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Progress and prospects of engineered sequence-specific DNA modulating technologies for the management of liver diseases

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World Journal of Hepatology 2015年第6期7卷 859-873页

作者： Samantha A nicholson buhle Moyo Patrick b Arbuthnot Wits/SA MRC Antiviral Gene Therapy Research Unit School of Pathology Health Sciences Faculty University of the Witwatersrand

Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viralhepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins(ZFPs), transcription activator-like effectors(TALEs), homing endonucleases(HEs) and clustered regularly interspaced palindromic repeats(CRISPR) and CRISPR associated(Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases.

关键词：基因治疗锌手指抄写像使活跃之物的受动器定期聚类短 palindromic 重复的 interspaced Homing endonucleases 肝疾病

CIS controls the functional polarization of GM-CSF-derived macrophages

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Cellular & Molecular Immunology 2023年第1期20卷 65-79页

作者： Shengbo Zhang Jai Rautela Naiara G.bediaga Tatiana b.Kolesnik Yue You Junli Nie Laura F.Dagley Justin bedo Hanqing Wang Li Sun Robyn Sutherland Elliot Surgenor Nadia Iannarella Rhys Allan Fernando Souza-Fonseca-Guimaraes Yi Xie Qike Wang Yuxia Zhang Yuekang Xu Stephen L.Nutt Andrew M.Lew Nicholas D.Huntington Sandra E.nicholson Michaël Chopin Yifan Zhan Walter and Eliza Hall Institute of Medical Research ParkvilleVICAustralia Department of Medical biology University of MelbourneParkvilleVICAustralia Department of biochemistry and Molecular biology Biomedicine Discovery InstituteMonash UniversityClaytonVICAustralia oNKo-Innate Pty Ltd Moonee PondsVICAustralia Department of Computing and Information Systems University of MelbourneParkvilleVICAustralia Department of Respiratory Medicine Guangzhou Institute of PediatricsGuangzhou Women and Children’s Medical CentreState Key Laboratory of Respiratory DiseasesGuangzhou Medical UniversityGuangzhouGuangdongChina College of biological Science Anhui Normal UniversityHefeiChina University of Queensland Diamantina Institute University of QueenslandTranslational Research InstituteBrisbaneQLDAustralia Program in Cardiovascular and Metabolic Disorders Duke-NUS Medical SchoolDukeSingapore Drug Discovery Shanghai Huaota BiopharmShanghaiChina

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.

关键词： CIS GM-CSF Macrophage M2 M1

The Pliocene-Recent Euphrates river system:Sediment facies and architecture as an analogue for subsurface reservoirs

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能源地球科学(英文)

能源地球科学(英文) 2020年第3期1卷 174-193页

作者： Dorrik Stow Uisdean nicholson Samantha Kearsey Dominic Tatum Andy Gardiner Amer Ghabra Mahmoud Jaweesh EGIS-IGE Heriot-Watt UniversityEdinburghEH144ASUK Glasgow International College 56 Dumbarton RoadGlasgowG116NUUK Department of Geology and Petroleum Exploration Engineering Faculty of Petroleum EngineeringSyrian Private UniversityDamascusSyria School of Geography University of BirminghamBirminghamB152TTUK

The Tigris-Euphrates is a continental-scale fluvial system,around 2800 km in length,which drains over 1 million km2 of SWAsia.The system originated in the Late Miocene and developed into the principal axial drainage system of the region,which follows broad regional structural features of the Mesopotamian Foreland basin.Good preservation and outcropping of the Pliocene and Quaternary Euphrates deposits yield a viable local analogue for subsurface fluvial reservoirs in the region,and for other fluvial systems that have developed in foreland basin settings.This paper documents the first detailed study of the sedimentary characteristics of these Pliocene and Quaternary fluvial deposits along the middle reaches of the present-day Euphrates in Syria.The Euphrates fluvial system developed from small and probably short-lived isolated cut-and-fill channels in the Pliocene,characterised by abundant debrite and slump facies,through to a broad meandering system at present.The Quaternary deposits represent a braided to meandering system that was more energetic than that of the modern day Euphrates.The Quaternary facies include a dominance of gravels,pebbly sands and sands as channel associations,coupled with sands,muds and paleosols representing channel abandonment,overbank and crevasse-splay associations.Channel widths,where observed,range from 50 to 500 m,and minimum fill thicknesses range from 3 to 7 m.The combined channel-fill for stacked channels is up to 25 m thick.Lateral correlation of channel elements over at least 1 km of section indicates that rapid and extensive lateral migration has occurred.Crevasse splay lobes can be identified in the overbank deposits,with a width of 30e60 m and sand thickness of 0.5e1.5 m.The geometry,nature and dimensions of these architectural elements provide a useful analogue for subsurface reservoirs.The high-energy channel facies of the Quaternary system show very good reservoir attributes,with good correlation and connectivity.At the bed-scale there is significant heterogeneity of char

关键词： Euphrates river Fluvial facies Fluvial architecture Reservoir analogue

Quantified gene expression levels for phase Ⅰ/Ⅱ metabolizing enzyme and estrogen receptor levels in benign prostate from cohorts designated as high-risk （UK） versus low-risk （India）for adenocarcinoma at this organ site：a preliminary study

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Asian Journal of Andrology 2010年第2期12卷 203-214页

作者： Paras b. Singh Narasimhan Ragavan Katherine M. Ashton Prabir basu Sayeed M. Nadeem Caroline M. nicholson R. K. Gopala Krishna Shyam S. Matanhelia Francis L. Martin Centre for biophotonics Lancaster Environment Centre Lancaster University Bailrigg Lancaster LA1 4YQ UK Lancashire Teaching Hospitals NHS Trust Fulwood Preston PR2 9HT UK Wockhardt Hospitals ＆ Kidney Institute Kolkata 700029 India

Risk of clinically significant prostate adenocarcinoma （CAP） varies worldwide,although there is a uniform prevalence of latent disease. A hormone-responsive tissue,the prostate possesses the metabolizing capacity to biotransform a variety of environmental procarcinogens or endogenous hormones. Whether such metabolizing capacity or estrogen receptor （ER） status underlies these demographic differences in susceptibility to CaP remains unclear. With appropriate ethical permission,verified-benign tissues were obtained following transurethral resection of the prostate from a high-risk region （n = 12 UK-resident Caucasians） and a typically low-risk region （n = 14 India-resident Asians）. Quantitative gene expression analysis was employed for cytochrome P450 （CYP）1b1,N-acetyltransferase （NAT）1,NAT2,catechol-O-methyl transferase （ COMT）,sulfotransferase （ SULT） 1A1,ERα,ERβ and aromatase （CYP To quantify the presence or absence of CYP1b1,ERα or ERβ,and to identify ther in situ localization,immunohistochemistry was carried out. The two cohorts had reasonably well-matched serum levels of prostate-specific antigen or hormones. Expression levels for the candidate genes investigated were similar.However,clear differences in protein levels for CYP1b1 and ERβ were noted. Staining for CYP1b1 tended to be nuclear-associated in the basal glandular epithelial cells,and in UK-resident Caucasian tissues was present at a higher （P = 0.006） level compared with that from India-resident Asians. In contrast,a higher level of positive ERβ staining was noted in prostates from India-resident Asians. These study findings point to differences in metabolizing capacity and ER status in benign prostate tissues that might modulate susceptibility to the emergence of clinically significant CaP in demographically distinct populations.

关键词： CYP1b1,estrogen receptor,immunohistochemistry,inter-ethnic,prostate,real-time reverse transcriptase-polymerase chain reaction

Progesterone receptors A and b differentially modulate corticotropin-releasing hormone gene expression through a cAMP regulatory element

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第二军医大学学报 2005年第4期26卷 435-435页

作者： Smith R nicholson RC Department of Physiology Second Military Medical UniversityShanghai 200433 ChinaDepartment of Physiology Second Military Medical UniversityShanghai 200433 China

Corticotrophin-releasing hormone (CRH) plays a major role in mechanisms controlling human pregnancy and parturition. Gene regulation by progesterone may be a key point in the control of placental CRH production. Studies in primary placental cells show that antagonism of progesterone activity or production by RU486 or trilostane leads to an increase in CRH promoter activity. This effect can be reversed by the addition of progesterone. Overexpression of progesterone receptor A (PR-A) or glucocorticoid receptor resulted in a decrease in CRH promoter activity following progesterone treatment, whereas an increase in promoter activity was observed with overexpressed PR-b. Studies including mutation of the cAMP regulatory element (CRE) confirm this site to be essential for the progesterone-mediated effects. In summary, our results demonstrate that progesterone regulates CRH gene transcription via a CRE in the CRH promoter and that PR-A and PR-b exhibit different actions in the regulation of CRH gene expression.

关键词：黄体酮激素释放激素因子 cAMP

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荒漠化、干旱与植被——以西非萨赫勒为例

气象科技 2000年第2期28卷 41-46页

作者： C.J.Tucker M.b.ba S.E.nicholson 张文哲孙力晏晓英 NOAA数据与信息中心佛罗里达州立大学气象系

关于西非荒漠化的本质和特征存在着许多看法。该文将追溯其历史 ,回顾荒漠化对气候影响的研究现状 ,并介绍一些有关研究结果。对荒漠化的认识通常为“沙漠”的扩张 ,是一个总体上不可逆转的人为过程。其过程与地表反照率增强 ,风沙加大... 详细信息

关于西非荒漠化的本质和特征存在着许多看法。该文将追溯其历史 ,回顾荒漠化对气候影响的研究现状 ,并介绍一些有关研究结果。对荒漠化的认识通常为“沙漠”的扩张 ,是一个总体上不可逆转的人为过程。其过程与地表反照率增强 ,风沙加大以及土地生产力下降相联系。研究表明 ,在最近 1 6年里撒哈拉沙漠的边界和萨赫勒植被均变化不大 ,从植被水分有效利用率来看 ,“生产力”没有系统性降低 ,地表反照率也没有多少改变。自 2 0世纪 50年代以来反照率仅增加 0 .1 %。

关键词：荒漠化干旱植被西非萨赫勒地区

Analysis of Hydro-Climatical Variability in the Mo basin in Togo

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Journal of Water Resource and Protection 2021年第12期13卷 1043-1060页

作者： Koko Zébéto Houédakor Dametoti Yamoula Department of Geography Faculty of Human and Social Sciences Université de Lomé Lomé Togo

Climate changes are affecting water resources around the world and the Mo basin (Mb) in Togo is no exception to this observation. This study aims at analyzing the influence of hydro-climatical data in the Mo basin. To achieve this, Pettit’s stationarity break tests, Hubert’s segmentation, nicholson’s [1] reduced centered index, Lamb [2] and flow coefficients have been applied. In addition, temperature, precipitation, evapotranspiration, relative humidity and discharge data from 1961 to 2018 have been used for this purpose. While rainfall is decreasing despite an increase of 22.8% at the Fazao station and 2.8% at Sotouboua station, the flow coefficients evolve synchronously with the precipitation data and show a strong link between both parameters. The climatic balance sheet is positive six months in the year (May to October), throughout the period of observation (1961-2018). Only 1962 and 1963 recorded an annual rainfall greater than the annual evapotranspiration. The other years undergo a climatic drought, increasingly pronounced, which strongly impacts the hydrology of rivers. This has a strong impact on water resources and food security and resources of the Fazao-Malfakassa reserve in the region.

关键词： Climate Variability Hydro-Climatic balance Mo basin Togo

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吸烟病人非特异性间质肺炎的CT研究

国际医学放射学杂志 2009年第5期32卷 507-508页

作者： K.Marten D.Milne K.M.Antoniou A.G.nicholson R.C.Tennant T.T.Hansel 高莉 Department of Radiology Georg August University of GtingenRobert-Koch-Str.4037075 GttingenGermany

本研究的目的是寻找吸烟病人中的部分非特异性间质肺炎（NSIP）发病原因的间接证据。10例目前仍旧吸烟和8例曾经吸烟的NSIP病人与对照组的137例没有已知间质肺炎的吸烟者和11例不吸烟但有NSIP的病人进行对照研究。分别对比18例NSIP的吸... 详细信息

本研究的目的是寻找吸烟病人中的部分非特异性间质肺炎（NSIP）发病原因的间接证据。10例目前仍旧吸烟和8例曾经吸烟的NSIP病人与对照组的137例没有已知间质肺炎的吸烟者和11例不吸烟但有NSIP的病人进行对照研究。分别对比18例NSIP的吸烟病人与符合慢性阻塞性肺病金标准的病人（COPD，A组，n=34）和正常的吸烟者（FEV正常，b组，n=103）的肺气肿范围及分布。

关键词：非特异性间质肺炎肺纤维化肺气肿吸烟

New Generation of Experiments for the Investigation of Stellar (p,γ) Reaction Rates Using SAMURAI

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原子核物理评论 2016年第2期33卷 146-151页

作者： V. Panin[ K. Yoneda M. Kurokawa J. blackmon Z. Elekes D. Kim T. Motobayashi H. Otsu b. C. Rasco A. Saastamoinen L. Sobotka L. Trache T. Uesaka RIKEN Nishina Center 2-1 Hirosawa Wako Saitama 351-0198 Japan Louisiana State University 211-A Nicholson Hal Tower Dr. Baton Rouge LA 708030-4001 USA MTA Atomki Bern tdr 18/c H-4026 Debrecen Hungary Ewha Womans University Seoul South Korea Texas A&M University USA Department of Chemistry Washington University Saint Louis MO 63130 USA IFIN-HH str. Reactorului 30 Bucharest-Magurele R0-77125 Romania

The future experimental campaign with the SAMURAI setup at RIKEN will explore a wide range of neutron-deficient nuclei with a particular focus on the most critical(p, γ) reaction rates relevant to the astrophysical rp-process in type-I X-ray bursts(XRb). Intense radioactive-ion(RI) beams at an energy of a few hundred Me V/nucleon will be deployed to populate proton-unbound states in the nuclei of interest through the Coulomb excitation or nucleon-removal processes. The decay of these states into a proton and a heavy residue will be measured using complete kinematics and the information about time reversal proton-capture process will be obtained. This method will provide the vital experimental data on the resonances, which dominate the stellar(p, γ) reaction rates, as well as on the direct proton-capture process for some other cases. The experimental setup will utilize for the first time the High-Resolution90?-mode of the SAMURAI spectrometer in combination with the existing detection systems, including custom-designed Si-strip detectors for simultaneous detection and tracking of heavy ions and protons emitted from the target. The details of the experimental method and the utilized apparatus are discussed in this paper.

关键词： type-I X-ray burst rp-process (p γ) reaction rate neutron-deficient RI beam