Journal of molecular graphics & modelling最新文献

{"title":"The potential of Chlorella spp. as antiviral source against African swine fever virus through a virtual screening pipeline","authors":"Albert Neil G. Dulay ,&nbsp;John Christian C. de Guzman ,&nbsp;Zyra Ysha D. Marquez ,&nbsp;Elisha Sofia D. Santana ,&nbsp;Jessamine Arce ,&nbsp;Fredmoore L. Orosco","doi":"10.1016/j.jmgm.2024.108846","DOIUrl":"10.1016/j.jmgm.2024.108846","url":null,"abstract":"<div><p>African swine fever (ASF) causes high mortality in pigs and threatens global swine production. There is still a lack of therapeutics available, with two vaccines under scrutiny and no approved small-molecule drugs. Eleven (11) viral proteins were used to identify potential antivirals in <em>in silico</em> screening of secondary metabolites (127) from <em>Chlorella</em> spp. The metabolites were screened for affinity and binding selectivity. High-scoring compounds were assessed through <em>in silico</em> ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions, compared to structurally similar drugs, and checked for off-target docking with prepared swine receptors. Molecular dynamics (MD) simulations determined binding stability while binding energy was measured in Molecular Mechanics - Generalized Born Surface Area (MMGBSA) or Poisson-Boltzmann Surface Area (MMPBSA). Only six (6) compounds passed until MD analyses, of which five (5) were stable after 100 ns of MD runs. Of these five compounds, only three had binding affinities that were comparable to or stronger than controls. Specifically, phytosterols 24,25-dihydrolanosterol and CID 4206521 that interact with the RNA capping enzyme (pNP868R), and ergosterol which bound to the Erv-like thioreductase (pB119L). The compounds identified in this study can be used as a theoretical basis for <em>in vitro</em> screening to develop potent antiviral drugs against ASFV.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108846"},"PeriodicalIF":2.7,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hex-star phosphorene nanosheets as sequencing material for DNA/RNA strands – A first-principles investigation","authors":"V. Nagarajan ,&nbsp;N. Reseeka ,&nbsp;R. Chandiramouli","doi":"10.1016/j.jmgm.2024.108845","DOIUrl":"10.1016/j.jmgm.2024.108845","url":null,"abstract":"<div><p>In this study, we utilised hex-star phosphorene as the main detecting material to identify the nucleobases. Nucleobases, being crucial carriers of hereditary information are identified through specific hydrogen bonding and steric interactions such as adenine pairing with thymine (or) uracil and guanine pairing with cytosine. The stable hex-star phosphorene possesses negative formation energy of −5.194 eV. The hex-star phosphorene exhibits a semiconductor nature with an energy band gap of 1.658 eV, which is deployed as the adsorbing substrate for nucleobases. Based on the Mulliken charge analysis, adsorption energy, relative band gap variation, and the detection efficiency of hex-star phosphorene towards nucleobases are examined. The outcome confirms the physisorption of nucleobases on hex-star phosphorene and strongly supports that hex-star phosphorene can be used as sequencing material for <span>DNA</span> and RNA.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108845"},"PeriodicalIF":2.7,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141978769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining machine learning, molecular dynamics, and free energy analysis for (5HT)-2A receptor modulator classification","authors":"Xian Yu,&nbsp;Yasmine Eid,&nbsp;Maryam Jama,&nbsp;Diane Pham,&nbsp;Marawan Ahmed,&nbsp;Melika Shabani attar,&nbsp;Zainab Samiuddin,&nbsp;Khaled Barakat","doi":"10.1016/j.jmgm.2024.108842","DOIUrl":"10.1016/j.jmgm.2024.108842","url":null,"abstract":"<div><p>The 5-Hydroxytryptamine (5HT)-2A receptor, a key target in psychoactive drug development, presents significant challenges in the design of selective compounds. Here, we describe the construction, evaluation and validation of two machine learning (ML) models for the classification of bioactivity mechanisms against the (5HT)-2A receptor. Employing neural networks and XGBoost models, we achieved an overall accuracy of around 87 %, which was further enhanced through molecular modelling (MM) (<em>e.g.</em> molecular dynamics simulations) and binding free energy analysis. This ML-MM integration provided insights into the mechanisms of direct modulators and prodrugs. A significant outcome of the current study is the development of a ‘binding free energy fingerprint’ specific to (5HT)-2A modulators, offering a novel metric for evaluating drug efficacy against this target. Our study demonstrates the prospective of employing a successful workflow combining AI with structural biology, offering a powerful tool for advancing psychoactive drug discovery.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108842"},"PeriodicalIF":2.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Boosting the performance of molecular property prediction via graph–text alignment and multi-granularity representation enhancement","authors":"Zhuoran Zhao ,&nbsp;Qing Zhou ,&nbsp;Chengkai Wu ,&nbsp;Renbin Su ,&nbsp;Weihong Xiong","doi":"10.1016/j.jmgm.2024.108843","DOIUrl":"10.1016/j.jmgm.2024.108843","url":null,"abstract":"<div><p>Deep learning is playing an increasingly important role in accurate prediction of molecular properties. Prior to being processed by a deep learning model, a molecule is typically represented in the form of a text or a graph. While some methods attempt to integrate these two forms of molecular representations, the misalignment of graph and text embeddings presents a significant challenge to fuse two modalities. To solve this problem, we propose a method that aligns and fuses graph and text features in the embedding space by using contrastive loss and cross attentions. Additionally, we enhance the molecular representation by incorporating multi-granularity information of molecules on the levels of atoms, functional groups, and molecules. Extensive experiments show that our model outperforms state-of-the-art models in downstream tasks of molecular property prediction, achieving superior performance with less pretraining data. The source codes and data are available at <span><span>https://github.com/zzr624663649/multimodal_molecular_property</span><svg><path></path></svg></span>.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108843"},"PeriodicalIF":2.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of surface-active ionic solutions on the structure and function of laccase from trametes versicolor: Insights from molecular dynamics simulations","authors":"Azam Roohi ,&nbsp;Mohammad Reza Housaindokht ,&nbsp;Mohammad Reza Bozorgmehr ,&nbsp;Mohammad Vakili","doi":"10.1016/j.jmgm.2024.108844","DOIUrl":"10.1016/j.jmgm.2024.108844","url":null,"abstract":"<div><p>Many protein-ionic liquid investigations have examined laccase interactions. Laccases are a class of poly-copper oxidoreductases that retain significant biotechnological relevance owing to their notable oxidative capabilities and their application in the elimination of synthetic dyes, phenolic compounds, insecticides, and various other substances. This study investigates the impact of surface active ionic liquids (SAILs), namely, decyltrimethylammonium bromide [N₁₀₁₁₁][Br] and 1-decyl-3-methylimidazolium chloride [C_10mim][Cl] as cationic surfactant ionic liquids and cholinium decanoate [Chl][Dec], an anionic surfactant ionic liquid, on the structure and function of laccase from the fungus Trametes versicolor (TvL) by the molecular dynamics (MD) simulation method. In summary, this study showed that laccase solvent-accessible surface area increased in the ionic liquid [Chl][Dec] while it decreased in the other two ionic liquids. Interestingly, [Chl][Dec] ionic liquid components formed hydrogen bonds with laccase, while [N₁₀₁₁₁][Br] and [C_10mim][Cl] components were unable to form hydrogen bonds with laccase. The quantity of hydrogen bonds formed between water molecules and the enzyme was also diminished in the presence of [Chl][Dec] in comparison to the other two ionic liquids. especially at a concentration of 250 mM. In 250 mM concentrations of [N₁₀₁₁₁][Br] and [C_10mim][Cl], clusters of long-chain cations are likely to form near the copper T1 site. However, even at low [Chl][Dec] concentrations, long [Dec]^- chains were observed to penetrate the enzyme near the copper T1 site, and at 250 mM [Chl][Dec], a large cluster of anions occupied the opening of the active site. The results of the analysis also show that the interaction between the [Dec]^- anion and the enzyme is stronger than the interaction between [N₁₀₁₁₁]⁺ and [C_10mim]⁺ with laccase; in addition, the [Dec]^- anion, compared to [Br]^- and [Cl]^- has a much greater tendency to bind with the enzyme residues.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108844"},"PeriodicalIF":2.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of constant electric field on the crack growth process of aluminum nanosheet using molecular dynamics simulation","authors":"Jinping Chen ,&nbsp;Abrar A. Mohammed ,&nbsp;Dalal Abbas Fadhil ,&nbsp;Mohammed Al-Bahrani ,&nbsp;Soheil Salahshour ,&nbsp;Rozbeh Sabetvand","doi":"10.1016/j.jmgm.2024.108841","DOIUrl":"10.1016/j.jmgm.2024.108841","url":null,"abstract":"<div><p>Aluminum nanosheets are a form of Al nanoparticle that have been recently manufactured on an industrial scale and have a variety of uses. Al nanoparticles are extensively used in a variety of sectors, including aerospace, construction, medical, chemistry, and marine industries. Crack propagation in various constructions must be investigated thoroughly for structural design purposes. Cracks in nanoparticles may occur during the production of nanosheets (NSs) or when different mechanical or thermal pressures were applied. In this work, the effect of a continuous electric field on the fracture formation process of aluminum nanosheets was investigated. For this study, molecular dynamics simulation and LAMMPS software were used. The effects of various electric fields on several parameters, including as stress, velocity (Velo), and fracture length, were explored, and numerical data were retrieved using software. The results show that the amplitude of the electric field parameter affected the atomic development of modeled Al nanosheets throughout the fracture operation. This effect resulted in atomic resonance (amplitude) fluctuations, which affected the mean interatomic forces and led the temporal evolution of atoms to converge to certain specified initial conditions. The crack length in our modeled samples ranged from 22.88 to 32.63 Å, depending on the electric field parameter (0.1–1 V/Å). Finally, it was determined that the crack growth of modeled Al nanosheets may be controlled using CEF parameters in real-world situations.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108841"},"PeriodicalIF":2.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure based computational RNA design towards MafA transcriptional repressor implicated in multiple myeloma","authors":"Güneş Yıldırım Akdeniz ,&nbsp;Ahmet Can Timuçin","doi":"10.1016/j.jmgm.2024.108839","DOIUrl":"10.1016/j.jmgm.2024.108839","url":null,"abstract":"<div><p>Multiple myeloma is recognized as the second most common hematological cancer. MafA transcriptional repressor is an established mediator of myelomagenesis. While there are multitude of drugs available for targeting various effectors in multiple myeloma, current literature lacks a candidate RNA based MafA modulator. Thus, using the structure of MafA homodimer-consensus target DNA, a computational effort was implemented to design a novel RNA based chemical modulator against MafA. First, available MafA-consensus DNA structure was employed to generate an RNA library. This library was further subjected to global docking to select the most plausible RNA candidates, preferring to bind DNA binding region of MafA. Following global docking, MD-ready complexes that were prepared via local docking program, were subjected to 500 ns of MD simulations. First, each of these MD simulations were analyzed for relative binding free energy through MM-PBSA method, which pointed towards a strong RNA based MafA binder, RNA1. Second, through a detailed MD analysis, RNA1 was shown to prefer binding to a single monomer of the dimeric DNA binding domain of MafA using higher number of hydrophobic interactions compared with positive control MafA-DNA complex. At the final phase, a principal component analyses was conducted, which led us to identify the actual interaction region of RNA1 and MafA monomer. Overall, to our knowledge, this is the first computational study that presents an RNA molecule capable of potentially targeting MafA protein. Furthermore, limitations of our study together with possible future implications of RNA1 in multiple myeloma were also discussed.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108839"},"PeriodicalIF":2.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in silico studies of the inclusion complexation of 8-bromobaicalein with β-cyclodextrins","authors":"Noriyuki Yasuda ,&nbsp;Saba Ali ,&nbsp;Aamir Aman ,&nbsp;Kuakarun Krusong ,&nbsp;Noval Herfindo ,&nbsp;Warinthorn Chavasiri ,&nbsp;Kiattawee Choowongkomon ,&nbsp;Peter Wolschann ,&nbsp;Panupong Mahalapbutr ,&nbsp;Thanyada Rungrotmongkol ,&nbsp;Supot Hannongbua","doi":"10.1016/j.jmgm.2024.108840","DOIUrl":"10.1016/j.jmgm.2024.108840","url":null,"abstract":"<div><p>Baicalein, a flavone derived from <em>Scutellaria baicalensis</em> Georgi, exhibits potent anti-inflammatory, antiviral, and anticancer properties. Its derivative, known as 8-bromobaicalein (BB), has been found to have strong cytotoxic effect on MCF-7 human breast cancer cells. However, its limited solubility in water has hindered its potential for wider applications. To address this issue, we investigated the use of cyclodextrins specifically βCD, 2,6-di-O-methyl-β-cyclodextrin (DMβCD), and hydroxypropyl-β-cyclodextrin (HPβCD) to improve the solubility of BB through inclusion complexation. During 250 ns molecular dynamics simulations, it was found that BB can form inclusion complexes with all βCDs. These complexes exhibit two distinct orientations: chromone group insertion (C-form) and phenyl group insertion (P-form). The formation of these complexes is primarily driven by van der Waals interactions. DMβCD has the highest number of atom contacts with BB and the lowest solvent accessibility in the hydrophobic cavity. These results coincide with the highest binding affinity from the MM/GBSA-based free energy calculation method. Experimental phase solubility diagrams revealed a 1:1 stoichiometric ratio (A_L type) between BB and βCDs, in which BB/DMβCD showed the highest stability. The formation of inclusion complexes was confirmed by differential scanning calorimetry and scanning electron microscope methods. Additionally, the BB/DMβCD inclusion complex demonstrated significantly higher anticancer activity against MCF-7 human breast cancer cells compared to BB alone. These findings underscore the potential of DMβCD for formulating BB in pharmaceutical and medical applications.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108840"},"PeriodicalIF":2.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of mechanical behavior of porous carbon-based matrix by molecular dynamics simulation: Effects of Si doping","authors":"Weifeng Ma ,&nbsp;Ali Basem ,&nbsp;Soheil Salahshour ,&nbsp;Zainab Younus Abdullah ,&nbsp;Mohammed Al-Bahrani ,&nbsp;Raman Kumar ,&nbsp;Sh. Esmaeili","doi":"10.1016/j.jmgm.2024.108836","DOIUrl":"10.1016/j.jmgm.2024.108836","url":null,"abstract":"<div><p>Understanding the mechanical properties of porous carbon-based materials can lead to advancements in various applications, including energy storage, filtration, and lightweight structural components. Also, investigating how silicon doping affects these materials can help optimize their mechanical properties, potentially improving strength, durability, and other performance metrics. This research investigated the effects of atomic doping (Si particle up to 10 %) on the mechanical properties of the porous carbon matrix using molecular dynamics methods. Young's modulus, ultimate strength, radial distribution function, interaction energy, mean square displacement and potential energy of designed samples were reported. MD outputs predict the Si doping process improved the mechanical performance of porous structures. Numerically, Young's modulus of the C-based porous matrix increased from 234.33 GPa to 363.82 GPa by 5 % Si inserted into a pristine porous sample. Also, the ultimate strength increases from 48.54 to 115.93 GPa with increasing Si doping from 1 % to 5 %. Silicon doping enhances the bonding strength and reduces defects in the carbon matrix, leading to improved stiffness and load-bearing capacity. This results in significant increases in mechanical performance. However, excess Si may disrupt the optimal bonding network, leading to weaker connections within the matrix. Also, considering the negative value of potential energy in different doping percentages, it can be concluded that the amount of doping added up to 10 % does not disturb the initial structure and stability of the system, and the structure still has structural stability. So, we expected our introduced atomic samples to be used in actual applications.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108836"},"PeriodicalIF":2.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational discovery of tripeptide inhibitors targeting monkeypox virus A42R profilin-like protein","authors":"Thi-Thuy-Duong Pham ,&nbsp;Quynh Mai Thai ,&nbsp;Pham Nguyen Kim Tuyen ,&nbsp;Huong Thi Thu Phung ,&nbsp;Son Tung Ngo","doi":"10.1016/j.jmgm.2024.108837","DOIUrl":"10.1016/j.jmgm.2024.108837","url":null,"abstract":"<div><p>Monkeypox is an infectious disease caused by the monkeypox virus (MPXV), a member of the Orthopoxvirus genus closely related to smallpox. The structure of the A42R profilin-like protein is the first and only available structure among MPXV proteins. Biochemical studies of A42R were conducted in the 1990s and later work also analyzed the protein's function in viral replication in cells. This study aims to screen tripeptides for their potential inhibition of the A42R profilin-like protein using computational methods, with implications for MPXV therapy. A total of 8000 tripeptides underwent molecular docking simulations, resulting in the identification of 20 compounds exhibiting strong binding affinity to A42R. To validate the docking results, molecular dynamics simulations and free energy perturbation calculations were performed. These analyses revealed two tripeptides with sequences TRP-THR-TRP and TRP-TRP-TRP, which displayed robust binding affinity to A42R. Markedly, electrostatic interactions predominated over van der Waals interactions in the binding process between tripeptides and A42R. Three A42R residues, namely Glu9, Ser12, and Arg38, appear to be pivotal in mediating the interaction between A42R and the tripeptide ligands. Notably, tripeptides containing two or three tryptophan residues demonstrate a pronounced binding affinity, with the tripeptide comprising three tryptophan amino acids showing the highest level of affinity. These findings offer valuable insights for the selection of compounds sharing a similar structure and possessing a high affinity for A42R, potentially capable of inhibiting its enzyme activity. The study highlights a structural advantage and paves the way for the development of targeted therapies against MPXV infections.</p></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"132 ","pages":"Article 108837"},"PeriodicalIF":2.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}