Discovery of novel anticancer compounds based on a quinoxalinehydrazine pharmacophore

Quinoxalinehydrazines represent a novel class of compounds with excellent potency in a panel of cancer cell lines. A prototype compound, SC144, showed significant in vivo efficacy in mice xenograft models of human breast cancer cells. The subsequent structure-activity relationship study resulted in the discovery of SC161 with better potency in cancer cell lines. Further exploring the possible conformational space by a 10 ns molecular dynamics simulation as presented herein, resulted in various pharmacophore orientations. The trajectory analysis indicated that in most of the simulation time, the molecule stays favorably in a compact planarlike orientation. We therefore built a pharmacophore model based on the cluster containing the highest number of frames to represent the most probable orientation. The model was used to screen a subset of our small molecule database containing 350,000 compounds. We selected 35 compounds for the initial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazine and quinoline class displayed cytotoxicity in various cancer cell lines. Five of them, compounds 2, 6, 15, 16, and 19, all bearing an oxadiazolopyrazine scaffold, showed IC(50) values <3 muM in certain tumor cell lines. The most potent compound, 2, showed IC(50) values <2 muM in HCT116 p53(+/+), HCT116 p53(-/-), and HEY cells, and 8 muM in NIH3T3 cells. This study shows that conformational sampling of a lead small molecule followed by representative pharmacophore model development is an efficient approach for the rational design of novel anticancer agents with similar or better potency than the original lead but with different physicochemical properties.     

Planning and monitoring the execution of web service requests

Interaction with web services enabled marketplaces would be greatly facilitated if users were given a high level service request language to express their goals in complex business domains. This can be achieved by using a planning framework which monitors the execution of planned goals against predefined standard business processes and interacts with the user to achieve goal satisfaction. We present a planning architecture that accepts high level requests, expressed in a service request language known as XSRL. The planning framework is based on the principle of interleaving planning and execution. This is accomplished on the basis of refinement and revision as new service-related information is gathered from service repositories such as UDDI and web services instances, and as execution circumstances necessitate change. The planning system interacts with the user whenever confirmation or verification is needed.     

Service Orientation and the Smart Grid state and trends

The energy market is undergoing major changes, the most notable of which is the transition from a hierarchical closed system toward a more open one highly based on a ??smart?? information-rich infrastructure. This transition calls for new information and communication technologies infrastructures and standards to support it. In this paper, we review the current state of affairs and the actual technologies with respect to such transition. Additionally, we highlight the contact points between the needs of the future grid and the advantages brought by service-oriented architectures.     

Long latency evoked potentials in a case of corpus callosum agenesia

Following monoaural stimulation, long latency auditory evoked potentials (LLAEPs) recorded from contralateral temporal areas have a shorter latency and larger amplitude than those recorded from the ipsilateral temporal areas. This observation agrees with the operational model drawn up in 1967 by Kimura, which assumes that only anatomically prevailing crossed auditory pathways are active during dichotic hearing, while direct pathways are inhibited. The inputs may then be conveyed to the contralateral cortex, from where they finally reach the ipsilateral temporal areas by means of interhemispheric commissures. It is this mechanism which may underline the right ear advantage for verbal stimuli and the left ear advantage for melodies observed when administering dichotic listening tasks. With the aim of verifying this hypothesis, we recorded temporal LLAEPs in a 21 year-old woman suffering from complex partial seizures, whose CT scan and MRI showed corpus callosum agenesia. Our data support the hypothesis that ipsilateral pathways are greatly inhibited by the contralateral pathways, and therefore auditory stimuli can be supposed to reach the contralateral auditory cortex from where they are transferred through the corpus callosum to the ipsilateral auditory cortex.     

带热浸铝涂层MANET Ⅱ马氏体钢的氢渗透性能研究

在300～450℃温度范围内,分别在氢气相和液态铅锂合金相中,开展了带热浸铝涂层MANET Ⅱ马氏体钢的氢渗透性能研究.结果表明,实验所得到的氢渗透率减低因子(PRF),在气相中为620～263,在液态铅锂合金相中为45～30.但仍然没有满足DEMO聚变堆的设计要求.涂层的自修复效应在400 ℃以上是明显和有效的.从渗透通量与样品上游氢压的关系来看,涂层使得表面效应对渗透过程的影响很大.在上游小流量及在液态铅锂合金中鼓泡充氢可以导致渗透通量升高.扫描电镜和能谱分析(SEM-EDS)的结果表明,样品表面被液态铅锂合金所浸润的部分出现微裂纹,而未浸润部分没有出现微裂纹.微裂纹很肤浅,仅仅影响涂层的最外表面薄层,没有贯穿整个渗铝层而到达基体.未浸润表面的Al/O原子比约为2/3,浸润表面约为1/1,表明液态铅锂合金对渗铝层表面的Al2O3薄层造成了损伤.总的看来,造成氢渗透阻挡层性能退化的原因,是涂层外表面与液态铅锂合金相互作用,以及涂层在升、降温过程中产生热应力释放.     

How Important Are Genes to Achieve Longevity?

Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite efforts and new technologies, only two genes, APOE and FOXO3A, involved in the protection of cardiovascular diseases, have been shown to be associated with longevity in nearly all studies. This happens because the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. In fact, population-specific genes are thought to play a greater role in the attainment of longevity than those shared between different populations. Hence, it is not surprising that GWAS replicated associations of common variants with longevity have been few, if any, as these studies pool together different populations. An alternative way might be the study of long-life families. This type of approach is proving to be an ideal resource for uncovering protective alleles and associated biological signatures for healthy aging phenotypes and exceptional longevity.     

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR–HLA genes/groups of these three different infected populations with healthy Sicilian donors from the literature. We showed that the inhibitory KIR3DL1 gene and the KIR3DL1/HLA-B Bw4 pairing were more prevalent in individual CHB. At the same time, the frequency of HLA-C2 was increased in CHB compared to other groups. In contrast, the HLA-C1 ligand seems to have no contribution to CHB progression whereas it was significantly higher in COVID-19 and HIV-positive than healthy controls. These results suggest that specific KIR–HLA combinations can predict the outcome/susceptibility of these viral infections and allows to plan successful customized therapeutic strategies.     

Effects of supercritical and liquid carbon dioxide extraction on hemp (Cannabis sativa L.) seed oil

The increase in the popularity of hemp-based products is mainly linked to the presence of non-psychoactive cannabinoids that provide relief from aches, pain and anxiety. In this study, hemp seed oils were produced by two innovative and environmentally friendly extraction techniques: supercritical and liquid carbon dioxide (CO₂) extraction. The chemical composition of the two oils was analysed and compared with that of a control oil obtained by solvent (n-hexane) extraction. Both oils obtained by liquid and supercritical CO₂ extraction presented interesting compositions: they contained large amounts of cannabinoids, polyphenols and tocopherols and were less oxidised than the control and contained a large amount of hexanal, which provided a pleasant aroma. The maximum cannabinoid content was found in the oil obtained by liquid CO₂ extraction (71.51 mg of cannabidiol per kg of oil and 113.92 mg of cannabinol per kg of oil). Carotenoids were prevalent in the oil obtained by supercritical CO₂ extraction (61.00 mg kg⁻¹ of oil).