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This work considers the video frame inpainting problem, where several former and latter frames are given, and the goal is to predict the middle frames. The state-of-the-art solution has applied bidirectional long short-term memory (LSTM) networks, which has a spatial-temporal mismatch problem. In this paper, we propose a trapezoid-structured LSTM architecture called T-LSTM-sbm for video frame inpainting with three designs: (i) segregated spatial-temporal gates, (ii) bridge joints, and (iii) multi-kernel LSTM. To prevent the spatial-temporal mismatch problem, while features are being passed through multi-layered LSTM nodes, the trapezoid structure reduces its number of LSTM nodes by two after each layer. This makes the model converge to the inpainted results more effectively. The separated temporal and spatial gates design can learn better spatial and temporal features by using individual gates. To relieve the information loss problem during the convergence of the trapezoidal layers, we use bridge joints among layers to better preserve useful information. The multiple kernels in LSTM are to enable extracting multi-scale information flows. T-LSTM-sbm is proved to outperform the state-of-the-art solutions in peak signal-to-noise ratio (PSNR) and structural similarity (SSIM) on three common datasets, KTH Action, HMDB-51, and UCF-101. [ABSTRACT FROM AUTHOR]

Felids are the only definitive hosts of Toxoplasma gondii. To lay a foundation for screening the T. gondii-felids interaction factors, we have developed a reproducible primary culture method for cat intestinal epithelial cells (IECs). The primary IECs were isolated from a new born cat's small intestine jejunum region without food ingress, and respectively in vitro cultured by tissue cultivation and combined digestion method with collagenase XI and dispase I, then purified by trypsinization. After identification, the ds cDNA of cat IECs was synthesized for constructing pGADT7 homogenization three-frame plasmid, and transformed into the yeast Y187 for generating the cDNA library. Our results indicated that cultivation of primary cat IECs relays on combined digestion to form polarized and confluent monolayers within 3 days with typical features of normal epithelial cells. The purified cells cultured by digestion method were identified to be nature intestinal epithelial cells using immunohistochemical analysis and were able to maintain viability for at least 15 passages. The homogenizable ds cDNA, which is synthesized from the total RNA extracted from our cultured IECs, distributed among 0.5-2.0 kb, and generated satisfying three-frame cDNA library with the capacity of 1.2 × 106 and the titer of 5.2 × 107 pfu/mL. Our results established an optimal method for the culturing and passage of cat IECs model in vitro, and laid a cDNA library foundation for the subsequent interaction factors screening by yeast two-hybrid. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play important roles in multiple biological processes and have attracted much scientific attention recently. Their expression can be altered by environmental factors (EFs), which are associated with many diseases. Identification of the phenotype-genotype relationships among miRNAs, EFs, and diseases at the network level will help us to better understand toxicology mechanisms and disease etiologies. In this study, we developed a computational systems toxicology framework to predict new associations among EFs, miRNAs and diseases by integrating EF structure similarity and disease phenotypic similarity. Specifically, three comprehensive bipartite networks: EF-miRNA, EF-disease and miRNA-disease associations, were constructed to build predictive models. The areas under the receiver operating characteristic curves using 10-fold cross validation ranged from 0.686 to 0.910. Furthermore, we successfully inferred novel EF-miRNA-disease networks in two case studies for breast cancer and cigarette smoke. Collectively, our methods provide a reliable and useful tool for the study of chemical risk assessment and disease etiology involving miRNAs. [ABSTRACT FROM AUTHOR]

Development of sugar-based fluorescence (FL) chemo-probes is of much interest since sugars are biocompatible, water-soluble and structurally rigid natural starting materials. We report here that fluorescent glycoligands with two triazolyl coumarin moieties installed onto the different positions of an identical glucosyl nucleus exert completely reversed optical response to a metal ion. C3,4-, C2,3- and C4,6-di-substituted coumarin glucosides synthesized by a click reaction similarly showed a selective FL variation in the presence of silver (I) among a range of metal cations in an aqueous solution. However, the variation was determined to be converse: the FL of the C3,4-ligand was quenched whereas that of the C2,3/ C4,6-ligand tangibly enhanced. FL andNMRtitrations suggested that this divergence was due to the distinct complexation modes of the conformationally constrained ligands with the ion. The optimal motifs of the ligand-ion complexation were predicted by a computational simulation. Finally, the C2,3-ligand was determined to be of low cytotoxicity and applicable in the FL imaging of silver ions internalized by live cells. [ABSTRACT FROM AUTHOR]

To probe the selective mechanism of agonists binding to three opioid receptor subtypes, ligand-based and receptor-based methods were implemented together and subtype characteristics of opioid agonists were clearly described. Three pharmacophore models of opioid agonists were generated by the Catalyst/HypoGen program. The best pharmacophore models for μ, δ and κ agonists contained four, five and five features, respectively. Meanwhile, the three-dimensional structures of three receptor subtypes were modeled on the basis of the crystal structure of β2-adrenergic receptor, and molecular docking was conducted further. According to these pharmacophore models and docking results, the similarities and differences among agonists of three subtypes were identified. μ or δ agonists, for example, could form one hydrogen bond separately with Tyr129 and Tyr150 at TMIII, whereas κ ones formed a π-π interaction in that place. These findings may be crucial for the development of novel selective analgesic drugs. [ABSTRACT FROM AUTHOR]

The interplay between light and matter is the basis of many fundamental processes and various applications. Harnessing light–matter interactions in principle allows operation of solid state devices under new physical principles: for example, the a.c. optical Stark effect (OSE) has enabled coherent quantum control schemes of spins in semiconductors, with the potential for realizing quantum devices based on spin qubits. However, as the dimension of semiconductors is reduced, light–matter coupling is typically weakened, thus limiting applications at the nanoscale. Recent experiments have demonstrated significant enhancement of nanoscale light–matter interactions, albeit with the need for a high-finesse cavity, ultimately preventing device down-scaling and integration. Here we report that a sizable OSE can be achieved at substantial energy detuning in a cavity-free colloidal metal–semiconductor core–shell hetero-nanostructure, in which the metal surface plasmon is tuned to resonate spectrally with a semiconductor exciton transition. We further demonstrate that this resonantly enhanced OSE exhibits polarization dependence and provides a viable mechanism for coherent ultrafast spin manipulation within colloidal nanostructures. The plasmon–exciton resonant nature further enables tailoring of both OSE and spin manipulation by tuning plasmon resonance intensity and frequency. These results open a pathway for tailoring light–matter–spin interactions through plasmon–exciton resonant coupling in a judiciously engineered nanostructure, and offer a basis for future applications in quantum information processing at the nanoscale. More generally, integrated nanostructures with resonantly enhanced light–matter interactions should serve as a test bed for other emerging fields, including nano-biophotonics and nano-energy. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) and its mutation recently emerged as a significant research area, due to its resistance against organophosphate and carbamate insecticides. Residue G265, which is always a conservative residue, mutated to A265 is the most frequent mutant of AChE in Drosophila populations. However, only this mutation caused a ‘butterfly effect’ that gives high insecticidal resistance. Herein, the models of sensitive strain (Dm-S) and the resistance strain (Dm-R) were constructed, to give a total of 2000 ps molecular dynamics simulation and to reveal the insecticidal resistance mechanism, with implied, the active gorge of Dm-R was much less flexible than that of Dm-S. The “back door” channel was widened to accelerate the detoxication against insecticides by the conformation changing of W83 and I161. All the distances (S238-H480, S238-G150, S238-G151, Y71-M153) in Dm-R became smaller than those in Dm-S, which may deeply influence the binding between the insecticides and DmAChE. [ABSTRACT FROM AUTHOR]

Abstract  Two chemical function-based pharmacophore models of selective κ-opioid receptor agonists were generated by using two different programs: Catalyst/HypoGen and Phase. The best output hypothesis (Hypo1) of HypoGen consisted of five features: one hydrogen-bond acceptor (HA), three hydrophobic points (HY), and one positive ionizable function (PI). The highest scoring model (Hypo2) produced by Phase comprised four features: one acceptor (A), one positive ionizable function (P), and two aromatic ring features (R). These two models (Hypo1 and Hypo2) were then validated by test set prediction and enrichment factors. They were shown to be able to identify highly potent κ-agonists within a certain range, and satisfactory enrichments were achieved. The features of these two pharmacophore models were similar and consistent with experiment data. The models produced here were also generally in accord with other reported models. Therefore, our pharmacophore models were considered as valuable tools for 3D virtual screening, and could be useful for designing novel κ-agonists. [ABSTRACT FROM AUTHOR]

Aim: To characterize the functional and pharmacological features of a symmetrical 1-pyrrolidineacetamide, N,N′-(methylene-di-4,1-phenylene) bis-1-pyrrolidineacetamide, as a new anti-HIV compound which could competitively inhibit HIV-1 integrase (IN) binding to viral DNA. Methods: A surface plasma resonance (SPR)-based competitive assay was employed to determine the compound's inhibitory activity, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell assay was used to qualify the antiviral activity. The potential binding sites were predicted by molecular modeling and determined by site-directed mutagenesis and a SPR binding assay. Results: 1-pyrrolidineacetamide, N,N′-(methylene-di-4,1-phenylene) bis- 1-pyrrolidineacetamide could competitively inhibit IN binding to viral DNA with a 50% inhibitory concentration (IC50) value of 7.29±0.68 μmol/L as investigated by SPR-based investigation. Another antiretroviral activity assay showed that this compound exhibited inhibition against HIV-1(IIIB) replication with a 50% effective concentration (EC50) value of 40.54 μmol/L in C8166 cells, and cytotoxicity with a cytotoxic concentration value of 173.84 μmol/L in mock-infected C8166 cells. Molecular docking predicted 3 potential residues as 1-pyrrolidineacetamide, N,N′-(methylene-di-4,1-phenylene) bis-1-pyrrolidineacetamide binding sites. The importance of 3 key amino acid residues (Lys 103, Lys 173, and Thr 174) involved in the binding was further identified by site-directed mutagenesis and a SPR binding assay. Conclusion: This present work identified a new anti-HIV compound through a new IN-binding site which is expected to supply new potential drug-binding site information for HIV-1 integrase inhibitor discovery and development. [ABSTRACT FROM AUTHOR]

Aim: To explore the binding mode of 2-substituted 1-indanone derivatives with acetylcholinesterase (AChE) and provide hints for the future design of new derivatives with higher potency and specificity. Methods: The GOLD-docking conformations of the compounds in the active site of the enzyme were used in subsequent studies. The highly reliable and predictive three-dimensional quantitative structure-activity relationship (3D-QSAR) models were achieved by comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. The predictive capabilities of the models were validated by an external test set. Moreover, the stabilities of the 3D-QSAR models were verified by the leave-4-out cross-validation method. Results: The CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient ( q2) and a non-cross-validated coefficient ( r2). The q2 and r2 obtained from the leave-1-out cross validation method were 0.784 and 0.974 in the CoMFA model and 0.736 and 0.947 in the CoMSIA model, respectively. The coefficient isocontour maps obtained from these models were compatible with the geometrical and physi-cochemical properties of AChE. Conclusion: The contour map demonstrated that the binding affinity could be enhanced when the small protonated nitrogen moiety was replaced by a more hydrophobic and bulky group with a highly partial positive charge. The present study provides a better understanding of the interaction between the inhibitors and AChE, which is helpful for the discovery of new compounds with more potency and selective activity. [ABSTRACT FROM AUTHOR]

Aim: The downregulation of phospholamban (PLB) and FKBP12.6 as a result of β-receptor activation is involved in the pathway(s) of congestive heart failure. We hypothesized that the endothelin (ET)-1 system may link to downregulated PLB and FKBP12.6. Methods: Rats were subjected to ischemia/reperfusion (I/R) to cause heart failure (HF). 1 mg/kg isoproterenol (ISO) was injected subcutaneously (sc) for 10 d to worsen HF. 30 mg/kg CPU0213 (sc), a dual ET receptor (ETAR/ETBR) antagonist was given from d 6 to d 10. On d 11, cardiac function was assessed together with the determination of mRNA levels of ryanodine receptor 2, calstabin-2 (FKBP12.6), PLB, and sarcoplasmic reticulum Ca2+-ATPase. Isolated adult rat ventricular myocytes were incubated with ISO at 1×10−6 mol/L to set up an in vitro model of HF. Propranolol (PRO), CPU0213, and darusentan (DAR, an ETAR antagonist) were incubated with cardiomyocytes at 1×10−5 mol/L or 1×10−6 mol/L in the presence of ISO (1×10−6 mol/L). Immunocytochemistry and Western blotting were applied for measuring the protein levels of PLB and FKBP12.6. Results: The worsened hemodynamics produced by I/R were exacerbated by ISO pretreatment. The significant downregulation of the gene expression of PLB and FKBP12.6 and worsened cardiac function by ISO were reversed by CPU0213. In vitro ISO 1×10−6 mol/L produced a sharp decline of PLB and FKBP12.6 proteins relative to the control. The downregulation of the protein expression was significantly reversed by the ET receptor antagonist CPU0213 or DAR, comparable to that achieved by PRO. Conclusion: This study demonstrates a role of ET in mediating the downregulation of the cardiac Ca2+-handling protein by ISO. [ABSTRACT FROM AUTHOR]

Metal nanoparticles (NPs) with size comparable to their electron mean free path possess unusual properties and functionalities, serving as model systems to explore quantum and classical coupling interactions as well as building blocks of practical applications. Although advances in strategies for synthesizing metal NPs have enabled control of size, composition and shape, the requirement that defects are simultaneously controlled, to ensure essential perfect nanocrystallinity for physics modelling as well as device optimization, is a potentially more significant issue, but has posed substantial technological challenges. Here we report that crystallinity of monodisperse silver NPs can be well controlled by judicious choice of functional groups of molecular precursors, thus facilitating investigation of their scope for versatile applications. We demonstrate how nanoscale chemical transformation, electron–phonon interactions and nanomechanical properties are modified by nanocrystallinity. Lastly, we find that performance of NP-based molecular sensing devices can be optimized with significant improvement of figure of merit if perfect single-crystalline NPs are applied. Our approach represents a versatile synthetic route for other metal nanomaterials with unprecedented control of their structure, creating a rational pathway for understanding and manipulating nanoscale chemical and physical processes as well as technological applications of metal NPs. [ABSTRACT FROM AUTHOR]

Abstract  Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses using CoMFA and CoMSIA methods were conducted on a series of fluoropyrrolidine amides as dipeptidyl peptidase IV (DP-IV) inhibitors. The selected ligands were docked into the binding site of the 3D model of DP-IV using the GOLD software, and the possible interaction models between DP-IV and the inhibitors were obtained. Based on the binding conformations of these fluoropyrrolidine amides and their alignment inside the binding pocket of DP-IV, predictive 3D-QSAR models were established by CoMFA and CoMSIA analyses, which had conventional r 2 and cross-validated coefficient values ($$ r^{2}_{{{\text{cv}}}} $$) up to 0.982 and 0.555 for CoMFA and 0.953 and 0.613 for CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were in the testing set. Structure-based investigations and the final 3D-QSAR results provide the guide for designing new potent inhibitors. [ABSTRACT FROM AUTHOR]

Abstract??Hopf bifurcation of a unified chaotic system ? the generalized Lorenz canonical form (GLCF) ? is investigated. Based on rigorous mathematical analysis and symbolic computations, some conditions for stability and direction of the periodic obits from the Hopf bifurcation are derived. [ABSTRACT FROM AUTHOR]

Abstract  Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the κ-receptor, comparative 3D–QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions for the κ-receptor were obtained with the CoMFA standard model (q 2=0.686, r 2=0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q 2=0.678, r 2=0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r 2 values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category κ-agonists from orvinols.

[ABSTRACT FROM AUTHOR]

Aim: To further investigate the analgesic pharmacophore of (+)-meptazinol. Methods: Two different opioid pharmacophores, Pharm-I and Pharm-II, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines. Two conformers of (+)-meptazinol (Conformer-I and Conformer-II) detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modeling tool kit for molecular design and analysis. Results: Conformer-I fit Pharm-I from typical opiates well. However, Conformer-II fit none of these pharmacophores. Instead, it was found to be similar to another potent analgesic, benzofuro[2,3- c] pyridin-6-ol, whose pharmacophore was suggested to hold the transitional state between the two established pharmacophores. Unlike typical analgesics derived from 4-aryl piperidine (eg, meperidine) with one conformer absolutely overwhelming, the (+)-meptazinol exists in two conformers with similar amounts in solution. Furthermore, both conformers can not transform to each other freely in ordinary conditions based on our NMR results. Conclusion: (+)-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol. [ABSTRACT FROM AUTHOR]

A thermophilic Bacillus strain NG80-2 growing within the temperature range of 45–73°C (optimum at 65°C) was isolated from a deep subterranean oil-reservoir in northern China. The strain was able to utilize crude oil and liquid paraffin as the sole carbon sources for growth, and the growth with crude oil was accompanied by the production of an unknown emulsifying agent. Further examination showed that NG80-2 degraded and utilized only long-chain (C15–C36) n-alkanes, but not short-chain (C8–C14) n-alkanes and those longer than C40. Based on phenotypic and phylogenic analyses, NG80-2 was identified as Geobacillus thermodenitrificans. The strain NG80-2 may be potentially used for oily-waste treatment at elevated temperature, a condition which greatly accelerates the biodegradation rate, and for microbial enhancing oil recovery process. [ABSTRACT FROM AUTHOR]

Molecular docking has been performed to investigate the binding mode of (−)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 Å). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (−)-MEP seemed to bind with the enzyme catalytic site in an open-gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (−)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (−)-MEP as new AChE inhibitors. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of action of a potent analgesic,(±)-Meptazinol.The structure of meptazinol enantiomers were compared with opioid pharmacophore and tramadol.Neither enantionmer of meptazional fitted any patterns among the opioid pharmacophore and tramadol, although they did share some structural and pharmacological similarities. However, the structure superpositions implied that both enantiomers of meptazinol might share some similar analgesic mechanisms with typical opiate analgesics.Meptazionol should have a different mechanism of action to known analgesics, which would be helpful in further investigations of meptazional in the search for non-addictive analgesics. [ABSTRACT FROM AUTHOR]

We report structural models of the full-length integrase enzyme (IN) of the human immunodeficiency virus type 1 (HIV-1) and its complex with viral and human DNA. These were developed by means of molecular modeling techniques using all available experimental evidence, including X-ray crystallographic and NMR structures of portions of the full-length protein. Special emphasis was placed on obtaining a model of the enzyme’s active site with the viral DNA apposed to it, based on the hypothesis that such a model would allow structure-based design of inhibitors that retain activity in vivo. This was because bound DNA might be present in vivo after 3’-processing but before strand transfer. These structural models were used to study the potential binding modes of various diketo-acid HIV-1 IN inhibitors (many of them preferentially inhibiting strand transfer) for which no experimentally derived complexed structures are available. The results indicate that the diketo-acid IN inhibitors probably chelate the metal ion in the catalytic site and also prevent the exposure of the 3’-processed end of the viral DNA to human DNA. [ABSTRACT FROM AUTHOR]

Some basic problems on the level set methods were discussed, such as the method used to preserve the distance function, the existence and uniqueness of solution for the level set equations. The main contribution is to prove that in a neighborhood of the initial zero level set, the level set equations with the restriction of the distance function have a unique solution, which must be the signed distance function with respect to the evolving surface. Some skillful approaches were used: Noticing that any solution for the original equation was a distance function, the original level set equations were transformed into a simpler alternative form. Moreover, since the new system was not a classical one, the system was transformed into an ordinary one, for which the implicit function method was adopted. [ABSTRACT FROM AUTHOR]

It was proved in [5] that every finite collapsible polyhedron admits of an injective metric. In this paper, by using some new techniques, we extend the conclusions in [5] to the infinite case. [ABSTRACT FROM AUTHOR]