Current Signal Transduction Therapy最新文献

{"title":"Functional Roles of Long Non-coding RNAs on Stem Cell-related Pathways in Glioblastoma","authors":"Arya Moftakhar, S. E. Khoshnam, Maryam Farzaneh, Mahrokh Abouali Gale Dari","doi":"10.2174/0115743624311471240703071345","DOIUrl":"https://doi.org/10.2174/0115743624311471240703071345","url":null,"abstract":"\u0000\u0000Long non-coding RNAs (lncRNAs), characterized by their length exceeding 200 nucleotides\u0000and lack of protein-coding capacity, are intricately associated with a wide array of cellular\u0000processes, encompassing cell invasion, differentiation, proliferation, migration, apoptosis,\u0000and regeneration. Perturbations in lncRNA expression have been observed in numerous diseases\u0000and have emerged as pivotal players in the pathogenesis of diverse tumor types. Glioblastoma, a\u0000highly malignant primary tumor of the central nervous system (CNS), remains a formidable\u0000challenge even with the advent of novel therapeutic interventions, as primary glioblastomas invariably\u0000exhibit therapy resistance and aggressive behavior. Glioblastomas can arise from progenitor\u0000cells or neuroglial stem cells, revealing profound cellular heterogeneity, notably in the\u0000form of glioblastoma stem cells (GSCs) possessing stem-like properties. Glioblastomas comprise\u0000neural precursors that harbor essential characteristics of neural stem cells (NSCs). Several\u0000signaling pathways have been implicated in the regulation of self-renewal in both cancer cells\u0000and stem cells. In addition to their involvement in therapy resistance and survival of glioblastoma,\u0000lncRNAs are implicated in the modulation of GSC behaviors through diverse pathways and\u0000the intricate regulation of various genes and proteins. This review aims to comprehensively discuss\u0000the interplay between lncRNAs, their associated pathways, and GSCs, shedding light on\u0000their potential implications in glioblastoma.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"83 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141682957","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":"Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic\u0000Derivatives through Computational Design","authors":"Anuradha Mehra, Aryan Mehra","doi":"10.2174/0115743624282326240418104054","DOIUrl":"https://doi.org/10.2174/0115743624282326240418104054","url":null,"abstract":"\u0000\u0000Deficiency of insulin signaling in type 2 diabetes results from insulin\u0000resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin,\u0000SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing\u0000the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a\u0000prominent target in the management of type 2 diabetes.\u0000\u0000\u0000\u0000This study aimed to carry out the molecular docking and ADMET prediction of novel\u0000imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors.\u0000\u0000\u0000\u0000The chemical structures of 108 molecules were drawn by using ChemDraw Professional\u000015.0. Further, their energy minimization was also carried out by using Chem Bio Draw\u0000three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual\u0000Docker to identify the best-fitting molecules and to identify the potential leads on the basis\u0000of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five,\u0000such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of\u0000rotatable bonds of the selected compounds, were predicted using pKCSM software.\u0000\u0000\u0000\u0000About 108 molecules were designed by employing different substitutions on imidazothiadiazole\u0000nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better\u0000interactions with the active site of SGLT2 protein and the highest dock scores compared to\u0000canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking\u0000scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the\u0000best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic\u0000profile as per Lipinski's rule of five (orally active drugs).\u0000\u0000\u0000\u0000Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed,\u0000and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor\u0000yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal\u0000ADMET properties in adherence to Lipinski's rule of five and favourable noncarcinogenic\u0000profile.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"60 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140664228","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":"Exploring Squalene's Impact on Epidermal Thickening and Collagen\u0000Production: Molecular Docking Insights","authors":"Mohsen Safaei, Arash Goodarzi, Fariba Nouri, Ahmad Reza Farmani, S. Kouhpayeh, Zahra Abpeikar","doi":"10.2174/0115743624288465240307062332","DOIUrl":"https://doi.org/10.2174/0115743624288465240307062332","url":null,"abstract":"\u0000\u0000Aging is a progressive deterioration characterized by the gradual buildup\u0000of physiological alterations as time passes. The aging phenomenon encompasses various interconnected\u0000systems within the body, such as the skin, bones, cartilage, and hair.\u0000\u0000\u0000\u0000In this study, based on the appropriate properties of squalene, including\u0000antioxidant, anti-inflammatory, and skin repair properties, a molecular docking study was designed\u0000for the drug squalene and proteins related to the dermis and epidermis pathway and collagen\u0000production (including Col3A1, Col1A2, FBN1, Decorin, and HAS2).\u0000\u0000\u0000\u0000The docking results indicated that the interaction of squalene with hyaluronan\u0000synthetase 2 (HAS2) possessed the highest negative binding free energy value of -10.90\u0000KCal/mol, followed by decorin with a value of -9.99 KCal/mol. Also, the inhibition constant values\u0000of squalene- HAS2 and squalene-decorin complexes were equal to 1.61 and 7.51 μM, respectively.\u0000It has been stated that decorin (as a small proteoglycan) and HAS2 are involved in controlling\u0000the assembly of skin fibrils and the biosynthesis of glucosaminoglycans, respectively.\u0000\u0000\u0000\u0000Considering that proteoglycans and glucosaminoglycans play a role in the skin aging\u0000process, squalene may be used as an anti-aging agent to induce these pathways and for different\u0000purposes. Squalene may be used as a potential agent alone or in combination with other\u0000compounds in tissue engineering scaffolds for cosmetic, anti-aging, wound healing, and tissue\u0000repair applications.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"25 40","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140226785","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":"Atopic Dermatitis and Abrocitinib: Unraveling the Therapeutic Potential","authors":"A. Memon, Habibun Nisa, Muhammad Osama, Calvin R. Wei","doi":"10.2174/0115743624291067240307051246","DOIUrl":"https://doi.org/10.2174/0115743624291067240307051246","url":null,"abstract":"\u0000\u0000Atopic dermatitis (AD) is a chronic immune-mediated skin condition seriously affecting both children and adults and impacting their quality of life. This complex condition involves\u0000genetic predisposition, immune system impairment, and environmental factors. The Janus kinase\u0000signal transducer and activator of transcription (JAK-STAT) pathway plays a key role in AD\u0000pathogenesis and progression. Abrocitinib presents a hopeful avenue for managing moderate to\u0000severe AD, offering significant symptom relief and potential long-term benefits. Its targeted approach to modulating the JAK-STAT pathway holds promise for improved AD management.\u0000This comprehensive review explores AD pathogenesis, the chemistry and clinical pharmacology\u0000of Abrocitinib, and its safety and efficacy in various trials.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140248531","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":"The Role of Long Non-Coding RNAs in the Pathogenesis of Essential\u0000Hypertension","authors":"Shirin Azizidoost, Fatemeh Khojasteh pour, Sajad Najafi, Farhoodeh Ghaedrahmati, Z. Nazeri, Dian Dayer, Zahra Shabani, Maryam Farzaneh, Ava Nasrolahi","doi":"10.2174/0115743624283095240308072648","DOIUrl":"https://doi.org/10.2174/0115743624283095240308072648","url":null,"abstract":"\u0000\u0000Hypertension, a condition characterized by elevated blood pressure, poses a significant medical risk, particularly in relation to the development of cardiovascular disease. The\u0000pathogenesis of hypertension can be influenced by a combination of genetic and environmental\u0000factors. Recent scientific studies have shed light on the involvement of long-non-coding RNAs\u0000(lncRNAs) in various diseases, including pulmonary arterial and essential hypertension. These\u0000lncRNAs have been found to play crucial roles at the transcriptional, post-transcriptional, and\u0000post-translational levels. By targeting endothelial cell proliferation, migration, apoptosis, and\u0000angiogenesis, lncRNAs can induce dysfunction in arterial endothelial cells, contributing to the\u0000progression of hypertension-related pathological events. Therefore, the abnormal expression of\u0000lncRNAs has emerged as a significant factor in the understanding of essential hypertension and\u0000its associated mechanisms. To further our understanding, we conducted a comprehensive review\u0000focusing on unraveling the functional roles of lncRNAs in essential hypertension.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"38 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140253464","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":"Atrial Natriuretic Peptide as a Biomarker and Therapeutic Target in\u0000Cancer: A Focus on Colorectal Cancer","authors":"S. Mehrabadi, Mahla Velayati, Nima Zafari, S. Mollazadeh, Amir Avan","doi":"10.2174/0115743624292634240223094729","DOIUrl":"https://doi.org/10.2174/0115743624292634240223094729","url":null,"abstract":"\u0000\u0000One of the most prevalent cancers throughout the world is colorectal cancer (CRC).\u0000Natriuretic peptides are important hormones that have a crucial role in the physiology of humans\u0000and other animals. There are a variety of treatments for colon cancer. However, conventional\u0000therapies have many side effects and low efficacy in the treatment of this disease. Atrial Natriuretic\u0000Peptide (ANP) is one of the most well-known natriuretic peptides involved in regulating\u0000blood pressure and blood volume. Studies have demonstrated that ANP has a therapeutic effect\u0000on different cancer types. The anti-tumor effect of ANP is exerted by inhibiting DNA synthesis\u0000but not inducing apoptosis. The anti-proliferative role of ANP has been reported in human\u0000breast, prostate, colon, pancreatic, lung, and ovarian cancer and in many other tumors. Therefore,\u0000we review the recent papers on natriuretic peptides in CRC as a common malignancy in\u0000adults to assess the pathways of ANP involved in the progression of CRC and its effects on the\u0000prevention or treatment of CRC and other cancer types.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"47 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140252365","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":"Exploration of Potential Cyclin-dependent Kinases and their Inhibitors to Combat Abnormal Signalling and Cancer","authors":"P. Pilania, Sisir Nandi, Dinesh Kumar Meena, Brij K. Sharma","doi":"10.2174/0115743624279638240211170045","DOIUrl":"https://doi.org/10.2174/0115743624279638240211170045","url":null,"abstract":"\u0000\u0000Regulation of cell proliferation depends on stimulatory and inhibitory factors that act\u0000in a coordinated manner in response to external signals. Various agents, including mitogens,\u0000growth factors, cytokines, and other external factors, can impact the mitotic cell cycle, resulting\u0000in either provoking growth, differentiation, or apoptosis. Many kinases, such as protein kinases,\u0000regulate mitotic cell proliferation through normal signalling. One of the major protein kinase\u0000family members is cyclin-dependent kinases (CDK), which are responsible for the regulation of\u0000cell cycle progression. If the cell cycle-regulatory mechanisms are permanently altered, it can\u0000cause abnormal proliferation that leads to neoplasia. This can result in tumour development,\u0000where the availability and expression of CDKs become altered, contributing significantly to impaired\u0000cell proliferation. Changes like these are often a characteristic of cancer. CDK inhibitors\u0000have shown significant clinical benefits in treating various types of tumours in recent years. The\u0000output has been achieved by the clinical approvals of particular CDK inhibitors. Researchers\u0000have also been studying the proteolysis-targeting chimera (PROTAC) molecule for the last two\u0000decades. This molecule uses ubiquitin-mediated proteasome mechanisms to break down specific\u0000targets, making it a promising method for targeted protein degradation (TPD). TPD has become\u0000a promising therapeutic option for tackling disease-causing proteins that are otherwise challenging\u0000to treat using traditional small molecules. This review provides an overview of the state of\u0000knowledge and a general understanding of selective or nonselective CDK inhibitors and\u0000PROTAC degraders currently under development or clinically approved congeners, focusing on\u0000improving cancer therapy.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140441774","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":"Therapeutic Potential of MSC-conditioned Medium: A Multifactorial\u0000Approach to Enhance Wound Healing","authors":"Amir Anbiyaiee, Shirin Azizidoost, Maryam Farzaneh","doi":"10.2174/0115743624266715240202104221","DOIUrl":"https://doi.org/10.2174/0115743624266715240202104221","url":null,"abstract":"\u0000\u0000Wound healing is a highly intricate process that involves a coordinated interplay of\u0000various cellular and molecular events. In recent years, mesenchymal stem cells (MSCs) have\u0000garnered significant attention as a promising therapeutic modality due to their remarkable regenerative properties. In addition to their capacity for direct tissue repair and differentiation,\u0000MSCs release a diverse repertoire of bioactive factors into the surrounding microenvironment,\u0000collectively termed an MSC-conditioned Medium (MSC-CM). This review aims to elucidate the\u0000therapeutic potential of MSC-CM as a multifactorial approach to enhance wound healing. MSCCM encompasses an extensive range of factors, including growth factors, cytokines, chemokines, extracellular matrix proteins, and non-coding RNAs, which collectively orchestrate and\u0000stimulate multiple cellular processes crucial for effective wound healing. Notably, these factors\u0000play pivotal roles in promoting angiogenesis, stimulating the proliferation and migration of various cell types involved in wound repair, modulating the immune response, and facilitating extracellular matrix remodeling. Moreover, compelling evidence from preclinical and clinical\u0000studies demonstrates that MSC-CM administration accelerates wound closure, enhances reepithelialization, and improves the quality of granulation tissue. By harnessing the therapeutic\u0000potential of MSC-CM, we can pave the way for significant advancements in wound care, ultimately leading to improved patient outcomes.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"239 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139843054","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":"Therapeutic Potential of MSC-conditioned Medium: A Multifactorial\u0000Approach to Enhance Wound Healing","authors":"Amir Anbiyaiee, Shirin Azizidoost, Maryam Farzaneh","doi":"10.2174/0115743624266715240202104221","DOIUrl":"https://doi.org/10.2174/0115743624266715240202104221","url":null,"abstract":"\u0000\u0000Wound healing is a highly intricate process that involves a coordinated interplay of\u0000various cellular and molecular events. In recent years, mesenchymal stem cells (MSCs) have\u0000garnered significant attention as a promising therapeutic modality due to their remarkable regenerative properties. In addition to their capacity for direct tissue repair and differentiation,\u0000MSCs release a diverse repertoire of bioactive factors into the surrounding microenvironment,\u0000collectively termed an MSC-conditioned Medium (MSC-CM). This review aims to elucidate the\u0000therapeutic potential of MSC-CM as a multifactorial approach to enhance wound healing. MSCCM encompasses an extensive range of factors, including growth factors, cytokines, chemokines, extracellular matrix proteins, and non-coding RNAs, which collectively orchestrate and\u0000stimulate multiple cellular processes crucial for effective wound healing. Notably, these factors\u0000play pivotal roles in promoting angiogenesis, stimulating the proliferation and migration of various cell types involved in wound repair, modulating the immune response, and facilitating extracellular matrix remodeling. Moreover, compelling evidence from preclinical and clinical\u0000studies demonstrates that MSC-CM administration accelerates wound closure, enhances reepithelialization, and improves the quality of granulation tissue. By harnessing the therapeutic\u0000potential of MSC-CM, we can pave the way for significant advancements in wound care, ultimately leading to improved patient outcomes.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"24 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139783216","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":"Removal of Interference from Electromyogram based on Empirical Mode\u0000Decomposition and Correlation Coefficient Thresholding","authors":"M. Karuna, S. R. Guntur","doi":"10.2174/0115743624268804231222042118","DOIUrl":"https://doi.org/10.2174/0115743624268804231222042118","url":null,"abstract":"\u0000\u0000Electromyography (EMG) signals are contaminated by various noise\u0000components. These noises directly degrade the EMG processing performance, thereby affecting\u0000the classification accuracy of the EMG signals for implementing various hand movements of the\u0000prosthetic arm from the amputee’s residual muscle.\u0000\u0000\u0000\u0000This study mainly aims to denoise the EMG signals using the empirical mode decomposition\u0000(EMD) and correlation coefficient thresholding (CCT) methods. The noisy EMG signal\u0000is obtained from NinaPro Database 2. Then, EMD is used to decompose it into intrinsic mode\u0000functions. Each hand movement noise is identified within specific modes and removed separately\u0000using correlation coefficient–dependent thresholding and wavelet denoising. The performance\u0000metrics signal-to-noise ratio (SNR) and root mean square error (RMSE) were used to evaluate\u0000the noise removal performance from the EMG signals of five intact subjects. The proposed\u0000method outperforms the wavelet denoising method in terms of noise interference removal. In\u0000this method, the SNR is obtained in the 17-22 dB range with a very low RMSE.\u0000\u0000\u0000\u0000The experimental results illustrate that the proposed method removes noise from six\u0000repetitions of six movements performed by five subjects. This study explores the special characteristics\u0000of EMD and demonstrates the possibility of using the EMD-based CCT filter for denoising\u0000EMG signals.\u0000\u0000\u0000\u0000The proposed filter is more efficient than wavelet denoising in removing noise interference.\u0000It can also be used in any application that requires EMG signal filtering at the preprocessing\u0000stage, such as EMG pattern recognition.\u0000","PeriodicalId":10868,"journal":{"name":"Current Signal Transduction Therapy","volume":"65 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140503092","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}