Subattomole sensitivity in biological accelerator mass spectrometry

The Uppsala University 5 MV Pelletron tandem accelerator has been used to study (14)C-labeled biological samples utilizing accelerator mass spectrometry (AMS) technology. We have adapted a sample preparation method for small biological samples down to a few tens of micrograms of carbon, involving among others, miniaturizing of the graphitization reactor. Standard AMS requires about 1 mg of carbon with a limit of quantitation of about 10 amol. Results are presented for a range of small sample sizes with concentrations down to below 1 pM of a pharmaceutical substance in human blood. It is shown that (14)C-labeled molecular markers can be routinely measured from the femtomole range down to a few hundred zeptomole (10 (-21) mol), without the use of any additional separation methods.     

Multistage mass spectrometric sequencing of keratan sulfate-related oligosaccharides

To establish a universal protocol for sequencing keratan sulfate (KS) using mass spectrometry (MS), systematic electrospray ionization-MSn fragmentation experiments were carried out for 10 KS-related oligosaccharides of defined structure. Under the experimental conditions employed, fully charged molecular-related ions were observed as dominant peaks in all MS(1) spectra, which clearly reflected the number of sulfates and sialic acids in the oligosaccharide structures. In the subsequent MS2, almost all of the oligosaccharides gave fragment ions corresponding to their dehydrated molecular-related ions as well as (0,2)A(r) scission ions (according to the nomenclature developed by Domon and Costello, where "r" represents the reducing end in this study). Further fragmentation of the (0,2)A(r) ions in MS3 predominantly yielded the corresponding (2,4)A(r) ions. Finally, in MS(4), these (2,4)A(r) ions were subjected to extensive glycosidic cleavage. Hence, the MS4 data of KS oligosaccharides provided sufficient information for their sequence determination. In addition, some important features of MSn fragmentation became evident. These findings should lead to the establishment of consensus rules applied for KS oligosaccharides, including those previously unidentified, and also accelerate functional studies on KS, i.e., KS-related glycosaminoglycomics.     

Fast finite-element solver for a reluctance mass accelerator

By choosing an appropriate method for partitioning and linearizing the system equations that describe a time-domain finite-element model of a reluctance mass accelerator, it is possible to reduce the computation time considerably over a traditional material reluctance model. In this work, we have constructed an axisymmetric magnetic field finite-element solver based on the induced magnetization of the saturable materials, instead of the more common field-dependent reluctance model. Eddy currents and driving circuit elements are also included in the model. Using this platform, we demonstrate how a well-conditioned set of field equations is produced and how a simple nonlinear iteration scheme can produce reliable results without repeated factorization of the finite-element matrix. Some comparisons with an established simplified model and experimental results help to verify the model.     

Sample preparation for quantitation of tritium by accelerator mass spectrometry

The capability to prepare samples accurately and reproducibly for analysis of tritium (3H) content by accelerator mass spectrometry (AMS) greatly facilitates isotopic tracer studies in which attomole levels of 3H can be measured in milligram-sized samples. A method has been developed to convert the hydrogen of organic samples to a solid, titanium hydride, which can be analyzed by AMS. Using a two-step process, the sample is first oxidized to carbon dioxide and water. In the second step, the water is transferred within a heated manifold into a quartz tube, reduced to hydrogen gas using zinc, and reacted with titanium powder. The 3H/1H ratio of the titanium hydride is measured by AMS and normalized to standards whose ratios were determined by decay counting to calculate the amount of 3H in the original sample. Water, organic compounds, and biological samples with 3H activities measured by liquid scintillation counting were utilized to develop and validate the method. The 3H/1H ratios were quantified in samples that spanned 5 orders of magnitude, from 10(-10) to 10(-15), with a detection limit of 3.0 x 10(-15), which is equivalent to 0.02 dpm tritium/mg of material. Samples smaller than 2 mg were analyzed following addition of 2 mg of a tritium-free-hydrogen carrier. Preparation of organic standards containing both 14C and 3H in 2-mg organic samples demonstrated that this sample preparation methodology can also be applied to quantify both of these isotopes from a single sample.     

On isobar separation and accelerator mass spectrometry of 205Pb

The prospects of identifying and counting ²⁰⁵Pb ions by accelerator mass spectrometry (AMS) at the concentration levels expected for the geological samples prepared in the ²⁰⁵Tl solar neutrino experiment are re-examined. For this purpose the data collected in an earlier AMS test experiment at the GSI UNILAC are analyzed in more detail. The results are extrapolated to higher energies in an attempt to define the most promising accelerator configuration for an AMS measurement of ²⁰⁵Pb.     

First application of calorimetric low-temperature detectors in accelerator mass spectrometry

For the first time, calorimetric low-temperature detectors were applied in accelerator mass spectrometry, a well-known method for determination of very small isotope ratios with high sensitivity. The aim of the experiment was to determine with high accuracy the isotope ratio of ²³⁶U/²³⁸U for several samples of natural uranium, ²³⁶U being known as a sensitive monitor for neutron flux. Measurements were performed at the VERA tandem accelerator at Vienna, Austria. The detectors consist of sapphire absorbers and superconducting transition edge thermometers operated at T≈ 1.5 K. The relative energy resolution obtained for 17.39 MeV ²³⁸U is ΔE/E=4–9×10⁻³, depending on the experimental conditions. This performance enabled to substantially reduce background from neighbouring isotopes and to increase the detection efficiency. Due to the high sensitivity achieved, a value of ²³⁶U/²³⁸U=6.5×10⁻¹² could be obtained, representing the smallest ²³⁶U/²³⁸U ratio measured until now.     

Integration of continuous-flow accelerator mass spectrometry with chromatography and mass-selective detection

Physical combination of an accelerator mass spectrometry (AMS) instrument with a conventional gas chromatograph-mass spectrometer (GC/MS) is described. The resulting hybrid instrument (GC/MS/AMS) was used to monitor mass chromatograms and radiochromatograms simultaneously when (14)C-labeled compounds were injected into the gas chromatograph. Combination of the two instruments was achieved by splitting the column effluent and directing half to the mass spectrometer and half to a flow-through CuO reactor in line with the gas-accepting AMS ion source. The reactor converts compounds in the GC effluent to CO2 as required for function of the ion source. With cholesterol as test compound, the limits of quantitation were 175 pg and 0.00175 dpm injected. The accuracy achieved in analysis of five nonzero calibration standards and three quality control standards, using cholesterol-2,2,3,4,4,6-d6 as injection standard, was 100 +/- 11.8% with selected ion monitoring and 100 +/- 16% for radiochromatography. Respective values for interday precision were 1.0-3.2 and 22-32%. Application of GC/MS/AMS to a current topic of interest was demonstrated in a model metabolomic study in which cultured primary hepatocytes were given [(14)C]glucose and organic acids excreted into the culture medium were analyzed.     

Multistage PRIM: patient rule induction method for optimisation of a multistage manufacturing process

Industries such as automotive, LCD, PDP, semiconductor and steel produce products through multistage manufacturing processes. In a multistage manufacturing process, performances of stages are not independent. Therefore, the relationship between stages should be considered when optimising the multistage manufacturing process. This study proposes a new procedure of optimising a multistage manufacturing process, called multistage PRIM (patient rule induction method). Multistage PRIM extends the scope of process optimisation from a single stage to the multistage process, and it can use the information encapsulated in the relationship between stages when maximising each stage's performance. A case study in a multistage steel manufacturing process is conducted to illustrate the proposed procedure.     

Yeast dynamic metabolic flux measurement in nutrient-rich media by HPLC and accelerator mass spectrometry

Metabolic flux, the flow of metabolites through networks of enzymes, represents the dynamic productive output of cells. Improved understanding of intracellular metabolic fluxes will enable targeted manipulation of metabolic pathways of medical and industrial importance to a greater degree than is currently possible. Flux balance analysis (FBA) is a constraint-based approach to modeling metabolic fluxes, but its utility is limited by a lack of experimental measurements. Incorporation of experimentally measured fluxes as system constraints will significantly improve the overall accuracy of FBA. We applied a novel, two-tiered approach in the yeast Saccharomyces cerevisiae to measure nutrient consumption rates (extracellular fluxes) and a targeted intracellular flux using a (14)C-labeled precursor with HPLC separation and flux quantitation by accelerator mass spectrometry (AMS). The use of AMS to trace the intracellular fate of (14)C-glutamine allowed the calculation of intracellular metabolic flux through this pathway, with glutathione as the metabolic end point. Measured flux values provided global constraints for the yeast FBA model which reduced model uncertainty by more than 20%, proving the importance of additional constraints in improving the accuracy of model predictions and demonstrating the use of AMS to measure intracellular metabolic fluxes. Our results highlight the need to use intracellular fluxes to constrain the models. We show that inclusion of just one such measurement alone can reduce the average variability of model predicted fluxes by 10%.     

The two-beam accelerator

A two-beam accelerator, in which one of the beams is an intense low energy beam made to undergo free electron lasing and the other beam is a compact bunch of high energy electrons, is shown to be an interesting possibility for a linear collider.     

Macromolecular ion accelerator

Presented herein are the development of macromolecular ion accelerator (MIA) and the results obtained by MIA. This new instrument utilizes a consecutive series of planar electrodes for the purpose of facilitating stepwise acceleration. Matrix-assisted laser desorption/ionization (MALDI) is employed to generate singly charged macromolecular ions. A regular Z-gap microchannel plate (MCP) detector is mounted at the end of the accelerator to record the ion signals. In this work, we demonstrated the detection of ions with the mass-to-charge (m/z) ratio reaching 30,000,000. Moreover, we showed that singly charged biomolecular ions can be accelerated with the voltage approaching 1 MV, offering the evidence that macromolecular ions can possess much higher kinetic energy than ever before.     

Biological/biomedical accelerator mass spectrometry targets. 2. Physical, morphological, and structural characteristics

The number of biological/biomedical applications that require AMS to achieve their goals is increasing, and so is the need for a better understanding of the physical, morphological, and structural traits of high quality of AMS targets. The metrics of quality included color, hardness/texture, and appearance (photo and SEM), along with FT-IR, Raman, and powder X-ray diffraction spectra that correlate positively with reliable and intense ion currents and accuracy, precision, and sensitivity of fraction modern ( F m). Our previous method produced AMS targets of gray-colored iron-carbon materials (ICM) 20% of the time and of graphite-coated iron (GCI) 80% of the time. The ICM was hard, its FT-IR spectra lacked the sp (2) bond, its Raman spectra had no detectable G' band at 2700 cm (-1), and it had more iron carbide (Fe 3C) crystal than nanocrystalline graphite or graphitizable carbon (g-C). ICM produced low and variable ion current whereas the opposite was true for the graphitic GCI. Our optimized method produced AMS targets of graphite-coated iron powder (GCIP) 100% of the time. The GCIP shared some of the same properties as GCI in that both were black in color, both produced robust ion current consistently, their FT-IR spectra had the sp (2) bond, their Raman spectra had matching D, G, G', D +G, and D ' bands, and their XRD spectra showed matching crystal size. GCIP was a powder that was easy to tamp into AMS target holders that also facilitated high throughput. We concluded that AMS targets of GCIP were a mix of graphitizable carbon and Fe 3C crystal, because none of their spectra, FT-IR, Raman, or XRD, matched exactly those of the graphite standard. Nevertheless, AMS targets of GCIP consistently produced the strong, reliable, and reproducible ion currents for high-throughput AMS analysis (270 targets per skilled analyst/day) along with accurate and precise F m values.     

Evaluating the mass content and the energy spectrum of a plasma jet in a conical pulse accelerator

Results are shown of an experimental study concerning the mass content and the energy spectrum of a plasma jet generated in a conical erosive accelerator. The effect of the dischargecircuit parameters on the ion component and on the electron temperature in the plasma has been established.Translated from Inzhenerno-Fizicheskii Zhurnal, Vol. 22, No. 6, pp. 1096–1099, June, 1972.     

An interface for direct analysis of (14)c in nonvolatile samples by accelerator mass spectrometry

We describe here apparatus and methods for direct analysis of (14)C in biological specimens by accelerator mass spectrometry (AMS). Liquid samples, including plasma and urine, are deposited by pipet into a bed of CuO powder that fills a space within a rigid, refractory support. Volatile components are removed under reduced pressure prior to analysis. The CuO matrix is locally heated with an infrared laser while it is contained within a sealed chamber that is swept with He carrier gas. Heating induces combustion of the applied sample, and the carrier gas transports the CO(2) that is formed to the AMS instrument's ion source, which is appropriately modified for use with CO(2). A rodent study of drug clearance with [(14)C]-acetaminophen was performed to provide plasma and urine specimens, which were analyzed with this overall approach and by liquid scintillation counting for comparison. Results presented here confirm the potential utility of laser-induced sample combustion as an alternative to graphite production for AMS analysis of (14)C. Anticipated benefits of the present approach include reduced risk of sample cross-contamination, decreased analysis time, and greater compatibility with robotics.     

在制品(WIP)多阶段优化控制方法研究

以离散式生产的IC制造车间为研究对象,根据该行业工艺多而复杂所引起的在制品（WIP）量多而分布不均的现象,提出了多阶段推-拉（MP-P）生产控制模式;同时在此生产模式下,根据生产提前期的算法为各区间的WIP量的制定和控制提供了依据。通过应用分析,有效解决了此类多工艺行业的投料与WIP量的控制问题,为生产控制提供了一种有效的、可行的解决方案。     

多级锐化的梳状抽取滤波器

针对传统的递归型级联积分-梳状抽取滤波器(CICDF)频响特性不理想、功耗较大、最大电路速率受限等问题,提出了一种多级锐化的梳状抽取滤波器(MSCDF)。该滤波器利用降序素数分解和部分多相分解相结合的方法将CICDF转化为多级多相结构以降低功耗和放宽对电路速率的限制,并从第二级开始逐级进行锐化处理从而使抽取器的频响得到改善。仿真结果表明,在抽取因子为非素数的情况下,MSCDF不仅能够有效地改善CICDF的通带衰减和混叠抑制性能,而且与频响相近的完全锐化抽取器(FSCDF)相比,功耗更小,最大电路速率更高。     

Superconducting linear accelerator cryostat

A large vertical cryostat for a superconducting linear accelerator using quarter wave resonators has been developed. The essential technical details, operational experience and performance are described.     

Gas-phase magnetohydrodynamic disk accelerator

A pulsed gas-phase magnetohydrodynamic (MHD) disk accelerator with a radial initial gas flow and radial electric current direction is described. Some working regime parameters and characteristics of the accelerated natural gas flow are reported. MHD accelerators of this type can be used for the investigation of chemical kinetics. Another promising application is related to the development of supersonic gas-phase endothermal chemical reactors with gasdynamic control.     

Biological/biomedical accelerator mass spectrometry targets. 1. optimizing the CO2 reduction step using zinc dust

Biological and biomedical applications of accelerator mass spectrometry (AMS) use isotope ratio mass spectrometry to quantify minute amounts of long-lived radioisotopes such as (14)C. AMS target preparation involves first the oxidation of carbon (in sample of interest) to CO 2 and second the reduction of CO 2 to filamentous, fluffy, fuzzy, or firm graphite-like substances that coat a -400-mesh spherical iron powder (-400MSIP) catalyst. Until now, the quality of AMS targets has been variable; consequently, they often failed to produce robust ion currents that are required for reliable, accurate, precise, and high-throughput AMS for biological/biomedical applications. Therefore, we described our optimized method for reduction of CO 2 to high-quality uniform AMS targets whose morphology we visualized using scanning electron microscope pictures. Key features of our optimized method were to reduce CO 2 (from a sample of interest that provided 1 mg of C) using 100 +/- 1.3 mg of Zn dust, 5 +/- 0.4 mg of -400MSIP, and a reduction temperature of 500 degrees C for 3 h. The thermodynamics of our optimized method were more favorable for production of graphite-coated iron powders (GCIP) than those of previous methods. All AMS targets from our optimized method were of 100% GCIP, the graphitization yield exceeded 90%, and delta (13)C was -17.9 +/- 0.3 per thousand. The GCIP reliably produced strong (12)C (-) currents and accurate and precise F m values. The observed F m value for oxalic acid II NIST SRM deviated from its accepted F m value of 1.3407 by only 0.0003 +/- 0.0027 (mean +/- SE, n = 32), limit of detection of (14)C was 0.04 amol, and limit of quantification was 0.07 amol, and a skilled analyst can prepare as many as 270 AMS targets per day. More information on the physical (hardness/color), morphological (SEMs), and structural (FT-IR, Raman, XRD spectra) characteristics of our AMS targets that determine accurate, precise, and high-hroughput AMS measurement are in the companion paper.     

Optimal Scheduling in a Multistage Flowshop

The combinatorial approach to solve the n-job, .M-machine flowshop scheduling problem is examined. The mathematical developments of the Dudek-Teuton algorithm shown are correct and valid if correctly interpreted. However, the optimality conditions developed by these authors are too stringent and as such the combinatorial analysis for the flowshop scheduling problem is extended and an algorithm is proposed for the solution of the multistage flowshop scheduling problem, where the objective is to minimize a specified measure of total production cost and jobs have their associated start and stop lags.