Absorption of drugs is the first step after dosing, and it largely affects drug bioavailability. Hence, estimating the fraction of absorption (Fa) in humans is important in the early stages of drug discovery. To achieve correct exclusion of low Fa compounds and retention of potential compounds, we developed a freely available model to classify compounds into 3 levels of Fa capacity using only the chemical structure. To improve Fa prediction, we added predicted binary classification results of membrane permeability measured using Caco-2 cell line (Papp) and dried–dimethyl sulfoxide solubility (accuracy, 0.836; kappa, 0.560). The constructed models can be accessed via a web application. 相似文献
Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.
Here, our aim was to study the interaction between BChE and fluoxetine.
Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the Vm, Km, kcat and kcat/Km values were found to be 20.59?±?0.36?U mg?1 protein, 194?±?14?µM, 1.3?×?108?s?1 and 6.7?×?105?µM?1s?1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC50 value of 104?µM and a Ki value of 36.3?±?4.7?µM.
Overall, both the low Ki value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.
ObjectiveDescribe the risk of poverty and social exclusion in children aged 8-11 years from Gipuzkoa and Valencia (Spain), through AROPE (At Risk Of Poverty or Social Exclusion) indicators, and evaluate their associated factors in the INMA Project (Childhood and Environment).MethodFamilies in Gipuzkoa and Valencia (394 and 382, respectively) completed a questionnaire in 2015-2016. Low work intensity (LWI), at risk of poverty (RP) and material deprivation (MD) were estimated. AROPE consisted in meeting any of the previous sub-indicators. Socio-demographic, family and parental characteristics were considered. Frequencies, Venn's diagrams, and chi-square and Fisher tests were used in bivariate analysis and logistic regression in multivariate analysis.ResultsFor LWI, RP, MD and AROPE, prevalence of 2.5%, 5.6%, 2.3% and 7.2% were obtained in Gipuzkoa, and 8.1%, 31.5%, 7.8% and 34.7% in Valencia, respectively. In the multivariate analysis, the AROPE was associated in both areas with maternal social class and non-nuclear families. In Gipuzkoa, it was also related to maternal education. In Valencia, other factors were the mother's foreign origin, and paternal education and smoking.ConclusionThere is higher AROPE prevalence in Valencia. Social class and family type were shared factors, but a differential pattern is observed in other social determinants. It is essential to implement social policies to reduce this axis of inequalities in health, especially in childhood. 相似文献
BackgroundMeasuring dynamic vertical ground reaction force allows for assessment of important clinical and physical capacity factors such as weight bearing asymmetry, force distribution, and rate of force development. However, current technologies for accurately assessing ground reaction force are typically expensive.Research QuestionThe aim of this study was to examine the validity and reliability of obtaining static and dynamic ground reaction force data from low-cost modified digital bathroom scales.MethodsFour modified bathroom scales, two units each of two different brands, were examined. Repeated mechanical loading trials were performed with known loads ranging from 0.01 to 65 kg, with acquired data compared against the known loading to calculate accuracy, hysteresis, and non-linearity. Dynamic trials consisting of 5 times sit-to-stand and weight-shifting were performed by 32 adults. Absolute and relative agreement intraclass correlation coefficient, and Pearson’s and Spearman’s correlations were performed to determine validity and reliability for the mechanical tests. Bland-Altmann plots were created for each comparison. Mean absolute error (MAE) and unbiased cross-correlation were performed on the dynamic data, comparing the calibrated data to the known values from a Bertec force platform.ResultsHysteresis and non-linearity were excellent (<0.2 % full-scale), and mechanical test results showed excellent reliability and validity. Cross-correlation results for the dynamic data were excellent, however MAE for the more rapid sit-to-stand task was higher than the slower weight-shifting test. This may have been due to the low default sampling rate for the lowest noise setting of the HX711 amplifier (10 Hz).SignificanceIn summary, our results suggest that digital bathroom scales can be easily and inexpensively modified to obtain accurate vertical ground reaction force data, with sensitivity to detect changes of as little as 0.01 kg. 相似文献
Introduction: It is now clear that circulating cell-free ribonucleic acids (ccfRNAs), including messenger RNA (mRNA) and miRNA, are potential cancer biomarkers. As ccfmiRNA is relatively more stable than ccfmRNA, research should concentrate on developing novel methods to preserve the stability of ccfmRNA and standardization of the protocol which includes extraction, detection, and multicenter validation.
Areas covered: This literature review concentrates on the potential of ccfRNA being used as a biomarker in cancer, with special focus on mRNAs and microRNAs (miRNAs).
Expert opinion: With the advancement of high-throughput technologies such as RNA sequencing, a panel of biomarkers will be used for the diagnosis, prognosis and therapeutic monitoring of cancer patients. In order to achieve this important target, bioinformatics education to pathologists, scientists, and technologists in molecular diagnostic laboratories is essential. Moreover, the panel of these new ccfRNAs biomarkers has to obtain approval or clearance from an authority such as the US Food and Drug Administration (FDA), and the standard of utilizing these new protocols has to be recognized via accreditation exercise. Therefore, there is still a long way to go before an extensively use of ccfRNA biomarkers in cancer patients can be realized. 相似文献