Tutorial review on validation of liquid chromatography–mass spectrometry methods: Part I

This is the part I of a tutorial review intending to give an overview of the state of the art of method validation in liquid chromatography mass spectrometry (LC–MS) and discuss specific issues that arise with MS (and MS/MS) detection in LC (as opposed to the “conventional” detectors). The Part I briefly introduces the principles of operation of LC–MS (emphasizing the aspects important from the validation point of view, in particular the ionization process and ionization suppression/enhancement); reviews the main validation guideline documents and discusses in detail the following performance parameters: selectivity/specificity/identity, ruggedness/robustness, limit of detection, limit of quantification, decision limit and detection capability. With every method performance characteristic its essence and terminology are addressed, the current status of treating it is reviewed and recommendations are given, how to determine it, specifically in the case of LC–MS methods.     

Structure and exchange in silicon-linked tetraradicals

The EPR spectroscopy, crystallography, and magnetic susceptibility of tetrakis(N-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)silane and tetrakis(4-N-tert-butyl-N-aminoxylphenyl)silane show that silicon acts as a weak intramolecular exchange linker for polynitroxides, although both tetraradicals show onset of inter-spin exchange at reduced temperatures.     

Radioactivity in the Baltic Sea: inventories and temporal trends of <Superscript>137</Superscript>Cs and <Superscript>90</Superscript>Sr in water and sediments

The Baltic Sea is ecologically unique as one of the world’s largest brackish water basins. It was significantly contaminated by radioactivity following the Chernobyl accident in 1986, the major contaminant being long-lived ¹³⁷Cs. Due to the slow exchange of water between the Baltic Sea and the North Sea and the relatively rapid sedimentation rates, radionuclides have prolonged residence times in the Baltic Sea. ¹³⁷Cs levels are consequently still clearly higher than in other water bodies around the world. In addition to the Chernobyl accident, artificial radionuclides in the Baltic Sea originate from the global fallout following nuclear weapons testing in the 1950s and 1960s, while discharges into the Baltic Sea from nuclear power plants and other facilities are of minor importance. Here, inventories and the temporal evolution of radionuclides both in seawater and sediments of the Baltic Sea are presented and discussed.     

Emission studies of InGaN layers and LEDs grown by plasma-assisted MBE

We prepared InGaN layers on GaN/sapphire substrates using rf-MBE. Photoluminescence (PL) from these layers, grown at different temperatures T_S, shows that there is a strong tendency of GaN to form a separate phase as T_S is increased from 600°C to 650°C. Concomitant with the phase separation, the PL from the InGaN phase broadens, which indicates that indium composition in this phase becomes increasingly non-uniform. Indium compositions measured by Rutherford backscattering (RBS) are consistent with these results. We also observed an increase in PL intensity for InGaN layers grown at higher temperatures. In this paper, we also report on preparing a top-contact InGaN/GaN light emitting diode. The device was operated at 447 nm and had the emission line width of 37 nm with no observable impurity related features. The turn-on voltage was 3.0 V. The output power was 20 μW at 60 mA drive current.     

Growth of strain-compensated GaInNAs/GaAsP quantum wells for 1.3 μm lasers

Strain-compensated GaInNAs/GaAsP quantum well structures and lasers were grown by gas source molecular beam epitaxy using a RF-plasma nitrogen radical beam source. The optimal growth condition for the quantum well structure was determined based on room-temperature photoluminescence measurements. Effects of rapid thermal annealing (RTA) on the optical properties of GaInNAs/GaAsP quantum well structures as well as laser diodes are examined. It was found to significantly increase the photoluminescence from the quantum wells and reduce the threshold current density of the lasers, due to a removal of N induced nonradiative centers from GaInNAs wells.     

Kinetics of bioconjugate nanoparticle label binding in a sandwich-type immunoassay

Nanoparticle labels have enhanced the performance of diagnostic, screening, and other measurement applications and hold further promise for more sensitive, precise, and cost-effective assay technologies. Nevertheless, a clear view of the biomolecular interactions on the molecular level is missing. Controlling the ratio of molecular recognition over undesired nonspecific adhesion is the key to improve biosensing with nanoparticles. To improve this ratio with an aim to disallow nonspecific binding, a more detailed perspective into the kinetic differences between the cases is needed. We present the application of two novel methods to determine complex binding kinetics of bioconjugate nanoparticles, interferometry, and force spectroscopy. Force spectroscopy is an atomic force microscopy technique and optical interferometry is a direct method to monitor reaction kinetics in second-hour timescale, both having steadily increasing importance in nanomedicine. The combination is perfectly suited for this purpose, due to the high sensitivity to detect binding events and the ability to investigate biological samples under physiological conditions. We have attached a single biofunctionalized nanoparticle to the outer tip apex and studied the binding behavior of the nanoparticle in a sandwich-type immunoassay using dynamic force spectroscopy in millisecond timescale. Utilization of the two novel methods allowed characterization of binding kinetics in a time range spanning from 50 ms to 4 h. These experiments allowed detection and demonstration of differences between specific and nonspecific binding. Most importantly, nonspecific binding of a nanoparticle was reduced at contact times below 100 ms with the solid-phase surface.

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Figure A single biofunctionalized nanoparticle was attached to the outer tip apex and the binding behavior of the nanoparticle in a sandwich-type immunoassay, A) without analyte, B) with analyte and C) saturating analyte concentration, was recorded using dynamic force spectroscopy in millisecond timescale. The setting allowed measurement of the association speed of nonspecific binding.

     

Analysis of commercial and public bioactivity databases

Activity data for small molecules are invaluable in chemoinformatics. Various bioactivity databases exist containing detailed information of target proteins and quantitative binding data for small molecules extracted from journals and patents. In the current work, we have merged several public and commercial bioactivity databases into one bioactivity metabase. The molecular presentation, target information, and activity data of the vendor databases were standardized. The main motivation of the work was to create a single relational database which allows fast and simple data retrieval by in-house scientists. Second, we wanted to know the amount of overlap between databases by commercial and public vendors to see whether the former contain data complementing the latter. Third, we quantified the degree of inconsistency between data sources by comparing data points derived from the same scientific article cited by more than one vendor. We found that each data source contains unique data which is due to different scientific articles cited by the vendors. When comparing data derived from the same article we found that inconsistencies between the vendors are common. In conclusion, using databases of different vendors is still useful since the data overlap is not complete. It should be noted that this can be partially explained by the inconsistencies and errors in the source data.     

An Interactive Multiple Criteria Approach to Ranking Alternatives

In this paper we are concerned with ranking various orderings of a set of alternatives to a composite order as a multiple criteria problem. The orderings (called preference orderings) can be real preference orderings or any natural orderings. The objective is to find the most preferred order of the decision maker using the preference orderings as criteria.In principle, the problem can be formulated as a multiple objective linear programming problem using the model of Bowman and Colantoni and then solved with the interactive method proposed by Zionts and Wallenius. However, the fact that we are dealing with integer variables prohibits us from applying this approach as such. We discuss the problem formulation and propose a modified approach to that of Zionts and Wallenius for solving the problem.     

Isoperimetric Inequalities and Imbedding Theorems in Irregular Domains

The paper proves several weighted imbedding theorems for domainswith fractal boundaries. The weights considered are distancesto the boundary to certain powers, and the domains are so-calleds-John domains. The paper also proves, in the general setting,that the existence of an imbedding implies compactness of theimbedding for lower exponents. Moreover, following Maz'ya, thepaper reformulates the imbedding theorems in the language oflocal isoperimetric and capacity estimates.