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31.
The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, , CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated. RJC02337相似文献
32.
Joshua P. Gray Md. Nasir Uddin Rajan Chaudhari Margie N. Sutton Hailing Yang Philip Rask Hannah Locke Brian J. Engel Nefeli Batistatou Jing Wang Brian J. Grindel Pratip Bhattacharya Seth T. Gammon Shuxing Zhang David Piwnica-Worms Joshua A. Kritzer Zhen Lu Robert C. Bast Jr. Steven W. Millward 《Chemical science》2021,12(10):3526
In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Unfortunately, chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B—two essential components of the autophagosome maturation machinery—with mid-nanomolar affinities and disrupted protein–protein interactions (PPIs) between LC3 and its binding partners in vitro. The most promising LC3-binding SUPR peptide accessed the cytosol at low micromolar concentrations as measured by chloroalkane penetration assay (CAPA) and inhibited starvation-mediated GFP-LC3 puncta formation in a concentration-dependent manner. LC3-binding SUPR peptides re-sensitized platinum-resistant ovarian cancer cells to cisplatin treatment and triggered accumulation of the adapter protein p62 suggesting decreased autophagic flux through successful disruption of LC3 PPIs in cell culture. In mouse models of metastatic ovarian cancer, treatment with LC3-binding SUPR peptides and carboplatin resulted in almost complete inhibition of tumor growth after four weeks of treatment. These results indicate that SUPR peptide mRNA display can be used to develop cell-penetrating macrocyclic peptides that target and disrupt the autophagic machinery in vitro and in vivo.SUPR peptide mRNA display was used to evolve a cell-permeable, macrocyclic peptide for autophagy inhibition. 相似文献
33.
We present a new approach that permits efficient performance analysis of kanban systems with general demand processes, material
arrival processes, and service times. The approach is based on parametric characterization of the traffic processes (arrival
and departure) in the network and uses two-moment approximations to estimate performance measures at individual stations.
We derive traffic flow constraints that are particular to closed queuing networks with synchronization stations and use these
to establish relationships between the parameters characterizing arrival and departure processes at the stations in the network.
The resultant set of non-linear equations is solved to estimate network performance measures. Numerical studies show that
the approach is not only fast but also reasonably accurate when compared to simulation. These studies also provide insights
with respect to the impact of different types of variability on the performance of a kanban system. This work also provides
a fundamental building block that can be used in the analysis of multi-stage kanban systems.
AMS Subject Classifications 68M20, 60K20, 90B05, 90B30 相似文献
34.
Yakov Ben-Haim Clifford C. Dacso Jonathon Carrasco Nithin Rajan 《International Journal of Approximate Reasoning》2009,50(7):1046
Physicians use clinical guidelines to inform judgment about therapy. Clinical guidelines do not address three important uncertainties: (1) uncertain relevance of tested populations to the individual patient, (2) the patient’s uncertain preferences among possible outcomes, and (3) uncertain subjective and financial costs of intervention. Unreliable probabilistic information is available for some of these uncertainties; no probabilities are available for others. The uncertainties are in the values of parameters and in the shapes of functions. We explore the usefulness of info-gap decision theory in patient-physician decision making in managing cholesterol level using clinical guidelines. Info-gap models of uncertainty provide versatile tools for quantifying diverse uncertainties. Info-gap theory provides two decision functions for evaluating alternative therapies. The robustness function assesses the confidence—in light of uncertainties—in attaining acceptable outcomes. The opportuneness function assesses the potential for better-than-anticipated outcomes. Both functions assist in forming preferences among alternatives. Hypothetical case studies demonstrate that decisions using the guidelines and based on best estimates of the expected utility are sometimes, but not always, consistent with robustness and opportuneness analyses. The info-gap analysis provides guidance when judgment suggests that a deviation from the guidelines would be productive. Finally, analysis of uncertainty can help resolve ambiguous situations. 相似文献
35.
Robust stability analysis of stochastic neural networks with Markovian jumping parameters and probabilistic time‐varying delays 下载免费PDF全文
Chandrasekar Pradeep Arunachalam Chandrasekar Rangasamy Murugesu Rajan Rakkiyappan 《Complexity》2016,21(5):59-72
This article discusses the issue of robust stability analysis for a class of Markovian jumping stochastic neural networks (NNs) with probabilistic time‐varying delays. The jumping parameters are represented as a continuous‐time discrete‐state Markov chain. Using the stochastic stability theory, properties of Brownian motion, the information of probabilistic time‐varying delay, the generalized Ito's formula, and linear matrix inequality (LMI) technique, some novel sufficient conditions are obtained to guarantee the stochastical stability of the given NNs. In particular, the activation functions considered in this article are reasonably general in view of the fact that they may depend on Markovian jump parameters and they are more general than those usual Lipschitz conditions. The main features of this article are described in the following: first one is that, based on generalized Finsler lemma, some improved delay‐dependent stability criteria are established and the second one is that the nonlinear stochastic perturbation acting on the system satisfies a class of Lipschitz linear growth conditions. By resorting to the Lyapunov–Krasovskii stability theory and the stochastic analysis tools, sufficient stability conditions are established using an efficient LMI approach. Finally, two numerical examples and its simulations are given to demonstrate the usefulness and effectiveness of the proposed results. © 2014 Wiley Periodicals, Inc. Complexity 21: 59–72, 2016 相似文献
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38.
Potential consequences of disasters involve overwhelming economic losses, large affected populations and serious environmental damages. Given these devastating effects, there is an increasing interest in developing measures in order to diminish the possible impact of disasters, which gave rise to the field of disaster operations management (DOM). In this paper we review recent OR/MS research in DOM. Our work is a continuation of a previous review from Altay and Green (2006). Our purpose is to evaluate how OR/MS research in DOM has evolved in the last years and to what extent the gaps identified by Altay and Green (2006) have been covered. Our findings show no drastic changes or developments in the field of OR/MS in DOM since the publication of Altay and Green (2006). Additionally to our comparative analysis, we present an original evaluation about the most common assumptions in recent OR/MS literature in DOM. Based on our findings we provide future research directions in order to make improvements in the areas where lack of research is detected. 相似文献
39.
Asymptotic synchronization of continuous/discrete complex dynamical networks by optimal partitioning method 下载免费PDF全文
The synchronization problem for both continuous and discrete‐time complex dynamical networks with time‐varying delays is investigated. Using optimal partitioning method, time‐varying delays are partitioned into l subintervals and generalized results are derived in terms of linear matrix inequalities (LMIs). New delay‐dependent synchronization criteria in terms of LMIs are derived by constructing appropriate Lyapunov–Krasovskii functional, reciprocally convex combination technique and some inequality techniques. Numerical examples are given to illustrate the effectiveness and advantage of the proposed synchronization criteria. © 2014 Wiley Periodicals, Inc. Complexity 21: 193–210, 2015 相似文献
40.
Erica L. Plambeck Bor-Ruey Fu Stephen M. Robinson Rajan Suri 《Mathematical Programming》1996,75(2):137-176
In this paper we propose a method for optimizing convex performance functions in stochastic systems. These functions can include
expected performance in static systems and steady-state performance in discrete-event dynamic systems; they may be nonsmooth.
The method is closely related to retrospective simulation optimization; it appears to overcome some limitations of stochastic
approximation, which is often applied to such problems. We explain the method and give computational results for two classes
of problems: tandem production lines with up to 50 machines, and stochastic PERT (Program Evaluation and Review Technique)
problems with up to 70 nodes and 110 arcs.
Sponsored by the National Science Foundation under grant number CCR-9109345, by the Air Force Systems Command, USAF, under
grant numbers F49620-93-1-0068 and F49620-95-1-0222, by the U.S. Army Research Office under grant number DAAL03-92-G-0408,
and by the U.S. Army Space and Strategic Defense Command under contract number DASG60-91-C-0144. The U.S. Government has certain
rights in this material, and is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding
any copyright notation thereon.
Sponsored by a Wisconsin/Hilldale Research Award, by the U.S. Army Space and Strategic Defense Command under contract number
DASG60-91-C-0144, and the Air Force Systems Command, USAF, under grant number F49620-93-1-0068.
Sponsored by the National Science Foundation under grant number DDM-9201813. 相似文献