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Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis

Neural regeneration research 2017年第8期12卷 1262-1267页

作者： rebecca M.Heidker mitchell r.emerson Steven M.Le Vine Department of Molecular and Integrative Physiology University of Kansas Medical Center Department of Pharmaceutical Sciences College of Pharmacy-Glendale Midwestern University

Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth： insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.

关键词： acetyl-coenzyme A carboxylase biotin estrogen iron Kynurenine pathway mitochondria thyroidhormone remyelination stem cells vitamin D

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Evolutionary and ecological genomics of non-model plants

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Journal of Systematics and Evolution 2011年第1期49卷 17-24页

作者： Thomas mitchell-OLDS Institute for Genome Sciences and Policy Department of Biology Duke University

Dissecting evolutionary dynamics of ecologically important traits is a long-term challenge for biologists. Attempts to understand natural variation and molecular mechanisms have motivated a move from laboratory model systems to non-model systems in diverse natural environments. Next generation sequencing methods, along with an expansion of genomic resources and tools, have fostered new links between diverse disciplines, including molecular biology, evolution, ecology, and genomics. Great progress has been made in a few non-model wild plants, such as Arabidopsis relatives, monkey flowers, and wild sunflowers. Until recently, the lack of comprehensive genomic information has limited evolutionary and ecological studies to larger QTL (quantitative trait locus) regions rather than single gene resolution, and has hindered recognition of general patterns of natural variation and local adaptation. Further efforts in accumulating genomic data and developing bioinformatic and biostatistical tools are now poised to move this field forward. Integrative national and international collaborations and research communities are needed to facilitate development in the field of evolutionary and ecological genomics.

关键词： candidate genes ecological genomics fitness natural selection population genomics QTL.

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Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity

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World Journal of Gastroenterology 2010年第19期16卷 2448-2450页

作者： Hartmut Jaeschke C David Williams mitchell r McGill Anwar Farhood Department of Pharmacology Toxicology and Therapeutics University of Kansas Medical Center Kansas City KS 66160 United States Department of Pathology Brackenridge Hospital Austin TX 78701 United States

Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminopheninduced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature.

关键词： Acetaminophen Drug hepatotoxicity Herbal extracts N-acetylcysteine

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Visualization of atomic scale reaction dynamics of supported nanocatalysts during oxidation and ammonia synthesis using in-situ environmental(scanning) transmission electron microscopy

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Journal of Energy Chemistry 2021年第6期30卷 281-290,I0007页

作者： Michael r.Ward robert W.mitchell Edward D.Boyes Pratibha L.Gai The York Nanocentre University of YorkYork YO105DDUK Department of Physics University of YorkYork YO105DDUK Department of Electronic Engineering University of YorkYork YO105DDUK Department of Chemistry University of YorkYork YO105DDUK

reaction dynamics in gases at operating temperatures at the atomic level are the basis of heterogeneous gas-solid catalyst reactions and are crucial to the catalyst *** noble metal nanocatalysts such as platinum are of interest in fuel cells and as diesel oxidation catalysts for pollution control,and practical ruthenium nanocatalysts are explored for ammonia *** and graphitic carbons are of interest as supports for the *** considerable literature on the catalytic processes on graphite and graphitic supports,reaction dynamics of the nanocatalysts on the supports in different reactive gas environments and operating temperatures at the single atom level are not well *** we present real time in-situ observations and analyses of reaction dynamics of Pt in oxidation,and practical ru nanocatalysts in ammonia synthesis,on graphite and related supports under controlled reaction environments using a novel in-situ environmental(scanning) transmission electron microscope with single atom *** recording snapshots of the reaction dynamics,the behaviour of the catalysts is *** images reveal single metal atoms,clusters of a few atoms on the graphitic supports and the support *** all play key roles in the mobility,sintering and growth of the *** experimental findings provide new structural insights into atomic scale reaction dynamics,morphology and stability of the nanocatalysts.

关键词： In-situ visualization Atomic scale reaction dynamics In-situ environmental scanning transmission electron microscopy with single atom resolution Supported nanoparticles Ammonia synthesis Oxidation reactions

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An Awareness-Adoption Matrix for Strategic Decision Making in Agricultural Development Projects: A Case Study in Yunnan Province, China

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Journal of Integrative Agriculture 2009年第9期8卷 1112-1119页

作者： M Subedi T J Hocking M A Fullen A r McCrea E Milne D J mitchell School of Applied Sciences The University of Wolverhampton Wolverhampton WV1 1LY UK Department of Geography University of Leicester Leicester LE1 7RH UK

Significant achievements have been made in generating sustainable agricultural technologies in developing countries. Usually, these new technologies have been more effective in increasing production and productivity than existing technologies. However, many new technologies considered ‘effective’ have not been successful in alleviating the associated sustainability problems, due to poor adoption by targeted users. Success of any novel technical intervention should be judged on the basis of how widespread adoption is in the target area by targeted users. In this context, a case study identified the factors affecting farmers’ adoption of improved technologies extended by an agricultural development project in a rural Village in Yunnan Province, China. Initial adoption/adaptation of project technologies was influenced by farmers’ awareness of the technology. Farmers were more aware of polythene mulch, contour cultivation, intercropping and tree planting technologies than others. This led to a comparatively high initial uptake of polythene mulch, contour cultivation, sweet chestnut, and intercropping technologies. Farmers had inadequate knowledge about some Project technologies, the adoption of which was particularly low. This reveals the need for increasing farmers’ awareness about the rationale for Project technologies to achieve greater adoption/adaptation of project technologies by farmers over wider areas. Farmers’ testing of the technology leads to better adoption/adaptation compared to mere awareness. However, considerable time and resources are required for testing/trying technologies. This justifies the usefulness of comparatively quick and less resource demanding options for awareness creation. Development of effective cropping technologies is important for sustainable agricultural development. The success of any agricultural development project, especially in terms of improving sustainability, depends on how widely those improved technologies are adopted/adap

关键词： awareness-adoption matrix sustainable agriculture China

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Acetaminophen-induced Liver Injury: from Animal Models to Humans

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Journal of Clinical and Translational Hepatology 2014年第3期2卷 153-161页

作者： Hartmut Jaeschke Yuchao Xie mitchell r.McGill Department of Pharmacology Toxicology & Therapeutics University of Kansas Medical Center Kansas City KS USA

Drug-induced liver injury is an important clinical problem and a challenge for drug *** progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models,enormous insight has been gained in the area of predictable hepatotoxins,in particular acetaminopheninduced liver injury,from a broad range of experimental ***,mechanisms of toxicity obtained with certain experimental systems,such as in vivo mouse models,primary mouse hepatocytes,and metabolically competent cell lines,are being confirmed in translational studies in patients and in primary human *** this progress,suboptimal models are still being used and experimental data can be confusing,leading to controversial ***,this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an *** compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity,discuss controversial topics in the mechanisms,and assess how these experimental findings can be translated to the *** success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.

关键词： Drug hepatotoxicity Translational studies Necrosis,Sterile inflammation

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resection of pancreatic cystic neoplasms in recurrent acute pancreatitis prevents recurrent pancreatitis but does not identify more malignancies

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World Journal of Gastroenterology 2021年第15期27卷 1630-1642页

作者： Thiruvengadam Muniraj Harry r Aslanian Loren Laine Priya A Jamidar James F Farrell Kisha A mitchell ronald r Salem Section of Digestive Diseases Department of MedicineYale University School of MedicineNew HavenCT 06510United States Department of Pathology Yale University School of MedicineNew HavenCT 06510United States Department of Surgery Yale University School of MedicineNew HavenCT 06510United States

BACKGrOUND recurrent acute pancreatitis(rAP)may be a presenting feature of and an indication for resection of pancreatic cysts,including intra-ductal papillary mucinous neoplasm(IPMN).Few data are available regarding the prevalence of malignancy and post-operative rAP in this *** To study the role of resection to help prevent rAP and analyze if presentation as rAP would be a predictor for *** This retrospective study assessed 172 patients who underwent surgical resection of pancreatic cystic neoplasms at a university hospital between 2002 and *** prevalence of preoperative high-risk cyst features,and of neoplasia was compared between patients with and without *** identify the cause of pancreatitis,all the patients had a detailed history of alcohol,smoking,medications obtained,and had cross-sectional imaging(contrast-enhanced computed tomography/magnetic resonance imaging)and endoscopic ultrasound to look for gallstone etiology and other structural causes for *** incidence of rAP post-resection was the primary *** IPMN accounted for 101 cases(58.7%){[branch duct(BD)59(34.3%),main duct(MD)42](24.4%)}.Twenty-nine(16.9%)presented with rAP(mean 2.2 episodes):15 had BD-IPMN,8 MD-IPMN,5 mucinous cystic neoplasm and 1 serous cystic *** was similar among those with vs without rAP for all patients[6/29(20.7%)vs 24/143(16.8%)]and IPMN patients[6/23(26.1%)vs 23/78(29.5%)],although tended to be higher with rAP in BD-IPMN,[5/15(33.3%)vs 3/44(6.8%),P=0.04].At mean follow-up of 7.2 years,1(3.4%)rAP patient had post-resection *** mean episodes of acute pancreatitis before vs after surgery were 3.4 vs 0.02(Preased in patients with pancreatic cystic neoplasms who have rAP compared to those without *** addition,specific cyst characteristics were not clearly associated with *** incidence of rAP was markedly decreased in almost all patients following cyst resect

关键词： Pancreatic cyst Pancreatic neoplasm Pancreatitis Malignancies

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MOLECULAr POLArITY IN DNA-PrOTEIN rECOGNITION——THE CASE OF λ-rEPrESSOr-OPErATOr SYSTEM

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Science China Chemistry 1985年第3期28卷 244-249页

作者：王家槐,mitchell LEWIS Institute of Biophysics Academia Sinica Beijing Smith Kline and French Laboratories Philadelphia Pennsylvania 19101 USA

The charge distribution of λ-repressor suggests that the molecular electrostatic polarity may accelerate the non-specific binding of the protein to the DNA molecule. The repressor molecule has a patch of positive charge within the first 26 residues which may contribute a non-specific binding surface. In addition, electrostatics may play an important role and account for why proteins form and use dimers in many specific DNA-protein recognition processes.

关键词： DNA rEPrESSOr-OPErATOr SYSTEM THE CASE OF MOLECULAr POLArITY IN DNA-PrOTEIN rECOGNITION

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An Evaluation of the Introduction of Modified Cropping Practices in Yunnan Province,China,Using Surveys of Farmers’ Households

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Agricultural Sciences in China 2009年第2期8卷 188-202页

作者： M Subedi T J Hocking M A Fullen A r McCrea E Milne D J mitchell WU Bo-zhi School of Applied Sciences University of Wolverhampton Wulfruna Street Wolverhampton WV1 1LY UK The Macaulay Institute Craigiebuckler Aberdeen AB15 8QH UK Yunnan Agricultural University Kunming 650201 P.R.China

Problems associated with land degradation are serious in China. Sloping land in South China has experienced a decline in crop productivity by 30-60% due to soil erosion and it has been predicted that most topsoil will be lost within the next 100 years if current erosion rates continue. Considering these situations, an agro-environmental research and development project （Sustainable Highland Agriculture in South-East Asia- SHASEA） was conducted in a catchment in Yunnan Province, China, to address the objectives of increasing crop productivity in sustainable and environmentally-friendly ways. A range of cropping practices was developed and implemented in a rural upland catchment （Wang Jia）. At the end of the project, farmers were surveyed to evaluate project effectiveness. All farmers from Wang Jia Catchment, who were involved in project implementation, were surveyed. A sample of farmers working in an adjacent catchment （not associated with the project） was surveyed for comparative purposes. Farmers had different perceptions of the cropping practices employed. Contour cultivation was preferred and likely to be adopted. Others practices such as straw mulching and intercropping were seen as less appropriate and unlikely to be adopted. Polythene mulch was recognized as effective, but likely to be adopted only if financial returns were favourable. The availability of relevant information had an important impact on the extent of technology testing by farmers and their willingness to adopt the practices in the future.

关键词： cropping practices farmers' perceptions household survey Yunnan China

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Mapping informal settlement indicators using object-oriented analysis in the Middle East

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International Journal of Digital Earth 2019年第7期12卷 802-824页

作者： Ahmad Fallatah Simon Jones David mitchell Divyani Kohli School of Science RMIT UniversityMelbourneAustralia Faculty for Geo-Information Science and Earth Observation(ITC) University of TwenteEnschedeThe Netherlands

Mapping informal settlements is crucial for resource and utility management and *** 2003,the UN-Habitat developed a process for mapping and monitoring urban inequality to support reporting against the sustainable development goals(SDGs).Informal settlement indicators are used as a framework to carry out image analysis,and include vegetation extent,lacunarity of housing structures/vacant land,road segment type and materials,texture measures of built-up areas,roofing extent of built-up areas and dwelling *** image analysis(OBIA)methods are recommended to identify informal *** paper documents the application of OBIA to map informal settlements,drawing on the ontology of Kohli et al.(2012)and the indicators of Owen and Wong(2013)for a Middle Eastern *** informal settlements with different land use histories were selected to represent old and new informal settlements in the city of Jeddah,Saudi *** extent was the most successful indicator detected,with 100% producer accuracy and over 84% user accuracy,followed by the road network,with 84% producer and user accuracies in older informal settlements and 73% producer accuracy and 96% user accuracy across all case *** of housing structures/vacant land was detected well in informal *** texture measure indicator was detected using GLCM_(Ent)(r)with low producer accuracy across all case *** roofing extent of the built-up area is detected with better producer and user accuracies than texture *** dwellings size indicator generally failed to distinguish formal from informal *** and formal were distinguished with an overall accuracy of 83%.This research concludes that OBIA is a useful method to map informal settlement indicators in Middle Eastern ***,a generic ruleset for mapping informal settlements remains elusive,and each indicator requires significant localised‘tuning’.

关键词： Informal settlement objectbased image analysis(OBIA) sustainable development goals informal indicators high spatial resolution imagery Middle Eastern cities

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