acsptsci.4c00445","DOIUrl":"10.1021/acsptsci.4c00445","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are a promising drug modality substantially expanding in both the discovery space and clinical development. Assessing the biotransformation of ADCs <i>in vitro</i> and <i>in vivo</i> is important in understanding their stability and pharmacokinetic properties. We previously reported biotransformation pathways for the anti-B7H4 topoisomerase I inhibitor ADC, AZD8205, puxitatug samrotecan, that underpin its structural stability <i>in vivo</i> using an intact protein liquid chromatography-high resolution mass spectrometry (LC-HRMS) approach. Herein, we employed a LC-high resolution multiple reaction monitoring (LC-MRM^HR) approach using both collision-induced dissociation (CID) and electron-activated dissociation (EAD) methods, confirming our earlier findings. Furthermore, we were able to obtain additional detailed structural information on the biotransformation products expanding on earlier intact analyses. We also highlight the high sensitivity of LC-MRM^HR for successfully identifying minor biotransformation products at low concentrations that were not detectable using the intact protein LC-HRMS workflow. Especially, EAD aided in the confirmation of biotransformation species that contain newly formed disulfide bonds due to the preferential dissociation of disulfide bonds using this method. We observed biotransformation reactions that vary between linker-payload (PL) conjugation sites on the antibody. For example, the trend toward constitutional isomerism in thio-succinimide linker hydrolysis, and the resulting positional isomers from thiol adduct formation following linker-PL deconjugation. The reported orthogonal analytical approaches highly complement and fortify the intact protein LC-HRMS data. This study sheds further light on detailed structural characterization of various ADC species and validates the proposed biotransformation pathways explaining the stability of AZD8205 <i>in vivo</i>.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"113-123"},"PeriodicalIF":4.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Oxidative Stress and Neuroinflammation on Sarco/Endoplasmic Reticulum Ca²⁺-ATPase 2b Downregulation and Endoplasmic Reticulum Stress in Temporal Lobe Epilepsy.","authors":"Vikas Yadav, Sudipta Nayak, Sandeep Guin, Awanish Mishra","doi":"10.1021/acsptsci.4c00556","DOIUrl":"10.1021/acsptsci.4c00556","url":null,"abstract":"<p><p>Epilepsy is one of the most common neurological disorders. Calcium dysregulation and neuroinflammation are essential and common mechanisms in epileptogenesis. Sarco/endoplasmic reticulum (ER) Ca²⁺-ATPase 2b (SERCA2b), a crucial calcium regulatory pump, plays pathological roles in various calcium dysregulation-related diseases. However, the link between SERCA2b and neuroinflammation in epilepsy remains undetermined. This study aimed to establish the relationship between SERCA2b, oxidative stress, and neuroinflammation in epilepsy to elucidate the underlying molecular mechanism in epileptogenesis. Neuroinflammation and oxidative stress were induced in N2a cells using lipopolysaccharide (LPS) and hydrogen peroxide (H₂O₂). However, experimental temporal lobe epilepsy (TLE) was induced in mice using pilocarpine. Further, effects of oxidative stress and neuroinflammation on SERCA2b and ER stress markers were assessed at protein and mRNA levels. Calcium imaging was employed to determine intracellular calcium levels. SERCA2b expression significantly decreased after LPS, H₂O₂, and pilocarpine exposure at both mRNA and protein levels, mediated by upregulating neuroinflammation. This downregulation of SERCA2b was associated with increased production of reactive oxygen species and elevated intracellular calcium levels, leading to elevated ER stress markers. Our findings highlight a link between oxidative stress, neuroinflammation and SERCA2b in TLE. The results suggest that targeting SERCA2b could restore calcium homeostasis and ER stress processes, potentially providing a therapeutic option for TLE. This study underscores the importance of SERCA2b in the pathophysiology of epilepsy and its potential as a therapeutic target.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"173-188"},"PeriodicalIF":4.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs","authors":"Jindrich Sedlacek*,&nbsp;","doi":"10.1021/acsptsci.4c0040810.1021/acsptsci.4c00408","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00408https://doi.org/10.1021/acsptsci.4c00408","url":null,"abstract":"<p >The 26S proteasome degrades the majority of cellular proteins and affects all aspects of cellular life. Therefore, the 26S proteasome abundance, proper assembly, and activity in different life contexts need to be precisely controlled. Impaired proteasome activity is considered a causative factor in several serious disorders. Recent advances in proteasome biology have revealed that the proteasome can be activated by different factors or small molecules. Thus, activated ubiquitin-dependent proteasome degradation has effects such as extending the lifespan in different models, preventing the accumulation of protein aggregates, and reducing their negative impact on cells. Increased 26S proteasome-mediated degradation reduces proteotoxic stress and can potentially improve the efficacy of engineered degraders, such as PROTACs, particularly in situations characterized by proteasome malfunction. Here, emerging ideas and recent insights into the pharmacological activation of the proteasome at the transcriptional and posttranslational levels are summarized.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"21–35 21–35"},"PeriodicalIF":4.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00408","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs.","authors":"Jindrich Sedlacek","doi":"10.1021/acsptsci.4c00408","DOIUrl":"10.1021/acsptsci.4c00408","url":null,"abstract":"<p><p>The 26S proteasome degrades the majority of cellular proteins and affects all aspects of cellular life. Therefore, the 26S proteasome abundance, proper assembly, and activity in different life contexts need to be precisely controlled. Impaired proteasome activity is considered a causative factor in several serious disorders. Recent advances in proteasome biology have revealed that the proteasome can be activated by different factors or small molecules. Thus, activated ubiquitin-dependent proteasome degradation has effects such as extending the lifespan in different models, preventing the accumulation of protein aggregates, and reducing their negative impact on cells. Increased 26S proteasome-mediated degradation reduces proteotoxic stress and can potentially improve the efficacy of engineered degraders, such as PROTACs, particularly in situations characterized by proteasome malfunction. Here, emerging ideas and recent insights into the pharmacological activation of the proteasome at the transcriptional and posttranslational levels are summarized.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"21-35"},"PeriodicalIF":4.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Oxidative Stress and Neuroinflammation on Sarco/Endoplasmic Reticulum Ca2+-ATPase 2b Downregulation and Endoplasmic Reticulum Stress in Temporal Lobe Epilepsy","authors":"Vikas Yadav,&nbsp;Sudipta Nayak,&nbsp;Sandeep Guin and Awanish Mishra*,&nbsp;","doi":"10.1021/acsptsci.4c0055610.1021/acsptsci.4c00556","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00556https://doi.org/10.1021/acsptsci.4c00556","url":null,"abstract":"<p >Epilepsy is one of the most common neurological disorders. Calcium dysregulation and neuroinflammation are essential and common mechanisms in epileptogenesis. Sarco/endoplasmic reticulum (ER) Ca²⁺-ATPase 2b (SERCA2b), a crucial calcium regulatory pump, plays pathological roles in various calcium dysregulation-related diseases. However, the link between SERCA2b and neuroinflammation in epilepsy remains undetermined. This study aimed to establish the relationship between SERCA2b, oxidative stress, and neuroinflammation in epilepsy to elucidate the underlying molecular mechanism in epileptogenesis. Neuroinflammation and oxidative stress were induced in N2a cells using lipopolysaccharide (LPS) and hydrogen peroxide (H₂O₂). However, experimental temporal lobe epilepsy (TLE) was induced in mice using pilocarpine. Further, effects of oxidative stress and neuroinflammation on SERCA2b and ER stress markers were assessed at protein and mRNA levels. Calcium imaging was employed to determine intracellular calcium levels. SERCA2b expression significantly decreased after LPS, H₂O₂, and pilocarpine exposure at both mRNA and protein levels, mediated by upregulating neuroinflammation. This downregulation of SERCA2b was associated with increased production of reactive oxygen species and elevated intracellular calcium levels, leading to elevated ER stress markers. Our findings highlight a link between oxidative stress, neuroinflammation and SERCA2b in TLE. The results suggest that targeting SERCA2b could restore calcium homeostasis and ER stress processes, potentially providing a therapeutic option for TLE. This study underscores the importance of SERCA2b in the pathophysiology of epilepsy and its potential as a therapeutic target.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"173–188 173–188"},"PeriodicalIF":4.9,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cemdomespib Therapy Slows the Progression of Neuromuscular Weakness and Demyelination in the R75W-Connexin 32 Animal Model of Charcot-Marie-Tooth 1X Disease.","authors":"Ryan M Lang, Riddhi Chawla, Sugandha Patel, Charles K Abrams, Rick T Dobrowsky","doi":"10.1021/acsptsci.4c00464","DOIUrl":"10.1021/acsptsci.4c00464","url":null,"abstract":"<p><p>Mutations in connexin 32 (Cx32) are a common cause of Charcot-Marie-Tooth 1X (CMT1X) disease, an inherited peripheral neuropathy characterized by progressive neuromuscular weakness and demyelination. There are no approved pharmacologic therapies for CMT1X, and identifying new treatments that slow the onset and severity of neuromuscular decline may aid disease management. Cemdomespib is an orally bioavailable small molecule that improved demyelination and neuromuscular junction (NMJ) morphology in mice lacking Cx32 expression. However, whether a similar efficacy may manifest in models of CMT1X arising from Cx32 mutations that cause the organellar accumulation of the protein was unclear. Additionally, it was unclear whether cemdomespib therapy slowed the rate of demyelination/NMJ degeneration or stabilized nerve and NMJ morphology to levels present at the initiation of drug therapy. To address these issues, 4-month-old R75W-Cx32 mice, which accumulate the mutant Cx32 in golgi, were treated for 0, 10, or 20 weeks with 0 or 3 mg/kg cemdomespib. Grip strength, motor nerve conduction velocity (MNCV), femoral nerve myelination, and NMJ morphology were quantified. Daily drug therapy significantly slowed the decline in grip strength over the course of treatment, while 20 weeks of drug treatment significantly improved MNCV and decreased the g-ratio and the number of thinly myelinated femoral nerve axons. Similarly, 20 weeks of cemdomespib therapy improved the NMJ morphology and the overlap between presynaptic (synaptophysin) and postsynaptic (α-bungarotoxin) markers. These data show that cemdomespib therapy slows the rate of neuromuscular decline and demyelination and may present a disease-modifying approach for patients with gain-of-function Cx32 mutations.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"124-135"},"PeriodicalIF":4.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Clinical Validation of Model-Informed Precision Dosing for Everolimus in Liver Transplant Recipients.","authors":"Jeayoon Lee, In-Wha Kim, Suk Kyun Hong, Nayoung Han, Kyung-Suk Suh, Jung Mi Oh","doi":"10.1021/acsptsci.4c00581","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00581","url":null,"abstract":"<p><p>Everolimus presents significant dosing challenges due to between- and within-patient pharmacokinetic variabilities. This study aimed to develop and validate a model-informed precision dosing strategy for everolimus in liver transplant recipients. The dosing strategy was initially developed using retrospective data, employing nonlinear mixed-effects modeling. The model included readily measurable covariates, body surface area, albumin, and tacrolimus trough concentration. The dosing strategy was subsequently validated in a prospective trial, recommending 1 to 1.75 mg dosages every 12 h, depending on covariates. Lower dosages were recommended for patients with lower body surface area and albumin with adjustments based on tacrolimus trough concentration. The estimated pharmacokinetic parameters (typical value ± standard error), apparent clearance (CL/<i>F</i>: 15.0 ± 0.5 L/h), and apparent volume of distribution (V_d/<i>F</i>: 862 ± 79.3 L) were refined using prospective clinical data from 20 patients, reducing interindividual variations. This research successfully developed and validated a population pharmacokinetic model for everolimus. The developed \"dosE\" web-based platform translates our pharmacokinetic model into a practical tool for healthcare providers, exemplifying the application of pharmaceutical research in clinical practice and potentially improving therapeutic outcomes in liver transplantation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"216-224"},"PeriodicalIF":4.9,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cemdomespib Therapy Slows the Progression of Neuromuscular Weakness and Demyelination in the R75W-Connexin 32 Animal Model of Charcot–Marie–Tooth 1X Disease","authors":"Ryan M. Lang,&nbsp;Riddhi Chawla,&nbsp;Sugandha Patel,&nbsp;Charles K. Abrams and Rick T. Dobrowsky*,&nbsp;","doi":"10.1021/acsptsci.4c0046410.1021/acsptsci.4c00464","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00464https://doi.org/10.1021/acsptsci.4c00464","url":null,"abstract":"<p >Mutations in connexin 32 (Cx32) are a common cause of Charcot–Marie–Tooth 1X (CMT1X) disease, an inherited peripheral neuropathy characterized by progressive neuromuscular weakness and demyelination. There are no approved pharmacologic therapies for CMT1X, and identifying new treatments that slow the onset and severity of neuromuscular decline may aid disease management. Cemdomespib is an orally bioavailable small molecule that improved demyelination and neuromuscular junction (NMJ) morphology in mice lacking Cx32 expression. However, whether a similar efficacy may manifest in models of CMT1X arising from Cx32 mutations that cause the organellar accumulation of the protein was unclear. Additionally, it was unclear whether cemdomespib therapy slowed the rate of demyelination/NMJ degeneration or stabilized nerve and NMJ morphology to levels present at the initiation of drug therapy. To address these issues, 4-month-old R75W-Cx32 mice, which accumulate the mutant Cx32 in golgi, were treated for 0, 10, or 20 weeks with 0 or 3 mg/kg cemdomespib. Grip strength, motor nerve conduction velocity (MNCV), femoral nerve myelination, and NMJ morphology were quantified. Daily drug therapy significantly slowed the decline in grip strength over the course of treatment, while 20 weeks of drug treatment significantly improved MNCV and decreased the g-ratio and the number of thinly myelinated femoral nerve axons. Similarly, 20 weeks of cemdomespib therapy improved the NMJ morphology and the overlap between presynaptic (synaptophysin) and postsynaptic (α-bungarotoxin) markers. These data show that cemdomespib therapy slows the rate of neuromuscular decline and demyelination and may present a disease-modifying approach for patients with gain-of-function Cx32 mutations.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"124–135 124–135"},"PeriodicalIF":4.9,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Clinical Validation of Model-Informed Precision Dosing for Everolimus in Liver Transplant Recipients","authors":"Jeayoon Lee,&nbsp;In-Wha Kim,&nbsp;Suk Kyun Hong,&nbsp;Nayoung Han,&nbsp;Kyung-Suk Suh and Jung Mi Oh*,&nbsp;","doi":"10.1021/acsptsci.4c0058110.1021/acsptsci.4c00581","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00581https://doi.org/10.1021/acsptsci.4c00581","url":null,"abstract":"<p >Everolimus presents significant dosing challenges due to between- and within-patient pharmacokinetic variabilities. This study aimed to develop and validate a model-informed precision dosing strategy for everolimus in liver transplant recipients. The dosing strategy was initially developed using retrospective data, employing nonlinear mixed-effects modeling. The model included readily measurable covariates, body surface area, albumin, and tacrolimus trough concentration. The dosing strategy was subsequently validated in a prospective trial, recommending 1 to 1.75 mg dosages every 12 h, depending on covariates. Lower dosages were recommended for patients with lower body surface area and albumin with adjustments based on tacrolimus trough concentration. The estimated pharmacokinetic parameters (typical value ± standard error), apparent clearance (CL/<i>F</i>: 15.0 ± 0.5 L/h), and apparent volume of distribution (V_d/<i>F</i>: 862 ± 79.3 L) were refined using prospective clinical data from 20 patients, reducing interindividual variations. This research successfully developed and validated a population pharmacokinetic model for everolimus. The developed “dosE” web-based platform translates our pharmacokinetic model into a practical tool for healthcare providers, exemplifying the application of pharmaceutical research in clinical practice and potentially improving therapeutic outcomes in liver transplantation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"216–224 216–224"},"PeriodicalIF":4.9,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00581","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}