Chemical-Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors

Bile acids have been reported as important cofactors promoting human and murine norovirus (NoV) infections in cell culture. The underlying mechanisms are not resolved. Through the use of chemical shift perturbation (CSP) NMR experiments, we identified a low-affinity bile acid binding site of a human GII.4 NoV strain. Long-timescale MD simulations reveal the formation of a ligand-accessible binding pocket of flexible shape, allowing the formation of stable viral coat protein–bile acid complexes in agreement with experimental CSP data. CSP NMR experiments also show that this mode of bile acid binding has a minor influence on the binding of histo-blood group antigens and vice versa. STD NMR experiments probing the binding of bile acids to virus-like particles of seven different strains suggest that low-affinity bile acid binding is a common feature of human NoV and should therefore be important for understanding the role of bile acids as cofactors in NoV infection.     

Friction compensation controller for load varying machine tool feed drive

The load applied to a machine tool feed drive changes during the machining process as material is removed. This load change alters the Coulomb friction of the feed drive. Because Coulomb friction accounts for a large part of the total friction the friction compensation control accuracy of the feed drives is limited if this nonlinear change in the applied load is not considered. This paper presents a new friction compensation method that estimates the machine tool load in real time and considers its effect on friction characteristics. A friction observer based on a Kalman filter with load estimation is proposed for friction compensation control considering the applied load change. A specially designed feed drive testbed that enables the applied load to be modified easily was constructed for experimental verification. Control performance and friction estimation accuracy are demonstrated experimentally using the testbed.     

New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity

Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.     

Graphite Oxide and Aromatic Amines: Size Matters

Experimental and theoretical studies are performed in order to illuminate, for first time, the intercalation mechanism of polycyclic aromatic molecules into graphite oxide. Two representative molecules of this family, aniline and naphthalene amine are investigated. After intercalation, aniline molecules prefer to covalently connect to the graphene oxide matrix via chemical grafting, while napthalene amine molecules bind with the graphene oxide surface through π–π interactions. The presence of intercalated aromatic molecules between the graphene oxide layers is demonstrated by X‐ray diffraction, while the type of interaction between graphene oxide and polycyclic organic molecules is elucidated by X‐ray photoelectron spectroscopy. Combined quantum mechanical and molecular mechanical calculations describe the intercalation mechanism and the aniline grafting, rationalizing the experimental data. The present work opens new perspectives for the interaction of various aromatic molecules with graphite oxide and the so‐called “intercalation chemistry”.     

Unusual Two-Step Assembly of a Minimalistic Dipeptide-Based Functional Hypergelator

Self-assembled peptide hydrogels represent the realization of peptide nanotechnology into biomedical products. There is a continuous quest to identify the simplest building blocks and optimize their critical gelation concentration (CGC). Herein, a minimalistic, de novo dipeptide, Fmoc-Lys(Fmoc)-Asp, as an hydrogelator with the lowest CGC ever reported, almost fourfold lower as compared to that of a large hexadecapeptide previously described, is reported. The dipeptide self-assembles through an unusual and unprecedented two-step process as elucidated by solid-state NMR and molecular dynamics simulation. The hydrogel is cytocompatible and supports 2D/3D cell growth. Conductive composite gels composed of Fmoc-Lys(Fmoc)-Asp and a conductive polymer exhibit excellent DNA binding. Fmoc-Lys(Fmoc)-Asp exhibits the lowest CGC and highest mechanical properties when compared to a library of dipeptide analogues, thus validating the uniqueness of the molecular design which confers useful properties for various potential applications.     

Activity-Directed Synthesis: A Flexible Approach for Lead Generation

Activity-directed synthesis (ADS) is a structure-blind, functional-driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules, which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed.     

Thermoplastic and low dielectric constants polyimides based on BPADA-BAPP

ABSTRACT

The thermoplastic and low dielectric constants polyimides were introduced. The polyimides were prepared by pyromellitic dianhydride (PMDA) or 4,4?-(4,4?-Isopropylidenediphenoxy)diphthalic anhydride (BPADA) as anhydride monomer and 4,4?-oxydianiline (ODA) or 2,2-bis(4-(4-aminephenoxy)phenyl)propane (BAPP) as amine monomer. The polyimides were well characterized by FT-IR, thermogravimetric analysis, dynamic thermomechanical analysis, dielectric measurement, and tensile test. The dielectric constants were 2.32–2.95 compared with 3.10 of ODA-PMDA polyimide, while partly polyimides were thermoplastic. The results indicated anhydride monomers, containing lateral methyl groups, made polyimides become thermoplastic. The results of molecular simulations via Materials Studio also proved this conclusion.     

Automated network management and configuration using Probabilistic Trans-Algorithmic Search

Online configuration of large-scale systems such as networks requires parameter optimization within a limited amount of time, especially when configuration is needed as a response to recover from a failure in the system. To quickly configure such systems in an online manner, we propose a Probabilistic Trans-Algorithmic Search (PTAS) framework which leverages multiple optimization search algorithms in an iterative manner. PTAS applies a search algorithm to determine how to best distribute available experiment budget among multiple optimization search algorithms. It allocates an experiment budget to each available search algorithm and observes its performance on the system-at-hand. PTAS then probabilistically reallocates the experiment budget for the next round proportional to each algorithm’s performance relative to the rest of the algorithms. This “roulette wheel” approach probabilistically favors the more successful algorithm in the next round. Following each round, the PTAS framework “transfers” the best result(s) among the individual algorithms, making our framework a trans-algorithmic one. PTAS thus aims to systematize how to “search for the best search” and hybridize a set of search algorithms to attain a better search. We use three individual search algorithms, i.e., Recursive Random Search (RRS) (Ye and Kalyanaraman, 2004), Simulated Annealing (SA) (Laarhoven and Aarts, 1987), and Genetic Algorithm (GA) (Goldberg, 1989), and compare PTAS against the performance of RRS, GA, and SA. We show the performance of PTAS on well-known benchmark objective functions including scenarios where the objective function changes in the middle of the optimization process. To illustrate applicability of our framework to automated network management, we apply PTAS on the problem of optimizing link weights of an intra-domain routing protocol on three different topologies obtained from the Rocketfuel dataset. We also apply PTAS on the problem of optimizing aggregate throughput of a wireless ad hoc network by tuning datarates of traffic sources. Our experiments show that PTAS successfully picks the best performing algorithm, RRS or GA, and allocates the time wisely. Further, our results show that PTAS’ performance is not transient and steadily improves as more time is available for search.