A chiral HPLC-MS/MS method for simultaneous quantification of warfarin enantiomers and its major hydroxylation metabolites of CYP2C9 and CYP3A4 in human plasma

Warfarin is an oral anticoagulant that requires frequent therapeutic drug monitoring due to a narrow therapeutic window, considerable interindividual variability in drug response, and susceptibility to drug-drug and drug-diet interactions. Enantiomeric separation and quantification of warfarin enantiomers and clinically important major hydroxylation metabolites are essential for drug interaction studies and phenotypic characterization of CYP2C9 and CYP3A4, the major Cytochrome P450 (CYP) enzymes involved in warfarin metabolism. Here, we describe the development and validation of a chiral high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)-based quantification of R-warfarin, S-warfarin, S-7-hydroxywarfarin (the major CYP2C9metabolite) and (9R; 10S)-10-hydroxywarfarin (the CYP3A4 metabolite) in human plasma. Simple protein precipitation-based extraction showed good recovery of analytes (82.9 - 96.9%). The developed method exhibited satisfactory intra-day and inter-day accuracy and precision. The lower limits of detection were 0.25nM (or ~0.08 ng/ml) for the warfarin enantiomers and 0.1nM (or ~0.04 ng/mL) for S-7-hydroxywarfarinand (9R; 10S)-10-hydroxywarfarin using only 50μL plasma during extraction. The validated method was successfully applied to analyze plasma samples obtained from a healthy human subject who enrolled in a clinical drug interaction study involving warfarin

Charmless Hadronic B-Meson Decays

We give an overview of the experimental measurements and the theoretical understanding of the branching fractions and CP-violating asymmetries of charmless B-meson decays. Most experimetal results are from the BABAR and Belle experiments during the past decade. The global features of these experimental results are typically well described by the QCD-motivated theories such as QCD factorization, pQCD and soft-collinear effective theory. The agreement between theory and experiment is generally satisfactory, though there remain some unsolved puzzles that pose a great challenge to both theorists and experimentalists.Comment: 33 pages, 11 figures, 1 table, invited review to appear in Ann. Rev. of Nucl. and Part. Scienc

A topological insulator surface under strong Coulomb, magnetic and disorder perturbations

Three dimensional topological insulators embody a newly discovered state of matter characterized by conducting spin-momentum locked surface states that span the bulk band gap as demonstrated via spin-resolved ARPES measurements . This highly unusual surface environment provides a rich ground for the discovery of novel physical phenomena. Here we present the first controlled study of the topological insulator surfaces under strong Coulomb, magnetic and disorder perturbations. We have used interaction of iron, with a large Coulomb state and significant magnetic moment as a probe to \textit{systematically test the robustness} of the topological surface states of the model topological insulator Bi$_2$Se$_3$. We observe that strong perturbation leads to the creation of odd multiples of Dirac fermions and that magnetic interactions break time reversal symmetry in the presence of band hybridization. We also present a theoretical model to account for the altered surface of Bi$_2$Se$_3$. Taken collectively, these results are a critical guide in manipulating topological surfaces for probing fundamental physics or developing device applications.Comment: 14 pages, 4 Figures. arXiv admin note: substantial text overlap with arXiv:1009.621

Myocardial Viability Imaging using Manganese-Enhanced MRI in the First Hours after Myocardial Infarction

Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping-manganese-enhanced MRI (MEMRI) reveals elevated and increasing Mn uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold-standard technique, late-gadolinium-enhanced MRI. These data, coupled with the re-emergence of clinical Mn -based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients

The Effect of Single, Binary and Ternary Anions of Chloride, Carbonate and Phosphate on the Release of 2,4-Dichlorophenoxyacetate Intercalated into the Zn–Al-layered Double Hydroxide Nanohybrid

Intercalation of beneficial anion into inorganic host has lead to an opportunity to synthesize various combinations of new organic–inorganic nanohybrids with various potential applications; especially, for the controlled release formulation and storage purposes. Investigation on the release behavior of 2,4-dichlorophenoxyacetate (2,4-D) intercalated into the interlayer of Zn–Al-layered double hydroxide (ZAN) have been carried out using single, binary and ternary aqueous systems of chloride, carbonate and phosphate. The release behavior of the active agent 2,4-D from its double-layered hydroxide nanohybrid ZANDI was found to be of controlled manner governed by pseudo-second order kinetics. It was found that carbonate medium yielded the highest accumulated release of 2,4-D, while phosphate in combination with carbonate and/or nitrate speeds up the release rate of 2,4-D. These results indicate that it is possible to design and develop new delivery system of latex stimulant compound with controlled release property based on 2,4-D that is known as a substance to increase latex production of rubber tree,Hevea brasiliensis

Bimetallic Fe-Mo sulfide/carbon nanocomposites derived from phosphomolybdic acid encapsulated in MOF for efficient hydrogen generation

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordTo tackle the energy crisis and achieve a more sustainable development, hydrogen as a clean and renewable energy resource has attracted great interest. Searching for cheap but efficient catalysts for hydrogen production from water splitting is urgently needed. In this report, bimetallic Fe-Mo sulfide/carbon nanocomposites that derived from a polyoxometalate phosphomolybdic acid encapsulated in metal organic framework MIL-100 (PMA@MIL-100) have been generated and their applications in electrocatalytic hydrogen generation were explored. The PMA@MIL-100 precursor is formed via a simple one-pot hydrothermal synthesis method and the bimetallic Fe-Mo sulfide/carbon nanocomposites were obtained by chemical vapour sulfurization of PMA@MIL-100 at high temperatures. The nanocomposite samples were fully characterized by a series of techniques including XRD, FT-IR, TGA, N2 gas sorption, SEM, TEM, XPS, and were further investigated as electrocatalysts for hydrogen production from water splitting. The hydrogen production activity of the best performed bimetallic Fe-Mo sulfide/carbon nanocomposite exhibits an overpotential of -0.321 V at 10 mA cm-2 and a Tafel slope of 62 mV dec-1 with a 53% reduction in overpotential compared to Mo-free counterpart composite. This dramatic improvement in catalytic performance of the FeMo sulfide/carbon composite is attributed to the homogeneous distribution of the nanosized iron sulfide, MoS2 particles and the formation Fe-Mo-S phases in the S-doped porous carbon matrix. This work has demonstrated a potential approach to fabricate complex heterogeneous catalytic materials for different applications.Engineering and Physical Sciences Research Council (EPSRC)Leverhulme TrustEuropean Unio

Recent Advances in Metal–Organic Frameworks Derived Nanocomposites for Photocatalytic Applications in Energy and Environment

This is the final version. Available from Wiley via the DOI in this record. Solar energy is a key sustainable energy resource, and materials with optimal properties are essential for efficient solar energy-driven applications in photocatalysis. Metal–organic frameworks (MOFs) are excellent platforms to generate different nanocomposites comprising metals, oxides, chalcogenides, phosphides, or carbides embedded in porous carbon matrix. These MOF derived nanocomposites offer symbiosis of properties like high crystallinities, inherited morphologies, controllable dimensions, and tunable textural properties. Particularly, adjustable energy band positions achieved by in situ tailored self/external doping and controllable surface functionalities make these nanocomposites promising photocatalysts. Despite some progress in this field, fundamental questions remain to be addressed to further understand the relationship between the structures, properties, and photocatalytic performance of nanocomposites. In this review, different synthesis approaches including self-template and external-template methods to produce MOF derived nanocomposites with various dimensions (0D, 1D, 2D, or 3D), morphologies, chemical compositions, energy bandgaps, and surface functionalities are comprehensively summarized and analyzed. The state-of-the-art progress in the applications of MOF derived nanocomposites in photocatalytic water splitting for H2 generation, photodegradation of organic pollutants, and photocatalytic CO2 reduction are systemically reviewed. The relationships between the nanocomposite properties and their photocatalytic performance are highlighted, and the perspectives of MOF derived nanocomposites for photocatalytic applications are also discussed.Leverhulme TrustEngineering and Physical Sciences Research Council (EPSRC

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behaviour concordant with the afferent imbalance, which is present at birth and non-progressive, indicating that sensory neuron identity is pre-natally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause mis-activation of Trk signalling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments

Two-dimensional universal conductance fluctuations and the electron-phonon interaction of topological surface states in Bi2Te2Se nanoribbons

The universal conductance fluctuations (UCFs), one of the most important manifestations of mesoscopic electronic interference, have not yet been demonstrated for the two-dimensional surface state of topological insulators (TIs). Even if one delicately suppresses the bulk conductance by improving the quality of TI crystals, the fluctuation of the bulk conductance still keeps competitive and difficult to be separated from the desired UCFs of surface carriers. Here we report on the experimental evidence of the UCFs of the two-dimensional surface state in the bulk insulating Bi2Te2Se nanoribbons. The solely-B\perp-dependent UCF is achieved and its temperature dependence is investigated. The surface transport is further revealed by weak antilocalizations. Such survived UCFs of the topological surface states result from the limited dephasing length of the bulk carriers in ternary crystals. The electron-phonon interaction is addressed as a secondary source of the surface state dephasing based on the temperature-dependent scaling behavior

Simulation of the many-body dynamical quantum Hall effect in an optical lattice

We propose an experimental scheme to simulate the many-body dynamical quantum Hall effect with ultra-cold bosonic atoms in a one-dimensional optical lattice. We first show that the required model Hamiltonian of a spin-1/2 Heisenberg chain with an effective magnetic field and tunable parameters can be realized in this system. For dynamical response to ramping the external fields, the quantized plateaus emerge in the Berry curvature of the interacting atomic spin chain as a function of the effective spin-exchange interaction. The quantization of this response in the parameter space with the interaction-induced topological transition characterizes the many-body dynamical quantum Hall effect. Furthermore, we demonstrate that this phenomenon can be observed in practical cold-atom experiments with numerical simulations.Comment: 8 pages, 3 figures; accepted in Quantum Information Processin