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Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

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Acta Pharmaceutica Sinica b 2020年第7期10卷 1309-1320页

作者： Vincent blay Mu-Chun Li Sunita P.Ho Mashall L.Stoller Hsing-Pang Hsieh douglas R.Houston Division of biomaterials and bioengineering School of DentistryUniversity of California San FranciscoSan FranciscoCA 94143USA Department of Urology School of MedicineUniversity of California San FranciscoSan FranciscoCA 94143USA Institute of biotechnology and Pharmaceutical Research National Health Research InstitutesZhunanTaiwan 350China University of Edinburgh Institute of Quantitative BiologyBiochemistry and BiotechnologyEdinburghScotlandEH93BFUK

Hepsin,a transmembrane serine protease abundant in renal endothelial cells,is a promising therapeutic target against several cancers,particularly prostate *** is involved in the release and polymerization of uromodulin in the urine,which plays a role in kidney stone *** this work,we design new potential hepsin inhibitors for high activity,improved specificity towards hepsin,and promising ADMET *** ligands were developed in silico through a novel hierarchical *** pipeline explicitly accounts for off-target binding to the related serine proteases matriptase and HGFA(human hepatocyte growth factor activator).We completed the pipeline incorporating ADMET properties of the candidate inhibitors into custom multi-objective optimization *** ligands designed show excellent prospects for targeting hepsin via the blood stream and the urine and thus enable key experimental *** computational pipeline proposed is remarkably costefficient and can be easily adapted for designing inhibitors against new drug targets.

关键词： Virtual screening Docking Library Hepsin Tamm-Horsfall protein biomineralization

侧吹气流方向对大功率CO_2激光焊缝成形的影响

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热加工工艺 2007年第19期36卷 23-25页

作者：李国华贾时君 douglas Steyer Kevin b Albaugh 吴毅雄上海交通大学焊接研究所上海200030 普莱克斯亚洲投资有限公司上海200120

激光深熔焊过程中会在熔池上方产生等离子体云,若该等离子体云过密,将降低激光入射到工件表面能量密度。在工业应用中,常采用侧吹辅助气体来减弱等离子体云的影响。本文通过试验,研究了在不同气体流量下。侧吹气体方向不同对焊接过程稳... 详细信息

激光深熔焊过程中会在熔池上方产生等离子体云,若该等离子体云过密,将降低激光入射到工件表面能量密度。在工业应用中,常采用侧吹辅助气体来减弱等离子体云的影响。本文通过试验,研究了在不同气体流量下。侧吹气体方向不同对焊接过程稳定性和焊缝成形的影响。结果发现:使用大功率CO_2激光焊接AH32时,侧吹气体方向对焊缝成形有着明显的影响。从熔池和等离子体两个方面,解释了侧吹气体方向的影响机制。

关键词：激光焊接侧吹气体焊接稳定性焊缝成形

Osteoblast-restricted Disruption of the Growth Hormone Receptor in Mice Results in Sexually Dimorphic Skeletal Phenotypes

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bone Research 2013年第1期1卷 85-97页

作者： Vandana Singhal brian C.Goh Mary L.bouxsein Marie-Claude Faugere douglas J.DiGirolamo Department of Orthopaedic Surgery Johns Hopkins University School of MedicineBaltimoreMDUSA Center for Advanced Orthopedic Studies Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMAUSA Albert b.Chandler Medical Center University of KentuckyLexingtonKYUSA

Growth hormone （GH） exerts profound anabolic actions during postnatal skeletal development, in part, through stimulating the production of insulin-like growth factor-1 （IGF-1） in liver and skeletal tissues. To examine the requirement for the GH receptor （GHR） in osteoblast function in bone, we used Cre-LoxP methods to disrupt the GHR from osteoblasts, both in vitro and in vivo. Disruption of GHR from primary calvarial osteoblasts in vitro abolished GH-induced signaling, as assessed by JAK2/STAT5 phosphorylation, and abrogated GH-induced proliferative and anti-apoptotic actions. Osteoblasts lacking GHR exhibited reduced IGF-l-induced Erk and Akt phosphorylation and attenuated IGF-1-induced proliferation and anti-apoptotic action. In addition, differentiation was modestly impaired in osteoblasts lacking GHR, as demonstrated by reduced alkaline phosphatase staining and calcium deposition. In order to determine the requirement for the GHR in bone in vivo, we generated mice lacking the GHR specifically in osteoblasts （△GHR）, which were born at the expected Mendelian frequency, had a normal life span and were of normal size. Three week-old, female AGHR mice had significantly reduced osteoblast numbers, consistent with the in vitro data. by six weeks of age however, female AGHR mice demonstrated a marked increase in osteoblasts, although mineralization was impaired; a phenotype similar to that observed previously in mice lacking IGF-1R specifically in osteoblasts. The most striking phenotype occurred in male mice however, where disruption of the GHR from osteoblasts resulted in a ＂feminization＂ of bone geometry in 16 week-old mice, as observed by faCT. These results demonstrate that the GHR is required for normal postnatal bone development in both sexes. GH appears to serve a primary function in modulating local IGF-1 action. However, the changes in bone geometry observed in male AGHR mice suggest that, in addition to facilitating IGF-1 action, GH may function to a greater

关键词： growth hormone osteoblasts knockout mice bone sexual dimorphism

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填充设计的最大部分平行类

中国科学：数学 2023年第2期53卷 217-232页

作者： douglas R.Stinson 卫瑞中 David R.Cheriton School of Computer Science University of WaterlooWaterlooON N2L 3G1Canada Department of Computer Science Lakehead UniversityThunder BayON L3V 0B9Canada

设整数β(ρ,v,k)是最大部分平行类大小为ρ的任意(v,k)-填充设计中所包含的最大区组数目.对于k=3,该问题由Stinson (2021)引入并研究.本文主要研究k=4的情形,获得β(ρ,v,4)的上下界.本文给出最大部分平行类大小为ρ的(v,4)-填充设计... 详细信息

设整数β(ρ,v,k)是最大部分平行类大小为ρ的任意(v,k)-填充设计中所包含的最大区组数目.对于k=3,该问题由Stinson (2021)引入并研究.本文主要研究k=4的情形,获得β(ρ,v,4)的上下界.本文给出最大部分平行类大小为ρ的(v,4)-填充设计的具体构造.对于小的ρ值,所构造的填充设计的区组数非常靠近上界β(ρ,v,4).本文的一些方法可以推广到k>4的情形.

关键词：最大部分平行类填充设计最优设计组合设计

Removal of Lithium Citrate from H3A for Determination of Plant Available P

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Open Journal of Soil Science 2017年第11期7卷 301-314页

作者： Richard L. Haney Elizabeth b. Haney douglas R. Smith Michael J. White USDA-ARS Grassland Soil and Water Research Laboratory Temple USA Texas A & M University Texas AgriLife Research and Extension Center Temple USA

The soil extractant, H3A, has undergone several iterations to extract calcium (Ca), iron (Fe), aluminum (Al), potassium (K), phosphorus (P), ammonium (NH4-N) and nitrate (NO3-N) under ambient soil conditions. Few soil extractants currently used by commercial and university soil testing laboratories can perform multi-nutrient extraction without over- or under-estimating at least one nutrient. Soil pH and plant root exudates have a strong influence on nutrient availability and H3A was developed to mimic soil conditions. Lithium citrate was previously used in the H3A formulation, but resulted in a cloudy supernatant in some samples, complicating laboratory analyses. In this study, we removed lithium citrate and compared the nutrients extracted from the modified (H3A-4) to the established (H3A-3) solutions. We found that the new extractant, H3A-4, produced a clear supernatant even in soils with low pH and high iron and aluminum concentrations. H3A-4 accurately predicts plant available nutrients and is a viable choice for commercial and laboratory settings due to its ease of use.

关键词： Phosphate Soil Extraction Lithium Citrate

犹他州中-西部中央塞维尔沙漠新生代扩展历史——据大陆反射剖面合作项目地震反射资料

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宝石和宝石学杂志(中英文) 1987年第2期 81-87+55页

作者： douglas b.Vontish 孙家振

大陆反射剖面合作项目(COCORP)地震反射资料揭示了塞维尔沙漠下面新生代扩展是沿着大范围的西倾面运动的.在塞维尔沙漠盆地内从已知时代的几套地层中获得了地震反射.这几套地层的几何关系表明至少发生过两次扩展.第一次扩展规模较大(20... 详细信息

大陆反射剖面合作项目(COCORP)地震反射资料揭示了塞维尔沙漠下面新生代扩展是沿着大范围的西倾面运动的.在塞维尔沙漠盆地内从已知时代的几套地层中获得了地震反射.这几套地层的几何关系表明至少发生过两次扩展.第一次扩展规模较大(20-30公里),从中渐新世后(26-28百万年)开始,持续到中新世.这次扩展之后可能有一短期的静止和剥蚀.第二次扩展规模较小(<8公里),自中上新世(4-2百万年)玄武岩喷发时期或喷发后开始.后一次扩展现在仍在活动,盆地内错断现代沉积物的断层崖证实了这一点.塞维尔沙漠扩展记录反映了沿下伏塞维尔沙漠挤离面的运动历史,它是一条大的低角度正断层,垂直断层走向已追踪达70多公里、深度达12-15公里.沿塞维尔沙漠挤离面的位移记录可以推断盆地和山脉区扩展的总历史.

关键词：新生代地层山脉岩石邦维尔沙漠荒漠第三纪晚中新世盆地地质构造正断层重力断层地质断层地震反射反射剖面地球物理剖面犹他州大陆地貌

Population dynamics of Amur tigers(Panthera tigris altaica)in Sikhote-Alin biosphere Zapovednik:1966–2012

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Integrative Zoology 2015年第4期10卷 315-328页

作者： Dale G.MIQUELLE Evgeny N.SMIRNOV Olga Yu.ZAUMYSLOVA Svetlana V.SOUTYRINA douglas H.JOHNSON Wildlife Conservation Society BronxNew YorkUSA Sikhote-Alin biosphere Zapovednik TerneiPrimorskii KraiRussia USGS Northern Prairie Wildlife Research Center Saint PaulMinnesotaUSA

In 2010,the world’s tiger(Panthera tigris)range countries agreed to the goal of doubling tiger numbers over 12 years,but whether such an increase is biologically feasible has not been ***-term monitoring of tigers in Sikhote-Alin biosphere Zapovednik(SAbZ),Russia provided an opportunity to determine growth rates of a recovering population.A 41-year growth phase was followed by a rapid decline in tiger *** growth rates during the growth phase averaged 4.6%,beginning near 10%in the earliest years but quickly dropping below 5%.Sex ratio(females per male)mirrored growth rates,declining as population size *** rapid decline from 2009 to 2012 appeared to be tied to multiple factors,including poaching,severe winters and *** indicators of this population are similar to those of bengal tiger populations,suggesting that growth rates may be *** results suggest that,first,tiger populations likely in general grow slowly:3–5%yearly increases are realistic and larger growth rates are likely only when populations are highly depressed,mortality rates are low and prey populations are high relative to numbers of adult ***,while more research is needed,it should not be assumed that tiger populations with high prey densities will necessarily grow more quickly than populations with low prey ***,while growth is slow,decline can be ***,because declines can happen so quickly,there is a constant need to monitor populations and be ready to respond with appropriate and timely conservation interventions if tiger populations are to remain ***,an average annual growth rate across all tiger populations of 6%,required to reach the Global Tiger Initiative’s goal of doubling tiger numbers in 12 years,is a noble but unlikely scenario.

关键词： Amur tiger growth rates population dynamics

Future impacts of climate change on forest fire danger in northeastern China

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Journal of Forestry Research 2011年第3期22卷 437-446页

作者： TIAN Xiao-rui SHU Li-fu ZHAO Feng-jun WANG Ming-yu douglas J. McRae State Forestry Administration＇s Key Open Laboratory of Forest Protec- tion Research Institute of Forest Ecology Environment and Protection Chinese Academy of Forestry Beijing 100091. Natural Resources Canada Canadian Forest Service 1219 Queen St. E.Sault Ste. Marie Ontario P6A 2E5.

Climate warming has a rapid and far-reaching impact on forest fire management in the boreal forests of China. Regional climate model outputs and the Canadian Forest Fire Weather Index （FWI） Sys- tem were used to analyze changes to fire danger and the fire season for future periods under IPCC Special Report on Emission Scenarios （SRES） A2 and b2, and the data will guide future fire management planning. We used regional climate in China （1961 1990） as our validation data, and the period （1991–2100） was modeled under SRES A2 and b2 through the weather simulated by the regional climate model system （PRECIS）. Meteorological data and fire danger were interpolated to 1 km 2 by using ANUSPLIN software. The average FWI value for future spring fire sea- sons under Scenarios A2 and b2 shows an increase over most of the region. Compared with the baseline, FWI averages of spring fire season will increase by 0.40, 0.26 and 1.32 under Scenario A2, and increase by 0.60, 1.54 and 2.56 under Scenario b2 in 2020s, 2050s and 2080s, respectively. FWI averages of autumn fire season also show an increase over most of the region. FWI values increase more for Scenario b2 than for Scenario A2 in the same periods, particularly during the 2050s and 2080s. Average future FWI values will increase under both scenarios for autumn fire season. The potential burned areas are expected to increase by 10% and 18% in spring for 2080s under Scenario A2 and b2, respectively. Fire season will be prolonged by 21 and 26 days under ScenariosA2 and b2 in 2080s respectively.

关键词： climate change fire season forest fire danger northeastern China

Experimental Investigation of Spoiler Deployment on Wing Stall

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Open Journal of Fluid Dynamics 2018年第3期8卷 308-320页

作者： Scott douglas Lindsay Paul Walsh Ryerson University Toronto Canada

Upper surface wing flaps, known as spoiler, are typically used to reduce lift and increase drag at touchdown;however spoilers have been shown to increase lift and reduce drag at near-stall conditions. The purpose of this experiment was to determine the spoilers’ impact on lift, drag, moment, and aerodynamic efficiency of a NACA 2412 airfoil at angles of attack (α) from −8 ° to 32 °. The experiment was conducted in the Ryerson Low-Speed Wind Tunnel (closed-circuit, 1 m × 1 m test section) at Re=783761, Ma=0.136. The lift coefficient (Cl), drag coefficient (Cd), moment coefficient about the quarter-chord () were captured with a changing spoiler deflection angle (δ) and spoiler length (b in percent chord). It was found that deflecting the spoiler resulted in an increase maximum lift of up to 2.497%. It was found that deflecting the spoiler by 8° was optimal for the b=10 cases. Any larger deflection reduced the lift gain, and a deflection of 25° caused the maximum lift to be 2.786% less than the clean configuration. In the b=15 case, δ=15° was optimal (1.760% maximum lift coefficient increase). The b=10 cases increased maximum lift coefficient between 0.35% and 2.10% higher than the b=15 cases. The source of the lift gain at high angles of attack is apparent in an analysis of the airfoil pressure distribution. The spoiler increased the suction peak on the airfoil surface upstream of the spoiler, and increased the pressure downstream. However the suction increase upstream is larger than the pressure increase downstream, resulting in a net increase in lift. The spoiler increased the stall angle 37.658% to 87.658% higher than the clean configuration. Stall angle increased with both δ and with an increased spoiler length. The spoiler airfoil produced less drag than the clean configuration at high angles of attack. The combination of the increased lift, and reduced drag resulted in an increase in aerodynamic efficiency at high angle of attack.

关键词： Aircraft Stall Wind-Tunnel Spoilers Low-Speed Aerodynamics