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Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington＇s Disease

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Frontiers in Biology 2016年第6期11卷 439-458页

作者： kimberly D. Girling Yu Tian Wang Djavad Mowafahian Centre for Brain Health & Department of Medicine University of British Columbia V6T 1Z3 Canada

BACKGROUND： Huntington＇s Disease （HD） is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors （NMDARs） has been shown to have a key role in the neuropathogenesis of liD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cell- survival activity of GluN2A-NMDARs. OBJECTIVE： This review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target. METHODS： A systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 235 articles were consulted for the review, with key search terms including ＂Huntington＇s Disease,＂＂excitotoxicity,＂＂NMDAR＂ and ＂therapeutics.＂ RESULTS： A wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs. CONCLUSION： The current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.

关键词： Huntington's Disease NMDA receptor excitotoxicity cell death therapeutics

Micromolded honeycomb scaffold design to support the generation of a bilayered RPE and photoreceptor cell construct

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Bioactive Materials 2023年第12期30卷 142-153页

作者： In-Kyu Lee Ruosen Xie Agustin Luz-Madrigal Seunghwan Min Jingcheng Zhu Jiahe Jin kimberly L.Edwards M.Joseph Phillips Allison L.Ludwig David M.Gamm Shaoqin Gong Zhenqiang Ma Department of Electrical and Computer Engineering University of Wisconsin-MadisonMadisonWI53706USA Wisconsin Institute for Discovery University of Wisconsin-MadisonMadisonWI53715USA Department of Ophthalmology and Visual Sciences University of Wisconsin-MadisonMadisonWI53705USA Department of Biomedical Engineering University of Wisconsin-MadisonMadisonWI53706USA McPherson Eye Research Institute University of Wisconsin-MadisonMadisonWI53705USA Waisman Center University of Wisconsin-MadisonMadisonWI53705USA Department of Comparative Biomedical Sciences University of Wisconsin–MadisonMadisonWI53706USA Department of Materials Science and Engineering University of Wisconsin-MadisonMadisonWI53706USA Department of Engineering Physics University of Wisconsin-MadisonMadisonWI53706USA Grainger Institute for Engineering University of Wisconsin-MadisonMadisonWI53706USA

Age-related macular degeneration(AMD)causes blindness due to loss of retinal pigment epithelium(RPE)and photoreceptors(PRs),which comprise the two outermost layers of the *** the small size of the macula and the importance of direct contact between RPE and PRs,the use of scaffolds for targeted reconstruction of the outer retina in later stage AMD and other macular dystrophies is particularly *** developed microfabricated,honeycomb-patterned,biodegradable poly(glycerol sebacate)(PGS)scaffolds to deliver organized,adjacent layers of RPE and PRs to the subretinal ***,an optimized process was developed to photocure PGS,shortening scaffold production time from days to *** resulting scaffolds robustly supported the seeding of human pluripotent stem cell-derived RPE and PRs,either separately or as a dual celllayered *** advanced,economical,and versatile scaffolds can accelerate retinal cell transplantation efforts and benefit patients with AMD and other retinal degenerative diseases.

关键词： Microfabrication Retina Scaffolds Stem cells Tissue engineering

The Psb32 Protein Aids in Repairing Photodamaged Photosystem II in the Cyanobacterium Synechocystis 6803

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Molecular Plant 2011年第6期4卷 1052-1061页

作者： kimberly M. Wegener Stefan Bennewitz Ralf Oelmuller Himadri B. Pakrasi Department of Biology Washington University St Louis MO 63130 USA Present address： Division of Biological Sciences University of Missouri Columbia MO 65211 USA Institute of Plant Physiology Friedrich-Schiller-University Jena Dornburger Str. 159 D-07743 Jena Germany

Photosystem II （PSII）, a membrane protein complex, catalyzes the photochemical oxidation of water to molecular oxygen. This enzyme complex consists of approximately 20 stoichiometric protein components. However, due to the highly energetic reactions it catalyzes as part of its normal activity, PSII is continuously damaged and repaired. With advances in protein detection technologies, an increasing number of sub-stoichiometric PSII proteins have been identified, many of which aid in the biogenesis and assembly of this protein complex. Psb32 （SII1390） has previously been identified as a protein associated with highly active purified PSII preparations from the cyanobacterium Synechocystis sp. PCC 6803. To investigate its function, the subcellular localization of Psb32 and the impact of deletion of the psb32 gene on PSII were analyzed. Here, we show that Psb32 is an integral membrane protein, primarily located in the thylakoid membranes. Al- though not required for cell viability, Psb32 protects cells from oxidative stress and additionally confers a selective fitness advantage in mixed culture experiments. Specifically, Psb32 protects PSII from photodamage and accelerates its repair. Thus, the data suggest that Psb32 plays an important role in minimizing the effect of photoinhibition on PSII.

关键词： Photosynthesis reactive oxygen species photoinhibition photodamage.

Vaccinations in immunosuppressive-dependent pediatric inflammatory bowel disease

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World Journal of Gastroenterology 2017年第42期23卷 7644-7652页

作者： Huyen-Tran Nguyen Phillip Minar kimberly Jackson Patricia C Fulkerson Division of Allergy and Immunology Department of Pediatrics Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Division of Gastroenterology Hepatology and Nutrition Department of Pediatrics Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine

AIM To determine the vaccination rates in pediatric immunosuppression-dependent inflammatory bowel disease(IBD) and review the safety and efficacy of vaccinations in this *** The electronic medical records from October 2009 to December 2015 of patients diagnosed with IBD at 10 years of age or younger and prescribed antitumor necrosis factor alpha(anti-TNF-α) therapy were reviewed for clinical history, medication history, vaccination history, and hepatitis B and varicella titers. Literature discussing vaccination response in IBD patients were identified through search of the MEDLINE database and reviewed using the key words "inflammatory bowel disease", "immunization", "vaccination", "pneumococcal", "varicella", and "hepatitis B". Non-human and non-English language studies were excluded. Search results were reviewed by authors toselect articles that addressed safety and efficacy of immunizations in inflammatory bowel *** A total of 51 patients diagnosed with IBD prior to the age of 10 and receiving anti-TNF-α therapy were identified. Thirty-three percent of patients(17/51) had incomplete or no documentation of vaccinations. Sixteen case reports, cohort studies, cross-sectional studies, and randomized trials were determined through review of the literature to describe the safety and efficacy of hepatitis B, pneumococcal, and varicella immunizations in adult and pediatric patients with IBD. These studies showed that patients safely tolerated the vaccines without significant adverse effects. Importantly, IBD patients receiving immunosuppressive medications, particularly anti-TNF-α treatment, have decreased vaccine response compared to controls. However, the majority of patients are still able to achieve protective levels of specific antibodies. CONCLUSION Immunizations have been shown to be well-tolerated and protective immunity can be achieved in patients with IBD requiring immunosuppressive therapy.

关键词： Vaccination Immunosuppression Earlyonset inflammatory bowel disease Very early-onset inflammatory bowel disease

Dynamics and mechanisms of permethrin resistance in a field population of the horn fly, Haematobia irritans irritans

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Insect Science 2009年第2期16卷 175-184页

作者： Andrew Y. Li kimberly H. Lohmeyer J. Allen Miller USDA ARS Knipling-Bushland US Livestock Insects Research Laboratory 2700 Fredericksburg Road Kerrville TX 78028 USA

A study was conducted at the Pressler ranch, near Kerrville, Texas, USA between 2002 and 2006 to determine the dynamics and mechanisms of resistance to permethrin in a field population of the horn fly, Haematobia irritans irritans （L.）. Changes of resistance to pyrethroid insecticide associated with use of a pour-on formulation of cyfluthrin in 2002 and use of diazinon ear tags in subsequent years were studied using a filter paper bioassay technique and a polymerase chain reaction assay that detects two sodium channel mutations, kdr and super-kdr resistance alleles. A maximum of 294-fold resistance to permethrin was observed in the summer of 2002. A significant decrease in the resistance level was observed in spring 2003, and resistance continued to decline after animals were treated with diazinon ear tags. In response to pyrethroid treatments, the allelic kdr and super-kdr frequency increased from 56.3% to 93.8% and from 7.5% to 43.8%, respectively in 2002, and decreased significantly in 2003 when the pyrethroid insecticide was no longer used to treat animals. Females were found to have a higher allelic super-kdr frequency than males in 2002, while no difference was detected between males and females in the allelic kdr frequency. There was a significant positive correlation between frequencies of the sodium channel mutations and levels ofpermethrin resistance, suggesting that the sodium channel mutations, kdr and super-kdr, are the major mechanisms of resistance to pyrethroids in this horn fly population. Results of synergist bioassays also indicated possible contributions of two metabolic detoxification mechanisms, the mixed function oxidases （MFO） and glutathione S-trans- ferases （GST）. Compared to a horn fly infestation of an untreated herd, treatments with the pyrethroid pour-on formulation failed to control horn flies at the Pressler ranch in 2002. Sustained control of horn flies was achieved with the use of diazinon ear tags in 2003 and subsequent years.

关键词： efficacy horn fly insecticide resistance PCR permethrin pyrethroids

Acquired segmental colonic hypoganglionosis in an adult Caucasian male:A case report

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World Journal of Gastrointestinal Surgery 2019年第2期11卷 101-111页

作者： Allan MF Kwok Andrew B Still kimberly Hart Department of Surgery Wollongong Hospital Department of Anatomical Pathology Wollongong Hospital

BACKGROUND Hypoganglionosis is a rare condition that most often presents with abnormal gastrointestinal transit and usually arises in early childhood or adolescence. Two types have been described(Type I and Type II). The adult-onset form(acquired hypoganglionosis) is extremely uncommon and is thought to arise due to cellular remodelling as a result of chronic inflammation. It differs from Hirschprung's disease in that there is a reduction in ganglion cells in the colonic neural plexuses as opposed to being completely *** SUMMARY A 31 year-old male presented to hospital with recurrent abdominal pain and vomiting over thirteen months. Abdominal computed tomography scans demonstrated thickening and stranding affecting the transverse, descending and sigmoid colon. Endoscopic appearances were non-specific but confirmed a mixed picture of mucosal inflammation and necrosis in various stages of *** investigations were performed to elucidate an underlying aetiology but neither an infective nor ischaemic cause could be proven. Biopsy features were not typical of inflammatory bowel disease. Due to persistence of his symptoms and failure of medical management, a segmental colectomy was performed. Histological examination of the specimen revealed an unexpected finding of segmental hypoganglionosis. Complete surgical excision of the diseased segment of colon was curative and since his operation the patient has had no recurrence of symptoms requiring *** Our case serves to raise awareness of acquired hypoganglionosis as a rare condition that can result from chronic colitis.

关键词： Acquired hypoganglionosis Hirschprung’s disease Adult Ganglion cells Acetylcholinesterase Calretinin Case report

Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders

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Frontiers in Biology 2012年第3期7卷 179-188页

作者： kimberly M. CHRISTIAN Hongjun SONG Guo-li MING Institute for Cell Engineering Johns Hopkins University School of Medicine Baltimore MD 21205 USA Department of Neurology Johns Hopkins University School of Medicine Baltimore MD 21205 USA The Solomon Snyder Department of Neuroscience Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individual and thus provides a unique opportunity for systematic investigation of genetic influences on neuronal pathophysiology. Although direct reprogramming of adult somatic cells to neurons is now possible, the majority of recent studies have used induced pluripotent stem cells （iPSCs） derived from patient fibroblasts to generate neural progenitors that can be differentiated to specific neural cell types. Investigations of monogenic diseases have established proof-of-principle for many aspects of cellular disease modeling, including targeted differentiation of neuronal populations and rescue of phenotypes in patient iPSC lines. Refinement of protocols to allow for efficient generation of iPSC lines from large patient cohorts may reveal common functional pathology and genetic interactions in diseases with a polygenic basis. We review several recent studies that illustrate the utility of iPSC-based cellular models of neurodevelopmental and neurodegenerative disorders to identify novel phenotypes and therapeutic approaches.

关键词： reprogramming iPSCs neurodevelopment neurodegeneration

气候变化和污染物的进化反应：证据和实验方法

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Current Zoology 2015年第4期61卷 690-701页

作者： David A. kimberly Department of Biology Westminster College 442 Meldrum Science Center Salt Lake City UT 84105 USA Department of Environmental Toxicology The Institute of Environmental and Human Health Texas Tech University 1207 Gilbert Drive Lubbock Texas 79416 USA Environmental Science and Studies Program Towson University 8000 York Rd. Towson MD 21252 USA

在生态毒理学的基本目的在于了解和预测污染物的影响。这个工作目标是更具挑战性的全球气候变化是一个环境的胁迫发生性接触的taminant。在这种多应激背景下，进化过程是特别重要的。在本文中，我们考虑了几种非“组学”的方法，其中的... 详细信息

在生态毒理学的基本目的在于了解和预测污染物的影响。这个工作目标是更具挑战性的全球气候变化是一个环境的胁迫发生性接触的taminant。在这种多应激背景下，进化过程是特别重要的。在本文中，我们考虑了几种非“组学”的方法，其中的进化压力的反应进行了研究，并讨论那些适合多个应激情况下。具体而言，我们讨论了共同的花园设计，人工和准自然选择，估计的自适应潜力，使用定量遗传学的方法研究进化反应的污染物和气候变化的情况下，昂贵的分子工具。虽然所有的方法都揭示了潜在的进化影响的应激暴露，他们也有局限性。这些包括后勤方面的限制，难以外推到真实的系统，和响应依赖于特定的类群，种群，和/或测试条件。最有效的方式来减少这些固有的局限性，可能是通过包含互补的生理和分子的工具，当可用。我们相信，一个污染和全球气候变化研究的进化背景是生态毒理学的一个高优先级和我们列出的方法，可以实现几乎任何研究也提供了宝贵的见解[当前生态61（4）：690-701，2015 ]。

关键词：全球气候变化进化过程污染物反应生态毒理学验方证据花园设计

Forage production and persistence characteristics of grazed native warm-season grass mixtures with or without nitrogen fertilizer

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Grassland Research 2022年第3期1卷 157-165页

作者： Caroline Nicole Chappell Marty Landon Marks Katie Michelle Mason Liliane Severino da Silva Joshua Luke Jacobs Mary kimberly Mullenix Sandra Leanne Dillard Russell Brian Muntifering Department of Animal Sciences Auburn UniversityAuburnAlabamaUSA Department of Animal Science University of TennesseeKnoxvilleTennesseeUSA Department of Animal and Veterinary Sciences Clemson UniversityClemsonSouth CarolinaUSA University of Kentucky Cooperative Extension Service CarlisleKentuckyUSA

Background:Native warm-season grass(NWSG)mixtures may provide a lownitrogen(N)-input summer perennial forage option to extensively managed forage-livestock ***:Mixed pastures of big bluestem(Andropogon gerardii Vitman),little bluestem(Schizachyrium scoparium Michx.),and indiangrass(Sorghastrum nutans L.)fertilized with 0 or 67 kgNha−1 were continuously stocked with beef heifers and *** mass,nutritive value,and canopy heights were determined every 2 weeks during the grazing *** persistence measures included the canopy cover and leaf area index(LAI)and plant crown density at spring emergence following 3 years of grazing ***:Forage mass,canopy height,and stocking densities were greater for N-fertilized NWSG than unfertilized NWSG for the first 30 days of the growing season across the 3-year *** NWSG fertilized with N had a greater decrease in LAI during the growing season(51%decrease)than unfertilized *** NWSG plant density estimates following 3 years of grazing did not differ across N management ***:Forage NWSG mixtures supported superior forage attributes and greater stocking densities early in the grazing season under low-level N than zero-N-input systems and may provide a low-N-input alternative for improved species use in southeastern US forage-livestock systems.

关键词： continuous stocking grazing native warm-season grass mixtures nitrogen fertilization