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51.
Pharmaceutical companies worldwide tend to apply chiral chromatographic separation techniques in their mass production strategy rather than asymmetric synthesis. The present work aims to investigate the predictability of chromatographic behavior of enantiomers using DryLab HPLC method development software, which is typically used to predict the effect of changing various chromatographic parameters on resolution in the reversed phase mode. Three different types of chiral stationary phases were tested for predictability: macrocyclic antibiotics‐based columns (Chirobiotic V and T), polysaccharide‐based chiral column (Chiralpak AD‐RH), and protein‐based chiral column (Ultron ES‐OVM). Preliminary basic runs were implemented, then exported to DryLab after peak tracking was accomplished. Prediction of the effect of % organic mobile phase on separation was possible for separations on Chirobiotic V for several probes: racemic propranolol with 97.80% accuracy; mixture of racemates of propranolol and terbutaline sulphate, as well as, racemates of propranolol and salbutamol sulphate with average 90.46% accuracy for the effect of percent organic mobile phase and average 98.39% for the effect of pH; and racemic warfarin with 93.45% accuracy for the effect of percent organic mobile phase and average 99.64% for the effect of pH. It can be concluded that Chirobiotic V reversed phase retention mechanism follows the solvophobic theory. Chirality 25:506–513, 2013. © 2013 Wiley Periodicals, Inc.  相似文献   
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Context: Urothelial carcinoma (UC) is common and highly recurrent. Diagnosis and follow-up involve invasive cystoscopies.

Objective: To evaluate H19 RNA in urine cells as diagnostic tool for UC.

Materials and methods: RT-PCR analysis of urine samples from healthy volunteers and UC patients.

Results: H19 RNA was unequivocally detected in the urine of 90.5% of patients and 25.9% of controls. H19 copies were three orders of magnitude higher in patients. Receiver operating characteristic analysis showed an area under the curve of 0.933.

Conclusions: This pilot study shows that urinary cell H19 is a highly sensitive test for UC and pending verification could transform patient management.  相似文献   

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Mutations in FBXL4 (F-Box and Leucine rich repeat protein 4), a nuclear-encoded mitochondrial protein with an unknown function, cause mitochondrial DNA depletion syndrome. We report two siblings, from consanguineous parents, harbouring a previously uncharacterized homozygous variant in FBXL4 (c.1750 T > C; p.Cys584Arg). Both patients presented with encephalomyopathy, lactic acidosis and cardiac hypertrophy, which are reported features of FBXL4 impairment. Remarkably, dichloroacetate (DCA) administration to the younger sibling improved metabolic acidosis and reversed cardiac hypertrophy. Characterization of FBXL4 patient fibroblasts revealed severe bioenergetic defects, mtDNA depletion, fragmentation of mitochondrial networks, and abnormalities in mtDNA nucleoids. These phenotypes, observed with other pathogenic FBXL4 variants, confirm the pathogenicity of the p.Cys584Arg variant. Although treating FBXL4 fibroblasts with DCA improved extracellular acidification, in line with reduced lactate levels in patients, DCA treatment did not improve any of the other mitochondrial functions. Nonetheless, we highlight DCA as a potentially effective drug for the management of elevated lactate and cardiomyopathy in patients with pathogenic FBXL4 variants. Finally, as the exact mechanism through which FBXL4 mutations lead to mtDNA depletion was unknown, we tested the hypothesis that FBXL4 promotes mitochondrial fusion. Using a photo-activatable GFP fusion assay, we found reduced mitochondrial fusion rates in cells harbouring a pathogenic FBXL4 variant. Meanwhile, overexpression of wildtype FBXL4, but not the p.Cys584Arg variant, promoted mitochondrial hyperfusion. Thus, we have uncovered a novel function for FBXL4 in promoting mitochondrial fusion, providing important mechanistic insights into the pathogenic mechanism underlying FBXL4 dysfunction.  相似文献   
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Sunitinib is a tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and gastrointestinal stromal tumors. In this study, two spectroscopic methods, spectrofluorometric and spectrophotometric, were utilized to quantify sunitinib in different matrices. In method I, the native fluorescence of erythrosine B was quenched by forming ion-pair complex with increasing quantities of sunitinib. This approach was utilized for measuring sunitinib in its dosage forms and spiked plasma. After excitation at 528 nm, the quenching of fluorescence is linearly related to the concentration across the range of 0.05–0.5 μg mL−1 at 550 nm in Britton–Robinson buffer (pH 4.0), with a correlation value of 0.9999 and a high level of sensitivity with detection limit down to 10 ng mL−1. Method II relies on spectrophotometric measurements of the produced complex at 550 nm across a range of 0.5–10.0 μg mL−1, with good correlation value of 0.9999. This method has a detection limit down to 0.16 μg mL−1. The proposed methodologies were validated according to International Conference on Harmonization (ICH) guidelines with satisfactory results. The stoichiometry of the reaction was determined through the application of Job's method, while the mechanism of quenching was investigated by employing the Stern–Volmer plot. The designated methods were used to estimate sunitinib in its capsules and in spiked human plasma. Additionally, the statistical analysis of the data revealed no substantial differences when compared to previous reported spectroscopic method. Green assessment tools provide further details about the eco-friendly nature of the methods.  相似文献   
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The present study describes a generic strategy using capillary electrophoretic (CE) method for chiral enantioseparation of anti‐Alzheimer drugs, namely, donepezil (DON), rivastigmine (RIV), and antifungal drugs, namely, ketoconazole (KET), Itraconazole (ITR), fluconazole (FLU), and sertaconazole (SRT) in which these drugs have different basic and acidic properties. Several modified cyclodextrins (CDs) were applied for enantioseparation of racemates such as highly sulfated α, γ CDs, hydroxyl propyl‐β‐CD, and Sulfobutyl ether‐β‐CD. The starting screening conditions consist of 50‐mM phosphate‐triethanolamine buffer at pH 2.5, an applied voltage of 15 kV, and a temperature of 25°C. The CE strategy implemented in the separation starts by screening prior to the optimization stage in which an experimental design is applied. The design of experiment (DOE) was based on a full factorial design of the crucial two factors (pH and %CD) at three levels, to make a total of nine (32) experiments with high, intermediate, and low values for both factors. Evaluation of the proposed strategy pointed out that best resolution was obtained at pH 2.5 for five racemates using low percentages of HS‐γ‐CD, while SBE‐β‐CD was the most successful chiral selector offering acceptable resolution for all the six racemates, with the best separation at low pH values and at higher %CD within 10‐min runtime. Regression study showed that the linear model shows a significant lack of fit for all chiral selectors, anticipating that higher orders of the factors are most likely to be present in the equation with possible interactions.  相似文献   
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Detection of exposure to biological threat agents has relied on ever more sensitive methods for pathogen identification, but that usually requires pathogen proliferation to dangerous, near untreatable levels. Recent events have demonstrated that assessing exposure to a biological threat agent well in advance of onset of illness or at various stages post-exposure is invaluable among the diagnostic options. There is an urgent need for better diagnostic tools that will be sensitive, rapid, and unambiguous. Since human clinical cases of illness induced by biothreat agents are, fortunately, rare, use of animal models that closely mimic the human illness is the only in vivo option. Such studies can be very difficult and expensive; therefore, maximizing the information obtained from in vitro exposures to peripheral blood mononuclear cells (PBMCs) provide an opportunity to investigate dose/time variability in host responses. In our quest to study staphylococcal enterotoxin B (SEB) induced host gene expression patterns, we addressed two core issues using microarray analysis and predictive modeling. Our first objective was to determine gene expression patterns in human PBMCs exposed to SEB in vitro. Second, we compared the in vitro data with host responses gene expression patterns in vivo using PBMCs from an animal model of SEB intoxication that closely replicates the progression of illness in humans. We used cDNA microarrays to study global gene expression patterns in piglets intoxicated with SEB. We applied a supervised learning method for class prediction based on the k-nearest neighbor algorithm for the data obtained in piglets exposed to SEB in vivo against a training data set. This data set included gene expression profiles derived from in vitro exposures to eight different pathogens (Bacillus anthracis, Yersinia pestis, Brucella melitensis, SEB, cholera toxin, Clostridium botulinum toxin A, Venezuelan equine encephalitis, and Dengue-2) in PBMCs. We found that despite differences in gene expression profiles between in vitro and in vivo systems, there exists a subset of genes that show correlations between in vitro and in vivo exposures, which can be used as a predictor of exposure to SEB in vivo.  相似文献   
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The present work aimed to investigate the predictability of the chromatographic behavior for the separation of underivatized amino acids on ristocetin A, known as Chirobiotic R, using a DryLab high‐performance liquid chromatography (HPLC) method development software, which is typically used to predict the effect of changing various chromatographic parameters on resolution in the reversed phase mode. After implementing the basic runs, and judging the predictability via the computed resolution map, it can be deduced that the chiral recognition mechanisms tend towards a hydrophilic interaction chromatography rather than the reversed phase mode, which limits the ability of DryLab software to predict separations on Chirobiotic R. Chirality 26:132–135, 2014. © 2014 Wiley Periodicals, Inc.  相似文献   
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