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This manuscript is presented to investigate peristaltic phenomenon of a flow driven peristaltically in an asymmetric inclined channel under the influence of externally applied magnetic field without employing the assumption of long wavelength and smaller Reynolds number assumptions which permit the effects of dominant inertial forces and to solve the Navier-Stokes equations in full form. The numerical results are obtained with help of finite element numerical scheme with Galerkin’s residual procedure. A comparative analysis for the obtained numerical data is performed in view of already reported studies and a favorable accuracy of results is noticed. The effects of other involved parameters are also presented in suitable graphs. Trapping and pumping phenomena is also discussed. It is found that trapped bolus shape is increased with increment of Hartmann number which tends to move towards central region of asymmetric channel and is predicted that trapped bolus will disappears at large Reynolds number. The pressure in peristaltic pumping region is enhanced by increasing angle of inclination.

Spectroscopic gas sensing technologies based on absorption and Raman scattering are fast, nondestructive, long-term stable and highly selective. By making use of an optically resonant cavity, the s...

We report a novel, to the best of our knowledge, and simple technique to lock a 642 nm multi-quantum well diode laser to an external linear power buildup cavity by directly feeding the cavity reflected light back to the diode laser for enhancement of gas Raman signals. The dominance of the resonant light field in the locking process is achieved by reducing the reflectivity of the cavity input mirror and thus making the intensity of the directly reflected light weaker than that of the resonant light. Compared with traditional techniques, stable power buildup in the fundamental transverse mode TEM00 is guaranteed without any additional optical elements or complex optical arrangements. An intracavity exciting light of 160 W is generated with a 40 mW diode laser. Using a backward Raman light collection geometry, detection limits at the ppm level are achieved for ambient gases (N2, O2) with an exposure time of 60 s.

Pre-B-cell leukemia transcription factor (PBX) proteins have important roles in the development of numerous organs. To date, four members of the PBX family have been identified to be involved in human cancer but little is known about their expression patterns and precise functions in breast cancer (BC) progression. The aim of the present study was to determine whether they have the potential to be prognostic biomarkers in patients with BC. The expression patterns of PBXs were evaluated using Oncomine, Cancer Cell Line Encyclopedia and Gene expression-based Outcome for Breast cancer Online algorithm analyses. The prognostic value of PBX1 was determined by Kaplan-Meier plotter analysis. It was observed that, among all PBX family members, only PBX1 was significantly upregulated in BC vs. normal tissues. Meta-analysis in the Oncomine database revealed that PBX1 was significantly upregulated in invasive breast carcinoma stroma, ductal breast carcinoma, invasive lobular breast carcinoma, invasive mixed breast carcinoma and male breast carcinoma compared with normal tissues. In addition, PBX1 was significantly correlated with forkhead box protein A1. Subtype analysis indicated that PBX1 overexpression was associated with luminal-like and hormone receptor-sensitive subtypes. In the survival analysis, a high expression level of PBX1 was associated with poor prognosis of patients with estrogen receptor (ER)-positive, luminal A and luminal B subtypes of BC. The results of the present study indicate that PBX1 may serve as a specific biomarker and essential prognostic factor for ER-positive, luminal A and luminal B subtypes of BC.

The revelation of protein folding is a challenging subject in both discovery and description. Except acquirement of accurate 3D structure for protein stable state, another big hurdle is how to discover structural flexibility for protein innate character. Even if a huge number of flexible conformations are known, difficulty is how to describe these conformations. A novel approach, protein structure fingerprint, has been developed to expose the comprehensive local folding variations, and then construct folding conformations for entire protein. The backbone of 5 amino acid residues was identified as a universal folden, and then a set of Protein Folding Shape Code (PFSC) was derived for completely covering folding space in alphabetic description. Sequentially, a database was created to collect all possible folding shapes of local folding variations for all permutation of 5 amino acids. Successively, Protein Folding Variation Matrix (PFVM) assembled all possible local folding variations along sequence for a protein, which possesses several prominent features. First, it showed the fluctuation with certain folding patterns along sequence which revealed how the protein folding was related the order of amino acids in sequence. Second, all folding variations for an entire protein can be simultaneously apprehended at a glance within PFVM. Third, all conformations can be determined by local folding variations from PFVM, so total number of conformations is no longer ambiguous for any protein. Finally, the most possible folding conformation and its 3D structure can be acquired according PFVM for protein structure prediction. Therefore, the protein structure fingerprint approach provides a significant means for investigation of protein folding problem.

Itraconazole is an antagonist of the component Smoothened of Hedgehog pathway, which can inhibit the growth of medulloblastoma, basal cell carcinoma, and melanoma, etc. To research the binding mechanism of the Smoothened and triazoles, we used docking and molecular dynamics simulations on the Smoothened crystal structure and six triazoles. Unlike vismodegib, itraconazole can effectively bind into the pocket in the C-terminal domain of the Smoothened crystal structure instead of the N-terminal domain. The binding of itraconazole can change the conformation of the N-terminal domain even although itraconazole only had limited area contacting with N-terminal domain of the Smoothened. Besides, the binding of Itraconazole will not affect the binding of vismodegib. The strong binding affinity could be demonstrated between itraconazole and the Smoothened. Posaconazole and ketoconazole also had the strong binding affinity and the similar binding mode with the Smoothened crystal structure.

Current analysis presents the mathematical modeling for peristaltic transport of nanofluid with applications of double-diffusive convection and Hall features. The flow has been induced by a convergent channel due to peristaltic propulsion. These rheological equations are transformed from fixed to wave frames by using a linear mathematical relation between these two frames. The dimensionless variables are used to transform these rheological equations into nondimensional forms. The flow analysis is carried out under two distinct scientific biological assumptions, one is known as long wavelength and the second one is low Reynolds number. The analytical solutions of these rheological equations are obtained with the help of a rigorous analytical method known as integration in the term of stream function. The physical effects of magnetic and Hall devices, respectively, on the flow features are also considered in the present analysis. The physical influences of dominant hydro-mechanical parameters on the axial velocity, pressure gradient, trapping, volumetric fraction of nanofluid, heat and mass transfer phenomena are studied. The complex scenario of biomimetic propulsions are considered in boundary walls to boost the proficiency of peristaltic micropumps.

In the present study, the Divide and Conquer MBAR (DC-MBAR) method is proposed to predict the free energies based on the data sampled by multi-states simulations. For DC-MBAR method, the overlap between any two alchemical states is calculated first and those with sufficient overlap are defined as the adjacent states. Unlike the traditional MBAR method, which calculates the free energy of each state using all the data at once, DC-MBAR focuses on predicting the free energy changes between adjacent states. To estimate the free energy changes accurately, the other states with overlaps with the two adjacent states bigger than the defined threshold are included in the MBAR equation. At a specific threshold, the free energies predicted by DC-MBAR are very close to those calculated by the traditional MABR method. Furthermore, DC-MBAR scheme can reduce both the computation and memory cost. One important characteristic of DC-MBAR method is linear scaling, which means the CPU time with the change of the number of states is a straight-line relation. As the pair-based calculations are mutually independent and parallelizable, all accessible CPU cores on the HPC cluster could be utilized, which makes DC-MBAR strategy more efficient.

In a coarse-grained heterogeneous multi-core system, the task map is responsible for allocating the cores for task execution. The existing user static mapping method has low programming friendliness. As the scale and density of system tasks increase, so does the complexity of manual programming by users, resulting in programming inefficiencies. Aiming at this problem, based on the existing heterogeneous multi-core platform, this paper studies a dynamic task mapping method with hotspot statistics, and uses the preprocessing of the mapping to reduce the time spent on the actual mapping. The hardware mapper is designed and implemented in Verilog, and the verification platform is built in the HDL environment. The experimental results show that the new mapping algorithm significantly improves the performance of the system, with an average of 32.50% and a maximum of 47.16%.

Additional file 1: Supplementary Figure S1. Map of the PD-L1 overexpression plasmids. According to the current genomic database of the CD274 gene. The targets were designed to include the upstream of the transcript. The PAM sequences of the target sites for CRISPR were TGG. Primers were synthesized, and the oligo dimer was inserted into the vector. DH5a competent cells were used for conversion. Plasmids A and B were mixed at a ratio of 1:1, and RPMECs were transfected with Lipofectamine 3000 reagent according to the instructions. (A) Map of plasmid 1 for MS2-P64-NSF1 expression. (B) Map of plasmid 2 for dCas9-vp64 and gRNA expression.

Complex cavity permeated with permeable media was influenced by magnetic field in current modeling. The flow encounters resistance in existence of Lorentz force and to improve thermal features, water was equipped with nano powders. Induce magnetic was ignored and to harness the permeability effect, non-Darcy approach was used. Current model acquired large attention in industry. For examine the correctness of code, the results of θ was compared with previous basic article and achieved graph illustrates nice conformity of current modeling. Two straight wall were adiabatic, lower and upper walls were confined to hot and cold temperature bath. Laminar flow was established and maximum of Ra is 105 and carrier fluid is incompressible. To incorporate the gravity force, Boussinesq principle was utilized. The bottom surface was subjected to hot source and gravity enforces the nanomaterial to go up and create rotating cell. The complex shape of isotherms pertains to stronger convection which is attributed to greater permeability. Involve of MHD, declines the distortion of isotherms and conduction becomes stronger in greater Ha. Rise of Ha leads to decrease in Ψ about 60% when Da = 100. Ψ augments about 100% with augment of Da when Ha = 0. Rise of Ha provides reduction in Nu about 11.48% and 9.37% when Da = 100 and 0.01, respectively. Rise of Rd offers 106.6% augmentation in Nu when Ha = 0. When Ha = 20 and Da = 100, rise of Ra leads to 99% augmentation in Nu.

A numerical analysis on the thermo-natural convection as well as entropy generation of Al2O3-H2O nanofluid enclosed by two circular cylinders in the presence of magnetic fields was performed. The internal hot cylinder is fitted with rectangular fins of different lengths. Irreversibilities related to the thermal effects, friction effects, magnetic effects were considered. FEM was selected as solving method. Results described the impact of active parameters on the thermo-natural convective flow and heat transfer behaviour as well as entropy generation characteristics. In addition, a basic economic analysis has been proposed to consider the cost of nanofluids in comparison to their contribution in enhancing heat transfer rate. Results show that significant effects of pertinent parameters e.g. Rayleigh, Hartmann, and fins' size on flow, heat transfer, and irreversibilities within annulus. It is also found that for low Rayleigh, irreversibility related to thermo-effects is predominant within the annulus, and by augmenting Rayleigh values, the irreversibility due to the thermo-effects is no longer the key contributor to overall entropy production. The magnetic forces help to increase thermo-effects irreversibility contribution to overall irreversibilities. Finally, thermal transfer enhancement in case of the presence of magnetic forces is found to be more costly in terms of nanofluid utilization.

Objective: Dysregulation of miR-34a has been reported for its implication in neuronal development. This study aims to explore the effect and possible mechanism of miR-34a on neuron apoptosis induced by Spinal Cord Injury (SCI). Materials and Methods: SCI model was established using Allen's weight-drop method and rats in the sham group were performed with laminectomy without weight-drop injury. Basso Bcattie Bresnahan (BBB) rating scale was applied to evaluate the locomotor function of rats. Pathological changes of spinal cord tissues in SCI rats were observed after hematoxylin and eosin (HE) staining. Rats were separately injected with miR-34a agomir, miR-34a agomir NC, si-CD47 and si- CD47 NC before their spinal cord tissues were collected for terminal-deoxynucleoitidyl Transferase Mediated nick end labeling (TUNEL) staining. Expressions of miR-34a, si-CD47, apoptosis related proteins and AKT pathway related proteins were measured by quantitative reverse transcription- polymerase chain reaction (qRT-PCR) and western blot. Results: SCI rat models were successfully established evidenced by decreased BBB scores and HE staining. Injection of miR-34a agomir and/or si-CD47 could suppress neuron cell apoptosis, with deceased apoptotic index (AI) and pro-apoptotic protein (cleaved caspase-3 and Bax) levels, and increased expressions of anti-apoptotic proteins (Bcl-2 and Mcl-1). Phosphorylated levels of phatidylinositol 3-kinase (PI3K) and AKT were further increased in rats injected with miR-34a agomir and si-CD47, compared with miR-34a agomir or si-CD47 injection alone. Conclusion: MiR-34a can downregulate CD47 expression to activate PI3K/AKT signal pathway, and thus inhibit SCI induced spinal neuron apoptosis.

In this paper, the simulations of Ansys HFSS and CST Microwave Studio for frequency selective surface (FSS) are discussed. The definitions of the Floquet modes, mesh density, and the distance between Floquet port and FSS surface affects the accuracy of the corresponding transmission coefficients. According to the example of a typical biplanar symmetric hybrid radome, the efficient simulation conditions of the two softwares for FSS are summarized.

Growing evidence suggests that alterations of gene expression including expression and activities of transcription factors are closely associated with carcinogenesis. Forkhead Box Class K (FOXK) proteins, FOXK1 and FOXK2, are a family of evolutionarily conserved transcriptional factors, which have recently been recognized as key transcriptional regulators involved in many types of cancer. Members of the FOXK family mediate a wide spectrum of biological processes, including cell proliferation, differentiation, apoptosis, autophagy, cell cycle progression, DNA damage and tumorigenesis. Therefore, the deregulation of FOXKs can affect the cell fate and they promote tumorigenesis as well as cancer progression. The mechanisms of FOXKs regulation including post-translational modifications (PTMs), microRNAs (miRNAs) and protein-protein interactions are well demonstrated. However, the detailed mechanisms of FOXKs activation and deregulation in cancer progression are still inconclusive. In this review, we summarize the regulatory mechanisms of FOXKs expression and activity, and their role in the development and progression of cancer. We have discussed whether FOXKs act as tumor suppressors/oncoproteins in tumor cells and their therapeutic applications in malignant diseases are also discussed. This review may assist in designing experimental studies involving FOXKs and it would strength the therapeutic potential of FOXKs as targets for cancers.

To detect the influence of MHD on migration of hybrid nanopowders, CVFEM has been employed in this paper. Mixture of Fe3O4 and MWCNT was added in water and for calculating properties, experimental formulas were utilized. To increase the convective mode, porous media has been used and tank was experienced in the horizontal magnetic field. In governing equations, there exist two new terms, one for permeable media and the other for MHD effect. Such complex physics needs special numerical approach and CVFEM has been utilized for this goal. Final formulation of PDEs did not have pressure terms and the stream function scalar was introduced. As permeability of zone enhances, nanopowders can transfer faster and the interaction of them with wall enhances, so, Nusselt number augments as well as stream function. Besides, employing higher Ha, the force against the buoyancy force increases and the velocity of operating fluid declines which provides lower convective flow. With rise of Ha, stream function declines about 48% and Nu declines about 31.92% when [Formula: see text]. As Da rises, Nu rises about 33.43% when [Formula: see text]. Augment of Rd leads to augmentation of Nu.

The progressive and enhanced thermal mechanisms of nanoparticles has motivated researchers to give attention to this topic in recent years. The synthesizing and versatile applications of such materials include cooling and heating controlling processes, solar systems, energy production, nanoelectronics, hybrid-powered motors, cancer treatments, and renewable energy systems. Moreover, the bioconvection of nanofluids allows for some motivating applications in this era of bioengineering and biotechnology, such as biofuels, biosensors, and enzymes. With these interesting motivations and applications, this study elucidated upon the three-dimensional bioconvection flow of a Sisko fluid (base fluid) in the presence of a nanofluid over a stretched surface. The additional thermal features of radiation were also incorporated to modify the analysis. The rheological features of shear thinning and shear thickening that are associated with the Sisko nanofluid were comprehensively studied. The problem was formulated using highly nonlinear and coupled differential equations, which were numerically simulated via a shooting scheme. The salient physical applications of flow parameters were graphically underlined in view of shear-thinning and shear-thickening scenarios. The results showed that a decrease in velocity in the presence of buoyancy ratio forces was more conducive to the shear-thinning phenomenon. The increase in temperature profile due the thermal Biot number and surface heating source parameter seemed to be more inflated in the shear-thinning scenario. A lower motile microorganism profile was noted for the bioconvection Lewis number.

The growing development in the thermal engineering and nano-technology, much attention has been paid on the thermal properties of nanoparticles which convey many applications in industrial, technological and medical era of sciences. The noteworthy applications of nano-materials included heat transfer enhancement, thermal energy, solar systems, cooling of electronics, controlling the heat mechanisms etc. Beside this, entropy generation is an optimized scheme which reflects significances in thermodynamics systems to control the higher energy efficiency. On this end, present work presents the slip flow of Jeffrey nanofluid over a stretching sheet with applications of activation energy and viscous dissipation. The entropy generation features along with Bejan number significance is also addressed in present analysis. Buongiorno model of nanofluid is used to discuss the heat and mass transfer. The formulated flow equations are attained into non-dimensional form. An appropriate ND MATHEMATICA built-in scheme is used to find the solution. The solution confirmation is verified by performing the error analysis. For developed flow model and impacted parameters, a comprehensive graphical analysis is performed. It is observed that slip phenomenon is used to decays the velocity profile. Temperature and concentration are in direct relation with Brownian motion parameter and activation energy respectively. Entropy and Bejan number have same results for greater diffusion parameter.

Mutations of CYP51A protein (Cytochrome P450 14-α Sterol demethylase) play a central role in the azole resistance of Aspergillus fumigatus The available structural models of CYP51A protein ofA. fumigatus are built based on that of Homo sapiens and that of Mycobacterium tuberculosis, of which the amino acid homology is only 38% and 29% compared with CYP51A protein ofA. fumigatus, respectively. In the present study, we constructed a new 3D structural model ofA. fumigatus CYP51A protein based on a recently resolved crystal structure of the homologous protein in the fungus S. cerevisiae, which shares 50% amino acid homology with A. fumigatus CYP51A protein. Three azole molecules, itraconazole, voriconazole, and posaconazole, were docked to the wild-type and the mutant A. fumigatus CYP51A protein models, respectively, to illustrate the impact of cyp51A mutations to azole-resistance. We found the mutations that occurred at L98, M220, and Y431 positions would decrease the binding affinity of azoles to the CYP51A protein and therefore would reduce their inhibitory effects. Additionally, the mutations of L98 and G432 would reduce the stability of the protein, which might lead to conformational change of its binding pocket and eventually the resistance to azoles.

Drought stress hinders plant growth and development, and abscisic acid (ABA) stimulates plants to respond to drought. Here, to increase plant tolerance to drought, we designed three synthetic promoters (Ap, Dp, ANDp) to determine transcription activity and drought stress resistance in plants resulting from combinations of (1) synthetic promoters and (2) the functional genes CARK1 (cytosolic ABA receptor kinase 1) and RCAR11 (regulatory components of ABA receptor 11). Transient expression of eGFP and the dual-luciferase assay demonstrated that the basal transcriptional activities of Ap and ANDp were present at low levels under normal conditions, while the synthetic promoters were apparently induced upon either treatment of exogenous ABA or co-transformation with effector DREB2A (dehydration-responsive element binding protein 2A). Analysis of the transgenic plants (Ap:CARK1, Dp:CARK1, ANDp:CARK1, and Dp:RCAR11-Ap:CARK1) showed that the synthetic promoters Ap, Dp, and ANDp increased the expression of exogenous genes in transgenic plants upon treatment of ABA or d-mannitol. ANDp:CARK1 and Dp:RCAR11-Ap:CARK1 transgenic plants were sensitive to ABA and d-mannitol during cotyledon greening and root growth. A drought tolerance assay revealed that ANDp:CARK1 and Dp:RCAR11-Ap:CARK1 exhibited a higher survival rate than others upon drought stress. These results indicate that the combinations ANDp:CARK1 and Dp:RCAR11-Ap:CARK1 can be used to generate drought stress resistance in plants.

CARK1 preferentially interacts with and phosphorylates ABA receptors of subfamily III; the phosphorylation site RCAR11T78 plays a substantial role in the activation of the ABA response pathway., Abscisic acid (ABA) plays a vital role in responses to abiotic stresses that allow plants to cope with environmental challenges. In this study, we analyzed ABA receptors of subfamily III as the potential targets of Cytosolic ABA Receptor Kinase 1 (CARK1). We previously found that CARK1 phosphorylated the subfamily III member RCAR11 at a distinct threonine residue (T78). Our study now shows the physical interaction of CARK1 with the receptors RCAR12/13/14 in vitro and in vivo. The catalytically inactive form CARK1-N204A did not interact with the receptors. Phosphorylation of these ABA receptors in vitro occurred at a serine/threonine amino acid residue corresponding to T78 in RCAR11, which is located in the loop of β3 within a conserved site. Further analysis revealed that the phosphorylation of RCAR11T78 could increase the sensitivity of the pyr1pyl1pyl2pyl4 quadruple mutant (1124) to ABA, including the inhibition of root elongation and increasing drought tolerance. The analysis of CARK1:1124 complementation and the expression of ABA-related genes indicated that CARK1 could rescue the insensitivity of 1124 to ABA. Our results indicate that CARK1 tends to phosphorylate subfamily III ABA receptors, and the phosphosites RCAR11T78, RCAR12T105, RCAR13T101, and RCAR14S81 are the major sites involved in the activation of the ABA response pathway.

π-π interactions are common and important noncovalent interactions that contribute to biochemical molecular interactions, but the tools for the convenient 3D visualization of π-π interactions are lacking. We have developed an open-source and easy-to-use tool for the automated identification and display of π-π stacking in 3D. It can percept the aromaticity of rings from any selected ligand and the surrounding residues, calculate the distances and dihedral angles between each pair of aromatic ring planes, as well as can highlight the various configurations of π-π interactions in 3D: the sandwich configuration, the T-shaped configuration, and the parallel-displaced configuration. In addition, the users can easily adjust or set their own criteria for π-π stacking.

Influenza is an acute respiratory infectious disease caused by influenza viruses. Its subtype can be distinguished based on the antigenicity of two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). One of the main challenges in anti-influenza drug development is the quick evolution of drug resistance due to virus mutations. One solution to this problem is to develop dual-targeting anti-influenza agents. In this paper, a new rationally designed virtual screening protocol that combines structure-based approaches (molecular docking and molecular dynamic simulations) and ligand-based approaches (support vector machines and 3D shape & electrostatic similarity algorithms) is reported for the virtual screening of dual-targeting agents against HA and NA. The final hits came from the consensus of the ligand- and receptor-based knowledge of HA and NA and were tested using ADMET predictions. Evidence from the binding energy calculations and binding mode analyses suggested that several of the hits are promising as dual-targeting anti-influenza agents. The virtual screening protocol may also lead to the identification of innovative drugs in other fields.

Background Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the biosynthesis of cholesterol and in the post-translational modification of signaling proteins. It has been reported that non-bisphosphonate FPPS inhibitors targeting its allosteric binding pocket are potentially important for the development of promising anti-cancer drugs. Methods The following methods were used: organic syntheses of non-bisphosphonate quinoline derivatives, enzyme inhibition studies, fluorescence titration assays, synergistic effect studies of quinoline derivatives with zoledronate, ITC studies for the binding of FPPS with quinoline derivatives, NMR-based HAP binding assays, molecular modeling studies, fluorescence imaging assay and MTT assays. Results We report our syntheses of a series of quinoline derivatives as new FPPS inhibitors possibly targeting the allosteric site of the enzyme. Compound 6b showed potent inhibition to FPPS without significant hydroxyapatite binding affinity. The compound showed synergistic inhibitory effect with active-site inhibitor zoledronate. ITC experiment confirmed the good binding effect of compound 6b to FPPS, and further indicated the binding ratio of 1:1. Molecular modeling studies showed that 6b could possibly bind to the allosteric binding pocket of the enzyme. The fluorescence microscopy indicated that these compounds could get into cancer cells. Conclusions Our results showed that quinoline derivative 6b could become a new lead compound for further optimization for cancer treatment. General significance The traditional FPPS active-site inhibitors bisphosphonates show poor membrane permeability to tumor cells, due to their strong polarity. The development of new non-bisphosphonate FPPS inhibitors with good cell membrane permeability is potentially important.

In the present study, we found that three enzymes, MVK, MDD and FPPS, in the mevalonate pathway (MVP) of cholesterol biosynthesis, can be simultaneously inhibited by two green tea polyphenols ((-)-epicatechin-3-gallate, ECG; (-)-epigallocatechin-3-gallate, EGCG). Molecular dynamics simulations and pharmacophore studies were carried out to elucidate the tri-targeted inhibition mechanisms. Our results indicate that similar triangular binding pockets exist in all three enzymes, which is essential for their binding with polyphenols. Two distinct binding poses for ECG and EGCG were observed in our MD simulations. These results shed light on the potential for further selective and multi-targeted inhibitor design for the treatment of hyperlipidemia.

Current drugs against central nervous system (CNS) disorders have limited symptomatic activities, and new approaches with neuroprotective and neurorestorative properties are urgently needed. The complex pathology of CNS disorders requires the development of multitargeted or multifunctional drugs towards several CNS targets. In the present work, employing the pharmacophore of fasudil, a Rho-associated coil kinase (ROCK) inhibitor, and alpha-lipoic acid (LA), a potent anti-oxidant, we have developed a novel multitargeted and neuroprotective drug, L-F 001. L-F 001 displayed potent inhibition towards both ROCK 1 (IC50 = 1.59 μM) and ROCK 2 (IC50 = 2.10 μM) and reduced the actin stress formation. Rat thoracic aorta assay showed that L-F 001 exerted potent vasodilation. Furthermore, the compound was capable of scavenging free radicals, increasing the level of glutathione, and preventing HT 22 cell death caused by glutamate (Glu). Moreover, the new entity had higher brain permeation over fasudil according to in vitro and in vivo blood–brain barrier (BBB) permeability tests. These results indicate that L-F 001 is a promising multifunctional agent for the treatment of CNS disorders.

In this paper, we describe the first prospective application of the shape-comparison program, WEGA (weighted Gaussian algorithm), to find new scaffolds for anti-tumor agents. A series of sixteen carbazole alkaloids extracted from Clausena vestita D. D. Tao, which have anti-tumor activities at the cellular level, were used as query molecules. A compound library was screened by ranking molecules based upon their 3D shape and pharmacophore similarities to known inhibitors. The relationship between the structures and activities was also studied through comparative molecular field analysis (CoMFA). Twelve hits show comparable growth inhibition activity against HepG2 cells (a hit rate of 60%); eight of the hits have new scaffolds (in comparison with known inhibitors). These results indicate that a shape-based screening approach, such as WEGA, can be efficiently used for scaffold hopping in a lead identification process.

Background: Interleukin-1 receptor type I (IL-1RI) is critical for both innate immunity and inflammation. IL-1RI stimulates thymocyte proliferation and the release of several interleukin cytokines. These properties have increased interest in targeting IL-1RI for the treatment of inflammatory diseases. Here, an IL-1RI antagonist, K(D)PT (Lys-D-Pro-Thr), was tested in an allergic rhinitis model. The mechanism of action was then investigated. Methods: HEK293/IL-1RI cells and an allergic rhinitis animal model were treated with K(D)PT to evaluate its therapeutic effects. Fifty nanosecond (ns) molecular dynamic (MD) simulations were performed on the K(D)PT/IL-1RI complex, unliganded IL-1RI, and the IL-1β/IL-1RI complex to explore the mechanism of action of K(D)PT. Results: K(D)PT down-regulated the IL-1RI-mediated induction of IL-2 and IL-4 mRNA expression by IL-1β in HEK293/IL-1RI cells. In addition, nose itching was alleviated in mice treated with K(D)PT. Serum levels of IL-2 and IL-4 as well as eosinophil infiltration were also reduced. The data suggested that IL-1RI was highly expressed in the nasal mucosa of mice with allergic rhinitis. MD simulations revealed the following: (1) IL-1RI remains in the open conformation in the IL-1RI/IL-1β complex; (2) in unliganded IL-1RI, domains I and III randomly moved closer and apart without any significant energetic changes; (3) K(D)PT locks the C- and N- terminals of IL-1RI by forming hydrogen bonds with both terminals to adopt a closed conformation and consequently minimizes the system energy. Conclusions: IL-1RI antagonist K(D)PT effectively treated allergic rhinitis. The molecular mechanism of action indicated that K(D)PT connects the C- and N- terminals of IL-1RI via hydrogen bond formation to establish a stable conformation and consequently minimize the system energy of IL-1RI.

RhoA/Rho-kinase pathway plays a pivotal role in numerous fundamental cellular functions including contraction, motility, proliferation, differentiation and apoptosis. The pathway is also involved in the development of many diseases such as vasospasm, pulmonary hypertension, cancer and central nervous systems (CNS) disorders. The inhibitors of Rho kinase have been extensively studied since the Rho/Rho-kinase pathway was verified as a target for a number of diseases. Herein, we reviewed the advances in the studies of the roles of Rho/Rho-kinase in diseases and the development of Rho-kinase inhibitors in recent five years.

High-performance computing (HPC) has become a state strategic technology in a number of countries. One hypothesis is that HPC can accelerate biopharmaceutical innovation. Our experimental data demonstrate that HPC can significantly accelerate biopharmaceutical innovation by employing molecular dynamics-based virtual screening (MDVS). Without using HPC, MDVS for a 10K compound library with tens of nanoseconds of MD simulations requires years of computer time. In contrast, a state of the art HPC can be 600 times faster than an eight-core PC server is in screening a typical drug target (which contains about 40K atoms). Also, careful design of the GPU/CPU architecture can reduce the HPC costs. However, the communication cost of parallel computing is a bottleneck that acts as the main limit of further virtual screening improvements for drug innovations.

The cytochrome P450 CYP6ER1 has been reported to play an important role in imidacloprid resistance of the brown planthopper (BPH), Nilaparvata lugens, and is overexpressed in most resistant populations. In the present study, we confirmed that CYP6ER1 expression can be induced by certain levels of imidacloprid. Developmental expression analysis revealed that CYP6ER1 was expressed highly in the adult stage, and tissue distribution analysis showed that CYP6ER1 was expressed mainly in the fat body and midgut. RNA interference (RNAi) of CYP6ER1 and transgenic expression of CYP6ER1 in Drosophila melanogaster both suggested that the expression of CYP6ER1 is sufficient to confer imidacloprid resistance. Furthermore, we analyzed the interaction of imidacloprid and CYP6ER1 monooxygenase by using dynamic simulations and molecular docking. We found that Nitrogen atoms in the heterocycle of the imidacloprid molecule may bind to iron atoms in the center of the homology model of CYP6ER1 via 4,5-dihedro-1H-imidazole. This finding contributes to a better understanding of how CYP6ER1 takes part in the insecticide metabolism.

Iron pyrite has received significant attention due to its high optical absorption. However, the loss of open circuit voltage (Voc) prevents its further application in photovoltaics. Herein, we have studied the photophysics of pyrite by ultrafast laser spectroscopy to understand fundamental limitation of low Voc by quantifying photocarrier losses in high quality, stoichiometric, and phase pure {100} faceted pyrite nanocubes. We found that fast carrier localization of photoexcited carriers to indirect band edge and shallow trap states is responsible for major carrier loss. Slow relaxation component reflects high density of defects within the band gap which is consistent with the observed Mott-variable range hopping (VRH) conduction from transport measurements. Magnetic measurements strikingly show the magnetic ordering associated with phase inhomogeneity, such as FeS2−δ (0 ≤ δ ≤ 1). This implies that improvement of iron pyrite solar cell performance lies in mitigating the intrinsic defects (such as sulfur vacancies) by blocking the fast carrier localization process. Photocarrier generation and relaxation model is presented by comprehensive analysis. Our results provide insight into possible defects that induce midgap states and facilitate rapid carrier relaxation before collection. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore)

Human chemokine receptor CXCR3 (hCXCR3) antagonists have potential therapeutic applications as antivirus, antitumor, and anti-inflammatory agents. A novel virtual screening protocol, which combines pharmacophore-based and structure-based approaches, was proposed. A three-dimensional QSAR pharmacophore model and a structure-based docking model were built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist binding site was constructed by homology modeling and molecular dynamics (MD) simulation. By combining the structure-based and ligand-based screenings results, 95% of the compounds satisfied either pharmacophore or docking score criteria and would be chosen as hits if the union of the two searches was taken. The false negative rates were 15% for the pharmacophore model, 14% for the homology model, and 5% for the combined model. Therefore, the consistency of the pharmacophore model and the structural binding model is 219/273 = 80%. The hit rate for the virtual screening protocol is 273/286 = 95%. This work demonstrated that the quality of both the pharmacophore model and homology model can be measured by the consistency of the two models, and the false negatives in virtual screening can be reduced by combining two virtual screening approaches.

In this paper, we synthesize three Re(I) complexes of Re(CO)3(PPO)Br, Re(CO)3(PTO)Br, and Re(CO)3(PBI)Br, where PPO=2-phenyl-5-(pyridin-2-yl)-1,3,4-oxadiazole, PTO=2-(pyridin-2-yl)-5-p-tolyl-1,3,4-oxadiazole, PBI=2-(pyridin-2-yl)-1H-benzo[d]imidazole. Their single crystals and photophysical properties are measured and discussed in detail. The correlation between ligand structure and corresponding PL characteristics of Re(I) complex has been investigated. It is found that a ligand with strong electron-donor can efficiently increase both absorption and emissive energy of Re(I) complex. In addition, electron-rich ligand can increase the electron density of the complex and thus enhance the oscillator strength of electronic transition, improving the photoluminescence performance.

Based on the first-principles within the density functional theory, the geometric structures of perfect zinc blend ZnSe, that with Zn vacancies (Zn0.875Se) and Cu-doped ZnSe (Zn0.875Cu0.125Se) were optimized using the plane-wave ultrasoft pseudopotential method. The defect formation energy, band structure, density of states, Mulliken charges, and optical spectra were calculated and discussed in detail. The results demonstrated that in Zn0.875Se and Zn0.875Cu0.125Se systems, because of the introduction of the vacancy acceptor level or acceptor impurity level, the band gap is reduced, and the absorption peaks show a remarkable redshift. Cu doping into the ZnSe system was found to be relatively stable, while the monovacancy system was not.

Glycogen synthase kinase 3β (GSK-3β) is a potential therapeutic target for cancer, type-2 diabetes, and Alzheimer's disease. This paper proposes a new lead identification protocol that predicts new GSK-3β ATP competitive inhibitors with topologically diverse scaffolds. First, three-dimensional quantitative structure-activity relationship (3D QSAR) models were built and validated. These models are based upon known GSK-3β inhibitors, benzofuran-3-yl-(indol-3-yl) maleimides, by means of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Second, 28 826 maleimide derivatives were selected from the PubChem database. After filtration via Lipinski's rules, 10 429 maleimide derivatives were left. Third, the FlexX-dock program was employed to virtually screen the 10 429 compounds against GSK-3β. This resulted in 617 virtual hits. Fourth, the 3D QSAR models predicted that from the 617 virtual hits, 93 compounds would have GSK-3β inhibition values of less than 15 nM. Finally, from the 93 predicted active hits, 23 compounds were confirmed as GSK-3β inhibitors from literatures; their GSK-3β inhibition ranged from 1.3 to 480 nM. Therefore, the hits rate of our virtual screening protocol is greater than 25%. The protocol combines ligand- and structure-based approaches and therefore validates both approaches and is capable of identifying new hits with topologically diverse scaffolds.

Recently, reversible antagonists of the P2Y(12) receptor have been reported. However, the mechanisms of binding have not been elucidated. To this end, a number of homology models were built by means of three programs from four templates. A consensus model was derived from those initial models. The final model was created by refining the consensus model with molecular dynamics simulations. The agonist and antagonists of P2Y(12) have been docked in the final model. For the agonist, the Arg256, Lys280, and Phe252 are "hot" residues. For the antagonists, the Lys280 and Phe252 are "hot" residues that have hydrogen bonding contacts and π-π interactions, respectively. These results can explain the observations of mutation experiments and can guide the design of new inhibitors.

In this paper, we report the synthesis of four diimine ligands incorporated with an electron donor/acceptor, as well as their corresponding Cu(I) complexes with bis(2-(diphenylphosphanyl)phenyl) ether as an ancillary ligand, resulting in four phosphorescent Cu(I) complexes. Their crystal structures as well as photophysical and thermal properties are discussed in detail. Experimental data and theoretical calculations confirm that electron donor moieties and limited conjugation system may self-restrict geometry relaxation in excited states, leading to narrowed and blue-shifted emission bands. On the other hand, electron acceptor moieties and large coplanar conjugation system are ineffective in restricting geometry relaxation, leading to broadened and red-shifted emission bands. However, the introduction of electron donors compromises thermal stability of Cu(I) complexes. We also explore one of the Cu(I) complexes as a dopant for electroluminescence application, and a maximum luminance of 680 cd/m2 peaking at 620 nm is achieved.

Objective: Although the surgical‐pathological classification can be considered the ‘gold standard’ of T-N staging, it could not provide satisfactory and accurate estimation of survival rates in early-stage non-small cell lung cancer (NSCLC). Methods: In our study, the expression of carcinoembryonic antigen (CEA), p53 and intracytoplasmic keratin (AE1/AE3) using haematoxylin‐eosin (HE) staining negative lymph nodes (LNs) in 28 patients with early-stage NSCLC were analysed using fluorescent quantitation reverse transcription‐polymerase chain reaction (FQ‐PCR) and immunohistochemistry (IHC). Results: One hundred and ninety-three LNs were analysed. Two patients staged as I upstaged to II, and six patients staged as II up-staged to III. About 32, 19 and 36 LNs were positive, respectively, for CEA mRNA (32/193, 16.6%), p53 (19/193, 9.84%) and AE1/AE3 (36/193, 18.65%) compared with control LNs. Only FQ‐PCR test for CEA mRNA could detect micrometastases in stage I NSCLC patients with N0 LNs (2/13, 15.4%). Disease-free time in patients with CEA mRNA (P ¼ 0.000), p53 protein (P ¼ 0.013) and AE1/AE3 (P ¼ 0.003) positive were significantly inferior to those with micrometastases negative. Moreover, the results demonstrated that the positive LNs for CEA mRNA (P ¼ 0.028), p53 protein (P ¼ 0.048) and AE1/AE3 (P ¼ 0.007) were associated with the relapse time, respectively. However, Cox proportional hazards test showed that only clinical stage was the independent risk factor of relapse, and denied the correlation between micrometastases in LNs and recurrence. Conclusions: Detection of CEA mRNA, p53, AE1/AE3 in HE-negative LNs may improve veracity of N staging and predict its prognosis in patients with early-stage NSCLC. Furthermore, micrometastases in stage I may be performed by FQ‐PCR more sensitive than IHC.

Background Obstructive jaundice is associated with enhanced susceptibility to hypotensive shock, renal failure, and toxic effects of endotoxin, which results in high perioperative morbidity and mortality. Since the normal arterial baroreflex function is necessary for hemodynamic homeostasis and improving survival in sepsis, this study aimed to determine whether baroreflex sensitivity was impaired in jaundiced patients. Methods Thirty-five patients with obstructive jaundice scheduled for surgery were included, and 30 nonjaundiced patients served as controls. A modified Oxford pharmacologic technique was used for evaluating baroreflex sensitivity immediately before the surgery. Potential factors that may affect baroreflex sensitivity in jaundice, such as liver biochemistry, plasma concentrations of methionine-enkephalin, atrial natriuretic peptide and nitrate, were also measured. Results Patients with obstructive jaundice had decreased sensitivity in both the sympathetic and vagal components of the baroreflex, as compared with the controls (P < 0.01). There was a significant inverse correlation between plasma atrial natriuretic peptide concentration and decreased sympathetic baroreflex sensitivity in the jaundiced group (r = -0.44, P = 0.008). Conclusions Baroreflex sensitivity is impaired in patients with obstructive jaundice, which may contribute to their enhanced susceptibility to the well-known perioperative complications. The underlying mechanisms for such a change may be associated with an increased level of plasma atrial natriuretic peptide.

Objective HOXB7 gene is a kind of transcription regulator over-expressed in malignant melanoma (MM) cell lines. It can specifically up-regulate the expression of angiogenic factors and tumor growth factors such as bFGF, GROa, VEGF and induce angiogenesis in melanoma, resulting in the proliferation and metastasis of tumor cells. We designed and synthesized HOXB7 specific siRNA to study its interfering effect on the expressions of HOXB7 and bFGF genes in melanoma A375 cell line and the biologic characteristics of A375 cells.

Ceruloplasmin (CP) is essential for brain iron homeostasis. However, little is known about the effect of iron on CP expression in the brain. Also, the role of CP in brain iron transport has not been well determined. In this study, we investigated the effects of iron on CP expression and the role of CP in iron transport in the C6 rat glioma cells. Our data showed that treatment of the cells with iron (cell iron overload) or iron chelators (cell iron deficiency) did not induce a significant change in the expression of CP mRNA. However, western blotting analysis demonstrated that cell iron overload induced a significant decrease in CP protein content in the cells and that treatment with iron chelators led to a significant increase in CP protein level in the cells. These findings suggest a translational regulation of CP expression by iron in the cells. We also examined the effects of CP on iron transport in the cells. We found that glycosylphosphatidylinositol-anchored CP did not have any impact on iron uptake by normal iron or iron-deficient cells nor on iron release from normal iron or iron-sufficient cells. However, low concentrations of soluble CP (2–8 μg/ml) increased iron uptake by iron-deficient C6 glioma cells, while the same concentrations of CP had no effect on iron uptake by normal iron cells and iron release from normal iron and iron-sufficient cells. The possible reason for the difference between our results in vitro and those obtained from in vivo studies was discussed.