@article{ZwaagHorstBlaženovićetal.2020, author = {Zwaag, Jelle and Horst, Rob ter and Blaženović, Ivana and St{\"o}ßel, Daniel and Ratter, Jacqueline and Worseck, Josephine M. and Schauer, Nicolas and Stienstra, Rinke and Netea, Mihai G. and Jahn, Dieter and Pickkers, Peter and Kox, Matthijs}, title = {Involvement of lactate and pyruvate in the anti-inflammatory effects exerted by voluntary activation of the sympathetic nervous system}, series = {Metabolites}, volume = {10}, journal = {Metabolites}, number = {4}, publisher = {MDPI}, address = {Basel}, issn = {2218-1989}, doi = {10.3390/metabo10040148}, pages = {1 -- 18}, year = {2020}, abstract = {We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1 beta and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects.}, language = {en} } @phdthesis{Stoessel2018, author = {St{\"o}ßel, Daniel}, title = {Biomarker Discovery in Multiple Sclerosis and Parkinson's disease}, school = {Universit{\"a}t Potsdam}, pages = {135}, year = {2018}, abstract = {Neuroinflammatory and neurodegenerative diseases such as Parkinson's (PD) and multiple sclerosis (MS) often result in a severe impairment of the patient´s quality of life. Effective therapies for the treatment are currently not available, which results in a high socio-economic burden. Due to the heterogeneity of the disease subtypes, stratification is particularly difficult in the early phase of the disease and is mainly based on clinical parameters such as neurophysiological tests and central nervous imaging. Due to good accessibility and stability, blood and cerebrospinal fluid metabolite markers could serve as surrogates for neurodegenerative processes. This can lead to an improved mechanistic understanding of these diseases and further be used as "treatment response" biomarkers in preclinical and clinical development programs. Therefore, plasma and CSF metabolite profiles will be identified that allow differentiation of PD from healthy controls, association of PD with dementia (PDD) and differentiation of PD subtypes such as akinetic rigid and tremor dominant PD patients. In addition, plasma metabolites for the diagnosis of primary progressive MS (PPMS) should be investigated and tested for their specificity to relapsing-remitting MS (RRMS) and their development during PPMS progression. By applying untargeted high-resolution metabolomics of PD patient samples and in using random forest and partial least square machine learning algorithms, this study identified 20 plasma metabolites and 14 CSF metabolite biomarkers. These differentiate against healthy individuals with an AUC of 0.8 and 0.9 in PD, respectively. We also identify ten PDD specific serum metabolites, which differentiate against healthy individuals and PD patients without dementia with an AUC of 1.0, respectively. Furthermore, 23 akinetic-rigid specific plasma markers were identified, which differentiate against tremor-dominant PD patients with an AUC of 0.94 and against healthy individuals with an AUC of 0.98. These findings also suggest more severe disease pathology in the akinetic-rigid PD than in tremor dominant PD. In the analysis of MS patient samples a partial least square analysis yielded predictive models for the classification of PPMS and resulted in 20 PPMS specific metabolites. In another MS study unknown changes in human metabolism were identified after administration of the multiple sclerosis drug dimethylfumarate, which is used for the treatment of RRMS. These results allow to describe and understand the hitherto completely unknown mechanism of action of this new drug and to use these findings for the further development of new drugs and targets against RRMS. In conclusion, these results have the potential for improved diagnosis of these diseases and improvement of mechanistic understandings, as multiple deregulated pathways were identified. Moreover, novel Dimethylfumarate targets can be used to aid drug development and treatment efficiency. Overall, metabolite profiling in combination with machine learning identified as a promising approach for biomarker discovery and mode of action elucidation.}, language = {en} } @article{StobieckiSkiryczKerhoasetal.2006, author = {Stobiecki, Maciej and Skirycz, Aleksandra and Kerhoas, L. and Kachlicki, P. and Muth, D. and Einhorn, J. and Mueller-Roeber, Bernd}, title = {Profiling of phenolic glycosidic conjugates in leaves of Arabidopsis thaliana using LC/MS}, series = {Metabolomics : the official journal of the Metabolomics Society}, volume = {2}, journal = {Metabolomics : the official journal of the Metabolomics Society}, publisher = {Springer}, address = {New York}, issn = {1573-3882}, doi = {10.1007/s11306-006-0031-5}, pages = {197 -- 219}, year = {2006}, abstract = {Profiling of plant secondary metabolites is still a very difficult task. Liquid chromatography (LC) or capillary electrophoresis hyphenated with different kinds of detectors are methods of choice for analysis of polar, thermo labile compounds with high molecular masses. We demonstrate the applicability of LC combined with UV diode array or/and mass spectrometric detectors for the unambiguous identification and quantification of flavonoid conjugates isolated from Arahidopsis thaliana leaves of different genotypes and grown in different environmental conditions. During LC/UV/MS/MS analyses we were able to identify tetra-, tri, and di-glycosides of kaempferol, quercetin and isorhamnetin. Based on our results we can conclude that due to the co-elution of different chemical compounds in reversed phase H PLC systems the application of UV detectors does not allow to precisely profile all flavonoid conjugates existing in A. thaliana genotypes. Using MS detection it was possible to unambiguously recognize the glycosylation patterns of the aglycones. However, from the mass spectra we could not conclude neither the anomeric form of the C-1 carbon atoms of sugar moieties in glycosidic bonds between sugars or sugar and aglycone nor the position of the second carbon involved in disaccharides. The applicability of collision induced dissociation techniques (CID MS/MS) for structural analyses of the studied group of plant secondary metabolites with two types of analyzers (triple quadrupole or ion trap) was demonstrated.}, language = {en} } @article{SchwahnNikoloski2018, author = {Schwahn, Kevin and Nikoloski, Zoran}, title = {Data reduction approaches for dissecting transcriptional effects on metabolism}, series = {Frontiers in plant science}, volume = {9}, journal = {Frontiers in plant science}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-462X}, doi = {10.3389/fpls.2018.00538}, pages = {12}, year = {2018}, abstract = {The availability of high-throughput data from transcriptomics and metabolomics technologies provides the opportunity to characterize the transcriptional effects on metabolism. Here we propose and evaluate two computational approaches rooted in data reduction techniques to identify and categorize transcriptional effects on metabolism by combining data on gene expression and metabolite levels. The approaches determine the partial correlation between two metabolite data profiles upon control of given principal components extracted from transcriptomics data profiles. Therefore, they allow us to investigate both data types with all features simultaneously without doing preselection of genes. The proposed approaches allow us to categorize the relation between pairs of metabolites as being under transcriptional or post-transcriptional regulation. The resulting classification is compared to existing literature and accumulated evidence about regulatory mechanism of reactions and pathways in the cases of Escherichia coil, Saccharomycies cerevisiae, and Arabidopsis thaliana.}, language = {en} } @article{RohrmannTohgeAlbaetal.2011, author = {Rohrmann, Johannes and Tohge, Takayuki and Alba, Rob and Osorio, Sonia and Caldana, Camila and McQuinn, Ryan and Arvidsson, Samuel Janne and van der Merwe, Margaretha J. and Riano-Pachon, Diego Mauricio and M{\"u}ller-R{\"o}ber, Bernd and Fei, Zhangjun and Nesi, Adriano Nunes and Giovannoni, James J. and Fernie, Alisdair R.}, title = {Combined transcription factor profiling, microarray analysis and metabolite profiling reveals the transcriptional control of metabolic shifts occurring during tomato fruit development}, series = {The plant journal}, volume = {68}, journal = {The plant journal}, number = {6}, publisher = {Wiley-Blackwell}, address = {Malden}, issn = {0960-7412}, doi = {10.1111/j.1365-313X.2011.04750.x}, pages = {999 -- 1013}, year = {2011}, abstract = {Maturation of fleshy fruits such as tomato (Solanum lycopersicum) is subject to tight genetic control. Here we describe the development of a quantitative real-time PCR platform that allows accurate quantification of the expression level of approximately 1000 tomato transcription factors. In addition to utilizing this novel approach, we performed cDNA microarray analysis and metabolite profiling of primary and secondary metabolites using GC-MS and LC-MS, respectively. We applied these platforms to pericarp material harvested throughout fruit development, studying both wild-type Solanum lycopersicum cv. Ailsa Craig and the hp1 mutant. This mutant is functionally deficient in the tomato homologue of the negative regulator of the light signal transduction gene DDB1 from Arabidopsis, and is furthermore characterized by dramatically increased pigment and phenolic contents. We choose this particular mutant as it had previously been shown to have dramatic alterations in the content of several important fruit metabolites but relatively little impact on other ripening phenotypes. The combined dataset was mined in order to identify metabolites that were under the control of these transcription factors, and, where possible, the respective transcriptional regulation underlying this control. The results are discussed in terms of both programmed fruit ripening and development and the transcriptional and metabolic shifts that occur in parallel during these processes.}, language = {en} } @article{LisecRoemischMarglNikoloskietal.2011, author = {Lisec, Jan and R{\"o}misch-Margl, Lilla and Nikoloski, Zoran and Piepho, Hans-Peter and Giavalisco, Patrick and Selbig, Joachim and Gierl, Alfons and Willmitzer, Lothar}, title = {Corn hybrids display lower metabolite variability and complex metabolite inheritance patterns}, series = {The plant journal}, volume = {68}, journal = {The plant journal}, number = {2}, publisher = {Wiley-Blackwell}, address = {Malden}, issn = {0960-7412}, doi = {10.1111/j.1365-313X.2011.04689.x}, pages = {326 -- 336}, year = {2011}, abstract = {We conducted a comparative analysis of the root metabolome of six parental maize inbred lines and their 14 corresponding hybrids showing fresh weight heterosis. We demonstrated that the metabolic profiles not only exhibit distinct features for each hybrid line compared with its parental lines, but also separate reciprocal hybrids. Reconstructed metabolic networks, based on robust correlations between metabolic profiles, display a higher network density in most hybrids as compared with the corresponding inbred lines. With respect to metabolite level inheritance, additive, dominant and overdominant patterns are observed with no specific overrepresentation. Despite the observed complexity of the inheritance pattern, for the majority of metabolites the variance observed in all 14 hybrids is lower compared with inbred lines. Deviations of metabolite levels from the average levels of the hybrids correlate negatively with biomass, which could be applied for developing predictors of hybrid performance based on characteristics of metabolite patterns.}, language = {en} } @article{JueppnerMubeenLeisseetal.2017, author = {J{\"u}ppner, Jessica and Mubeen, Umarah and Leisse, Andrea and Caldana, Camila and Brust, Henrike and Steup, Martin and Herrmann, Marion and Steinhauser, Dirk and Giavalisco, Patrick}, title = {Dynamics of lipids and metabolites during the cell cycle of Chlamydomonas reinhardtii}, series = {The plant journal}, volume = {92}, journal = {The plant journal}, publisher = {Wiley}, address = {Hoboken}, issn = {0960-7412}, doi = {10.1111/tpj.13642}, pages = {331 -- 343}, year = {2017}, abstract = {Metabolites and lipids are the final products of enzymatic processes, distinguishing the different cellular functions and activities of single cells or whole tissues. Understanding these cellular functions within a well-established model system requires a systemic collection of molecular and physiological information. In the current report, the green alga Chlamydomonas reinhardtii was selected to establish a comprehensive workflow for the detailed multi-omics analysis of a synchronously growing cell culture system. After implementation and benchmarking of the synchronous cell culture, a two-phase extraction method was adopted for the analysis of proteins, lipids, metabolites and starch from a single sample aliquot of as little as 10-15million Chlamydomonas cells. In a proof of concept study, primary metabolites and lipids were sampled throughout the diurnal cell cycle. The results of these time-resolved measurements showed that single compounds were not only coordinated with each other in different pathways, but that these complex metabolic signatures have the potential to be used as biomarkers of various cellular processes. Taken together, the developed workflow, including the synchronized growth of the photoautotrophic cell culture, in combination with comprehensive extraction methods and detailed metabolic phenotyping has the potential for use in in-depth analysis of complex cellular processes, providing essential information for the understanding of complex biological systems.}, language = {en} } @phdthesis{Bulut2023, author = {Bulut, Mustafa}, title = {Assessing the genetic architecture underlying systemic responses to variable environments in crops using multi-omics}, school = {Universit{\"a}t Potsdam}, pages = {180, IV}, year = {2023}, abstract = {Plant metabolism serves as the primary mechanism for converting assimilated carbon into essential compounds crucial for plant growth and ultimately, crop yield. This renders it a focal point of research with significant implications. Despite notable strides in comprehending the genetic principles underpinning metabolism and yield, there remains a dearth of knowledge regarding the genetic factors responsible for trait variation under varying environmental conditions. Given the burgeoning global population and the advancing challenges posed by climate change, unraveling the intricacies of metabolic and yield responses to water scarcity became increasingly important in safeguarding food security. Our research group has recently started to work on the genetic resources of legume species. To this end, the study presented here investigates the metabolic diversity across five different legume species at a tissue level, identifying species-specific biosynthesis of alkaloids as well as iso-/flavonoids with diverse functional groups, namely prenylation, phenylacylation as well as methoxylation, to create a resource for follow up studies investigation the metabolic diversity in natural diverse populations of legume species. Following this, the second study investigates the genetic architecture of drought-induced changes in a global common bean population. Here, a plethora of quantitative trait loci (QTL) associated with various traits are identified by performing genome-wide association studies (GWAS), including for lipid signaling. On this site, overexpression of candidates highlighted the induction of several oxylipins reported to be pivotal in coping with harsh environmental conditions such as water scarcity. Diverging from the common bean and GWAS, the following study focuses on identifying drought-related QTL in tomato using a bi-parental breeding population. This descriptive study highlights novel multi-omic QTL, including metabolism, photosynthesis as well as fruit setting, some of which are uniquely assigned under drought. Compared to conventional approaches using the bi-parental IL population, the study presented improves the resolution by assessing further backcrossed ILs, named sub-ILs. In the final study, a photosynthetic gene, namely a PetM subunit of the cytochrome b6f complex encoding gene, involved in electron flow is characterized in an horticultural important crop. While several advances have been made in model organisms, this study highlights the transition of this fundamental knowledge to horticultural important crops, such as tomato, and investigates its function under differing light conditions. Overall, the presented thesis combines different strategies in unveiling the genetic components in multi-omic traits under drought using conventional breeding populations as well as a diverse global population. To this end, it allows a comparison of either approach and highlights their strengths and weaknesses.}, language = {en} } @article{BalazadehSchildhauerAraujoetal.2014, author = {Balazadeh, Salma and Schildhauer, Joerg and Araujo, Wagner L. and Munne-Bosch, Sergi and Fernie, Alisdair R. and Proost, Sebastian and Humbeck, Klaus and M{\"u}ller-R{\"o}ber, Bernd}, title = {Reversal of senescence by N resupply to N-starved Arabidopsis thaliana: transcriptomic and metabolomic consequences}, series = {Journal of experimental botany}, volume = {65}, journal = {Journal of experimental botany}, number = {14}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0022-0957}, doi = {10.1093/jxb/eru119}, pages = {3975 -- 3992}, year = {2014}, abstract = {Leaf senescence is a developmentally controlled process, which is additionally modulated by a number of adverse environmental conditions. Nitrogen shortage is a well-known trigger of precocious senescence in many plant species including crops, generally limiting biomass and seed yield. However, leaf senescence induced by nitrogen starvation may be reversed when nitrogen is resupplied at the onset of senescence. Here, the transcriptomic, hormonal, and global metabolic rearrangements occurring during nitrogen resupply-induced reversal of senescence in Arabidopsis thaliana were analysed. The changes induced by senescence were essentially in keeping with those previously described; however, these could, by and large, be reversed. The data thus indicate that plants undergoing senescence retain the capacity to sense and respond to the availability of nitrogen nutrition. The combined data are discussed in the context of the reversibility of the senescence programme and the evolutionary benefit afforded thereby. Future prospects for understanding and manipulating this process in both Arabidopsis and crop plants are postulated.}, language = {en} }