Non-fragile Dynamic Output Feedback H∞ Control for a Class of Uncertain Switched Systems with Time-varying Delay

The problem of non-fragile dynamic output feedback H∞ control for a class of uncertain switched systems with time-varying delay is discussed. Firstly, the form of non-fragile dynamic output feedback H∞ controller is given. Under the condition that the upper bound of time delay and the upper bound of delay derivative are limited simultaneously, Lyapunov functional and its corresponding switching rules are constructed by using single Lyapunov function method and convex combination technique; Secondly, we use the inequality lemma to scale the derived Lyapunov functional in order to eliminate the time-varying delay term in the inequality, and then introduce the J-function to obtain a nonlinear matrix inequality that satisfies the H∞ performance index γ, we also employ Schur complement lemma to transform the nonlinear matrix inequality into set of linear matrix inequalities consisting of two linear matrix inequalities, a sufficient condition for the existence of a non-fragile dynamic output feedback H∞ controller and satisfying the H∞ performance index γ is concluded for a class of uncertain switching systems with variable time delay; Finally, a switched system composed of two subsystems is considered and the effectiveness and practicability of the theorem are illustrated by numerical simulation with LMI toolbox.

The People's Republic of China's financial markets: Are they deep and liquid enough for renminbi internationalization?

Domestic financial market development is a key determinant of a currency's international status, and financial depth and market liquidity are two essential attributes for an international currency. This paper discusses the status of the People's Republic of China's (PRC) financial markets and their depth and liquidity conditions. The paper also compares the PRC's financial markets with those in developed and emerging economies, contemporaneously and historically. The paper finds that the PRC's financial markets are not as deep and liquid as those in developed economies, and are much less so than those with international currencies. To support the internationalization of the renminbi, the PRC needs to remove several major obstacles to deepen its financial markets and improve their liquidity conditions

Neuroevolution of Self-Interpretable Agents

Inattentional blindness is the psychological phenomenon that causes one to miss things in plain sight. It is a consequence of the selective attention in perception that lets us remain focused on important parts of our world without distraction from irrelevant details. Motivated by selective attention, we study the properties of artificial agents that perceive the world through the lens of a self-attention bottleneck. By constraining access to only a small fraction of the visual input, we show that their policies are directly interpretable in pixel space. We find neuroevolution ideal for training self-attention architectures for vision-based reinforcement learning (RL) tasks, allowing us to incorporate modules that can include discrete, non-differentiable operations which are useful for our agent. We argue that self-attention has similar properties as indirect encoding, in the sense that large implicit weight matrices are generated from a small number of key-query parameters, thus enabling our agent to solve challenging vision based tasks with at least 1000x fewer parameters than existing methods. Since our agent attends to only task critical visual hints, they are able to generalize to environments where task irrelevant elements are modified while conventional methods fail. Videos of our results and source code available at https://attentionagent.github.io/Comment: To appear at the Genetic and Evolutionary Computation Conference (GECCO 2020) as a full pape

APH(3’)-Ie, an aminoglycoside-modifying enzyme discovered in a rabbit-derived Citrobacter gillenii isolate

BackgroundAminoglycoside-modifying enzymes (AMEs) play an essential role in bacterial resistance to aminoglycoside antimicrobials. With the development of sequencing techniques, more bacterial genomes have been sequenced, which has aided in the discovery of an increasing number of novel resistance mechanisms.MethodsThe bacterial species was identified by 16S rRNA gene homology and average nucleotide identity (ANI) analyses. The minimum inhibitory concentration (MIC) of each antimicrobial was determined by the agar dilution method. The protein was expressed with the pCold I vector in E. coli BL21, and enzyme kinetic parameters were examined. The whole-genome sequence of the bacterium was obtained via the Illumina and PacBio sequencing platforms. Reconstruction of the phylogenetic tree, identification of conserved functional residues, and gene context analysis were performed using the corresponding bioinformatic techniques.ResultsA novel aminoglycoside resistance gene, designated aph(3’)-Ie, which confers resistance to ribostamycin, kanamycin, sisomicin and paromomycin, was identified in the chromosome of the animal bacterium Citrobacter gillenii DW61, which exhibited a multidrug resistance phenotype. APH(3’)-Ie showed the highest amino acid identity of 74.90% with the functionally characterized enzyme APH(3’)-Ia. Enzyme kinetics analysis demonstrated that it had phosphorylation activity toward four aminoglycoside substrates, exhibiting the highest affinity (Km, 4.22 ± 0.88 µM) and the highest catalytic efficiency [kcat/Km, (32.27 ± 8.14) × 104] for ribomycin. Similar to the other APH(3’) proteins, APH(3’)-Ie contained all the conserved functional sites of the APH family. The aph(3’)-Ie homologous genes were present in C. gillenii isolates from different sources, including some of clinical significance.ConclusionIn this work, a novel chromosomal aminoglycoside resistance gene, designated aph(3’)-Ie, conferring resistance to aminoglycoside antimicrobials, was identified in a rabbit isolate C. gillenii DW61. The elucidation of the novel resistance mechanism will aid in the effective treatment of infections caused by pathogens carrying such resistance genes

Rapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies

22 p.-9 fig.-8 tab.Butyrylcholinesterase is regarded as a promising drug target in advanced Alzheimer’s disease. In order to identify highly selective and potent BuChE inhibitors, a 53-membered compound library was constructed via the oxime-based tethering approach based on microscale synthesis. Although A2Q17 and A3Q12 exhibited higher BuChE selectivity versus acetylcholinesterase, the inhibitory activities were unsatisfactory and A3Q12 did not inhibit Aβ1-42 peptide self-induced aggregation. With A2Q17 and A3Q12 as leads, a novel series of tacrine derivatives with nitrogen-containing heterocycles were designed based on conformation restriction strategy. The results demonstrated that 39 (IC50 = 3.49 nM) and 43 (IC50 = 7.44 nM) yielded much improved hBuChE inhibitory activity compared to the lead A3Q12 (IC50 = 63 nM). Besides, the selectivity indexes (SI = AChE IC50 / BChE IC50) of 39 (SI = 33) and 43 (SI = 20) were also higher than A3Q12 (SI = 14). The results of the kinetic study showed that 39 and 43 exhibited a mixed-type inhibition against eqBuChE with respective Ki values of 1.715 nM and 0.781 nM. And 39 and 43 could inhibit Aβ1-42 peptide self-induced aggregation into fibril. X-ray crystallography structures of 39 or 43 complexes with BuChE revealed the molecular basis for their high potency. Thus, 39 and 43 are deserve for further study to develop potential drug candidates for the treatment of Alzheimer’s disease.We gratefully acknowledge financial support from the Shandong Provincial Key Research and Development Project (No. 2019JZZY021011), Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31), Foreign Cultural and Educational Experts Project (GXL20200015001), Qilu Young Scholars Program of Shandong University, Distinguished Young and Middle-aged Scholar of Shandong University, the Taishan Scholar Program at Shandong Province, and MINECO (Grants SAF2016-76693-R to A.M), F.C., F.N. and X.B. were supported by the French Ministry of Armed Forces (Direction Générale de l'Armement and Service de Santé des Armées, NBC-5-C-4210). Authors would like to thank the ESRF for long-term beamtime access (MX2329 IBS BAG).Peer reviewe

Inhibition of CDC25B With WG-391D Impedes the Tumorigenesis of Ovarian Cancer

Novel inhibitors are urgently needed for use as targeted therapies to improve the overall survival (OS) of patients with ovarian cancer. Here, we show that cell division cycle 25B (CDC25B) is over-expressed in ovarian tumors and associated with poor patient prognosis. All previously reported CDC25B inhibitors have been identified by their ability to reversibly inhibit the catalytic dephosphorylation activity of CDC25B in vitro; however, none of these compounds have entered clinical trials for ovarian cancer therapy. In this study, we synthesized a novel small molecule compound, WG-391D, that potently down-regulates CDC25B expression without affecting its catalytic dephosphorylation activity. The inhibition of CDC25B by WG-391D is irreversible, and WG-391D should therefore exhibit potent antitumor activity against ovarian cancer. WG-391D induces cell cycle progression arrest at the G2/M phase. Half maximal inhibitory concentration (IC50) values of WG-391D for inhibition of the proliferation and migration of eight representative ovarian cancer cell lines (SKOV3, ES2, OVCAR8, OVTOKO, A2780, IGROV1, HO8910PM, and MCAS) and five primary ovarian tumor cell lines (GFY004, GFY005, CZ001, CZ006, and CZ008) were lower than 10 and 1 μM, respectively. WG-391D inhibited tumor growth in nude mice inoculated with SKOV3 cells or a patient-derived xenograft (PDX). The underlying mechanisms were associated with the down-regulation of CDC25B and subsequent inactivation of cell division cycle 2 (CDC2) and the serine/threonine kinase, AKT. In conclusion, this study demonstrates that WG-391D exhibits strong antitumor activity against ovarian cancer and indicates that the down-regulation of CDC25B by inhibitors could provide a rationale for ovarian cancer therapy

NFATc1 Regulation of TRAIL Expression in Human Intestinal Cells

TNF-related apoptosis-inducing ligand (TRAIL; Apo2) has been shown to promote intestinal cell differentiation. Nuclear factor of activated T cells (NFAT) participates in the regulation of a variety of cellular processes, including differentiation. Here, we examined the role of NFAT in the regulation of TRAIL in human intestinal cells. Treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187 (Io) increased NFAT activation and TRAIL expression; pretreatment with the calcineurin inhibitor cyclosporine A (CsA), an antagonist of NFAT signaling, diminished NFAT activation and TRAIL induction. In addition, knockdown of NFATc1, NFATc2, NFATc3, and NFATc4 blocked PMA/Io increased TRAIL protein expression. Expression of NFATc1 activated TRAIL promoter activity and increased TRAIL mRNA and protein expression. Deletion of NFAT binding sites from the TRAIL promoter did not significantly abrogate NFATc1-increased TRAIL promoter activity, suggesting an indirect regulation of TRAIL expression by NFAT activation. Knockdown of NFATc1 increased Sp1 transcription factor binding to the TRAIL promoter and, importantly, inhibition of Sp1, by chemical inhibition or RNA interference, increased TRAIL expression. These studies identify a novel mechanism for TRAIL regulation by which activation of NFATc1 increases TRAIL expression through negative regulation of Sp1 binding to the TRAIL promoter

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)