The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21

Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2H-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N-acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiokbased nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made dear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.Molecular Physiolog

Thermal Partition Functions for S-branes

We calculate the thermal partition functions of open strings on the S-brane backgrounds (the bouncing or rolling tachyon backgrounds) both in the bosonic and superstring cases. According to hep-th/0302146, we consider the discretized temperatures compatible with the pure imaginary periodicity of tachyon profiles. The ``effective Hagedorn divergence'' is shown to appear no matter how low temperature is chosen (including zero-temperature). This feature is likely to be consistent with the large rate of open string pair production discussed in hep-th/0209090 and also emission of closed string massive modes hep-th/0303139. We also discuss the possibility to remove the divergence by considering the space-like linear dilaton backgrounds as in hep-th/0306132.Comment: 33 pages, no figure; v2 typos corrected, a reference adde

Coherent spin valve phenomena and electrical spin injection in ferromagnetic/semiconductor/ferromagnetic junctions

Coherent quantum transport in ferromagnetic/ semiconductor/ ferromagnetic junctions is studied theoretically within the Landauer framework of ballistic transport. We show that quantum coherence can have unexpected implications for spin injection and that some intuitive spintronic concepts which are founded in semi-classical physics no longer apply: A quantum spin-valve (QSV) effect occurs even in the absence of a net spin polarized current flowing through the device, unlike in the classical regime. The converse effect also arises, i.e. a zero spin-valve signal for a non-vanishing spin-current. We introduce new criteria useful for analyzing quantum and classical spin transport phenomena and the relationships between them. The effects on QSV behavior of spin-dependent electron transmission at the interfaces, interface Schottky barriers, Rashba spin-orbit coupling and temperature, are systematically investigated. While the signature of the QSV is found to be sensitive to temperature, interestingly, that of its converse is not. We argue that the QSV phenomenon can have important implications for the interpretation of spin-injection in quantum spintronic experiments with spin-valve geometries.Comment: 15 pages including 11 figures. To appear in PR

Spin injection into a ballistic semiconductor microstructure

A theory of spin injection across a ballistic ferromagnet-semiconductor-ferromagnet junction is developed for the Boltzmann regime. Spin injection coefficient $\gamma$ is suppressed by the Sharvin resistance of the semiconductor $r_N^*=(h/e^2)(\pi^2/S_N)$, where $S_N$ is the Fermi-surface cross-section. It competes with the diffusion resistances of the ferromagnets $r_F$, and $\gamma\sim r_F/r_N^*\ll 1$ in the absence of contact barriers. Efficient spin injection can be ensured by contact barriers. Explicit formulae for the junction resistance and the spin-valve effect are presented.Comment: 5 pages, 2 column REVTeX. Explicit prescription relating the results of the ballistic and diffusive theories of spin injection is added. To this end, some notations are changed. Three references added, typos correcte

Systematic Review of Medicine-Related Problems in Adult Patients with Atrial Fibrillation on Direct Oral Anticoagulants

New oral anticoagulant agents continue to emerge on the market and their safety requires assessment to provide evidence of their suitability for clinical use. There-fore, we searched standard databases to summarize the English language literature on medicine-related problems (MRPs) of direct oral anticoagulants DOACs (dabigtran, rivaroxban, apixban, and edoxban) in the treatment of adults with atri-al fibrillation. Electronic databases including Medline, Embase, International Pharmaceutical Abstract (IPA), Scopus, CINAHL, the Web of Science and Cochrane were searched from 2008 through 2016 for original articles. Studies pub-lished in English reporting MRPs of DOACs in adult patients with AF were in-cluded. Seventeen studies were identified using standardized protocols, and two reviewers serially abstracted data from each article. Most articles were inconclusive on major safety end points including major bleeding. Data on major safety end points were combined with efficacy. Most studies inconsistently reported adverse drug reactions and not adverse events or medication error, and no definitions were consistent across studies. Some harmful drug effects were not assessed in studies and may have been overlooked. Little evidence is provided on MRPs of DOACs in patients with AF and, therefore, further studies are needed to establish the safety of DOACs in real-life clinical practice