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

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

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Infection,Pain,and Itch

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Neuroscience Bulletin 2018年第1期34卷 109-119页

作者： isaac m.Chiu Department of microbiology and Immunobiology Division of Immunology Harvard Medical School

Pain and itch are unpleasant sensations that often accompany infections caused by viral, bacterial, parasitic, and fungal pathogens. Recent studies show that sensory neurons are able to directly detect pathogens to mediate pain and itch. Nociceptor and pruriceptor neurons respond to pathogen-associated molecular patterns, including Toll-like receptor ligands, N-formyl peptides, and bacterial toxins. Other pathogens are able to silence neuronal activity to produce analgesia during infection. Pain and itch could lead to neuronal modulation of the immune system or behavioral avoidance of future patho- gen exposure. Conversely, pathogens could modulate neuronal signaling to potentiate their pathogenesis and facilitate their spread to other hosts. Defining how pathogens modulate pain and itch has critical implications for sensory neurobiology and our understanding of host- microbe interactions.

关键词： Pain Itch Bacteria Pathogens Infection Inflammation Viruses

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The role of cellular and molecular neuroimmune crosstalk in gut immunity

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Cellular & molecular Immunology 2023年第11期20卷 1259-1269页

作者： Daping Yang Nicole Almanzar isaac m.Chiu Department of Immunology Harvard Medical SchoolBostonMA02115USA

The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by the immune *** two systems critically coordinate the sensations of and adaptations to dietary,microbial,and damaging stimuli from the external and internal microenvironment during tissue homeostasis and *** brain receives and integrates ascending sensory signals from the gut and transduces descending signals back to the gut via autonomic *** regulate intestinal immune responses through the action of local axon reflexes or through neuronal circuits via the gut-brain *** neuroimmune crosstalk is critical for gut homeostatic maintenance and disease *** this review,we discuss the roles of distinct types of gut-innervating neurons in the modulation of intestinal mucosal *** will focus on the molecular mechanisms governing how different immune cells respond to neural signals in host defense and *** also discuss the therapeutic potential of strategies targeting neuroimmune crosstalk for intestinal diseases.

关键词： Neuroimmunology Neuroimmune Host defense Gut Sensory

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HyDeploy:The UK’s First Hydrogen Blending Deployment Project

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Clean Energy 2019年第2期3卷 114-125页

作者： Tommy isaac Principal Engineer Progressive Energy LtdSwan House-Bonds MillsStonehouseGloucestershire GL103RFUK

The HyDeploy project is the UK’s first practical project to demonstrate that hydrogen can be safely blended into the natural-gas distribution system without requiring changes to appliances and the associated *** project is funded under Ofgem’s Network Innovation Competition and is a collaboration between Cadent Gas,Northern Gas Networks,Progressive Energy Ltd,Keele University(Keele),Health&Safety Laboratory and ITm *** and Northern Gas Networks are the Gas Distribution Network sponsors of the *** University is the host site,providing the gas-distribution network,which will receive the hydrogen *** University is the largest campus university in the ***&Safety Laboratory provides the scientific laboratories and experimental *** Power provides the electrolyser that produces the *** Energy Ltd is the project developer and project *** is structured into three distinct *** first is an extensive technical programme to establish the necessary detailed evidence base in support of an application to the Health&Safety Executive for Exemption to Schedule 3 of the Gas Safety(management)Regulations(GS(m)R)to permit the injection of hydrogen at 20 mol%.This is required to allow hydrogen to be blended into a natural-gas supply above the current British limit of 0.1 mol%.The second phase comprises the construction of the electrolyser and grid entry unit,along with the necessary piping and valves,to allow hydrogen to be mixed and injected into the Keele University gas-distribution network and to ensure all necessary training of operatives is conducted before *** third phase is the trial itself,which is due to start in the summer of 2019 and last around 10 *** trial phase also provides an opportunity to undertake further experimental activities related to the operational network to support the pathway to full deployment of blended *** outcome of HyDeploy is principally develo

关键词： HyDeploy hydrogen blending demonstration project

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Geomechanical effects of stress shadow created by large-scale destress blasting

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Journal of Rock mechanics and Geotechnical Engineering 2017年第6期9卷 1085-1093页

作者： isaac Vennes Hani mitri Department of mining and materials Engineering McGill UniversityMontrealH3A 0E8Canada

This study aims to determine if large-scale choked panel destress blasting can provide sufficient beneficial stress reduction in highly-stressed remnant ore pillar that is planned for production. The orebody is divided into 20 stopes over 2 levels, and 2 panels are choke-blasted in the hanging wall to shield the ore pillar by creating a stress shadow around it. A linear-elastic model of the mining system is constructed with finite difference code FLAC3 D. The effect of destress blasting in the panels is simulated by applying a fragmentation factor(α) to the rock mass stiffness and a stress reduction factor(β) to the current state of stress in the region occupied by the destress panels. As an extreme case, the destress panel is also modeled as a void to obtain the maximum possible beneficial effects of destressing and stress *** stopes are mined in the stress shadow of the panels in 6 lifts and then backfilled. The effect of destress blasting on the remnant ore pillar is quantified based on stress change and brittle shear ratio(BSR) in the stress shadow zone compared to the base case without destress blasting. To establish realistic rock fragmentation and stress reduction factors, model results are compared to measured stress changes reported for case studies at Fraser and Brunswick mines. A 1.5 mPa immediate stress decrease was observed 20 m away from the panel at Fraser mine, and a 4 mPa immediate stress decrease was observed 25 m away at Brunswick mine. Comparable results are obtained from the current model with a rock fragmentation factor α of 0.2 and a stress reduction factor α of 0.8. It is shown that a destress blasting with these parameters reduces the major principal stress in the nearest stopes by 10-25 *** yields an immediate reduction of BSR, which is deemed sufficient to reduce volume of ore at risk in the pillar.

关键词： Destress blasting Preconditioning Rockbursts Strainbursts Numerical modeling Rock failure

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Supervised and Semi-supervised methods for Abdominal Organ Segmentation: A Review

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International Journal of Automation and computing 2021年第6期18卷 887-914页

作者： isaac Baffour Senkyire Zhe Liu School of Computer Science and Communication Engineering Jiangsu UniversityZhenjiang 212013China Computer Science Department Ghana Communication Technology UniversityAccraGhana

Abdominal organ segmentation is the segregation of a single or multiple abdominal organ(s) into semantic image segments of pixels identified with homogeneous features such as color and texture, and intensity. The abdominal organ(s) condition is mostly connected with greater morbidity and mortality. most patients often have asymptomatic abdominal conditions and symptoms, which are often recognized late;hence the abdomen has been the third most common cause of damage to the human body. That notwithstanding,there may be improved outcomes where the condition of an abdominal organ is detected earlier. Over the years, supervised and semi-supervised machine learning methods have been used to segment abdominal organ(s) in order to detect the organ(s) condition. The supervised methods perform well when the used training data represents the target data, but the methods require large manually annotated data and have adaptation problems. The semi-supervised methods are fast but record poor performance than the supervised if assumptions about the data fail to hold. Current state-of-the-art methods of supervised segmentation are largely based on deep learning techniques due to their good accuracy and success in real world applications. Though it requires a large amount of training data for automatic feature extraction, deep learning can hardly be used. As regards the semi-supervised methods of segmentation, self-training and graph-based techniques have attracted much research attention. Self-training can be used with any classifier but does not have a mechanism to rectify mistakes early. Graph-based techniques thrive on their convexity, scalability, and effectiveness in application but have an out-of-sample problem. In this review paper, a study has been carried out on supervised and semi-supervised methods of performing abdominal organ segmentation. An observation of the current approaches, connection and gaps are identified, and prospective future research opportunities are enu

关键词： Abdominal organ supervised segmentation semi-supervised segmentation evaluation metrics image segmentation machine learning

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Anthropogenic land use substantially increases riverine CO_(2) emissions

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Journal of Environmental Sciences 2022年第8期34卷 158-170页

作者： Shijie Gu Siyue Li isaac R.Santos School of River and Ocean Engineering Chongqing Jiaotong UniversityChongqing 400074China Key Laboratory of Reservoir Aquatic Environment Chongqing Institute of Green and Intelligent TechnologyChinese Academy of SciencesChongqing 400714China Chongqing School University of Chinese Academy of SciencesChongqing 400714China Research Center for Environmental Ecology and Engineering Institute of Changjiang Water Environment and Ecological SecuritySchool of Environmental Ecology and Biological EngineeringKey Laboratory for Green Chemical Process of Ministry of EducationKey Laboratory of Novel Reactor and Green Chemical Technology of Hubei ProvinceEngineering Research Center of Phosphorus Resources Development and Utilization of Ministry of EducationWuhan Institute of TechnologyWuhan 430205China Department of marine Sciences University of GothenburgGothenburg 41296Sweden National marine Science Centre Southern Cross UniversityCoffs HarbourNSW 2450Australia

Carbon dioxide(CO_(2)) emissions from inland waters to the atmosphere are a pivotal component of the global carbon budget. Anthropogenic land use can influence riverine CO_(2) emissions, but empirical data exploring cause-effect relationships remain limited. Here, we investigated CO_(2) partial pressures(pCO_(2)) and degassing in a monsoonal river(Yue River)within the Han River draining to the Yangtze in China. Almost 90% of river samples were supersaturated in CO_(2) with a mean ± standard deviation of 1474 ± 1614 μatm, leading to emissions of 557-971 mmol/m^(2)/day from river water to the atmosphere. Annual CO_(2) emissions were 1.6-2.8 times greater than the longitudinal exports of riverine dissolved inorganic and organic carbon. pCO_(2) was positively correlated to anthropogenic land use(urban and farmland), and negatively correlated to forest cover. p CO_(2) also had significant and positive relationships with total dissolved nitrogen and total dissolved phosphorus. Stepwise multiple regression models were developed to predict p CO_(2) . Farmland and urban land released nutrients and organic matter to the river system, driving riverine p CO_(2) enrichment due to enhanced respiration in these heterotrophic rivers. Overall, we show the crucial role of land use driving riverine pCO_(2) , which should be considered in future large-scale estimates of CO_(2) emissions from streams. Land use change can thus modify the carbon balance of urban-river systems by enhancing river emissions, and reforestation helps carbon neutral in rivers.

关键词： River carbon Inland waters Greenhouse gases Climate change Water quality Headwater streams

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Large-scale destress blasting for seismicity control in hard rock mines:A case study

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International Journal of mining Science and Technology 2020年第2期30卷 141-149页

作者： isaac Vennes Hani mitri Damodara Reddy Chinnasane mike Yao Department of mining and materials Engineering McGill UniversityMontrealQuebec H3A 0E8Canada Copper Cliff mine Vale Canada LtdSudbury P0M 1N0Canada

Destress blasting is a rockburst control technique where highly stressed rock is blasted to reduce the local stress and stiffness of the rock,thereby reducing its burst *** technique is commonly practiced in deep hard rock mines in burst prone developments,as well as in sill or crown pillars which become burst-prone as the orebody is ***-scale destressing is a variant of destress blasting where panels are created parallel to the orebody strike with a longhole,fanning blast pattern from cross cut drifts situated in the host *** aim of panel destressing is to reduce the stress concentration in the ore blocks or pillars to be *** paper focuses on the large-scale destress blasting program conducted at Vale's Copper Cliff mine(CCm)in Ontario,*** merits of panel destressing are examined through field measurements of mining induced stress changes in the *** destressing mechanism is simulated with a rock fragmentation factor(a)and stress reduction/dissipation factor(b).A 3D model is built and validated with measured induced stress *** is shown that the best correlation between the numerical model and field measurements is obtained when the combination of a and b indicates that the blast causes high fragmentation(a=0.05)and high stress release(b=0.95)in the destress *** is demonstrated that the burst proneness of the ore blocks in the panel stress shadow is reduced in terms of the brittle shear ratio(BSR)and the burst potential index(BPI).

关键词： Destress blasting Preconditioning Rockbursts Strainbursts Numerical modeling

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Do age-associated changes of voltage-gated sodium channel isoforms expressed in the mammalian heart predispose the elderly to atrial fibrillation?

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World Journal of Cardiology 2020年第4期12卷 123-135页

作者： Emmanuel isaac Stephanie m Cooper Sandra A Jones mahmoud Loubani Department of Cardiothoracic Surgery Hull University Teaching HospitalsCottingham HU165JQUnited Kingdom Department of Biomedical Sciences University of HullHull HU67RXUnited Kingdom

Atrial fibrillation(AF)is the most common cardiac arrhythmia *** prevalence of the disease increases with age,strongly implying an age-related process underlying the *** a time when people are living longer than ever before,an exponential increase in disease prevalence is predicted *** unraveling the underlying mechanics of the disease is paramount for the development of innovative treatment and prevention *** role of voltage-gated sodium channels is fundamental in cardiac electrophysiology and may provide novel insights into the arrhythmogenesis of ***_v1.5 is the predominant cardiac isoform,responsible for the action potential *** studies have demonstrated that Na_v1.8(an isoform predominantly expressed within the peripheral nervous system)is responsible for cellular arrhythmogenesis through the enhancement of pro-arrhythmogenic *** studies have shown a decline in Na_v1.5 leading to a diminished action potential upstroke during phase ***,the study of human tissue demonstrates an inverse expression of sodium channel isoforms;reduction of Na_v1.5 and increase of Na_v1.8 in both heart failure and ventricular *** strongly suggests that the expression of voltage-gated sodium channels play a crucial role in the development of arrhythmias in the diseased *** aberrant sodium currents has led to novel therapeutic approaches in tackling AF and continues to be an area of emerging *** review will explore how voltage-gated sodium channels may predispose the elderly heart to AF through the examination of laboratory and clinical based evidence.

关键词： Voltage-gated Sodium channels Ageing Atrial fibrillation Nav1.5 Nav1.8 Late sodium current Cardiac electrophysiology

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Re-engineering artificial muscle with microhydraulics

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microsystems & Nanoengineering 2017年第1期3卷 278-285页

作者： Jakub Kedzierski Eric Holihan Rafmag Cabrera isaac Weaver massachusetts Institute of Technology Lincoln Laboratory LexingtonMA 02420USA

We introduce a new type of actuator,the microhydraulic stepping actuator(mSA),which borrows design and operational concepts from biological muscle and stepper *** offer a unique combination of power,efficiency,and scalability not easily achievable on the *** actuator works by integrating surface tension forces produced by electrowetting acting on scaled droplets along the length of a thin *** muscle,mSAs have liquid and solid functional components and can displace a large fraction of their *** 100μm pitch mSA presented here already has an output power density of over 200 W kg^(−1),rivaling the most powerful biological muscles,due to the scaling of surface tension forces,mSA’s power density grows quadratically as its dimensions are reduced.

关键词： artificial muscle electrowetting linear actuator microactuator microsystem microhydraulic stepping actuator

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