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Methotrexate (MTX) is a therapeutic drug that is widely used in clinic for treatment of a variety of cancers. However, MTX has limited selectivity and serious cytotoxicity, at the same time, there are problems such as narrow therapeutic window and large individual variability in metabolism and excretion of MTX. Therefore, blood concentration monitoring is required for MTX administration in clinical practice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has the advantages of strong specificity, good separation characteristics, high sensitivity and fast detection speed, which has become the internationally recognized “gold standard” for blood concentration monitoring of drugs. In this study, an isotope dilution mass spectrometry method was developed for accurate measurement of MTX in serum by the house-made QLIT-6610MD quadrupole-linear ion trap liquid chromatography-mass spectrometer. Unlike the traditional triple quadrupole QqQ tandem mass spectrometer, the quadrupole-linear ion trap (Q-LIT) mass spectrometer adopts the quadrupole-linear ion trap direct axial coupling design, i.e., a single linear ion trap is used to replace the QqQ tandem mass spectrometer’s back-end fragmentation cell and the quadrupole, and no other components are installed between the quadrupole and linear ion trap, which greatly streamlines the quality and efficiency of the mass spectrometer while ensuring the original performance of the instrument. With this unique configuration, the QLIT-6610MD instrument uses a simultaneous fragmentation and accumulation technique, which remarkedly reduces matrix-induced interferences and effectively reduces space charge effects. Serum samples were pretreated with methanol to precipitate proteins and the supernatants were measured by QLIT-6610MD spectrometer. The linear correlation coefficient (R2＞0.999 0) is obtained for MTX in the range of 10-5 000 μg/L. The limit of quantification is 10 μg/L. The precision of the quality control is better than 6.94%, and the recoveries of spiked serum samples are 86.39%-97.84% with a coefficient of variation less than 8.04%. We used the QLIT-6610MD and AB QTRAP 6500+ liquid chromatography-mass spectrometers to analyze 70 clinical serum samples for comparison of the performance of the house-made instrument by means of Pearson’s coefficient and BLand-ALtman method. The results showed that the QLIT-6610MD mass spectrometry achieves a similar level of performance to AB ATRAP 6500+ instrument, and provides a new domestic instrument option for clinical mass spectrometry. In addition, this study explores the possibility applying the multi-stage fragmentation technique (MSn) to determine MTX in serum, gaining fundamental data for future studies.

Methotrexate (MTX) is a therapeutic drug that is widely used in clinic for treatment of a variety of cancers. However, MTX has limited selectivity and serious cytotoxicity, at the same time, there are problems such as narrow therapeutic window and large individual variability in metabolism and excretion of MTX. Therefore, blood concentration monitoring is required for MTX administration in clinical practice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has the advantages of strong specificity, good separation characteristics, high sensitivity and fast detection peed, which has become the internationally recognized “ gold standard” for blood concentration monitoring of drugs. In this study, an isotope dilution mass spectrometry method was developed for accurate measurement of MTX in serum by the house-made QLIT-6610MD quadrupole-linear ion trap liquid chromatography-mass spectrometer. Unlike the traditional triple quadrupole QqQ tandem mass spectrometer, the quadrupole-linear ion trap (Q-LIT) mass spectrometer adopts the quadrupolelinear ion trap direct axial coupling design, i.e., a single linear ion trap is used to replace the QqQ tandem mass spectrometer’s back-end fragmentation cell and the quadrupole, and no other components are installed between the quadrupole and linear ion trap, which greatly streamlines the quality and efficiency of the mass spectrometer while ensuring the original performance of the instrument. With this unique configuration, the QLIT-6610MD instrument uses a simultaneous fragmentation and accumulation technique, which remarkedly reduces matrix-induced interferences and effectively reduces space charge effects. Serum samples were pretreated with methanol to precipitate proteins and the supernatants were measured by QLIT-6610MD spectrometer. The linear correlation coefficient (R²>0.999 0) is obtained for MTX in the range of 10-5 000 μg/L. The limit of quantification is 10 μg/L. The precision of the quality control is better than 6.94%, and the recoveries of spiked serum samples are 86.39%-97.84% with a coefficient of variation less than 8.04%. We used the QLIT-6610MD and AB QTRAP 6500+ liquid chromatography-mass spectrometers to analyze 70 clinical serum samples for comparison of the performance of the house-made instrument by means of Pearson’s coefficient and BLand-ALtman method. The results showed that the QLIT-6610MD mass spectrometry achieves a similar level of performance to AB ATRAP 6500+ instrument, and provides a new domestic instrument option for clinical mass spectrometry. In addition, this study explores the possibility applying the multi-stage fragmentation technique (MSn) to determine MTX in serum, gaining fundamental data for future studies. [ABSTRACT FROM AUTHOR]

The demand for accurate mass spectrometry measurement in the field of clinical diagnosis is increasing. In the face of foreign monopoly, our team has developed new technologies and new methods for the selective enrichment of trace targets in complex matrices by ion traps, and has developed a quadrupole-linear ion trap (quadrupole-linear ion trap, Q-LIT) tandem mass spectrometer with independent intellectual property rights and a liquid chromatography tandem mass spectrometry system (model QLIT-6610MD), which have obtained a medical device registration certificate in China. In this study, a home-built Q-LIT liquid chromatography-tandem mass spectrometer QLIT-6610MD was developed to measure vancomycin in serum with high accuracy . After protein precipitation and liquid-liquid extraction, the samples were analyzed by QLIT-6610MD. The endogenous substances in the samples did not interfere with the quantification. The results showed that vancomycin has a good linear relationship of signal intensity vs. concentration in the range of 1.56-50.0 mg/L with the linear correlation coefficient (R2)≥0.99, and the limit of detection and limit of quantitation are 0.19 and 1.56 mg/L, respectively. Intra-day and inter-day precisions are 1.62%-3.82% and 2.07%-5.07%, respectively. The recoveries of vancomycin in serum samples are 95.97%-97.74%. The coefficient of variability (CV) of matrix effect normalization factor is less than 7.60%, CV of sample stability is better than 4.26%, and CV of long interval sample analysis is better than 2.13%. The method was verified by the determination of low, medium and high quality controls, and the results were all within the range of target values. QLIT-6610MD, AB API4000 and YS EXACT 9900MD were used to determine 42 real clinical serum samples. The correlation and consistency of the data were analyzed by Deming regression, Bland-Altman analysis and Pearson correlation analysis. The results showed good consistency among the results obtained by the three spectrometers, indicating that the data of three instruments are comparable, which prove that the home-made QLIT-6610MD can reach the quantitative accuracy of triple quadrupole-mass spectrometer. The instrument can effectively reduce the interference of matrix ions and enhance the capture efficiency of target ions, based on quadrupole-linear ion trap tandem mass spectrometric technique. QLIT-6610MD has great potential to provide a new instrumentation solution for real-time clinical analysis in the future.

In order to ensure the measurement accuracy of ion trap mass spectrometer, it is necessary to perform mass calibration on the instrument when there is a mass shift. Mass calibration can be achieved by improving the stability of the electrical components or upgrading the hardware with significant technical costs. Compared with hardware optimization. mass calibration based on software algorithms can better utilize the performance of existing instruments. Mass calibration can be achieved by manually inputting standard samples or calibration solution parameters. However, mass axis calibration in this way still requires setting specific segmentation points based on the actual situation and manually adjusting them to achieve the desired accuracy. Therefore, to improve the low efficiency with manual segmentation during mass calibration, an automatic segmented calibration algorithm was proposed to improve the calibration accuracy and facilitate rapid operation. The algorithm used point by point fitting to deter- mine whether the segment interval met the requirements and also determined each segment interval. At the same time, the mass axis was automatically segmented to reduce the mass deviation of each checkpoint. This method was compared with traditional method, different deviation thresholds were explored, and multiple instruments were selected to verify this method. The results showed that the algorithm can reasonably segment the mass axis and establish a new linear relationship between electrical parameters and m/z under existing conditions, allowing the deviation of each checkpoint to be controlled within a lower preset range (±0.1 u), thus improving the instrument's calibration efficiency and measurement accuracy. reducing the difficulty of personnel operation. The significance of this study is that the algorithm only adjusts and optimizes the signals generated by the hardware without changing the structure of the instrument itself, which is helpful for improving the overall performance and stability of the instrument. Moreover, the principle and conclusion of the algorithm are independent of the experimental platform. so it can be applied to a variety of other types of mass spectrometers. For the insufficient points. firstly, the upper limit of accuracy provided by the algorithm itself is still determined by the hardware accuracy of the instrument, so it is only possible to calibrate and optimize the mass axis within a certain accuracy range. Secondly, because the calibration process requires a certain number of reference points. which poses certain requirements for the selection of calibration solutions. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency and insufficiency is a global health issue that afflicts people of different age groups all over the world. As a reliable indicator for the evaluation of vitamin D, 25OHD is usually determined by LC-MS/MS. The tandem mass spectrometry based on ion trap has the characteristics of simple structure and high sensitivity. However, there are some problems such as narrow linear range and space charge effect, which limit its analysis of trace substances in complex matrix samples. In this study, the device and technology of a new quadrupole linear ion trap mass spectrometry was used to reduce the space charge interference of trace or ultra trace target ions by high abundance impurity ions in complex matrices. For the first time, isotope dilution mass spectrometry for accurate measurement of serum 25OHD was established by QLIT-6610MD, which is quadrupole-linear ion trap tandem mass spectrometer, and was independently developed by Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology. Serum samples were precipitated with methanol, extracted with n-hexane, dried with liquid nitrogen, redissolved in the initial mobile phase, and determined by QLIT-6610MD. The matrix-matched standard curve was used for quantification. The linear ranges of 25OHD2 and 25OHD3 were in the range of 0.78-50 μg/L and 1.56-100 μg/L with R2>0.999 9, respectively. The detection and quantification limits of 25OHD2 and 25OHD3 were 0.06, 0.12 μg/L and 0.02, 0.06 μg/L, respectively. The precision of quality control was better than 4.06%. The recoveries ranged from 99.25% to 108.38%, and the coefficients of variation were all less than 5.1%. After the method confirmation, the quantitative results of clinical samples were compared with triple quadrupole tandem mass spectrometry. 50 Clinical serum samples were measured and compared by QLIT-6610MD, AB 4500MD and YS EXACT 9900MD. The correlation and consistency of the data were analyzed by Pearson and Bland-Altman. The correlation coefficient of the three groups data was R≥0.998 0, P

Accurate and highly sensitive analysis of folpet and captan was accomplished using liquid chromatography-triple quadrupole linear ion trap mass spectrometry (LC-QqQIT) with selective ion mode; mass filtering, collision, and trapping condition. Dimensional mass spectrometry (MS3) parameters were optimized for the residue detection of folpet and captan in six food commodities (apples, tomatoes, sweet pepper, wheat flour, sesame seeds, and fennel seeds). The sample preparation method was based on the known QuEChERS protocol, except a mixture of acetonitrile/acetone was used for the sample extraction from the sesame seeds. The robustness and reliability of the developed MS3 method were demonstrated by performing a full validation, according to SANTE/11312/2021, at 0.01–0.25 mg/kg. Recovery ranged from 83 to 118% with a relative standard deviation below 19% in all the tested commodities, and limits of quantifications (LOQs) were 0.01 mg/kg in apples and tomatoes; 0.03 mg/kg in sweet pepper; and 0.05 mg/kg in wheat flour, sesame seeds, and fennel seeds. Monitoring results showed that about 90% of apples contained captan residue, and in sweet pepper, concentrations of captan and folpet as high as 1.57 and 0.97 mg/kg were found, respectively. The novel developed MS3 method enabled more reliable identification of these commonly problematic fungicides at lower LOQs than previously reported methods. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency and insufficiency is a global health issue that afflicts people of different age groups all over the world. As a reliable indicator for the evaluation of vitamin D, 25OHD is usually determined by LC-MS/MS. The tandem mass spectrometry based on ion trap has the characteristics of simple structure and high sensitivity. However, there are some problems such as narrow linear range and space charge effect, which limit its analysis of trace substances in complex matrix samples. In this study, the device and technology of a new quadrupole linear ion trap mass spectrometry was used to reduce the space charge interference of trace or ultra trace target ions by high abundance impurity ions in complex matrices. For the first time, isotope dilution mass spectrometry for accurate measurement of serum 25OHD was established by QLIT-6610 MD, which is quadrupole-linear ion trap tandem mass spectrometer, and was independently developed by Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology. Serum samples were precipitated with methanol, extracted with n-hexane, dried with liquid nitrogen, redissolved in the initial mobile phase, and determined by QLIT-6610 MD. The matrix-matched standard curve was used for quantification. The linear ranges of 25OHD2 and 25OHD3 were in the range of 0.78-50 μg/L and 1.56-100 μg/L with R²＞0.999 9, respectively. The detection and quantification limits of 25OHD2 and 25OHD3 were 0.06, 0.12 μg/L and 0.02, 0.06 μg/L, respectively. The precision of quality control was better than 4.06%. The recoveries ranged from 99.25% to 108.38%, and the coefficients of variation were all less than 5.1%. After the method confirmation, the quantitative results of clinical samples were compared with triple quadrupole tandem mass spectrometry. 50 Clinical serum samples were measured and compared by QLIT-6610 MD, AB 4500 MD and YS EXACT 9900 MD. The correlation and consistency of the data were analyzed by Pearson and Bland-Altman. The correlation coefficient of the three groups data was R≥0.998 0, P＜0.01, and the results of Bland-Altman analysis showed good consistency, indicating that the results measured by the three instruments were consistent, which meant that QLIT-6610 MD can meet the needs of clinical diagnosis. QLIT-6610 MD achieved the same level of triple quadrupole mass spectrometry to determine the concentration of 25OHD in serum. It can not only become a new choice for clinical mass spectrometry, but also lay a foundation for the development of domestic mass spectrometer. Based on the direct axial coupling technology of quadrupole and linear ion trap, QLIT-6610 MD can greatly reduce the interference of matrix ions and make the ion trap detect target ions more effectively. This technology has a strong potential to further improve the measurement accuracy of trace or ultra trace targets in complex matrices. In the future, it can be applied to mass spectrometry monitoring scenarios that needs to meet the requirements of high accuracy, high sensitivity, on-site speed and low cost at the same time. [ABSTRACT FROM AUTHOR]

The miniaturization of ion trap mass analyzers is an important direction in the development of mass spectrometers. In this work, we proposed two models of miniaturized HreLIT with a field radius of about 2 mm based on the existing research on conventional HreLIT and other ion traps, one with ions ejection slits on one pair of electrodes only (2-slit model) and the other with the same slits on all electrodes (4-slit model). The relationship of mass resolution with r/rx and the "stretch" distance of electrodes in the ejection direction is investigated by theoretical simulations. Trends of electric fields inside the ion traps were discussed as well. The comparable maximum resolution is observed at r/rx = 2/1.4 in both models, but stretching simulations revealed that the peak resolution of the 2-slit model was higher than that of the other model by about 8%. The highest value of 517 was obtained when stretching 1.1 mm. Furthermore, the resolution of ions with m/z = 119 could exceed 1000 when the scan rate was reduced to 800 Th/s. The mass spectrometry capability of miniature HreLIT has been confirmed theoretically, and it laid the foundation for the subsequent fabrication with MEMS technology. [ABSTRACT FROM AUTHOR]

Ion trajectory numerical simulation is used to find the linear ion trap excitation contour in the second stability region. The effects of initial conditions, the ejection Mathieu parameter, scan speed, dipole excitation voltage and gas damping are studied. Modeling shows that in the stability region center the resolution power is ≈200000 (at full width half height of a peak, FWHM) at pressure 0.1 mTorr and 100 % excitation efficiency (not taking into account the space charge).

Linear ion traps and quadrupole mass spectrometers play vital roles in quantum technologies and classical mass spectrometry respectively. Therefore, such systems with nearly same operational principles, are very well studied both theoretically and experimentally. Despite such vast knowledge base, linear ion traps continue to be an important research topic, particularly the effect of small perturbations from ideal conditions. Here, non-degenerate nonlinear resonances of the ion dynamics in a linear three-segmented round-rod radio-frequency ion trap have been studied. Purposefully designed perturbation from an ideal 4-rod symmetric structure results in additional instabilities in the dynamics of the trapped ions. The weightage of the dodecapole potential increases by an order of magnitude in such an asymmetric setup compared to that present in usual symmetric setup of nearly equivalent geometry. The experimental results are corroborated by ion dynamics simulations with commercial software SIMION. Increased dodecapole potential in the asymmetric structure leads to resolution of the frequency of ion oscillation in two mutually perpendicular directions in the radial plane which is otherwise unresolved in a symmetric structure in absence of dc potential. Such asymmetric linear trap, in principle, finds importance in the study of Coulomb crystal, mass spectrometry and relevant trapped ion dynamics. It also opens up the possibility to remove undesired ion species (often known as dark ion) within a chain of physical qubits. • One middle electrode in a three-segmented linear ion trap is taken of different diameter making the trap setup asymmetric. • Nonlinear resonances appear as non-degenerate in the rf stability diagram. • Weightage of the dodecapole potential is larger by an order of magnitude compared to symmetric setup of equivalent geometry. • Increased dodecapole potential has promising applications in mass spectrometry, dark ion elimination from trapped ion-chain. [ABSTRACT FROM AUTHOR]

The miniaturization of ion trap mass analyzers is an important direction in the development of mass spectrometers. In this work, we proposed two models of miniaturized HreLIT with a field radius of about 2 mm based on the existing research on conventional HreLIT and other ion traps, one with ions ejection slits on one pair of electrodes only (2-slit model) and the other with the same slits on all electrodes (4-slit model). The relationship of mass resolution with r/rx and the “stretch” distance of electrodes in the ejection direction is investigated by theoretical simulations. Trends of electric fields inside the ion traps were discussed as well. The comparable maximum resolution is observed at r/rx = 2/1.4 in both models, but stretching simulations revealed that the peak resolution of the 2-slit model was higher than that of the other model by about 8%. The highest value of 517 was obtained when stretching 1.1 mm. Furthermore, the resolution of ions with m/z = 119 could exceed 1000 when the scan rate was reduced to 800 Th/s. The mass spectrometry capability of miniature HreLIT has been confirmed theoretically, and it laid the foundation for the subsequent fabrication with MEMS technology.

The detection of volatile organic compounds (VOCs) in water faces challenges due to the presence of complex matrix interferences and low concentration. This paper presented a portable gas chromatography linear ion trap mass spectrometer (GC-LIT-MS) coupled with dynamic headspace sampling (DHS) system for sensitive and rapid on-site analysis of VOCs in water. The instrument weighs 18 kg and has compact dimensions of 43 cm × 35 cm x 20 cm, offering portability and convenience. A low thermal mass (LTM) chromatographic column, utilizing resistive heating, enables rapid heating and cooling within the runtime of GC. The linear ion trap, for the first time, has been integrated as a mass analyser in portable gas chromatography-mass spectrometer (GC-MS). Its ability to store a greater number of ions within the trap expands the dynamic range of the instrument. The influence of dynamic headspace injection conditions on the purging efficiency of VOCs was investigated and the equilibrium temperature was optimized. The GC-LIT-MS method was demonstrated to be capable to identify and separate 55 VOCs in water within 4 min, with most of them exhibiting detection limits of less than 1 μg L−1. The calibration of 4 VOCs with concentrations ranged from 2 parts per million (ppm) to 200 ppm showed excellent linearity (R2 > 0.99) and dynamic range more than five orders of magnitude. Resolution superior to unit mass was achieved within the range of 15 AMU to 550 AMU. [Display omitted] • A portable gas chromatography linear ion trap mass spectrometer was developed. • The great ion storage capacity of the linear ion trap extends the dynamic range of the instrument. • Coupled with dynamic headspace sampling, the GC-LIT-MS was capable to identify and separate 55 VOCs in water within 4 min, exhibiting excellent performances. [ABSTRACT FROM AUTHOR]

We report here a novel approach for the extraction and analysis of thyroid hormones (TH) and their metabolites (THM) from human serum samples. Our method features a compact, 96-well micro-titre plate-based pre-analytic extraction/clean-up workflow combined with an isotope dilution LC-MS/MS-MS3 analytical method. In particular, these features make possible the detection of iodothyronines at their endogenous concentrations in serum differing by a factor of ca. 104, with potential to semi-automate the pre-analytics. The method was validated by the assessment of linearity, lower limits of quantification and detection (LLOQ and LLOD respectively), intra- and inter-day accuracy, precision, process efficiency (PE), matrix effect (ME) and relative recovery (RE). Calibration curves were linear in the concentration range in sample matrix from 0.1–250 nM for T3, rT3, T4 and 3-T1AM and from 0.005–1 nM for 3,5-T2 and 3,3′-T2. Using a 200-μL sample volume, the analyte dependant LLOQ were in the range 0.005 (3,5-T2) to 0.25 (T4) nM and LLOD were between 0.002 (3,5-T2) and 0.052 nM (T4). We applied the LC-MS/MS-MS3 method to the analysis of a cross section of patients with disorders of the thyroid hormone axis. T4, T3 and rT3 concentrations (± standard deviation) were 120 ± 18, 1.9 ± 0.4 and 0.45 ± 0.09 nM respectively. 3,3′-T2 concentrations (± standard deviation) were 0.079 ± 0.022 nM; 3,5-T2 concentrations were below the LLOQ and/or LLOD in all but a single sample (0.013 nM). This method expands the analytical spectrum to endogenous thyroid hormone metabolites such as 3,5-T2 which exert biological actions and rT3 which may act as surrogate markers for disturbed thyroid hormone metabolism. [ABSTRACT FROM AUTHOR]

Liquid chromatography coupled with tandem mass spectrometry has long been employed for the quantitation of molecules. With judicious selection of precursor and fragment ions, multiple-reaction monitoring assays can be developed rapidly for these experiments. However, there are cases where analyses struggle due to high background signals caused by matrix effects that interfere with the analytical signal. An alternative to MRMs involves using two stages of tandem mass spectrometry - an MS3 experiment. Although this technique can provide greater selectivity than MS/MS experiments, cycle times for MS3 experiments are typically longer than MRM-type experiments. Here, we present a quantitation technique employing an MS3 method with shorter cycle times than traditional linear ion trap MS3 scans. Termed 'scan-free' MS3, this technique performs 'mass analysis' by isolating the ions of interest in the linear ion trap and then emptying the trap of these ions. The signal will be due only to those preselected ions, resulting in an MS3 experiment with up to a ∼35% reduction in cycle times relative to standard MS3 experiments without loss of sensitivity. We compare the analytical performance of this method with MRMs, as well as standard MS3 experiments, finding equivalent or better performance from the scan-free MS3 method. [ABSTRACT FROM AUTHOR]

Mass spectrometry (MS)-based precursor ion isolation, collision-induced dissociation (CID) fragmentation, and detection using linear ion-trap multiple-stage mass spectrometry (LIT MSn) in combination with high resolution mass spectrometry (HRMS) provides a unique tool for structural characterization of complex mixture without chromatographic separation. This approach permits not only separation of various lipid families and their subfamilies, but also stereoisomers, thereby, revealing the structural details. In this report, we describe the LIT MSn approach to unveil the structures of a 2,3-diacyl trehalose (DAT) family isolated from the cell envelope of Mycobacterium tuberculosis, in which more than 30 molecular species, and each species consisting of up to six isomeric structures were found. LIT MSn performed on both [M + Na]+ and [M + HCO2]− ions of DAT yield complimentary structural information for near complete characterization of the molecules, including the location of the fatty acyl substituents on the trehalose backbone. This latter information is based on the findings of the differential losses of the two fatty acyl chains in the MS2 and MS3 spectra; while the product ion spectra from higher stage LIT MSn permit confirmation of the structural assignment.

Listeria monocytogenes ( L. monocytogenes) is a facultative, Gram-positive, food-borne bacterium, which causes serious infections. Although it is known that lipids play important roles in the survival of Listeria, the detailed structures of these lipids have not been established. In this contribution, we described linear ion-trap multiple-stage mass spectrometric approaches with high-resolution mass spectrometry toward complete structural analysis including the identities of the fatty acid substituents and their position on the glycerol backbone of the polar lipids, mainly phosphatidylglycerol, cardiolipin (CL), and lysyl-CL from L. monocytogenes. The location of the methyl side group along the fatty acid chain in each lipid family was characterized by a charge-switch strategy. This is achieved by first alkaline hydrolysis to release the fatty acid substituents, followed by tandem mass spectrometry on their N-(4-aminomethylphenyl) pyridinium (AMPP) derivatives as the M+ ions. Several findings in this study are unique: (1) we confirm the presence of a plasmalogen PG family that has not been previous reported; (2) an ion arising from a rare internal loss of lysylglycerol residue was observed in the MS spectrum of lysyl-CL, permitting its distinction from other CL subfamilies. [ABSTRACT FROM AUTHOR]

A high precision electric field simulation method is employed to investigate micron-size geometry deviation effects on the electric field distributions as well as on mass resolutions in linear ion traps. Translational and angular displacements within three linear ion traps with different electrode geometries, hyperbolic, circular and rectangular electrodes, were studied. It is found that the linear ion trap with rectangular electrodes is more sensitive to translational displacements, while the linear ion trap with circular electrodes is more sensitive to angular displacements in general. As a guideline, the results could be used in the design and fabrication process of a linear ion trap. [ABSTRACT FROM AUTHOR]

This work reports implementation of an optimized linear ion trap (LIT) mass analyzer manufactured using digital light processing (DLP), a low cost rapid prototyping technique. To satisfy requirements for a portable commercial instrument, our previous DLP LIT has been improved by using polymer material for electrodes and housing with higher heat deflection temperature and much improved metal coating of the electrodes. In this way, a polymer-based LIT can operate at higher pressures with more stable voltages, low outgassing and with much longer electrode lifetime. This paper demonstrates non-scanning operation of a DLP LIT based on ceramic resin with specially electroplated electrodes. Non-scanning mode is suitable for applications in which only specific mass fragments are targeted such as security and forensics. Experimental results from a DLP LIT are therefore shown for simulants of cocaine, TNT and sarin. [ABSTRACT FROM AUTHOR]

Ion trajectory numerical simulation is used to find the linear ion trap excitation contour in the second stability region. The effects of initial conditions, the ejection Mathieu parameter, scan speed, dipole excitation voltage and gas damping are studied. Modeling shows that in the stability region center the resolution power is ≈ 200 000 (at full width half height of a peak, FWHM) at pressure 0.1 mTorr and 100 % excitation efficiency (not taking into account the space charge)., Competing Interests: The authors declare no competing interests., (© 2022 Published by Elsevier Ltd.)

Highlights: [•] We present experimental selective mass isolation for a linear ion trap (LIT) operating in a non-scanning mode. [•] Ion source lens system (ISLS) coupled to a non-scanning LIT was simulated using CPO program. [•] Simulation study of ion injection, trapping and ejection was done to optimize LIT sensitivity. [•] Our results have shown that an optimized ISLS can improve LIT sensitivity by a factor of 4 compared to commercial ion source lens systems. [ABSTRACT FROM AUTHOR]

Linear ion traps exhibit greater space charge capacity compared to conventional 3D Paul traps. Commercial ion traps are made of electrodes of hyperbolic shape. The present work investigates the possibilities of designing linear ion traps from simple electrodes, which are relatively cheap and handy for manufacturing and, at the same time, are comparable to commercial ion traps in resolving power of mass analysis. Using computer simulations and optimization of resonance ejection scan, it is shown linear ion traps can be made of electrodes of triangular cross-section with an ejection slit width of 16% of the trap inradius; the resolving power of the mass spectrum is more than 18000. [ABSTRACT FROM AUTHOR]

The analytical suitabilities of three different liquid chromatography–tandem mass spectrometry (LC-MS/MS) systems, (1) triple quadrupole (QqQ), (2) conventional 3D ion trap (IT), and (3) quadrupole–linear IT (QqLIT), to determine trace levels of perfluorinated compounds (PFCs) in fish and shellfish were compared. Sample preparation was performed using alkaline extraction and solid-phase-extraction cleanup. This evaluation was focused on both quantitative (sensitivity, precision, and accuracy) and qualitative (identification capabilities) aspects. In the three instruments, the former facet was evaluated using selected reaction monitoring (SRM), which is the standard mode for quantitative LC-MS/MS analysis. Accuracy was similar in the three systems, with recoveries always over 70 %. Precision was better for the QqLIT and QqQ systems (7–15%) than for the IT system (10–17%). The QqLIT (working in SRM mode) and QqQ systems offered a linear dynamic range of at least 3 orders of magnitude, whereas that of the IT system was 2 orders of magnitude. The QqLIT system achieved at least 20-fold higher sensitivity than the QqQ system, and this was at least tenfold higher sensitivity than for the IT system. In the IT system, identification was based on sensitive full mass range acquisition and MS fragmentation and in the QqLIT system, it was based on the use of an information-dependent-acquisition scan function, which allows the combination of an SRM or MS full scan acting as the survey scan and an enhanced product ion scan followed by MS as the dependent scan in the same analysis. Three instruments were applied to monitor the content in fish and shellfish (anchovies, swordfish, tuna, mussels, and oysters) obtained from Valencia and Barcelona markets (Spain). The eight target PFCs were detected at mean concentrations in the range from 10 ng kg (perfluoro-7-methyloctanoic acid and perfluoro-1-decanesulfonate) to 4,200 ng kg (perfluoropentanoic acid). Furthermore, perfluoroheptanoic and perfluoroundecanoic acids (not covered as target analytes) were identified in some samples. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

In clinical or forensic toxicology, general unknown screening procedures are used to identify as many xenobiotics as possible, belonging to numerous chemical classes. We present here a general unknown screening procedure based on liquid chromatography coupled with use of a single linear ion trap mass spectrometer, and focus on the identification of pesticides and/or metabolites in whole blood. After solid-phase extraction (SPE), the compounds of interest were separated using a reversed-phase column and identified by the mass spectrometer operated first in the full-scan mass spectrometry (MS) mode, in the positive and negative polarities, followed by MS2 and MS3 scanning of ions selected in data-dependent acquisition. The total scan time was 2.45 s. Two mass spectral libraries (MS2 and MS3), each of 450 spectra, were created for the 320 pesticides and metabolites detected after injection of pure solutions. Robustness of the spectra and matrix effects were studied and were satisfactory for the present application. Detection limits for the 320 compounds were studied by extracting 1 mL spiked blood at concentrations between 10 µg/L and 10 mg/L. If necessary, it was possible to decrease the detection limits of some compounds by 10–100-fold by scanning MS2 in only one polarity, owing to a shorter total scan time. However, at the same time, the detection specificity decreased as no confirmation could be recorded in the following MS3 scan and no information could be registered in the other polarity. So, in these rare cases, confirmation by another method was required. [ABSTRACT FROM AUTHOR]

Abstract: Electron transfer dissociation (ETD) of multi-protonated 6–20-mer oligonucleotides and 12- and 14-mer duplexes is compared to collision activated dissociation (CAD). ETD causes efficient charge reduction of the multi-protonated oligonucleotides in addition to limited backbone cleavages to yield sequence ions of low abundance. Subsequent CAD of the charge-reduced oligonucleotides formed upon electron transfer, in a net process termed electron transfer collision activated dissociation (ETcaD), results in rich fragmentation in terms of , a, z, and d products, with a marked decrease in the abundance of base loss ions and internal fragments. Complete sequencing was possible for nearly all oligonucleotides studied. ETcaD of an oligonucleotide duplex resulted in specific backbone cleavages, with conservation of weaker non-covalent bonds. [Copyright &y& Elsevier]

Mass scan methods utilizing quadrupolar direct current (DC) scan were described and performed with a linear ion trap (LIT) through a home-built MS apparatus designed for ion/ion reactions. Both quadrupolar DC downscan and upscan are applicable to the LIT due to the shape of the related Mathieu stability diagram. Besides, a supplementary AC signal could be added to the DC scan process for resonant ejection, which largely enhances the signal-to-noise (S/N) ratios of the spectra. Compared with conventional resonance ejection RF scans, the scannable mass-to-charge (m / z) range in quadrupolar DC scan is much wider. Several protein cations were chosen as test molecules with a m / z scannable range larger than 140,000 Th. Besides, compared with three-dimensional (3D) quadrupolar ion traps (QIT), the LIT is a more suitable mass analyzer for ions with large m / z ratios due to large ion capacity and deep pseudopotential well depths for ions inside the trap. In general, DC scan with LIT offers a new way of rapid detection of ions with extra wide m / z scannable ranges, which has potential applications in research fields such as "top-down" proteomics and native mass spectrometry in the future. [Display omitted] • The quadrupolar DC scan experiments were performed with a linear ion trap (LIT) through a home-built mass spectrometer. • Both quadrupolar DC downscan and upscan are applicable to the LIT. • A supplementary AC signal could be added to the DC scan process for resonant ejection. • A mass-to-charge (m / z) scannable range larger than 140,000 Th was achieved through protein test molecules. [ABSTRACT FROM AUTHOR]

Abstract: The conversion of deprotonated bradykinin, as well as anions derived from other polypeptides, to protonated species has been demonstrated via ion/ion reactions with multiply protonated polypropylenimine diaminobutane (DAB) dendrimers and proteins in a linear ion trap. The charge inversion characteristics of both the proteins and the dendrimers were examined with emphasis on the extent of charging of the analyte and the tendency for adduct formation. Multiply protonated proteins, for example, tended to result in significant adduct formation whereas the multiply protonated amino-terminated dendrimers showed essentially no adduct formation. Ions derived from five dendrimer generations were examined as charge inversion reagents with deprotonated bradykinin serving as a peptide model. Both the size and the charge state of the dendrimer reagent ion played a role in determining the number of protons transferred from the reagent cation to the peptide anion. For a given dendrimer generation, the tendency is for increasing numbers of protons to transfer with increasing dendrimer charge. For a given charge state, the numbers of protons transferred tends to be inversely related to dendrimer size. All of the observed data are consistent with charge inversion taking place via a long-lived intermediate complex with the ultimate products being determined by the fate of the complex (i.e., stabilization of the complex versus break-up into one of several competitive dissociation channels). [Copyright &y& Elsevier]

Human body fluids have been rediscovered in the post-genomic era as a great source of biological markers and perhaps as source of potential biomarkers of disease. Recently, it has been found that not only proteins but also peptides and their modifications can be indicators of early pathogenic processes. This paper reports the identification of free phosphopeptides in human fluids using an improved IMAC strategy coupled to iterative mass spectrometry-based scanning techniques (neutral loss, precursor ion, multiple reaction monitoring). Many peptides were detected in the enriched extract samples when submitted to the MS-integrated strategy, whereas they were not detected in the initial extract samples. The combination of the IMAC-modified protocol with selective 'precursor ion' and constant 'neutral loss' triple quadrupole scan modes confers a high sensitivity on the analysis, allowing rapid phosphopeptide identification and characterization, even at low concentrations. To the best of our knowledge this work represents the first report exclusively focused on the detection of free phosphorylated peptides in biological fluids. [ABSTRACT FROM AUTHOR]

Abstract: Ion motion with auxiliary dipole excitation and collisional damping in a linear radiofrequency quadrupole ion trap incorporating small amounts of even higher order multipoles is studied analytically. The ion motion is modeled in a pseudopotential that is mostly quadratic with small amounts of higher spatial harmonics. Ion motion along x and y axes is characterized by two uncoupled forced and damped anharmonic oscillator equations. A multiple time scales method is used to solve the equations of motion of ions with a first order perturbation correction. Analytical relations between the oscillation amplitudes at steady state (the stationary amplitudes) and excitation frequency are calculated. The frequency response curves show that in some cases bistable behavior might be obtained, i.e., there are two stable stationary amplitudes for a given excitation frequency. [Copyright &y& Elsevier]

The gas-phase fragmentation reactions of singly protonated aromatic amino acids, their simple peptides as well as simple models for intermolecular disulfide bonds have been examined using a commercially available hybrid linear ion trap–Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. Low-energy collision-induced dissociation (CID) reactions within the linear ion trap are compared with electron-induced dissociation (EID) reactions within the FT-ICR cell. Dramatic differences are observed between low-energy CID (which occurs via vibrational excitation) and EID. For example, the aromatic amino acids mainly fragment via competitive losses of NH3 and (H2O+CO) under CID conditions, while side-chain benzyl cations are major fragment ions under EID conditions. EID also appears to be superior in cleaving the S–S and S–C bonds of models of peptides containing an intermolecular disulfide bond. Systematic studies involving fragmentation as a function of electron energy reveal that the fragmentation efficiency for EID occurs at high electron energy (more than 10 eV) compared with the low-electron energy (less than 0.2 eV) typically observed for electron capture dissociation fragmentation. Finally, owing to similarities between the types of fragment ions observed under EID conditions and those previously reported in ultraviolet photodissociation experiments and the electron-ionization mass spectra, we propose that EID results in fragmentation via electronic excitation and vibrational excitation. EID may find applications in analyzing singly charged molecular ions formed by matrix-assisted laser desorption ionization. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: An electrospray ionization interface incorporating an electrodynamic ion funnel has been designed and implemented on a linear ion trap mass spectrometer (Thermo Electron, LTQ). We found ion transmission to be greatly improved by replacing the standard capillary–skimmer interface with the capillary–ion funnel interface. An infusion study using a serial dilution of a reserpine solution showed that ion injection (accumulation) times to fill the ion trap at a given automatic gain control (AGC) target value were reduced by ∼90% which resulted in an ∼10-fold increase in peak intensities. In liquid chromatography tandem MS (LC–MS/MS) experiments performed using a global protein digest sample from the bacterium, Shewanella oneidensis, more peptides and proteins were identified when the ion funnel interface was used in place of the standard interface. This improvement was most pronounced at lower sample concentrations, where extended ion accumulation times are required, resulting in an ∼2-fold increase in the number of protein identifications. Implementation of the ion funnel interface on a LTQ Fourier transform (FT) mass spectrometer showed a ∼25–50% reduction in spectrum acquisition time. The duty cycle improvement in this case was due to the ion accumulation event contributing a larger portion to the total spectrum acquisition time. [Copyright &y& Elsevier]

Abstract: We describe a new intermediate-pressure MALDI linear ion trap mass spectrometer and its capabilities for imaging mass spectrometry. The instrument design is described and is characterized in terms of four performance issues (1) MALDI performance at intermediate pressure; (2) analysis of samples on non-conductive and conductive glass slides; (3) critical importance of tandem mass spectrometry (both MS2 and MS3) for identification of analyte species and imaging of isobaric species; (4) capability for repeated analysis of the same tissue section. Application of the new instrument to imaging phospholipids in rat brain sections is described in detail. [Copyright &y& Elsevier]

The plant system is a highly dynamic structure on all molecular levels, transcripts, proteins, and metabolites. Thus, protein analysis has to cope with a highly dynamic range of concentrations. A severe problem is the detection of low-abundance proteins in the presence of housekeeping proteins. Basically three approaches are facilitated to measure protein abundance in a comprehensive manner: 2DE and one- or multi-dimensional shotgun proteomics, with or without stable-isotope labelling. These comparative techniques allow for the identification of altered protein levels compared with a reference state. However, they are limited to the analysis of medium/high-abundance proteins. Using stable-isotope dilution techniques it is possible to target the quantitative analysis to low-abundance proteins and to measure absolute concentrations of proteins. Based on multi-dimensional non-gel shotgun proteomics in Arabidopis thaliana, a list of tryptic peptides comprising >1000 proteins was generated. A strategy for quantitative plant proteomics is proposed using this master-list for selecting signature peptides of proteins. To prove the concept, a liquid chromatography–high-resolution triple quadrupole multiple reaction monitoring–mass spectrometry technique is described to determine the absolute amount of a low-abundance sucrose synthase isoform out of an ultra-complex A. thaliana protein extract. [ABSTRACT FROM PUBLISHER]

Abstract: Here, we present the results of extensive SIMION 7.0 modelling of a new linear octopole ion trap. The octopole was designed to increase the efficiency of an electrospray ion source coupled to a Fourier Transform Ion Cyclotron Resonance (FTICR) mass spectrometer. This improvement was achieved by applying a pulsed axial field to the octopole to eject the ion packet with a time and energy distribution that better match the acceptance criteria of the FTICR cell, thus increasing the trapping efficiency and sensitivity. The axial field was produced by applying a pulsed dc potential to the custom-designed ejection electrodes located between the octopole rods. The time and energy profiles of the ejected ion packets for several electrode shapes were calculated and are discussed in terms of their compatibility with efficient trapping of the ion packet in the FTICR cell. Preliminary experimental results show increased signal using the dc ejection electrodes of approximately 100%. [Copyright &y& Elsevier]

Chemical warfare agents (CWAs) are devastating weapons of terror due to their highly lethal and dispersive nature. Powerful analytical tools are required to help create a knowledge base that will contribute to preventing attacks using these agents. Highly sensitive measurements must be made quickly with high selectivity for a wide range of potential molecular targets. Portable mass spectrometers have emerged as a robust platform for in-situ detection of chemical threats. However, due to size, weight, and power constraints, they are typically limited to a single mass analyzer with limited MS/MS capabilities, most notably the provision of full scan and product ion MS/MS spectra. Here we demonstrate the application of a new, highly efficient scanning methodology that uses a single linear quadrupole ion trap to acquire two-dimensional mass spectrometry data (2D MS/MS). With only a single scan, we show that it is possible to acquire mass-to-charge information on V-series chemical warfare agents– namely,: (1) Ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate (V1), (2) N , N -diethyl-2-(methyl-(2-methylpropoxy)phosphoryl)sulfanylethanamine (VR), (3) O-Butyl S-[2-(diethylamino)ethyl] methylphosphonothioate (VX) and (4) S-[2-(Diethylamino)ethyl] O-ethyl methylphosphonothioate (VM) - as precursors while simultaneously (in the same scan) acquiring product ion spectra for each CWA via mass spectral microfeatures. For mixtures of V-series agents, 2D MS/MS is a time- and sample-efficient method for obtaining MS/MS data. Discussed here are advantages and limitations of 2D MS/MS compared to conventional data-dependent product ion MS/MS scans. Image 1 • Detection of V series chemical warfare agents using 2D MS/MS. • Comparison of 2D MS/MS with conventional product ion MS/MS on a linear ion trap. • Differentiation of isobaric species via unique 2D MS/MS patterns. [ABSTRACT FROM AUTHOR]