Amyloid oligomer formation probed by water proton magnetic resonance spectroscopy.

Formation of amyloid oligomers, the most toxic species of amyloids in degenerative diseases, is critically coupled to the interplay with surrounding water. The hydrophobic force driving the oligomerization causes water removal from interfaces, changing the surface-hydration properties. Here, we show that such effects alter the magnetic relaxation response of local water in ways that may enable oligomer detection. By using water proton magnetic resonance spectroscopy, we measured significantly longer transverse magnetic relaxation (T(2)) times in mixtures of serum and amyloidogenic Aß(1-42) peptides versus similar concentration solutions of serum and nonamyloidogenic scrambled Aß(42-1) peptides. Immunochemistry with oligomer-specific antibodies, electron microscopy and computer simulations demonstrated that the hyperintense magnetic signal correlates with Aß(1-42) oligomerization. Finding early biophysical markers of the oligomerization process is crucial for guiding the development of new noninvasive imaging techniques, enabling timely diagnosis of amyloid-related diseases and pharmacological intervention.

Grain formation modulated by molecular hydrogen evaporation in the interstellar medium.

A mechanism for grain growth and formation in the interstellar medium is proposed. In this mechanism, hydrogen molecules act as moderators. The process begins when they physisorb to the surface of the grain. Then, when a collision with a heavy atom occurs, the bonding energy is carried away by the evaporation of hydrogen molecules. Estimates are made of the number of hydrogen molecules bound to the surface of a grain that would be sufficient to facilitate this mechanism at 13 K for amorphous carbon and 8 K for a silicate grain.

Principal component analysis of potential energy surfaces of large clusters: allowing the practical calculation of the master equation.

The number of variables in many-particle systems is typically unmanageably large; some way to reduce that number and still retain access to the important information about the system of interest is one of the great challenges in the broad topic of complexity. Principal components and principal coordinates provide a powerful means to extract--from unwieldy, large data sets--a reduced collection of variables that provide the information one needs, in a relatively efficient way and useful form. We investigate the application of principal components to the analysis of kinetics of the atomic motions in atomic clusters, particularly of clusters that are large enough so that a full description in terms of the entire high-dimensional potential surface is entirely impractical. A specific application is the use of principal components linking minima with their adjacent saddles, permitting the evaluation of rate coefficients (in the context of transition state theory) as ratios of partition functions of only one or two key variables.

Phase transitions in metal clusters and cluster catalysts.

Comparing the phase transitions of metal clusters with those of dielectric clusters shows that although the relative energies of the phase transitions for metals is typically less than those of dielectrics, other parameters of the phase transitions such as the entropy jumps and the relative widths of the coexistence bands are comparable for the two kinds of clusters. The dominating special characteristic of metal clusters is the large number of isomers with low excitation energy, in contrast with dielectric clusters, whose liquid aggregate states, generated by configurational excitation requiring fairly significant energies (relative to the atomic bond energy), have a significantly smaller density. This is partially due to the contribution of low-lying electronic excited states of the metal clusters. We analyze hysteresis in the phase transitions of large metal clusters as a result of cluster heating and cooling. The experimental and theoretical aspects of metal clusters as catalysts are considered.

Hydrophobe-water interactions: methane as a model.

Recent molecular-dynamics simulations have demonstrated that the use of an empirical hydrophobic potential displaying two minima, i.e., one for hydrophobes in close contact and one for hydrophobes separated by a hydration layer, leads to a marked improvement in protein structure prediction. This potential is supported by experimental data and simulations, but its physical origin and mathematical formulation have not been derived as yet. Here we show that water-mediated attraction (the "wetting regime") between two hydrophobic molecules originates in the interaction between the dipoles induced at the surface of the hydrophobes by the surrounding structured water. As an example, we derive the effective hydrophobic potential that describes the interaction between two methane molecules, a classical model of a double-well energy function. We found an excellent agreement with published results from all-atom, explicit solvent molecular-dynamics simulations of this interaction. The approach presented here provides the theoretical basis for implementing an adequate representation of the wetting regime of the hydrophobic interactions in force fields used for structure prediction. The results are useful for modeling both protein folding and binding.

Electron-atom superelastic scattering in magnesium at millielectron volt energies.

The energy dependence of superelastic scattering is measured for electrons on Mg(3(1)P) from threshold to 270 meV with a novel technique. The method uses photoelectrons produced by a narrow bandwidth laser as an approximately monoenergetic incident electron source to collide with excited atoms. Measurements are made at energies as low as 1.5 meV with a resolution of 1 meV near threshold. An efficient magnetic-bottle time-of-flight electron spectrometer allows for the simultaneous measurement of multiple scattering channels. Above-threshold ionization is also observed. The measured energy dependence for transitions from the 3(1)P state to both the 3(3)P and 3(1)S are found to be inversely proportional to the energy from 10 to 270 meV. Below 10 meV, the dependencies are different, with the 3(3)P transition having an E(-1/2) dependence and the 3(1)S channel retaining an E(-1) dependence.

Nomenclature of magnetic, incommensurate, composition-changed morphotropic, polytype, transient-structural and quasicrystalline phases undergoing phase transitions. II. Report of an IUCr Working Group on Phase Transition Nomenclature.

A general nomenclature applicable to the phases that form in any sequence of transitions in the solid state has been recommended by an IUCr Working Group [Acta Cryst. (1998). A54, 1028-1033]. The six-field notation of the first Report, hereafter I, was applied to the case of structural phase transitions, i.e. to transformations resulting from temperature and/or pressure changes between two crystalline (strictly periodic) phases involving modifications to the atomic arrangement. Extensive examples that illustrate the recommendations were provided. This second Report considers, within the framework of a similar six-field notation, the more complex nomenclature of transitions involving magnetic phases, incommensurate phases and transitions that occur as a function of composition change. Extension of the nomenclature to the case of phases with less clearly established relevance to standard schemes of transition in equilibrium systems, namely polytype phases, radiation-induced and other transient phases, quasicrystalline phases and their transitions is recommended more tentatively. A uniform notation for the translational periodicity, propagation vector or wavevector for magnetic and/or incommensurate substances is specified. The notation adopted for incommensurate phases, relying partly on the existence of an average structure, is also consistent with that for commensurate phases in a sequence. The sixth field of the nomenclature is used to emphasize the special features of polytypes and transient phases. As in I, illustrative examples are provided for each category of phase sequence.

Dynamical hierarchy in transition states: why and how does a system climb over the mountain?

How a reacting system climbs through a transition state during the course of a reaction has been an intriguing subject for decades. Here we present and quantify a technique to identify and characterize local invariances about the transition state of an N-particle Hamiltonian system, using Lie canonical perturbation theory combined with microcanonical molecular dynamics simulation. We show that at least three distinct energy regimes of dynamical behavior occur in the region of the transition state, distinguished by the extent of their local dynamical invariance and regularity. Isomerization of a six-atom Lennard--Jones cluster illustrates this: up to energies high enough to make the system manifestly chaotic, approximate invariants of motion associated with a reaction coordinate in phase space imply a many-body dividing hypersurface in phase space that is free of recrossings even in a sea of chaos. The method makes it possible to visualize the stable and unstable invariant manifolds leading to and from the transition state, i.e., the reaction path in phase space, and how this regularity turns to chaos with increasing total energy of the system. This, in turn, illuminates a new type of phase space bottleneck in the region of a transition state that emerges as the total energy and mode coupling increase, which keeps a reacting system increasingly trapped in that region.

Topology to geometry in protein folding: beta-lactoglobulin.

Evolution of protein structure from random coil to native is first represented topologically by its time-dependent sequences of discretized Ramachandran basins occupied by successive backbone residues. Introducing energetic and entropic criteria at each instant of observation transforms the description from a structurally ambiguous topological representation to an unambiguous geometric picture of the folding process. The method is applied with success to folding of beta-lactoglobulin, traditionally perplexing because of its reputed nonhierarchical folding pattern. This molecule passes through a stage, ca. 0.1 microseconds duration, of transient, "flickering" alpha-helical structure, until a bit of tertiary structure forms that stabilizes the system long enough to allow it to pass to its native beta-sheet.

From residue matching patterns to protein folding topographies: general model and bovine pancreatic trypsin inhibitor.

A coarse-grained model for protein-folding dynamics is introduced based on a discretized representation of torsional modes. The model, based on the Ramachandran map of the local torsional potential surface and the class (hydrophobic/polar/neutral) of each residue, recognizes patterns of both torsional conformations and hydrophobic-polar contacts, with tolerance for imperfect patterns. It incorporates empirical rates for formation of secondary and tertiary structure. The method yields a topological representation of the evolving local torsional configuration of the folding protein, modulo the basins of the Ramachandran map. The folding process is modeled as a sequence of transitions from one contact pattern to another, as the torsional patterns evolve. We test the model by applying it to the folding process of bovine pancreatic trypsin inhibitor, obtaining a kinetic description of the transitions between the contact patterns visited by the protein along the dominant folding pathway. The kinetics and detailed balance make it possible to invert the result to obtain a coarse topographic description of the potential energy surface along the dominant folding pathway, in effect to go backward or forward between a topological representation of the chain conformation and a topographical description of the potential energy surface governing the folding process. As a result, the strong structure-seeking character of bovine pancreatic trypsin inhibitor and the principal features of its folding pathway are reproduced in a reasonably quantitative way.

Linking topography of its potential surface with the dynamics of folding of a protein model.

The "3-color, 46-bead" model of a folding polypeptide is the vehicle for adapting to proteins a mode of analysis used heretofore for atomic clusters, to relate the topography of the potential surface to the dynamics that lead to formation of selected structures. The analysis is based on sequences of stationary points-successive minima, joined by saddles-that rise monotonically in energy from basin bottoms. Like structure-seeking clusters, the potential surface of the model studied here is staircase-like, rather than sawtooth-like, with highly collective motions required for passage from one minimum to the next. The surface has several deep basins whose minima correspond to very similar structures, but which are separated by high energy barriers.

Rapid diagnosis of Bancroftian filariasis by acridine orange staining of centrifuged parasites.

A rapid diagnostic test for detection of microfilaremia using a microhematocrit tube precoated with acridine orange (the Quantitative Buffy Coat [QBC] tube) was compared with a conventional 50 microliters-thick blood film (TF) in 119 volunteers in an area of Recife, Brazil that was endemic for Wuchereria bancrofti. Both the QBC and the TF techniques were 100% specific, and thus positive predictive values were equal at 100% for each technique in all subjects studied. Both techniques had equal negative predictive values of 100% in subjects with microfilarial counts > 100 per milliliter (mf/ml). Counts < 20 mf/ml are below a cutoff equal to the calculated limit of sensitivity of each of the two techniques. For those individuals with counts between 20 and 99 mf/ml, negative predictive values were, for practical diagnostic purposes, equivalent at 97.5% for the QBC technique and 99.0% for the TF. Because the QBC technique has predictive values as high as conventional TF, the convenience and rapidity of the technique will make the QBC technique a desirable alternative diagnostic method in those clinical settings where the equipment is available. A positive result will be available in less than six min after obtaining the specimen in individuals with counts < 100 mf/ml, and individuals with lower or no microfilaremia will have a result within 6-12 min.

Hepatotoxicity associated with sustained-release niacin.

Niacin (nicotinic acid) is a widely used agent in the treatment of hyperlipidemias characterized by elevated low-density lipoprotein and very-low-density lipoprotein. The tendency of the conventional crystalline niacin to cause flushing has limited its use in many patients. Sustained-release (SR) niacin preparations are increasingly utilized due to a lower incidence of flushing and convenient dosing frequency. Although gastrointestinal and hepatotoxic side effects are common to both formulations, they are more frequent and occasionally more severe with the SR preparations. We describe a patient who developed an acute illness characterized by hypothermia, hypotension, metabolic acidosis, and severe hepatic dysfunction 2 days after substitution of an SR preparation for a previously well-tolerated crystalline niacin.

Alternative perspective on photosynthetic yield and enhancement.

In the traditional Z scheme of photosynthesis the Emerson effects of red drop (decline in yield of photosynthesis in far-red light) and enhancement (of far-red yield by supplementary short-wavelength light) are taken to be evidence for the coupling in series of two photosystems that absorb unsymmetrically in the far-red region of the spectrum. An alternative explanation for red drop and enhancement is proposed here that does not invoke the series-coupling hypothesis. It is suggested that the Emerson effects may be due to the drop in intensity of radiation from sample absorption, which causes a photochemical loss when the reaction shuts off at depth in the medium. The effects of oxygen, carbon dioxide, and temperature on the yield may also be interpreted in terms of this model.

Finite-time thermodynamics: Engine performance improved by optimized piston motion.

The methods of finite-time thermodynamics are used to find the optimal time path of an Otto cycle with friction and heat leakage. Optimality is defined by maximization of the work per cycle; the system is constrained to operate at a fixed frequency, so the maximum power is obtained. The result is an improvement of about 10% in the effectiveness (second-law efficiency) of a conventional near-sinusoidal engine.