Chemical markup, XML and the World-Wide Web. 2. Information objects and the CMLDOM

We describe the development of a structured method of representing chemistry on the World-Wide Web using an object-oriented approach to information objects. We show how a document object model (DOM) for chemistry can be constructed using as its basis Chemical Markup Language (CML). Application of the CMLDOM to the development of chemical tools is described.     

A new micropatterning method of soft substrates reveals that different tumorigenic signals can promote or reduce cell contraction levels

In tissues, cell microenvironment geometry and mechanics strongly impact on cell physiology. Surface micropatterning allows the control of geometry while deformable substrates of tunable stiffness are well suited for the control of the mechanics. We developed a new method to micropattern extracellular matrix proteins on poly-acrylamide gels in order to simultaneously control cell geometry and mechanics. Microenvironment geometry and mechanics impinge on cell functions by regulating the development of intra-cellular forces. We measured these forces in micropatterned cells. Micropattern geometry was streamlined to orient forces and place cells in comparable conditions. Thereby force measurement method could be simplified and applied to large-scale experiment on chip. We applied this method to mammary epithelial cells with traction force measurements in various conditions to mimic tumoral transformation. We found that, contrary to the current view, all transformation phenotypes were not always associated to an increased level of cell contractility.     

Ultra-short columns and ballistic gradients: considerations for ultra-fast chromatographic liquid chromatographic-tandem mass spectrometric analysis

Ultra-fast chromatographic separations has enabled fast chromatographic method development and rapid analysis for sample quantification. Decreasing over-all analytical time has become a factor of major importance for all aspects of drug discovery. However, merely decreasing chromatographic analysis time by decreasing k' can lead to inconsistent quantitative or qualitative results due to ineffective separations in complex matrices. We have found that by changing column length and gradient slope we can maintain chromatographic integrity of chemically diverse analytes and achieve the analytical speed required for bioanalytical drug discovery quantitative analysis. We have optimized method development strategy by performing separations on 2x20 mm HPLC columns at flow-rates of 1.5 ml/min to 2 ml/min with full linear gradients achieved in 1 min for the quantification of pharmaceuticals and their metabolites from biological matrices. This method development strategy can be readily adapted to other matrices. This paper will discuss the effects of column length and gradient time in ultra-fast chromatographic resolution.     

Towards a special-purpose computer for Hartree–Fock computations

We propose the development of a special- purpose computer for the Hartree–Fock method, which generally suffers quartic time scaling. We conduct a qualitative assessment of the various computational components, with a focus on electron repulsion integrals (ERI), and consequently map various architectural traits to the various computational components. A quantitative analysis of one component is also presented. We go on to mull over the idea of mixed precision arithmetic. These analyses will aid the practical development of a specialized high performance multi-architecture computer. Contribution to the Mark S. Gordon 65th Birthday Festschrift Issue.     

Computer-assisted high-performance liquid chromatography method development with applications to the isolation and analysis of phytoplankton pigments

We used chromatography modeling software to assist in HPLC method development, with the goal of enhancing separations through the exclusive use of gradient time and column temperature. We surveyed nine stationary phases for their utility in pigment purification and natural sample analysis. For purification, a complex algal matrix was separated on an efficient monomeric column, from which partially purified fractions were collected and purified on polymeric columns that exaggerated resolution between pigments of interest. Additionally, we feature an HPLC method that is simple, fast, demonstrates excellent transferability and is ideal for quantitative analysis of pigments in dilute natural water samples.     

Quantification of oxygenated volatile organic compounds in seawater by membrane inlet-proton transfer reaction/mass spectrometry

The role of the ocean in the cycling of oxygenated volatile organic compounds (OVOCs) remains largely unanswered due to a paucity of datasets. We describe the method development of a membrane inlet-proton transfer reaction/mass spectrometer (MI-PTR/MS) as an efficient method of analysing methanol, acetaldehyde and acetone in seawater. Validation of the technique with water standards shows that the optimised responses are linear and reproducible. Limits of detection are 27 nM for methanol, 0.7 nM for acetaldehyde and 0.3 nM for acetone. Acetone and acetaldehyde concentrations generated by MI-PTR/MS are compared to a second, independent method based on purge and trap-gas chromatography/flame ionisation detection (P&T-GC/FID) and show excellent agreement. Chromatographic separation of isomeric species acetone and propanal permits correction to mass 59 signal generated by the PTR/MS and overcomes a known uncertainty in reporting acetone concentrations via mass spectrometry. A third bioassay technique using radiolabelled acetone further supported the result generated by this method. We present the development and optimisation of the MI-PTR/MS technique as a reliable and convenient tool for analysing seawater samples for these trace gases. We compare this method with other analytical techniques and discuss its potential use in improving the current understanding of the cycling of oceanic OVOCs.     

基于刻蚀反应的纳米结构空心化（英文）

中空纳米材料的可控合成使其在催化、能量转换与储存、生物医药等领域具有广阔的应用前景.本专论旨在揭示刻蚀反应对纳米结构空心过程的关键影响.讨论了通过增强纳米粒子表面在刻蚀液中的相对稳定性来精确操纵中空化过程的策略,主要关注3种刻蚀策略,包括硬模板法、氧化还原辅助中空法和表面钝化自模板法.最后,对基于刻蚀反应的纳米结构空心化可控合成未来的发展方向进行了展望.     

Analysis of similarity of electrophoretic patterns in mRNA differential display

We present a novel method of statistical analysis for the comparison of electrophoretic data. The method is based on the squared Euclidian distance of normalized signal data vectors of electrophoretic lanes. The differences in the electrophoretic patterns are evaluated by a statistical test based on Hubert's statistics which measures the significance of the signal grouping. We demonstrate the validity and applicability of the method in a large data set derived from automated fluorescent mRNA differential display analysis of the expression of acute-phase proteins during experimental Escherichia coli infection in mice. The current testing method is capable of finding theoretically similar natural groupings to be similar in a statistically significant way whereas theoretically dissimilar or random groupings can be recognized to be artifactual. We also show how the calculated pairwise signal distances can be utilized in methodological problem solving. These analytical methods can be applied to the study of other related problems of similarity analysis of electrophoretic patterns, and also provide useful tools for the development of automated recognition of differentially expressed mRNAs.     

Prediction of solubility of drugs by conductor-like screening model for real solvents

The solubility of drugs in solvents is fundamentally important for drug development and manufacturing. As the experimental measurements of the solubility are extremely laborious tasks, reliable prediction methods are highly required. We have employed the conductor-like screening model for real solvents (COSMO-RS) in predicting the solubility of drugs and drug-like compounds in various solvent systems. We also evaluated the salt effect on the solubility of caffeine using this method. The present results demonstrated that COSMO-RS has reasonably reproduced the experimental data and have proved that this method is generally available in predicting the solubility of drugs.     

Efficient reconstruction of complex free energy landscapes by multiple walkers metadynamics

Recently, we have introduced a new method, metadynamics, which is able to sample rarely occurring transitions and to reconstruct the free energy as a function of several variables with a controlled accuracy. This method has been successfully applied in many different fields, ranging from chemistry to biophysics and ligand docking and from material science to crystal structure prediction. We present an important development that speeds up metadynamics calculations by orders of magnitude and renders the algorithm much more robust. We use multiple interacting simulations, walkers, for exploring and reconstructing the same free energy surface. Each walker contributes to the history-dependent potential that, in metadynamics, is an estimate of the free energy. We show that the error on the reconstructed free energy does not depend on the number of walkers, leading to a fully linear scaling algorithm even on inexpensive loosely coupled clusters of PCs. In addition, we show that the accuracy and stability of the method are much improved by combining it with a weighted histogram analysis. We check the validity of our new method on a realistic application.     

Targeted three-dimensional liquid chromatography: a versatile tool for quantitative trace analysis in complex matrices

Targeted multidimensional liquid chromatography (MDLC), commonly referred to as 'coupled-column' or 'heartcutting', has been used extensively since the 1970s for analysis of low concentration constituents in complex biological and environmental samples. A primary benefit of adding additional dimensions of separation to conventional HPLC separations is that the additional resolving power provided by the added dimensions can greatly simplify method development for complex samples. Despite the long history of targeted MDLC, nearly all published reports involve two-dimensional methods, and very few have explored the benefits of adding a third dimension of separation. In this work we capitalize on recent advances in reversed-phase HPLC to construct a three-dimensional HPLC system for targeted analysis built on three very different reversed-phase columns. Using statistical peak overlap theory and one of the most recent models of reversed-phase selectivity we use simulations to show the potential benefit of adding a third dimension to a MDLC system. We then demonstrate this advantage experimentally by developing targeted methods for the analysis of a variety of broadly relevant molecules in different sample matrices including urban wastewater treatment effluent, human urine, and river water. We find in each case that excellent separations of the target compounds from the sample matrix are obtained using one set of very similar separation conditions for all of the target compound/sample matrix combinations, thereby significantly reducing the normally tedious method development process. A rigorous quantitative comparison of this approach to conventional 1DLC-MS/MS also shows that targeted 3DLC with UV detection is quantitatively accurate for the target compounds studied, with method detection limits in the low parts-per-trillion range of concentrations. We believe this work represents a first step toward the development of a targeted 3D analysis system that will be more effective than previous 2D separations as a tool for the rapid development of robust methods for quantitation of low concentration constituents in complex mixtures.     

Phosphate ore beneficiation via determination of phosphorus-to-silica ratios by Laser Induced Breakdown Spectroscopy

We report development and application of an in-situ applicable method to determine phosphate ore rock quality based on Laser-Induced Breakdown Spectroscopy (LIBS). This is an economically viable method for real-time evaluation of ore phosphate rocks in order to separate high-silica pebbles prior to deep beneficiation. This is achieved by monitoring relative emission line intensities from key probe elements via single laser ablation shots: the ratio of the phosphorous to silica line intensities (P/Si ratio) provides a simple and reliable indicator of ore rock quality. This is a unique LIBS application where no other current analytical spectroscopic method (ICP or XRF) can be applied. Method development is discussed, and results with actual ore samples are presented.     

Microwave-assisted organic synthesis of a high-affinity pyrazolo-pyrimidinyl TSPO ligand

We herein report a dramatically improved total synthesis of the high-affinity translocator protein (TSPO) ligand DPA-714, featuring microwave-assisted organic synthesis (MAOS). Compared with previously described approaches, our novel MAOS method dramatically reduces overall reaction time without adversely effecting reaction yields. We envision that the described MAOS protocol may be suitably applied to high-throughput, diversity-oriented synthesis of novel compounds based on the pyrazolo-pyrimidinyl scaffold. Such an approach could accelerate the development of focused libraries of novel TSPO ligands with potential for future development as molecular imaging and therapeutic agents.     

Intelligent automation of high-performance liquid chromatography method development by means of a real-time knowledge-based approach

We describe the development, attributes and capabilities of a novel type of artificial intelligence system, called LabExpert, for automation of HPLC method development. Unlike other computerised method development systems, LabExpert operates in real-time, using an artificial intelligence system and design engine to provide experimental decision outcomes relevant to the optimisation of complex separations as well as the control of the instrumentation, column selection, mobile phase choice and other experimental parameters. LabExpert manages every input parameter to a HPLC data station and evaluates each output parameter of the HPLC data station in real-time as part of its decision process. Based on a combination of inherent and user-defined evaluation criteria, the artificial intelligence system programs use a reasoning process, applying chromatographic principles and acquired experimental observations to iteratively provide a regime for a priori development of an acceptable HPLC separation method. Because remote monitoring and control are also functions of LabExpert, the system allows full-time utilisation of analytical instrumentation and associated laboratory resources. Based on our experience with LabExpert with a wide range of analyte mixtures, this artificial intelligence system consistently identified in a similar or faster time-frame preferred sets of analytical conditions that are equal in resolution, efficiency and throughput to those empirically determined by highly experienced chromatographic scientists. An illustrative example, demonstrating the potential of LabExpert in the process of method development of drug substances, is provided.     

Efficiency of alchemical free energy simulations. I. A practical comparison of the exponential formula, thermodynamic integration, and Bennett's acceptance ratio method

We investigate the relative efficiency of thermodynamic integration, three variants of the exponential formula, also referred to as thermodynamic perturbation, and Bennett's acceptance ratio method to compute relative and absolute solvation free energy differences. Our primary goal is the development of efficient protocols that are robust in practice. We focus on minimizing the number of unphysical intermediate states (λ-states) required for the computation of accurate and precise free energy differences. Several indicators are presented which help decide when additional λ-states are necessary. In all tests Bennett's acceptance ratio method required the least number of λ-states, closely followed by the "double-wide" variant of the exponential formula. Use of the exponential formula in only strict "forward" or "backward" mode was not found to be competitive. Similarly, the performance of thermodynamic integration in terms of efficiency was rather poor. We show that this is caused by the use of the trapezoidal rule as method of numerical quadrature. A systematic study focusing on the optimization of thermodynamic integration is presented in a companion paper.     

Long-range molecular organization of an organic monolayer grafted on a mineral substrate.

Structured and functional materials are of the utmost importance for the development of microelectronic technology. We report on a method to obtain a highly ordered organic molecular layer on a mineral substrate. We took advantage of the regular array of reactive sites present at the single-crystal surface of topaz to perform a liquid-phase silanization reaction. The grazing-incidence diffraction technique was used to characterize the bare and covalently coated surfaces. The ordering of the monomolecular organic layer reproduces the perfect single-crystal structure of the cleaved surface over millimeter distances.     

A new four-step hybrid type method with vanished phase-lag and its first derivatives for each level for the approximate integration of the Schrödinger equation

In this paper we present a new methodology for the development of four-step hybrid type methods of sixth algebraic order with vanished phase-lag and its derivatives. The methodology is based on the vanishing of the phase-lag and its derivatives on its level of the hybrid method. We present a comparative error and stability analysis for the produced new method. The efficiency of the new obtained methods is examined by application to the resonance problem of the Schrödinger equation.     

Massively parallel spin–orbit configuration interaction

We describe a new approach to incorporating quantum effects into chemical reaction rate theory using quantum trajectories. Our development is based on the entangled trajectory molecular dynamics method for simulating quantum processes using trajectory integration and ensemble averaging. By making dynamical approximations similar to those underlying classical transition state theory, quantum corrections are incorporated analytically into the quantum rate expression. We focus on a simple model of quantum decay in a metastable system and consider the deep tunneling limit where the classical rate vanishes and the process is entirely quantum mechanical. We compare our approximate estimate with the well-known WKB tunneling rate and find qualitative agreement.     

Simultaneous quantification of lipopeptide isoforms by UPLC-MS in the fermentation broth from Bacillus subtilis CNPMS22

Analytical and Bioanalytical Chemistry - The rapid and accurate quantification of lipopeptide families in biological samples are challenging. We present the development and validation of a method...