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1.
Alzheimers Dement ; 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39316411

RESUMO

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

2.
Biotechnol Bioeng ; 119(2): 435-451, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34811743

RESUMO

Mammalian cell culture processes rely heavily on empirical knowledge in which process control remains a challenge due to the limited characterization/understanding of cell metabolism and inability to predict the cell behaviors. This study facilitates control of Chinese hamster ovary (CHO) processes through a forecast-based feeding approach that predicts multiple essential amino acids levels in the culture from easily acquired viable cell density data. Multiple cell growth behavior forecast extrapolation approaches are considered with logistic curve fitting found to be the most effective. Next, the nutrient-minimized CHO genome-scale model is combined with the growth forecast model to generate essential amino acid forecast profiles of multiple CHO batch cultures. Comparison of the forecast with the measurements suggests that this algorithm can accurately predict the concentration of most essential amino acids from cell density measurement with error mitigated by incorporating off-line amino acids concentration measurements. Finally, the forecast algorithm is applied to CHO fed-batch cultures to support amino acid feeding control to control the concentration of essential amino acids below 1-2 mM for lysine, leucine, and valine as a model over a 9-day fed batch culture while maintaining comparable growth behavior to an empirical-based culture. In turn, glycine production was elevated, alanine reduced and lactate production slightly lower in control cultures due to metabolic shifts in branched-chain amino acid degradation. With the advantage of requiring minimal measurement inputs while providing valuable and in-advance information of the system based on growth measurements, this genome model-based amino acid forecast algorithm represent a powerful and cost-effective tool to facilitate enhanced control over CHO and other mammalian cell-based bioprocesses.


Assuntos
Algoritmos , Aminoácidos Essenciais , Técnicas de Cultura Celular por Lotes/métodos , Proliferação de Células/genética , Meios de Cultura , Aminoácidos Essenciais/análise , Aminoácidos Essenciais/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Meios de Cultura/química , Meios de Cultura/metabolismo , Genoma/genética , Modelos Genéticos
3.
Anal Chem ; 85(5): 2717-23, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23402265

RESUMO

A simultaneous on-tissue proteolytic digestion and extraction method is described for the in situ analysis of proteins from spatially distinct areas of a tissue section. The digestion occurs on-tissue within a hydrogel network, and peptides extracted from this gel are identified with liquid chromatography tandem MS (LC-MS/MS). The hydrogels are compatible with solubility agents (e.g., chaotropes and detergents) known to improve enzymatic digestion of proteins. Additionally, digestions and extractions are compatible with imaging mass spectrometry (IMS) experiments. As an example application, an initial IMS experiment was conducted to profile lipid species using a traveling wave ion mobility mass spectrometer. On-tissue MS/MS was also performed on the same tissue section to identify lipid ions that showed spatial differences. Subsequently, the section underwent an on-tissue hydrogel digestion to reveal 96 proteins that colocalized to the rat brain cerebellum. Hematoxylin and eosin (H & E) staining was then performed to provide additional histological information about the tissue structure. This technology provides a versatile workflow that can be used to correlate multiple complementary analytical approaches in the analysis of a single tissue section.


Assuntos
Fracionamento Químico/métodos , Hidrogéis/química , Proteínas/isolamento & purificação , Proteínas/metabolismo , Proteólise , Animais , Cérebro/metabolismo , Cromatografia Líquida , Peso Molecular , Proteínas/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem
4.
Anal Chem ; 85(15): 7191-6, 2013 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-23829295

RESUMO

Transmembrane proteins are greatly underrepresented in data generated by imaging mass spectrometry (IMS) because of analytical challenges related to their size and solubility. Here, we present the first example of MALDI IMS of two highly modified multitransmembrane domain proteins, myelin proteolipid protein (PLP, 30 kDa) and DM-20 (26 kDa), from various regions of rat brain, namely, the cerebrum, cerebellum, and medulla. We utilize a novel tissue pretreatment aimed at transmembrane protein enrichment to show the in situ distribution of fatty acylation of these proteins, particularly of post-translational palmitoylation. Additionally, we demonstrate the utility of protease-encapsulated hydrogels for spatially localized on-tissue protein digestion and peptide extraction for subsequent direct coupling to LC-MS/MS for protein identification.


Assuntos
Encéfalo/metabolismo , Imagem Molecular/métodos , Proteína Proteolipídica de Mielina/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Ratos , Ratos Sprague-Dawley , Tripsina/metabolismo
5.
Alzheimers Res Ther ; 15(1): 168, 2023 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-37803386

RESUMO

Tauopathies are a group of neurodegenerative disorders characterized by the aggregation of the microtubule-associated protein tau. Aggregates of misfolded tau protein are believed to be implicated in neuronal death, which leads to a range of symptoms including cognitive decline, behavioral change, dementia, and motor deficits. Currently, there are no effective treatments for tauopathies. There are four clinical candidates in phase III trials and 16 in phase II trials. While no effective treatments are currently approved, there is increasing evidence to suggest that various therapeutic approaches may slow the progression of tauopathies or improve symptoms. This review outlines the landscape of therapeutic drugs (indexed through February 28, 2023) that target tau pathology and describes drug candidates in clinical development as well as those in the discovery and preclinical phases. The review also contains information on notable therapeutic programs that are inactive or that have been discontinued from development.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Humanos , Encéfalo/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Proteínas tau/metabolismo , Disfunção Cognitiva/metabolismo , Doença de Alzheimer/patologia
6.
Analyst ; 137(13): 3039-44, 2012 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-22606690

RESUMO

Significant developments in the field of ambient desorption/ionization mass spectrometry (MS) have led to high-throughput direct analysis and imaging capabilities. However, advances in coupling ambient ionization techniques with standalone drift tube ion mobility spectrometry (DTIMS) have been comparatively slower, despite the attractive ruggedness and simplicity of IMS. In this study, we have developed and characterized a laser ablation/desorption electrospray ionization (LADESI) DTIMS platform, and applied it to the detection of active pharmaceutical ingredients (APIs) in antimalarial tablets collected in developing countries. The overarching goal of this work was to perform an initial evaluation of LADESI DTIMS as a technique with the potential for constituting the core of a portable drug quality-testing platform. The set-up consisted of an IR laser for desorption and an electrospray ionizer for capturing the ablated plume coupled to a high-resolution monolithic resistive glass drift tube ion mobility spectrometer. For more confident API identification, tablet extracts were also investigated via electrospray IM MS to correlate LADESI DTIMS reduced mobility (K(0)) values to m/z values. Overall, it was found that the IR LADESI DTIMS platform provided distinct ion mobility spectral fingerprints that could be used to detect the presence of the expected APIs, helping to distinguish counterfeit drugs from their genuine counterparts.


Assuntos
Antimaláricos/farmacologia , Espectrometria de Massas por Ionização por Electrospray/métodos , Pressão Atmosférica
7.
Anal Chem ; 83(6): 1908-15, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21319810

RESUMO

Current and future chemical threats to homeland security motivate the need for new chemical detection systems to provide border, transportation, and workplace security. We present the first successful coupling of a commercial direct analysis in real time (DART) ion source to a resistive glass monolithic drift tube ion mobility spectrometer (DTIMS) as the basis for a low maintenance, versatile, and robust chemical monitoring system. in situ ionization within the electric field gradient of the instrument enhances sensitivity and provides a safe sampling strategy. The instrument uses nitrogen as both the DART discharge and DTIMS drift gases, allowing for a high electric field to be used for ion separation while keeping cost-of-use low. With the use of a traditional signal averaging acquisition mode, the 95% probability of detection (POD) for analytes sampled from melting point capillary tubes was 11.81% v/v for DMMP, 1.13% v/v for 2-CEES, and 10.61 mM for methamidophos. Sensitivity was improved via a prototype transmission-mode geometry interface, resulting in an almost 2 orders of magnitude decrease in the POD level for DMMP (0.28% v/v). As an alternative to transmission mode operation, digital multiplexing of the DTIMS ion injection step was also implemented, finding a 3-fold improvement in signal-to-noise ratios for 200 µs gate injections and a 4.5-fold for 400 µs gate injections.

8.
Malar J ; 10: 352, 2011 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-22152094

RESUMO

BACKGROUND: Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. METHODS: Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. RESULTS: Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. CONCLUSIONS: Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.


Assuntos
Antimaláricos/química , Antimaláricos/provisão & distribuição , Artemisininas/química , Artemisininas/provisão & distribuição , Medicamentos Falsificados/química , Medicamentos Falsificados/provisão & distribuição , Lactonas/química , Lactonas/provisão & distribuição , Qualidade da Assistência à Saúde/estatística & dados numéricos , África , Ásia , Técnicas de Química Analítica/métodos , Embalagem de Medicamentos/estatística & dados numéricos , Humanos
9.
Anal Chem ; 82(22): 9159-63, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20968300

RESUMO

Desorption electrospray ionization (DESI) is rapidly becoming established as one of the most powerful ionization techniques allowing direct surface analysis by mass spectrometry (MS) in the ambient environment. DESI provides a significant number of unique analytical capabilities for a broad range of applications, both quantitative and qualitative in nature including biological tissue imaging, pharmaceutical quality control, in vivo analysis, proteomics, metabolomics, forensics, and explosives detection. Despite its growing adoption as a powerful high throughput analysis tool, DESI-MS analysis at trace levels often suffers from background chemical interferences generated during the electrospray ionization processes. In order to improve sensitivity and selectivity, a differential mobility (DM) ion separation cell was successfully interfaced to a custom-built DESI ion source. This new hybrid platform can be operated in two modes: the "DM-off" mode for standard DESI analysis and "DM-on mode" where DESI-generated ions are detected after discrimination by the differential mobility cell. The performance of the DESI-DM-MS platform was tested with several samples typically amenable to DESI analysis, including counterfeit pharmaceuticals and binary mixtures of isobaric chemicals of importance in the pharmaceutical and food industries. In the DM-on mode, DESI-MS signal-to-noise ratios were improved by 70-190% when compared to the DM-off mode. Also, the addition of the DM cell enabled selective in-source ion activation of specific DESI-generated precursor ions, providing tandem MS-like spectra in a single stage mass spectrometer.

10.
Anal Chem ; 82(6): 2178-81, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20155978

RESUMO

Presented here is a novel ambient ion source termed infrared laser ablation metastable-induced chemical ionization (IR-LAMICI). IR-LAMICI integrates IR laser ablation and direct analysis in real time (DART)-type metastable-induced chemical ionization for open air mass spectrometry (MS) ionization. The ion generation in the IR-LAMICI source is a two step process. First, IR laser pulses impinge the sample surface ablating surface material. Second, a portion of ablated material reacts with the metastable reactive plume facilitating gas-phase chemical ionization of analyte molecules generating protonated or deprotonated species in positive and negative ion modes, respectively. The successful coupling of IR-laser ablation with metastable-induced chemical ionization resulted in an ambient plasma-based spatially resolved small molecule imaging platform for mass spectrometry (MS). The analytical capabilities of IR-LAMICI are explored by imaging pharmaceutical tablets, screening counterfeit drugs, and probing algal tissue surfaces for natural products. The resolution of a chemical image is determined by the crater size produced with each laser pulse but not by the size of the metastable gas jet. The detection limits for an active pharmaceutical ingredient (acetaminophen) using the IR-LAMICI source is calculated to be low picograms. Furthermore, three-dimensional computational fluid dynamic simulations showed improvements in the IR-LAMICI ion source are possible.

11.
Analyst ; 135(4): 712-9, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20309445

RESUMO

Transmission-mode direct analysis in real time (TM-DART) is presented as an alternative sampling strategy to traditional methods of sample introduction for DART MS analysis. A custom-designed sample holder was fabricated to rapidly and reproducibly position insecticide-treated nets normal to the ionizing metastable gas stream, enabling transmission of desorbed analyte ions through the holder cavity and into the MS. Introduction of the sample at this fixed geometry eliminates the need for optimizing sample position and allows spectra based on factors such as metastable gas temperature and flow to be systematically evaluated. The results presented here, supported by computational fluid dynamic simulations, demonstrate the effects of these factors on the resulting mass spectra and the potential of this sampling strategy to be used for qualitative and quantitative analyses. Transmission-mode desorption electrospray ionization (TM-DESI) experiments on similar insecticide-treated nets were performed for comparison purposes.


Assuntos
Mosquiteiros Tratados com Inseticida , Malária/prevenção & controle , Espectrometria de Massas por Ionização por Electrospray/métodos , Inseticidas/análise , Inseticidas/química , Nitrilas/análise , Nitrilas/química , Permetrina/análise , Permetrina/química , Piretrinas/análise , Piretrinas/química , Espectrometria de Massas por Ionização por Electrospray/instrumentação
13.
Anal Chem ; 81(1): 322-9, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19117459

RESUMO

Since its inception, Direct Analysis in Real Time (DART) has seen utility in a wide range of applications including chemical reaction monitoring, pharmaceutical screening, and forensic mass spectrometry. Despite the growing interest in DART applications, there has been limited research into the fundamental physiochemical phenomena affecting sampling, ionization, and atmospheric ion transport. Presented here are the first experimentally validated finite element method simulations of an ambient DART-type metastable-induced chemical ionization source. It was found that complex coupled fluid dynamics, heat transfer, and electrostatic phenomena within the sampling region determine the variability in ion transmission efficiencies affecting the overall sensitivity of analysis. Particle tracing plots of a circular acetaminophen tablet placed in various positions and orientations yielded insight into optimal sample placement and evidence for sweet spots conducive to better ion transport. Experiments in a wide range of electric field conditions were performed, finding that under optimum sample placement, sensitivity could be improved by as much as 128% if ion mobility contributions were minimized.

14.
Anal Chem ; 81(12): 4803-12, 2009 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-19453162

RESUMO

During the past decade, there has been a marked increase in the number of reported cases involving counterfeit medicines in developing and developed countries. Particularly, artesunate-based antimalarial drugs have been targeted, because of their high demand and cost. Counterfeit antimalarials can cause death and can contribute to the growing problem of drug resistance, particularly in southeast Asia. In this study, the complementarity of two-dimensional diffusion-ordered (1)H nuclear magnetic resonance spectroscopy (2D DOSY (1)H NMR) with direct analysis in real-time mass spectrometry (DART MS) and desorption electrospray ionization mass spectrometry (DESI MS) was assessed for pharmaceutical forensic purposes. Fourteen different artesunate tablets, representative of what can be purchased from informal sources in southeast Asia, were investigated with these techniques. The expected active pharmaceutical ingredient was detected in only five formulations via both nuclear magnetic resonance (NMR) and mass spectrometry (MS) methods. Common organic excipients such as sucrose, lactose, stearate, dextrin, and starch were also detected. The graphical representation of DOSY (1)H NMR results proved very useful for establishing similarities among groups of samples, enabling counterfeit drug "chemotyping". In addition to bulk- and surface-average analyses, spatially resolved information on the surface composition of counterfeit and genuine antimalarial formulations was obtained using DESI MS that was performed in the imaging mode, which enabled one to visualize the homogeneity of both genuine and counterfeit drug samples. Overall, this study suggests that 2D DOSY (1)H NMR, combined with ambient MS, comprises a powerful suite of instrumental analysis methodologies for the integral characterization of counterfeit antimalarials.


Assuntos
Antimaláricos/análise , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Composição de Medicamentos , Espectroscopia de Ressonância Magnética/instrumentação , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Comprimidos/química
15.
Analyst ; 133(10): 1297-301, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18810277

RESUMO

Ambient ionization techniques enable the interrogation of a variety of samples in their native state by mass spectrometry, and are rapidly advancing all fields where screening for the presence of various analytes in a broadband and/or high-throughput fashion is desirable. This Highlight article provides an introduction to the field, and showcases the different ionization approaches reported since 2004, with an emphasis on the most recent developments.

17.
EuPA Open Proteom ; 4: 87-100, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25414814

RESUMO

Although physicochemical fractionation techniques play a crucial role in the analysis of complex mixtures, they are not necessarily the best solution to separate specific molecular classes, such as lipids and peptides. Any physical fractionation step such as, for example, those based on liquid chromatography, will introduce its own variation and noise. In this paper we investigate to what extent the high sensitivity and resolution of contemporary mass spectrometers offers viable opportunities for computational separation of signals in full scan spectra. We introduce an automatic method that can discriminate peptide from lipid peaks in full scan mass spectra, based on their isotopic properties. We systematically evaluate which features maximally contribute to a peptide versus lipid classification. The selected features are subsequently used to build a random forest classifier that enables almost perfect separation between lipid and peptide signals without requiring ion fragmentation and classical tandem MS-based identification approaches. The classifier is trained on in silico data, but is also capable of discriminating signals in real world experiments. We evaluate the influence of typical data inaccuracies of common classes of mass spectrometry instruments on the optimal set of discriminant features. Finally, the method is successfully extended towards the classification of individual lipid classes from full scan mass spectral features, based on input data defined by the Lipid Maps Consortium.

18.
J Am Soc Mass Spectrom ; 23(1): 153-61, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22045544

RESUMO

Presented here are findings describing the spatial-dependence of sensitivity and ion suppression effects observed with direct analysis in real time (DART). Continuous liquid infusion of dimethyl methyl phosphonate (DMMP) revealed that ion yield "hot spots" did not always correspond with the highest temperature regions within the ionization space. For instance, at lower concentrations (50 and 100 µM), the highest sensitivities were in the middle of the ionization region at 200 °C where there was a shorter ion transport distance, and the heat available to thermally desorb neutrals was moderate. Conversely, at higher DMMP concentrations (500 µM), the highest ion yield was directly in front of the DART source at 200 °C where it was exposed to the highest temperature for thermal desorption. In matching experiments, differential analyte volatility was observed to play a smaller role in relative ion suppression than differences in proton affinity and the relative sampling positions of analytes. At equimolar concentrations sampled at the same position, suppression was as high as 26× between isoquinoline (proton affinity 952 kJ mol(-1), boiling point 242 °C) and p-anisidine (proton affinity 900 kJ mol(-1), boiling point 243 °C). This effect was exacerbated when sampling positions of the two analytes differed, reaching levels of relative suppression as high as 4543.0× ± 1406.0. To mitigate this level of relative ion suppression, sampling positions and molar ratios of the analytes were modified to create conditions in which ion suppression was negligible.


Assuntos
Substâncias para a Guerra Química/química , Espectrometria de Massas/métodos , Compostos de Anilina/química , Temperatura Alta , Íons/química , Isoquinolinas/química , Compostos Organofosforados/química , Sensibilidade e Especificidade
19.
J Immigr Minor Health ; 13(6): 1183-6, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20890659

RESUMO

This study documented the types and quality of sexual health medications obtained by immigrant Latinos from non-medical sources. Samples of the medications were purchased from non-medical sources in the rural Southeast by trained native Spanish-speaking "buyers". Medications were screened the presence of active pharmaceutical ingredients using mass spectrometry. Eleven medications were purchased from tiendas and community members. Six were suggested to treat sexually transmitted diseases, one was to treat sexual dysfunction, one was to prevent pregnancy, and two were to assist in male-to-female transgender transition or maintenance. All medications contained the stated active ingredients. Findings suggest that medications are available from non-medical sources and may not be used as indicated. Interventions that target immigrant Latinos within their communities and rely on existing structures may be effective in reducing barriers to medical and healthcare services and increasing the proper use of medications to reduce potential harm.


Assuntos
Comércio , Emigrantes e Imigrantes/educação , Acessibilidade aos Serviços de Saúde , Preparações Farmacêuticas/provisão & distribuição , Saúde Reprodutiva , Informação de Saúde ao Consumidor , Feminino , Humanos , Masculino , População Rural , Sudeste dos Estados Unidos
20.
J Am Soc Mass Spectrom ; 21(5): 855-63, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20181493

RESUMO

The internal energy (E(int)) distributions of a series of p-substituted benzylpyridinium ions generated by both direct analysis in real time (DART) and electrospray ionization (ESI) were compared using the "survival yield" method. DART mean E(int) values at gas flow rates of 2, 4, and 6 L min(-1), and at set temperatures of 175, 250, and 325 degrees C were in the 1.92-2.21 eV range. ESI mean E(int) at identical temperatures in aqueous and 50% methanol solutions ranged between 1.71 and 1.96 eV, and 1.53 and 1.63 eV, respectively. Although the results indicated that ESI is a "softer" ionization technique than DART, there was overlap between the two techniques for the particular time-of-flight mass spectrometer used. As a whole, there was an increase in E(int) with increasing reactive and drying gas temperatures for DART and ESI, respectively, indicating thermal ion activation. Three dimensional computational fluid dynamic simulations in combination with direct temperature measurements within the DART ionization region revealed complex inversely coupled fluid-thermal phenomena affecting ion E(int) values during atmospheric transport. Primarily, that DART gas temperature in the ionization region was appreciably less than the set gas temperature of DART due to the set gas flow rates. There was no evidence of E(int) deposition pathways from metastable-stimulated desorption, but fragmentation induced by high-energy helium metastables was observed at the highest gas flow rates and temperatures.

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