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Thèses sur le sujet « Targeted and untargeted metabolomics »

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Auteur : Grafiati
Publié le 10 mars 2023

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1

Cichon, Morgan Julienne. « Investigating the Role of Tomato Phytochemicals through Targeted and Untargeted Metabolomics ». The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449226913.

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2

Yang, Kundi. « Assessing and Evaluating Biomarkers and Chemical Markers by Targeted and Untargeted Mass Spectrometry-based Metabolomics ». Miami University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=miami1605044640528563.

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Zhong, Fanyi. « DEVELOPMENT AND APPLICATIONS OF HPLC-MS/MS BASED METABOLOMICS ». Miami University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=miami1524792637748877.

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Tamimi, Sara <1987&gt. « Metabolomics investigations towards formulated natural complex products by untargeted and targeted mass spectrometry-based approaches ». Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amsdottorato.unibo.it/8559/1/Tamimi_Sara_tesi.pdf.

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Although the last decade has witnessed a marked growth in the market of plant-based natural products, their high complexity in terms of composition makes a challenging task the guarantee of quality, efficacy and safety requirements. In such scenario, the recently approved European regulation EU 2017/745 has created a breaking point in the regulation of medical devices forcing the manufactures to investigate the overall qualitative composition of devices made of substances and quantitative information for the main constituents or for the components responsible for the desired effect. In view of this stricter standardization of plant-based medical devices, an intense research towards advanced technologies and robust analytical protocols is required. Based on these considerations, Grintuss® syrup was selected as a case study of formulated natural complex products for quali-quantitative metabolomics investigations. In particular, in the first part, an untargeted metabolomic approach for monitoring the batch-quality of Grintuss® syrup by electrospray ionization mass spectrometry flow injection analysis was developed. After having assessed the validity of the model by using multivariate statistical process control, the quality verification of new batches under investigation was achieved by comparing their profile with the fingerprinting profile of batches prepared according to the optimized and validated manufacturing process. The second task was aimed at profiling the metabolites contained in Grintuss® syrup by applying a targeted metabolomic LC-MS-based approach. Thus, an in-house database of high-purity standard reference compounds was built. Then, after the acquisition of MS/MS spectra of standard compounds of interest, the matching between the detected metabolites from samples and standard reference compounds from the database was assessed. Finally, the quantitative analysis of the recognized metabolites was performed and the results thus achieved have been combined with information deriving from the analysis of additional compounds allowing to reach the knowledge of >99.9% of the overall composition of Grintuss® syrup.
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Torres, Gené Sònia. « Advances on thirdhand smoke using targeted and untargeted approaches ». Doctoral thesis, Universitat Rovira i Virgili, 2021. http://hdl.handle.net/10803/672209.

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El fum de tabac residual (thirdhand smoke en anglès, THS) és una via d'exposició a compostos tòxics de fum tabac poc estudiada fins ara. El THS es produeix per la deposició de parEcules i gasos en superFcies i pols, on es poden reemetre i/o reaccionar produint nous compostos tòxics, alguns d'ells carcinògens. Malgrat les creixents evidències, els riscos inherents a l'exposició a THS encara no s'han descrit completament. L'objecKu principal d'aquesta tesi és avançar en la caracterització química del THS i dels efectes per a la salut derivats d'aquesta exposició mitjançant l'aplicació de mètodes analíKcs dirigits i no dirigits. Aquesta tesi presenta el desenvolupament de un nou mètode analíKc per determinar simultàniament tòxics del tabac en pols domèsKca, mitjançant cromatografia líquida (UHPLC). En aquesta tesi, també s'ha desenvolupat un mètode d'anàlisi no dirigit basat en l'adquisició de mostres per UHPLC acoblada a espectrometria de masses d'alta resolució (HR-MS), amb l'aplicació d'estratègies avançades de processament de dades, la priorització estadísKca d’ions rellevants i una nova estratègia per a l'anotació de compostos. La combinació d'aquests dos mètodes va proporcionar per primera vegada l'anotació de dotzenes de tòxics relacionats amb la contaminació per THS adherits a la pols domèsKca. Pel que fa als efectes sobre la salut, presentem el primer estudi metabolòmic no dirigit en fetge de ratolins exposats a THS. L'aplicació de les tècniques UHPLC-HRMS i ressonància magnèKca nuclear (RMN) va permetre idenKficar dotzenes de metabòlits hepàKcs alterats, mentre que les imatges d'espectrometria de masses (MSI) van mostrar la distribució espacial diferencial de lípids en fetge induïda per THS. Aquests resultats confirmen els perills de l'exposició a THS i el paper clau de la introducció de noves estratègies metodològiques en la invesKgació en salut ambiental.
El humo de tabaco residual (thirdhand smoke en inglés, THS) es una vía de exposición a compuestos tóxicos del humo del tabaco poco estudiada hasta la fecha. El THS se produce por la deposición de parBculas y gases en superficies y polvo, dónde se pueden reemiEr y/o reaccionar produciendo nuevos compuestos tóxicos, algunos de ellos carcinógenos. A pesar de las crecientes evidencias, los riesgos inherentes a la exposición a THS aún no se han descrito por completo. El objeEvo principal de esta tesis es avanzar en la caracterización química del THS y de los efectos para la salud derivados de esta exposición mediante la aplicación de métodos analíEcos dirigidos y no dirigidos. Esta tesis presenta el desarrollo de un nuevo método analíEco para determinar simultáneamente tóxicos del tabaco en polvo domésEco mediante cromatograMa líquida (UHPLC). En esta tesis, también se ha desarrollado un método de análisis no dirigido basado en la adquisición de muestras por UHPLC acoplada a espectrometría de masas de alta resolución (HR-MS), con la aplicación de estrategias avanzadas de procesamiento de datos, la priorización estadísEca de iones relevantes y una nueva estrategia para la anotación de compuestos. La combinación de estos dos métodos proporcionó por primera vez la anotación de docenas de tóxicos relacionados con la contaminación por THS adheridos al polvo domésEco.Respecto a los efectos sobre la salud, presentamos el primer estudio metabolómico no dirigido en hígado de ratones expuestos a THS. La aplicación de las técnicas UHPLC-HRMS y resonancia magnéEca nuclear (RMN) permiEó idenEficar docenas de metabolitos hepáEcos alterados, mientras que las imágenes de espectrometría de masas (MSI) mostraron la distribución espacial diferencial de lípidos en hígado inducida por THS. Estos resultados confirman los peligros de la exposición a THS y el papel clave de nuevos enfoques metodológicos en la invesEgación en salud ambiental.
Thirdhand tobacco smoke (THS) is a novel and poorly understood pathway of tobacco exposure produced by the deposi=on and ageing of tobacco smoke par=cles and toxicants in surfaces and dust. This aged tobacco smoke could reemit into the air or react with other atmospheric chemicals to yield new toxicants, including carcinogens and becoming increasingly toxic with age. Although growing evidences of THS hazards, its chemical characteriza=on and the related health effects remain to be fully elucidated. Hence, this thesis aims to advance on the current knowledge on THS chemical characteriza=on and on the health effects derived from THS exposure by applying novel targeted and untargeted approaches. To advance on THS chemical characteriza=on, we have developed an efficient, quick and robust analy=cal method for simultaneously determining tobacco-specific compounds in household dust by ultra-highperformance liquid-chromatography coupled to tandem mass spectrometry (UHPLC-MSMS). We applied this target method in combina=on with untargeted strategies for a comprehensive characteriza=on of THS toxicants aNached to household dust. The developed untargeted workflow combines the sample acquisi=on by UHPLC coupled to high-resolu=on mass spectrometry (HR-MS) with the applica=on of advanced data processing strategies, the sta=s=cal priori=za=on of relevant features and a novel strategy for compound annota=on. The combina=on of these two approaches provided for the first =me the annota=on of dozens of toxicants related to THS contamina=on. To advance on the health effects, this thesis presents the first mul=plaQorm untargeted metabolomics study to unravel the molecular altera=ons of liver from mice exposed to THS. UHPLC-HRMS and nuclear magne=c resonance (NMR) revealed dozens of hepa=c metabolites altered in THS-exposed mice whilst mass spectrometry imaging (MSI) showed the differen=al spa=al distribu=on of lipids induced by THS. The results presented here confirm the hazards of THS exposure and the key role of combined untargeted and targeted methods in environmental health research.
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POLONIATO, GABRIELE. « Approccio metabolomico untargeted e targeted per lo studio della sepsi neonatale ». Doctoral thesis, Università degli studi di Padova, 2022. https://hdl.handle.net/11577/3464351.

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La sepsi è una delle principali problematiche in ambito neonatologico. La sepsi neonatale è una sindrome da risposta infiammatoria sistemica indotta da infezione comune nei neonati prematuri e a termine. È una delle principali cause di morte e morbilità neonatale e si ritiene che abbia un ruolo chiave nella maggior parte dei disturbi infiammatori che causano o contribuiscono allo sviluppo delle principali morbilità che colpiscono il prematuro (displasia broncopolmonare, danno della sostanza bianca cerebrale, enterocolite necrotizzante e retinopatia del prematuro). La sepsi nel neonato è solitamente classificata come sepsi ad esordio precoce (EOS), quando l'infezione si manifesta entro tre giorni dalla nascita, o sepsi ad esordio tardivo (LOS) se si sviluppa in seguito. La diagnosi precoce della sepsi neonatale e la pronta somministrazione di una terapia antibiotica ad ampio spettro possono prevenirne il decorso clinico verso lo shock settico e la morte, ma non è facile diagnosticare precocemente la sepsi neonatale. L'emocoltura è ancora considerata il gold standard, anche se ci vuole tempo per ottenere i risultati e i falsi negativi non sono rari perché la batteriemia neonatale è spesso intermittente e il trattamento antibiotico intrapartum può limitare il valore diagnostico della coltura. La sepsi neonatale viene quindi ipotizzata principalmente sulla base di segni e sintomi clinici non specifici; per di più, nessuno dei biomarcatori più utilizzati è un indicatore del tutto affidabile di sepsi nei neonati. Pertanto, l'identificazione di nuovi biomarcatori per EOS è di cruciale importanza. Inoltre, mentre le terapie di supporto promuovono la sopravvivenza dei neonati settici, non esistono terapie per alterare la fisiopatologia sottostante, e ciò è in parte dovuto alla parziale conoscenza delle complesse vie biologiche alla base della fisiopatologia della sepsi. Lo scopo dello studio era confrontare i profili metabolici di campioni di plasma e urina raccolti alla nascita da neonati pretermine con e senza sepsi ad esordio precoce (EOS) per identificare le perturbazioni metaboliche che potrebbero orientare la ricerca di nuovi biomarcatori precoci. Tutti i neonati prematuri ammessi all'unità di terapia intensiva neonatale erano eleggibili per questo studio prospettico caso-controllo. I neonati sono stati arruolati come "casi" se hanno sviluppato EOS e come "controlli" in caso contrario. I campioni di plasma raccolti alla nascita e i campioni di urina raccolti entro 24 ore dalla nascita sono stati sottoposti ad analisi metabolomica targeted e untargeted tramite spettrometria di massa accoppiata a cromatografia liquida UPLC. Sono state poi applicate analisi statistiche univariate e multivariate. Di 123 neonati idonei, 15 hanno sviluppato EOS. Questi 15 neonati corrispondevano ai controlli per età gestazionale e peso. L'analisi UPLC-MS dei campioni di urina ha rivelato un cluster di casi di EOS rispetto ai neonati sani. Inoltre, esiste una differenza metabolica per distinguere i neonati che sviluppano sepsi dai soggetti sani e sono stati scoperti marcatori putativi che discriminano tra casi di EOS e controlli. L'analisi dei pathways ha evidenziato gli squilibri metabolici maggiormente coinvolti in caso di EOS. Le vie metaboliche più significative sono state studiate utilizzando un'analisi targetd su campioni di plasma prelevati dagli stessi neonati, confermando l’evidente perturbazione delle vie metaboliche del triptofano e del glutatione nei neonati con EOS. In conclusione, i neonati con EOS presentavano un profilo metabolico alla nascita che li distingueva chiaramente da quelli senza sepsi, e i metaboliti delle vie del glutatione e del triptofano sono promettenti come nuovi biomarcatori della sepsi neonatale.
Sepsis is a major concern in neonatology. Neonatal sepsis is an infection-induced, systemic inflammatory response syndrome common in premature and term neonates. It is one of the leading causes of neonatal death and morbidity and is believed to have a key role in most inflammatory disorders that cause or enhance the main morbidities affecting the preterm (bronchopulmonary dysplasia, white matter injury, necrotizing enterocolitis, and retinopathy of prematurity). Sepsis in the newborn is typically classified as either early-onset sepsis (EOS), when the infection occurs within three days after birth, or late-onset sepsis (LOS) if it develops afterward. Early detection of neonatal sepsis and prompt administration of broad-spectrum antibiotic therapy can prevent its clinical course towards septic shock and death, but it is not easy to diagnose neonatal sepsis early on. Blood culture is still considered the gold standard, even though it takes time to obtain the results, and false-negative findings are not uncommon because neonatal bacteremia is often intermittent, and intrapartum antibiotic treatment may limit the culture’s diagnostic value. Neonatal sepsis is therefore mainly suspected on the grounds of non-specific clinical signs and symptoms; moreover, none of the most widely used biomarkers are entirely reliable indicators of sepsis in newborns. Hence, identifying new biomarkers for EOS is of crucial importance. Furthermore, while supportive therapies promote the survival of septic neonates, there are no mechanistic therapies to alter the underlying pathophysiology, and this is partly due to partial knowledge of the complex biological pathways underlying the pathophysiology of sepsis. The aim of the study was to compare the metabolic profiles of plasma and urine samples collected at birth from preterm neonates with and without early-onset sepsis (EOS) to identify metabolic perturbations that might orient the search for new early biomarkers. All preterm newborns admitted to the neonatal intensive care unit were eligible for this proof-of-concept, prospective case-control study. Infants were enrolled as “cases” if they developed EOS, and as “controls” if they did not. Plasma samples collected at birth and urine samples collected within 24 h of birth underwent untargeted and targeted metabolomic analysis using mass spectrometry coupled with ultra-performance liquid chromatography. Univariate and multivariate statistical analyses were applied. Of 123 eligible newborns, 15 developed EOS. These 15 newborns matched controls for gestational age and weight. UPLC–MS analysis of urine samples revealed a clustering of cases of EOS compared with healthy neonates. Furthermore, a metabolic signature exists to distinguish neonates that develop sepsis and healthy subjects and putative markers discriminating between EOS cases and controls were discovered. Pathway analysis showed metabolic derangements most involved in EOS. The most significant metabolic pathways were investigated using a targeted analysis on plasma samples collected from the same neonates, confirming the marked disruption of the tryptophan and glutathione metabolic pathways in the neonates with EOS. In conclusion, neonates with EOS had a metabolic profile at birth that clearly distinguished them from those without sepsis, and metabolites of glutathione and tryptophan pathways are promising as new biomarkers of neonatal sepsis.
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Abily-Donval, Lénaïg. « Exploration des mécanismes physiopathologiques des mucopolysacharidoses et de la maladie de Fabry par approches "omiques" et modulation de l'autophagie. Urinary metabolic phenotyping of mucopolysaccharidosis type I combining untargeted and targeted strategies with data modeling Unveiling metabolic remodeling in mucopolysaccharidosis type III through integrative metabolomics and pathway analysis ». Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR108.

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Les pathologies lysosomales sont des maladies liées au déficit quantitatif ou qualitatif d’une hydrolase ou d’un transporteur à l’origine d’une atteinte multiviscérale potentiellement sévère. Certaines de ces pathologies sont accessibles à des traitements mais ces thérapeutiques sont uniquement symptomatiques et ne guérissent pas les patients. Même si le phénomène de surcharge peut expliquer entre autres la symptomatologie observée, la physiopathologie de ces maladies est complexe et non précisément connue. Une meilleure connaissance de ces pathologies pourrait permettre d’améliorer leur prise en charge globale. L’objectif de ce travail était dans un premier temps d’appliquer des techniques « omiques » dans deux groupes de maladies : les mucopolysaccharidoses et la maladie de Fabry. Cette étude a permis la mise en place d’une méthodologie métabolomique non ciblée basée sur une stratégie analytique multidimensionnelle comportant la spectrométrie de masse à haute résolution couplée à la chromatographie liquide ultra-haute performance et la mobilité ionique. Dans les mucopolysaccharidoses, l’étude des voies métaboliques a mis en évidence des modifications dans le métabolisme de plusieurs acides aminés et du système oxydatif du glutathion. Dans la maladie de Fabry, des modifications ont été observées dans l’expression de l’interleukine 7 et du facteur de croissance FGF2. La deuxième partie du travail s’est intéressée à la modulation de l’autophagie dans la maladie de Fabry. Notre étude a montré une diminution du flux autophagique avec un retard d’adressage de l’enzyme au lysosome dans les cellules Fabry. L’inhibition de l’autophagie permet de diminuer l’accumulation du substrat accumulé (Gb3) et améliore l’efficacité de l’enzymothérapie substitutive. En conclusion ce travail a permis une meilleure compréhension des mécanismes physiopathologiques des pathologies lysosomales et a montré la complexité du fonctionnement du lysosome. Ces données permettent d’espérer l’amélioration des stratégies thérapeutiques et diagnostiques dans ces maladies
Lysosomal diseases caused by quantitative or qualitative hydrolase or transporter defect induce multiorgan features. Some specific symptomatic treatments are available but they do not cure patients. Pathophysiological bases of lysosomal disease are poorly understood and cannot be due to storage only. A better knowledge of these pathologies could improve their management. The first aim of this study was to apply “omics” strategies in mucopolysaccharidosis and in Fabry disease. This thesis allowed the implementation of an untargeted metabolomic methodology based on a multidimensional analytical strategy including high-resolution mass spectrometry coupled with ultra-high-performance liquid chromatography and ion mobility. Analysis of metabolic pathways showed a major remodeling of the amino acid metabolisms as well as oxidative stress via glutathione metabolism. In Fabry disease, changes were observed in expression of interleukin 7 and FGF2. The second study focused on modulation of autophagy in Fabry disease. In this work, we have shown a disruption of the autophagic process and a delay in enzyme targeting to the lysosome in Fabry disease. Autophagic inhibition reduced accumulation of accumulated substrate (Gb3) and improved the efficiency of enzyme replacement therapy. This work allowed a better knowledge of the physiopathological mechanisms implicated in lysosomal diseases and showed the complexity of lysosome. These data could ameliorate management of these disease and are associated with hope for patients
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Jones, Christina Michele. « Applications and challenges in mass spectrometry-based untargeted metabolomics ». Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/54830.

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Metabolomics is the methodical scientific study of biochemical processes associated with the metabolome—which comprises the entire collection of metabolites in any biological entity. Metabolome changes occur as a result of modifications in the genome and proteome, and are, therefore, directly related to cellular phenotype. Thus, metabolomic analysis is capable of providing a snapshot of cellular physiology. Untargeted metabolomics is an impartial, all-inclusive approach for detecting as many metabolites as possible without a priori knowledge of their identity. Hence, it is a valuable exploratory tool capable of providing extensive chemical information for discovery and hypothesis-generation regarding biochemical processes. A history of metabolomics and advances in the field corresponding to improved analytical technologies are described in Chapter 1 of this dissertation. Additionally, Chapter 1 introduces the analytical workflows involved in untargeted metabolomics research to provide a foundation for Chapters 2 – 5. Part I of this dissertation which encompasses Chapters 2 – 3 describes the utilization of mass spectrometry (MS)-based untargeted metabolomic analysis to acquire new insight into cancer detection. There is a knowledge deficit regarding the biochemical processes of the origin and proliferative molecular mechanisms of many types of cancer which has also led to a shortage of sensitive and specific biomarkers. Chapter 2 describes the development of an in vitro diagnostic multivariate index assay (IVDMIA) for prostate cancer (PCa) prediction based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS) metabolic profiling of blood serum samples from 64 PCa patients and 50 healthy individuals. A panel of 40 metabolic spectral features was found to be differential with 92.1% sensitivity, 94.3% specificity, and 93.0% accuracy. The performance of the IVDMIA was higher than the prevalent prostate-specific antigen blood test, thus, highlighting that a combination of multiple discriminant features yields higher predictive power for PCa detection than the univariate analysis of a single marker. Chapter 3 describes two approaches that were taken to investigate metabolic patterns for early detection of ovarian cancer (OC). First, Dicer-Pten double knockout (DKO) mice that phenocopy many of the features of metastatic high-grade serous carcinoma (HGSC) observed in women were studied. Using UPLC-MS, serum samples from 14 early-stage tumor DKO mice and 11 controls were analyzed. Iterative multivariate classification selected 18 metabolites that, when considered as a panel, yielded 100% accuracy, sensitivity, and specificity for early-stage HGSC detection. In the second approach, serum metabolic phenotypes of an early-stage OC pilot patient cohort were characterized. Serum samples were collected from 24 early-stage OC patients and 40 healthy women, and subsequently analyzed using UPLC-MS. Multivariate statistical analysis employing support vector machine learning methods and recursive feature elimination selected a panel of metabolites that differentiated between age-matched samples with 100% cross-validated accuracy, sensitivity, and specificity. This small pilot study demonstrated that metabolic phenotypes may be useful for detecting early-stage OC and, thus, supports conducting larger, more comprehensive studies. Many challenges exist in the field of untargeted metabolomics. Part II of this dissertation which encompasses Chapters 4 – 5 focuses on two specific challenges. While metabolomic data may be used to generate hypothesis concerning biological processes, determining causal relationships within metabolic networks with only metabolomic data is impractical. Proteins play major roles in these networks; therefore, pairing metabolomic information with that acquired from proteomics gives a more comprehensive snapshot of perturbations to metabolic pathways. Chapter 4 describes the integration of MS- and NMR-based metabolomics with proteomics analyses to investigate the role of chemically mediated ecological interactions between Karenia brevis and two diatom competitors, Asterionellopsis glacialis and Thalassiosira pseudonana. This integrated systems biology approach showed that K. brevis allelopathy distinctively perturbed the metabolisms of these two competitors. A. glacialis had a more robust metabolic response to K. brevis allelopathy which may be a result of its repeated exposure to K. brevis blooms in the Gulf of Mexico. However, K. brevis allelopathy disrupted energy metabolism and obstructed cellular protection mechanisms including altering cell membrane components, inhibiting osmoregulation, and increasing oxidative stress in T. pseudonana. This work represents the first instance of metabolites and proteins measured simultaneously to understand the effects of allelopathy or in fact any form of competition. Chromatography is traditionally coupled to MS for untargeted metabolomics studies. While coupling chromatography to MS greatly enhances metabolome analysis due to the orthogonality of the techniques, the lengthy analysis times pose challenges for large metabolomics studies. Consequently, there is still a need for developing higher throughput MS approaches. A rapid metabolic fingerprinting method that utilizes a new transmission mode direct analysis in real time (TM-DART) ambient sampling technique is presented in Chapter 5. The optimization of TM-DART parameters directly affecting metabolite desorption and ionization, such as sample position and ionizing gas desorption temperature, was critical in achieving high sensitivity and detecting a broad mass range of metabolites. In terms of reproducibility, TM-DART compared favorably with traditional probe mode DART analysis, with coefficients of variation as low as 16%. TM-DART MS proved to be a powerful analytical technique for rapid metabolome analysis of human blood sera and was adapted for exhaled breath condensate (EBC) analysis. To determine the feasibility of utilizing TM-DART for metabolomics investigations, TM-DART was interfaced with traveling wave ion mobility spectrometry (TWIMS) time-of-flight (TOF) MS for the analysis of EBC samples from cystic fibrosis patients and healthy controls. TM-DART-TWIMS-TOF MS was able to successfully detect cystic fibrosis in this small sample cohort, thereby, demonstrating it can be employed for probing metabolome changes. Finally, in Chapter 6, a perspective on the presented work is provided along with goals on which future studies may focus.
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Miller, Jenna Lauren. « Discovering potential urinary biomarkers of tomato consumption using untargeted metabolomics ». The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594632758364348.

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Mendez, Kevin Milton. « Untargeted metabolomics of childhood asthma exacerbations from retrospectively collected serum samples ». Thesis, Mendez, Kevin Milton (2017) Untargeted metabolomics of childhood asthma exacerbations from retrospectively collected serum samples. Honours thesis, Murdoch University, 2017. https://researchrepository.murdoch.edu.au/id/eprint/40063/.

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Asthma is a common chronic inflammatory disease of the airways, affecting 360 million people globally. It is characterised by chronic inflammation, recurrent episodes of bronchoconstriction and mucosal hypersecretion. Symptoms include chest tightness, shortness of breath, coughing and wheezing. Oral corticosteroids used for the treatment of asthma have adverse effects, including bone mineralisation and adrenal suppression. Not all children with acute asthma-like symptoms will have persistent asthma in the future. This is particularly common at a pre-school age. This persistence is only known retrospectively. Identifying children early in their disease course can better direct treatment. Additionally, further understanding of the underlying disease mechanisms can direct novel therapies. Metabolomics is the systematic study of metabolites in a biological system. Metabolites are low molecular weight biochemical that are reactants, intermediates and end products of biological reactions. They are highly sensitive and are a snapshot of a particular biochemistry and/or pathophysiology. However, they are also highly sensitive to analytical variation. Thus, there were three aims in this study: to assess the impact of potentially limiting factors of retrospectively collected serum samples on metabolomic analysis; to determine whether metabolomics can identify potential biomarkers to distinguish wheeze/asthma exacerbation and control groups; and to determine whether metabolomics-derived biomarkers can identify differences between preschool-aged and school-aged phenotypes. Serum samples were curated from the Mechanisms of Acute Viral Respiratory Infections in Children (MAVRIC) study. This cohort study recruited children upon presentation to the emergency department at Princess Margaret Hospital with acute lower respiratory illnesses including wheeze/asthma. One–hundred and sixty-one samples were from children with acute wheeze/asthma, and 51 were from healthy controls. Samples were previously stored between 0.8 to 7.9 years at −80 °C. Samples were extracted, derivatised and subsequently analysed using GC-QTOF-MS. SpectralWorks’ AnalyzerPro® was used for the deconvolution and untargeted processing of the metabolite data. The quality control-robust spline correction (QC-RSC) algorithm was used for inter- and intra- batch correction. Putative identification of metabolites was made using the NIST (v2.0) library. Fifty-two metabolites were included in the data analysis, with 24 putatively identified metabolites. The effects of storage time on metabolites were determined via Spearman’s correlation. There was a significant difference (p-value < 0.05) in metabolite abundances for succinate, serine and tryptophan; however, the correlation was weak. A two-way Analysis of Variance was performed to compare acute wheeze/asthma vs. healthy, pre-school vs. school age and the associated interactions. Twenty-nine metabolites were found to be significantly different (p-value < 0.05) between the acute wheeze/asthma and the control group. The sub-classes of metabolites include amino acids, fatty acids and sugars. Principal Component Analysis showed a difference in spread between the acute wheeze/asthma and control group. However, there was no clear difference between preschool and school-aged brackets for each group. Arabinofuranose and creatinine were significantly different (p-value < 0.05) between pre-school and school-aged subjects with acute wheeze/asthma. Creatinine is potentially being indicative of higher ASM stress and damage in the school-aged subjects with acute wheeze/asthma.
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Mitchell, Joshua Merritt. « Computational Tools for the Untargeted Assignment of FT-MS Metabolomics Datasets ». UKnowledge, 2019. https://uknowledge.uky.edu/biochem_etds/42.

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Metabolomics is the study of metabolomes, the sets of metabolites observed in living systems. Metabolism interconverts these metabolites to provide the molecules and energy necessary for life processes. Many disease processes, including cancer, have a significant metabolic component that manifests as differences in what metabolites are present and in what quantities they are produced and utilized. Thus, using metabolomics, differences between metabolomes in disease and non-disease states can be detected and these differences improve our understanding of disease processes at the molecular level. Despite the potential benefits of metabolomics, the comprehensive investigation of metabolomes remains difficult. A popular analytical technique for metabolomics is mass spectrometry. Advances in Fourier transform mass spectrometry (FT-MS) instrumentation have yielded simultaneous improvements in mass resolution, mass accuracy, and detection sensitivity. In the metabolomics field, these advantages permit more complicated, but more informative experimental designs such as the use of multiple isotope-labeled precursors in stable isotope-resolved metabolomics (SIRM) experiments. However, despite these potential applications, several outstanding problems hamper the use of FT-MS for metabolomics studies. First, artifacts and data quality problems in FT-MS spectra can confound downstream data analyses, confuse machine learning models, and complicate the robust detection and assignment of metabolite features. Second, the assignment of observed spectral features to metabolites remains difficult. Existing targeted approaches for assignment often employ databases of known metabolites; however, metabolite databases are incomplete, thus limiting or biasing assignment results. Additionally, FT-MS provides limited structural information for observed metabolites, which complicates the determination of metabolite class (e.g. lipid, sugar, etc. ) for observed metabolite spectral features, a necessary step for many metabolomics experiments. To address these problems, a set of tools were developed. The first tool identifies artifacts with high peak density observed in many FT-MS spectra and removes them safely. Using this tool, two previously unreported types of high peak density artifact were identified in FT-MS spectra: fuzzy sites and partial ringing. Fuzzy sites were particularly problematic as they confused and reduced the accuracy of machine learning models trained on datasets containing these artifacts. Second, a tool called SMIRFE was developed to assign isotope-resolved molecular formulas to observed spectral features in an untargeted manner without a database of expected metabolites. This new untargeted method was validated on a gold-standard dataset containing both unlabeled and 15N-labeled compounds and was able to identify 18 of 18 expected spectral features. Third, a collection of machine learning models was constructed to predict if a molecular formula corresponds to one or more lipid categories. These models accurately predict the correct one of eight lipid categories on our training dataset of known lipid and non-lipid molecular formulas with precisions and accuracies over 90% for most categories. These models were used to predict lipid categories for untargeted SMIRFE-derived assignments in a non-small cell lung cancer dataset. Subsequent differential abundance analysis revealed a sub-population of non-small cell lung cancer samples with a significantly increased abundance in sterol lipids. This finding implies a possible therapeutic role of statins in the treatment and/or prevention of non-small cell lung cancer. Collectively these tools represent a pipeline for FT-MS metabolomics datasets that is compatible with isotope labeling experiments. With these tools, more robust and untargeted metabolic analyses of disease will be possible.
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Gorityala, Shashank. « TARGETED AND UNTARGETED OMICS FOR DISEASE BIOMARKERS USING LC-MS ». Cleveland State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1547093694357568.

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Lundin, Ulrika. « Biomarker Discovery in Diabetic Nephropathy by Targeted Metabolomics ». Thesis, Linköping University, The Department of Physics, Chemistry and Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-15640.

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Diabetic nephropathy is a chronic kidney disease and one of the more severe complications from diabetes mellitus type 2. The glomerular and tubular dysfunctions usually lead to end stage renal disease and the treatments of these patients (dialysis, kidney transplants) are a huge economic burden for the society. Due to an epidemiologic increase of type 2 diabetes, conventional diagnostic markers like creatinine and albumin are not sufficient, since they are only able to identify already existing kidney damage. With targeted metabolomics, the analysis of small molecules produced from metabolism, this project aimed at finding novel and more sensitive metabolic biomarkers from several different classes of metabolites. The different assays were performed with flow injection analysis, high performance liquid chromatography, gas chromatography and mass spectrometry, and with principal component analysis and discriminant analysis, up-and down-regulated metabolites could be identified and their respective biochemical pathways, if possible, explained. In diabetics significantly elevated concentrations of very long chain fatty acids (impaired peroxisomal β-oxidation), urinary sugars and acylcarnitines in plasma could be recognized. Markers indicating kidney damage included significantly increased plasma concentrations of asymmetric dimethylarginine (inhibition of nitric oxide synthase resulting in decreased endothelial functionality) and histamine (indication of uremic pruritus). Oxidative stress was also found to be a potential prognostic marker as indicated by the raised methionine-sulfoxide to methionine ratio in nephrotic patients. To summarize, this project succeeded in identifying metabolic biomarkers both for diabetes type 2 and nephropathy, which in the future might become important tools in slowing down progression or diagnosing these diseases.

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Hellmuth, Christian. « LC-MS/MS applications in Targeted Clinical Metabolomics ». Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168254.

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Bell, Madison. « Developing Statistical and Analytical Methods for Untargeted Analysis of Complex Environmental Matrices ». Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41626.

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The main objective of this thesis was to develop statistical and analytical methods for untargeted analyses of complex environmental matrices like soil and sediment. Untargeted analyses are notoriously difficult to perform in matrices like soil and sediment because of the complexity of organic matter composition within these matrices. This thesis aimed to (1) Develop and compare extraction methods for untargeted analyses of soil and sediment while also developing data handling and quality control protocols; (2) Investigate novel applications of untargeted analyses for environmental classification and monitoring; and (3) Investigate the experimental factors that can influence the organic matter composition of untargeted extractions. CHAPTER TWO is a literature review of metabolomics protocols, and these protocols were incorporated into a proposed workflow for performing untargeted analysis in oil, soil, and sediment. This thesis contains the first application of untargeted analysis to freshwater lake sediment organic matter (i.e. sedimentomics) in CHAPTER THREE, and this has implications for discovering new biomarkers for paleolimnology (APPENDIX ONE). I demonstrated successful extraction methods for both sedimentomics and soil metabolomics studies in CHAPTER THREE and CHAPTER FIVE, respectively, using the proposed workflow from CHAPTER TWO. I also applied sedimentomics to the classification of lake sediments using machine learning and geostatistics based on sediment organic matter compositions in CHAPTER FOUR; this was a novel application of sedimentomics that could have implications for ecosystem classifications and advance our knowledge of organic matter cycling in lake sediments. Lastly, in CHAPTER FIVE I determined microbial activity, extraction method, and soil type can all influence the composition of soil organic matter extracts in soil metabolomics experiments. I also developed novel quality controls and quantitative methods that can help control these influences in CHAPTER FIVE and APPENDIX THREE. APPENDIX TWO was written in collaboration with multiple researchers and is a review of all “omics” types of analyses that can be performed on soil or sediment, and how methods like the untargeted analysis of soil and sediment organic matter can be linked with metagenomics, metatranscriptomics, and metaproteomics for a comprehensive metaphenomics analysis of soil and sediment ecosystems. In CHAPTER SIX the conclusions and implications for each chapter and overall for this thesis are detailed and I describe future directions for the field. In the end the overall conclusions of this thesis were: 1) Quality controls are necessary for sedimentomics and soil metabolomics studies, 2) Sedimentomics is a valid technique to highlight changes in sediment organic matter, 3) Soil metabolomics and sedimentomics yield more information about carbon cycling than traditional measurements, and 4) Soil metabolomics organic matter extractions are more variable and require more quality controls.
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GHISONI, SILVIA. « UNTARGETED METABOLOMIC FINGERPRINTING FOR AUTHENTICITY AND TRACEABILITY OF FOODS ». Doctoral thesis, Università Cattolica del Sacro Cuore, 2020. http://hdl.handle.net/10280/72714.

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La globalizzazione del mercato agroalimentare ha determinato una crescente attenzione da parte dei consumatori verso i prodotti alimentari, non solo in termini di qualità e di sicurezza, ma anche di origine geografica. Infatti, il territorio d’origine ha un forte impatto sull’alimento, dovuto alle condizioni pedoclimatiche che ne determinano le caratteristiche. Poiché non esistono dei metodi analitici di routine per l’autenticazione della provenienza geografica, lo scopo del progetto di ricerca è quello di determinare l’origine geografica e l’autenticità degli alimenti mediante profiling dei composti fenolici e steroli, grazie all’applicazione di tecnologie omiche, tecniche statistiche e chemometriche. La componente fenolica e/o steroli dei campioni, viene analizzata tramite cromatografia liquida (UHPLC) accoppiata ad uno spettrometro di massa (Q-TOF-MS). I dati così ottenuti, vengono elaborati mediante statistica multivariata. L’applicazione combinata di avanzate tecnologie omiche e tecniche statistiche chemometriche ha portato come risultato l’effettiva identificazione della provenienza geografica e autenticità di numerose matrici alimentari. I dati ottenuti dimostrano che i metaboliti secondari possiedono proprietà discriminanti. L’approccio di metabolomica UHPLC/Q-TOF-MS combinato a una statistica multivariata risulta essere adeguato per identificare potenziali markers. Il lavoro attuale è focalizzato sulla ricerca di nuovi metaboliti che, insieme a fenoli e steroli possano confermare la potenza di questo approccio.
Nowadays, food traceability is a growing consumer interest worldwide. Food traceability could be considered a fundamental tool for ensuring safety and high quality of food. Food quality is based not only on the safety and integrity of food, but also on the authenticity, the genuineness of the raw material and the geographical origin. The aim of the work was to investigate the potential of untargeted metabolomics to ensure the authenticity and traceability of foods. Secondary metabolites, like polyphenols and sterols, could be conveniently used to meet this goal due to their chemical diversity and their responses to environmental stimuli. Samples were analyzed through UHPLC-ESI/QTOF-MS. The obtained data were subjected to multivariate statistical analysis. The obtained results showed that secondary metabolites can be efficiently used for authenticity and traceability purposes, with regards to cultivars and geographical origin. These information confirm the role of environmental factors in shaping the actual profile of secondary metabolites in plant foods. The markers found could be used for a target quantification method, a less expensive and less sophisticated analysis, in order to provide an efficient tool that could help to guarantee food quality on routine basis.
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GHISONI, SILVIA. « UNTARGETED METABOLOMIC FINGERPRINTING FOR AUTHENTICITY AND TRACEABILITY OF FOODS ». Doctoral thesis, Università Cattolica del Sacro Cuore, 2020. http://hdl.handle.net/10280/72714.

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La globalizzazione del mercato agroalimentare ha determinato una crescente attenzione da parte dei consumatori verso i prodotti alimentari, non solo in termini di qualità e di sicurezza, ma anche di origine geografica. Infatti, il territorio d’origine ha un forte impatto sull’alimento, dovuto alle condizioni pedoclimatiche che ne determinano le caratteristiche. Poiché non esistono dei metodi analitici di routine per l’autenticazione della provenienza geografica, lo scopo del progetto di ricerca è quello di determinare l’origine geografica e l’autenticità degli alimenti mediante profiling dei composti fenolici e steroli, grazie all’applicazione di tecnologie omiche, tecniche statistiche e chemometriche. La componente fenolica e/o steroli dei campioni, viene analizzata tramite cromatografia liquida (UHPLC) accoppiata ad uno spettrometro di massa (Q-TOF-MS). I dati così ottenuti, vengono elaborati mediante statistica multivariata. L’applicazione combinata di avanzate tecnologie omiche e tecniche statistiche chemometriche ha portato come risultato l’effettiva identificazione della provenienza geografica e autenticità di numerose matrici alimentari. I dati ottenuti dimostrano che i metaboliti secondari possiedono proprietà discriminanti. L’approccio di metabolomica UHPLC/Q-TOF-MS combinato a una statistica multivariata risulta essere adeguato per identificare potenziali markers. Il lavoro attuale è focalizzato sulla ricerca di nuovi metaboliti che, insieme a fenoli e steroli possano confermare la potenza di questo approccio.
Nowadays, food traceability is a growing consumer interest worldwide. Food traceability could be considered a fundamental tool for ensuring safety and high quality of food. Food quality is based not only on the safety and integrity of food, but also on the authenticity, the genuineness of the raw material and the geographical origin. The aim of the work was to investigate the potential of untargeted metabolomics to ensure the authenticity and traceability of foods. Secondary metabolites, like polyphenols and sterols, could be conveniently used to meet this goal due to their chemical diversity and their responses to environmental stimuli. Samples were analyzed through UHPLC-ESI/QTOF-MS. The obtained data were subjected to multivariate statistical analysis. The obtained results showed that secondary metabolites can be efficiently used for authenticity and traceability purposes, with regards to cultivars and geographical origin. These information confirm the role of environmental factors in shaping the actual profile of secondary metabolites in plant foods. The markers found could be used for a target quantification method, a less expensive and less sophisticated analysis, in order to provide an efficient tool that could help to guarantee food quality on routine basis.
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Morrison, Natasha Louise. « Characterising biochemical changes to hepatocellular carcinoma (HepG2) cells upon exposure to green tea extract using untargeted metabolomics ». Thesis, Morrison, Natasha Louise (2019) Characterising biochemical changes to hepatocellular carcinoma (HepG2) cells upon exposure to green tea extract using untargeted metabolomics. Honours thesis, Murdoch University, 2019. https://researchrepository.murdoch.edu.au/id/eprint/53997/.

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Complementary and alternative medicines (CAMs) have become the preferred medicine for many in replacement of conventional medicines due to cultural or financial reasons. Herbal CAMS, in particular, have become a popular choice of medicine for their purported health benefits. Green tea extract (GTE) contains the major catechins epigallocatechin-3-gallate, epicatechin gallate, epigallocatechin and epicatechin, all of which vary across different GTE products and have become the focus on research into its purported health benefits. However, there have been cases of GTE-induced hepatotoxicity, for which the biochemical pathways have not been characterised. This study elucidates compounds similarities and changes in catechin levels within several different GTE products, and biochemical pathways related to reactive oxygen species (ROS) production affected by acute GTE supplementation in an in vitro setting using metabolomic techniques. It was found that GTE hepatotoxicity significantly decreased amino acids, oxoacids and carboxylic acids at 1 mg/mL exposure but produced a different metabolite profile upon 0.1 mg/mL exposure. The results demonstrate that GTE hepatotoxicity is a dose-dependent process that induces ROS production, ATP depletion and apoptosis, which corroborates prior knowledge on this topic. These results utilise a novel field of research, metabolomics, to add insight into the biochemical mechanisms of GTE hepatotoxicity and to observe the mass spectral pattern and levels of four catechins in different GTE products: (+)-catechin, (-)-epicatechin, (-)-epigallocatechin and (-)-epigallocatechin-3-gallate. This will allow consumers to become more aware of herb-induced liver injury and provide data to aid the regulation of herbal CAMs.
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Kuhlisch, Constanze [Verfasser], Georg [Gutachter] Pohnert, Severin [Gutachter] Sasso et Dieter [Gutachter] Spiteller. « Physiological plasticity of marine phytoplankton revealed by untargeted metabolomics / Constanze Kuhlisch ; Gutachter : Georg Pohnert, Severin Sasso, Dieter Spiteller ». Jena : Friedrich-Schiller-Universität Jena, 2019. http://d-nb.info/1179805321/34.

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Teegarden, Matthew D. « Understanding the stability, biological impact, and exposure markers of black raspberries and strawberries using an untargeted metabolomics approach ». The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1522335050171997.

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Tengstrand, Erik. « Data analysis of non-targeted mass spectrometry experiments ». Doctoral thesis, Stockholms universitet, Institutionen för miljövetenskap och analytisk kemi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-116820.

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Data processing tools are valuable to the analytical chemist as they can speed up the analysis, and sometimes solve problems that are not feasible to solve in a traditional manner. However, the complexity of many data processing tools can make their use daunting for the inexperienced user. This thesis includes two applications and two tools for data processing. The first application focuses on minimizing the manual input, reducing the time required for a simple task. The second application required more manual input, in the form of parameter selection, but process far more data.  The data processing tools both include features that simplify the manual work required. The first by including visual diagnostics tools that helps in setting the parameters. The second via internal validation that makes the tool’s process more robust and reliable, and thereby less sensitive to small changes in the parameters. No matter how good or precise a data processing tool is, if it is so cumbersome that it is not used by the analytical chemists that need it, it is useless. Therefore, the main focus of this thesis is to make data processing easier.

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Submitted.

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Calderón, Castro Carlos [Verfasser], et Michael [Akademischer Betreuer] Lämmerhofer. « Development and application of lipidomics workflows : from untargeted towards targeted enantioselective lipidomics / Carlos Calderón Castro ; Betreuer : Michael Lämmerhofer ». Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/120164464X/34.

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De, Poi Rossella. « Mass spectrometry as an emerging tool for the detection of proteins in complex matrices : from untargeted to targeted analysis ». Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3425394.

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My PhD was performed in Mérieux NutriSciences, a company which provides analytical services. During my PhD I worked on three projects, whose common determinant was the application of mass spectrometry (MS) to the analysis of proteins. The main study deals with MS as a new tool for the analysis of food allergens. Food allergy is an important health problem involving immunological reactions that arise following exposure to protein allergens. In the absence of a cure, patients need to avoid the offending food to prevent allergic reactions. In the European Union, 14 allergens must be indicated in food labels when intentionally added. However, one of the main causes triggering allergic reactions is represented by undesired contamination of food by allergens in production facilities. Even tiny amounts of allergens can trigger severe manifestations; thus, to protect consumers sensitive analytical methods are required. Recently, methods based on MS have received increasing attention for the quantification of food allergens in complex matrices. In the present study, the development of a method based on MS for the simultaneous detection of egg, milk, tree nuts and peanuts allergens into bakery products is described. The method is based on the detection of specific peptides generated from the enzymatic hydrolysis of the target allergens and employs a technique called Multiple Reaction Monitoring, in which the mass spectrometer is operated to selectively acquire signals deriving from specific couples of m/z values, corresponding to a peptide ion and to one of its fragments. The method developed allows to detect target allergens in a specific way and with acceptable sensitivities and can be considered as a valuable alternative to other common analytical techniques, such as ELISA and PCR. A second topic of this thesis is bovine beta-casein, a polymorphic protein for which 12 genetic variants have been identified, the most common being A1 and A2. Some reports suggested a possible association between the consumption of A1 beta-casein and the etiology of some human diseases, including ischemic heart disease and diabetes. At the basis of the effects caused by A1 beta-casein there would be a bioactive peptide with opioid-like activity, released by proteolytic enzymes upon gastrointestinal digestion. This peptide, called beta-casomorphin-7, was shown to be produced only from certain beta-casein isoforms, having a histidine in position 67, including the A1 variant. On the other hand, variants possessing a proline in position 67, such as the A2 variant, would not be able to generate beta-casomorphin-7. Based on these assumptions, some companies now sell “A2 milk”, a milk containing only A2 beta-casein. In this project, a LC-MS analytical method was developed to discriminate between A2 milk and commercial milk, which typically contains a mixture of A1 and A2 beta-casein. The final purpose is to offer milk producers an analytical tool to certify that a milk labeled as “A2 milk” is really as such, eventually capable to identify possible frauds or contaminations. Finally, in this thesis a minor project is described, having as object the enzyme transglutaminase (TGase) from microbial origin. TGase catalyses the formation of isopeptide bonds between carboxamides of glutamine residues and amine groups of lysine, resulting in protein cross-linking. The action of TGase can determine significant changes in the physico-chemical properties of proteins, leading to changes in viscosity, thermal stability and elasticity. For these reasons, TGase finds application as an additive in the food industry. In this study a TGase from an unknown microbial source has been characterized and identified by applying a bottom-up proteomic approach. The identified enzyme is produced from a bacterial strain different from the one most commonly used in food industrial applications, S. mobaraense. Moreover, a method for the measurement of TGase enzymatic activity by the hydroxamate assay has been set up and has now become a service offered by the Mérieux NutriSciences.
Il mio dottorato di ricerca si è svolto in Mérieux NutriSciences, un’ azienda che fornisce servizi analitici. Durante il mio periodo di dottorato ho lavorato su tre progetti, il cui determinante comune era l'applicazione della spettrometria di massa (SM) all'analisi delle proteine. Lo studio principale riguarda la SM applicata all'analisi degli allergeni alimentari. L'allergia alimentare è una patologia importante, dovuta a reazioni immunologiche che insorgono a seguito dell'esposizione di un soggetto ad allergeni proteici. Poiché ad oggi non esiste cura, per prevenire le reazioni allergiche i pazienti devono evitare di assumere alimenti contenenti allergeni. Nell'Unione Europea, 14 allergeni devono essere indicati sulle etichette degli alimenti se aggiunti intenzionalmente. Tuttavia, una delle principali cause di reazione allergica è rappresentata dalla contaminazione indesiderata degli alimenti con allergeni all'interno degli impianti di produzione. Anche piccole quantità di allergene possono scatenare gravi reazioni; dunque, per proteggere i consumatori sono necessari metodi analitici sensibili. Recentemente, i metodi basati sulla SM hanno ricevuto crescente attenzione per la quantificazione degli allergeni alimentari in matrici complesse. Nel presente studio viene descritto lo sviluppo di un metodo basato sulla SM per il rilevamento simultaneo di allergeni da uova, latte, arachidi e frutta secca in prodotti da forno. Il metodo si basa sull'identificazione di specifici peptidi generati dall'idrolisi enzimatica degli allergeni target ed impiega una tecnica chiamata Multiple Reaction Monitoring, in cui lo spettrometro di massa è utilizzato per acquisire selettivamente segnali derivanti da coppie di specifici valori m/z, corrispondenti a uno ione peptidico e ad uno dei suoi frammenti. Il metodo sviluppato consente di rilevare gli allergeni target in modo specifico e con sensibilità accettabile e può essere considerato una valida alternativa ad altre comuni tecniche analitiche, come l’ELISA e la PCR. Un secondo argomento trattato in questa tesi riguarda la beta-caseina bovina, una proteina polimorfica per la quale sono state identificate 12 varianti genetiche, fra cui le più comuni sono la A1 e la A2. Alcuni studi hanno suggerito una possibile associazione fra il consumo di beta-caseina A1 e l'eziologia di alcune malattie, tra cui l’ischemia cardiaca e il diabete. Alla base degli effetti causati dalla beta-caseina A1 ci sarebbe un peptide bioattivo con attività simil-oppiode, rilasciato da specifici enzimi proteolitici durante la digestione. Questo peptide, chiamato beta-casomorphin-7, viene generato solo a partire da alcune isoforme di beta-caseina, contenenti un'istidina in posizione 67, inclusa la variante A1. Al contrario, le varianti che possiedono una prolina in posizione 67, come la variante A2, non sarebbero in grado di generare il peptide beta-casomorphin-7. Sulla base di queste ipotesi, alcune aziende vendono ora il cosiddetto "latte A2", un tipo di latte contenente solo beta-caseina A2. In questo progetto di dottorato è stato sviluppato un metodo analitico LC-MS per discriminare il latte A2 dal latte commerciale, che tipicamente contiene una miscela di beta-caseina A1 e A2. Lo scopo finale è offrire ai produttori di latte uno strumento analitico per certificare che un latte etichettato come "latte A2" sia realmente tale, ed eventualmente in grado di identificare possibili frodi o contaminazioni. Infine, in questa tesi viene descritto un progetto che ha come oggetto l'enzima transglutaminasi (TGasi) di origine microbica. La TGasi catalizza la formazione di legami isopeptidici tra residui di glutammina e di lisina, determinando la formazione di cross-linking fra proteine. L'azione della TGasi può determinare cambiamenti significativi nelle proprietà fisico-chimiche delle proteine, portando a modifiche nella viscosità, nella stabilità termica e nella elasticità. Per questi motivi, la TGasi trova applicazione come additivo nell'industria alimentare. In questo studio, una specie di TGasi di origine microbica è stata caratterizzata e identificata applicando un approccio proteomico “bottom-up”. L'enzima identificato viene prodotto da un ceppo batterico diverso da quello più comunemente utilizzato nelle applicazioni industriali alimentari, denominato S. mobaraense. Infine, è stato sviluppato un metodo per la misurazione dell'attività enzimatica della TGasi mediante il saggio dell'idrossammato, che è ora diventato un servizio analitico offerto da Mérieux NutriSciences.
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Waldhier, Magdalena C. [Verfasser], et Frank-Michael [Akademischer Betreuer] Matysik. « Towards Chiralomics : Targeted and Untargeted Gas Chromatography-Mass Spectrometry based Enantioselective Metabolome Analysis / Magdalena C. Waldhier. Betreuer : Frank-Michael Matysik ». Regensburg : Universitätsbibliothek Regensburg, 2016. http://d-nb.info/108154340X/34.

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Meiß, Ernst [Verfasser]. « Entwicklung von Massenspektrometrie-basierten Non-Targeted- und Targeted-Metabolomics-Methoden zur Identifizierung neuer und quantitativen Bestimmung bekannter potentieller Biomarker zu Diabetes mellitus / Ernst Meiß ». München : Verlag Dr. Hut, 2017. http://d-nb.info/1137024291/34.

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Kaever, Alexander [Verfasser], Burkhard [Akademischer Betreuer] Morgenstern et Ivo [Akademischer Betreuer] Feussner. « Development of a statistical framework for mass spectrometry data analysis in untargeted Metabolomics studies / Alexander Kaever. Gutachter : Burkhard, Morgenstern ; Ivo Feussner. Betreuer : Burkhard, Morgenstern ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2014. http://d-nb.info/1063776317/34.

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Hartiala, Jaana A., Tang W. H. Wilson, Zeneng Wang, Amanda L. Crow, Alexandre F. R. Stewart, Robert Roberts, Ruth McPherson et al. « Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease ». NATURE PUBLISHING GROUP, 2016. http://hdl.handle.net/10150/623257.

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Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identified two significantly associated loci on chromosomes 2q34 and 5q14.1. The lead variant on 2q24 (rs715) localizes to carbamoyl-phosphate synthase 1 (CPS1), which encodes a mitochondrial enzyme that catalyses the first committed reaction and rate-limiting step in the urea cycle. Rs715 is also significantly associated with decreased levels of urea cycle metabolites and increased plasma glycine levels. Notably, rs715 yield a strikingly significant and protective association with decreased risk of CAD in only women. These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis.
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Wörmann, Kilian [Verfasser], Philippe [Akademischer Betreuer] Schmitt-Kopplin, Rainer [Akademischer Betreuer] Lehmann et Michael [Akademischer Betreuer] Rychlik. « New prognostic and diagnostic biomarkers in diabetic nephropathy using comprehensive targeted and non-targeted metabolomics / Kilian Wörmann. Gutachter : Philippe Schmitt-Kopplin ; Rainer Lehmann ; Michael Rychlik. Betreuer : Philippe Schmitt-Kopplin ». München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1076625525/34.

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Ghosson, Hikmat. « Development of a novel universal proxy to assess the environmental fate and impact of complex (bio)pesticides by Mass Spectrometry-based Metabolomics ». Electronic Thesis or Diss., Perpignan, 2020. http://www.theses.fr/2020PERP0029.

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Malgré la prise de conscience écologique et sanitaire, la consommation mondiale de pesticides est en augmentation. Étant donné que ces produits chimiques présentent de nombreux effets néfastes sur la santé humaine et l'environnement, des mesures doivent être prises afin de limiter leurs effets. Les produits de biocontrôle sont proposés comme une solution alternative aux produits synthétiques. En effet, ces « biopesticides » sont présumés être moins nocifs et relativement moins persistants. Toutefois, cet a priori doit être examiné et une évaluation stricte des risques de ces nouvelles substances doit être envisagée.Le développement de solutions de biocontrôle passe d'abord par les protocoles proposés pour étudier leur activité, leur devenir et leur impact environnemental. Actuellement, le temps de demi-vie (t½) est utilisé pour évaluer le devenir environnemental des pesticides synthétiques. Cependant, l'approche t½ ne donne que des informations sur la persistance des pesticides dans l'environnement, mais aucune indication concernant la formation de produits de dégradation ou son impact sur la biodiversité n'est apportée. De plus, les produits de biocontrôle sont des mélanges (bio)chimiques complexes. La t½ n'est pas applicable pour ces produits complexes. Par conséquent, de nouvelles approches analytiques doivent être envisagées afin de surmonter ces difficultés.Une nouvelle approche basée sur la méta-métabolomique et la Spectrométrie de Masse; « Empreinte Métabolique Environnementale » (EMF), a été récemment introduite. Elle offre un nouveau proxy universel et intégratif; le « temps de résilience », dédié à l'évaluation du devenir environnemental et de l'impact des (bio)pesticides complexes dans des matrices environnementales (ex. sol, sédiments). Néanmoins, le développement d'une telle approche de méta-métabolomique non ciblée basée sur la Spectrométrie de Masse doit être étudié en profondeur. Plusieurs tâches doivent alors être abordées: 1) les protocoles d'extraction performants et les méthodes analytiques basées sur la GC/LC-(HR)MS doivent être mis en place, 2) le traitement de données et les outils chimiométriques appropriés doivent être développés pour maitriser la complexité des ensembles des données générées, 3) l'impact de la complexité du xénométabolome sur les analyses basées sur la MS doit être évalué, et 4) l'étude des résidus volatiles doit être envisagée et nécessite donc le développement de nouvelles méthodologies analytiques.Le travail a été mené sur 3 axes principaux. Le premier axe portait sur 1) le développement de protocoles d'extraction et des méthodes LC-HRMS pour analyser à la fois les xénométabolites des pesticides et les endométabolites du sol, et 2) le développement d'une nouvelle approche chimiométrique pour évaluer les performances d'extraction. De nouveaux protocoles d'extraction se sont avérés optimaux pour l'EMF, et l'approche chimiométrique a donc été validée. Le deuxième axe a évalué l'impact de la complexité du xénométabolome sur la détermination des biomarqueurs environnementaux. La suppression d'ion a été révélée et une stratégie pragmatique a donc été élaborée pour surmonter son influence. Le troisième axe visait à mettre en place une nouvelle méthodologie pour analyser les résidus volatils de pesticides complexes. Des analyses HS-SPME-GC-MS ont été couplées à la chimiométrie afin de réaliser des études cinétiques et de suivre la transformation des résidus volatils. Le workflow chimiométrique a prouvé sa fiabilité pour expliquer la transformation du pesticide et de nouveaux xénométabolites et sous-produits ont été identifiés.En conclusion, une avancée significative a été apportée à l’EMF. Elle a été consolidée pour les applications en laboratoire et sur le terrain qui doivent être étudiées afin d'améliorer le proxy et de le valider comme une approche fiable pour l'évaluation des risques des pesticides
Despite the ecological and sanitary awareness, worldwide consumption of pesticides is increasing. As these chemical products represent several adverse effects on human health and environment, measures should be taken in order to limit their impacts. Biocontrol products are proposed as an alternative solution of the synthetic products. In fact, these “biopesticides” are presumed to be less harmful and relatively less persistent. However, this a priori must be examined and strict risk assessment of those new substances should be considered.The development of biocontrol solutions proceeds first of all through the proposed protocols to study their activity and their environmental fate and impact. Currently, half-life (DT50) is used in order to evaluate the environmental fate of synthetic pesticides. However, DT50 approach gives only information about pesticides' persistence in the environment, but no indications concerning the formation of degradation products or its impact on biodiversity are provided. Furthermore, biocontrol products are complex (bio)chemical mixes. The DT50 is not applicable for such complex products. Therefore, novel analytical approaches should be considered in order to overcome these difficulties.A novel approach based on meta-metabolomics and Mass Spectrometry; the “Environmental Metabolic Footprinting” (EMF), was recently introduced. It affords a novel universal and integrative proxy; the “resilience time”, dedicated to assess the environmental fate and impact of complex (bio)pesticides in environmental matrices (e.g. soil, sediment). Nonetheless, the development of such Mass Spectrometry-based untargeted meta-metabolomics approach needs to be in-depth studied. Several tasks should be addressed: 1) performant extraction protocols and GC/LC-(HR)MS-based analytical methods should be set up, 2) suitable data processing and chemometric tools should be developed to deal with the complexity of the generated datasets, 3) the impact of xenometabolome complexity on MS-based analyses should be assessed, and 4) the study of the volatile residues should be considered and thus needs new analytical methodologies to be developed.The work was carried out following 3 main axes. The first axis addressed 1) the development of extraction protocols and LC-HRMS methods to analyze both pesticides xenometabolites and soil endometabolites, and 2) the development of a novel chemometric approach to assess the extraction performance. Novel extraction protocols have been proven optimal for the EMF, and the chemometric approach was thus validated. The second axis assessed the impact of xenometabolome complexity on the determination of environmental biomarkers. Ion suppression was revealed and thus a pragmatic strategy has been developed to overcome its influence. The third axis aimed to set-up a novel methodology in order to analyze the volatile residues of complex pesticides. HS-SPME-GC-MS analyses were coupled to chemometrics in order to perform kinetics studies and to follow the transformation of the volatile residues. The chemometric workflow proved its reliability to explain pesticide’s transformation and novel xenometabolites and by-products were identified.In conclusion, significant advances were carried to the EMF. It has been consolidated for laboratory and field applications that must be investigated in order to improve the proxy and to validate it as a reliable approach for pesticides risk evaluation
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Drotleff, Bernhard [Verfasser], et Michael [Akademischer Betreuer] Lämmerhofer. « Development and Optimization of Targeted/Untargeted Lipidomic Screening Methodologies in Pharmaceutical and Clinical Bioanalysis by Liquid Chromatography-High Resolution-Mass Spectrometry / Bernhard Drotleff ; Betreuer : Michael Lämmerhofer ». Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1202271537/34.

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Perera, Munasinhage Venura Lakshitha. « Metabolic profiling of plant disease : from data alignment to pathway predictions ». Thesis, University of Exeter, 2011. http://hdl.handle.net/10036/3906.

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Understanding the complex metabolic networks present in organisms, through the use of high throughput liquid chromatography coupled mass spectrometry, will give insight into the physiological changes responding to stress. However the lack of a proper work flow and robust methodology hinders verifiable biological interpretation of mass profiling data. In this study a novel workflow has been developed. A novel Kernel based feature alignment algorithm, which outperformed Agilent’s Mass profiler and showed roughly a 20% increase in alignment accuracy, is presented for the alignment of mass profiling data. Prior to statistical analysis post processing of data is carried out in two stages, noise filtering is applied to consensus features which were aligned at a 50% or higher rate. Followed by missing value imputation a method was developed that outperforms both at model recovery and false positive detection. The use of parametric methods for statistical analysis is inefficient and produces a large number of false positives. In order to tackle this three non-parametric methods were considered. The histogram method for statistical analysis was found to yield the lowest false positive rate. Data is presented which was analysed using these methods to reveal metabolomic changes during plant pathogenesis. A high resolution time series dataset was produced to explore the infection of Arabidopsis thaliana by the (hemi) biotroph Pseudomonas syringe pv tomato DC3000 and its disarmed mutant DC3000hrpA, which is incapable of causing infection. Approximately 2000 features were found to be significant through the time series. It was also found that by 4h the plants basal defence mechanism caused the significant ‘up-regulation’ of roughly 400 features, of which 240 were found to be at a 4-fold change. The identification of these features role in pathogenesis is supported by the fact that of those features found to discriminate between treatments a number of pathways were identified which have previously been documented to be active due to pathogenesis
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Bilbrey, Emma A. « Seeding Multi-omic Improvement of Apple ». The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594907111820227.

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Forcisi, Sara [Verfasser], Philippe [Akademischer Betreuer] Schmitt-Kopplin, Michael [Akademischer Betreuer] Rychlik et Rainer [Akademischer Betreuer] Lehmann. « Chromatography and mass spectrometry-based non-targeted metabolomics forType2 Diabetes studies / Sara Forcisi. Gutachter : Michael Rychlik ; Rainer Lehmann ; Philippe Schmitt-Kopplin. Betreuer : Philippe Schmitt-Kopplin ». München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1044073675/34.

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Flögel, Anna [Verfasser], et Reinhard [Akademischer Betreuer] Busse. « Serum metabolites and their association with risk of type 2 diabetes and cardiovascular diseases : a targeted metabolomics approach in EPIC-Potsdam / Anna Flögel. Betreuer : Reinhard Busse ». Berlin : Universitätsbibliothek der Technischen Universität Berlin, 2013. http://d-nb.info/1035276291/34.

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Breier, Michaela [Verfasser], Jerzy [Akademischer Betreuer] [Gutachter] Adamski et Hannelore [Gutachter] Daniel. « Targeted metabolomics analyses reveal the impact of pre-analytics and drug intake on the human metabolome / Michaela Breier ; Gutachter : Hannelore Daniel, Jerzy Adamski ; Betreuer : Jerzy Adamski ». München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1138359653/34.

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Hellmuth, Christian [Verfasser], et Berthold [Akademischer Betreuer] Koletzko. « LC-MS/MS applications in Targeted Clinical Metabolomics : method development and validation with focus on sulphur-containing amino acids and nonesterified fatty acids / Christian Hellmuth. Betreuer : Berthold Koletzko ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1049891201/34.

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Förster, Jana [Verfasser], Heiner [Akademischer Betreuer] Boeing et Reinhard [Akademischer Betreuer] Busse. « Treelet transform for untargeted metabolomics data : treelet transform generates serum metabolite and lipid components that are correlated to anthropometry and intestinal microbiota in a cross-sectional EPIC-Potsdam sub-study / Jana Förster. Gutachter : Heiner Boeing ; Reinhard Busse. Betreuer : Heiner Boeing ». Berlin : Technische Universität Berlin, 2014. http://d-nb.info/1067386602/34.

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Mbongwa, Hlengiwe Prosperity. « Characterisation of the SULT1A1 polymorphism in a South African Tswana population group / y Hlengiwe P. Mbongwa ». Thesis, North-West University, 2010. http://hdl.handle.net/10394/4225.

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This dissertation brings to the fore the “Characterization of the SULT1A1 polymorphism in a South Africa Tswana population group.” The primary experimental group studied came from South African homogeneous Tswana individuals who participated voluntarily in an ongoing large-scale epidemiological Prospective Urban and Rural Epidemiological (PURE) study the North-West University (Potchefstroom Campus) participates in, as one of the 16 low- middleand high-income countries across the world. The primary aspect investigated was the comprehensive profile of the single nucleotide polymorphism (SNP) and copy number variation (CNP) of the SULT1A1 gene. Using the PCRbased RFLP method, SULT1A1 genotypes, and allele frequency distributions in an experimental group of 1 867 individuals were determined. According to the literature this is by far the largest and most homogeneous group from which such information has been acquired to date. The SULT1A1*1, SULT1A1*1/*2 and SULT1A1*2 genotypes were found to be present at a percentage of 43.76, 47.12 and 9.11 respectively. In comparison to similar studies in other population groups, results from this study indicate that there are ethnic differences in the SULT1A1 genotypes incidence. Asian group differs from Caucasian and Tswana groups because of its exceptionally high prevalence of individuals with the SULT1A1*1 genotype and a very low incidence of the SULT1A1*2 genotype. The SULT1A1*1 genotype profiles of Caucasian and Tswana groups were comparable, but notable differences were observed for the SULT1A1*2 genotype. Using a quantitative multiplex PCR method for the CNV study, the numbers of copies of the SULT1A1 gene in the Tswana population were determined, and the results showed 1 to ~5 copies: only 0.65% of the subjects had a single copy, whereas 59.69% of the subjects had 3 or more copies. This result shows a significant discrepancy between the Caucasian-American samples, which showed that only 26% from that group had more than three copies. However, there is a significant relationship with the African-American population, which presented 63% with 3 or more copies. This finding confirms results from a much smaller African-American study, and suggests a possible genetic link between the African Tswana and the heritage of the African-Americans. These findings were submitted for publication to the South African Journal of Science, as that journal specializes in publication of new knowledge that has a regional focus on Africa. Simultaneous phenotypic consequences of the SNP and CNP of the SULT1A1 gene, as well as the thermo-stable and thermo-labile forms of the sulfotransferases were determined. For this, the formation of [35S]-4-nitrophenyl sulphate from 4-nitrophenol and [35S]-3’-phosphoadenosine- 5’-phosphosulfate ([35S]-PAPS) in platelet homogenates were measured, with the data normalized to a common platelet count. This investigation required fresh blood for enzyme activity. These samples came from 98 Caucasian subjects who voluntarily participated in this part of the study. The experimental data presented a unique challenge to develop a statistical model to accommodate the complexity of the distribution of the data in the phenotype and genotype components, which could be achieved by the development of a mixed model. The model indicated that product formation increased through increasing copy number, but did not differ for SULT1A1*1 and SULT1A1*1/*2. However, the rate of increase in product for the thermo-stable forms of the SULTs was greater than that of thermo-labile forms. In contrast, copy number effect for SULT1A1*2 differed considerably from that of the other two genotypes. Since genotype is also a significant factor, it was concluded from Tukey post-hoc tests that the population group means for product formation differ significantly (for all levels). These results are presently being prepared for publication in an accredited international journal. Finally, perturbations in 23 biochemical parameters measured in the PURE study were analyzed as a function of the SULT1A1 SNP and CNP were evaluated. No group separation in this regard could be found. It could be shown however, that sulfonation of the iodothyronines, which are endogenous substrates for the SULTs, was influenced by the SULT1A1 genotype. The relative concentrations in plasma of the sulphonated iodothyronines may be expressed as T2S > T3S >> T4S, which coincides with the substrate preference of the SULT1A1 enzymes. This observation may, however, only be qualitatively interpreted as (1) the targeted metabolomics mass spectrometric method used for the quantitative analysis of these substances needs further development, and (2) the influence of deiodonation was not taken into account in these studies. In conclusion, three perspectives are given at the end of the thesis which might be considered for further investigations.
Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2010.
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Merz, Benedikt [Verfasser]. « Metabolic markers as determinants of future waist-gaining or hip-gaining phenotype in weight-gaining individuals – A targeted metabolomics approach in population-based prospective German cohort studies / Benedikt Alexander Merz ». Bonn : Universitäts- und Landesbibliothek Bonn, 2016. http://d-nb.info/1107541786/34.

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Merz, Benedikt Alexander [Verfasser]. « Metabolic markers as determinants of future waist-gaining or hip-gaining phenotype in weight-gaining individuals – A targeted metabolomics approach in population-based prospective German cohort studies / Benedikt Alexander Merz ». Bonn : Universitäts- und Landesbibliothek Bonn, 2016. http://d-nb.info/1107541786/34.

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Wenk, Deborah [Verfasser], Monika [Akademischer Betreuer] Pischetsrieder et Monika [Gutachter] Pischetsrieder. « Establishment and application of mass spectrometry-based methods of untargeted and targeted proteomics to analyze the response of HEK293T cells to treatment with balanced and biased dopamine receptor D2 ligands / Deborah Wenk ; Gutachter : Monika Pischetsrieder ; Betreuer : Monika Pischetsrieder ». Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1229194231/34.

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Ariza, Castro Nancy. « Occurrence et produits de transformation des résidus de médicaments dans l'environnement aquatique (milieu et organismes) par approche ciblée et non-ciblée en spectrométrie de masse ». Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTG082.

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La croissance démographique et l'urbanisation exercent des pressions anthropiques sur les ressources en eau et leurs écosystèmes. Parmi les polluants anthropiques, les produits pharmaceutiques à usage humain sont rejetés dans l'environnement principalement par les eaux usées traitées et non traitées. Plusieurs études ont déterminé l’occurrence de ces composés dans les eaux continentales en Europe et en Amérique du Nord. Cependant, dans les pays du Sud, peu d’informations sont connues ce qui justifie de poursuivre les efforts pour renseigner l’état de contamination des milieux aquatiques par les résidus de médicaments. L'exposition continue des organismes aquatiques à ces substances biologiquement actives peut favoriser leur bioaccumulation. Des publications récentes suggèrent qu’il est nécessaire d'élaborer des scénarios sur l’exposition et les implications, en termes de risques, des résidus de médicaments et de leurs produits de transformation sur ces organismes non ciblés. Dans ce contexte, les approches ciblées et plus récemment les approches non ciblées à l'aide de la chromatographique liquide couplée à la spectrométrie de masse sont des méthodologies prometteuses à utiliser pour renseigner l'état de contamination des eaux et des organismes marins par les produits pharmaceutiques. Compte tenu de ce qui précède, ce travail s'est appuyé sur des analyses dirigées et non dirigées qui ont été appliquées sur des échantillons environnementaux (matrices aqueuses et biote). Au final, cette étude a permis: 1) de faire le premier diagnostic du niveau de contamination des eaux de surface et souterraines par les produits pharmaceutiques au Cameroun, autour de sa capitale Yaoundé et 2) de caractériser les métabolites de l'antidépresseur Venlafaxine dans les moules (Mytilus Galloprovincialis)
Population growth and urbanization are exerting anthropogenic pressures on water resources and their ecosystems. Among anthropogenic pollutants, pharmaceuticals for human use are released into the environment mainly through treated and untreated wastewater. Several studies have determined the occurrence of these compounds in inland waters in Europe and North America. However, in the countries of the South, little information is known, which justifies continuing efforts to inform the state of contamination of aquatic environments by drug residues. Continued exposure of aquatic organisms to these biologically active substances can promote their bioaccumulation. Recent publications suggest the need to develop scenarios on the exposure and risk implications of drug residues and their transformation products on these non-target organisms. In this context, targeted approaches and, more recently, non-targeted approaches using liquid chromatography coupled with mass spectrometry are promising methodologies to be used to inform the state of pharmaceutical contamination of waters and marine organisms.In view of the above, this work was based on directed and non-directed analyses that were applied to environmental samples (aqueous matrices and biota). In the end, this study made it possible: 1) to make the first diagnosis of the level of contamination of surface and groundwater by pharmaceutical products in Cameroon, around its capital Yaoundé and 2) to characterize the metabolites of the antidepressant Venlafaxine in mussels (Mytilus Galloprovincialis)
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Slimani, Kahina. « Produits biocides désinfectants dans les produits laitiers : méthodes quantitatives d'analyse des résidus et étude de l'impact des procédés de transformation du lait sur l'apparition de produits néoformés selon des approches d'analyse ciblée et non ciblée par spectrométrie de masse ». Thesis, Rennes 1, 2018. http://www.theses.fr/2018REN1B011/document.

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Le travail de thèse décrit dans ce manuscrit porte sur l’étude de la présence de biocides désinfectants dans les produits laitiers et sur l’impact des procédés de transformation du lait sur l’apparition de produits néoformés. Les biocides désinfectants sont des composés chimiques utilisés quotidiennement en industrie laitière lors des procédures de nettoyage-désinfection (ND) des surfaces en contact avec les aliments. Les ammoniums quaternaires de type chlorure de Benzalkonium (BACs) et chlorure de dialkyldimethylammonium (DDACs), et l’Aminopropyldodécylpropane diamine sont les désinfectants les plus largement utilisés en industrie laitière. Ces biocides peuvent entrainer des résidus sur les surfaces alimentaires, ce qui présente un risque pour la santé du consommateur. Dans le but de mesurer l’exposition des consommateurs, deux méthodes analytiques fiables ont été développées pour l'analyse de ces substances dans les produits laitiers impliquant la chromatographie liquide couplée à la spectrométrie de masse en tandem. Le lait cru de vache, la poudre de lait entier, les fromages à pâte pressée cuite et les fromages fondus ont été sélectionnés pour représenter la diversité des produits laitiers. L'évaluation des performances de chacune des méthodes a été réalisée par une approche globale basée sur le profil d'exactitude. Pour la plupart des composés et des matrices étudiés, les méthodes d'analyse ont été validées sur l’intervalle de dosage de 5 à 150 μg / kg. Pour répondre au questionnement de l'impact des procédés de transformation du lait sur les résidus de biocides désinfectants, l'évolution des teneurs en composés et leur devenir dans les différentes matrices issues du lait ont été étudiées. Pour cela, deux études de faisabilité mettant en oeuvre des comparaisons d'empreintes chimiques globales, acquises par spectrométrie de masse à haute résolution, de fromages fondus et de fromages à pâte dure (contaminés vs témoins) ont été réalisées. Ces études ont permis de détecter 4 ions discriminants liés à la présence de biocides dans le fromage fondu. Leur identification reste à réaliser. Tout ce travail a été réalisé à des fins de sécurité alimentaire. La première partie est à l'élaboration de méthodes analytiques ciblées pour les résidus de biocides dans le lait et les produits laitiers permettant ainsi de mesurer les résidus de biocides sur les denrées alimentaires. Ces mesures sont nécessaires pour effectuer une analyse du risque liée à ces résidus. La deuxième partie est en relation avec la question du comportement des résidus de biocides lors de la transformation du lait présentant la stratégie, les résultats que nous pourrions obtenir et la perspective de travaux futurs
The thesis work focuses on the presence of disinfectants biocides in dairy products and on the impact of milk processing on the possible appearance of process-induced food contaminants related to the exposition of milk with biocides. Disinfectants biocides are chemicals daily used in the dairy industry in cleaning-disinfection (CD) processes of food contact surfaces. Quaternary ammoniums as benzalkonium chloride (BACs) and dialkyldimethylammonium chloride (DDACs), and the Aminopropyldodecylpropane diamine are the most widely used disinfectants in dairy industry. These biocides can lead residues on the surfaces of food contact materials therefore present a health risk for the consumer. With aim of measuring consumers exposure, two reliable analytical methods have been developed for the analysis of these substances in dairy products involving liquid chromatography hyphenated with tandem mass spectrometry. Raw cow's milk, whole milk powder, hard pressed and processed cheeses were selected as representing the diversity of dairy products. The evaluation of the performances of each of the methods was carried out by the global approach based on the accuracy profile. For most of compounds and matrices studied, analytical methods were validated within the range of 5 to 150 μg/kg. To answer to the questioning of the impact of milk processes on biocides disinfectants residues, the evolution of compounds contents and their fate in the various matrices resulting from the milk were studied. For this, two proof-of-concept studies implementing global chemical fingerprint comparisons, acquired by High Resolution Mass Spectrometry, of processed cheese and hard pressed cheese (contaminated vs control) samples were carried out. These studies allowed to detect 4 discriminant ions linked to the presence of biocides in processed cheese. Their identification remains to be done. Whole this work is related for food safety purposes. The first part was linked to elaborate targeted analytical methods for biocides residues in milk and milk products thus allowing the measurement of biocides residues on food. These measurements are necessary for the risk analysis linked to these residues. The second part is in relation with the question of the behavior of biocides residues within milk processing presenting the strategy, the results we could obtain and the perspective for future works
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Fall, Fanta. « Étude métabolomique de la polarisation des macrophages pulmonaires humains A split-range acquisition method for the non-targeted metabolomic profiling of human plasma with hydrophilic interaction chromatography - high-resolution mass spectrometry Metabolomic changes during the M1- and M2-polarization of human lung macrophages ». Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLV064.

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Les macrophages pulmonaires sont des cellules immunitaires essentielles pour la défense contre les agents pathogènes qui colonisent les voies respiratoires et sont aussi impliqués dans la physiopathologie des maladies pulmonaires inflammatoires telles que l’asthme. Les macrophages peuvent être sujets à une polarisation vers deux phénotypes appelés M1 et M2. Le phénotype M1 est induit par les agonistes des Toll-like Récepteurs et promeut la réponse inflammatoire tandis que le phénotype M2 est induit par les cytokines Th2 canoniques IL-4 et IL-13 et exerce principalement des fonctions immunorégulatrices. Cette différenciation se traduit par des modifications du phénotype (expression de protéines de membrane, production de cytokines) et des fonctions cellulaires. La polarisation a aussi un impact sur le métabolisme et la production de médiateurs intracellulaires.Notre objectif etait de caractériser les altérations métabolomiques survenant aux cours de la polarisation M1/M2 de macrophages pulmonaires humains. Dans un premier temps, des méthodes métabolomiques non-ciblées et ciblées par chromatographie liquide couplée à la spectrométrie de masse haute résolution et par chromatographie en phase gazeuse couplée à la spectrométrie de masse ont été développées. Ces approches ont ensuite permis d’identifier des voies métaboliques altérées au cours de la polarisation M1/M2 (cycle de Krebs, voie des kunurénines et de l’acide arachidonique) et de quantifier les des médiateurs impliqués dans la régulation de la réaction inflammatoire, dont les oxystérols. Ces travaux permettent une meilleure compréhension du métabolisme cellulaire au cours de la polarisation des macrophages pulmonaires humains
Lung macrophages are essential immune cells for defense against pathogens that colonize the respiratory tract and are also involved in the pathophysiology of inflammatory lung diseases such as asthma. Macrophages can be subject to polarization towards two phenotypes called M1 and M2. The M1 phenotype is induced by Toll-like Receptor agonists and promotes the inflammatory response while the M2 phenotype is induced by the canonical Th2 cytokines IL-4 and IL-13 and mainly performs immunoregulatory functions. This differentiation results in changes in phenotype (expression of membrane proteins, production of cytokines) and cellular functions. Polarization also has an impact on metabolism and the production of intracellular mediators.Our objective was to characterize the metabolomic alterations occurring during the M1/M2 polarization in human lung macrophages. Initially, non-targeted and targeted metabolomic methods by liquid chromatography coupled with high-resolution mass spectrometry and gas chromatography coupled with mass spectrometry were developed. These approaches were then applied to identify altered metabolic pathways during M1/M2 polarization (Krebs cycle, kynurenin and arachidonic acid pathways) and to quantify the mediators involved in regulating the inflammatory response, including oxysterols. This work provides a better understanding of cellular metabolism during the polarization of human lung macrophages
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Espinoza, Christian. « Approche métabolomique non-ciblée pour révéler les réponses métaboliques des prunus à l'infection par le PPV, conduisant au développement d'un outil de détection innovant pour la détection précoce de la maladie de la sharka et la sauvegarde des vergers en Occitanie ». Thesis, Perpignan, 2022. http://www.theses.fr/2022PERP0018.

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La maladie de la sharka, causée par le Plum pox virus (PPV), est responsable d’importantes pertes économiques chez les Prunus. Toutefois, aucun traitement préventif ou curatif n’est à ce jour disponible et peu de sources de résistance naturelle ont été retrouvées. En France, une approche prophylactique, qui repose essentiellement sur la détection et l’élimination rapide des arbres infectés, a été adoptée afin de réduire la propagation du virus. Néanmoins, certaines contraintes technico-économiques ne permettent pas la détection précoce et efficace du PPV à grande échelle par des méthodes conventionnelles. Le département des Pyrénées Orientales (France) est le plus touché par cette maladie (85% des contaminations). Ces enjeux ont motivé la création du projet Antishark, issu d'une collaboration entre AkiNaO, l'Université de Perpignan Via Domitia, la FDGDON66 et les producteurs locaux. L'objectif du projet consiste à développer une méthode innovante de détection précoce, en ciblant les réponses métaboliques de Prunus persica à un stade précoce de l'infection. Par conséquence, deux études en conditions contrôlées utilisant une approche métabolomique non-ciblée (UHPLC-HRMS) ont été réalisées. Cette approche constitue un outil prometteur pour mettre en évidence les interactions métaboliques entre le PPV et son hôte. Dans une première étude, la réponse métabolique globale à l'infection par le PPV (souches Dideron et Marcus), intégrant les feuilles symptomatiques et asymptomatiques, a permis de discriminer les profils métaboliques provenant de feuilles infectées par le PPV et de feuilles saines. Bien qu’il existe une réponse commune aux deux souches, des différences métaboliques ont également été révélées, mettant en évidence des altérations métaboliques souche-dépendante. De fait, cette observation pourrait amener à terme, la possibilité d’identifier la ou les souches virales responsables d’une infection. De plus, il est possible de discriminer les plants infectés par le PPV (feuilles symptomatiques et asymptomatiques) des plants sains et des plants infectés par un autre virus phytopathogène. Ces observations suggèrent l’existence d’une réponse spécifique potentielle à la maladie de la sharka. L’ensemble de nos résultats corroborent l'hypothèse selon laquelle les arbres asymptomatiques mais infectés par le PPV, pourraient être détectés via les altérations métaboliques provoquées le virus. Par ailleurs, les réponses métaboliques observées sur les feuilles asymptomatiques pourraient être considérées comme des réponses précoces, déclenchées avant l’apparition des symptômes. Dans un deuxième temps, des altérations métaboliques précoces, avant l’apparition des symptômes sharka, ont été confirmées par une étude cinétique et ce, malgré des tests moléculaires négatives (RT-qPCR). Nos résultats indiquent que la détection précoce des plantes infectées par le PPV, en ciblant les réponses métaboliques de Prunus persica, est de facto une stratégie prometteuse. Finalement, des corrélations statistiques entre les deux études ont été retrouvées. Bien que les cultivars présentent des profils métaboliques significativement différents, certaines variables discriminantes sont communes entre les différents cultivars testés (GF-305, nectarine jaune, pêche jaune) et également entre les différents stades d’infection du virus (symptomatique et asymptomatique). Cependant, une co-infection PPV et oïdium observée le long de l’étude cinétique en conditions contrôlées, serait susceptible d’altérer l'impact de l'infection par le PPV. Par conséquent, une nouvelle étude cinétique sans co-infection est en cours pour confirmer ou infirmer ces observations. De plus, l'identification de biomarqueurs liés à la maladie, également en cours, permettrait de mieux comprendre les interactions métaboliques entre la pêche et le PPV. Enfin, d'autres expérimentations en conditions naturelles sont en cours afin d'évaluer la robustesse de nos potentiels biomarqueurs
Sharka disease, caused by Plum pox virus (PPV), is responsible for significant economic losses in Prunus. However, no preventive or curative treatments are currently available and only a few sources of natural resistance have been found. In France, a prophylactic approach has been adopted in an attempt to limit the spread of the PPV, which is essentially based on the rapid detection and removal of infected trees. However, certain technical and economic limitations do not allow the early andeffective detection of PPV on a large scale by conventional methods. The department of Pyrénées Orientales (France) is the most affected by this disease (85% of infections). These issues motivated the creation of the Antishark project, which is the result of a collaboration between AkiNaO, the University of Perpignan Via Domitia, FDGDON66 and local producers. The objective of the project was to develop an innovative method of early detection, targeting the metabolic responses of Prunuspersica at an early stage of the infection. Consequently, two studies under monitored conditions using an untargeted metabolomics approach (UHPLC-HRMS) were carried out. This approach is a promising tool to reveal the metabolic interactions between PPV and its host. In a first study, the global metabolic response to PPV-infection (Dideron and Marcus strains), including symptomatic and asymptomatic leaves, allowed the discrimination of metabolic profiles from PPV-infected and healthy leaves. Although there was a common response between the two strains, metabolic differences were also revealed, notably highlighting strain-specific metabolic alterations. In fact, this novel result could eventually lead to the possibility of identifying the viral strain(s) responsible for the infection. Furthermore, it was possible to discriminate PPV-infected plants (symptomatic and asymptomatic leaves) from healthy plants and from plants infected by another plant pathogenic virus. These observations suggest the existence of a potential specific response to the sharka disease. Based on all these findings, the hypothesis that asymptomatic PPVinfected trees could be detected through virus-induced metabolic alterations is supported.Furthermore, the metabolic responses collected from asymptomatic leaves could be considered as early responses to PPV-infection, i.e., before the appearance of symptoms. In a second step, early metabolic alterations, before the appearance of sharka symptoms, were confirmed by a kinetic study, despite negative molecular tests (RT-qPCR). Our results indicate that early detection of PPVinfected plants by targeting metabolic responses in Prunus persica was a promising strategy. Finally,statistical correlations between the two studies were found. Although the cultivars showed significantly different metabolic profiles, some discriminant features were common between the different cultivars tested (GF-305, yellow nectarine, yellow peach) and also between the different stages of the virus infection (symptomatic and asymptomatic). Nevertheless, a co-infection of PPV and powdery mildew observed during the kinetic experiment under monitored conditions could alter the impact of PPV-infection. Consequently, a new kinetic study without co-infection, is ongoing to confirm or refute these first observations. In addition, the identification of biomarkers related to the sharka disease, also in progress, would provide a betterunderstanding of the metabolic interactions between peach and PPV. Finally, other experiments under natural conditions are underway to evaluate the robustness of our potential biomarkers
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Saint-Lary, Laure. « Évaluation de l’approche métabolomique pour l’authentification des extraits naturels utilisés dans le secteur arômes et parfums ». Thesis, Nice, 2015. http://www.theses.fr/2015NICE4025/document.

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Certains extraits naturels sont très rares et onéreux. La tentation est alors forte pour les producteurs de matières premières ou intermédiaires d’avoir recours à des adultérations. Le mélange avec des extraits issus d’origines botaniques apparentées, d’origines géographiques différentes, l’ajout d’un composé synthétique présent dans l’extrait naturel ou d’un autre extrait végétal, l’utilisation de produits phytosanitaires réglementés, la mise en place de procédés d’extractions non standardisés, en sont quelques exemples. Ces différences de qualité sont de plus en plus difficilement décelables. Cette thèse a pour objet de mettre au point une méthodologie rapide, efficace et non ciblée. Une approche métabolomique en UHPLC-HRMS est développée pour identifier ces défauts ou pratiques frauduleuses pour les absolues destinées au secteur arômes et parfums. Cette mise en évidence est réalisée par la détection de métabolites marqueurs. Les absolues présentent un défi particulier : entre 50 et 95 % de l’extrait peut être constitué de composés non volatils, rarement décrits dans la littérature. La recherche d’authenticité de ces extraits est alors plus complexe que dans le cas d’un extrait volatil tel qu’une huile essentielle, dont la composition peut être plus facilement déterminée par des techniques analytiques éprouvées et l’utilisation de bases de données. Deux plantes emblématiques de la parfumerie ont été étudiées : la violette (Viola odorata) et la rose (Rosa damascena et Rosa centifolia). Des marqueurs d’origine géographique ont été identifiés dans le cas de la violette, et des marqueurs d’origine botanique dans le cas de la rose
Some natural extracts are very scarce and expensive. The temptation is therefore very high for producers or brokers to resort to adulterations. Mixing of extracts from related botanical origins, from different geographical origins, addition of synthetic compounds with natural occurrence in the extract, or addition of another vegetal extract, use of phytosanitary products, non-standardized extraction processes, are some examples. The quality differences are more and more difficult to detect. The objective of this PhD study was to develop a fast, efficient and non-targeted methodology. Metabolomics approach in UHPLC-HRMS was developped to identify defects or fraudulent practices in absolutes used in flavour and fragrances. These identifications are realized by the detection of chemical markers. Absolutes are a great challenge: between 50 and 95 % of the extracts consist of non-volatile compounds; moreover these products are seldom described in literature. The quest for validation for authenticity is then much more complex than in cases of volatile extracts such as essential oils, whose composition can be more easily determined by robust analytical instruments and numerous databases. Two symbolic plants used in perfumery were studied: viola (Viola odorata) and rose (Rosa damascena and Rosa centifolia). Markers of French origin were identified for viola, and markers of R. centifolia were identified for rose. Their characterizations were nevertheless the fundamental limit for this technique being at trace level in the extract. This work demonstrated the performance and limitation of the non-targeted metabolomics approach on absolutes, which are specialties of perfumery
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Dumas, Thibaut. « Les approches –omiques, métabolomique et protéomique, pour l’étude de la relation de cause à effet entre contaminants émergents, produits pharmaceutiques et organismes marins, Mytilus galloprovincialis ». Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTG026.

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Ces travaux de thèse s’insèrent dans le contexte de la contamination du milieu marin par les contaminants émergents, tels que les produits pharmaceutiques (PP), et de leurs effets sur les organismes marins. L’étude des liens de cause à effet entre l’exposition à un ou plusieurs contaminants et la réponse de la moule méditerranéenne, Mytilus galloprovincialis, a été l’axe central des recherches présentées dans cette thèse. Afin de renseigner les mécanismes d’action et les potentiels effets toxiques des PP, données manquantes dans la littérature, les approches –omiques telles que la métabolomique et la protéomique ont été favorisées. Les effets de l’antiépileptique carbamazépine (CBZ), un PP fréquemment détecté dans le milieu marin, ont dans un premier temps été investigués sur M. galloprovincialis à travers une approche intégrée de la métabolomique et de la protéogénomique. La stratégie de fusion des données appliquée a mis en évidence des signatures protéiques et métaboliques corrélées entre elles en réponse à l’exposition. L’utilisation d’outils bioinformatiques remettant les protéines et métabolites dans leur contexte biologique a ainsi révélé des changements concernant la synthèse des protéines, la dégradation des acides gras, la métabolisation des acides aminés et des glucides, et la programmation de la mort cellulaire. Bien que l’étude des effets d’un seul contaminant soit essentielle pour obtenir des informations d’ordre mécanistique, elle s’éloigne en revanche de la pertinence d’une exposition environnementale, les organismes étant exposés simultanément à une multitude de contaminants. Dans le but d’intégrer cette complexité, les moules M. galloprovincialis ont été exposées à un rejet de station d’épuration (STEP), voie d’entrée principale des PP dans le milieu marin. L’analyse des empreintes métaboliques générées a d’abord été effectuée sur les moules mâles afin d’écarter la variabilité biologique liée au sexe (susceptible de masquer la réponse à l’exposition). Plusieurs voies métaboliques ont ainsi été révélées comme impactées (ex. acides aminés, bases puriques et pyrimidiques, cycle de Krebs, neurohormones, etc.) pouvant perturber plusieurs fonctions et processus biologiques (ex. métabolisme énergétique, système immunitaire, osmorégulation, reproduction, formation du byssus, etc.) et avoir des conséquences néfastes sur l’organisme. En se basant sur la littérature, des hypothèses de relation de cause à effet ont pu être établies entre certains contaminants détectés dans le rejet de STEP (38 PP et 4 pesticides) et les effets observés. A partir de cette même expérimentation, le facteur sexe a ensuite été intégré dans le traitement des données issues des individus mâles/femelles et exposés/non-exposés afin de comprendre le rôle du sexe dans la réponse à l’exposition. Pour cela, l’approche statistique Analyse of variance Multiblock Orthogonal Partial Least Square s’est révélée pertinente pour ce genre de design expérimental multifactoriel. Cette approche a ainsi pu associer la variabilité des données métabolomiques à leur(s) facteur(s) d’origine(s). Une réponse commune entre les deux sexes, reliée au facteur exposition, a été mise en évidence à travers la modulation de plusieurs lysophospholipides induite par un stress oxydant. Tandis qu’une réponse sexe-dépendante, reliée à l’interaction entre les facteurs sexe et exposition, a été décrite suite à une modulation de certains lipides polaires selon le sexe et une perturbation de la voie de la kynurénine uniquement chez les mâles. Ces travaux de thèse ont pu renforcer les connaissances sur les effets d’un PP préoccupant pour l’environnement, la CBZ, exclue de tout cadre réglementaire, ainsi que sur les effets d’une exposition proche des conditions environnementales reconstituées à travers un rejet de STEP. Des approches originales d’investigation des effets et d’analyses des données ont été pertinemment appliquées
This PhD thesis takes place in a context of the contamination of marine environment by emerging contaminants, such as pharmaceutical active compounds (PhAC), and their effects on marine organisms. The study of causal relationships between exposure to one or more contaminants and the response of the Mediterranean mussel, Mytilus galloprovincialis, was the central focus of the research presented in this thesis. In order to provide information on the mechanisms of action and potential toxic effects of PhAC, data lacking in the literature, -omic approaches such as metabolomics and proteomics were applied. The effects of the antiepileptic carbamazepine (CBZ), a PhAC frequently detected in the marine environment, were first investigated on M. galloprovincialis through an integrated approach of metabolomics and proteogenomics. The data fusion strategy applied revealed correlated protein and metabolic signatures in response to exposure. The use of bioinformatics tools that put proteins and metabolites into their biological context thus highlighted changes in protein synthesis, fatty acid degradation, amino acid and carbohydrate metabolism, and cell death programming. Although the study of the effects of a single contaminant is essential to obtain mechanistic information, it is far removed from the relevance of environmental exposure, since organisms are exposed simultaneously to a multitude of contaminants. In order to integrate this complexity, mussels M. galloprovincialis were exposed to a wastewater treatment plant (WWTP) effluent, the main pathway of PhAC into the marine environment. Analysis of the metabolic fingerprints generated was first performed on male mussels to rule out gender-related biological variability (which could hide the response to exposure). Several metabolic pathways were thus revealed to be impacted (e.g. amino acids, purines and pyrimidines, Krebs cycle, neurohormones, etc.) which can disrupt several biological functions and processes (e.g. energy metabolism, immune system, osmorregulation, reproduction, byssal formation, etc.) and have adverse consequences on the organism. Based on the literature, hypotheses of causal relationships have been established between certain contaminants detected in the WWTP effluent (38 PPs and 4 pesticides) and the effects observed. Based on the same experiment, the gender factor was then integrated into the processing of data acquired from male/female and exposed/unexposed individuals in order to understand the role of gender in the response to exposure. To this end, the statistical approach of Analysis of Variance Multiblock Orthogonal Partial Least Square proved to be relevant for this kind of multifactorial experimental design. This approach was thus able to characterize and relate the variability of metabolomics data to its different factors of origin. A common response between the two genders, related to the exposure factor, was demonstrated through the modulation of several lysophospholipids induced by oxidative stress. While a gender-specific response, related to the interaction between gender and exposure factors, has been described following a modulation of certain polar lipids according to gender and a disruption of the kynurenin pathway only in males. This thesis work was able to strengthen knowledge on the effects of a PhAC of concern for the environment, CBZ, excluded from any regulatory framework, as well as on the effects of an exposure close to the environmental conditions reconstituted through a WWTP effluent. Original approaches to effects investigation and data analysis have been pertinently applied
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Cecchini, Tiphaine. « Caractérisation de bactéries par analyses protéomiques en spectrométrie de masse ». Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1064.

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Grâce à la spectrométrie de masse de type MALDI-TOF, l'identification des bactéries est maintenant possible en quelques minutes. Mais le taux de mortalité des patients augmente lorsqu'une antibiothérapie inappropriée est utilisée et les instruments MALDI-TOF ne sont pas capables d'analyser rapidement et exhaustivement la résistance bactérienne. Actuellement, 6 à 24 heures sont nécessaires pour déterminer le phénotype de résistance. En couplant une chromatographie liquide et un spectromètre de masse à ionisation électrospray (LC-MS/MS), nous avons identifié les marqueurs de résistance en 1 à 2 heures. En 30 min, nous avons pu détecter les mécanismes de résistance aux β-lactamines, aux glycopeptides, à la méthicilline et aux fluoroquinolones, à l'aide de méthodes de type "Suivi de Réactions Sélectionnées", ou "Selected Reaction Monitoring" (SRM). Au cours de la même analyse multiplexée, des dizaines de protéines peuvent être détectées de façon hautement spécifique et sensible. Comme l'illustre l'étude de la résistance multifactorielle chez Acinetobacter baumannii, cette approche permet en outre une analyse quantitative d'un grand intérêt pour certains mécanismes de résistance. Cependant, malgré ces perspectives attrayantes, la LC-MS/MS reste, aujourd'hui, loin d'une possible implantation en routine dans les laboratoires de microbiologie. Les instruments sont trop coûteux et la technologie trop complexe pour un usage pour du diagnostic in vitro. La spectrométrie de masse pourrait déjà avantageusement compléter les technologies actuelles de biologie moléculaire. Aujourd'hui, le séquençage de nouvelle génération est la méthode de référence pour la caractérisation moléculaire des bactéries. Mais, comme démontré dans ce travail, l'annotation des gènes est perfectible. Pour quelques dizaines d'euros et quelques heures d'analyse, les peptides identifies par spectrométrie de masse facilitent l'assemblage des séquences (« scaffolds ») et la détection des gènes. De surcroît, la spectrométrie de masse permet une quantification précise des protéines. Elle apporte ainsi une nouvelle dimension analytique et une vision moléculaire plus proche du phénotype. En conclusion, la spectrométrie de masse LC-MS/MS peut être une technologie complémentaire attractive, voir une future alternative, à la biologie moléculaire pour la caractérisation des bactéries
Thanks to MALDI-TOF mass spectrometry, identification of isolated bacteria is now possible within a few minutes. But doctors also need to rapidly know the phenotype of resistance of the bacteria. Indeed, the patient mortality rate increases when the antibiotherapy is not appropriate. However, MALDI-TOF instruments are not able to analyze antibacterial resistance rapidly and comprehensively.Today, 6 to 24 hours are nedded for antibiotic susceptibility testing. When combining a liquid chromatography and a mass spectrometer with electrospray ionization (LC-MSMS), the detection of resistance biomarkers was possible within 1 to 2 hours. Using a Selected Reaction Monitoring (SRM) method, resistance mechanisms to beta-lactams, methicillin, glycopeptides and fluoroquinolones were detected in strains within 30 minutes. Tens of resistance determinants can be analyzed in a single multiplexed assay, with high specificity and sensitivity. Illustrated by the study of multifactorial resistance in Acinetobacter baumannii, the technology allows furthermore a quantitative analysis, which is of great value for some resistance mechanisms. Similarly, we identified virulent strains of enterohemorrhagic Escherichia coli by targeting toxins and serotype biomakers in the same assay. Mass spectrometry offered deeper bacterial characterization than conventional serotyping using polyclonal antibodies. However, despite all these favorable prospects, LC-MS/MS remains today far from reaching a routine use in microbiological hospital laboratories. Instruments are too expensive and the technology is too cumbersome for a daily in vitro diagnostic use. Waiting for a more suitable use, mass spectrometry could yet advantageously complement current molecular technologies. Today, the gold standard to study bacteria at molecular level is next generation sequencing. However, as demonstrated during this work, gene annotation remains imperfect. For tens of euros and few hours of analysis, peptides identified by mass spectrometry analysis of a bacteria might improve scaffold assembly and gene detection. Moreover, mass spectrometry gives an accurate protein quantitation and brings a new analytical dimension, potentially closer to the phenotype than molecular techniques. In conclusion, LC-MS/MS mass spectrometry could be an attractive complementary, or alternative technology in a near future, to conventional molecular biology techniques for deep characterization of bacteria
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Larabi, Islam Amine. « Nouveaux produits de synthèse : analyse, consommation et métabolisme ; Applications cliniques et médicolégales Rapid and simultaneous screening of new psychoactive substances and conventional drugs of abuse. A comparative study of Biochip Array Technology versus LC-MS/MS in whole blood and urine Development of a sensitive untargeted liquid chromatography– high resolution mass spectrometry screening devoted to hair analysis through a shared MS2 spectra database : A step toward early detection of new psychoactive substances Validation of an UPLC-MS/MS method for the determination of sixteen synthetic cannabinoids in human hair. Application to document chronic use of JWH-122 following a non-fatal overdose Development and validation of liquid chromatography-tandem mass spectrometry targeted screening of 16 fentanyl analogs and U-47700 in hair : Application to 137 authentic samples Prevalence and Surveillance of Synthetic Cathinones Use by Hair Analysis : An Update Review Prevalence of New Psychoactive Substances(NPS) and conventional drugs of abuse (DOA) in high risk populations from Paris(France) and its suburbs A cross sectional study by hair testing(2012–2017) Evaluation of drug abuse by hair analysis and self-reported use among MSM under PrEP : Results from a sub-study of the ANRS-IPERGAY trial. Hair testing for 3‑fluorofentanyl, furanylfentanyl, methoxyacetylfentanyl, carfentanil, acetylfentanyl and fentanyl by LC–MS/MS after unintentional overdose Drug‐facilitated sexual assault (DFSA) involving 4‐methylethcathinone (4‐MEC),3,4‐Methylenedioxypyrovalerone (MDPV), and doxylamine highlighted by hair analysis Metabolic Profiling of Deschloro-N-ethyl-ketamine (O-PCE) and identification of new target metabolites in urine and hair using human liver microsomes and high-resolution accurate mass spectrometry ». Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL029.

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L’objectif de ce travail a été de développer deux approches analytiques dédiées à l’analyse toxicologique des nouveaux produits de synthèse (NPS) dans différentes matrices biologiques (sang, urine et cheveux). La première est basée sur le criblage non ciblé par chimiluminescence sur biopuces et chromatographie liquide couplée à la spectrométrie de masse haute résolution (LC-HRMS) et la deuxième correspond à un criblage ciblé par spectrométrie de masse en tandem (LC-MS/MS). Ces deux approches ont ensuite été appliquées dans des études observationnelles pour évaluer la consommation de NPS dans des populations à risques de surdosage, de pharmacodépendance ou de soumission chimique dans un contexte clinique ou médico-judiciaire.La dernière partie a été consacrée au développement d’un nouvel outil analytique de traitement des données issues de la LC-HRMS qui a permis d’étudier le métabolisme de 9 NPS in vitro sur des cultures de microsomes du foie humain (HLM) et in vivo sur des échantillons biologiques d’usagers de ces drogues. Cette dernière approche a permis la création d’une bibliothèque de spectres de haute résolution composée de 228 métabolites dont certains ont été proposés comme marqueurs pertinents d’exposition aux NPS dont ils sont issus.Ce travail a été concrétisé par la rédaction de 10 publications scientifiques et a permis d’initier plusieurs collaborations pluridisciplinaires
The aim of the present work was to develop two analytical approaches dedicated to the analysis of new psychoactive substances in different biological matrices (blood, urine and hair). The first approach is based on untargeted screening by both biochip array technology chemiluminescence assay and liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and the second corresponds to a targeted screening by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). These two approaches were then applied in observational studies to assess the consumption of NPS in high risk populations (overdose, drug abuse, drug facilitated crimes) in clinical and forensic settings. The last part of the work was devoted to the development of a new analytical tool for LC-HRMS data processing which made it possible to study the metabolism of 9 NPS In vitro on human liver microsomes (HLM) and In vivo in biological samples from drug users. This approach has enabled the creation of HRMS spectral library containing 228 metabolites, some of which have been proposed as relevant markers of NPS exposure.This work has resulted on 10 scientific publications and allowed to initiate many multidisciplinary collaborations
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Ancillotti, Claudia. « Development and application of targeted and untargeted LC-MS/MS methods for metabolomics studies : from vegetal to biological matrixes ». Doctoral thesis, 2018. http://hdl.handle.net/2158/1130704.

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In the present work, LC-MS and LC-MS/MS methods have been developed and applied for the analysis of polyphenols in different biological system (i.e. plant tissues, fruits and biofluids). For this purpose, both targeted and untargeted approaches were applied for metabolomics analysis in different field, from environmental to food science and clinical researches.
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