Measurement of very low-molecular weight metabolites by traveling wave ion mobility and its use in human urine samples

The collision cross-sections(CCS)measurement using ion mobility spectrometry(IMS)in combination with mass spectrometry(MS)offers a great opportunity to increase confidence in metabolite identification.However,owing to the lack of sensitivity and resolution,IMS has an analytical challenge in studying the CCS values of very low-molecular-weight metabolites(VLMs250 Da).Here,we describe an analytical method using ultrahigh-performance liquid chromatography(UPLC)coupled to a traveling wave ion mobility-quadrupole-time-of-flight mass spectrometer optimized for the measurement of VLMs in human urine samples.The experimental CCS values,along with mass spectral properties,were reported for the 174 metabolites.The experimental data included the mass-to-charge ratio(m/z),retention time(RT),tandem MS(MS/MS)spectra,and CCS values.Among the studied metabolites,263 traveling wave ion mobility spectrometry(TWIMS)-derived CCS values(TWCCSN2)were reported for the first time,and more than 70%of these were CCS values of VLMs.The TWCCSN2 values were highly repeatable,with inter-day variations of<1%relative standard deviation(RSD).The developed method revealed excellent TWCCSN2 accuracy with a CCS difference(DCCS)within±2%of the reported drift tube IMS(DTIMS)and TWIMS CCS values.The complexity of the urine matrix did not affect the precision of the method,as evidenced by DCCS within±1.92%.According to the Metabolomics Standards Initiative,55 urinary metabolites were identified with a confidence level of 1.Among these 55 metabolites,53(96%)were VLMs.The larger number of confirmed compounds found in this study was a result of the addition of TWCCSN2 values,which clearly increased metabolite identification confidence.

Drug adulteration analysis based on complexation with cyclodextrin and metal ions using ion mobility spectrometry

Drug adulteration and contamination are serious threats to human health therefore,their accurate monitoring is very important.Allopurinol(Alp)and theophylline(Thp)are commonly used drugs for the treatment of gout and bronchitis,while their isomers hypoxanthine(Hyt)and theobromine(Thm)have no effect and affect the efficacy of the drug.In this work,the drug isomers of Alp/Hyt and Thp/Thm are simply mixed withα-,β-,γ-cyclodextrin(CD)and metal ions and separated using trapped ion mobility spectrometry-mass spectrometry(TIMS-MS).TIMS-MS results showed that Alp/Hyt and Thp/Thm isomers could interact with CD and metal ions and form corresponding binary or ternary complexes to achieve their TIMS separation.Different metal ions and CDs showed different separation effect for the isomers,among which Alp and Hyt could be successfully distinguished from the complexes of[Alp/Hyt+γ-CD+Cu–H]^(+)with separation resolution(RP–P)of 1.51;whereas Thp and Thm could be baseline separated by[Thp/Thm+γ-CD+Ca–H]^(+)with RP–P of 1.96.Besides,chemical calculations revealed that the complexes were in the inclusion forms,and microscopic interactions were somewhat different,making their mobility separation.Moreover,relative and absolute quantification was investigated with an internal standard to determine the precise isomers content,and good linearity(R^(2)>0.99)was obtained.Finally,the method was applied for the adulteration detection where different drugs and urine were analyzed.In addition,due to the advantages of fast speed,simple operation,high sensitivity,and no chromatographic separation required,the proposed method provides an effective strategy for the drug adulteration detection of isomers.

Breath-by-breath measurement of exhaled ammonia by acetonemodifier positive photoionization ion mobility spectrometry via online dilution and purging sampling

Exhaled ammonia(NH_(3))is an essential noninvasive biomarker for disease diagnosis.In this study,an acetone-modifier positive photoionization ion mobility spectrometry(AM-PIMS)method was developed for accurate qualitative and quantitative analysis of exhaled NH_(3)with high selectivity and sensitivity.Acetone was introduced into the drift tube along with the drift gas as a modifier,and the characteristic NH_(3)product ion peak of(C_(3)H_(6)O)_(4)NH_(4)^(+)(K_(0)=1.45 cm^(2)/V·s)was obtained through the ion-molecule reaction with acetone reactant ions(C_(3)H_(6)O)_(2)H^(+)(K_(0)=1.87 cm^(2)/V·s),which significantly increased the peak-to-peak resolution and improved the accuracy of exhaled NH_(3)qualitative identification.Moreover,the interference of high humidity and the memory effect of NH_(3)molecules were significantly reduced via online dilution and purging sampling,thus realizing breath-by-breath measurement.As a result,a wide quantitative range of 5.87-140.92μmol/L with a response time of 40 ms was achieved,and the exhaled NH_(3)profile could be synchronized with the concentration curve of exhaled CO_(2).Finally,the analytical capacity of AM-PIMS was demonstrated by measuring the exhaled NH_(3)of healthy subjects,demonstrating its great potential for clinical disease diagnosis.

Separation of Ions from Volatile Organic Compounds Using High-Field Asymmetric Waveform Ion Mobility Spectrometry-Mass Spectrometer

A combination of high-field asymmetric waveform ion mobility spectrometry （FAIMS） with mass spectrometer （MS） was analyzed. FAIMS separates ions from the volatile organic compounds in the gas-phase as an ion-filter for MS. The sample ions were created at ambient pressure by ion source, which was equipped with a 10.6 eV UV discharge lamp （A=116.5 nm）. The drift tube of FAIMS is composed of two parallel planar electrodes and the dimension is 10 mm×8 mm×0.5 mm. FAIMS was investigated when driven by the high-filed rectangular asymmetric waveform with the peak-to-peak voltage of 1.36 kV at the frequency of 1 MHz and the duty cycle of 30%. The acetone, the butanone, and their mixture were adopted to characterize the FAIMS-MS. The mass spectra obtained from MS illustrate that there are ion-molecular reactions between the ions and the sample neutral molecular. And the proton transfer behavior in the mixture of the acetone and the butanone is also observed. With the compensation voltage tuned from -30 V to 10 V with a step size of 0.1 V, the ion pre-separation before MS is realized.

Electron Attachment Studies for CHCl3 Using Ion Mobility Spectrometry

The dissociative electron attachment process for CHCl3 at different electric field have been studied with nitrogen as drift and carrier gas using corona discharge ionization source ion mobility spectrometry （CD-IMS）. The corresponding electron attachment rate constants varied from 1.26×10-8 cm3/（molecules s） to 8.24×10-9 cm3/（molecules s） as the electric field changed from 200 V/cm to 500 V/cm. At a fixed electric field in the drift region, the attachment rate constants are also detected at different sample concentration. The ionmolecule reaction rate constants for the further reaction between Cl^- and CHCl3 are also detected, which indicates that the technique maybe becomes a new method to research the rate constants between ions and neural molecules. And the reaction rate constants between Cl- and CHCl3 are the first time detected using CD-IMS.

Molecular Structural Characterization and Quantitative Prediction of Reduced Ion Mobility Constants for Diversified Organic Compounds

Based on two-dimensional topological structures, a novel molecular electronegativity interaction vector with hybridization （MEHIV） was developed to describe atomic hybridization state in different molecular environments. Five quantitative models by MEHIV characterization and multiple linear regression modeling were successfully established to predict reduced ion mobility constants （Ko） of alkanes, aromatic hydrocarbons, fatty alcohols, fatty aldehydes and ketones and carboxylic esters. The correlation coefficients Roy by leave-one-out cross-validation are 0.792, 0.787, 0,949, 0.972 and 0.981, respectively, and the standard deviations SDcv are 0.067, 0.086, 0.064, 0.043 and 0.042, respectively. These results suggested that MEHIV is an excellent topological index descriptor with many advantages such as straightforward physicochemical meaning, high characterization competence, convenient expansibility and easy manipulation.

Peak Profile Analysis in High Field Asymmetric Wave Ion Mobility Spectrometry

High field asymmetric wave ion mobility spectrometry （FAIMS） is a powerful tool to detect and characterize gas-phase ions, while the unsolvable partial differential equation of ions moving in ion drift tube poses a big challenge to FAIMS spectral peak analysis. In this work, a universal and effective model of FAIMS spectral peak profile has been proposed by introducing ion trajectory and loss height. With this model, the influence of the structure of ion drift tube, dispersion voltages, compensation voltages, and carrier gas flow rate on the FAIMS spectral peak characteristics like peak shape, full width at half maximum and peak height is analyzed and discussed. The results show that the influence of different factors on the FAIMS spectral peak profile can be qualitatively described by the model which agrees with the experimental data.

Determination of alcohol compounds using corona discharge ion mobility spectrometry

Ion mobility spectrometry （IMS） is a very fast, highly sensitive, and inexpensive technique, it permits efficient monitoring of volatile organic compounds like alcohols. In this article, positive ion mobility spectra for six alcohol organic compounds have been systematically studied for the first time using a high-resolution IMS apparatus equipped with a discharge ionization source. Utilizing protonated water cluster ions （H2O）nH^＋ as the reactant ions and clean air as the drift gas, alcohol organic compounds, ethanol, 1- propanol, 2-propanol, 1-butanol, 1-pentanol and 2-octanol, all exhibit product ion characteristic peaks in their respective ion mobility spectrometry, that is a result of proton transfer reactions between the alcohols and reaction ions （H2O）nH^＋. The mixture of these alcohols, including two isomers, has been detected, and the results showed that they could be distinguished effectively in the ion mobility spectrum. The reduced mobility values have been determined, which are in very well agreement with the traditional ^63Ni-IMS experimental values. The exponential dilution method was used to calibrate the alcohol concentrations, and a detection limit available for the alcohols is in order of magnitude of a few ng/L.

Factors Influencing the Electron Yield of Needle-Ring Pulsed Corona Discharge Electron Source for Negative Ion Mobility Spectrometer

A simple negative ion mobility spectrometer （IMS） is designed and used to investi- gate the factors that influence the number and efficiency of electrons generated by the needle-ring pulsed corona discharge electron source. Simulation with Ansoft Maxwell 12 is carried out to analyze the electric field distribution within the IMS, and to offer the basis and foundation for analyzing the measurement results. The measurement results of the quantities of electrons show that when the drift electric field strength and the ring inner diameter rise, both the number of ef- fective electrons and the effective electron rate are increased. When the discharge voltage becomes stronger, the number of effective electrons goes up while the effective electron rate goes down. In light of the simulation results, mechanisms underlying the effects of drift electric field strength, ring inner diameter, and discharge voltage on the effective electron number and effective electron rate are discussed. These will make great sense for designing negative ion mode IMS using the needle-ring pulsed corona discharge as the electron source.

Dimension-Enhanced Ultra-High Performance Liquid Chromatography/Ion Mobility-Quadrupole Time-of-Flight Mass Spectrometry Combined with Intelligent Peak Annotation for the Rapid Characterization of the Multiple Components from Seeds of Descurainia sophia

The complex composition of herbal metabolites necessitates the development of powerful analytical techniques aimed to identify the bioactive components.The seeds of Descurainia sophia(SDS)are utilized in China as a cough and asthma relieving agent.Herein,a dimension-enhanced integral approach,by combining ultra-high performance liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry(UHPLC/IMQTOF-MS)and intelligent peak annotation,was developed to rapidly characterize the multicomponents from SDS.Good chromatographic separation was achieved within 38 min on a UPLC CSH C18(2.1×100 mm,1.7μm)column which was eluted by 0.1%formic acid in water(water phase)and acetonitrile(organic phase).Collision-induced dissociation-MS^(2)data were acquired by the data-independent high-definition MS^(E)(HDMS^(E))in both the negative and positive electrospray ionization modes.A major components knockout strategy was applied to improve the characterization of those minor ingredients by enhancing the injection volume.Moreover,a self-built chemistry library was established,which could be matched by the UNIFI software enabling automatic peak annotation of the obtained HDMS^(E)data.As a result of applying the intelligent peak annotation workflows and further confirmation process,a total of 53 compounds were identified or tentatively characterized from the SDS,including 29 flavonoids,one uridine derivative,four glucosides,one lignin,one phenolic compound,and 17 others.Notably,four-dimensional information related to the structure(e.g.,retention time,collision cross section,MS^(1)and MS^(2)data)was obtained for each component by the developed integral approach,and the results would greatly benefit the quality control of SDS.

Rapid authentication of sesame oil using ion mobility spectrometry and chemometrics

To ensure authenticity of sesame oil,an authentication technology was proposed using ion mobility spectrometry(IMS)and chemometrics.One-class classification(OCC)methods including one-class partial least squares(OCPLS)and one-class support vector machine(OCSVM)were employed to build authentication models for sesame oil.Subsequently,an independent test set was used to validate the constructed models.Validation set of 45 adulterated oils indicated that prediction correction rate of OCPLS model reached 95.6%(43 out of 45).Moreover,the complete set of sesame oils adulterated by sesame oil essence could be identified as counterfeit.Compared with previous studies,OCPLS model could work to identify untargeted adulteration.In conclusion,OCC method could effectively detect adulterated sesame oils containing as little as 10%other vegetable oils.This study provided a rapid screening method for adulterated sesame oil in market surveillance and a reference for developing authentication methods of other edible oils.

Structures of Stoichiometric Sodium Oxide Cluster Cations Studied by Ion Mobility Mass Spectrometry

Structures of stable compositions of sodium oxide cluster cations (NanOm+,n≤11) have been investigated by ion mobility mass spectrometry. Stoichiometric compositions series, Na(Na2O)(n-1)/2^+(n=3, 5, 7, 9, and 11), were observed as stable composition series, and NaO(Na2O)(n-1)/2^+ series (n=5, 7, 9, and 11) were observed as secondary stable series in the mass spectra. To assign the structures of these cluster ion series, collision cross sections between the ions and helium buffer gas were determined experimentally from the ion mobility measurements. Theoretical collision cross sections were also calculated for optimized structures of these compositions. Finally, the structures of Na(Na2O)(n-1)/2^+ and NaO(Na2O)(n-1)/2^+ were assigned to those having similar structural frames for each n except for n=9. All bonds in the assigned structures of Na(Na2O)(n-1)/2^+ were between sodium and oxygen. On the other hand, there was one O-O bond in addition to Na-O bonds in NaO(Na2O)(n-1)/2^+. This result indicates that NaO(Na2O)(n-1)/2^+ have a peroxide ion (O22-) as a substitute for an oxide ion (O2-) of Na(Na2O)(n-1)/2^+. As a result, both stable series, Na(Na2O)(n-1)/2^+ and NaO(Na2O)(n-1)/2^+, are closed-shell compositions. These closed-shell characteristics have a strong influence on the stability of sodium oxide cluster cations.

Measurement of Ion Mobilities of Selected Amines by Ion Mobility Spectrometry

The ion mobilities of selected amines were measured by IMS. The minimum detection limits and linear ranges of selected amines were detected.

MALDI coupled with laser-postionization and trapped ion mobility spectrometry contribute to the enhanced detection of lipids in cancer cell spheroids

Cancer cell spheroids(CCS) are a valuable three-dimensional cell model in cancer studies because they could replicate numerous characteristics of solid tumors. Increasing researches have used matrix-assisted laser desorption/ionization mass spectrometry imaging(MALDI-MSI) to investigate the spatial distribution of endogenous compounds(e.g., lipids) in CCS. However, only limited lipid species can be detected owing to a low ion yield by using MALDI. Besides, it is still challenging to fully characterize the structural diversity of lipids due to the existence of isomeric/isobaric species. Here, we carried out the initial application of MALDI coupled with laser-postionization(MALDI-2) and trapped ion mobility spectrometry(TIMS) imaging in HCT116 colon CCS to address these challenges. We demonstrated that MALDI-2 is capable of detecting more number and classes of lipids in HCT116 colon CCS with higher signal intensities than MALDI. TIMS could successfully separate numerous isobaric/isomeric species of lipids in CCS. Interestingly, we found that some isomeric/isobaric species have totally different spatial distributions in colon CCS. Further MS/MS imaging analysis was employed to determine the compositions of fatty acid chains for isomeric species by examining disparities in signal intensities and spatial distributions of product ions. This work stresses the robust ability of TIMS and MALDI-2 imaging in analyzing endogenous lipids in CCS, which could potentially become powerful tools for future cancer studies.

Influence of Humidity and Air Pressure on the Ion Mobility Based on Drift Tube Method

The measurement of ion mobility is important for calculating the corona loss of the transmission lines,and for establishing corona loss and ion current models that take humidity and air pressure into consideration.This paper describes a needle-ring corona discharge experiment setup based on a prior study,which simulates different humidity and air pressure conditions;it is observed that the execution of the ion gate is improved in this experiment from off-on-off to off-on to achieve higher ion current amplitude.Additionally,positive and negative ion mobility under different humidity and air pressure is obtained,with the positive ion mobility measurements in the range of 1.1126 to 1.9167 cm2/V·s,and the negative ion mobility measurements in the range of 1.3574 to 2.5643 cm2/V·s.The experimental results indicate that ion mobility decreases nonlinearly with increase in humidity,but trends towards saturation in the 30%–70%relative humidity range.Finally,a parameter correction method for calibrating the relationship among the ion mobility,humidity,and air pressure is proposed.

Volatile organic compounds sensing based on Bennet doubler-inspired triboelectric nanogenerator and machine learning-assisted ion mobility analysis

Ion mobility analysis is a well-known analytical technique for identifying gas-phase compounds in fastresponse gas-monitoring systems.However,the conventional plasma discharge system is bulky,operates at a high temperature,and inappropriate for volatile organic compounds(VOCs)concentration detection.Therefore,we report a machine learning(ML)-enhanced ion mobility analyzer with a triboelectric-based ionizer,which offers good ion mobility selectivity and VOC recognition ability with a small-sized device and non-strict operating environment.Based on the charge accumulation mechanism,a multi-switched manipulation triboelectric nanogenerator(SM-TENG)can provide a direct current(DC)bias at the order of a few hundred,which can be further leveraged as the power source to obtain a unique and repeatable discharge characteristic of different VOCs,and their mixtures,with a special tip-plate electrode configuration.Aiming to tackle the grand challenge in the detection of multiple VOCs,the ML-enhanced ion mobility analysis method was successfully demonstrated by extracting specific features automatically from ion mobility spectrometry data with ML algorithms,which significantly enhance the detection ability of the SM-TENG based VOC analyzer,showing a portable real-time VOC monitoring solution with rapid response and low power consumption for future internet of things based environmental monitoring applications.

Comparison of Ion Mobility Fuzzy Chromatography Mass Spectrometric(imFCMS)Fingerprinting and FCMS Fingerprinting for Differentiation of American Cranberry Cultivars

Fuzzy chromatography mass spectrometric(FCMS)fingerprinting methods in combination with principal component analysis(PCA)and soft independent modeling by class analogy(SIMCA)were developed for phenolic profiling and differentiation of American cranberry cultivars.Two FCMS fingerprinting methods,ion mobility fuzzy chromatography mass spectrometric(imFCMS)and conventional FCMS,are compared in the study.PCA and SIMCA successfully differentiated the cultivars with both methods.The six cultivars used formed three distinct groups in the PCA score plots,and each group contained one wild selection cultivar and its genetically related hybrid(s).Compared with FCMS fingerprinting,imFCMS fingerprinting provided better intra-cultivar sample clustering and inter-cultivar sample separation in PCA and superior sample classifica-tion sensitivity in SIMCA.Ultra-performance liquid chromatography-high-resolution mass spectrometry(UPLC-HRMS)analysis was conducted on selected samples to profile the phenolic difference between the cultivars.Compound identification using UPLC-HRMS revealed that flavonoid compounds,including flavonol glycosides,proanthocyanidins and anthocyanins,are major components that contribute to the phenolic profile variation among cultivars.

Modeling of Ions Mobility in Plasma Like Concept and Transfer Processes in Electrolyte Solutions

Plasma like concept of ions in electrolyte solutions is accepted as a basis for development of equation mobility for transfer processes （viscosity, diffusion, thermal conductivity and electrical conductivity）. The examples of isomorphism of dissipative processes are given in the article. The integrated assessment equation of transfer properties is developed based on the ion-dipole, dipole-dipole and ion-ion interactions and the force of liquid dielectric resistance to oscillating solvated particles. It is shown that the estimated magnitude of viscosity, diffusion, electrical conductivity and thermal conductivity are comparable with the current knowledge and experimental values in a wide range of electrolyte concentrations.

Evidence for reversible oxygen ion movement during electrical pulsing:enabler of emerging ferroelectricity in binary oxides

Ferroelectric HfO_(2)-based materials and devices show promising potential for applications in information technology but face challenges with inadequate electrostatic control,degraded reliability,and serious variation in effective oxide thickness scaling.We demonstrate a novel interface-type switching strategy to realize ferroelectric characteristics in atomic-scale amorphous binary oxide films,which are formed in oxygen-deficient conditions by atomic layer deposition at low temperatures.This approach can avoid the shortcomings of reliability degradation and gate leakage increment in scaling polycrystalline doped HfO_(2)-based films.Using theoretical modeling and experimental characterization,we show the following.(1)Emerging ferroelectricity exists in ultrathin oxide systems as a result of microscopic ion migration during the switching process.(2)These ferroelectric binary oxide films are governed by an interface-limited switching mechanism,which can be attributed to oxygen vacancy migration and surface defects related to electron(de)trapping.(3)Transistors featuring ultrathin amorphous dielectrics,used for non-volatile memory applications with an operating voltage reduced to±1 V,have also been experimentally demonstrated.These findings suggest that this strategy is a promising approach to realizing next-generation complementary metal-oxide semiconductors with scalable ferroelectric materials.

基于离子淌度质谱技术的离子光谱研究进展

离子光谱结合了质谱的高灵敏度和光谱的分子结构特异性的优势,可对蛋白质、多肽、糖类、寡核苷酸等复杂体系进行结构表征和鉴定。但当存在同分异构体时,离子光谱难以从叠加的谱图中得到单个异构体的光谱信息。离子淌度质谱技术可通过区分待测离子质荷比和分子空间尺寸差异来实现异构体的分离。离子淌度可以对异构体分离后分别引入到后续的光谱和质谱分析中,减少了由异构体引起的光谱叠加问题,光谱可以进一步验证离子淌度的分离效果,因此质谱、光谱、离子淌度谱的有机结合在得到异构体精确光谱的同时,也为离子淌度质谱分析带来了新的维度和深度。本文概述了近20年来基于各类离子淌度质谱技术的光谱仪器发展和应用情况,总结目前存在的问题,并展望多维度结构质谱的新需求。