Fragment-Based Drug Discovery for RNA Targets

Rapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR spectroscopy, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small-molecule RNA binders provides an overview on both the currently limited guidelines within RNA-targeting fragment library design, and future possibilities. Finally, future perspectives are provided on screening and hit validation methods not yet used in combination with both fragment screening and RNA targets.     

Peptides to Tackle Leishmaniasis: Current Status and Future Directions

Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources—amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others—or inspired by natural toxins or proteins. This review details the biochemical and structural characteristics of over one hundred peptides and their potential use as molecular frameworks for the design of antileishmanial drug leads. Additionally, we detail the main chemical modifications or substitutions of amino acid residues carried out in the peptide sequence, and their implications in the development of antileishmanial candidates for clinical trials. Our bibliographic research highlights that the action of leishmanicidal peptides has been evaluated mainly using in vitro assays, with a special emphasis on the promastigote stage. In light of these findings, and considering the advances in the successful application of peptides in leishmaniasis chemotherapy, possible approaches and future directions are discussed here.     

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.     

Characterization of New DNA Aptamers for Anti-HIV-1 Reverse Transcriptase

HIV-1 RT is a necessary enzyme for retroviral replication, which is the main target for antiviral therapy against AIDS. Effective anti-HIV-1 RT drugs are divided into two groups; nucleoside inhibitors (NRTI) and non-nucleoside inhibitors (NNRTI), which inhibit DNA polymerase. In this study, new DNA aptamers were isolated as anti-HIV-1 RT inhibitors. The selected DNA aptamer (WT62) presented with high affinity and inhibition against wild-type (WT) HIV-1 RT and gave a KD value of 75.10±0.29 nM and an IC₅₀ value of 84.81±8.54 nM. Moreover, WT62 decreased the DNA polymerase function of K103 N/Y181 C double mutant (KY) HIV-1 RT by around 80 %. Furthermore, the ITC results showed that this aptamer has small binding enthalpies with both WT and KY HIV-1 RTs through which the complex might form a hydrophobic interaction or noncovalent bonding. The NMR result also suggested that the WT62 aptamer could bind with both WT and KY mutant HIV-1 RTs at the connection domain.     

Acquiring logistics process intelligence: Methodology and an application for a Chinese bulk port

The processes of logistics service providers are considered as highly human-centric, flexible and complex. Deviations from the standard operating procedures as described in the designed process models, are not uncommon and may result in significant uncertainties. Acquiring insight in the dynamics of the actual logistics processes can effectively assist in mitigating the uncovered risks and creating strategic advantages, which are the result of uncertainties with respectively a negative and a positive impact on the organizational objectives.In this paper a comprehensive methodology for applying process mining in logistics is presented, covering the event log extraction and preprocessing as well as the execution of exploratory, performance and conformance analyses. The applicability of the presented methodology and roadmap is demonstrated with a case study at an important Chinese port that specializes in bulk cargo.     

Self-scaling cooperative discovery of service compositions in unstructured P2P networks

We propose an efficient technique for improving the performance of automatic and cooperative compositions in unstructured Peer-to-Peer networks during service discovery. The technique exploits a probabilistic forwarding algorithm that uses different sources of knowledge, such as network density and service grouping, to reduce the amount of messages exchanged in the network. The technique, analysed in several network configurations by using a simulator to observe resolution time, recall and message overhead, presents good performance especially in dense and large-scale service networks.     

基于粗糙集的焦炉加热工序控制规则提取

应用粗糙集(RS)理论对焦炉直行温度的控制规则进行了提取。首先收集人工成功控制直行温度的原始样本,添加可控与不可控参数,得到初始决策表;指出模糊控制方法因输入参数过少,从而会导致不确定性决策;然后利用RS理论对初始决策表进行约简,发现了关键影响因素及潜在规律,最终得到两组仅含有三个参数,简洁、一致、完备的控制规则,并经实际运行检验了规则的适用性。     

A trustworthy QoS-based collaborative filtering approach for web service discovery

Many network services which process a large quantity of data and knowledge are available in the distributed network environment, and provide applications to users based on Service-Oriented Architecture (SOA) and Web services technology. Therefore, a useful web service discovery approach for data and knowledge discovery process in the complex network environment is a very significant issue. Using the traditional keyword-based search method, users find it difficult to choose the best web services from those with similar functionalities. In addition, in an untrustworthy real world environment, the QoS-based service discovery approach cannot verify the correctness of the web services’ Quality of Service (QoS) values, since such values guaranteed by a service provider are different from the real ones. This work proposes a trustworthy two-phase web service discovery mechanism based on QoS and collaborative filtering, which discovers and recommends the needed web services effectively for users in the distributed environment, and also solves the problem of services with incorrect QoS information. In the experiment, the theoretical analysis and simulation experiment results show that the proposed method can accurately recommend the needed services to users, and improve the recommendation quality.     

基于概率主题模型的物联网服务发现

针对物联网中服务数量的大规模性、服务描述的异构性以及设备服务的资源高度受限性和移动性等特点,提出了一种基于概率主题模型的物联网服务发现方法.该方法的主要特点是：1） 利用英文Wikipedia 构建高质量的主题模型,并对类似短文本的服务文本描述进行语义扩充,使主题模型能够更有效地估计服务文本描述的隐含主题;2） 提出利用非参数主题模型学习服务文本的隐含主题,降低模型训练时间;3） 利用服务隐含主题对服务进行自动分类和文本相似度计算,快速减少服务匹配数量,加速服务文本相似度计算;4） 提出能够同时支持WSDL-based 和RESTful 两种物联网服务的signature 匹配算法.实验结果表明：与现有的物联网服务发现方法相比,该方法的准确率（precision）和归一化折损累积增益（NDCG）都有较大幅度的提高.