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Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

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Protein & Cell 2010年第4期1卷 384-392页

作者： Areej M.Abuhammad Edward D.Lowe Elizabeth Fullam Martin Noble Elspeth F.Garman edith sim Department of Pharmacology University of OxfordMansfield RoadOxford OX13QTUK Department of Biochemistry University of OxfordSouth Parks RoadOxford OX13QUUK

Treatment of latent tuberculosis infection remains an important goal of global TB *** this end,targets that are essential for intracellular survival of Mycobacterium tuberculosis are particularly *** N-acetyltransferase(NAT)represents such a target as it is,along with the enzymes encoded by the associated gene cluster,essential for mycobacterial survival inside macrophages and involved in cholesterol *** is likely to be the fuel for *** inside *** the nat gene and inhibiting the NAT enzyme prevents survival of the microorganism in macrophages and induces cell wall alterations,rendering the mycobacterium sensitive to antibiotics to which it is normally *** date,NAT from ***(MMNAT)is considered the best available model for NAT from ***(TBNAT).The enzyme catalyses the acetylation and propionylation of arylamines and *** is a good acetyl and propionyl acceptor for both MMNAT and *** MMNAT structure has been solved to 2.1Åresolution following crystallisation in the presence of hydralazine and is compared to available NAT *** the mode of ligand binding,features of the binding pocket can be identified,which point to a novel mechanism for the acetylation reaction that results in a 3-methyltriazolo[3,4-a]phthalazine ring compound as product.

关键词： Mycobacterium tuberculosis Mycobacterium marinum tuberculosis arylamine N-acetyltransferase 3D crystal structure binding pocket

Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars

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Protein & Cell 2010年第1期1卷 82-95页

作者： Isaac M.Westwood Sanjib Bhakta Angela J.Russell Elizabeth Fullam Matthew C.Anderton Akane Kawamura Andrew W.Mulvaney Richard J.Vickers Veemal Bhowruth Gurdyal S.Besra Ajit Lalvani Stephen G.Davies edith sim Department of Pharmacology University of OxfordOxford OX13QTUnited Kingdom Chemistry Research Laboratory Department of Organic ChemistryUniversity of OxfordOxford OX13QLUnited Kingdom School of Biosciences University of BirminghamEdgbastonBirmingham B152TTUnited Kingdom Tuberculosis Immunology Group Department of Respiratory MedicineNational Heart and Lung InstituteWright Fleming Institute of Infection and ImmunityImperial College LondonNorfolk PlaceLondon W21PGUnited Kingdom Structure-Based Drug Design Team Sections of Structural Biology and Cancer TherapeuticsInstitute of Cancer ResearchChester Beatty LaboratoriesLondon SW36JBUnited Kingdom Institute of Structural and Molecular Biology Department of Biological ScienceBirkbeckUniversity of LondonLondon WC1E 7HXUnited Kingdom

New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting *** have a unique cell *** of the gene for arylamine N-acetyltransferase(NAT)decreases mycobacterial cell wall lipids,particularly the distinctive mycolates,and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis *** nat gene and its associated gene cluster are almost identical in sequence in *** BCG and *** gene cluster is essential for intracellular survival of *** have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT ***,we characterize one class of such molecules—triazoles—in relation to its effects on the target enzyme and on both *** BCG and *** most potent triazole mimics the effects of deletion of the nat gene on growth,lipid disruption and intracellular *** also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth,and use ligand-protein analysis to give further insight into the structure-activity *** conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved.

关键词： N-acetyltransferase Mycobacterium tuberculosis triazoles screening

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

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Neural Regeneration Research 2025年第2期20卷 394-401页

作者： Josep Tomàs Víctor Cilleros-Mañé Laia Just-Borràs Marta Balanyà-Segura Aleksandra Polishchuk Laura Nadal Marta Tomàs Carolina Silvera-simón Manel M.Santafé Maria A.Lanuza Unitat d’Histologia i Neurobiologia(UHNeurob) Facultat de Medicina i Ciències de la SalutUniversitat Rovira i VirgiliReusSpain

During the development of the nervous system,there is an overproduction of neurons and *** competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or *** have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse *** purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this *** particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental *** dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific *** describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon *** downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary ***,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to red

关键词： acetylcholine release adenosine receptors axonal competition brain-derived neurotrophic factor calcium channels motor end-plate muscarinic acetylcholine receptors postnatal synapse elimination serine kinases tropomyosin-related kinase receptorB

Differential response of injured and healthy retinas to syngeneic and allogeneic transplantation of a clonal cell line of immortalized olfactory ensheathing glia:a double-edged sword

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Neural Regeneration Research 2025年第8期20卷 2395-2407页

作者： María Norte-Muñoz María Portela-Lomba Paloma Sobrado-Calvo Diana simón Johnny Di Pierdomenico Alejandro Gallego-Ortega Mar Pérez JoséMCabrera-Maqueda Javier Sierra Manuel Vidal-Sanz María Teresa Moreno-Flores Marta Agudo-Barriuso Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la SaludMurciaSpain Experimental Sciences Faculty Universidad Francisco de VitoriaPozuelo de AlarcónMadridSpain Anatomy Histology and Neuroscience DepartmentMedicine FacultyUniversidad Autónoma de MadridMadridSpain Center of Neuroimmunology Service of NeurologyLaboratory of Advanced Imaging in Neuroimmunological DiseasesHospital Clínic of BarcelonaInstitut d’Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS)and Universitat de BarcelonaBarcelonaSpain Medicine Faculty Universidad Francisco de VitoriaPozuelo de AlarcónMadridSpain

Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic ***,it is unknown whether olfactory ensheathing glia also have neuroprotective *** ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion ***,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve *** ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive *** and gene expression analyses were *** bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡ*** and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an *** axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 *** these retinas,microglial anatomical activation was higher than after optic nerve crush *** intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or ***,neuroprotection of axotomized retinal ganglion cells did not improve with these *** different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.

关键词： cell therapy immune recognition major histocompatibility complex class II(MHCII) neuroprotection olfactory ensheathing glia retinal ganglion cells

Teaching of pharmacology in Universiti Malaya and the other medical schools in Malaysia - a historical perspective

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Acta Pharmacologica Sinica 2004年第9期25卷 107-117页

作者： Si Mui sim 50603 Kuala Lumpur Department of Pharmacology Faculty of Medicine Malaysia University of Malaya

Traditional pharmacology teaching has focused more on drug instead of therapeutics, such that although pharmacological knowledge is acquired, practical skills in prescribing remain weak. In Malaysia many new medical schools (both public and private) have been set up in the last 12 years due to a change in government policy, resulting in a wide spectrum of medical curricula. Universiti Malaya (UM) being the oldest medical school in

关键词： pharmacology teaching basic sciences Malaysian medical schools integrated curriculum problem-based learning

A New Approach to Multivariate Network Traffic Analysis

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Journal of Computer Science & Technology 2019年第2期34卷 388-402页

作者： Jinoh Kim Alex sim Department of Computer Science Texas A&M University Commerce 75428 U.S.A. Computational Research Division Lawrence Berkeley National Laboratory Berkeley CA 94720 U.S.A.

Network traffic analysis is one of the core functions in network monitoring for effective network operations and *** online traffic analysis has been widely studied,it is still intensively challenging due to several *** of the primary challenges is the heavy volume of traffic to analyze within a finite amount of time due to the increasing network *** important challenge for effective traffic analysis is to support multivariate functions of traffic variables to help administrators identify unexpected network events *** this end,we propose a new approach with the multivariate analysis that offers a high-level summary of the online network *** this approach,the current state of the network will display patterns compiled from a set of traffic variables,and the detection problems in network monitoring(e.g.,change detection and anomaly detection)can be reduced to a pattern identification and classification *** this paper,we introduce our preliminary work with clustered patterns for online,multivariate network traffic analysis with the challenges and limitations we *** then present a grid-based model that is designed to overcome the limitations of the clustered pattern-based *** will discuss the potential of the new model with respect to the technical challenges including streaming-based computation and robustness to outliers.

关键词： network traffic analysis multivariate analysis time-series similarity network monitoring

A review on the scale-up of high-shear wet granulation processes and the impact of process parameters

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Particuology 2024年第9期92卷 180-195页

作者： Ana Rita Alves Marta Filipe simões Sérgio simões João Gomes University of Coimbra CERESDepartment of Chemical EngineeringFaculty of Sciences and TechnologyRua Sílvio Lima3030-790CoimbraPortugal Bluepharma-Indústria Farmacêutica São Martinho do BispoCoimbra3045-016Portugal Faculty of Pharmacy University of CoimbraAzinhaga de Santa Comba3000-548CoimbraPortugal

Wet granulation is one of the most important agglomeration processes,and high-shear granulation(HSG)one of the most employed technologies in the pharmaceutical *** most critical process parameters of HSG are discussed in this *** main concern in scaling up the wet granulation process is the differences between scales,which prevent the particles from having the same experience across all *** scale-up of wet granulation processes is commonly divided into two categories:engineering and attribute-based *** engineering-based scale-up approach is a strategy based on dimensional analysis and an attribute-based supported on the principles of“equifinality”,where process variables are adjusted to obtain equivalent granule *** work presents the effect of different HSG process parameters on the scale-up,as well as the use of process analytical tools(PAT)and modelling *** aim is to review applied scale-up approaches in HSG and discuss benefits and *** is proven why the scale-up for oral solid pharmaceutical products is still considered a hot topic and a very challenging task for development and engineering teams.

关键词： High-shear wetgranulation Parametric-based Attribute-based Physics-based modelling Impeller design Scale-up

Existence results for degenerate p(x)-Laplace equations with Leray-Lions type operators

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Science China Mathematics 2017年第1期60卷 133-146页

作者： HO Ky sim Inbo Department of Mathematics University of Ulsan Ulsan 680-749 South Korea

We show the existence and multiplicity of solutions to degenerate p(x)-Laplace equations with Leray-Lions type operators using direct methods and critical point theories in Calculus of Variations and prove the uniqueness and nonnegativeness of solutions when the principal operator is monotone and the nonlinearity is nonincreasing. Our operator is of the most general form containing all previous ones and we also weaken assumptions on the operator and the nonlinearity to get the above results. Moreover, we do not impose the restricted condition on p(x) and the uniform monotonicity of the operator to show the existence of three distinct solutions.

关键词： p(x)-Laplacian weighted variable exponent Lebesgue-Sobolev spaces multiplicity a priori bound Leray-Lions type operators

Topical ocular administration of DPP-Ⅳ inhibitors:a new approach for treating diabetes-induced retinal neurodegeneration

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Neural Regeneration Research 2024年第4期19卷 713-714页

作者： Rafael simó Cristina Hernández Diabetes and Metabolism Research Unit Vall d’Hebron Research Institute(VHIR) Department of Medicine Autonomous University of Barcelona Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas(CIBERDEM) Instituto de Salud CarlosⅢ(ICSⅢ)

Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy(DR),the leading cause of preventable *** fact,the American Diabetes Association has defined DR as a highly specific neurovascular complication(Solomon et al.,2017).Therefore,it is no longer acceptable to consider DR as merely a microvascular *** this regard,the term diabetic retinal disease(DRD)has been proposed as a broader term comprising microangiopathy and ***,there are currently no treatments available that directly target the neurodegenerative changes of *** paper will give new insights into the translational research in this field with particular emphasis on glucagon-like peptide 1/dipeptidyl peptidase IV(GLP-1/DPP-IV)inhibitors.

关键词： neurodegeneration ocular insight