Biomolecules & Therapeutics最新文献

{"title":"Regulatory Mechanisms Governing the Autophagy-Initiating VPS34 Complex and Its inhibitors.","authors":"Yongook Lee, Nguyen Minh Tuan, Gi Jeong Lee, Boram Kim, Jung Ho Park, Chang Hoon Lee","doi":"10.4062/biomolther.2024.094","DOIUrl":"10.4062/biomolther.2024.094","url":null,"abstract":"<p><p>VPS34 is a crucial protein in cells, essential for handling cellular stress through its involvement in autophagy and endocytosis. This protein functions as a Class III phosphatidylinositol 3-kinase, producing phosphatidylinositol 3-phosphate, which is necessary for autophagy and vesicle trafficking. Additionally, VPS34 forms two mutually exclusive complexes, each playing a vital role in autophagy and endocytic sorting. These complexes share common subunits, including VPS15, VPS34, and Beclin 1, with complex I having ATG14 as a specific subunit. Due to its association with various human diseases, regulation of the VPS34 complex I has garnered significant interest, emerging as a potential therapeutic target for drug discovery. Summaries of the structure, function of VPS34 complexes, and developed VPS34 inhibitors have been provided, along with discussions on the regulation mechanism of VPS34, particularly in relation to the initiation complex I of autophagy. This offers valuable insights for treating autophagy-related diseases.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"723-735"},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies.","authors":"Seong Min Choi, Ju-Hee Lee, Soyeon Ko, Soon-Sun Hong, Hyo-Eon Jin","doi":"10.4062/biomolther.2024.146","DOIUrl":"10.4062/biomolther.2024.146","url":null,"abstract":"<p><p>Bispecific antibodies represent a significant advancement in therapeutic antibody engineering, offering the ability to simultaneously target two distinct antigens. This dual-targeting capability enhances therapeutic efficacy, especially in complex diseases, such as cancer and autoimmune disorders, where drug resistance and incomplete target coverage are prevalent challenges. Bispecific antibodies facilitate immune cell engagement and disrupt multiple signaling pathways, providing a more comprehensive treatment approach than traditional monoclonal antibodies. However, the intricate structure of bispecific antibodies introduces unique pharmacokinetic challenges, including issues related to their absorption, distribution, metabolism, and excretion, which can significantly affect their efficacy and safety. This review provides an in-depth analysis of the structural design, mechanisms of action, and pharmacokinetics of the currently approved bispecific antibodies. It also highlights the engineering innovations that have been implemented to overcome these challenges, such as Fc modifications and advanced dimerization techniques, which enhance the stability and half-life of bispecific antibodies. Significant progress has been made in bispecific antibody technology; however, further research is necessary to broaden their clinical applications, enhance their safety profiles, and optimize their incorporation into combination therapies. Continuous advancements in this field are expected to enable bispecific antibodies to provide more precise and effective therapeutic strategies for a range of complex diseases, ultimately improving patient outcomes and advancing precision medicine.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"708-722"},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142494494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translation Initiation Factor-2S2 (eIF2S2) Contributes to Cervical Carcinogenesis by Inhibiting the TGF-β/SMAD4 Signaling Pathway.","authors":"Juthika Kundu, Hobin Yang, Saerom Moon, Mi Ran Byun, Young Kee Shin, Kyoung Song, Joon-Seok Choi","doi":"10.4062/biomolther.2024.024","DOIUrl":"10.4062/biomolther.2024.024","url":null,"abstract":"<p><p>The deregulation of protein translational machinery and the oncogenic role of several translation initiation factors have been extensively investigated. This study aimed to investigate the role of eukaryotic translation initiation factor 2S2 (eIF2S2, also known as eIF2β) in cervical carcinogenesis. Immunohistochemical analysis of human cervical carcinoma tissues revealed a stage-specific increase in eIF2S2 expression. The knockdown of eIF2S2 in human cervical cancer (SiHa) cells significantly reduced growth and migration properties, whereas its overexpression demonstrated the opposite effect. Immunoprecipitation and Bimolecular fluorescence complementation (BiFC) assay confirmed the previous photo array finding of the interaction between eIF2S2 and SMAD4 to understand the tumorigenic mechanism of eIF2S2. The results indicated that the N-terminus of eIF2S2 interacts with the MH-1 domain of SMAD4. The interaction effect between eIF2S2 and SMAD4 was further evaluated. The knockdown of eIF2S2 increased SMAD4 expression in cervical cancer cells without changing SMAD4 mRNA expression, whereas transient eIF2S2 overexpression reduced SMAD4 expression. This indicates the possibility of post-translational regulation of SMAD4 expression by eIF2S2. Additionally, eIF2S2 overexpression was confirmed to weaken the expression and/or promoter activity of p15 and p27, which are SMAD4-regulated antiproliferative proteins, by reducing SMAD4 levels. Therefore, our study indicated the pro-tumorigenic role of eIF2S2, which diminishes both SMAD4 expression and function as a transcriptional factor in cervical carcinogenesis.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"767-777"},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytotherapeutic BS012 and Its Active Component Ameliorate Allergic Asthma via Inhibition of Th2-Mediated Immune Response and Apoptosis.","authors":"Siqi Zhang, Joonki Kim, Gakyung Lee, Hong Ryul Ahn, Yeo Eun Kim, Hee Ju Kim, Jae Sik Yu, Miso Park, Keon Wook Kang, Hocheol Kim, Byung Hwa Jung, Sung Won Kwon, Dae Sik Jang, Hyun Ok Yang","doi":"10.4062/biomolther.2024.058","DOIUrl":"10.4062/biomolther.2024.058","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory disorder of the lungs that results in airway inflammation and narrowing. BS012 is an herbal remedy containing <i>Asarum sieboldii</i>, <i>Platycodon grandiflorum</i>, and <i>Cinnamomum cassia</i> extracts. To elucidate the anti-asthma effect of BS012, this study analyzed the immune response, respiratory protection, and changes in metabolic mechanisms in an ovalbumin-induced allergic asthma mouse model. Female BALB/c mice were exposed to ovalbumin to induce allergic asthma. Bronchoalveolar lavage fluid and plasma were analyzed for interleukin and immunoglobulin E levels. Histological analyses of the lungs were performed to measure morphological changes. Apoptosis-related mediators were assayed by western blotting. Plasma and lung tissue metabolomic analyses were performed to investigate the metabolic changes. A T-helper-2-like differentiated cell model was used to identify the active components of BS012. BS012 treatment improved inflammatory cell infiltration, mucus production, and goblet cell hyperplasia in lung tissues. BS012 also significantly downregulated ovalbumin-specific immunoglobulin E in plasma and T-helper-2-specific cytokines, interleukin-4 and -5, in bronchoalveolar lavage fluid. The lungs of ovalbumin-inhaled mice exhibited nerve growth factor-mediated apoptotic protein expression, which was significantly attenuated by BS012 treatment. Ovalbumin-induced abnormalities in amino acid and lipid metabolism were improved by BS012 in correlation with its anti-inflammatory properties and normalization of energy metabolism. Additionally, the differentiated cell model revealed that <i>N</i>-isobutyl-dodecatetraenamide is an active component that contributes to the anti-allergic properties of BS012. The current findings demonstrate the anti-allergic and respiratory protective functions of BS012 against allergic asthma, which can be considered a therapeutic candidate.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"744-758"},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Multifaceted Role of Epithelial Membrane Protein 2 in Cancer: from Biomarker to Therapeutic Target.","authors":"Ji Yun Jang, Mi Kyung Park, Chang Hoon Lee, Ho Lee","doi":"10.4062/biomolther.2024.168","DOIUrl":"10.4062/biomolther.2024.168","url":null,"abstract":"<p><p>Tetraspanin superfamily proteins not only facilitate the trafficking of specific proteins to distinct plasma membrane domains but also influence cell-to-cell and cell-extracellular matrix interactions. Among these proteins, Epithelial Membrane Protein 2 (EMP2), a member of the growth arrest-specific gene 3/peripheral myelin protein 22 (GAS3/PMP22) family, is known to affect key cellular processes. Recent studies have revealed that EMP2 modulates critical signaling pathways and interacts with adhesion molecules and growth factor receptors, underscoring its potential as a biomarker for cancer diagnosis and prognosis. These findings suggest that EMP2 expression patterns could provide valuable insights into tumorigenesis and metastasis. Moreover, EMP2 has emerged as a promising therapeutic target, with approaches aimed at inhibiting or modulating its activity showing potential to disrupt tumor growth and metastasis. This review provides a comprehensive overview of recent advances in understanding the multifaceted roles of EMP2 in cancer, with a focus on its underlying mechanisms and clinical significance.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"697-707"},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyronaridine Inhibited <i>MUC5AC</i> Mucin Gene Expression by Regulation of Nuclear Factor Kappa B Signaling Pathway in Human Pulmonary Mucoepidermoid Cells.","authors":"Rajib Hossain, Hyun Jae Lee, Choong Jae Lee","doi":"10.4062/biomolther.2024.072","DOIUrl":"10.4062/biomolther.2024.072","url":null,"abstract":"<p><p>In this study, the potential effects of pyronaridine, an antimalarial agent, on airway <i>MUC5AC</i> mucin gene expression were investigated. The human pulmonary epithelial NCI-H292 cells were pretreated with pyronaridine for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA) for 24 h. The effect of pyronaridine on the PMA-induced nuclear factor kappa B (NF-κB) signaling pathway was also examined. Pyronaridine inhibited glycoprotein production and mRNA expression of <i>MUC5AC</i> mucins induced by PMA through the inhibition of degradation of inhibitory kappa Bα and NF-κB p65 nuclear translocation. These results suggest that pyronaridine suppresses gene expression of mucin through regulation of the NF-κB signaling pathway in human pulmonary epithelial cells.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"540-545"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis.","authors":"Jiangxin Xu, Xiangliang Huang, Yourong Zhou, Zhifei Xu, Xinjun Cai, Bo Yang, Qiaojun He, Peihua Luo, Hao Yan, Jie Jin","doi":"10.4062/biomolther.2023.209","DOIUrl":"10.4062/biomolther.2023.209","url":null,"abstract":"<p><p>Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"647-657"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Lapachone Exerts Hypnotic Effects via Adenosine A₁ Receptor in Mice.","authors":"Do Hyun Lee, Hye Jin Jee, Yi-Sook Jung","doi":"10.4062/biomolther.2024.106","DOIUrl":"10.4062/biomolther.2024.106","url":null,"abstract":"<p><p>Sleep is one of the most essential physiological phenomena for maintaining health. Sleep disturbances, such as insomnia, are often accompanied by psychiatric or physical conditions such as impaired attention, anxiety, and stress. Medication used to treat insomnia have concerns about potential side effects with long-term use, so interest in the use of alternative medicine is increasing. In this study, we investigated the hypnotic effects of β-lapachone (β-Lap), a natural naphthoquinone compound, using pentobarbital-induced sleep test, immunohistochemistry, real-time PCR, and western blot in mice. Our results indicated that β-Lap exerts a significant hypnotic effect by showing a decrease in sleep onset latency and an increase in total sleep time in pentobarbital-induced sleep model. The results of c-Fos immunostaining showed that β-Lap decreased neuronal activity in the basal forebrain and lateral hypothalamus, which are wakefulness-promoting brain regions, while increasing in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A₁ receptor (A₁R) antagonist. Western blot analysis showed that β-Lap increased extracellular signalregulated kinase phosphorylation and nuclear factor-kappa B translocation from the cytoplasm to the nucleus; these effects were inhibited by DPCPX. Additionally, β-Lap increased the mRNA levels of A₁R. Taken together, these results suggest that β-Lap exerts hypnotic effects, potentially through A₁R.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"531-539"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycogen Phosphorylase Inhibitor Promotes Hair Growth via Protecting from Oxidative-Stress and Regulating Glycogen Breakdown in Human Hair follicles.","authors":"Bomi Park, Daeun Kim, Hairu Zhao, SoonRe Kim, Byung Cheol Park, Sanghwa Lee, Yurim Lee, Hee Dong Park, Dongchul Lim, Sunyoung Ryu, Jae Sung Hwang","doi":"10.4062/biomolther.2024.098","DOIUrl":"10.4062/biomolther.2024.098","url":null,"abstract":"<p><p>Hair growth cycles are mainly regulated by human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs). Protecting hDPCs from excessive oxidative stress and hORSCs from glycogen phosphorylase (PYGL) is crucial to maintaining the hair growth phase, anagen. In this study, we developed a new PYGL inhibitor, Hydroxytrimethylpyridinyl Methylindolecarboxamide (HTPI) and assessed its potential to prevent hair loss. HTPI reduced oxidative damage, preventing cell death and restored decreased level of anagen marker ALP and its related genes induced by hydrogen peroxide in hDPCs. Moreover, HTPI inhibited glycogen degradation and induced cell survival under glucose starvation in hORSCs. In ex-vivo culture, HTPI significantly enhanced hair growth compared to the control with minoxidil showing comparable results. Overall, these findings suggest that HTPI has significant potential as a therapeutic agent for the prevention and treatment of hair loss.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"640-646"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gilteritinib Reduces FLT3 Expression in Acute Myeloid Leukemia Cells.","authors":"Thị Lam Thái, Sun-Young Han","doi":"10.4062/biomolther.2023.215","DOIUrl":"10.4062/biomolther.2023.215","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a genetically diverse and challenging malignancy, with mutations in the FLT3 gene being particularly common and deleterious. Gilteritinib, a potent FLT3 inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib was developed based on its inhibitory activity against FLT3 kinase, it is important to understand the precise mechanisms of its antileukemic activity in managing drug resistance and discovering biomarkers. This study was designed to elucidate the effect of gilteritinib on the FLT3 expression level. The results showed that gilteritinib induced a dose-dependent decrease in both FLT3 phosphorylation and expression. This reduction was particularly pronounced after 48 h of treatment. The decrease in FLT3 expression was found to be independent of changes in FLT3 mRNA transcription, suggesting post-transcriptional regulatory mechanisms. Further studies were performed in various AML cell lines and cells with both FLT3 wild-type and FLT3 mutant exhibited FLT3 reduction by gilteritinib treatment. In addition, other FLT3 inhibitors were evaluated for their ability to reduce FLT3 expression. Other FLT3 inhibitors, midostaurin, crenolanib, and quizartinib, also reduced FLT3 expression, consistent with the effect of gilteritinib. These findings hold great promise for optimizing gilteritinib treatment in AML patients. However, it is important to recognize that further research is warranted to gain a full understanding of these mechanisms and their clinical implications in the context of FLT3 reduction.</p>","PeriodicalId":8949,"journal":{"name":"Biomolecules & Therapeutics","volume":" ","pages":"577-581"},"PeriodicalIF":3.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11392668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}