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1.
The 2011 AASHTO Roadside Design Guide (RDG) contains perhaps the most widely used procedure for choosing an appropriate length of need (LON) for roadside barriers. However, this procedure has several limitations. The procedure uses a highly simplified model of vehicle departure, and the procedure does not allow designers to specify an explicit level of protection. A new procedure for choosing LON that addresses these limitations is presented in this paper. This new procedure is based on recent, real-world road departure trajectories and uses this departure data in a more realistic way. The new procedure also allows LON to be specified for a precisely known level of protection – a level which can be based on number of crashes, injury outcomes or even estimated crash cost – while still remaining straightforward and quick to use like the 2011 RDG procedure. 相似文献
2.
Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
3.
Hook T.B. Brown J. Cottrell P. Adler E. Hoyniak D. Johnson J. Mann R. 《Electron Devices, IEEE Transactions on》2003,50(9):1946-1951
Lateral scattering of retrograde well implants is shown to have an effect on the threshold voltage of nearby devices. The threshold voltage of both NMOSFETs and PMOSFETs increases in magnitude for conventional retrograde wells, but for triple-well isolated NMOSFETs the threshold voltage decreases for narrow devices near the edge of the well. Electrical data, SIMS, and SUPREM4 simulations are shown that elucidate the phenomenon. 相似文献
4.
Students may choose to play drinking games not only for reasons related to alcohol consumption but also because of incentives related to other aspects of play (competition, fun, interpersonal dominance, etc.). College students (120 men and 167 women) completed measures of motives for playing (based on T. J. Johnson, S. Hamilton, & V. L. Sheets, 1999) and consequences of playing drinking games. Exploratory principal-components analysis identified 8 reasons for playing. Men and women differed in their endorsement of the factors. Motives for play directly predicted consequences of play independently of alcohol consumption. Specific motives predicted specific types of consequences. In multiple regression analyses, Conformity motives were negatively related to consequences and may represent a form of protective motive. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
5.
Pressurized fabric tubes, pressure-stabilized beams (known as air beams) and air-inflated structures are considered to be valuable technologies for lightweight, rapidly deployable structures. Design optimization of an inflated structure depends on a thorough understanding of woven fabric mechanics. In this paper the bending response of woven pressure-stabilized beams have been experimentally tested and analytically investigated. Additionally, the micromechanical effects of interacting tows have been studied through finite element models containing contact surfaces and nonlinear slip/stick conditions. Local unit cell models consisting of pairs of woven tows were created to characterize the effective constitutive relations. The material properties from the unit cell models were then used for the global continuum model subjected to 4-point flexure. An experimental set-up was designed and manufactured for testing of Vectran and PEN air beams. The air beam mid-span deflections were measured as functions of inflation pressure and bending load. Plots of the elastic and shear moduli with respect to the pressure and coefficient of friction have been generated. It was determined that the effective elastic and shear moduli were functions of inflation pressure, the material used and the geometry of the weave. It was shown that pneumatic or pressurized tube structures differ fundamentally from conventional metal structures. 相似文献
6.
Examination of the wreckage of a light aircraft revealed that approximately 20 cm was missing from one tip of the aluminum
alloy propeller. Fractographic and metallographic examination of the remaining portion of the propeller revealed extensive
grain-boundary separation in the vicinity of the fracture, and grain edges and corners rounded by corrosion on the fracture
surface. Energy dispersive X-ray analysis (EDXA) revealed fluorine on, and in the vicinity of, the fracture surface. In the
ensuing litigation, it was asserted that the crash occurred because the propeller fractured in flight as the result of intergranular
attack caused by the use of a fluorine-bearing cleaner. 相似文献
7.
SH Kaufmann D Peereboom CA Buckwalter PA Svingen LB Grochow RC Donehower EK Rowinsky 《Canadian Metallurgical Quarterly》1996,88(11):734-741
BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). RESULTS: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or antimicrotubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo. 相似文献
8.
9.
Some specific characteristics of the aging of the Brazilian population in different areas, states and communities all over the country, have shown significant variations. Historical series of demographic and health indicators for the population in their sixties and over in Brazil, state of S. Paulo and in the municipal district of Araraquara are listed as follows: level of education and urban population growth rate, income distribution, mortality rates and main causes of death. In 1991 the aged constituted were 7.8% of the Brazilian population and 9.7% in Araraquara community. The elderly population (of 70 years of aged and above) as a proportion of the whole, has increased and already stands for 40%. The same trend holds good for both the proportion of aged within the urban population and their level of education which increased to 90% in 1991. The main causes of death are chronic degenerative diseases which have replaced the infectious illness: first, the diseases of the circulatory system (which account for more than 40% of all deaths) and the neoplasms (which let to 15% of the deaths). On the basis of these health and demographic data relating to people of 60 years of age and over, this study suggests some procedures for the improvement of the quality of the assistance given to the target population: a) the assistance give to the aged should be improved by providing gerontological training for general physicians and nurses, both of public and private clinics; b) the already existing educational activities for the aged, for health workers and for teachers of secondary education should be further developed; c) the number of day-hospitals should be increased for the purpose of avoiding unnecessary confinement so as maintain the low rate of institutionalization in homes for the elderly (0.7% in Araraquara). It is reported that at least 35% of the aged population in this area is entitled to private health assistance, which brings out the importance of including such services in the local health programs for this group. 相似文献
10.
Y Bourne B Bolgiano MP Nésa P Penfold D Johnson T Feizi C Cambillau 《Canadian Metallurgical Quarterly》1994,235(2):787-789
The soluble 14 kDa beta-galactoside-binding lectin from bovine heart, a member of the S-type lectin family, has been crystallized in a form suitable for X-ray diffraction analysis. The crystals, in the absence of a saccharide ligand, diffract beyond 2.5 A resolution. They are obtained from polyethylene glycol 6000 at pH 6.0. Crystals grow as monoclinic plates, space group P2(1), with cell dimensions: a = 35.47 A, b = 64.33 A, c = 58.78 A and beta = 91.7 degrees. The asymmetric unit contains two molecules related by a 2-fold non-crystallographic axis. Two lectin monomers in the asymmetric unit give a Vm of 2.4 A3/Da, i.e. a solvent content of approximately 50%. The complex of lectin with the saccharide ligand, N-acetyllactosamine, crystallizes in the space group P2(1)2(1)2 with cell dimensions: a = 63.55 A, b = 82.13 A and c = 62.39 A. Crystals of this complex diffract beyond 2.0 A resolution. Two complexes in the asymmetric unit lead to a Vm value of 2.8 A3/Da (57% solvent). 相似文献