Towards the Desirable Decision Boundary by Moderate-Margin Adversarial Training

Adversarial training, as one of the most effective defense methods against adversarial attacks, tends to learn an inclusive decision boundary to increase the robustness of deep learning models. However, due to the large and unnecessary increase in the margin along adversarial directions, adversarial training causes heavy cross-over between natural examples and adversarial examples, which is not conducive to balancing the trade-off between robustness and natural accuracy. In this paper, we propose a novel adversarial training scheme to achieve a better trade-off between robustness and natural accuracy. It aims to learn a moderate-inclusive decision boundary, which means that the margins of natural examples under the decision boundary are moderate. We call this scheme Moderate-Margin Adversarial Training (MMAT), which generates finer-grained adversarial examples to mitigate the cross-over problem. We also take advantage of logits from a teacher model that has been well-trained to guide the learning of our model. Finally, MMAT achieves high natural accuracy and robustness under both black-box and white-box attacks. On SVHN, for example, state-of-the-art robustness and natural accuracy are achieved

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

The aim of this study is to investigate the effects of CYP3A4 genetic polymorphisms on the metabolism of cyclosporine (CsA) in vitro and identify drugs that interact with CsA. An enzymatic incubation system was developed to evaluate the kinetic parameters of CYP3A4 on CsA catalysis. A total of 132 drugs were screened to identify potential drug–drug interactions. Sprague–Dawley rats were used to determine the interaction between CsA and nimodipine and nisoldipine. The metabolite AM1 was measured by ultra-performance liquid chromatography–tandem mass spectrometry. The results demonstrate that 16 CYP3A4 variants (CYP3A4.7, 8, 9, 12, 13, 14, 16, 18, 19, 23, 24, 28, 31, 32, 33, and 34) have a lower metabolic capacity for CsA, ranging from 7.19% to 72.10%, than CYP3A4.1. In contrast, the relative clearance rate of CYP3A4.5 is significantly higher than that of CYP3A4.1. Moreover, CYP3A4.20 loses its catalytic ability, and five other variants have no significant difference. A total of 12 drugs, especially calcium channel blockers, were found to remarkably inhibit the metabolism of CsA with an inhibitory rate of over 80%. Nimodipine inhibits the activity of CsA in rat liver microsomes with an IC50 of 20.54 ± 0.93 μM, while nisoldipine has an IC50 of 16.16 ± 0.78 μM. In in vivo, three groups of Sprague–Dawley rats were administered CsA with or without nimodipine or nisoldipine; the AUC(0-t) and AUC(0-∞) of CsA were significantly increased in the nimodipine group but not obviously in the nisoldipine group. Mechanistically, the inhibition mode of nimodipine on cyclosporine metabolism is a mixed inhibition. Our data show that gene polymorphisms of CYP3A4 and nimodipine remarkably affect the metabolism of CsA, thus providing a reference for the precise administration of CsA

Simultaneous determination of cortisone and cortisol in serum by HPLC-DAD and application for pharmacokinetics

To develop a high performance liquid chromatography method for the simultaneous determination of cortisone and cortisol in rat serum and apply it for pharmacokinetics. After addition of pirfenidone as internal standard (IS), a liquid-liquid extraction with ethylacetate was employed for the sample preparation. Samples were separated on Zorbax SB-C18 column at 25 ºC using mobile phase consisting of acetonitrile-water-0.1 % trifluoroacetic acid with flow rate of 0.9 mL/min, utilizing DAD detection at 246 nm. Excellent liner relationships of the cortisone and cortisol concentrations were obtained from 50 to 6000 ng/mL, with r = 0.9997, 0.9999 respectively, and the lower limit of quantitation (LLOQ) were both 50 ng/mL. The developed method was successfully applied to pharmacokinetic studies of cortisone and cortisol in rats following single dose of 20 mg/kg via intraperitoneal injection.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Far from just a poke : Common painful needle procedures and the development of needle fear

Background: Vaccine injections are the most common painful needle procedure experienced throughout the lifespan. Many strategies are available to mitigate this pain; however, they are uncommonly utilized, leading to unnecessary pain and suffering. Some individuals develop a high level of fear and subsequent needle procedures are associated with significant distress. Objective: The present work is part of an update and expansion of a 2009 knowledge synthesis to include the management of vaccinerelated pain across the lifespan and the treatment of individuals with high levels of needle fear. This article will provide a conceptual foundation for understanding: (a) painful procedures and their role in the development and maintenance of high levels of fear; (b) treatment strategies for preventing or reducing the experience of pain and the development of fear; and (c) interventions for mitigating high levels of fear once they are established. Results: First, the general definitions, lifespan development and functionality, needle procedure-related considerations, and assessment of the following constructs are provided: pain, fear, anxiety, phobia, distress, and vasovagal syncope. Second, the importance of unmitigated pain from needle procedures is highlighted from a developmental perspective. Third, the prevalence, course, etiology, and consequences of high levels of needle fear are described. Finally, the management of needle-related pain and fear are outlined to provide an introduction to the series of systematic reviews in this issue. Discussion: Through the body of work in this supplement, the authors aim to provide guidance in how to treat vaccination-related pain and its sequelae, including high levels of needle fear

Automatic Extraction of Power Lines from Aerial Images of Unmanned Aerial Vehicles

Automatic power line extraction from aerial images of unmanned aerial vehicles is one of the key technologies of power line inspection. However, the faint power line targets and complex image backgrounds make the extraction of power lines a greater challenge. In this paper, a new power line extraction method is proposed, which has two innovative points. Innovation point one, based on the introduction of the Mask RCNN network algorithm, proposes a block extraction strategy to realize the preliminary extraction of power lines with the idea of “part first and then the whole”. This strategy globally reduces the anchor frame size, increases the proportion of power lines in the feature map, and reduces the accuracy degradation caused by the original negative anchor frames being misclassified as positive anchor frames. Innovation point two, the proposed connected domain group fitting algorithm solves the problem of broken and mis-extracted power lines even after the initial extraction and solves the problem of incomplete extraction of power lines by background texture interference. Through experiments on 60 images covering different complex image backgrounds, the performance of the proposed method far exceeds that of commonly used methods such as LSD, Yolact++, and Mask RCNN. DSCPL, TPR, precision, and accuracy are as high as 73.95, 81.75, 69.28, and 99.15, respectively, while FDR is only 30.72. The experimental results show that the proposed algorithm has good performance and can accomplish the task of power line extraction under complex image backgrounds. The algorithm in this paper solves the main problems of power line extraction and proves the feasibility of the algorithm in other scenarios. In the future, the dataset will be expanded to improve the performance of the algorithm in different scenarios

A Decision-Making Model Using Machine Learning for Improving Dispatching Efficiency in Chengdu Shuangliu Airport

Due to the increasing number of people traveling by air, the passenger flow at the airport is increasing, and the problem of passenger drop-off and pickup has a huge impact on urban traffic. The difficulty of taking a taxi at the airport is still a hot issue in the society. Aiming at the problem of optimizing the allocation of taxi resource, this paper is based on the cost-benefit analysis method to determine the factors that affect the taxi driver’s decision-making. The mathematical methods such as function equation, BP neural network algorithm, and queuing theory were used to establish a complete decision-making model for taxi drivers and an optimization model of dispatching efficiency at the airport. A conclusion has been drawn that the allocation of airport taxi resource should be arranged closely related to drivers’ revenue and the layout of airport line

The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism

This study aimed to investigate the interactions between icotinib/apatinib and oxycodone in rats and to unveil the underlying mechanism. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine oxycodone and its demethylated metabolite simultaneously. In vivo, Sprague–Dawley (SD) male rats were administered oxycodone with or without icotinib or apatinib. Blood samples were collected and subjected to UPLC-MS/MS analysis. An enzyme incubation assay was performed to investigate the mechanism of drug–drug interaction using both rat and human liver microsomes (RLM and HLM). The results showed that icotinib markedly increased the AUC(0–t) and AUC(0–∞) of oxycodone but decreased the CLz/F. The Cmax of oxycodone increased significantly upon co-administration of apatinib. In vitro, the Km value of oxycodone metabolism was 101.7 ± 5.40 μM and 529.6 ± 19.60 μM in RLMs and HLMs, respectively. Icotinib and apatinib inhibited the disposition of oxycodone, with a mixed mechanism in RLM (IC50 = 3.29 ± 0.090 μM and 0.95 ± 0.88 μM, respectively) and a competitive and mixed mechanism in HLM (IC50 = 22.34 ± 0.81 μM and 0.48 ± 0.05 μM, respectively). In conclusion, both icotinib and apatinib inhibit the metabolism of oxycodone in vitro and in vivo. Therefore, the dose of oxycodone should be reconsidered when co-administered with icotinib or apatinib

Differential roles of abscisic acid in maize roots in the adaptation to soil drought

Abstract Maize yield reduction occurs frequently due to soil drought. Abscisic acid (ABA) is an important hormonal signal indicating drought. However, it remains unclear about the specific roles of root ABA in the adaptation to soil drought in maize. This study applied five different soil water potentials (SWP), referring to maintaining SWP at −15, −30, −45, −60, and −75 kPa, respectively, and investigated the ABA content in roots and the activities and gene expression levels of key enzymes involved in the ABA biosynthesis, the leaf photosynthetic properties, root traits, and kernel yield. The results showed that maize root ABA content, the activities and gene expressions of key enzymes involved in the ABA biosynthesis were increased with the decrease of SWP. The leaf transpiration rate, and root dry weight, length, volume, surface area, and activity, and kernel yield of maize were increased first and then decreased with the severity of soil drying. The leaf photosynthetic rate was not significantly reduced with ABA accumulation at a low ABA content in roots. Root ABA content was significantly positively correlated with leaf transpiration efficiency and root activity when ABA content was relatively low (9.03–22.02 nmol g−1 DW), whereas root ABA content was negatively correlated with leaf photosynthetic rate, leaf transpiration efficiency, root volume, and root activity when ABA content was high (28.32–39.23 nmol g−1 DW). The results indicate that maize root ABA exhibit differential roles in the adaptation to soil drought, and can positively regulate the drought‐resistance of maize at an appropriate level

Influences of Corydalis decumbens on the Activities of CYP450 Enzymes in Rats with a Cocktail Approach

Corydalis decumbens, a Traditional Chinese Medicine, has been widely used for the alternative and/or complementary therapy of hypertension, arrhythmias rheumatoid arthritis, sciatica, stroke, hemiplegia, paraplegia, and vascular embolism. The aim of this study was to determinate the potential effects of Corydalis decumbens on the five cytochrome P450 (CYP) enzyme activities (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6) by cocktail approach. To evaluate whether concurrent use of Corydalis decumbens interferes with the effect of several prescription drugs, saline (control group) or Corydalis decumbens (XTW group) were administrated via gavage for 7 successive days. A probe cocktail solution (phenacetin, omeprazole, metoprolol, tolbutamide, and midazolam) was given 24 h after the last dose of saline or Corydalis decumbens. A specific and sensitive UHPLC–MS/MS method was validated for the determination of five substrates and their metabolites in control group and XTW group. Our results indicated that Corydalis decumbens could have inductive effects of CYP2C19 and inhibit the activities of CYP1A2 and CYP3A4. However, Corydalis decumbens had no significant influence on CYP2C9 and CYP2D6. The herb-drug interaction should require more attention by careful monitoring and appropriate drug dosing adjustments to the concurrent use of western medications which were metabolized by CYP1A2, CYP2C19, and CYP3A4 in human—Corydalis decumbens, Cytochrome P450, Cocktail, Pharmacokinetics, herb–drug interactions

Cyy-287, a novel pyrimidine-2,4-diamine derivative, efficiently mitigates inflammatory responses, fibrosis, and lipid synthesis in obesity-induced cardiac and hepatic dysfunction

Background Inflammation and metabolic disorders are important factors in the occurrence and development of obesity complications. In this study, we investigated the protective effect and underlying mechanism of a novel pyrimidine-2,4-diamine derivative, Cyy-287, on mice fed a high-fat diet (HFD). Methods The mice were randomly separated into four groups (n ≥ 7): control (regular diet), HFD, HFD with Cyy-287 (5 mg/kg), and HFD with Cyy-287 (20 mg/kg) following HFD feeding for 10 weeks. After a 10-week administration, ALT and AST enzymes, echocardiography, immunohistochemical (IHC), Western blot (WB), Masson and Sirius Red staining were used to evaluate functional and morphological changes to the heart and liver. Microsomes from the mouse liver were extracted to quantify the total amount of CYP450 enzymes after drug treatment. Results Cyy-287 decreased the levels of serum glucose, LDL, TC, ALT, and AST activities in HFD-treated mice. However, Cyy-287 administration increased ejection fraction (EF) and fractional shortening (FS) index of the heart. Cyy-287 inhibited histopathological changes in the heart and liver; decreased inflammatory activity; significantly diminished p38 mitogen-activated protein kinase (MAPK), the nuclear factor-kappa B (NF-κB) axis, and sterol regulatory element-binding protein-1c (SREBP-1c); and upregulated the AMP-activated protein kinase (AMPK) pathway in HFD-treated mice. Cyy-287 restored the content of hepatic CYP450 enzymes. Conclusion These findings demonstrated that Cyy-287 protected heart and liver cells from obesity-induced damage by inhibiting inflammation, fibrosis, and lipid synthesis