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Dr. Li Di Prof. Per Artursson Dr. Alex Avdeef Prof. Leslie Z. Benet Prof. J. Brian Houston Dr. Manfred Kansy Edward H. Kerns Prof. Hans Lennernäs Dr. Dennis A. Smith Prof. Kiyohiko Sugano 《ChemMedChem》2020,15(20):1862-1874
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients. 相似文献
3.
Dr. Emrah Kara Dr. Nis Valentin Nielsen Bergrun Eggertsdottir Dr. Bernd Thiede Dr. Sandip M. Kanse Dr. Geir Åge Løset 《Chembiochem : a European journal of chemical biology》2020,21(13):1875-1884
We describe a novel, easy and efficient combinatorial phage display peptide substrate-mining method to map the substrate specificity of proteases. The peptide library is displayed on the pVII capsid of the M13 bacteriophage, which renders pIII necessary for infectivity and efficient retrieval, in an unmodified state. As capture module, the 3XFLAG was chosen due to its very high binding efficiency to anti-FLAG mAbs and its independency of any post-translational modification. This library was tested with Factor-VII activating protease (WT-FSAP) and its single-nucleotide polymorphism variant Marburg-I (MI)-FSAP. The WT-FSAP results confirmed the previously reported Arg/Lys centered FSAP cleavage site consensus as dominant, as well as reinforcing MI-FSAP as a loss-of-function mutant. Surprisingly, rare substrate clones devoid of basic amino acids were also identified. Indeed one of these peptides was cleaved as free peptide, thus suggesting a broader range of WT-FSAP substrates than previously anticipated. 相似文献
4.
Hannerz Harald; Albertsen Karen; Nielsen Martin Lindhardt; Tüchsen Finn; Burr Hermann 《Canadian Metallurgical Quarterly》2004,23(3):283
This study explored whether factors related to the work environment could predict changes in body mass index (BMI) and whether the effect of psychosocial factors was dependent on baseline BMI. The sample consisted of 1,980 male employees from the Danish National Work Environment Cohort Study. Changes in BMI between 1995 and 2000 were analyzed, by multiple regression, as a function of background variables and a series of occupational variables obtained in 1995. Age, baseline BMI, job insecurity, and psychological demands predicted changes in BMI. Job insecurity and high or low psychological demands increased the likelihood of weight gain among obese employees, whereas they increased the likelihood of weight loss among employees with a low BMI. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
5.
Intensive fertilizer use has led to nitrate contamination of groundwater in many areas. This article examines the possibility of removing nitrates through the construction of artificial wetlands. A pilot study conducted in Denmark has found that the method is effective and economical, at least for small waterworks, though further treatment is necessary before an acceptable microbiological water quality is attained. 相似文献
6.
Morten
rregaard Nielsen 《时间序列分析杂志》2005,26(2):279-304
Abstract. We consider semiparametric estimation in time‐series regression in the presence of long‐range dependence in both the errors and the stochastic regressors. A central limit theorem is established for a class of semiparametric frequency domain‐weighted least squares estimates, which includes both narrow‐band ordinary least squares and narrow‐band generalized least squares as special cases. The estimates are semiparametric in the sense that focus is on the neighbourhood of the origin, and only periodogram ordinates in a degenerating band around the origin are used. This setting differs from earlier studies on time‐series regression with long‐range dependence, where a fully parametric approach has been employed. The generalized least squares estimate is infeasible when the degree of long‐range dependence is unknown and must be estimated in an initial step. In that case, we show that a feasible estimate which has the same asymptotic properties as the infeasible estimate, exists. By Monte Carlo simulation, we evaluate the finite‐sample performance of the generalized least squares estimate and the feasible estimate. 相似文献
7.
Sludge reed bed facilities: operation and problems. 总被引:1,自引:0,他引:1
S Nielsen 《Water science and technology》2005,51(9):99-107
Short operating periods and problems with dewatering efficiency, vegetation, mineralisation and odour are primarily caused by incorrect construction of the filter, poor capillary connections, an inadequate number of basins, insufficient basin area and overloading during commissioning and during subsequent operation. Dimensioning should be based on the sludge quality including the dewatering qualities and not solely on calculations of the sludge production. Loading after planting depends on the development level of the vegetation. The loading program should ensure that reed establishment is not impeded and should prevent the sludge residue from growing so quickly horizontally and vertically that the reeds cannot colonise the sludge residue. Overloading results in an anaerobic sludge residue with ensuing methane production. Typically, a sludge reed bed facility with a loading period of maximum 5 days, must be built with 10 basins to permit a rest phase of about 40 days. Facilities with 8 basins, where it is possible to load 1 basin for 7 days, will be able to have a 7-week rest phase before the first basin is loaded again. Facilities with for example 8-13 basins and loading period of between 4 and 10 days are able to achieve rest periods of up to 2 to 2(1/2) months, which results in the optimal evapotranspiration and minerilization. The conditions and thus the possibilities vary depending upon the type of sludge. 相似文献
8.
Per Johan Råsmark Čestmír Koňák Petr Štěpánek Christer Elvingson 《Polymer Bulletin》2005,54(4-5):335-342
Summary Dynamic light scattering was used to investigate the dynamics of sodium poly(styrene sulfonate) and fully neutralized poly(acrylic acid) gels as a function of the degree of swelling and weight ratio of cross-linking agent. It was shown that the collective diffusion coefficient increases with increasing degree of swelling and that the diffusion coefficient shows stronger concentration dependence than predicted by scaling arguments. For gel samples measured at the swelling equilibrium, the diffusion coefficient increases with increasing gel concentration for both gel systems. 相似文献
9.
Henrik Pettersson Tadeusz Gruszecki Lars-Henrik Johansson Per Johander 《Solar Energy Materials & Solar Cells》2003,77(4):6595
A manufacturing technique for monolithic dye-sensitised solar cells is presented. Encapsulated modules designed for indoor low-power applications have been prepared using industrial methods and equipment. Under certain conditions (light intensity <5000 lx, temperature between –10°C and 50°C, and relative humidity of appr. 50%), the modules have performed well and shown excellent long-term stability. Moreover, modules withstand illumination in combination with storage at 100% relative humidity. However, a certain degradation of the module performance takes place at illuminations exceeding 5000 lx and temperatures exceeding 50°C. 相似文献
10.
Per Hovstad Liching Sung 《International Journal of Satellite Communications and Networking》2005,23(2):91-110
The 1977 Broadcasting‐Satellite Service (BSS) Plan for Region 1 & 3 had been widely acknowledged to be out‐of‐date by the late 1980s. Development of digital modulation in the early 1990s provided an opportunity to update the technical provisions of the Plan to make it more economically viable. After a decade of work and three World Radiocommunication Conferences (WRCs), the revision of Region 1 & 3 BSS Plan was finally completed in 2003. The new Plan increased channel assignments from 5 to 10 analog‐equivalent channels for each country in Region 1, and from 4 to 12 channels for each country in Region 3. Yet, despite the increase in capacity, the new Plan is surprisingly similar to the original one in terms of the technical parameters. It is still based on national coverage, and the channel plan, orbital location, orbital spacing, and polarization are also the same. As a result, the new Plan is no more economically viable to implement than the old. To create economically viable BSS systems would most likely require modifications to the assignment in the Plan. Yet, modification procedures were made more difficult to apply after replanning. Less future implementation of BSS networks than would otherwise have occurred can be expected, and an inefficient usage of these frequency bands will likely result. On the other hand, less implemented systems will mean more capacity set aside for future use. This is important for countries that currently do not have satellite operations. In the end, BSS replanning reflects the eternal conflict between efficient usage and guaranteed future access. Copyright © 2005 John Wiley & Sons, Ltd. 相似文献