Electrophotocatalytic perfluoroalkylation by LMCT excitation of Ag(II) perfluoroalkyl carboxylates.

Molecular Ag(II) complexes are superoxidizing photoredox catalysts capable of generating radicals from redox-reticent substrates. In this work, we exploited the electrophilicity of Ag(II) centers in [Ag(bpy)2(TFA)][OTf] and Ag(bpy)(TFA)2 (bpy, 2,2'-bipyridine; OTf, CF3SO3-) complexes to activate trifluoroacetate (TFA) by visible light-induced homolysis. The resulting trifluoromethyl radicals may react with a variety of arenes to forge C(sp2)-CF3 bonds. This methodology is general and extends to other perfluoroalkyl carboxylates of higher chain length (RFCO2-; RF, CF2CF3 or CF2CF2CF3). The photoredox reaction may be rendered electrophotocatalytic by regenerating the Ag(II) complexes electrochemically during irradiation. Electrophotocatalytic perfluoroalkylation of arenes at turnover numbers exceeding 20 was accomplished by photoexciting the Ag(II)-TFA ligand-to-metal charge transfer (LMCT) state, followed by electrochemical reoxidation of the Ag(I) photoproduct back to the Ag(II) photoreactant.

Lewis Acid Supported Nickel Nitrenoids.

Metalation of the polynucleating ligand F,tbs LH6 (1,3,5-C6 H9 (NC6 H3 -4-F-2-NSiMe2 t Bu)3 ) with two equivalents of Zn(N(SiMe3 )2 )2 affords the dinuclear product (F,tbs LH2 )Zn2 (1), which can be further deprotonated to yield (F,tbs L)Zn2 Li2 (OEt2 )4 (2). Transmetalation of 2 with NiCl2 (py)2 yields the heterometallic, trinuclear cluster (F,tbs L)Zn2 Ni(py) (3). Reduction of 3 with KC8 affords [KC222 ][(F,tbs L)Zn2 Ni] (4) which features a monovalent Ni centre. Addition of 1-adamantyl azide to 4 generates the bridging µ3 -nitrenoid adduct [K(THF)3 ][(F,tbs L)Zn2 Ni(µ3 -NAd)] (5). EPR spectroscopy reveals that the anionic cluster possesses a doublet ground state (S = 1 / 2 ${{ 1/2 }}$ ). Cyclic voltammetry of 5 reveals two fully reversible redox events. The dianionic nitrenoid [K2 (THF)9 ][(F,tbs L)Zn2 Ni(µ3 -NAd)] (6) was isolated and characterized while the neutral redox isomer was observed to undergo both intra- and intermolecular H-atom abstraction processes. Ni K-edge XAS studies suggest a divalent oxidation state for the Ni centres in both the monoanionic and dianionic [Zn2 Ni] nitrenoid complexes. However, DFT analysis suggests Ni-borne oxidation for 5.

Light-Mediated Electrochemical Synthesis of Manganese Oxide Enhances Its Stability for Water Oxidation.

New methods are needed to increase the activity and stability of earth-abundant catalysts for electrochemical water splitting to produce hydrogen fuel. Electrodeposition has been previously used to synthesize manganese oxide films with a high degree of disorder and a mixture of oxidation states for Mn, which has led to electrocatalysts with high activity but low stability for the oxygen evolution reaction (OER) at high current densities. In this study, we show that multipotential electrodeposition of manganese oxide under illumination produces nanostructured films with significantly higher stability for the OER compared to films grown under otherwise identical conditions in the dark. Manganese oxide films grown by multipotential deposition under illumination sustain a current density of 10 mA/cm2 at 2.2 V versus reversible hydrogen electrode for 18 h (pH 13). Illumination does not enhance the activity or stability of manganese oxide films grown using a constant potential, and films grown by multipotential deposition in the dark undergo a complete loss of activity within 1 h of electrolysis. Electrochemical and structural characterization indicate that photoexcitation of the films during growth reduces Mn ions and changes the content and structure of intercalated potassium ions and water molecules in between the disordered layers of birnessite-like sheets of MnOx, which stabilizes the nanostructured film during electrocatalysis. These results demonstrate that combining multiple external stimuli (i.e., light and an external potential) can induce structural changes not attainable by either stimulus alone to make earth-abundant catalysts more active and stable for important chemical transformations such as water oxidation.

Crystal structure of a methyl benzoate quadruple-bonded dimolybdenum complex.

Quadruple-bond dimolybdenum complexes provide invaluable insight into the two-electron bond, with structural chemistry providing a foundation for examination of bond properties. The synthesis and solid-state structure of the quadruple-bonded dimolybdenum(II) complex tetra-kis-(µ-4-methyl-benzoato-κ 2 O:O')bis[(tetra-hydro-furan-κO)molybdenum(II)] tetra-hydro-furan disolvate, [Mo2(C8H7O2)4(C4H8O)2]·2C4H8O, are presented. This complex crystallizes in a triclinic cell with low-symmetry space group P . The dimolybdenum paddlewheel structure comprises four methyl-benzoate ligands and two axial THF ligands. The dimolybdenum bond distance of 2.1012 (4) Šis exemplary of this class of compounds.

Spontaneous Seed Formation during Electrodeposition Drives Epitaxial Growth of Metastable Bismuth Selenide Microcrystals.

Materials with metastable phases can exhibit vastly different properties from their thermodynamically favored counterparts. Methods to synthesize metastable phases without the need for high-temperature or high-pressure conditions would facilitate their widespread use. We report on the electrochemical growth of microcrystals of bismuth selenide, Bi2Se3, in the metastable orthorhombic phase at room temperature in aqueous solution. Rather than direct epitaxy with the growth substrate, the spontaneous formation of a seed layer containing nanocrystals of cubic BiSe enforces the metastable phase. We first used single-crystal silicon substrates with a range of resistivities and different orientations to identify the conditions needed to produce the metastable phase. When the applied potential during electrochemical growth is positive of the reduction potential of Bi3+, an initial, Bi-rich seed layer forms. Electron microscopy imaging and diffraction reveal that the seed layer consists of nanocrystals of cubic BiSe embedded within an amorphous matrix of Bi and Se. Using density functional theory calculations, we show that epitaxial matching between cubic BiSe and orthorhombic Bi2Se3 can help stabilize the metastable orthorhombic phase over the thermodynamically stable rhombohedral phase. The spontaneous formation of the seed layer enables us to grow orthorhombic Bi2Se3 on a variety of substrates including single-crystal silicon with different orientations, polycrystalline fluorine-doped tin oxide, and polycrystalline gold. The ability to stabilize the metastable phase through room-temperature electrodeposition in aqueous solution without requiring a single-crystal substrate broadens the range of applications for this semiconductor in optoelectronic and electrochemical devices.

Probing the Halide Effect in the δ-Bond with One- and Two-Photon Spectroscopy.

Two electrons in two orbitals give rise to four states. When the orbitals are weakly coupled as in the case for the dxy orbitals of quadruple bond species, two of the states are diradical in character with electrons residing in separate orbitals and two of the states are zwitterionic with electrons paired in one orbital or the other. By measuring one-and two-photon spectra, the one-electron (ΔW) and two-electron (K) energies may be calculated, which are the determinants of the state energies of the four-state model for the two-electron bond. The K energy is thus especially sensitive to the size of the orbital as K is dependent on the distance between electrons. To this end, one- and two-photon spectra of Mo2X4(PMe3)4 are sensitive to secondary bonding interactions of the δ-orbital manifold with the halide orbitals, as reflected in decreasing K energies along the series Cl > Br > I. Additionally, the calculated one-electron energies have been verified with the spectroelectrochemical preparation of the Mo2X4(PMe3)4+ complexes, where the δ bond is a one-electron bond, and K is thus absent. The δ → δ* transition shifts over 10,000 cm-1 upon oxidation of Mo2X4(PMe3)4 to Mo2X4(PMe3)4+, establishing that transitions within the two-electron δ bond are heavily governed by the two-electron exchange energy.

Pig Brains Have Homologous Resting-State Networks with Human Brains.

Many neurological and psychiatric diseases in humans are caused by disruptions to large-scale functional properties of the brain, including functional connectivity. There has been growing interest in discovering the functional organization of brain networks in larger animal models. As a result, the use of translational pig models in neuroscience has significantly increased in the past decades. The gyrencephalic pig brain resembles the human brain more in anatomy, growth, and development than the brains of commonly used small laboratory animals such as rodents. In this work, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) data were acquired from a group of pigs (n = 12). rs-fMRI data were analyzed for resting-state networks (RSNs) by using independent component analysis and sparse dictionary learning. Six RSNs (executive control, cerebellar, sensorimotor, visual, auditory, and default mode) were detected that resemble their counterparts in human brains, as measured by Pearson spatial correlations and mean ratios. Supporting evidence of the validity of these RSNs was provided through the evaluation and quantification of structural connectivity measures (mean diffusivity, fractional anisotropy, fiber length, and fiber density) estimated from the DTI data. This study shows that as a translational, large animal model, pigs demonstrate great potential for mapping connectome-scale functional connectivity in experimental modeling of human brain disorders.

Synthesis of a new disulfide Fmoc monomer for creating biologically susceptible linkages in peptide nucleic acid oligomers.

Peptide nucleic acids (PNA) are one of many synthetic mimics of DNA and RNA that have found applications as biological probes, as nano-scaffold components, and in diagnostics. In an effort to use PNA as constructs for cellular delivery we investigated the possibility of installing a biologically susceptible disulfide bond in the backbone of a PNA oligomer. Here we report the synthesis of a new abasic Fmoc monomer containing a disulfide bond that can be incorporated into a PNA oligomer (DS-PNA) using standard solid phase peptide synthesis. The disulfide bond survives cleavage from the resin and DS-PNA forms duplexes with complementary PNA oligomers. Initial studies aimed at determining if the disulfide bond is cleavable to reducing agents while in a duplex are explored using UV thermal analysis and HPLC.

All-optical regenerator of multi-channel signals.

One of the main reasons why nonlinear-optical signal processing (regeneration, logic, etc.) has not yet become a practical alternative to electronic processing is that the all-optical elements with nonlinear input-output relationship have remained inherently single-channel devices (just like their electronic counterparts) and, hence, cannot fully utilise the parallel processing potential of optical fibres and amplifiers. The nonlinear input-output transfer function requires strong optical nonlinearity, e.g. self-phase modulation, which, for fundamental reasons, is always accompanied by cross-phase modulation and four-wave mixing. In processing multiple wavelength-division-multiplexing channels, large cross-phase modulation and four-wave mixing crosstalks among the channels destroy signal quality. Here we describe a solution to this problem: an optical signal processor employing a group-delay-managed nonlinear medium where strong self-phase modulation is achieved without such nonlinear crosstalk. We demonstrate, for the first time to our knowledge, simultaneous all-optical regeneration of up to 16 wavelength-division-multiplexing channels by one device. This multi-channel concept can be extended to other nonlinear-optical processing schemes.Nonlinear optical processing devices are not yet fully practical as they are single channel. Here the authors demonstrate all-optical regeneration of up to 16 channels by one device, employing a group-delay-managed nonlinear medium where strong self-phase modulation is achieved without nonlinear inter-channel crosstalk.

On the electrostatic properties of homodimeric proteins.

A large fraction of proteins function as homodimers, but it is not always clear why the dimerization is important for functionality since frequently each monomer possesses a distinctive active site. Recent work (PLoS Computational Biology, 9(2), e1002924) indicates that homodimerization may be important for forming an electrostatic funnel in the spermine synthase homodimer which guides changed substrates toward the active centers. This prompted us to investigate the electrostatic properties of a large set of homodimeric proteins and resulted in an observation that in a vast majority of the cases the dimerization indeed results in specific electrostatic features, although not necessarily in an electrostatic funnel. It is demonstrated that the electrostatic dipole moment of the dimer is predominantly perpendicular to the axis connecting the centers of the mass of the monomers. In addition, the surface points with highest potential are located in the proximity of the interfacial plane of the homodimeric complexes. These findings indicate that frequently homodimerization provides specific electrostatic features needed for the function of proteins.

Automation of an interferon-γ release assay and comparison to the tuberculin skin test for screening basic military trainees for Mycobacterium tuberculosis infection.

We automated portions of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) and assessed its quality when performed concurrently with the tuberculin skin test (TST) among U.S. Air Force basic military trainees (BMTs). The volume of blood collected for QFT-GIT was monitored. At least one of the three tubes required for QFT-GIT had blood volume outside the recommended 0.8- to 1.2-mL range for 688 (29.0%) of 2,373 subjects who had their blood collected. Of the 2,124 subjects who had TST and QFT-GIT completed, TST was positive for 0.6%; QFT-GIT was positive for 0.3% and indeterminate for 2.0%. Among 2,081 subjects with completed TST and determinate QFT-GIT results, overall agreement was 99.5% but positive agreement was 5.6%. Specificity among the 1,546 low-risk BMTs was identical (99.7%). Indeterminate QFT-GIT results were 2.7 times more likely when mitogen tubes contained >1.2 mL blood than when containing 0.8- to 1.2-mL blood. Automation can facilitate QFT-GIT completion, especially if the recommended volume of blood is collected. Mycobacterium tuberculosis infection prevalence among BMTs based on TST and QFT-GIT is similar and low. Selectively testing those with significant risk may be more appropriate than universal testing of all recruits.

Variability of the QuantiFERON®-TB gold in-tube test using automated and manual methods.

BACKGROUND: The QuantiFERON®-TB Gold In-Tube test (QFT-GIT) detects Mycobacterium tuberculosis (Mtb) infection by measuring release of interferon gamma (IFN-γ) when T-cells (in heparinized whole blood) are stimulated with specific Mtb antigens. The amount of IFN-γ is determined by enzyme-linked immunosorbent assay (ELISA). Automation of the ELISA method may reduce variability. To assess the impact of ELISA automation, we compared QFT-GIT results and variability when ELISAs were performed manually and with automation. METHODS: Blood was collected into two sets of QFT-GIT tubes and processed at the same time. For each set, IFN-γ was measured in automated and manual ELISAs. Variability in interpretations and IFN-γ measurements was assessed between automated (A1 vs. A2) and manual (M1 vs. M2) ELISAs. Variability in IFN-γ measurements was also assessed on separate groups stratified by the mean of the four ELISAs. RESULTS: Subjects (N = 146) had two automated and two manual ELISAs completed. Overall, interpretations were discordant for 16 (11%) subjects. Excluding one subject with indeterminate results, 7 (4.8%) subjects had discordant automated interpretations and 10 (6.9%) subjects had discordant manual interpretations (p = 0.17). Quantitative variability was not uniform; within-subject variability was greater with higher IFN-γ measurements and with manual ELISAs. For subjects with mean TB Responses ±0.25 IU/mL of the 0.35 IU/mL cutoff, the within-subject standard deviation for two manual tests was 0.27 (CI95 = 0.22-0.37) IU/mL vs. 0.09 (CI95 = 0.07-0.12) IU/mL for two automated tests. CONCLUSION: QFT-GIT ELISA automation may reduce variability near the test cutoff. Methodological differences should be considered when interpreting and using IFN-γ release assays (IGRAs).

Protein Nano-Object Integrator (ProNOI) for generating atomic style objects for molecular modeling.

BACKGROUND: With the progress of nanotechnology, one frequently has to model biological macromolecules simultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or they are solid state entities. Because of that, the researchers have to investigate such nano systems by generating models of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it should allow generating composite objects with complex shape by combining basic geometrical figures and embedding biological macromolecules within the system. RESULTS: Here we report the Protein Nano-Object Integrator (ProNOI) which allows for generating atomic-style geometrical objects with user desired shape and dimensions. Unlimited number of objects can be created and combined with biological macromolecules in Protein Data Bank (PDB) format file. Once the objects are generated, the users can use sliders to manipulate their shape, dimension and absolute position. In addition, the software offers the option to charge the objects with either specified surface or volumetric charge density and to model them with user-desired dielectric constants. According to the user preference, the biological macromolecule atoms can be assigned charges and radii according to four different force fields: Amber, Charmm, OPLS and PARSE. The biological macromolecules and the atomic-style objects are exported as a position, charge and radius (PQR) file, or if a default dielectric constant distribution is not selected, it is exported as a position, charge, radius and epsilon (PQRE) file. As illustration of the capabilities of the ProNOI, we created a composite object in a shape of a robot, aptly named the Clemson Robot, whose parts are charged with various volumetric charge densities and holds the barnase-barstar protein complex in its hand. CONCLUSIONS: The Protein Nano-Object Integrator (ProNOI) is a convenient tool for generating atomic-style nano shapes in conjunction with biological macromolecule(s). Charges and radii on the macromolecule atoms and the atoms in the shapes are assigned according to the user's preferences allowing various scenarios of modeling. The default output file is in PQR (PQRE) format which is readable by almost any software available in biophysical field. It can be downloaded from: http://compbio.clemson.edu/downloadDir/ProNO_integrator.tar.gz.

Within-subject interlaboratory variability of QuantiFERON-TB gold in-tube tests.

BACKGROUND: The QuantiFERON®-TB Gold In-Tube test (QFT-GIT) is a viable alternative to the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. However, within-subject variability may limit test utility. To assess variability, we compared results from the same subjects when QFT-GIT enzyme-linked immunosorbent assays (ELISAs) were performed in different laboratories. METHODS: Subjects were recruited at two sites and blood was tested in three labs. Two labs used the same type of automated ELISA workstation, 8-point calibration curves, and electronic data transfer. The third lab used a different automated ELISA workstation, 4-point calibration curves, and manual data entry. Variability was assessed by interpretation agreement and comparison of interferon-γ (IFN-γ) measurements. Data for subjects with discordant interpretations or discrepancies in TB Response >0.05 IU/mL were verified or corrected, and variability was reassessed using a reconciled dataset. RESULTS: Ninety-seven subjects had results from three labs. Eleven (11.3%) had discordant interpretations and 72 (74.2%) had discrepancies >0.05 IU/mL using unreconciled results. After correction of manual data entry errors for 9 subjects, and exclusion of 6 subjects due to methodological errors, 7 (7.7%) subjects were discordant. Of these, 6 (85.7%) had all TB Responses within 0.25 IU/mL of the manufacturer's recommended cutoff. Non-uniform error of measurement was observed, with greater variation in higher IFN-γ measurements. Within-subject standard deviation for TB Response was as high as 0.16 IU/mL, and limits of agreement ranged from -0.46 to 0.43 IU/mL for subjects with mean TB Response within 0.25 IU/mL of the cutoff. CONCLUSION: Greater interlaboratory variability was associated with manual data entry and higher IFN-γ measurements. Manual data entry should be avoided. Because variability in measuring TB Response may affect interpretation, especially near the cutoff, consideration should be given to developing a range of values near the cutoff to be interpreted as "borderline," rather than negative or positive.

Multiple cytokines are released when blood from patients with tuberculosis is stimulated with Mycobacterium tuberculosis antigens.

BACKGROUND: Mycobacterium tuberculosis (Mtb) infection may cause overt disease or remain latent. Interferon gamma release assays (IGRAs) detect Mtb infection, both latent infection and infection manifesting as overt disease, by measuring whole-blood interferon gamma (IFN-γ) responses to Mtb antigens such as early secreted antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and TB7.7. Due to a lack of adequate diagnostic standards for confirming latent Mtb infection, IGRA sensitivity for detecting Mtb infection has been estimated using patients with culture-confirmed tuberculosis (CCTB) for whom recovery of Mtb confirms the infection. In this study, cytokines in addition to IFN-γ were assessed for potential to provide robust measures of Mtb infection. METHODS: Cytokine responses to ESAT-6, CFP-10, TB7.7, or combinations of these Mtb antigens, for patients with CCTB were compared with responses for subjects at low risk for Mtb infection (controls). Three different multiplexed immunoassays were used to measure concentrations of 9 to 20 different cytokines. Responses were calculated by subtracting background cytokine concentrations from cytokine concentrations in plasma from blood stimulated with Mtb antigens. RESULTS: Two assays demonstrated that ESAT-6, CFP-10, ESAT-6+CFP-10, and ESAT-6+CFP-10+TB7.7 stimulated the release of significantly greater amounts of IFN-γ, IL-2, IL-8, MCP-1 and MIP-1ß for CCTB patients than for controls. Responses to combination antigens were, or tended to be, greater than responses to individual antigens. A third assay, using whole blood stimulation with ESAT-6+CFP-10+TB7.7, revealed significantly greater IFN-γ, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1ß, and TNF-α responses among patients compared with controls. One CCTB patient with a falsely negative IFN-γ response had elevated responses with other cytokines. CONCLUSIONS: Multiple cytokines are released when whole blood from patients with CCTB is stimulated with Mtb antigens. Measurement of multiple cytokine responses may improve diagnostic sensitivity for Mtb infection compared with assessment of IFN-γ alone.

Synthesis and evaluation of azabicyclo[3.2.1]octane derivatives as potent mixed vasopressin antagonists.

A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V(1a)/V(2)-receptor antagonist standard.

Unexpected rearrangement of enantiomerically pure 3-aminoquinuclidine as a simple way of preparing diastereomeric octahydropyrrolo[2,3-c]pyridine derivatives.

Reaction of (S)- or (R)-3-aminoquinuclidine with 2-chloropyrimidine or 2-bromopyrimidine led to an unexpected formation of both cis- and trans-octahydropyrrolo [2,3]pyridine derivatives. A single-step synthesis of two of the four stereoisomers of these octahydropyrrolo[2,3]pyridine derivatives provides a convenient way of generating stereochemically defined isomers. Optimization of reaction conditions was carried out by (1)H NMR monitoring. The relative and absolute stereochemistry of all four stereoisomers was determined by a combination of (1)H, (13)C, and (15)N NMR spectroscopy and vibrational circular dichroism spectroscopy.

Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.

Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.