1,145 research outputs found
Redox functionality mediated by adsorbed oxygen on a Pd-oxide film over a Pd(100) thin structure: A first-principles study
Stable oxygen sites on a PdO film over a Pd(100) thin structures with a
(sqrt{5} times sqrt{5}) R27^circ surface-unit cell are determined using the
first-principles electronic structure calculations with the generalized
gradient approximation. The adsorbed monatomic oxygen goes to a site bridging
two 2-fold-coordinated Pd atoms or to a site bridging a 2-fold-coordinated Pd
atom and a 4-fold-coordinated Pd atom. Estimated reaction energies of CO
oxidation by reduction of the oxidized PdO film and N_2O reduction mediated by
oxidation of the PdO film are exothermic. Motion of the adsorbed oxygen atom
between the two stable sites is evaluated using the nudged elastic band method,
where an energy barrier for a translational motion of the adsorbed oxygen may
become sim 0.45 eV, which is low enough to allow fluxionality of the surface
oxygen at high temperatures. The oxygen fluxionality is allowed by existence of
2-fold-coordinated Pd atoms on the PdO film, whose local structure has
similarity to that of Pd catalysts for the Suzuki-Miyaura cross coupling.
Although NO_x (including NO_2 and NO) reduction is not always catalyzed only by
the PdO film, we conclude that there may happen continual redox reactions
mediated by oxygen-adsorbed PdO films over a Pd surface structure, when the
influx of NO_x and CO continues, and when the reaction cycle is kept on a
well-designed oxygen surface.Comment: 15 pages, 6 figures, submitted to J. Phys. Condens. Matte
An experimental and theoretical study into the facile, homogenous (N-Heterocyclic Carbene)2-Pd(0) catalyzed diboration of internal and terminal alkynes
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Pd(ITMe)(2)(PhC CPh) acts as a highly reactive pre-catalyst in the unprecedented homogenous catalyzed diboration of terminal and internal alkynes, yielding a number of novel and known syn-1,2-diborylalkenes in a 100% stereoselective manner. DFT calculations suggest that a similar reaction pathway to that proposed for platinum phosphine analogues is followed, and that destabilization of key intermediates by the NHCs is vital to the overall success for the palladium-catalyzed B-B addition to alkynes.62074617467EPSRC Standard Research Student (DTG) [EP/L505109/1]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2013/04813-6, 2015/11840-5, 2015/01491-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP
Computer-Aided Lead Optimization: Improved Small-Molecule Inhibitor of the Zinc Endopeptidase of Botulinum Neurotoxin Serotype A
Optimization of a serotype-selective, small-molecule inhibitor of botulinum neurotoxin serotype A (BoNTA) endopeptidase is a formidable challenge because the enzyme-substrate interface is unusually large and the endopeptidase itself is a large, zinc-binding protein with a complex fold that is difficult to simulate computationally. We conducted multiple molecular dynamics simulations of the endopeptidase in complex with a previously described inhibitor (Kiapp of 7±2.4 µM) using the cationic dummy atom approach. Based on our computational results, we hypothesized that introducing a hydroxyl group to the inhibitor could improve its potency. Synthesis and testing of the hydroxyl-containing analog as a BoNTA endopeptidase inhibitor showed a twofold improvement in inhibitory potency (Kiapp of 3.8±0.8 µM) with a relatively small increase in molecular weight (16 Da). The results offer an improved template for further optimization of BoNTA endopeptidase inhibitors and demonstrate the effectiveness of the cationic dummy atom approach in the design and optimization of zinc protease inhibitors
Functionalized Poly(3-hexylthiophene)s via Lithium–Bromine Exchange
Poly(3-hexylthiophene) (P3HT) is one of the most extensively investigated conjugated polymers and has been employed as the active material in many devices including field-effect transistors, organic photovoltaics and sensors. As a result, methods to further tune the properties of P3HT are desirable for specific applications. Herein, we report a facile postpolymerization modification strategy to functionalize the 4-position of commercially available P3HT in two simple steps–bromination of the 4-position of P3HT (Br–P3HT) followed by lithium−bromine exchange and quenching with an electrophile. We achieved near quantitative lithium–bromine exchange with Br–P3HT, which requires over 100 thienyl lithiates to be present on a single polymer chain. The lithiated-P3HT is readily combined with functional electrophiles, resulting in P3HT derivatives with ketones, secondary alcohols, trimethylsilyl (TMS) group, fluorine, or an azide at the 4-position. We demonstrated that the azide-modified P3HT could undergo Cu-catalyzed or Cu-free click chemistry, significantly expanding the complexity of the structures that can be appended to P3HT using this method.National Science Foundation (U.S.) (ECCS-0939514
Lymphocytes and the Dap12 Adaptor Are Key Regulators of Osteoclast Activation Associated with Gonadal Failure
Bone resorption by osteoclasts is necessary to maintain bone homeostasis. Osteoclast differentiation from hematopoietic progenitors and their activation depend on M-CSF and RANKL, but also requires co-stimulatory signals acting through receptors associated with DAP12 and FcRγ adaptors. Dap12 mutant mice (KΔ75) are osteopetrotic due to inactive osteoclasts but, surprisingly, these mice are more sensitive than WT mice to bone loss following an ovariectomy. Because estrogen withdrawal is known to disturb bone mass, at least in part, through lymphocyte interaction, we looked at the role of mature lymphocytes on osteoclastogenesis and bone mass in the absence of functional DAP12. Lymphocytes were found to stimulate an early osteoclast differentiation response from Dap12-deficient progenitors in vitro. In vivo, Rag1-/- mice lacking mature lymphocytes did not exhibit any bone phenotype, but lost their bone mass after ovariectomy like KΔ75 mice. KΔ75;Rag1-/- double mutant female mice exhibited a more severe osteopetrosis than Dap12-deficient animals but lost their bone mass after ovariectomy, like single mutants. These results suggest that both DAP12 and mature lymphocytes act synergistically to maintain bone mass under physiological conditions, while playing similar but not synergistic co-stimulatory roles in protecting bone loss after gonadal failure. Thus, our data support a role for lymphocytes during osteoclast differentiation and suggest that they may function as accessory cells when regular osteoclast function is compromised
Mifepristone Increases the Cytotoxicity of Uterine Natural Killer Cells by Acting as a Glucocorticoid Antagonist via ERK Activation
Background: Mifepristone (RU486), a potent antagonist of progesterone and glucocorticoids, is involved in immune regulation. Our previous studies demonstrated that mifepristone directly augments the cytotoxicity of human uterine natural killer (uNK) cells. However, the mechanism responsible for this increase in cytotoxicity is not known. Here, we explored whether the increased cytotoxicity in uNK cells produced by mifepristone is due to either anti-progesterone or anti-glucocorticoid activity, and also investigated relevant changes in the mitogen-activated protein kinase (MAPK) pathway. Methodology/Principal Findings: Uterine NK cells were isolated from decidual samples and incubated with different concentrations of progesterone, cortisol, or mifepristone. The cytotoxicity and perforin expression of uNK cells were detected by mitochondrial lactate dehydrogenase-based MTS staining and flow cytometry assays, respectively. Phosphorylation of components of the MAPK signaling pathway was detected by Western blot. Cortisol attenuated uNK cell-mediated cytotoxicity in a concentration-dependent manner whereas progesterone had no effect. Mifepristone alone increased the cytotoxicity and perforin expression of uNK cells; these effects were blocked by cortisol. Furthermore, mifepristone increased the phosphorylation of ERK1/2 in a cortisol-reversible manner. Specific ERK1/2 inhibitor PD98059 or U0126 blocked cortisol- and mifepristone-induced responses in uNK cells
Multi-pyridine decorated Fe(ii) and Ru(ii) complexes by Pd(0)-catalysed cross couplings: new building blocks for metallosupramolecular assemblies
Eight metal complexes of the type [M(tpy)2]2+ (tpy = 2,2′:6′,2′′-terpyridine) featuring four pendant pyridine rings are reported and characterised by NMR, MS, absorption spectroscopy and electrochemical methods. Palladium-mediated Suzuki and Sonogashira cross-coupling reactions were performed on both free 4′-(3,5- dibromophenyl)-tpy and its Ru(ii) complex in good yields. The ready N-alkylation of the pendant pyridyl units has significant influence on the absorption and electrochemical reduction of the complexes, processes which are localised on the periphery and leaves the [Ru(tpy)2]2+ core essentially unaffected. The binding of metal ions by the free pyridines is also demonstrated as means of assembling larger ordered non-covalent structures. This journal i
Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer)
Design and Synthesis of Heterocyclic Cations for Specific DNA Recognition: From AT-Rich to Mixed-Base-Pair DNA Sequences
The compounds synthesized in this research were designed with the goal of establishing a new paradigm for mixed-base-pair DNA sequence-specific recognition. The design scheme starts with a cell-permeable heterocyclic cation that binds to AT base pair sites in the DNA minor groove. Modifications were introduced in the original compound to include an Hbond accepting group to specifically recognize the G-NH that projects into the minor groove. Therefore, a series of heterocyclic cations substituted with an azabenzimidazole ring has been designed and synthesized for mixed-base-pair DNA recognition. The most successful compound, 12a, had an azabenzimidazole to recognize G and additional modifications for general minor groove interactions. It binds to the DNA site −AAAGTTT− more strongly than the −AAATTT− site without GC and indicates the design success. Structural modifications of 12a generally weakened binding. The interactions of the new compound with a variety of DNA sequences with and without GC base pairs were evaluated by thermal melting analysis, circular dichroism, fluorescence emission spectroscopy, surface plasmon resonance, and molecular modeling
Daidzein Prevents the Increase in CD4+CD28null T Cells and B Lymphopoesis in Ovariectomized Mice: A Key Mechanism for Anti-Osteoclastogenic Effect
Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4+CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4+ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4+CD28null T cells, however, treatment with Daid increased the percentage of CD4+CD28+ T cells. Co-culture of CD4+CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4+CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220+ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency
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