Detection-dependent kinetics as a probe of folding landscape microstructure

The folding landscapes of polypeptides and proteins exhibit a hierarchy of local minima. The causes range from proline isomerization all the way down to microstructure in the free energy caused by residual frustration inherent in even the best 20 amino acid design. The corresponding time scales range from hours to submicroseconds. The smallest microstructures are difficult to detect. We have measured the folding/unfolding kinetics of the engineered trpzip2 peptide at different tryptophan fluorescence wavelengths, each yielding a different rate. Wavelength-dependent folding kinetics on 0.1-2 mus time scales show that different microstructures with a range of solvent exposure and local dynamics are populated. We estimate a lower limit for the roughness of the free energy surface based on the range of rates observed.     

Characterization of CNS disorders and evaluation of therapy using structural and functional MRI

Modern drug development requires technologies that allow rapid translation from the preclinical to the clinical stage. It is obvious that non-invasive imaging modalities such as magnetic resonance imaging (MRI) will play a central role in this regard. This article reviews the use of structural and functional MRI readouts for characterization of central nervous system (CNS) disorders and evaluation of the efficacy of potential CNS drugs. Examples comprise dementia of Alzheimer's type, cerebral ischemia, and neuroinflammation covering both clinical and preclinical aspects. In these examples MRI has been used to obtain relevant structural information on brain atrophy, on the location and extent of ischemic brain areas, and on the number and distribution of demyelinated plaques. These structural data are complemented by readouts assessing the functional consequences associated with the pathomorphological changes. In the last decade, MRI has evolved into a standard tool for the development of CNS drugs. With regard to target-specific/molecular imaging applications MRI is limited by its inherently low sensitivity; complementary imaging modalities utilizing optical and radionuclear reporter systems will thus be required.     

Combined bond-polarization basis sets for accurate determination of dissociation energies. II. Basis set superposition error as a function of the parent basis set

The effect of the parent basis set on the basis set superposition error caused by bond functions is investigated systematically. An important difference between BSSE at the SCF and correlated levels is pointed out. Three new basis sets are defined, denoted 6-311 + G(d,p)B, 6-311 + G(2d,p)B, and 6-311 + G(2df,p)B. BSSE for the first-row hydrides seems to increase uniformly with increasing atomic number of the central atom. Expansion of the valence part of the basis set from 6-31G to 6-311G, as well as adding f functions, has a significant effect on the BSSE. Additional BSSEs incurred by bond functions are less than or equal to 1 kcal/mol for the 6-311 + G(2df,p)B basis set. For the dissociation energies of the first-row hydride species, agreement with experiment within only a few kcal/mol can be obtained even without resorting to isogyric reaction cycles. For high-quality calculations, adding bond functions seems to have definite advantages over expanding the polarization space beyond the [2d1f] level.     

Cluster Build-up Reactions using Di-gold Cationic Fragments: Synthesis and Structural Characterization of [Os7(CO)19(Au2dppm)]

The reaction of the di-gold cation [Au₂(dppx)]²⁺ with the heptanuclear cluster dianion [Os₇(CO)₂₀]^2– affords the mixed metal cluster [Os₇(CO)₂₀{Au₂(dppx)}] (x=m (1), e (2), b (3)). On standing, in solution, this complex undergoes decarbonylation to give the cluster [Os₇(CO)₁₉{Au₂(dppx)}] (x=m (4), e (5), b (6)). The complexes have been characterised spectroscopically, and an X-ray structure determination of the dppm derivative shows that it contains a metal core based on an Os₇ edge-bridged bicapped tetrahedron with the two ₃-Au atoms capping adjacent triangular Os₃ faces of the central tetrahedron. In an analogous reaction, the carbido anion [Os₇(H)C(CO)₁₉]^– affords the neutral cluster [Os₇C(CO)₁₉{Au₂(dppm)}] (7) when treated with [Au₂(dppm)]²⁺ in the presence of base.     

Synthesis of new mono-functionalised tetrathiafulvalene derivatives by reactions of etrathiafulvalenyllithium with aldehydes and ketones: X-ray crystal structures of TTF-CMe(OH)Fc, TTF-CMe(OMe)Fc and TTF-CH(OMe)TTF (Fc = ferrocenyl)

Reactions of tetrathiafulvalenyllithium (TTF-Li) with a range of aldehydes and ketones have been explored for the first time, to provide an efficient route to mono-functionalised TTF derivatives of general formulae TTF-CH(OH)R (R = alkyl, phenyl, tetrathiafulvalenyl and ferrocenyl) and TTF-CR(OH)R′ (R = alkyl, phenyl, R′ = alkyl, phenyl, tetrathiafulvalenyl, ferrocenyl, and R-R′ = fluorenyl). Subsequent transformations involving the reactive alcohol group of some of these compounds are reported. The structures of the three title compounds have been established by single-crystal X-ray analysis.     

The preparation of hot-pressed chalcogenide spinels. II. Stoichiometry and optical transparency in CdCr2S4 and CoCr2S4

The compounds CdCr₂S₄ and CoCr₂S₄ have been hot pressed into disks that are highly transparent in the infrared. Stoichiometry has been altered by varying the $\text{Cr}{}^{\mathrm{3+}}\text{M}{}^{\mathrm{2+}}$ ratio, where M²⁺ is Cd²⁺ or Co²⁺. The effects of nonstoichiometry on optical transmission were determined. Excess M²⁺ attenuates the transmission much more than excess Cr³⁺.     

Nouveaux exemples d'acétonides d'aldéhydosucres furanniques

Further examples of O-isopropylidenaldehydosugars in the furanose series Formyl-bearing furanose derivatives 1–3 (α-D -xylo or α-D -erythro configurations) and 5–8 (configurations α-D -ribo, α-D -lyxo, β-L -threo and D -arabino) have been prepared by classical synthetic steps and their properties mainly spectroscopic, reported. The coupling constant between the formyl and the vicinal proton is always small. Like other members of the series, these new aldehydosugars constitute very useful and flexible synthetic intermediates.     

Potassium addition to Fe/MgO, Ni/MgO and Ni/SiO2: Reducibility, dispersity and stabilization of the promoter by the support

The influence of potassium addition on the morphological properties of Fe/MgO and Ni/MgO has been investigated: KNO₃ addition to precursors results in a decrease of the reducibility and in a smaller dispersity of the metallic phase. A loss of potassium is observed at reduction temperatures in excess of 773 K. Silica-supported Ni behaves differently: silica inhibits the potassium volatilization and nickel reducibility is enhanced. This illustrates how promoter effects can be influenced by the nature of support.

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Fe/MgO Ni/MgO: KNO₃ . , 773 K. , : . .

     

An electron spin resonance study of radicals from chloramine-t-1 : Spin trapping of radicals produced in acid media

Under acid conditions aqueous solutions of chloramine-T form nitrogen-centred radicals via loss of the chlorine atom. The nitrogen radicals produced have been studied by ESR spectroscopy using the spintrapping method. Adducts of the spin trap phenyl-t-butyl nitrone are oxidized by chloramine-T in acid media to give a paramagnetic product in which the unpaired electron interacts with two inequivalent nitrogen atoms. The spin trap 5,5-dimethyl-2-pyrrolidine-1 -oxide is oxidized rapidly to 5,5-dimethyl-2-pyrrolidone-1-oxyl by chloramine-T under acid onditions. The water soluble trap α-4-pyridyl-1-oxide-N-t-butyl nitrone forms a stable nitroxide adduct with a nitrogen radical of chloramine-T in acid solution. Identical results were obtained with chloramine-B (sodium salt of N-chlorobenzene sulfonamide), indicating the involvement of the N-chloramine group in radical formation.     

Electrodynamic investigations of conduction processes in humid microcrystalline cellulose tablets

The conduction mechanism in microcrystalline cellulose (MCC) tablets at varying relative humidity (RH) has been investigated by using the techniques of low frequency dielectric spectroscopy and transient current analysis at room temperature. The dependence on RH on the measured conductivity and charge carrier density indicates that a high-power-law-exponent percolation process of cations being conducted on water molecules occupying available 6-OH units on the cellulose chains is the dominating dc conduction mechanism at RH below 3 wt % of moisture content. The experimentally observed decrease in charge carrier mobility with increasing moisture content shows that protons and H3O+ ions that are being blocked at empty 6-OH sites also contribute to the charge transport process in cellulose at low moisture contents.