Ion mobility spectrometry‐mass spectrometry (IMS‐MS) of small molecules: Separating and assigning structures to ions

The phenomenon of ion mobility (IM), the movement/transport of charged particles under the influence of an electric field, was first observed in the early 20th Century and harnessed later in ion mobility spectrometry (IMS). There have been rapid advances in instrumental design, experimental methods, and theory together with contributions from computational chemistry and gas‐phase ion chemistry, which have diversified the range of potential applications of contemporary IMS techniques. Whilst IMS‐mass spectrometry (IMS‐MS) has recently been recognized for having significant research/applied industrial potential and encompasses multi‐/cross‐disciplinary areas of science, the applications and impact from decades of research are only now beginning to be utilized for “small molecule” species. This review focuses on the application of IMS‐MS to “small molecule” species typically used in drug discovery (100–500 Da) including an assessment of the limitations and possibilities of the technique. Potential future developments in instrumental design, experimental methods, and applications are addressed. The typical application of IMS‐MS in relation to small molecules has been to separate species in fairly uniform molecular classes such as mixture analysis, including metabolites. Separation of similar species has historically been challenging using IMS as the resolving power, R, has been low (3–100) and the differences in collision cross‐sections that could be measured have been relatively small, so instrument and method development has often focused on increasing resolving power. However, IMS‐MS has a range of other potential applications that are examined in this review where it displays unique advantages, including: determination of small molecule structure from drift time, “small molecule” separation in achiral and chiral mixtures, improvement in selectivity, identification of carbohydrate isomers, metabonomics, and for understanding the size and shape of small molecules. This review provides a broad but selective overview of current literature, concentrating on IMS‐MS, not solely IMS, and small molecule applications. © 2012 Wiley Periodicals, Inc., Mass Spec Rev 32:43–71, 2013     

LIQUID CHROMATOGRAPHY–MASS SPECTROMETRY BOTTOM‐UP PROTEOMIC METHODS IN ANIMAL SPECIES ANALYSIS OF PROCESSED MEAT FOR FOOD AUTHENTICATION AND THE DETECTION OF ADULTERATIONS

This review offers an overview of the current status and the most recent advances in liquid chromatography–mass spectrometry (LC‐MS) techniques with both high‐resolution and low‐resolution tandem mass analyzers applied to the identification and detection of heat‐stable species‐speci?c peptide markers of meat in highly processed food products. We present sets of myofibrillar and sarcoplasmic proteins, which turned out to be the source of 105 heat‐stable peptides, detectable in processed meat using LC‐MS/MS. A list of heat‐stable species‐specific peptides was compiled for eleven types of white and red meat including chicken, duck, goose, turkey, pork, beef, lamb, rabbit, buffalo, deer, and horse meat, which can be used as markers for meat authentication. Among the 105 peptides, 57 were verified by multiple reaction monitoring, enabling identification of each species with high specificity and selectivity. The most described and monitored species by LC‐MS/MS so far are chicken and pork with 26 confirmed heat‐stable peptide markers for each meat. In thermally processed samples, myosin, myoglobin, hemoglobin, l ‐lactase dehydrogenase A and β‐enolase are the main protein sources of heat‐stable markers. © 2019 John Wiley & Sons Ltd. Mass Spec Rev     

Advances on the compositional analysis of glycosphingolipids combining thin‐layer chromatography with mass spectrometry

Glycosphingolipids (GSLs), composed of a hydrophilic carbohydrate chain and a lipophilic ceramide anchor, play pivotal roles in countless biological processes, including infectious diseases and the development of cancer. Knowledge of the number and sequence of monosaccharides and their anomeric configuration and linkage type, which make up the principal items of the glyco code of biologically active carbohydrate chains, is essential for exploring the function of GSLs. As part of the investigation of the vertebrate glycome, GSL analysis is undergoing rapid expansion owing to the application of novel biochemical and biophysical technologies. Mass spectrometry (MS) takes part in the network of collaborations to further unravel structural and functional aspects within the fascinating world of GSLs with the ultimate aim to better define their role in human health and disease. However, a single‐method analytical MS technique without supporting tools is limited yielding only partial structural information. Because of its superior resolving power, robustness, and easy handling, high‐performance thin‐layer chromatography (TLC) is widely used as an invaluable tool in GSL analysis. The intention of this review is to give an insight into current advances obtained by coupling supplementary techniques such as TLC and mass spectrometry. A retrospective view of the development of this concept and the recent improvements by merging (1) TLC separation of GSLs, (2) their detection with oligosaccharide‐specific proteins, and (3) in situ MS analysis of protein‐detected GSLs directly on the TLC plate, are provided. The procedure works on a nanogram scale and was successfully applied to the identification of cancer‐associated GSLs in several types of human tumors. The combination of these two supplementary techniques opens new doors by delivering specific structural information of trace quantities of GSLs with only limited investment in sample preparation. © 2009 Wiley Periodicals, Inc. Mass Spec Rev 29:425‐479, 2010     

Phospholipids as cancer biomarkers: Mass spectrometry‐based analysis

Lipids, particularly phospholipids (PLs), are key components of cellular membrane. PLs play important and diverse roles in cells such as chemical‐energy storage, cellular signaling, cell membranes, and cell–cell interactions in tissues. All these cellular processes are pertinent to cells that undergo transformation, cancer progression, and metastasis. Thus, there is a strong possibility that some classes of PLs are expected to present in cancer cells and tissues in cellular physiology. The mass spectrometric soft‐ionization techniques, electrospray ionization (ESI), and matrix‐assisted laser desorption/ionization (MALDI) are well‐established in the proteomics field, have been used for lipidomic analysis in cancer research. This review focused on the applications of mass spectrometry (MS) mainly on ESI‐MS and MALDI‐MS in the structural characterization, molecular composition and key roles of various PLs present in cancer cells, tissues, blood, and urine, and on their importance for cancer‐related problems as well as challenges for development of novel PL‐based biomarkers. The profiling of PLs helps to rationalize their functions in biological systems, and will also provide diagnostic information to elucidate mechanisms behind the control of cancer, diabetes, and neurodegenerative diseases. The investigation of cellular PLs with MS methods suggests new insights on various cancer diseases and clinical applications in the drug discovery and development of biomarkers for various PL‐related different cancer diseases. PL profiling in tissues, cells and body fluids also reflect the general condition of the whole organism and can indicate the existence of cancer and other diseases. PL profiling with MS opens new prospects to assess alterations of PLs in cancer, screening specific biomarkers and provide a basis for the development of novel therapeutic strategies. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 37:107‐138, 2018     

Utilization of laser‐assisted analytical methods for monitoring of lead and nutrition elements distribution in fresh and dried Capsicum annuum l. leaves

Laser induced breakdown spectroscopy (LIBS) and laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) have been applied for high‐resolution mapping of accumulation and distribution of heavy metal (lead) and nutrition elements (potassium, manganese) in leaves of Capsicum annuum L. samples. Lead was added in a form of Pb(NO₃)₂ at concentration up to 10 mmol L^?1 into the vessels that contained tap water and where the 2‐months old Capsicum annuum L. plants were grown another seven days. Two dimensional maps of the elements are presented for both laser‐assisted analytical methods. Elemental mapping performed on fresh (frozen) and dried Capsicum annuum L. leaves are compared. Microsc. Res. Tech., 2011. © 2010 Wiley‐Liss, Inc.     

Progress in SIFT‐MS: Breath analysis and other applications

The development of selected ion flow tube mass spectrometry, SIFT‐MS, is described from its inception as the modified very large SIFT instruments used to demonstrate the feasibility of SIFT‐MS as an analytical technique, towards the smaller but bulky transportable instruments and finally to the current smallest Profile 3 instruments that have been located in various places, including hospitals and schools to obtain on‐line breath analyses. The essential physics and engineering principles are discussed, which must be appreciated to design and construct a SIFT‐MS instrument. The versatility and sensitivity of the Profile 3 instrument is illustrated by typical mass spectra obtained using the three precursor ions H₃O⁺, NO⁺ and ${\rm O}_{{\rm 2}}^{{\rm + } \cdot }$ , and the need to account for differential ionic diffusion and mass discrimination in the analytical algorithms is emphasized to obtain accurate trace gas analyses. The performance of the Profile 3 instrument is illustrated by the results of several pilot studies, including (i) on‐line real time quantification of several breath metabolites for cohorts of healthy adults and children, which have provided representative concentration/population distributions, and the comparative analyses of breath exhaled via the mouth and nose that identify systemic and orally‐generated compounds, (ii) the enhancement of breath metabolites by drug ingestion, (iii) the identification of HCN as a marker of Pseudomonas colonization of the airways and (iv) emission of volatile compounds from urine, especially ketone bodies, and from skin. Some very recent developments are discussed, including the quantification of carbon dioxide in breath and the combination of SIFT‐MS with GC and ATD, and their significance. Finally, prospects for future SIFT‐MS developments are alluded to. © 2010 Wiley Periodicals, Inc., Mass Spec Rev 30:236–267, 2011     

Analytical strategies for identifying drug metabolites

With the dramatic increase in the number of new chemical entities (NCEs) arising from combinatorial chemistry and modern high-throughput bioassays, novel bioanalytical techniques are required for the rapid determination of the metabolic stability and metabolites of these NCEs. Knowledge of the metabolic site(s) of the NCEs in early drug discovery is essential for selecting compounds with favorable pharmacokinetic credentials and aiding medicinal chemists in modifying metabolic "soft spots". In development, elucidation of biotransformation pathways of a drug candidate by identifying its circulatory and excretory metabolites is vitally important to understand its physiological effects. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) have played an invaluable role in the structural characterization and quantification of drug metabolites. Indeed, liquid chromatography (LC) coupled with atmospheric pressure ionization (API) MS has now become the most powerful tool for the rapid detection, structure elucidation, and quantification of drug-derived material within various biological fluids. Often, however, MS alone is insufficient to identify the exact position of oxidation, to differentiate isomers, or to provide the precise structure of unusual and/or unstable metabolites. In addition, an excess of endogenous material in biological samples often suppress the ionization of drug-related material complicating metabolite identification by MS. In these cases, multiple analytical and wet chemistry techniques, such as LC-NMR, enzymatic hydrolysis, chemical derivatization, and hydrogen/deuterium-exchange (H/D-exchange) combined with MS are used to characterize the novel and isomeric metabolites of drug candidates. This review describes sample preparation and introduction strategies to minimize ion suppression by biological matrices for metabolite identification studies, the application of various LC-tandem MS (LC-MS/MS) techniques for the rapid quantification and identification of drug metabolites, and future trends in this field.     

Recent advances in mass spectrometry analysis of phenolic endocrine disruptors and related compounds

This article reviews recent literature on current methodologies based on chromatography coupled to mass spectrometry to analyze phenolic compounds with endocrine‐disrupting capabilities. For this review we chose alkylphenol ethoxylates, bisphenol A, bisphenol F, and their degradation products and halogenated derivatives, which are considered important environmental contaminants. Additionally, some related compounds such as bisphenol diglycidylethers were included. Growing attention has been paid to the mass spectrometric characterization of these compounds and the instrumentation and strategies used for their quantification and confirmation. The current use of gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry (LC–MS) methodologies with different mass spectrometers and ionization and monitoring modes is discussed. Practical aspects with regards to the use of these analytical techniques, such as derivatizing reagents in GC–MS, ion suppression in LC–MS, and the most problematic aspects of quantification, are included in the discussion. © 2009 Wiley Periodicals, Inc., Mass Spec Rev 29:776–805, 2010     

Accurate and precise determination of isotopic ratios by MC‐ICP‐MS: A review

For many decades the accurate and precise determination of isotope ratios has remained a very strong interest to many researchers due to its important applications in earth, environmental, biological, archeological, and medical sciences. Traditionally, thermal ionization mass spectrometry (TIMS) has been the technique of choice for achieving the highest accuracy and precision. However, recent developments in multi‐collector inductively coupled plasma mass spectrometry (MC‐ICP‐MS) have brought a new dimension to this field. In addition to its simple and robust sample introduction, high sample throughput, and high mass resolution, the flat‐topped peaks generated by this technique provide for accurate and precise determination of isotope ratios with precision reaching 0.001%, comparable to that achieved with TIMS. These features, in combination with the ability of the ICP source to ionize nearly all elements in the periodic table, have resulted in an increased use of MC‐ICP‐MS for such measurements in various sample matrices. To determine accurate and precise isotope ratios with MC‐ICP‐MS, utmost care must be exercised during sample preparation, optimization of the instrument, and mass bias corrections. Unfortunately, there are inconsistencies and errors evident in many MC‐ICP‐MS publications, including errors in mass bias correction models. This review examines “state‐of‐the‐art” methodologies presented in the literature for achievement of precise and accurate determinations of isotope ratios by MC‐ICP‐MS. Some general rules for such accurate and precise measurements are suggested, and calculations of combined uncertainty of the data using a few common mass bias correction models are outlined. © 2009 Crown in the right of Canada. Published by Wiley Periodicals, Inc., Mass Spec Rev 28:990–1011, 2009     

Chip‐mass spectrometry for glycomic studies

The introduction of micro‐ and nanochip front end technologies for electrospray mass spectrometry addressed a major challenge in carbohydrate analysis: high sensitivity structural determination and heterogeneity assessment in high dynamic range mixtures of biological origin. Chip‐enhanced electrospray ionization was demonstrated to provide reproducible performance irrespective of the type of carbohydrate, while the amenability of chip systems for coupling with different mass spectrometers greatly advance the chip/MS technique as a versatile key tool in glycomic studies. A more accurate representation of the glycan repertoire to include novel biologically‐relevant information was achieved in different biological sources, asserting this technique as a valuable tool in glycan biomarker discovery and monitoring. Additionally, the integration of various analytical functions onto chip devices and direct hyphenation to MS proved its potential for glycan analysis during the recent years, whereby a new analytical tool is on the verge of maturation: lab‐on‐chip MS glycomics. The achievements until early beginning of 2007 on the implementation of chip‐ and functional integrated chip/MS in systems glycobiology studies are reviewed here. © 2009 Wiley Periodicals, Inc., Mass Spec Rev 28:223–253, 2009     

Discovering new invertebrate neuropeptides using mass spectrometry

Neuropeptides are a complex set of messenger molecules controlling a wide array of regulatory functions and behaviors within an organism. These neuromodulators are cleaved from longer protein molecules and often experience numerous post-translational modifications to achieve their bioactive form. As a result of this complexity, sensitive and versatile analysis schemes are needed to characterize neuropeptides. Mass spectrometry (MS) through a variety of approaches has fueled the discovery of hundreds of neuropeptides in invertebrate species in the last decade. Particularly successful are direct tissue and single neuron analyses by matrix-assisted laser desorption/ionization (MALDI) MS, which has been used to elucidate approximately 440 neuropeptides, and examination of neuronal homogenates by electrospray ionization techniques (ESI), also leading to the characterization of over 450 peptides. Additional MS methods with great promise for the discovery of neuropeptides are MS imaging and large-scale peptidomics studies in combination with a sequenced genome.     

Biomedical application of MALDI mass spectrometry for small‐molecule analysis

Matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is an emerging analytical tool for the analysis of molecules with molar masses below 1,000 Da; that is, small molecules. This technique offers rapid analysis, high sensitivity, low sample consumption, a relative high tolerance towards salts and buffers, and the possibility to store sample on the target plate. The successful application of the technique is, however, hampered by low molecular weight (LMW) matrix‐derived interference signals and by poor reproducibility of signal intensities during quantitative analyses. In this review, we focus on the biomedical application of MALDI‐MS for the analysis of small molecules and discuss its favorable properties and its challenges as well as strategies to improve the performance of the technique. Furthermore, practical aspects and applications are presented. © 2010 Wiley Periodicals, Inc., Mass Spec Rev 30:101–120, 2011     

A tutorial in small molecule identification via electrospray ionization‐mass spectrometry: The practical art of structural elucidation

The identification of unknown molecules has been one of the cornerstone applications of mass spectrometry for decades. This tutorial reviews the basics of the interpretation of electrospray ionization‐based MS and MS/MS spectra in order to identify small‐molecule analytes (typically below 2000 Da). Most of what is discussed in this tutorial also applies to other atmospheric pressure ionization methods like atmospheric pressure chemical/photoionization. We focus primarily on the fundamental steps of MS‐based structural elucidation of individual unknown compounds, rather than describing strategies for large‐scale identification in complex samples. We critically discuss topics like the detection of protonated and deprotonated ions ([M + H]⁺ and [M ? H]^?) as well as other adduct ions, the determination of the molecular formula, and provide some basic rules on the interpretation of product ion spectra. Our tutorial focuses primarily on the fundamental steps of MS‐based structural elucidation of individual unknown compounds (eg, contaminants in chemical production, pharmacological alteration of drugs), rather than describing strategies for large‐scale identification in complex samples. This tutorial also discusses strategies to obtain useful orthogonal information (UV/Vis, H/D exchange, chemical derivatization, etc) and offers an overview of the different informatics tools and approaches that can be used for structural elucidation of small molecules. It is primarily intended for beginning mass spectrometrists and researchers from other mass spectrometry sub‐disciplines that want to get acquainted with structural elucidation are interested in some practical tips and tricks.

     

UPLC-Q-TOF MS定性定量分析淫羊藿中淫羊藿苷类似物

利用超高效液相色谱-四极杆飞行时间质谱(UPLC-Q-TOF MS)法分析淫羊藿标准药材,并根据淫羊藿苷对照品的裂解规律及相关文献报道对朝鲜淫羊藿中淫羊藿苷类似物进行定性定量分析。采用加压溶剂提取系统提取淫羊藿标准药材中的有效成分,以液相色谱-质谱法进行分析,通过总结对照品淫羊藿苷和朝藿定C的质谱裂解规律,分析检测标准药材中的淫羊藿苷类似物。结果表明,从标准药材朝鲜淫羊藿中检测出42个淫羊藿苷类似物,它们主要集中在15%~70%乙腈洗脱部分,其中有4种化合物是首次发现。该方法通过检测一类标准品进而检测标准药材中的目标成分,可为淫羊藿其他药材中淫羊藿苷类似物的研究及先导药物开发提供必要依据。     

STRATEGIES AND CHALLENGES IN METHOD DEVELOPMENT AND VALIDATION FOR THE ABSOLUTE QUANTIFICATION OF ENDOGENOUS BIOMARKER METABOLITES USING LIQUID CHROMATOGRAPHY‐TANDEM MASS SPECTROMETRY

Metabolomics is a dynamically evolving field, with a major application in identifying biomarkers for drug development and personalized medicine. Numerous metabolomic studies have identified endogenous metabolites that, in principle, are eligible for translation to clinical practice. However, few metabolomic‐derived biomarker candidates have been qualified by regulatory bodies for clinical applications. Such interruption in the biomarker qualification process can be largely attributed to various reasons including inappropriate study design and inadequate data to support the clinical utility of the biomarkers. In addition, the lack of robust assays for the routine quantification of candidate biomarkers has been suggested as a potential bottleneck in the biomarker qualification process. In fact, the nature of the endogenous metabolites precludes the application of the current validation guidelines for bioanalytical methods. As a result, there have been individual efforts in modifying existing guidelines and/or developing alternative approaches to facilitate method validation. In this review, three main challenges for method development and validation for endogenous metabolites are discussed, namely matrix effects evaluation, alternative analyte‐free matrices, and the choice of internal standards (ISs). Some studies have modified the equations described by the European Medicines Agency for the evaluation of matrix effects. However, alternative strategies were also described; for instance, calibration curves can be generated in solvents and in biological samples and the slopes can be compared through ratios, relative standard deviation, or a modified Stufour suggested approaches while quantifying mainly endogenous metabolitesdent t‐test. ISs, on the contrary, are diverse; in which seven different possible types, used in metabolomics‐based studies, were identified in the literature. Each type has its advantages and limitations; however, isotope‐labeled ISs and ISs created through isotope derivatization show superior performance. Finally, alternative matrices have been described and tested during method development and validation for the quantification of endogenous entities. These alternatives are discussed in detail, highlighting their advantages and shortcomings. The goal of this review is to compare, apprise, and debate current knowledge and practices in order to aid researchers and clinical scientists in developing robust assays needed during the qualification process of candidate metabolite biomarkers. © 2019 John Wiley & Sons Ltd. Mass Spec Rev     

High‐throughput continuous flow femtosecond laser‐assisted cell optoporation and transfection

We present a femtosecond‐laser based nanoprocessing system for transient optical cell membrane poration to allow the introduction of foreign molecules into the interior of a cell with very high throughput. In the setup, cells flow through a micro‐flow tube for spatial confinement and are simultaneously targeted by fs laser radiation. Beam‐shaping generates a focal geometry along a line which is scanned across the micro‐flow cell to increase the number of reachable cells. Successful cell membrane poration was observed indirectly by cell transfection even with cell‐light interaction times in the millisecond range. The system was characterized by experiments with Chinese hamster ovary cells regarding cell viability, the uptake of extrinsic molecules and cell transfection efficiency. The continuous flow of cells enables a tremendous increase of cell throughput compared to previous nonflow approaches by treating millions of cells, although with only limited efficiency. The setup opens the possibility to realize a completely automated high‐throughput laser‐assisted cell‐poration system which could be integrated in lab‐on‐a‐chip devices. Microsc. Res. Tech. 77:974–979, 2014. © 2014 Wiley Periodicals, Inc.     

Mass spectrometric based approaches in urine metabolomics and biomarker discovery

Urine metabolomics has recently emerged as a prominent field for the discovery of non‐invasive biomarkers that can detect subtle metabolic discrepancies in response to a specific disease or therapeutic intervention. Urine, compared to other biofluids, is characterized by its ease of collection, richness in metabolites and its ability to reflect imbalances of all biochemical pathways within the body. Following urine collection for metabolomic analysis, samples must be immediately frozen to quench any biogenic and/or non‐biogenic chemical reactions. According to the aim of the experiment; sample preparation can vary from simple procedures such as filtration to more specific extraction protocols such as liquid‐liquid extraction. Due to the lack of comprehensive studies on urine metabolome stability, higher storage temperatures (i.e. 4°C) and repetitive freeze‐thaw cycles should be avoided. To date, among all analytical techniques, mass spectrometry (MS) provides the best sensitivity, selectivity and identification capabilities to analyze the majority of the metabolite composition in the urine. Combined with the qualitative and quantitative capabilities of MS, and due to the continuous improvements in its related technologies (i.e. ultra high‐performance liquid chromatography [UPLC] and hydrophilic interaction liquid chromatography [HILIC]), liquid chromatography (LC)‐MS is unequivocally the most utilized and the most informative analytical tool employed in urine metabolomics. Furthermore, differential isotope tagging techniques has provided a solution to ion suppression from urine matrix thus allowing for quantitative analysis. In addition to LC‐MS, other MS‐based technologies have been utilized in urine metabolomics. These include direct injection (infusion)‐MS, capillary electrophoresis‐MS and gas chromatography‐MS. In this article, the current progresses of different MS‐based techniques in exploring the urine metabolome as well as the recent findings in providing potentially diagnostic urinary biomarkers are discussed. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:115–134, 2017.     

Quantitative high-throughput analysis of drugs in biological matrices by mass spectrometry

To support pharmacokinetic and drug metabolism studies, LC-MS/MS plays more and more an essential role for the quantitation of drugs and their metabolites in biological matrices. With the new challenges encountered in drug discovery and drug development, new strategies are put in place to achieve high-throughput analysis, using serial and parallel approaches. To speed-up method development and validation, generic approaches with the direct injection of biological fluids is highly desirable. Column-switching, using various packing materials for the extraction columns, is widely applied. Improvement of mass spectrometers performance, and in particular triple quadrupoles, also strongly influences sample preparation strategies, which remain a key element in the bioanalytical process.     

Recent trends of capillary electrophoresis‐mass spectrometry in proteomics research

Progress in proteomics research has led to a demand for powerful analytical tools with high separation efficiency and sensitivity for confident identification and quantification of proteins, posttranslational modifications, and protein complexes expressed in cells and tissues. This demand has significantly increased interest in capillary electrophoresis‐mass spectrometry (CE‐MS) in the past few years. This review provides highlights of recent advances in CE‐MS for proteomics research, including a short introduction to top‐down mass spectrometry and native mass spectrometry (native MS), as well as a detailed overview of CE methods. Both the potential and limitations of these methods for the analysis of proteins and peptides in synthetic and biological samples and the challenges of CE methods are discussed, along with perspectives about the future direction of CE‐MS. @ 2019 Wiley Periodicals, Inc. Mass Spec Rev 00:1–16, 2019.