ADME Evaluation in Drug Discovery. 8. The Prediction of Human Intestinal Absorption by a Support Vector Machine

Human intestinal absorption (HIA) is an important roadblock in the formulation of new drug substances. In silico models for predicting the percentage of HIA based on calculated molecular descriptors are highly needed for the rapid estimation of this property. Here, we have studied the performance of a support vector machine (SVM) to classify compounds with high or low fractional absorption (%FA > 30% or %FA ≤ 30%). The analyzed data set consists of 578 structural diverse druglike molecules, which have been divided into a 480-molecule training set and a 98-molecule test set. Ten SVM classification models have been generated to investigate the impact of different individual molecular properties on %FA. Among these studied important molecule descriptors, topological polar surface area (TPSA) and predicted apparent octanol−water distribution coefficient at pH 6.5 (logD_(6.5)) show better classification performance than the others. To obtain the best SVM classifier, the influences of different kernel functions and different combinations of molecular descriptors were investigated using a rigorous training-validation procedure. The best SVM classifier can give satisfactory predictions for the training set (97.8% for the poor-absorption class and 94.5% for the good-absorption class). Moreover, 100% of the poor-absorption class and 97.8% of the good-absorption class in the external test set could be correctly classified. Finally, the influence of the size of the training set and the unbalanced nature of the data set have been studied. The analysis demonstrates that large data set is necessary for the stability of the classification models. Furthermore, the weights for the poor-absorption class and the good-absorption class should be properly balanced to generate unbiased classification models. Our work illustrates that SVMs used in combination with simple molecular descriptors can provide an extremely reliable assessment of intestinal absorption in an early in silico filtering process

Combined signature of N7-methylguanosine regulators with their related genes and the tumor microenvironment: a prognostic and therapeutic biomarker for breast cancer

BackgroundIdentifying predictive markers for breast cancer (BC) prognosis and immunotherapeutic responses remains challenging. Recent findings indicate that N7-methylguanosine (m7G) modification and the tumor microenvironment (TME) are critical for BC tumorigenesis and metastasis, suggesting that integrating m7G modifications and TME cell characteristics could improve the predictive accuracy for prognosis and immunotherapeutic responses.MethodsWe utilized bulk RNA-sequencing data from The Cancer Genome Atlas Breast Cancer Cohort and the GSE42568 and GSE146558 datasets to identify BC-specific m7G-modification regulators and associated genes. We used multiple m7G databases and RNA interference to validate the relationships between BC-specific m7G-modification regulators (METTL1 and WDR4) and related genes. Single-cell RNA-sequencing data from GSE176078 confirmed the association between m7G modifications and TME cells. We constructed an m7G-TME classifier, validated the results using an independent BC cohort (GSE20685; n = 327), investigated the clinical significance of BC-specific m7G-modifying regulators by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, and performed tissue-microarray assays on 192 BC samples.ResultsImmunohistochemistry and RT-qPCR results indicated that METTL1 and WDR4 overexpression in BC correlated with poor patient prognosis. Moreover, single-cell analysis revealed relationships between m7G modification and TME cells, indicating their potential as indicators of BC prognosis and treatment responses. The m7G-TME classifier enabled patient subgrouping and revealed significantly better survival and treatment responses in the m7Glow+TMEhigh group. Significant differences in tumor biological functions and immunophenotypes occurred among the different subgroups.ConclusionsThe m7G-TME classifier offers a promising tool for predicting prognosis and immunotherapeutic responses in BC, which could support personalized therapeutic strategies

Fully Proprioceptive Slip-Velocity-Aware State Estimation for Mobile Robots via Invariant Kalman Filtering and Disturbance Observer

This paper develops a novel slip estimator using the invariant observer design theory and Disturbance Observer (DOB). The proposed state estimator for mobile robots is fully proprioceptive and combines data from an inertial measurement unit and body velocity within a Right Invariant Extended Kalman Filter (RI-EKF). By embedding the slip velocity into $\mathrm{SE}_3(3)$ Lie group, the developed DOB-based RI-EKF provides real-time accurate velocity and slip velocity estimates on different terrains. Experimental results using a Husky wheeled robot confirm the mathematical derivations and show better performance than a standard RI-EKF baseline. Open source software is available for download and reproducing the presented results.Comment: github repository at https://github.com/UMich-CURLY/slip_detection_DOB. arXiv admin note: text overlap with arXiv:1805.10410 by other author

Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. © 2011 Elsevier Ltd. All rights reserved

mainstreaming teaching methods for disabled children in china : a quantitative study

In this essay, in order to learn about the parents' and teacher' attitudes towards mainstreamig teaching methods in china, the authors used a sample from a middle school in Chengdu

The complete mitochondrial genome of Lucilia shenyangensis (Diptera: Calliphoridae)

Lucilia shenyangensis Fan, 1965 (Diptera: Calliphoridae) is of potential importance in epidemiology, veterinary medicine, and forensic entomology due to their necrophilous habit and behaviors associated with mammals. In this study, we report the complete mitochondrial genome (mitogenome) of L. shenyangensis. The mitogenome is 14,989 bp in length, comprising 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and a non-coding control region. The arrangement of genes is identical to that of the ancestral metazoan. Nucleotide composition revealed a high A/T bias, accounting for 76.50% total mitogenome nucleotides (A 39.2%, G 9.6%, C 14.0%, T 37.3%). Phylogenetic analysis indicated that L. shenyangensis was clear separated from other blow flies and emerged as the sister lineage to the rest species from genus Lucilia (L. illustris, L. sericata, L. coeruleiviridis, and L. porphyrina). The mitogenome data of L. shenyangensis could facilitate further evolutionary genetic researches on blow flies

Research on blended learning mode based on STEAM

With the continuous development of science and technology, how to integrate modern information technology with STEAM has become the direction of scholars’ exploration. Based on the STEAM education concept and relying on the Learning-through-education cloud platform, this study combines online and offline learning to build a STEAM based blended learning mode. Taking the unit of “Hot Air and Cold Air” of primary school science as a case, specific teaching activities are designed to explore the implementation scheme of this learning mode. The research conclusion is that the implementation of STEAM based blended learning mode can significantly improve students’ classroom participation, and cultivate students’ interdisciplinary knowledge integration ability, problem solving ability and independent learning ability

Mapping the Shifting Focus in Remote Sensing Literature: Technology, Methodology, and Applications

This paper characterizes the body of knowledge on remote sensing from 1999 to 2021 by employing bibliometric techniques based on the Science Citation Index databases and the Social Science Citation Index of the Web of Science, abbreviated to “SCI” and “SSCI”, respectively. A total of 28,438 articles were analyzed from various aspects of the publication characteristics, such as countries, institutes, subjects, journals, and keywords. Dynamic changes in published remote sensing research were examined by segregating the 19-year period into 4 stages. Co-occurrences of keywords from three aspects were evaluated, including technology, methodology, and applications. Results show that “hyperspectral remote sensing”, “classification”, “monitoring” and “MODIS” in the category of technology have emerged more frequently in recent years, and there are strong co-occurrences of “remote sensing” and “GIS” in the remote sensing technology category. In addition, there was a marked shift from traditional analytical methods (i.e., geostatistics and neural networks) to a variety of emerging methods, such as support vector machines, random forests, and feature extraction. Moreover, research hotspots are identified for remote sensing applications, which have expanded significantly with improvements in technology and methodology. In particular, “water quality”, “climate change”, and “urbanization” have become popular themes in recent years. Finally, future directions of remote sensing are identified, which would be beneficial for researchers and policy makers

A Universal Multi-Frequency Micro-Resistivity Array Imaging Method for Subsurface Sensing

In this paper, a universal multi–frequency micro-resistivity array imaging (UMMAI) system for subsurface sensing is developed and verified. Different from conventional micro-resistivity imaging equipments, UMMAI is capable to provide high-resolution fullbore formation images in multiple logging environments including an oil-based mud scene, water-based mud scene and water-oil mixed mud scene, owning to the large dynamic range and good linearity of transceivers. With the advantage of diversity in excitation signal frequency, UMMAI presents abundant amplitude–frequency characteristics response images and phase–frequency characteristics response images of subsurface formations at the same time, which is beneficial to multi–frequency image fusion in the future. The fullbore imaging ability of UMMAI is evaluated in three different field tests, and the results show that UMMAI can give satisfactory credible formation images with high resolution, which is suitable for subsurface formation discrimination and useful for reservoir identification