DNA依赖蛋白激酶抑制剂的CoMFA研究

运用比较分子力场分析方法(CoMFA),以DNA依赖蛋白激酶(DNA-PK)抑制剂分子为研究对象,建立1组对DNA依赖蛋白激酶有抑制活性化合物的三维定量构效关系(3D-QSAR)模型,探索其活性数据和三维结构参数的关系,所建最佳模型交叉验证相关系数q2=0.670,非交叉验证相关系数R2=0.993,标准偏差SD=0.053,说明该模型预测能力较好.根据CoMFA模型的三维等势图可知,小体积、电负性大的取代基团,能提高该类化合物的活性,为新型DNA-PK抑制剂分子的设计提供了理论依据.     

基于遗传算法的黄酮类化合物对PTKs抑制性的QSAR研究

用文献设定的结构参数和本文设定的结构参数,分别与由HyperChem7.5Student Evaluation计算得到的量化参数作为自变量构成2组数据,以逐步回归,遗传算法-偏最小二乘法(GA-PLS)和遗传算法-支持向量机(GA-SVM)等算法就黄酮类化合物对PTKs抑制性进行QSAR研究。用各算法模型处理数据,由本文设定的结构参数构成的数据集获得的预测结果更好,表明采用取代基团类型和取代位置结合的编码参数包含的信息更为丰富,对物质性质的描述更加合理。在各种算法中, GA-SVM模型均具有最佳预测效果,该算法对2组数据作留一法预测处理得到的相关系数R和PTKs抑制性实验值与预测值的平均绝对误差MAE分别为0.7595,0.2871和0.7864,0.2883。研究还表明,GA-PLS和GA-SVM联用算法的预测效果远高于单独使用的PLS和SVM算法;由逐步回归建立的MLR模型对2组数据进行计算处理,尽管拟合时相关系数R分别达到0.8136和0.8250,但作留一法交互验证时却下降到0.7113和0.7354,明显低于GA-PLS和GA-SVM联用算法。     

Pharmacophore modeling,virtual screening,docking and in silico ADMET analysis of protein kinase B (PKB β) inhibitors

Protein kinase B (PKB) is a key mediator of proliferation and survival pathways that are critical for cancer growth. Therefore, inhibitors of PKB are useful agents for the treatment of cancer. Herein, we describe pharmacophore-based virtual screening combined with docking study as a rational strategy for identification of novel hits or leads. Pharmacophore models of PKB β inhibitors were established using the DISCOtech and refined with GASP from compounds with IC₅₀ values ranging from 2.2 to 246 nM. The best pharmacophore model consists of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) site and two hydrophobic (HY) features. The pharmacophore models were validated through receiver operating characteristic (ROC) and Güner-Henry (GH) scoring methods indicated that the model-3 was statistically valuable and reliable in identifying PKB β inhibitors. Pharmacophore model as a 3D search query was searched against NCI database. Several compounds with different structures (scaffolds) were retrieved as hits. Molecules with a Q_fit value of more than 95 and three other known inhibitors were docked in the active site of PKB to further explore the binding mode of these compounds. Finally in silico pharmacokinetic and toxicities were predicted for active hit molecules. The hits reported here showed good potential to be PKB β inhibitors.     

Bees algorithm for design of dual‐beam linear antenna arrays with digital attenuators and digital phase shifters

This article describes a method of designing a reconfigurable dual‐beam linear antenna array using bees algorithm (BA). The BA is an optimization algorithm inspired by the behavior of the honey bees to find the optimal way of harvesting food resources around the hive. The proposed method is very simple and can be used directly in practice to synthesize multiple beam antenna arrays with digital attenuators and digital phase shifters. A good agreement between the desired pattern and the synthesized pattern using BA is obtained. © 2008 Wiley Periodicals, Inc. Int J RF and Microwave CAE, 2008.     

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

A three-dimensional (3D) pharmacophore modelling approach was applied to a diverse data set of known cyclin-dependent kinase 9 (CDK9) inhibitors. Diversity sampling and principal components analysis (PCA) were employed to ensure the rational selection of representative training sets. Twelve statistically robust pharmacophore models were generated using the HypoGen algorithm. The resulting models showed high homology and indicated great convergence in ascertaining pharmacophoric features essential for CDK9 inhibitory activity. One of the best models (Hypo 6) was assessed further by external predictive capability, randomization test, as well as its performance in virtual screening. The capability of the resulting models to reliably predict the inhibitory activity of external data sets and discriminate active structures from general databases would assist the identification and optimization of novel CDK9 inhibitors.     

Reconfigurable systolic arrays with fixed size and structure degradation

Reconfiguration algorithms are proposed for VLSI systolic arrays constructed from identical self-testing processors. The properties of fault-tolerant arrays with fixed size and structure degradation are considered.Translated from Kibernetika i Sistemnyi Analiz, No. 4, pp. 153–162, July–August, 1992.     

Querying datalog with arrays: Design and implementation issues

This paper deals with the implementation of logic queries where array structures are manipulated. Both top-down and bottom-up implementations of the presented logic language, called Datalog ^A , are considered. Indeed, SLD-resolution is generalized to realize Datalog ^A top-down query answering. Further, a fixpoint based evaluation of Datalog ^A queries is introduced, which forms the basis for efficient bottom-up implementation of queries obtained by generalizing rewriting techniques such as magic set method to the case of Datalog ^A programs.Work partially supported by a European Union grant under the EC-US project DEUS EX MACHINA: nondeterminism for deductive databases and by a MURST grant (40% share) under the project Sistemi formali e strumenti per basi di dati evolute.     

非线性折射和反射平面场景的实时光线跟踪

该文利用光学映射虚对象的概念，提出了实时计算平面折射虚物体的新方法，给出了在不同情况下实时计算平面折射虚顶点的计算公式，实现了基于三维图形硬件（加速卡）加速的实时光线跟踪算法。该算法能够处理非线性平面折射和反射问题，极大地提高了真实感图形绘制和显示的速度。这对于建筑物实时漫游、实时动画和虚拟现实等领域具有非常广阔的应用前景。     

An Exercise Collection Auto-Assembling Framework with Knowledge Tracing and Reinforcement Learning

In educational practice, teachers often need to manually assemble an exercise collection as a class quiz or a homework assignment. A well-assembled exercise collection needs to have the proper difficulty index and discrimination index so that it can better develop students' abilities. In this paper, we propose an exercise collection auto-assembling framework, in which a teacher provides the target values of difficulty and discrimination indices and a qualified exercise collection is automatically assembled. The framework consists of two stages. At the answer prediction stage, a knowledge tracing model is utilized to predict the students' answers to unseen exercises based on their history interaction records. In addition, to better represent the exercises in the model, we propose exercise embeddings and design a pre-training approach. At the collection assembling stage, we propose a deep reinforcement learning model to assemble the required exercise collection effectively. Since the knowledge tracing model in the first stage has different confidences in the predicted answers, it is also taken into account in the objective. Experimental results show the effectiveness and efficiency of the proposed framework.     

酪氨酸激酶抑制剂的虚拟受体模型方法研究

利用柔性原子受体模型(FLARM)方法对一系列的异黄酮和喹诺酮衍生物表皮生长因子受体酪氨酸激酶抑制剂进行了三维定量构效关系研究,得到了合理的构效关系模型。FLARM方法的计算结果还给出了虚拟的受体模型,该模型说明了抑制剂与受体之间可能的相互作用。这些相互作用包括两个氢键和一个硫-芳香相互作用,以上结果仅仅是由7个化合物得到的。     

Machine learning for anomaly detection and process phase classification to improve safety and maintenance activities

Anomaly detection is a crucial aspect for both safety and efficiency of modern process industries.This paper proposes a two-steps methodology for anomaly detection in industrial processes, adopting machine learning classification algorithms. Starting from a real-time collection of process data, the first step identifies the ongoing process phase, the second step classifies the input data as “Expected”, “Warning”, or “Critical”. The proposed methodology is extremely relevant where machines carry out several operations without the evidence of production phases. In this context, the difficulty of attributing the real-time measurements to a specific production phase affects the success of the condition monitoring. The paper proposes the comparison of the anomaly detection step with and without the process phase identification step, validating its absolute necessity. The methodology applies the decision forests algorithm, as a well-known anomaly detector from industrial data, and decision jungle algorithm, never tested before in industrial applications. A real case study in the pharmaceutical industry validates the proposed anomaly detection methodology, using a 10 months database of 16 process parameters from a granulation process.     

LFKT:学习与遗忘融合的深度知识追踪模型

知识追踪任务旨在根据学生历史学习行为实时追踪学生知识水平变化,并且预测学生在未来学习表现.在学生学习过程中,学习行为与遗忘行为相互交织,学生的遗忘行为对知识追踪影响很大.为了准确建模知识追踪中学习与遗忘行为,本文提出了一个兼顾学习与遗忘行为的深度知识追踪模型LFKT.LFKT模型综合考虑了四个影响知识遗忘因素,包括学生重复学习知识点的间隔时间、重复学习知识点的次数、顺序学习间隔时间以及学生对于知识点的掌握程度.结合遗忘因素,LFKT采用深度神经网络,利用学生答题结果作为知识追踪过程中知识掌握程度的间接反馈,建模融合学习与遗忘行为的知识追踪模型.通过在真实在线教育数据集上的实验,与当前知识追踪模型相比,LFKT可以更好地追踪学生知识掌握状态,并具有较好的预测性能.     

Fast Ray Tracing of Arbitrary Implicit Surfaces with Interval and Affine Arithmetic

Existing techniques for rendering arbitrary-form implicit surfaces are limited, either in performance, correctness or flexibility. Ray tracing algorithms employing interval arithmetic (IA) or affine arithmetic (AA) for root-funding are robust and general in the class of surfaces they support, but traditionally slow. Nonetheless, implemented efficiently using a stack-driven iterative algorithm and SIMD vector instructions, these methods can achieve interactive performance for common algebraic surfaces on the CPU. A similar algorithm can also be implemented stacklessly, allowing for efficient ray tracing on the GPU. This paper presents these algorithms, as well as an inclusion-preserving reduced affine arithmetic (RAA) for faster ray-surface intersection. Shader metaprogramming allows for immediate and automatic generation of symbolic expressions and their interval or affine extensions. Moreover, we are able to render even complex forms robustly, in real-time at high resolution .     

Detection and discrimination of coliform bacteria with gas sensor arrays

Electronic noses, which are used for characterizing complex vapors and aromas, may be useful for detection of bacterial contamination or diagnosis of infections, if minimal standards of selectivity and sensitivity can be met. A culture of Enterobacter aerogenes is readily discriminated from an Escherichia coli strain using principal components analysis (PCA) of data generated by an array of eight quartz microbalance (QMB), eight metal oxide semiconductor (MOX), and four electrochemical gas sensors. Two strains of E. coli were not discriminated under identical conditions. Retaining headspace air in a sealed vial containing growing bacteria results in an enhancement of sensitivity, so that a concentration of bacteria of about 5×10⁸/ml may be both detected and distinguished from other species. Improvements in sensitivity to levels useful for practical applications will require enhancement of sensors, sampling system, and pattern classification.     

Unravelling the structural interactions between PKR kinase domain and its small molecule inhibitors using computational approaches

The RNA-dependent protein kinase (PKR), an eIF2α kinase plays an important role in anti-viral response, apoptosis and cell survival. It is also implicated to play a role in several cancers, metabolic and neurodegenerative disorders. A few ATP competitive inhibitors of the PKR have been reported in the literature with promising results in vitro and in vivo. The aim of this study was to unravel the structural interactions between these inhibitors and the PKR kinase domain using molecular simulations and docking. Our study reveals that the reported inhibitors bind in the adenine pocket and form hydrogen bonds with the hinge region and vdW interactions with non-polar residues in the binding site. The most potent inhibitor has several favorable interactions with the binding site and induces the P-loop to fold inward, creating a significant hydrophobic enclosure for itself. The computed binding free energies of these inhibitors are in accord with experimental data (IC₅₀). Strategies to design potent and selective PKR inhibitors are discussed to overcome the reported promiscuity.     

Chk2抑制剂2-芳香基苯并咪唑类化合物活性的CoMFA研究

利用比较分子力场分析(CoMFA)法,研究训练集中的37个Chk2抑制剂2-芳香基苯并咪唑类化合物的生物活性,考察了互变异构对抑制剂活性的影响,建立了主成分为4的三维定量结构-活性关系模型.模型的交叉和非交叉验证回归系数(q2、r2)分别为0.660和0.908,是稳定性较高和预测能力较好的模型,立体场对活性的影响比静电场大.模型可用于指导设计新的Chk2抑制剂.