Chemical Science最新文献

{"title":"Formation of mono- and dual-labelled antibody fragment conjugates via reversible site-selective disulfide modification and proximity induced lysine reactivity","authors":"Ioanna Thanasi, Nathalie Bouloc, Cliona McMahon, Ning Wang, Peter Szijj, Tobias Butcher, Lea Rochet, Elizabeth Love, Andy Merritt, James R. Baker, Vijay Chudasama","doi":"10.1039/d4sc06500j","DOIUrl":"https://doi.org/10.1039/d4sc06500j","url":null,"abstract":"Many protein bioconjugation strategies focus on the modification of lysine residues owing to the nucleophilicity of their amine side-chain, the generally high abundance of lysine residues on a protein’s surface and the ability to form robustly stable amide-based bioconjugates. However, the plethora of solvent accessible lysine residues, which often have similar reactivity, is a key inherent issue when searching for regioselectivity and/or controlled loading of an entity. A relevant example is the modification of antibodies and/or antibody fragments, whose conjugates offer potential for a wide variety of applications. Thus, research in this area for the controlled loading of an entity via reaction with lysine residues is of high importance. In this article, we present an approach to achieve this by exploiting the quantitative and reversible site-selective modification of disulfides using pyridazinediones, which facilitates near-quantitative proximity-induced reactions with lysines to enable controlled loading of an entity. The strategy was appraised on several clinically relevant antibody fragments and enabled the formation of mono-labelled lysine-modified antibody fragment conjugates via the formation of stable amide bonds and the use of click chemistry for modular modification. Furthermore, through the use of multiple cycles of this novel strategy, an orthogonally bis-labelled lysine-modified antibody fragment conjugate was also furnished.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"15 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-target-directed therapeutic strategies for Alzheimer’s disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition","authors":"Jeasang Yoo, Jimin Lee, Byeongha Ahn, Jiyeon Han, Mi Hee Lim","doi":"10.1039/d4sc06762b","DOIUrl":"https://doi.org/10.1039/d4sc06762b","url":null,"abstract":"Alzheimer’s disease (AD) is the most prevalent neurodegenerative dementia, marked by progressive cognitive decline and memory impairment. Despite advances in therapeutic research, single-target-directed treatments often fall short in addressing the complex, multifactorial nature of AD. This arises from various pathological features, including amyloid-β (Aβ) aggregate deposition, metal ion dysregulation, oxidative stress, impaired neurotransmission, neuroinflammation, mitochondrial dysfunction, and neuronal cell death. This review illustrates their interrelationships, with a particular emphasis on the interplay among Aβ, metal ions, and AD-related enzymes, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), matrix metalloproteinase 9 (MMP9), lysyl oxidase-like 2 (LOXL2), acetylcholinesterase (AChE), and monoamine oxidase B (MAOB). We further underscore the potential of therapeutic strategies that simultaneously inhibit Aβ aggregation and address other pathogenic mechanisms. These approaches offer a more comprehensive and effective method for combating AD, overcoming the limitations of conventional therapies.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"8 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Late-stage installation and functionalization of alkyl pyridiniums: a general HTE amenable strategy to access diverse aryl alanine containing macrocyclic peptides","authors":"Ahmet Kekec, Lauren My-Linh Tran, Christopher W. Plummer, Dipannita Kalyani","doi":"10.1039/d4sc06837h","DOIUrl":"https://doi.org/10.1039/d4sc06837h","url":null,"abstract":"This manuscript describes a strategy to readily access diverse aryl and homoaryl alanine-containing pharmaceutically relevant macrocyclic peptides. A two-step sequence involving the late-stage installation of the pyridinium functionality on macrocyclic peptides followed by reductive couplings was implemented. These transformations are amenable to microscale high-throughput experimentation (HTE) and enable rapid access to aryl alanine-containing macrocyclic peptides that would otherwise be inaccessible <em>via</em> solid-phase peptide synthesis using commercially available amino acids. Numerous aryl and heteroaryl derivatives can be effectively used in these reactions. In addition, a systematic investigation was undertaken using an “informer” set of macrocyclic peptides which revealed the compatibility of the late-stage diversification with peptides containing diverse side chain functionalities.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"7 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrostatically tuning radical addition and atom abstraction reactions with distonic radical ions.","authors":"Oisin J Shiels, Samuel C Brydon, Berwyck L J Poad, David L Marshall, Sevan D Houston, Hui Xing, Paul V Bernhardt, G Paul Savage, Craig M Williams, David G Harman, Benjamin B Kirk, Gabriel da Silva, Stephen J Blanksby, Adam J Trevitt","doi":"10.1039/d4sc06333c","DOIUrl":"https://doi.org/10.1039/d4sc06333c","url":null,"abstract":"<p><p>Although electrostatic catalysis can enhance the kinetics and selectivity of reactions to produce greener synthetic processes, the highly directional nature of electrostatic interactions has limited widespread application. In this study, the influence of oriented electric fields (OEF) on radical addition and atom abstraction reactions are systematically explored with ion-trap mass spectrometry using structurally diverse distonic radical ions that maintain spatially separated charge and radical moieties. When installed on rigid molecular scaffolds, charged functional groups lock the magnitude and orientation of the internal electric field with respect to the radical site, creating an OEF which tunes the reactivity across the set of gas-phase carbon-centred radical reactions. In the first case, OEFs predictably accelerate and decelerate the rate of molecular oxygen addition to substituted phenyl, adamantyl, and cubyl radicals, depending on the polarity of the charged functional group and dipole orientation. In the second case, OEFs modulate competition between chlorine and hydrogen atom abstraction from chloroform based on interactions between charge polarity, dipole orientation, and radical polarizability. Importantly, this means the same charge polarity can induce different changes to reaction selectivity. Quantum chemical calculations of these reactions with DSD-PBEP86-D3(BJ)/aug-cc-pVTZ show correlations between the barrier heights and the experimentally determined reaction kinetics. Field effects are consistent between phenyl and cubyl scaffolds, pointing to through-space rather than through-bond field effects, congruent with computations showing that the same effects can be mimicked by point charges. These results experimentally demonstrate how internal OEFs generated by carefully placed charged functional groups can systematically control radical reactions.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper catalyzed selective methane oxidation to acetic acid using O₂.","authors":"Poorvi Gupta, Bharti Rana, Rishabh Maurya, Rahul Kalita, Manav Chauhan, Kuntal Manna","doi":"10.1039/d4sc06281g","DOIUrl":"10.1039/d4sc06281g","url":null,"abstract":"<p><p>The direct transformation of methane into C₂ oxygenates such as acetic acid selectively using molecular oxygen (O₂) is a significant challenge due to the chemical inertness of methane, the difficulty of methane C-H bond activation/C-C bond coupling and the thermodynamically favored over-oxidation. In this study, we have successfully developed a porous aluminium metal-organic framework (MOF)-supported single-site mono-copper(ii) hydroxyl catalyst [MIL-53(Al)-Cu(OH)], which is efficient in directly oxidizing methane to acetic acid in water at 175 °C with a remarkable selectivity using only O₂. This heterogeneous catalyst achieved an exceptional acetic acid productivity of 11 796 mmol_CH₃CO₂H mol_Cu ^-1 h^-1 in 9.3% methane conversion with 95% selectivity in the liquid phase and can be reused at least 6 times. Our experiments, along with computational studies and spectroscopic analyses, suggest a catalytic cycle involving the formation of a methyl radical (˙CH₃). The confinement of Cu-active sites within the porous MIL-53(Al) MOF facilitates C-C bond coupling, resulting in the efficient formation of acetic acid with excellent selectivity due to the internal mass transfer limitations. This work advances the development of efficient and chemoselective earth-abundant metal catalysts using MOFs for the direct transformation of methane into value-added products under mild and eco-friendly conditions.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into the visible-light-driven <i>O</i>-arylation of carboxylic acids catalyzed by xanthine-based nickel complexes.","authors":"Rafael E Rodriguez-Lugo, Joan Sander, Simon Dietzmann, Thomas Rittner, Jannes Rückel, Vanessa R Landaeta, Jiyong Park, Patrick Nuernberger, Mu-Hyun Baik, Robert Wolf","doi":"10.1039/d4sc04257c","DOIUrl":"10.1039/d4sc04257c","url":null,"abstract":"<p><p>We present a photocatalytic protocol for the <i>O</i>-arylation of carboxylic acids using nickel complexes bearing C8-pyridyl xanthines. Our studies suggest that the underlying mechanism operates independently of external photosensitizers. Stoichiometric experiments and crystallographic studies characterize the catalytically relevant Ni complexes. Spectroscopic and computational investigations propose a thermally controlled Ni(i)/Ni(iii) cycle followed by a photochemical regeneration of Ni(i) species. Furthermore, the pathways leading to the hydrodehalogenation of aryl halides, the comproportionation of Ni(i) and Ni(iii) species, the dimerization of Ni(i) intermediates and the influence of the counter ion on the cross-coupling reaction are unveiled. These investigations offer a comprehensive mechanistic understanding of the photocatalytic cross-coupling reaction catalyzed by a single Ni species and highlight key aspects of nickel-catalyzed metallaphotoredox reactions.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical proteomic profiling of lysine crotonylation using minimalist bioorthogonal probes in mammalian cells.","authors":"Yuan-Fei Zhou, Shouli Yuan, Bin Ma, Jinjun Gao, Chu Wang","doi":"10.1039/d4sc06745b","DOIUrl":"https://doi.org/10.1039/d4sc06745b","url":null,"abstract":"<p><p>Protein lysine crotonylation has been found to be closely related to the occurrence and development of various diseases. Currently, site identification of crotonylation is mainly dependent on antibody enrichment; however, due to the cost, heterogeneity, and specificity of antibodies, it is desired to develop an alternative chemical tool to detect crotonylation. Herein, we report an alkynyl-functionalized bioorthogonal chemical probe, Cr-alkyne, for the detection and identification of protein lysine crotonylation in mammalian cells. Our in-gel fluorescence and chemical proteomic analyses demonstrated that Cr-alkyne can be metabolically incorporated into lysine of histones and directly label known crotonylated proteins. We further applied Cr-alkyne to the proteome-wide profiling of crotonylation and revealed a large number of previously unreported modification sites, some of which could be validated by co-elution with synthetic peptides. Moreover, by integrating Cr-alkyne with quantitative chemical proteomics, we also explored the crotonylation sites regulated by HDACs, unveiling new HDAC regulated sites. Our study thus provides an enabling chemical tool for characterizing protein crotonylation and greatly expands our understanding of substrate proteins and functions of this important modification.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive approach for elucidating the interplay between 4fn+1 and 4fn5d1 configurations in Ln2+ complexes†","authors":"Maria J. Beltran-Leiva, William N. G. Moore, Tener F. Jenkins, William J. Evans, Thomas E. Albrecht and Cristian Celis-Barros","doi":"10.1039/D4SC05438E","DOIUrl":"10.1039/D4SC05438E","url":null,"abstract":"<p >Lanthanides (Ln) are typically found in the +3 oxidation state. However, in recent decades, their chemistry has been expanded to include the less stable +2 oxidation state across the entire series except promethium (Pm), facilitated by the coordination of ligands such as trimethylsilylcyclopentadienyl, C<small>₅</small>H<small>₄</small>SiMe<small>₃</small> (Cp′). The <img> complexes have been the workhorse for the synthesis and theoretical study of the fundamental aspects of divalent lanthanide chemistry, where experimental and computational evidence have suggested the existence of different ground state (GS) configurations, 4f<small>^<em>n</em>+1</small> or 4f<small>^<em>n</em></small>5d<small>¹</small>, depending on the specific metal. Standard reduction potentials and 4f<small>^<em>n</em>+1</small> to 4f<small>^<em>n</em></small>5d<small>¹</small> promotion energies have been two factors usually considered to rationalize the occurrence of these variable GS configurations, however the driving force behind this phenomenon is still not clear. In this work we present a comprehensive theoretical approach to shed light on this matter using the [LnCp<small>₃</small>]<small>⁻</small> model systems. We begin by calculating 4f<small>^<em>n</em>+1</small> to 4f<small>^<em>n</em></small>5d<small>¹</small> promotion energies and successfully correlate them with existing experimental data. Furthermore, we analyze how changes in the GS charge distribution between the Ln ions, LnCp<small>₃</small> and the reduced [LnCp<small>₃</small>]<small>⁻</small> complexes (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu) correlate with experimental trends in redox potentials and the calculated promotion energies. For this purpose, a comprehensive theoretical work that includes relativistic ligand field density functional theory (LFDFT) and relativistic <em>ab initio</em> wavefunction methods was performed. This study will help the rational design of suitable environments to tune the different GS configurations as well as modulating the spectroscopic properties of new Ln<small>²⁺</small> complexes.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" 4","pages":" 2024-2033"},"PeriodicalIF":7.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More π, please: What drives the formation of unsaturated molecules in the interstellar medium?","authors":"Jhoan Londoño-Restrepo, Santiago Gómez, Heidy Mayerly Quitián-Lara, Felipe Fantuzzi, Albeiro Restrepo","doi":"10.1039/d4sc07986h","DOIUrl":"https://doi.org/10.1039/d4sc07986h","url":null,"abstract":"We present a computational investigation into the fragmentation pathways of ethanolamine (C<small>₂</small>H<small>₇</small>NO, EtA), propanol (C<small>₃</small>H<small>₈</small>O, PrO), butanenitrile (C<small>₄</small>H<small>₇</small>N, BuN), and glycolamide (C<small>₂</small>H<small>₅</small>NO<small>₂</small>, GlA)—saturated organic molecules detected in the interstellar medium (ISM), particularly in the molecular cloud complex Sagittarius B2 (Sgr B2) and its molecular cloud G+0.693–0.027. Using electron-impact ionization data and Born–Oppenheimer molecular dynamics simulations, we investigate how cosmic rays, cosmic-ray-induced UV fields, and shock-induced heating can induce the fragmentation of these molecules, resulting in the formation of unsaturated species with extended π-bond networks. Despite the attenuation of external UV radiation in G+0.693–0.027, these energetic processes are capable of driving partial transformations of saturated into unsaturated molecules, supporting the coexistence of species like EtA and GlA alongside unsaturated nitriles such as cyanoacetylene (HC<small>₃</small>N), cyanopropyne (CH<small>₃</small>C<small>₃</small>N), and cyanoallene (CH<small>₂</small>CCHCN). Our findings underscore the significance of high-energy mechanisms in enhancing chemical complexity within molecular clouds and offer insights into the pathways that govern the evolution of organic molecules in the ISM.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"351 1","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Fang's fury: a computational study of the enzyme–membrane interaction and catalytic pathway of the snake venom phospholipase A2 toxin†","authors":"Juliana Castro-Amorim, Alexandre V. Pinto, Ashis K. Mukherjee, Maria J. Ramos and Pedro A. Fernandes","doi":"10.1039/D4SC06511E","DOIUrl":"10.1039/D4SC06511E","url":null,"abstract":"<p >Snake venom-secreted phospholipases A<small>₂</small> (svPLA<small>₂</small>s) are critical, highly toxic enzymes present in almost all snake venoms. Upon snakebite envenomation, svPLA<small>₂</small>s hydrolyze cell membrane phospholipids and induce pathological effects such as paralysis, myonecrosis, inflammation, or pain. Despite its central importance in envenomation, the chemical mechanism of svPLA<small>₂</small>s is poorly understood, with detrimental consequences for the design of small-molecule snakebite antidotes, which is highly undesirable given the gravity of the epidemiological data that ranks snakebite as the deadliest neglected tropical disease. We study a member of the svPLA<small>₂</small> family, the Myotoxin-I, which is part of the venom of the Central American pit viper terciopelo (<em>Bothrops asper</em>), a ubiquitous but highly aggressive and dangerous species responsible for the most problematic snakebites in its habitat. Furthermore, PLA<small>₂</small> enzymes are a paradigm of interfacial enzymology, as the complex membrane–enzyme interaction is as important as is crucial for its catalytic process. Here, we explore the detailed interaction between svPLA<small>₂</small> and a 1 : 1 POPC/POPS membrane, and how enzyme binding affects membrane structure and dynamics. We further investigated the two most widely accepted reaction mechanisms for svPLA<small>₂</small>s: the ‘single-water mechanism’ and the ‘assisted-water mechanism’, using umbrella sampling simulations at the PBE/MM level of theory. We demonstrate that both pathways are catalytically viable. While both pathways occur in two steps, the single-water mechanism yielded a lower activation free energy barrier (20.14 kcal mol<small>⁻¹</small>) for POPC hydrolysis, consistent with experimental and computational values obtained for human PLA<small>₂</small>. The reaction mechanisms are similar, albeit not identical, and can be generalized to svPLA<small>₂</small> from most viper species. Furthermore, our findings demonstrate that the sole small molecule inhibitor currently undergoing clinical trials for snakebite is a perfect transition state analog. Thus, understanding snake venom sPLA<small>₂</small> chemistry will help find new, effective small molecule inhibitors with anti-snake venom efficacy.</p>","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":" 4","pages":" 1974-1985"},"PeriodicalIF":7.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2025/sc/d4sc06511e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}