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排序方式: 共有304条查询结果,搜索用时 15 毫秒
1.
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
2.
The architecture of normal colonic mucosa suggest that terminally differentiated epithelial cells near the top of the crypt are extruded into the colonic lumen. Morphological studies have identified apoptotic cells among the differentiated phenotypes near the crypt-lumen interface, suggesting a link between pathways of differentiation, apoptosis, and cellular shedding. We studied these processes in HT29 and SW620 cells and found that compared to adherent cells, those cells which were shed during standard, uninduced culture conditions exhibited nonrandom DNA fragmentation characteristic of apoptosis. Moreover, these apoptotic cells, which accumulate in the media, exhibited a more differentiated phenotype. Because short-chain fatty acids (SCFAs) are natural effectors of colonic cell differentiation in vivo, we investigated the specificity of three 4-carbon atom SCFAs on potentiating differentiation and apoptosis, and thus accumulation of shed cells in the conditioned media, in these colonic carcinoma cell lines. Whereas the unbranched SCFA butyrate induced a more differentiated phenotype and enhanced apoptosis, two derivatives of butyrate, branched isobutyric acid and a nonmetabolizable fluorine-substituted analogue, heptafluorobutyric acid, were ineffective in inducing either differentiation or apoptosis. Thus, potentiated differentiation and apoptosis in colonic carcinoma cells were linked to SCFA structure and, most likely, utilization. 相似文献
3.
Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors
M Rubinger DS Houston N Schwetz DM Woloschuk SJ Israels JB Johnston 《Canadian Metallurgical Quarterly》1997,56(2):112-118
Increased detection thresholds for pure tones were observed in a large cohort of children exposed to lead environmentally while smaller studies in lead-exposed workers have reported conflicting results on assessments of auditory function. Pure tone detection thresholds were determined in a group of monkeys (Macaca fascicularis) dosed with 2 mg/kg/day of lead from birth through testing at 13 years of age. Blood lead concentrations were stable at about 30 micrograms/dl until monkeys were 10-11 years of age at which time they increased to between 50 and 70 micrograms/dl. Five age- and rearing-matched monkeys served as controls. Detection thresholds were determined at six frequencies between 0.125 and 31.5 kHz. Ear phones were fit over both ears, and thresholds were determined for each ear separately. The monkey signaled detection of the tone by breaking contact with a stainless steel bar. Three lead-exposed monkeys exhibited normal pure tone detection functions. Three monkeys had thresholds outside of the control range at some frequencies; there was a tendency for higher frequencies to be differentially more affected. These findings are consistent with reports of elevated pure tone thresholds in humans exposed to lead developmentally, although the effect is smaller than might have been predicted given the concurrent blood lead concentrations of these monkeys. 相似文献
4.
Tan W.S. Uren M.J. Houston P.A. Green R.T. Balmer R.S. Martin T. 《Electron Device Letters, IEEE》2006,27(1):1-3
A novel guarded surface leakage test structure is used to isolate the surface and bulk leakage contributions to gate current in AlGaN/GaN HFETs. Passivation with various recipes of SiN/sub x/ always resulted in the commonly observed increase in gate leakage, which was found to be dominated by bulk leakage through the AlGaN. However, high temperature deposited SiN/sub x/ recipes gave a 1-2 orders reduction in surface leakage, whereas low temperature deposition gave an increase. Gate lag measurements were found to correlate closely with the surface leakage component, giving direct evidence that the key device problem of current slump is associated with current flow at the AlGaN surface. 相似文献
5.
Glass GA Dymnikov AD Rout B Dias JF Houston LM LeBlanc J 《The Review of scientific instruments》2008,79(3):036102
A high energy focused ion beam microprobe using a doublet arrangement of short magnetic quadrupole lenses was used to focus 1-3 MeV protons to spot sizes of 1x1 microm2 and 1-4.5 MeV carbon and silicon ion beams to spot sizes of 1.5x1.5 microm2. The results presented clearly demonstrate that this simple doublet configuration can provide high energy microbeams for microanalysis and microfabrication applications. 相似文献
6.
A high-accuracy cryogenic radiometer has been developed at the National Institute of Standards and Technology to serve as a primary standard for optical power measurements. This instrument is an electrical-substitution radiometer that can be operated at cryogenic temperatures to achieve a relative standard uncertainty of 0.021% at an optical power level of 0.8 mW. The construction and operation of the high-accuracy cryogenic radiometer and the uncertainties in optical power measurements are detailed. 相似文献
7.
8.
A new method for evaluating antiarrhythmic drug efficacy 总被引:1,自引:0,他引:1
M Sami H Kraemer DC Harrison N Houston C Shimasaki RF DeBusk 《Canadian Metallurgical Quarterly》1980,62(6):1172-1179
To develop standards for distinguishing antiarrhythmic drug effect from spontaneous variability of premature ventricular complexes (PVCs), 21 males (mean age 56 +/- 8 years) with chronic ischemic heart disease and PVCs underwent symptom-limited treadmill exercise testing and 24-hour ambulatory monitoring before and after 2 weeks of placebo medication. Linear regression analysis was used to describe the relationship between baseline and placebo PVC frequency for various indexes of ventricular ectopic activity and to establish 95% and 99% one-tailed confidence intervals for this relationship within the group of 21 patients. The lower limit of baseline PVC frequency for which the procedure could distinguish a placebo from a true drug response, termed the "sensitivity threshold," was an average frequency of 2.2 PVCs/hour for ambulatory electrocardiographic monitoring and 1.2 PVCs/min for treadmill exercise testing. All patients exceeded the sensitivity threshold on baseline ambulatory ECGs, but only 38% of patients did so on baseline treadmill exercise tests. To establish antiarrhythmic efficacy with 95% confidence, the minimal percent reduction of PVCs between baseline and placebo visits was 68% for treadmill exercise testing and 65% for ambulatory electrocardiography. Although these standards were developed in patients with chronic ischemic heart disease, the model can be used to establish antiarrhythmic drug efficacy in any patient group. 相似文献
9.
Molecular design of interfacial layers based on conjugated polythiophenes for polymer and hybrid solar cells 下载免费PDF全文
Judith E Houston Sébastien Richeter Sébastien Clément Rachel C Evans 《Polymer International》2017,66(10):1333-1348
In the past two decades, bulk heterojunction organic photovoltaic (OPV) devices have emerged as attractive candidates for solar energy conversion due to their lightweight design and potential for low‐cost, high‐throughput, solution‐phase processability. Interfacial engineering is a proven efficient approach to achieve OPV devices with high power conversion efficiencies. This mini‐review provides an overview of the key structural considerations necessary when undertaking the molecular design of conjugated polyelectrolytes, for application as interfacial layers (ILs). The different roles of ILs are outlined, together with the advantages and disadvantages of competing classes of IL materials. Particular emphasis is placed on the design and synthesis of water‐soluble polythiophene‐based IL materials and the influence of their structural characteristics on their performance as a promising class of IL material. Finally, the challenges and opportunities for polythiophenes as IL materials for OPV devices and other solution‐processed solar cell technologies (e.g. perovskite solar cells) are discussed. © 2017 Society of Chemical Industry 相似文献
10.
Jasdeep S. Gill Vasileios Theofylaktopoulos Andreas Mitsios Sarah Houston Ahmed M. Hagag Adam M. Dubis Mariya Moosajee 《International journal of molecular sciences》2022,23(8)
Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 μm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint. 相似文献