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Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus

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Neural Regeneration Research 2020年第8期15卷 1546-1553页

作者： Courtney j.Mycroft-West Anthony j.Devlin Lynsay C.Cooper Patricia Procter gavin j.miller David G.Fernig Marco Guerrini Scott E.Guimond Marcelo A.Lima Edwin A.Yates Mark Andrew Skidmore Molecular&Structural Biosciences School of Life SciencesKeele UniversityHuxley BuildingKeeleStaffordshireST55BGUK Lennard-jones Laboratory School of Chemical and Physical SciencesKeele UniversityKeeleStaffordshireST55BGUK Department of Biochemistry Institute of Integrative BiologyUniversity of LiverpoolCrown StreetLiverpoolL697ZBUK Istituto di Ricerche Chimiche e Biochimiche G.Ronzoni Via G.Colombo 8120133 MilanItaly School of Medicine KeeleStaffordshireST55BGUK

The pharmaceutical and anticoagulant agent heparin,a member of the glycosaminoglycan family of carbohydrates,has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target,the primary neuronalβ-secretase,β-site amyloid precursor protein cleaving enzyme 1(BACE1).The anticoagulant activity of heparin has,however,precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease ***,a glycosaminoglycan extract,composed predominantly of 4-sulfated chondroitin sulfate,has been isolated from Sardina pilchardus,which possess the ability to inhibit BACE1(IC50[half maximal inhibitory concentration]=4.8μg/mL),while displaying highly attenuated anticoagulant activities(activated partial thromboplastin time EC50[median effective concentration]=403.8μg/mL,prothrombin time EC50=1.3 mg/mL).The marine-derived,chondroitin sulfate extract destabilizes BACE1,determined via differential scanning fluorimetry(ΔTm–5°C),to a similar extent as heparin,suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action,which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.

关键词： amyloid-β aspartyl protease carbohydrates galactosaminoglycans heparan sulfate heparin marine polysaccharide pilchards sardines therapeutics

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Higgs boson searches at the Tevatron

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Frontiers of physics 2013年第3期8卷 270-284页

作者： gavin j. Davies Imperial College London London SW7 2AZ United Kingdom

This article reviews the Higgs searches at the Tevatron, as presented over the summer of 2012; both standard model （SM） and beyond the standard model （BSM） results are discussed as detailed （arXiv： 1207.0449; Phys. Rev. Lett., 2012, 109： 071804; Phys. Rev. D, 2012, 85： 032005）. We discuss the combination of searches by the CDF and DO Collaborations for the standard model Higgs boson in the mass range 100-200 GeV/c2 produced in the the gg →H, WH, ZH, tfH, and vector boson fusion production modes, and decaying in the H → bb, H → W＋W-, H → ZZ, H →π＋π-, and H →γγ modes. The data, collected at the Fermilab Tevatron collider in p/5 collisions at √s = 1.96 TeV, correspond to integrated luminosities of up to 10 fb^-1. In the absence of signal, we expect to exclude the regions 100 〈 mH 〈 120 GeV/c2 and 139 〈 mH 〈 184 GeV/c2. We exclude, at the 95% C.L., two regions： 100 〈 mH 〈 103 GeV/c2, and 147 〈 mH 〈 180 GeV/c2. We observe a significant excess of events in the mass range between 115 and 140 GeV/c2. The local significance corresponds to 3.0 standard deviations at mH = 120 GeV/ce; the global significance （incorporating the lookelsewhere effect） for such an excess anywhere in the full mass range investigated is approximately 2.5 standard deviations. Furthermore, we separately combine searches for H→ bb-, H → W＋W- and H →γγ. We find that the excess is concentrated in the H →bb channel, appearing in the searches over a broad range of raN; the maximum local significance of 3.3 standard deviations corresponds to a global significance of approximately 3.1 standard deviations. The observed signal strengths in all channels are consistent with the expectation for a standard model Higgs boson at mH = 125 GeV/c2. The production of neutral Higgs bosons in association with b-quarks can be significantly enhanced in various beyond the standard model scenarios, including Supersymmetry. The recent combination of such searches from the two collaborations is discussed.

关键词： Higgs Tevatron

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A review of bridge scour monitoring techniques

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journal of Rock Mechanics and Geotechnical Engineering 2014年第2期6卷 138-149页

作者： L.j.Prendergast K.gavin School of Civil.Structural and Environmental Engineering University College Dublin

The high profile failure of the Malahide Viaduct in Dublin, Ireland, which is a part of the EU TEN-T network of critical transport links, was caused by foundation scour. Scour is a common soil-structure interaction problem. In light of current changes in climate, increasing frequency of flooding, coupled with the increasing magnitude of these flood events, will lead to a higher risk of bridge failure. Moni- toring scour is of paramount importance to ensure the continued safe operation of the aging bridge asset network. Most monitoring regimes are based on expensive underwater instrumentation that can often be subjected to damage during times of flooding, when scour risk is at its highest. This paper presents a critical review of existing scour monitoring equipments and methodologies with a particular focus on those using the dynamic response of the structure to indicate the existence and severity of the scour phenomenon affecting the structure. A sensitivity study on a recently developed monitoring method is also undertaken.

关键词： Scour Dynamics Monitoring Instruments Bridge failure

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Modeling the dose-response rate/associations between VO2max and self-reported Physical Activity Questionnaire in children and adolescents

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journal of Sport and Health Science 2020年第1期9卷 90-95页

作者： Alan M.Nevill Michael j.Duncan gavin Sandercock Faculty of Education Health and WellbeingUniversity of WolverhamptonWalsall CampusWalsallWS13BDUK Faculty of Health and Life Sciences Coventry UniversityCoventryCV15FBUK School of Biological Sciences University of EssexColchesterCO43SQUK

Background'. This study sought to explore the dose—response rate/association between aerobic fitness (VC)2max) and self-reported physical activity(PA) and to assess whether this association varies by sex, age, and weight ***. VO2max was assessed using the 20・m shuttle・run test. PA was assessed using the Physical Activity Questionnaire (PAQ) for Adolescents(aged > 11 years, PAQ-A) or for Children (aged <11 years, PAQ-C). The associations between V02raax and PAQ were analyzed using analysisof covariance (ANCOVA), adopting PAQ and PAQ2 as covariates but allowing the intercepts and slope parameters of PAQ and PAQ2 tovary with the categorical variables sex, age group, and weight ***: ANCOVA identified a curvilinear association between VO2max and PAQ, with positive linear PAQ terms that varied for both sex andweight status but with a negative PAQ2 term of —0.39 (95% confidence interval (CI): —0.57 to —0.21) that was common for all groups in regardto age, sex, and weight status. These curvilinear (inverted U) associations suggest that the benefits of increasing PA (same dose) on VO2max isgreater when children report lower levels of PA compared to children who report higher levels of PA. These dose-response rates were alsosteeper for boys and were steeper for lean children compared to overweight/obese ***'. Health practitioners should be aware that encouraging greater PA (same dose) in inactive and underweight children will result ingreater gains in V02max (response) compared with their active and overweight/obese counterparts.

关键词： Aerobic fitness Curvilinear association Sex Slope parameters Weight status

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三维炭纤维预型体上烷烃气的催化炭沉积(英文)

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新型炭材料 2009年第3期24卷 251-259页

作者： Matthew j Thornton gavin S Walker School of Mechanical Materials and Manufacturing EngineeringUniversity of NottinghamUniversity ParkNottingham

研究了承载镍催化剂的三维(3D)炭纤维预型体,在含氢或无氢条件下,乙烷和合成天然气在其上面化学气相沉积形成的炭沉积率和碳纳米构结物。观察了炭沉积所获石墨纳米纤维、碳纳米管和石墨碳壳,得知沉积碳的纳米结构取决于沉积温度和碳源... 详细信息

研究了承载镍催化剂的三维(3D)炭纤维预型体,在含氢或无氢条件下,乙烷和合成天然气在其上面化学气相沉积形成的炭沉积率和碳纳米构结物。观察了炭沉积所获石墨纳米纤维、碳纳米管和石墨碳壳,得知沉积碳的纳米结构取决于沉积温度和碳源气组成。在650℃～800℃温间,总沉积时程直至12h,研究了烃类碳源气在氢气平衡下,从体积分数100%到20%变化情况。经Ni(NO3)2-6H2O甲醇溶液浸渍的3D炭纤维预型体在炭沉积前因溶液分解可还原出Ni。采用质量变化测定法、热谱-质谱分析仪、SEM、TEM和XRD对样品进行表征。结果表明:纤维状炭与囊包炭的比率随氢气含量的增加而增加,随反应温度的增高而减少。出乎意料的是,氢气的添加并不延长催化剂的寿命。该工艺过程对炭/炭复合材料的制备展示出良好的潜力。

关键词：催化生长炭炭纤维烷烃气浸渍显微镜方法

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A review of CPT based axial pile design in the Netherlands

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Underground Space 2021年第1期6卷 85-99页

作者： Kenneth gavin Meho Sasa Kovacevic David Igoe TU Delft Geo-Engineering SectionFaculty of Civil Engineering and GeosciencesDelft University of TechnologyBuilding 23Stevinweg 1PO-Box 50482628 CN Delft/2600 GA DelftNetherlands University of Zagreb Croatia Trinity College Dublin Ireland

Because of the deltaic nature of the Netherlands,deep soft soil deposits are *** to the population density exploitation of underground space is vital for commercial developments and transport *** are used as primary support elements in deep excavations,cut and cover tunnels,quay walls,flood defences and to provide uplift resistance to the base of tunnels and *** paper examines empirical correlations linking the Cone Penetration Test(CPT)end resistance qc and the resistance of deep foundations in *** is found that correlations between qc and pile end resistance are independent of pile ***,the impact of installation method,residual load,plugging and sand creep should be *** the case of shaft resistance,constant correlation factors between qc and average shaft resistance are possible for non-displacement *** the case of displacement piles,correlations that include the effects of friction fatigue and pile plugging during installation are recommended.

关键词： Piles Sand CPT based methods Design codes

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The role of rumen epithelial urea transport proteins in urea nitrogen salvage:A review

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Animal Nutrition 2022年第2期9卷 304-313页

作者： Chongliang Zhong Ruijun Long gavin S.Stewart College of Ecology State Key Laboratory of Grassland Agro-ecosystemsLanzhou UniversityLanzhouChina School of Biology and Environmental Science University College DublinDublinIreland

The symbiotic relationship between the host and the rumen microbiome plays a crucial role in ruminant *** of the most important processes enabling this relationship is urea nitrogen salvaging(UNS).This process is important for both maintaining ruminant nitrogen balance and supporting production of their major energy supply,bacterially-derived short chain fatty acids(SCFA).The key step in UNS is the trans-epithelial movement of urea across the ruminal wall and this is a highly regulated *** the molecular level,the key transport route is via the facilitative urea transporter-B2,localized to ruminal papillae epithelial *** urea transport through aquaporins(AQP),such as AQP3,is now also viewed as ***-term regulation of these ruminal urea transport proteins appears to mainly involve dietary fermentable carbohydrates;whereas,transepithelial urea transport is finely regulated by local conditions,such as CO_(2) levels,pH and SCFA *** the key principles of ruminal urea transport physiology are now understood,there remains much that is unknown regarding the regulatory *** reason for this is the limited number of techniques currently used in many studies in the ***,future research in this area that combines a greater range of techniques could facilitate improvements to livestock efficiency,and potentially,reductions in the levels of waste nitrogen entering the environment.

关键词： Urea nitrogen salvaging Rumen Urea transporter Aquaporin UT-B AQP

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Environmental exposure as a risk-modifying factor in liver diseases:Knowns and unknowns

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3768-3778页

作者： juliane I.Beier gavin E.Arteel Department of Medicine Division of GastroenterologyHepatology and NutritionUniversity of PittsburghPittsburghPA 15213USA Pittsburgh Liver Research Center and University of Pittsburgh PittsburghPA 15213USA Department of Environmental and Occupational Health University of PittsburghPA 15213USA

Liver diseases are considered to predominantly possess an inherited or xenobiotic ***,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive *** "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or *** purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other *** exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a *** review also discusses key new tools and approaches that will likely be critical to address this question in the *** together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."

关键词： Hepatic injury Exposomics Liver disease Drug-induced liver injury Alcoholic liver disease Non-alcoholic liver disease Inherited liver disease Autoimmune liver disease

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Approximation on Two-point Homogeneous Spaces

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数学进展 2004年第5期33卷 635-638页

作者： gavin Brown 戴峰

1Introduction This paper is a short research announcement of the results obtained in [BD],which will appear soon.

关键词：黎曼定理拉普拉斯变换泛函分析存在性容积公式

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The emergence of pandemic influenza viruses

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Protein & Cell 2010年第1期1卷 9-13页

作者： Yi Guan Dhanasekaran Vijaykrishna justin Bahl Huachen Zhu jia Wang gavin j.D.Smith State Key Laboratory of Emerging Infectious Diseases Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina

Pandemic influenza has posed an increasing threat to public health worldwide in the last *** the 20th century,three human pandemic influenza outbreaks occurred in 1918,1957 and 1968,causing significant mortality.A number of hypotheses have been proposed for the emergence and development of pandemic viruses,including direct introduction into humans from an avian origin and reassortment between avian and previously circulating human viruses,either directly in humans or via an intermediate mammalian ***,the evolutionary history of the pandemic viruses has been controversial,largely due to the lack of background genetic information and rigorous phylogenetic *** pandemic that emerged in early April 2009 in North America provides a unique opportunity to investigate its emergence and development both in human and animal *** genetic analyses of data accumulated through long-term influenza surveillance provided insights into the emergence of this novel pandemic *** this review,we summarise the recent literature that describes the evolutionary pathway of the pandemic *** also discuss the implications of these findings on the early detection and control of future pandemics.

关键词： pandemic influenza influenza virus pandemics control

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