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Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial

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Advances in Alzheimer's Disease 2013年第3期2卷 83-98页

作者： Timothy Nicholas Sridhar Duvvuri Claire Leurent David Raunig Tracey Rapp Phil Iredale Carolyn Rowinski robert carr Patrick roberts Athan Spiros Hugo Geerts ICON North Wales USA In Silico Biosciences Lexington USA Pfizer Global Research and Development Groton USA

Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.

关键词： Systems Pharmacology 5-HT4 Receptor Partial Agonist Scopolamine-Reversal

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SARS-COV-2 infection(coronavirus disease 2019)for the gastrointestinal consultant

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World Journal of Gastroenterology 2020年第14期26卷 1546-1553页

作者： Kaveh Hajifathalian Srihari Mahadev robert E Schwartz Shawn Shah Kartik Sampath Felice Schnoll-Sussman robert S Brown Jr David carr-Locke David E Cohen Reem Z Sharaiha Division of Gastroenterology and Hepatology Weill Cornell MedicineNew York-Presbyterian HospitalNew YorkNY 10021United States

The current pandemic due to the severe acute respiratory syndrome coronavirus 2 has caused an extreme burden for health care systems globally,and the number of cases is expected to continue to increase,at least in the immediate future.The virus is estimated to have infected more than 1.5 million individuals.The available reports suggest that gastrointestinal(GI)involvement in coronavirus disease 2019(COVID-19)is common and in some cases the GI symptoms may precede the respiratory symptoms.In addition to direct effects of severe acute respiratory syndrome coronavirus 2,the infected patients remain at risk for the complications commonly managed by gastroenterology and hepatology consultants.The most commonly reported GI manifestation of COVID-19 is diarrhea,which is reported in a third to up to more than half of the patients.Mild to moderate elevation of the liver enzymes are also common,although no case of acute liver failure has been reported so far.Many of the medications used for treatment of COVID-19 can also be associated with GI symptoms or liver injury and can be included in the differential diagnosis in these patients.Although the diagnosis of the infection is currently based on RNA analysis in respiratory samples,the available literature on fecal shedding of this virus suggests that fecal RNA testing might prove to be a useful diagnostic test.It is reasonable to delay all non-urgent endoscopic procedures during the peak of the pandemic and use additional protective equipment such as N95 respirators during endoscopy while most patients can be considered high risk for having been exposed to the virus.

关键词： SARS-CoV-2 COVID-19 Gastroenterology Hepatology Liver

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2-[18F]-fluoro-2-desoxy-D-glucose positron emission tomography initial staging impacts on survival in Hodgkin lymphoma

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World Journal of Radiology 2013年第12期5卷 484-490页

作者： Juliano J Cerci Camila C G Linardi Luís F Pracchia José Soares Junior Evelinda Trindade Dominique Delbeke Rodrigo J Cerci robert carr José C Meneghetti Valeria Buccheri Department of Nuclear Medicine Heart Institute (InCor) University of Sāo Paulo Medical School Division of PET/CT Quanta-Diagnóstico Nuclear Division of Hematology Clinical Hospital of the University of Sāo Paulo Medical School Health Technology Assessment/Executive Direction Heart Institute (InCor) University of Sāo Paulo Medical School Department of Radiology and Radiological Sciences Vanderbilt University Medical Center Department of Haematology St Thomas’ Hospital

AIM:To assess the prognostic value and risk classification improvement of metabolic staging(MS)with Initial2-[18F]-fluoro-2-desoxy-D-glucose positron emission tomography(FDG-PET)in initial staging of Hodgkin’s Lymphoma(HL)patients to predict 5 years overall survival(5y-OS)and event free survival(EFS).METHODS:A total of 275 patients were included in this retrospective study,155 patients were staged with conventional anatomical staging(AS),and 120 also submitted to MS(FDG-PET).Prognostic analysis compared 5y-OS and 5y-EFS of patients staged with AS and MS.Risk-adjusted models incorporated clinical risk factors,computed tomography and FDG-PET staging.RESULTS:During the follow up of 267 evaluated patients,220(122 AS and 98 MS)achieved complete remission after first-line therapy(median follow-up:70±29 mo),treatment failure occurred in 79 patients and 34 died.The 5y-EFS for early vs advanced disease in AS patients was 79.3%and 66.7%,and 85.6%and53.6%in MS patients,respectively(P<0.01).The5y-OS for early and advanced disease with AS was91.3%and 81.5%,and 97.5%and 80.7%for patients staged with MS,respectively.Cox proportional hazards analysis demonstrated that FDG-PET added signifcant prognostic information and improved risk prediction(P=0.02).CONCLUSION:Initial staging FDG-PET could be used as an accurate and independent predictor of OS and EFS in HL,with impact in 5y-EFS and OS.

关键词： Hodgkin disease Positron-emission tomography 2-[18F]-fluoro-2-desoxy-D-glucose positron emission tomography Neoplasm staging Prognosis

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MASS SPECTROMETRLC STUDY OF THE CHEMLCALKINETICS OF THE CH2CIO OXY RADLCAL REACTIONS

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质谱学报 1999年第Z1期 25-26页

作者： Fuxiang WU, robert.carr (Department of Chemical Engineering and Materials ScienceUniversity of Minnesota 421 Washington Avenue S.E, Minneapolis MN 55455, USA)

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燃煤发电厂袋滤器技术

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四川电力技术 1984年第4期 39-47页

作者： robert C. carr 张慧明四川化工学院

本文概述了美国电力公用事业燃煤发电厂袋滤器技术会议的情况及结论。这次会议着重总结了当前公用事业部门袋滤器应用技术的经验,明确了滤袋及袋滤器设计。运行等参数是至关重要的问题,并且得到了大量的重要结论。目前,袋滤器已成为捕... 详细信息

本文概述了美国电力公用事业燃煤发电厂袋滤器技术会议的情况及结论。这次会议着重总结了当前公用事业部门袋滤器应用技术的经验,明确了滤袋及袋滤器设计。运行等参数是至关重要的问题,并且得到了大量的重要结论。目前,袋滤器已成为捕集飞灰最有效的除尘器,但是,在袋滤器设计、运行、滤料选择、以及滤袋的清灰技术等方面,仍然存在一系列问题,其中特别是要求袋滤器的尺寸、费用及压力降尽可能的小。第二届燃煤发电厂袋滤器技术会议定于1983年春季召开。

关键词：滤袋滤料捕集过滤材料袋滤器燃煤发电厂粉尘层反吹风清灰机械振动清灰粉尘粒子

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声表面波(SAW)器件用的新材料

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压电与声光 1978年第3期 106-112页

作者： robert M.O’Connell Paul H.carr 陈新华

SAW器件技术现状的进展要求比目前更好的基片材料。对包括石英衍生物块磷铝矿(AlFO)和β-锂霞石(β-LiAlSiO),某些磺酸盐和复合材料等的SAW性能计算,得到了比ST切石英的压电祸合大的几种温度补偿的结晶取向。这些材料有可能促使改进性... 详细信息

SAW器件技术现状的进展要求比目前更好的基片材料。对包括石英衍生物块磷铝矿(AlFO)和β-锂霞石(β-LiAlSiO),某些磺酸盐和复合材料等的SAW性能计算,得到了比ST切石英的压电祸合大的几种温度补偿的结晶取向。这些材料有可能促使改进性能与温度无关的宽带低插入损耗器件发展。还正在研究改进氮化铝(AlN)的生长方法,因为这种材料的SAW速度约为目前采用材料的两倍,AlN可望使SAW器件的上限频率扩展到2千兆赫以上。

关键词：温度补偿石英压电温度校正硅氧矿物 SAW 器件铝矿温度系数

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扩散波光谱法

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国外分析仪器技术与应用 1997年第1期 32-34页

作者： carr,R 黄惠忠

应用微生物和研究中心的Ｄｒ．ＲｏｂｅｒｔＣａｒｒ描述了一种新的基于光子关联光谱学的分析技术，它能用于研究不适透明体，稠密悬浮和乳胶。

关键词：扩用波光谱法光子关联光谱学

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Spatial Distribution of Hemlock Woolly Adelgid Induced Hemlock Mortality in the Southern Appalachians

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Open Journal of Forestry 2014年第5期4卷 492-506页

作者： Tuula Kantola Paivi Lyytikainen-Saarenmaa robert N.Coulson Sheryl Strauch Maria D.Tchakerian Markus Holopainen Hannu Saarenmaa Douglas A.Streett Knowledge Engineering Laboratory Department of EntomologyTexas A&M UniversityCollege StationTXUSA Department of Forest Sciences University of HelsinkiHelsinkiFinland SIB Labs School of ComputingUniversity of Eastern FinlandJoensuuFinland Alexandria Forestry Center USDA Forest ServiceSouthern Research StationPinevilleLAUSA

Hemlock woolly adelgid (Adelges Tsugae Annand, HWA) outbreaks are posing a major threat to eastern hemlock (Tsuga canadensis L. carr.) and Carolina hemlock (Tsuga caroliniana Engelm.) forest landscapes in the eastern USA. As foundation species, hemlocks play a variety of functional roles in forest landscapes. These species usually occur as isolated canopies and mixed species in landscapes where variation in topography is extreme. Spatially explicit inventory information on HWA induced hemlock mortality at landscape scale does not exist. High resolution aerial imageries enable landscape scale assessment even at the individual tree level. Accordingly, our goal was to investigate spatial pattern and distribution of HWA induced hemlock mortality using a high resolution aerial image mosaic in the Linville River Gorge, Southern Appalachians, western North Carolina. Our study objectives were: 1) to detect dead trees within the Lower Linville River watershed;2) to estimate the area occupied by dead trees in the forest canopy surface;3) to investigate the relationship of dead hemlocks and topography;and 4) to define the spatial pattern of the dead trees. We found ca. 10,000 dead trees within the study area, occupying over 7 ha of the canopy surface with an average area of 36 m2 per dead tree. The density of the dead trees was higher in proximity to the Linville River, at higher elevations, and on northern and northwestern aspects. Spatial pattern of the dead trees was generally clustered at all spatial scales. We suggest that although the reduction in plant biomass resulting from herbivory within the landscapes is modest, impact of the clustered distribution of hemlock mortality, especially in the riparian zones, is noteworthy. Our analysis of the pattern of hemlock decline provides new means for projecting future impacts of HWA on the range of hemlock distribution in eastern North America.

关键词： Adelges Tsugae Eastern Hemlock Southern Appalachians Spatial pattern Topography Tree Mortality Tsuga

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禽白血病毒单克隆抗体的特性

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福建省农科院学报 1986年第1期 1-10页

作者：程由铨 Lucy F.lee robert F.Silva FugeneJ.Smith LymanB.Crittenden 福建省农业科学院畜牧兽医研究所美国农业部农业科学研究署地区家禽研究所

建立了分泌抗禽白血病毒（ALV）结构蛋白P27和P19的单克隆抗体（McAb）杂交瘤细胞。酶联免疫吸附试验（ELISA）,McAb-6AL20（属于IgG1）分别与外源性ALV:A.B.D亚群的RPL-40、AMV、RAV-2和carr-Zilber RSV（CZ-RSV）发生特异性反应,而不... 详细信息

建立了分泌抗禽白血病毒（ALV）结构蛋白P27和P19的单克隆抗体（McAb）杂交瘤细胞。酶联免疫吸附试验（ELISA）,McAb-6AL20（属于IgG1）分别与外源性ALV:A.B.D亚群的RPL-40、AMV、RAV-2和carr-Zilber RSV（CZ-RSV）发生特异性反应,而不与内源性ALV:RAV-O（E亚群）发生反应。McAb-6AL22（属于IgG1）除了上述特性外,还能与劳斯氏肉瘤病毒Prague株（Prc-RSV、属于C亚群）发生反应。这二个McAb均能与〔35S〕甲硫氨酸标记的RPL-40和RAV-1病毒的P19蛋白出现免疫沉淀。但是,它们不与RAV-O病毒的P19蛋白发生免疫沉淀。所以,McAb可用于区别ALV结构蛋白P19（亚群特异性位点的多肽）。应用这二个McAb进行ELISA和免疫沉淀与聚丙烯酰胺凝胶电泳试验可区分RPL-40和RAV-O感染。McAb-6AL42（属于IgG2a）可与以上几个亚群（A.B.C和D）的毒株发生反应,其ELISA的抗体滴度比与RAV-O（E亚群）毒株高1000倍以上。McAb-6AL42可与P27和pr76（群特异性抗原的前体蛋白）发生免疫沉淀。试验用McAb-6AL42作为第一抗体和兔抗P27血清的过氧化物酶标记物作为第二抗体（指示抗体）建立了双抗体夹心ELISA试验。用这种ELISA试验可区分未经稀释的卵蛋白中RAV-O和RPL-40群特异性抗原。

关键词：卵蛋白 RPL 免疫沉淀标本抗体滴度 ELISA RAV 禽白血病

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