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1.
J Proteome Res ; 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32202427

RESUMO

Proteomics by mass spectrometry (MS) allows for the identification of amino acid/peptide sequences in complex mixtures. Peptide analysis and quantitation enables screening of protein biomarkers and targeted protein biomarker analysis for clinical applications. Whereas miniature mass spectrometers have primarily demonstrated point-of-care analyses with simple procedures aiming at drugs and lipids, it would be interesting to explore their potential in analyzing proteins and peptides. In this work, we adapted a miniature MS instrument for peptide analysis. A mass range as wide as 100-2000 m/z was achieved for obtaining peptide spectra using this instrument with dual linear ion traps. MS2 and MS3 can be performed to analyze a wide range of peptides. The parameters of pressure, electric potentials, and solution conditions were optimized to analyze peptides with molecular weights between 900 and 1800 Da. The amino acid sequences were identified using both beam-type and in-trap collision-induced dissociation, and the results were comparable to those obtained by a commercial quadrupole time-of-flight mass spectrometer. With product ion monitoring scan mode, peptide quantitation was performed with a limit of detection of 20 nM achieved for the Met peptide. The method developed has also been applied to the analysis of the trypsin-digested cell lysate of SKBR3 cells with a low expression level of the Met gene.

2.
Anal Chim Acta ; 1101: 74-80, 2020 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-32029121

RESUMO

There is an increasing need for rapid and on-site detection of emerging drugs of abuse. In this work, we developed a method using a miniature dual-LIT (linear ion trap) mass spectrometer recently developed with comprehensive tandem mass spectrometry analysis capability, for qualitative and quantitative analysis of multiple drugs of abuse. Paper-capillary spray cartridges were used with related workflow established to simplify overall analysis procedure. Quantitation of ketamine and methamphetamine was achieved by beam-type collision-induced dissociation on the miniature dual-LIT mass spectrometer and a linear concentration range of 100-5000 ng/mL was obtained. The system has been applied in analysis of real urine samples from individuals addicted to morphine and methamphetamine use. The changes of the ratio of cocaine to its metabolite benzoylecgonine were also explored to estimate the time of cocaine intaking.

3.
J Am Chem Soc ; 142(7): 3499-3505, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31994883

RESUMO

The [2 + 2] photocycloaddition of alkenes and carbonyls is of fundamental interest and practical importance, as this process is extensively involved in oxetane-ring constructions. Although individual carbonyl group or alkene moiety has been utilized as photoactive species for oxetane formations upon ultraviolet photoexcitation, direct excitation of the entire noncovalent complex involving alkene and carbonyl substrates to achieve [2 + 2] photocycloadditions is rarely addressed. Herein, complexes with noncovalent interactions between benzophenone and C═C bonds in unsaturated lipids have been successfully characterized, and for the first time a [2 + 2] cycloaddition leading to the formation of oxetanes has been identified under visible-light irradiation. The mechanism of this reaction is distinctly different from the well-studied Paternò-Büchi reaction. The entire complexes characterized as dimeric proton-bonded alkene and carbonyl substrates can be excited under visible light, leading to electron transfer from the alkene moiety in fatty acyls to the carbonyl group within the complex. These results provide new insight into utilizing noncovalent complexes for the synthesis of oxetanes in which the excitation wavelength becomes independent of each individual substrate.

4.
J Am Soc Mass Spectrom ; 31(2): 429-433, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31940196

RESUMO

Computation of the space charge effect within an ion trap may cost a few days to even years in clusters. Here, we report a statistical algorithm that can compute the space charge effect within a few minutes via a personal computer, without scarifying the accuracy. The key technology developed here was an effective electric field extracted from the statistics of N ions to replace the time-consuming computation of ion-ion Coulombic interactions, therefore reducing the computational burden from ∼N2 to ∼N; then, the burden was further reduced by shrinking the sampling size to Nsim = 500. For a linear ion trap (LIT) with an ion capacity N = 1 × 10 5∼1 × 106, this indicated an improved efficiency of N2/Nsim , i.e., 20 million∼2 billion-fold. Using the algorithm, space charge effects under different trapping conditions were explored, and the acquired knowledge enabled the spectral correction of the mass shift and peak broadening due to the effect in a miniature dual-LIT mass spectrometer.

5.
Anal Chim Acta ; 1098: 66-74, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948588

RESUMO

A streamlined analytical workflow was developed for the analysis of infant drink samples using a miniature mass spectrometry system preceded by solid-phase microextraction (SPME) and extraction nano-electrospray ionization. Potential chemical contaminants in infant drinks (milk, lactic acid bacteria beverage, and fruit juice) were extracted and enriched using a custom-made stainless-steel SPME probe, which was coated with a thin layer of polyaniline and multi-walled carbon nanotubes nanocomposites (PANI/MWCNTs) by electrochemical deposition. The resulting porous microstructure has a larger surface area and enhanced microextraction efficiency, with enrichment factors ranging from 3055 to 8695 for exemplary analytes of antibiotics, bisphenol A, and perfluorinated compounds. The enriched analytes on the electrochemically fabricated SPME probe were simultaneously desorbed and ionized within a pulled glass capillary by extraction nano-electrospray ionization. The ionized species were subjected to instrumental analysis on a miniature ion trap mass spectrometer with adequate tandem mass spectrometry capability. The developed method was optimized and validated in terms of sensitivity, linearity, repeatability, and recovery. The integrated experimental protocol combining SPME, ambient ionization, and miniature mass spectrometry is promising for rapid, on-site screening of hazardous substances in food to ensure consumer health.

6.
Anal Bioanal Chem ; 412(6): 1465, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31953716

RESUMO

Unfortunately, after online publication, a formatting mistake was found in Table 1 (Chemical structures and MRM transitions used for quantitation). The original article has been corrected.

7.
Anal Chem ; 92(3): 2573-2579, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31940171

RESUMO

Ion mobility (IM) has been increasingly used in combination with mass spectrometry (MS) for chemical and biological analysis. While implementation of IM with MS usually requires complex instrumentation with delicate controls, in this study we explored the potential of performing IM separation using dual-linear ion traps (LITs) in a miniature mass spectrometer, which was originally developed for performing comprehensive MS/MS scan functions with a simple instrumentation configuration. The IM separation was achieved by ion transfer between the LITs with dynamic gas flow. Its performance was characterized for analysis of a broad range of chemical and biological compounds including small organic compounds such as trisaccharides, raffinose, cellotriose, and melezitose, as well as protein conformers. The demonstrated technique serves as another example of developing powerful hybrid instrument functions with simple configurations and miniaturized sizes.

8.
Anal Bioanal Chem ; 412(6): 1243-1249, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897555

RESUMO

Inadequate adherence to chronic medications is a far-reaching problem with financial and human health consequences. By a wide margin, non-adherence is the leading cause of therapeutic failures of HIV pre-exposure chemoprophylaxis (PrEP) and antiretroviral therapy (ART). It has been proven that HIV infection can be prevented by daily dosing of emtricitabine and tenofovir disoproxil fumarate. Measurement of intracellular tenofovir diphosphate in red blood cells has been established as an effective way to assess cumulative adherence, however, the LC-MS-based analytical method developed for the purpose is both complicated and expensive. Here, we report a simple method for adherence monitoring based on direct MS quantification of intracellular tenofovir diphosphate in human whole blood. The method requires only microliters of whole blood, employs special membranes to perform plasma separation and concomitant desalting during blood collection, and uses nanoelectrospray on a triple quadrupole instrument. Quantitative performance in this proof-of-concept study includes RSDs of < 15% and successful analysis of a small number of patient samples with medium to high adherence levels. The results correlate with those of a validated LC-MS/MS method, and an R2 value of 0.9962 is achieved. This methodology has promise for extension to point-of-care testing using miniature mass spectrometers. Graphical abstract.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/sangue , Organofosfatos/sangue , Espectrometria de Massas em Tandem/métodos , Adenina/sangue , Adenina/normas , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/normas , Cromatografia Líquida/métodos , Humanos , Organofosfatos/normas , Estudo de Prova de Conceito , Padrões de Referência
9.
Nat Commun ; 11(1): 375, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953382

RESUMO

Lipids play a pivotal role in biological processes and lipid analysis by mass spectrometry (MS) has significantly advanced lipidomic studies. While the structure specificity of lipid analysis proves to be critical for studying the biological functions of lipids, current mainstream methods for large-scale lipid analysis can only identify the lipid classes and fatty acyl chains, leaving the C=C location and sn-position unidentified. In this study, combining photochemistry and tandem MS we develop a simple but effective workflow to enable large-scale and near-complete lipid structure characterization with a powerful capability of identifying C=C location(s) and sn-position(s) simultaneously. Quantitation of lipid structure isomers at multiple levels of specificity is achieved and different subtypes of human breast cancer cells are successfully discriminated. Remarkably, human lung cancer tissues can only be distinguished from adjacent normal tissues using quantitative results of both lipid C=C location and sn-position isomers.

10.
ACS Appl Mater Interfaces ; 11(49): 46140-46148, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31729222

RESUMO

Mass spectrometry imaging (MSI) serves as a powerful tool for biological research, and laser desorption ionization (LDI) is used as a major sampling ionization method. Study of materials for LDI represents a major field in the MSI research, either for matrices in matrix-assisted LDI (MALDI) or sample substrates allowing matrix-free LDI. In this study, we developed a composite substrate using polydopamine (PDA) film to coat an antireflection (AR) surface for LDI-MSI. The AR material has been previously shown to confine UV energy within the micro-/nanostructures, leading to a highly localized temperature rise to facilitate analyte thermal desorption. PDA coating on the AR material further enhances the light-to-heat conversion and improves the contact between the substrate surface and the biological sample materials. With this substrate, desorption and ionization of lipids from raw human plasma samples and biological tissue sections have been achieved. Matrix-free LDI-MSI of around 30 lipid species in mouse brain sections was achieved with a significantly simplified MSI procedure at a spatial resolution of 50 µm. This method was applied to determine mouse fatty liver disease through monitoring the abundances and distributions of triacylglycerols and glycerophospholipids. Dramatic differences in the lipid profiles were subsequently identified between the liver tissues from the wild-type and obese mice.

11.
Anal Bioanal Chem ; 411(30): 7929-7933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31754769

RESUMO

Knowledge of the isocitrate dehydrogenase (IDH) mutation status of glioma patients could provide insights for decision-making during brain surgery. However, pathology is not able to provide such information intraoperatively. Here we describe the first application of a miniature mass spectrometer (MS) to the determination of IDH mutation status in gliomas intraoperatively. The instrumentation was modified to be compatible with use in the operating room. Tandem MS was performed on the oncometabolite, 2-hydroxyglutarate, and a reference metabolite, glutamate, which is not involved in the IDH mutation. Ratios of fragment ion intensities were measured to calculate an IDH mutation score, which was used to differentiate IDH mutant and wild-type tissues. The results of analyzing 25 biopsies from 13 patients indicate that reliable determination of IDH mutation status was achieved (p = 0.0001, using the Kruskal-Wallis non-parametric test). With its small footprint and low power consumption and noise level, this application of miniature mass spectrometers represents a simple and cost-effective platform for an important intraoperative measurement. Graphical abstract.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Isocitrato Desidrogenase/genética , Mutação , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Biópsia , Neoplasias Encefálicas/patologia , Estudos de Coortes , Glioma/patologia , Humanos , Período Intraoperatório
12.
J Am Soc Mass Spectrom ; 30(12): 2750-2755, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31659717

RESUMO

Ion trapping using radio-frequency (RF) devices has been widely used in mass spectrometry (MS). The pseudopotential well (PW) model enables the use of a pseudopotential depth, D, to evaluate the ion trapping capability of the RF devices in the pure electric field. It remains unclear how gas pressures regulate the ion trapping and D. Here, we calculated the D of a linear ion trap (LIT) from 1 mTorr to 2 Torr, a pressure range critical for the operation of the RF devices, through ion cloud simulations. Compared with the case of pure electric field, ion-neutral collision effects at pressures of 1 to 100 mTorr were beneficial for the ion trapping and revealed an optimal trapping depth, D, at around 10 mTorr. We explained the mechanism and validated the observation via ion trapping experiments performed in a home-made dual LIT mass spectrometer. We also showed that near the stability boundary, the RF heating became comparable with the D, which led to the decrement of ion trapping capability characterized by the available D.

13.
Anal Chem ; 91(11): 6986-6990, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31074609

RESUMO

The transition of mass spectrometry for clinical analysis is highly desirable, and major progress has been made with direct sampling ionization for operation simplification. High-precision quantitation, however, remains a major challenge in this transition. Herein, a novel method was developed for direct quantitation of biofluid samples, using an extremely simplified procedure for incorporation of internal standards selected against the traditional rules. Slug flow microextraction was used for the development, with conditions predicted by a theoretical model, viz., using internal standards of partition coefficients very different from the analytes and large sample-to-extraction solvent volume ratios. Direct quantitation of drug compounds in urine and blood samples was demonstrated. This development enabled an extremely simplified protocol that is expected to have a significant impact on on-site or clinical analysis.

14.
Nat Commun ; 10(1): 918, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30783110

RESUMO

The original version of this Article contained an error in Fig. 2f, in which the phospholipid was incorrectly labelled 'PE' rather than the correct 'PC'. This has now been corrected in the PDF and HTML versions of the Article.

15.
Angew Chem Int Ed Engl ; 58(18): 6064-6069, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30805967

RESUMO

A porous polymer coating transfer enrichment method is developed for the direct mass spectrometry (MS) analysis of lipids. The enrichment is fast (ca. 1 min) and enables the profiling and quantitation of lipids in small-volume biofluid samples. Coupled with a photochemical Paternò-Büchi reaction, this method enables the fast determination of lipid structure at the C=C location level and point-of-care lipid biomarker analysis.

16.
Anal Bioanal Chem ; 411(8): 1503-1508, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30710208

RESUMO

Isocitrate dehydrogenase (IDH) I and II mutations in gliomas cause an abnormal accumulation of 2-hydroxyglutarate (2-HG) in these tumor cells. These mutations have potential prognostic value in that knowledge of the mutation status can lead to improved surgical resection. Information on mutation status obtained by immunohistochemistry or genomic analysis is not available during surgery. We report a rapid extraction nanoelectrospray ionization (nESI) method of determining 2-HG. This should allow the determination of IDH mutation status to be performed intraoperatively, within minutes, using a miniature mass spectrometer. This study demonstrates that the combination of tandem mass spectrometry with low-resolution mass spectrometry allows this analysis to be performed with confidence. Graphical Abstract.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Espectrometria de Massas em Tandem/instrumentação , Desenho de Equipamento , Humanos , Papel , Espectrometria de Massas por Ionização por Electrospray/economia , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/economia , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo
17.
Nat Commun ; 10(1): 79, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30622271

RESUMO

Mass spectrometry-based lipidomics is the primary tool for the structural analysis of lipids but the effective localization of carbon-carbon double bonds (C=C) in unsaturated lipids to distinguish C=C location isomers remains challenging. Here, we develop a large-scale lipid analysis platform by coupling online C=C derivatization through the Paternò-Büchi reaction with liquid chromatography-tandem mass spectrometry. This provides rich information on lipid C=C location isomers, revealing C=C locations for more than 200 unsaturated glycerophospholipids in bovine liver among which we identify 55 groups of C=C location isomers. By analyzing tissue samples of patients with breast cancer and type 2 diabetes plasma samples, we find that the ratios of C=C isomers are much less affected by interpersonal variations than their individual abundances, suggesting that isomer ratios may be used for the discovery of lipid biomarkers.


Assuntos
Neoplasias da Mama/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Glicerofosfolipídeos/análise , Sistemas Automatizados de Assistência Junto ao Leito , Adulto , Idoso , Animais , Biomarcadores/análise , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carbono/química , Bovinos , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Estudos de Viabilidade , Feminino , Glicerofosfolipídeos/química , Glicerofosfolipídeos/metabolismo , Humanos , Isomerismo , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Processos Fotoquímicos , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
18.
Anal Chem ; 91(2): 1391-1398, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30444599

RESUMO

Miniature mass spectrometers are of an increasing interest for in-situ analyses, and their coupling with the ambient ionization sources is a valid path for direct analysis of complex samples. In this study, a miniature mass spectrometer using discontinuous atmospheric pressure interface was developed with a dual-LIT (linear ion trap) configuration. The comprehensive scan modes were enabled for tandem mass spectrometry analysis, which are critical for high-quality qualitative and quantitative analysis. A real-time pressure control was implemented to facilitate the ion transfer and collision induced dissociation (CID). Beam-type CID could be performed for tandem analysis at a high number of stages. In-trap CID at high q could also be performed with the fragment ions accumulated in a second trap. A precursor ion scan mode for analyzing target analytes has also been demonstrated.

19.
Anal Chem ; 91(1): 1157-1163, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30525456

RESUMO

The combination of direct sampling ionization and miniature mass spectrometer presents a promising technical pathway of point-of-care analysis in clinical applications. In this work, a miniature mass spectrometry system was used for analysis of tissue samples. Direct tissue sampling coupled with extraction spray ionization was used with a home-built miniature mass spectrometer, Mini 12. Lipid species in tissue samples were well profiled in rat brain, kidney, and liver in a couple of minutes. By incorporating a photochemical (Paternò-Büchi) reaction, fast identification of lipid C═C location was realized. Relative quantitation of the lipid C═C isomer was performed by calculating the intensity ratio C═C diagnostic product ions, by which FA 18:1 (Δ9)/FA 18:1 (Δ11) was found to change significantly in mouse cancerous breast tissue samples. Accumulation of 2-hydroxylglutarate in human glioma samples, not in normal brains, can also be easily identified for rapid diagnosis.

20.
Analyst ; 144(4): 1034-1051, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30520890

RESUMO

Direct sampling mass spectrometry (MS) has been advancing aggressively, showing immense potential in translating MS into the clinical field. Unlike traditional MS analysis involving extensive sample preparation and chromatographic separation, quick and simple procedures with minimal sample pretreatment or purification became available with direct sampling. An overview of the development in this field is provided, including some representative ambient ionization and fast extraction methods. Quantitative applications of these methods are emphasized and their efficacy are highlighted from a clinical aspect; non-quantitative applications in clinical analysis are also discussed. This review also discusses the integration of direct sampling MS with miniature mass spectrometers and its future outlook as an emerging clinical tool for point-of-care analysis.


Assuntos
Espectrometria de Massas/métodos , Humanos , Espectrometria de Massas/instrumentação , Sistemas Automatizados de Assistência Junto ao Leito , Manejo de Espécimes
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