Folding and unfolding of helix-turn-helix motifs in the gas phase

Ion mobility measurements and molecular dynamic simulations have been performed for a series of peptides designed to have helix-turn-helix motifs. For peptides with two helical sections linked by a short loop region: AcA(14)KG(3)A(14)K+2H(+), AcA(14)KG(5)A(14)K+2H(+), AcA(14)KG(7)A(14)K+2H(+), and AcA(14)KSar(3)A(14)K+2H(+) (Ac = acetyl, A = alanine, G = glycine, Sar = sarcosine and K = lysine); a coiled-coil geometry with two anti-parallel helices is the lowest energy conformation. The helices uncouple and the coiled-coil unfolds as the temperature is raised. Equilibrium constants determined as a function of temperature yield enthalpy and entropy changes for the unfolding of the coiled-coil. The enthalpy and entropy changes depend on the length and nature of the loop region. For a peptide with three helical sections: protonated AcA(14)KG(3)A(14)KG(3)A(14)K; a coiled-coil bundle with three helices side-by-side is substantially less stable than a geometry with two helices in an antiparallel coiled-coil and the third helix collinear with one of the other two.     

Biphenylalkoxyamine Derivatives–Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity

Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H₃ receptors (H₃Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H₃R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H₃R ligands. Most of these compounds show high affinity for human H₃R (K_i < 150 nM) and submicromolar inhibition of BuChE (IC₅₀ < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H₃R, with a K_i value of 33.9 nM, and for equine serum BuChE, with an IC₅₀ of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC₅₀ of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.     

Fall-Off of Eigenfunctions for Non-Local Schrödinger Operators with Decaying Potentials

We study the spatial decay of eigenfunctions of non-local Schrödinger operators whose kinetic terms are generators of symmetric jump-paring Lévy processes with Kato-class potentials decaying at infinity. This class of processes has the property that the intensity of single large jumps dominates the intensity of all multiple large jumps. We find that the decay rates of eigenfunctions depend on the process via specific preference rates in particular jump scenarios, and depend on the potential through the distance of the corresponding eigenvalue from the edge of the continuous spectrum. We prove that the conditions of the jump-paring class imply that for all eigenvalues the corresponding positive eigenfunctions decay at most as rapidly as the Lévy intensity. This condition is sharp in the sense that if the jump-paring property fails to hold, then eigenfunction decay becomes slower than the decay of the Lévy intensity. We furthermore prove that under reasonable conditions the Lévy intensity also governs the upper bounds of eigenfunctions, and ground states are comparable with it, i.e., two-sided bounds hold. As an interesting consequence, we identify a sharp regime change in the decay of eigenfunctions as the Lévy intensity is varied from sub-exponential to exponential order, and dependent on the location of the eigenvalue, in the sense that through the transition Lévy intensity-driven decay becomes slower than the rate of decay of the Lévy intensity. Our approach is based on path integration and probabilistic potential theory techniques, and all results are also illustrated by specific examples.     

Small-time sharp bounds for kernels of convolution semigroups

We study small-time bounds for transition densities of convolution semigroups corresponding to pure jump Lévy processes in R ^d , d ≥ 1, including the processes with jump measures which are exponentially and subexponentially localized at ∞. For a large class of Lévy measures, not necessarily symmetric or absolutely continuous with respect to Lebesgue measure, we find the optimal upper bound in both time and space for the corresponding heat kernels at ∞. In case of Lévy measures that are symmetric and absolutely continuous with densities g such that g(x) ? f(|x|) for non-increasing profile functions f, we also prove the full characterization of the sharp two-sided transition densities bounds of the form

$${p_t}\left( x \right) \asymp h{\left( t \right)^{ - d}} \cdot {1_{\left\{ {\left| x \right| \leqslant \theta h\left( t \right)} \right\}}} + tg\left( x \right) \cdot {1_{\left\{ {\left| x \right| \geqslant \theta h\left( t \right)} \right\}}},t \in \left( {0,{t_0}} \right),{t_0} > 0,x \in {\mathbb{R}^d}.$$

This is done for small and large x separately. Mainly, our argument is based on new precise upper bounds for convolutions of Lévy measures. Our investigations lead to a surprising dichotomy correspondence of the decay properties at ∞ for transition densities of pure jump Lévy processes. All results are obtained solely by analytic methods, without use of probabilistic arguments.

     

Microstructure and magnetic properties of bulk amorphous and nanocrystalline Fe61Co10Zr2.5Hf2.5Nb2W2B20 alloy

The microstructure and magnetic properties, i.e. the initial magnetic susceptibility, its disaccommodation, core losses and approach to ferromagnetic saturation of the bulk amorphous and partially crystallized Fe₆₁Co₁₀Zr_2.5Hf_2.5Nb₂W₂B₂₀ alloy are studied. From X-ray, Mössbauer spectroscopy and electron microscopy studies we have stated that all samples in the as-quenched state are fully amorphous. However, after annealing the samples at 850 K for 30 min the crystalline α-FeCo grains embedded in the amorphous matrix are found. Moreover, from Mössbauer spectra analysis we have stated that the crystalline phase in those samples exhibits the long-range order. The alloy in the as-quenched state shows good thermal stability of the initial magnetic susceptibility. Furthermore, the intensity of the magnetic susceptibility disaccommodation in the rod is lower than in the ribbon. It is due to low quenching rate during the rod preparation which involves the reduction of free volumes. From the analysis of the isochronal disaccommodation curves, assuming the Gaussian distribution of relaxation times, we have found that activation energies of the elementary processes responsible for this phenomenon range from 1.2 to 1.4 eV. After the annealing of the samples the initial susceptibility slightly enhances and disaccommodation drastically decreases. From high-field magnetization studies we have learned that the size of structural defects depends on the quenching rate (the shape of the samples) and changes after annealing.     

Strong fluorescence enhancement of 2-bromo-3-(1H-indol-3-yl)maleimide upon coordination to a Lewis-acidic metal complex

The emission intensity of an indolyl maleimide derivative increases approximately 80-fold by reversible coordination to (1,4,7,11-tetraazacyclododecane)zinc(II), which makes the system a promising new signalling motif for molecular sensors.     

Peptide pinwheels

Electrospraying a mixture of Ac-(GA)7K and Ac-A(GA)7K (Ac = acetyl, G = glycine, A = alanine, and K = lysine) peptides produces strong signals for unsolvated dimers and trimers. The conformations of these multimers have been examined with use of ion mobility measurements in conjunction with molecular dynamics simulations. The results suggest that the trimers adopt a pinwheel arrangement of helices with the C-termini tethered together by the protonated lysine side chain from one peptide interacting with the C-terminus of a neighboring helix. This arrangement leads to a cooperative electrostatic stabilization of all the helices through the interaction of the combined charge with the helix dipoles. The dimer adopts a related V-shaped arrangement of helices which is also cooperatively stabilized.     

7α-methoxy-2-[(substituted)methylene]cephem sulfones as inhibitors of human leukocyte elastase and thrombin

A series of 7-methoxy-2-[(substituted)methylene]cephem sulfones was synthesized. The compounds with an acetoxy group at the C-3 position as a leaving group were found to be potent inhibitors of HLE. Selected compounds are also found to be antithrombin agents.SynPhar Laboratories Inc. #2 Taiho Alberta Centre, 4290-91A Street, Edmonton, Canada T6E 5V2. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1510–1516, November, 1998.     

Radical polymerization of 1‐alkenes catalyzed by lithium salts of carboranes

Radical polymerization of selected 1‐alkenes, (1‐hexene, 1‐octene and 2‐methyl‐1‐heptene), initiated with classical radical initiators and catalyzed by lithium salts of selected carboranes was studied. In accordance with recently published results it was found that the use of radical initiators under catalysis by “naked” lithium cation of carboranes promotes the radical polymerization of 1‐alkenes, otherwise nonpolymerizable by the radical mechanism. However, although in our experiments relatively high monomers conversions are reached for some of the thermal initiators used, only low‐molecular‐weight oligomers with M_n < 1000 are formed, regardless of the initiator and carborane anion used. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011