ACS Pharmacology and Translational Science最新文献

{"title":"Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder","authors":"Boshi Huang,&nbsp;Hongguang Ma,&nbsp;Piyusha P. Pagare,&nbsp;Mengchu Li,&nbsp;Rolando E. Mendez,&nbsp;James C. Gillespie,&nbsp;Justin L. Poklis,&nbsp;Matthew S. Halquist,&nbsp;David L. Stevens,&nbsp;William L. Dewey,&nbsp;Dana E. Selley and Yan Zhang*,&nbsp;","doi":"10.1021/acsptsci.4c0059310.1021/acsptsci.4c00593","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00593https://doi.org/10.1021/acsptsci.4c00593","url":null,"abstract":"<p >The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound <b>6</b> (NTZ) exhibited improved opioid receptor selectivity, enhanced <i>in vivo</i> antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4165–4182 4165–4182"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00593","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842429","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":"Discovery of 6α-Thiazolylcarboxamidonaltrexamine Derivative (NTZ) as a Potent and Central Nervous System Penetrant Opioid Receptor Modulator with Drug-like Properties for Potential Treatment of Opioid Use Disorder.","authors":"Boshi Huang, Hongguang Ma, Piyusha P Pagare, Mengchu Li, Rolando E Mendez, James C Gillespie, Justin L Poklis, Matthew S Halquist, David L Stevens, William L Dewey, Dana E Selley, Yan Zhang","doi":"10.1021/acsptsci.4c00593","DOIUrl":"10.1021/acsptsci.4c00593","url":null,"abstract":"<p><p>The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound <b>6</b> (NTZ) exhibited improved opioid receptor selectivity, enhanced <i>in vivo</i> antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4165-4182"},"PeriodicalIF":4.9,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855397","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":"Advancements in the Treatment of Atherosclerosis: From Conventional Therapies to Cutting-Edge Innovations","authors":"Yan Liu,&nbsp;Kuan Lu,&nbsp;Ruru Zhang,&nbsp;Dongliang Hu,&nbsp;Zhe Yang,&nbsp;Jianfeng Zeng* and Wu Cai*,&nbsp;","doi":"10.1021/acsptsci.4c0057410.1021/acsptsci.4c00574","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00574https://doi.org/10.1021/acsptsci.4c00574","url":null,"abstract":"<p >Atherosclerosis is a leading cause of morbidity and mortality worldwide, driven by a complex interplay of lipid dysregulation, inflammation, and vascular pathology. Despite advancements in understanding the multifactorial nature of atherosclerosis and improvements in clinical management, existing therapies often fall short in reversing the disease, focusing instead on symptom alleviation and risk reduction. This review highlights recent strides in identifying genetic markers, elucidating inflammatory pathways, and understanding environmental contributors to atherosclerosis. It also evaluates the efficacy and limitations of current pharmacological treatments, revascularization techniques, and the impact of these interventions on patient outcomes. Furthermore, we explore innovative therapeutic strategies, including the promising fields of nanomedicine, nucleic acid-based therapies, and immunomodulation, which offer potential for targeted and effective treatment modalities. However, integrating these advances into clinical practice is challenged by regulatory, economic, and logistical barriers. This review synthesizes the latest research and clinical advancements to provide a comprehensive roadmap for future therapeutic strategies and emphasize the critical need for innovative approaches to fundamentally change the course of atherosclerosis management.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3804–3826 3804–3826"},"PeriodicalIF":4.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850518","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":"Advancements in the Treatment of Atherosclerosis: From Conventional Therapies to Cutting-Edge Innovations.","authors":"Yan Liu, Kuan Lu, Ruru Zhang, Dongliang Hu, Zhe Yang, Jianfeng Zeng, Wu Cai","doi":"10.1021/acsptsci.4c00574","DOIUrl":"10.1021/acsptsci.4c00574","url":null,"abstract":"<p><p>Atherosclerosis is a leading cause of morbidity and mortality worldwide, driven by a complex interplay of lipid dysregulation, inflammation, and vascular pathology. Despite advancements in understanding the multifactorial nature of atherosclerosis and improvements in clinical management, existing therapies often fall short in reversing the disease, focusing instead on symptom alleviation and risk reduction. This review highlights recent strides in identifying genetic markers, elucidating inflammatory pathways, and understanding environmental contributors to atherosclerosis. It also evaluates the efficacy and limitations of current pharmacological treatments, revascularization techniques, and the impact of these interventions on patient outcomes. Furthermore, we explore innovative therapeutic strategies, including the promising fields of nanomedicine, nucleic acid-based therapies, and immunomodulation, which offer potential for targeted and effective treatment modalities. However, integrating these advances into clinical practice is challenged by regulatory, economic, and logistical barriers. This review synthesizes the latest research and clinical advancements to provide a comprehensive roadmap for future therapeutic strategies and emphasize the critical need for innovative approaches to fundamentally change the course of atherosclerosis management.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3804-3826"},"PeriodicalIF":4.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855788","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":"Evaluating the Role of Lin-11, Isl-1, and Mec-3 Kinases in Dopaminergic Neurodegeneration in a Subacute 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Model of Parkinson’s Disease","authors":"Kritika Bhardwaj,&nbsp;Abhishek Roy,&nbsp;Lahanya Guha and Hemant Kumar*,&nbsp;","doi":"10.1021/acsptsci.4c0042310.1021/acsptsci.4c00423","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00423https://doi.org/10.1021/acsptsci.4c00423","url":null,"abstract":"<p >The malfunctioning of microtubules is highly correlated with neurodegenerative disorders such as Parkinson’s disease (PD), although whether it is a cause or an effect of neurodegeneration is yet unknown. Lin-11, Isl-1, and Mec-3 kinases (LIMKs), being one of the important kinases, regulate the neuronal cytoskeleton by controlling the phosphorylation of the cofilin/actin-depolymerizing factor. Recently, we showed that upregulation of phosphorylated LIMK1 (p-LIMK1) affects the microtubule dynamics in a central nervous system traumatic injury. The goal of this study is to correlate the expression of LIMK1 with dopaminergic neuron death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD, one of the well-established subacute models of PD, where the neurotoxin acts via inhibition of mitochondrial complex I of the electron transport chain. Herein, we found that LIMK1 expression was increased and correlated to dopaminergic neuronal death. Finally, we demonstrated that the treatment with LIMK inhibitor BMS-5 significantly reversed the neurodegeneration, along with an upregulation of the dynamic tubulins, indicating the relevance of LIMKs and microtubule dynamics in neurodegeneration. Therefore, targeting the microtubules, an integral part of the neuronal cytoskeleton and neurite formation, can be a promising strategy to combat degeneration of dopaminergic neurons.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3879–3888 3879–3888"},"PeriodicalIF":4.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842160","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":"Evaluating the Role of Lin-11, Isl-1, and Mec-3 Kinases in Dopaminergic Neurodegeneration in a Subacute 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Model of Parkinson's Disease.","authors":"Kritika Bhardwaj, Abhishek Roy, Lahanya Guha, Hemant Kumar","doi":"10.1021/acsptsci.4c00423","DOIUrl":"10.1021/acsptsci.4c00423","url":null,"abstract":"<p><p>The malfunctioning of microtubules is highly correlated with neurodegenerative disorders such as Parkinson's disease (PD), although whether it is a cause or an effect of neurodegeneration is yet unknown. Lin-11, Isl-1, and Mec-3 kinases (LIMKs), being one of the important kinases, regulate the neuronal cytoskeleton by controlling the phosphorylation of the cofilin/actin-depolymerizing factor. Recently, we showed that upregulation of phosphorylated LIMK1 (p-LIMK1) affects the microtubule dynamics in a central nervous system traumatic injury. The goal of this study is to correlate the expression of LIMK1 with dopaminergic neuron death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD, one of the well-established subacute models of PD, where the neurotoxin acts via inhibition of mitochondrial complex I of the electron transport chain. Herein, we found that LIMK1 expression was increased and correlated to dopaminergic neuronal death. Finally, we demonstrated that the treatment with LIMK inhibitor BMS-5 significantly reversed the neurodegeneration, along with an upregulation of the dynamic tubulins, indicating the relevance of LIMKs and microtubule dynamics in neurodegeneration. Therefore, targeting the microtubules, an integral part of the neuronal cytoskeleton and neurite formation, can be a promising strategy to combat degeneration of dopaminergic neurons.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3879-3888"},"PeriodicalIF":4.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855616","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":"A High-Throughput and Logarithm-Serial-Dilution Microfluidic Chip for Combinational Drug Screening on Tumor Organoids.","authors":"Xingyang Yan, Deng Tan, Lei Yu, DanYu Li, Wei Huang, Weiren Huang, Hongkai Wu","doi":"10.1021/acsptsci.4c00565","DOIUrl":"10.1021/acsptsci.4c00565","url":null,"abstract":"<p><p>Tumor organoids are biological models for studying precision medicine. Microfluidic technology offers significant benefits for high throughput drug screening using tumor organoids. However, the range of concentrations achievable with traditional linear gradient generators in microfluidics is restricted, generating logarithmic drug concentration gradients by adjusting the channel ratio in the chip is confined to single-drug dilution chips, significantly restricting the application of microfluidics in drug screening. Here, we presented a microfluidic chip featuring continuous dilution capabilities, which generates logarithmic stepwise drug concentration gradients. We have devised a \"mathematical-circuit-chip\" model for designing such chips, and based on this model, we have developed and fabricated a device capable of providing 36 distinct drug concentration conditions for two types of drugs. The chip is composed of two structurally identical yet orthogonally arranged layers, each containing a dilution network capable of forming a 5-fold gradient and a tumor organoid culture module. Drug and culture medium delivery to the open culture chamber array is driven by syringe pumps. We have conducted drug screening experiments on patient-derived tumor organoids. This device facilitates high-throughput drug screening for patient-derived organoids, representing a significant stride toward the realization of precision medicine.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4135-4143"},"PeriodicalIF":4.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855786","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":"A High-Throughput and Logarithm-Serial-Dilution Microfluidic Chip for Combinational Drug Screening on Tumor Organoids","authors":"Xingyang Yan,&nbsp;Deng Tan,&nbsp;Lei Yu,&nbsp;DanYu Li,&nbsp;Wei Huang,&nbsp;Weiren Huang and Hongkai Wu*,&nbsp;","doi":"10.1021/acsptsci.4c0056510.1021/acsptsci.4c00565","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00565https://doi.org/10.1021/acsptsci.4c00565","url":null,"abstract":"<p >Tumor organoids are biological models for studying precision medicine. Microfluidic technology offers significant benefits for high throughput drug screening using tumor organoids. However, the range of concentrations achievable with traditional linear gradient generators in microfluidics is restricted, generating logarithmic drug concentration gradients by adjusting the channel ratio in the chip is confined to single-drug dilution chips, significantly restricting the application of microfluidics in drug screening. Here, we presented a microfluidic chip featuring continuous dilution capabilities, which generates logarithmic stepwise drug concentration gradients. We have devised a “mathematical-circuit-chip” model for designing such chips, and based on this model, we have developed and fabricated a device capable of providing 36 distinct drug concentration conditions for two types of drugs. The chip is composed of two structurally identical yet orthogonally arranged layers, each containing a dilution network capable of forming a 5-fold gradient and a tumor organoid culture module. Drug and culture medium delivery to the open culture chamber array is driven by syringe pumps. We have conducted drug screening experiments on patient-derived tumor organoids. This device facilitates high-throughput drug screening for patient-derived organoids, representing a significant stride toward the realization of precision medicine.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4135–4143 4135–4143"},"PeriodicalIF":4.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842321","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":"Challenging Reported Frizzled-Targeting Compounds in Selective Assays Reveals Lack of Functional Inhibition and Claimed Profiles.","authors":"Alexey Koval, Cédric Boudou, Vladimir L Katanaev","doi":"10.1021/acsptsci.4c00570","DOIUrl":"10.1021/acsptsci.4c00570","url":null,"abstract":"<p><p>Selective inhibitors of Frizzled (FZD) GPCRs are highly sought after as potentially highly efficacious and safe treatments for cancer as well as tools in regenerative medicine and fundamental science. In recent years, there have been several reports claiming the identification of small molecule agents that are selective toward certain FZD proteins using a variety of approaches. However, the majority of these studies lacked a selective functional assay to validate their functionality. In this study, we describe the development and application of a selective assay for individual FZD proteins. Our findings indicate that the majority of reported compounds lack the capacity to inhibit the functioning of the claimed FZD proteins when stimulated by a Wnt ligand in the canonical pathway. Instead, the compounds demonstrate a broad range of off-target effects, including inhibition of downstream pathway component(s) (3235-0367, SRI35959, carbamazepine, niclosamide), lack of activity (FzM1), and surprising antagonism of firefly luciferase (F7H). The only compound that fulfills the expected selectivity profile is peptide Fz7-21. These results highlight the necessity of implementing rigorous testing of the screening-derived compounds in selective functional assays and are important for the field of drug discovery and development targeting the highly demanded Wnt-FZD pathway.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4144-4154"},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855793","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":"Long-Term Treatment with Fluoroethylnormemantine (FENM) Alleviated Memory Deficits, Amyloid Pathology, and Microglial Reaction in APP/PS1 Mice","authors":"Aline Freyssin,&nbsp;Allison Carles,&nbsp;Barbara Moha,&nbsp;Gilles Rubinstenn and Tangui Maurice*,&nbsp;","doi":"10.1021/acsptsci.4c0052210.1021/acsptsci.4c00522","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00522https://doi.org/10.1021/acsptsci.4c00522","url":null,"abstract":"<p >Fluoroethylnormemantine (FENM, RST-01) shows different pharmacological properties from Memantine. The drug is neuroprotective in pharmacological and transgenic mouse models of Alzheimer’s disease (AD), particularly limiting the neuroinflammatory response to amyloid-β (Aβ) accumulation. In order to define early therapeutic intervention aimed at preventing AD and targeting the early activation of proinflammatory pathways, we examined the impact of chronic FENM treatment starting presymptomatically in APP_swe/PSEN1^∂E9 (APP/PS1) mice. APP/PS1 (32 males and 36 females) and wild-type (WT, 23 males and 36 females) mice received FENM (0, 1, and 5 mg/kg/day) in the drinking bottle between 3 and 12 months of age. They were tested once a month for spontaneous alternation and, at the end of the treatment, for object recognition, water-maze learning, and passive avoidance. Amyloid plaques, astrocytes, and microglia were assessed by immunofluorescence, and guanidine-soluble and insoluble Aβ_1–40/42 levels were determined in the hippocampal formation. Spontaneous alternation performances regularly decreased in APP/PS1, but not in WT mice. The FENM treatments (1 and 5 mg/kg) prevented the deficit. At 12 months of age, APP/PS1 treated with 1 mg/kg FENM showed significant improvements in all behavioral procedures tested. The astroglial reaction was not significantly attenuated by FENM in the <i>stratum radiatum</i>, <i>stratum moleculare,</i> and polymorph layer of the dentate gyrus. The microglial reaction was significantly decreased in the two latter areas. In the polymorph layer, a significant effect on amyloid plaques was measured. Global analyses of amyloid load showed attenuations of soluble and insoluble Aβ_1–40 levels and a significant decrease in the level of insoluble Aβ_1–42. Moreover, significant negative correlations were observed for FENM impacts on amyloid load or microglial activation and the alternation score. FENM confirmed, under a chronic presymptomatic treatment, its neuroprotective efficacy in AD. Our data particularly suggested that an impact on Aβ and microglia could be related to the preservation of cognitive functions.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4069–4082 4069–4082"},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842466","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}