Nickel oxide morphology synthesized with a hydrothermal method for inverted perovskite solar cells.

In this paper, a hydrothermal method is used to synthesize a nickel oxide nanostructure (nano-NiO) for its application to inverted perovskite solar cells. These pore nanostructures were employed to increase both the contact and channel between the hole transport and perovskite layers of an ITO/nano-N i O/C H 3 N H 3 P b I 3/P C B M/A g device. The purpose of this research is twofold. First, three different nano-NiO morphologies were synthesized at temperatures of 140°C, 160°C, and 180°C. Then, a Raman spectrometer was used to check the phonon vibration and magnon scattering characteristics after an annealing temperature of 500°C. Second, nano-NiO powders were dispersed in isopropanol for subsequent spin coating on the inverted solar cells. The nano-NiO morphologies were multi-layer flakes, microspheres, and particles at synthesis temperatures of 140°C, 160°C, and 180°C, respectively. When the microsphere nano-NiO was used as the hole transport layer, the perovskite layer had a larger coverage of 83.9%. The grain size of the perovskite layer was analyzed by x-ray diffraction, and strong crystal orientations of (110) and (220) peaks were found. Despite this, the power conversion efficiency could affect the promotion, which is 1.37 times higher than the poly(3,4-ethylenedioxythiophene) polystyrene sulfonate element conversion efficiency of the planar structure.

Non-canonical modulators of nuclear receptors.

Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research.

Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.

Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aß) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aß levels was detected.

[Design, synthesis and in vitro antifungal activity of 3-substituted-methylenechroman-4-ones].

Substituted phenols as the starting materials were transformed into substituted chromanones by substitution reaction and cyclization reaction, and then 3-(hydroxymethylene)chroman-4-ones were synthesized from substituted chromanones by condensation reaction; at last, the target compounds were synthesized from 3-(hydroxymethylene)chroman-4-ones by chlorination reaction. Their structures were confirmed by 1H NMR and MS. The antifungal activity of the target compounds in vitro was measured by consecutive double dilution, and the result of antifungal experiment indicated that the target compounds had good antifungal action on most fungi tested in vitro. The MIC value of compounds 4c, 4e, 4g and 4h on M. gypseum is 1 microg x mL(-1), better than fluconazole and amphotericin B.

Is a boosting dose of granulocyte-colony-stimulating factor necessary for healthy PBSC donors undergoing secondary apheresis? An institute's experience.

Successful allogeneic PBSC transplantation depends upon the infusion of an adequate number of CD34+ cells to patients. Granulocyte-colony-stimulating factors (G-CSF) mobilized PBSC were harvested on 5th day after stimulation from donors. When the CD34+ cell target yield was not achieved; secondary apheresis was performed the following day. Before September 2006, 67 donors (Group A) received five doses of G-CSF. After September 2006, a sixth dose of G-CSF was administered to 35 donors (Group B) to improve CD34+ yield. The mean CD34+-cell concentration of the second PBSC harvest was significantly higher in Group B (1,087 x 10(6)/l vs. 767 x 10(6)/l; P = 0.031).

Factors associated with peripheral blood stem cell yield in volunteer donors mobilized with granulocyte colony-stimulating factors: the impact of donor characteristics and procedural settings.

Peripheral blood stem cells (PBSCs) are increasingly used as the source of hematopoietic stem cells, but there are large variations in harvest outcome between individuals mobilized by granulocyte colony-stimulating factor (G-CSF). We examined the effects of donor characteristics and procedure factors on the day 1 CD34+ cell yield in 373 unrelated healthy donors. G-CSF was administered subcutaneously at a planned dose of 8.3 to 11 microg/kg daily for 5 days, followed by harvest started on day 5 of G-CSF treatment. Of the 373 donors, 159 (42.6%) had the radial artery as the inlet access for harvest. Poor day 1 cell yield was defined as <10x10(6) CD34+ cells/L of processed blood for the first apheresis; 62 donors (16.6%) did not attain this threshold. The male donors had significantly higher yields at harvest compared with the female donors. The female donors had higher CD34+ cell yields if the circulation access was through an artery than if is was through a vein. In a multiple regression analysis, donor age, sex, body mass index (BMI), preharvest white blood cell and circulating immature cell counts, access type, and flow rate correlated with day 1 yield. Female sex, older age, venous access, and a higher flow rate were significantly associated with greater risk for a day 1 poor yield of CD34+ cells (odds ratio=3.0074, 1.045, 4.3362, and 1.1131, respectively). A higher BMI may decrease the risk (odds ratio=0.8472). In donors at higher risk for poor CD34+ cell yield, strategies for increasing CD34+ cells must be considered.

Microbial contamination of the Tzu-Chi Cord Blood Bank from 2005 to 2006.

BACKGROUND: In total, 4502 units of cord blood (CB) were collected during a 2-year period from 2005 to 2006 by the Buddhist Tzu-Chi Stem Cells Center. The aim of this study was to analyze the incidence of microbial contamination and type of organism present in the cord blood. The clinical impact of microbial contamination on hematopoietic progenitor cell (HPC) grafts used for HPC transplantation is also discussed. METHODS: First and second specimens were obtained for microbial assessment. These were collected in laboratory after cord blood collection and after cord blood unit manipulation, respectively. The samples were cultured and the results reviewed. RESULTS: The overall incidence of microbiological contamination was 1.8% (82/4502). Three CB units were contaminated with two different organisms. Infectious organisms comprised 9.4% (8/85) of total isolated microbes. These infectious microorganisms were beta-Streptococci group B, Candida tropicalis and Staphylococcus aureus which were isolated in 6, 1 and 1 of CB units respectively. Escherichia coli, Bacteroides fragilis, Lactobacillus spp., Enterococcus, beta-Streptococcus Group B, Bacteroides valgatus, Corynebacterium spp., Klebsiella pneumonia and Peptococcus spp. were the most frequently encountered microorganisms. A higher contamination rate of the CB units was noted after vaginal delivery (2.16%) compared to caesarian section (0.85%) (p < 0.01). CONCLUSIONS: Extensive training in CB collection, good procedures and good protocols can decrease the rate of microbial contamination. The use of a closed collecting system and an ex utero method have the advantage of a lower contamination rate. In our cord blood bank, we use a closed system but an in utero method. Similar to other studies, most of microorganisms reported here as contaminants are non-pathogenic.

Molecular basis for the enantioselective binding of a novel class of cytochrome bc1 complex inhibitors.

The recently solved co-crystal structures of mitochondrial cytochrome bc1 complex with inhibitors have provided an important structural framework for the elucidation of modes of binding of various bc1 complex inhibitors. N-Phenyl triazolones, a novel class of bc1 complex ubiquinol oxidation (Qo)-site inhibitors, were found to exhibit atropisomerism; in few cases, the atropisomers were resolved and shown to express different biological activities. However, the underlying mechanism for such differential binding of the enantiomers to bc1 complex is unknown. Here molecular docking is used to examine the binding modes of the N-phenyl triazolones fungicides. Our docking studies allow the molecular basis for the enantioselective binding of atropisomeric triazolones to be elucidated. Furthermore, the mode of binding of azoxystrobin has also been clarified.

A novel class of inhibitors of peptide deformylase discovered through high-throughput screening and virtual ligand screening.

Peptide deformylase (PDF) has been identified as a promising antibacterial and herbicide target. A structurally novel class of inhibitors containing a 2-thioxo-thiazolidin-4-one heterocycle substituted by an arylidene group at the 5-position and a hexanoic acid side chain at the 3-position was discovered independently via high-throughput screening and virtual ligand screening. Data mining and analogue synthesis established a structure--activity relationship for the side chain region that is consistent with the docked structure.

[Study on a back propogation neural network-based predictive model for prevalence of birth defect].

OBJECTIVE: To evaluate the value of a back propogation (BP) network on prediction of birth defect and to give clues on its prevention. METHODS: Data of birth defect in Shenyang from 1995 to 2005 were used as a training set to predict the prevalence rate of birth defect. Neural network tools box of Software MATLAB 6.5 was used to train and simulate BP Artificial Neural Network. RESULTS: When using data of the year 1995-2003 to predict the prevalence rate of birth defect in 2004-2005, the results showed that: the fitting average error of prevalence rate was 1.34%, RNL was 0.9874, and the prediction of average error was 1.78%. Using data of the year 1995-2005 to predict the prevalence rate of birth defect in 2006-2007, the results showed that: the fitting average error was 0.33%, RNL was 0.9954, the prevalence rates of birth defect in 2006-2007 were 11.00% and 11.29%. CONCLUSION: Compared to the conventional statistics method, BP not only showed better prediction precision, but had no limit to the type or distribution of relevant data, thus providing a powerful method in epidemiological prediction.

Computational Characterization of Metal Binding Groups for Metalloenzyme Inhibitors.

The mode of action of many pest or disease control agents involves inhibition of some metalloenzyme that is essential for the survival of the target organism. These inhibitors typically consist of a functional group that is capable of a primary binding interaction with the metal and a scaffold that is capable of secondary interactions with the remainder of the enzyme. To characterize the binding ability of various metal binding groups (BGs), we have performed electronic structure calculations on ligand displacement reactions in a model system related to the metalloenzyme, peptide deformylase: E-M-R + BG → E-M-BG + R. Here E represents a model coordination environment for the metal M, and R is a reference ligand (e.g., water) that may be displaced by a metal binding group. Since the oxidation state of many of the metals considered allows for multiple spin states, we also studied the influence of spin state on the coordination environment. Qualitative considerations of electronic structure inspired by the calculations provide an understanding of binding energy trends across a variety of ligands for a given metal and across a variety of metals for a given ligand.

Examination of a reaction intermediate in the active site of riboflavin synthase.

The riboflavin synthase catalyzed reaction proceeds through a pentacyclic intermediate of undetermined stereochemistry. Calculations at the B3LYP/6-31G(d) level of theory indicate that the trans pentacyclic structure is favored over the cis by 3.3kcal/mol. A model of the the trans, but not the cis, pentacycle in the enzyme active site shows good fitness and the availability of highly conserved protein residues for catalytic interactions. The model of the trans intermediate complements the model of the two substrates in the active site and allows for a hypothetical mechanism of the roles of specific protein residues in catalysis to be proposed.

Roles of substrate distortion and intramolecular hydrogen bonding in enzymatic catalysis by scytalone dehydratase.

Alternative substrates and site-directed mutations of active-site residues are used to probe factors controlling the catalytic efficacy of scytalone dehydratase. In the E1cb-like, syn-elimination reactions catalyzed, efficient catalysis requires distortion of the substrate ring system to facilitate proton abstraction from its C2 methylene and elimination of its C3 hydroxyl group. Theoretical calculations indicate that such distortions are more readily achieved in the substrate 2,3-dihydro-2,5-dihydroxy-4H-benzopyran-4-one (DDBO) than in the physiological substrates vermelone and scytalone by approximately 2 kcal/mol. A survey of 12 active-site amino acid residues reveals 4 site-directed mutants (H110N, N131A, F53A, and F53L) have higher relative values of k(cat) and k(cat)/K(m) for DDBO over scytalone and for DDBO over vermelone than the wild-type enzyme, thus suggesting substrate-distortion roles for the native residues in catalysis. A structural link for this function is in the modeled enzyme-substrate complex where F53 and H110 are positioned above and below the substrate's C3 hydroxyl group, respectively, for pushing and pulling the leaving group into the axial orientation of a pseudo-boat conformation; N131 hydrogen-bonds to the C8 hydroxyl group at the opposite end of the substrate, serving as a pivot for the actions of F53 and H110. Deshydroxyvermelone lacks the phenolic hydroxyl group and the intramolecular hydrogen bond of vermelone. The relative values of k(cat) (95) and k(cat)/K(m) (1800) for vermelone over deshydroxyvermelone for the wild-type enzyme indicate the importance of the hydroxyl group for substrate recognition and catalysis. Off the enzyme, the much slower rates for the solvolytic dehydration of deshydroxyvermelone and vermelone are similar, thus specifying the importance of the hydroxyl group of vermelone for enzyme catalysis.

Protein engineering of nitrile hydratase activity of papain: molecular dynamics study of a mutant and wild-type enzyme.

The mechanism of hydrolysis of the nitrile (N-acetyl-phenylalanyl-2-amino-propionitrile, I) catalyzed by Gln19Glu mutant of papain has been studied by nanosecond molecular dynamics (MD) simulations. MD simulations of the complex of mutant enzyme with I and of mutant enzyme covalently attached to both neutral (II) and protonated (III) thioimidate intermediates were performed. An MD simulation with the wild-type enzyme.I complex was undertaken as a reference. The ion pair between protonated His159 and thiolate of Cys25 is coplanar, and the hydrogen bonding interaction S(-)(25).HD1-ND1(159) is observed throughout MD simulation of the mutant enzyme.I complex. Such a sustained hydrogen bond is absent in nitrile-bound wild-type papain due to the flexibility of the imidazole ring of His159. The nature of the residue at position 19 plays a critical role in the hydrolysis of the covalent thioimidate intermediate. When position 19 represents Glu, the imidazolium ion of His159-ND1(+).Cys25-S(-) ion pair is distant, on average, from the nitrile nitrogen of substrate I. Near attack conformers (NACs) have been identified in which His159-ImH(+) is positioned to initiate a general acid-catalyzed addition of Cys-S(-) to nitrile. Though Glu19-CO(2)H is distant from nitrile nitrogen in the mutant.I structure, MD simulations of the mutant.II covalent adduct finds Glu19-CO(2)H hydrogen bonded to the thioimide nitrogen of II. This hydrogen bonded species is much less stable than the hydrogen bonded Glu19-CO(2)(-) with mutant-bound protonated thioimidate (III). This observation supports Glu19-CO(2)H general acid catalysis of the formation of mutant.III. This is the commitment step in the Gln19Glu mutant catalysis of nitrile hydrolysis.

Structural definition of the active site and catalytic mechanism of 3,4-dihydroxy-2-butanone-4-phosphate synthase.

X-ray crystal structures of L-3,4-dihydroxy-2-butanone-4-phosphate synthase from Magnaporthe grisea are reported for the E-SO(4)(2-), E-SO(4)(2-)-Mg(2+), E-SO(4)(2)(-)-Mn(2+), E-SO(4)(2)(-)-Mn(2+)-glycerol, and E-SO(4)(2)(-)-Zn(2+) complexes with resolutions that extend to 1.55, 0.98, 1.60, 1.16, and 1.00 A, respectively. Active-site residues of the homodimer are fully defined. The structures were used to model the substrate ribulose 5-phosphate in the active site with the phosphate group anchored at the sulfate site and the placement of the ribulose group guided by the glycerol site. The model includes two Mg(2+) cations that bind to the oxygen substituents of the C2, C3, C4, and phosphate groups of the substrate, the side chains of Glu37 and His153, and water molecules. The position of the metal cofactors and the substrate's phosphate group are further stabilized by an extensive hydrogen-bond and salt-bridge network. On the basis of their proximity to the substrate's reaction participants, the imidazole of an Asp99-His136 dyad from one subunit, the side chains of the Asp41, Cys66, and Glu174 residues from the other subunit, and Mg(2+)-activated water molecules are proposed to serve specific roles in the catalytic cycle as general acid-base functionalities. The model suggests that during the 1,2-shift step of the reaction, the substrate's C3 and C4 hydroxyl groups are cis to each other. A cis transition state is calculated to have an activation barrier that is 2 kcal/mol greater than that of the trans transition state in the absence of the enzyme.

Reaction of 2,2-bis(trifluoromethyl)-1,1-dicyanoethylene with 6,6-dimethylfulvene: cycloadditions and a rearrangement.

Reaction of 2,2-bis(trifluoromethyl)-1,1-dicyanoethylene (BTF; 1) with 6,6-dimethylfulvene (2) affords the expected Diels-Alder cycloadduct, 7-(1-methylethylidene)-3,3-bis(trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2,2-dicarbonitrile (3), in good yield. The cycloadduct 3 is unstable and exists in equilibrium with the starting materials in less polar solvents. In more polar environment, the [4 + 2] adduct 3 either reverts to starting materials, or, in a competing process, is converted to the formal [2 + 2] adduct, 2-(1-methylethylidene)-7,7-bis(trifluoromethyl)bicyclo[3.2.0]hept-3-ene-6,6-dicarbonitrile (6). In the presence of acid, 3 is converted to a third isomeric form, 1,3a,5,6-tetrahydro-7-methyl-5,5-bis(trifluoromethyl)-4H-indene-4,4-dicarbonitrile (8). Both 6 and 8 are formed with complete regiospecificity. Quantum mechanical calculations and X-ray crystallographic studies of this ensemble of reactions by BTF, and the analogous set of reactions by its progenitor, tetracyanoethylene (TCNE), reveal several interesting facets. The conversion of 3 to 6 occurs in certain polar solvents, in the presence of silica gel and alumina, as well as in the solid state. Single crystals of 3 were observed by X-ray crystallography to undergo crystal-to-crystal rearrangement to 6. The conversion of 3 to 8 proceeds by the initial retro-Diels-Alder reaction followed by isomerization of the fulvene to 1-isopropenyl-1,3-cyclopentadiene that then reacts with BTF to give the alternative Diels-Alder product as a single regioisomer. A hybrid density functional theory (DFT) method at the B3LYP/6-31G(d) level of theory gave calculated relative energies of 0.0, -9.0, and -18.8 kcal/mol for 3, 6, and 8, respectively. The same method was also used to correctly predict the regiochemical outcome of the cycloaddition of BTF with 1-isopropenyl-1,3-cyclopentadiene. Finally, an explanation is offered for the preference of the persubstituted cyanoolefins BTF and TCNE to add to the exocyclic diene portion of 1-isopropenyl-1,3-cyclopentadiene and the contrasting preference of 2-acetyloxy-2-propenenitrile to add to the endocyclic diene.