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AbstractUncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose‐dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low‐dose exposure response in chronic exposure. A simple one‐compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up‐ or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects.

The European Union (EU) has introduced statutory limits for patulin in fruit products. Species definitions need to be unambiguous for this capability, especially to determine 'weak spots' in food, drink and feed production. Fungi were analysed for the isoepoxydon dehydrogenase (IDH) gene of the patulin metabolic pathway to indicate potential patulin production. In several cases inhibition of PCR product formation was indicated. Dilution as a means of overcoming PCR inhibition and to determine optimal concentrations was assessed and the ramifications for nucleic acid analysis in general are highlighted. The inhibitors may be secondary metabolites. However, inhibition was not involved obviously for Penicillium brevicompactum. The gene was detected frequently from Aspergillus section Clavati and Penicillium subgenus Penicillium species. Some strains within certain species were negative for the gene. Detection of the gene product in Byssochlamys is reported. ; UK Food Standards Agency - contract no. ...

Iron is an essential micronutrient that participates as a cofactor in a broad range of metabolic processes including mitochondrial respiration, DNA replication, protein translation and lipid biosynthesis. Adaptation to iron deficiency requires the global reorganization of cellular metabolism directed to optimize iron utilization. The budding yeast Saccharomyces cerevisiae has been widely used to characterize the responses of eukaryotic microorganisms to iron depletion. In this report, we used a genomic approach to investigate the contribution of transcription rates to the modulation of mRNA levels during adaptation of yeast cells to iron starvation. We reveal that a decrease in the activity of all RNA polymerases contributes to the down-regulation of many mRNAs, tRNAs and rRNAs. Opposite to the general expression pattern, many genes including components of the iron deficiency response, the mitochondrial retrograde pathway and the general stress response display a remarkable increase in both transcription rates and mRNA levels upon iron limitation, whereas genes encoding ribosomal proteins or implicated in ribosome biogenesis exhibit a pronounced fall. This expression profile is consistent with an activation of the environmental stress response. The phosphorylation stage of multiple regulatory factors strongly suggests that the conserved nutrient signaling pathway TORC1 is inhibited during the progress of iron deficiency. These results suggest an intricate crosstalk between iron metabolism and the TORC1 pathway that should be considered in many disorders. ; This work was supported by predoctoral contracts from the Spanish Ministry of Science, Innovation and Universities (MICINN) to AMR and LRA; a fellowship from the "Generalitat de Catalunya" (Spain) to SMM; European Union Funds (FEDER) and MICINN grants BIO2017-87828-C2-1-P to SP, BIO2017-87828-C2-2-P to MATR, BFU2016-77728-C3-3-P to JEPO, and BFU2015-71978-REDT to SP and JEPO; and Regional Government of Valencia PROMETEOII 2015/006 grant to JEPO.

Publisher's version (útgefin grein). ; Background: Lactobacillus reuteri is a heterofermentative Lactic Acid Bacterium (LAB) that is commonly used for food fermentations and probiotic purposes. Due to its robust properties, it is also increasingly considered for use as a cell factory. It produces several industrially important compounds such as 1,3-propanediol and reuterin natively, but for cell factory purposes, developing improved strategies for engineering and fermentation optimization is crucial. Genome-scale metabolic models can be highly beneficial in guiding rational metabolic engineering. Reconstructing a reliable and a quantitatively accurate metabolic model requires extensive manual curation and incorporation of experimental data. Results: A genome-scale metabolic model of L. reuteri JCM 1112T was reconstructed and the resulting model, Lreuteri_530, was validated and tested with experimental data. Several knowledge gaps in the metabolism were identified and resolved during this process, including presence/absence of glycolytic genes. Flux distribution between the two glycolytic pathways, the phosphoketolase and Embden-Meyerhof-Parnas pathways, varies considerably between LAB species and strains. As these pathways result in different energy yields, it is important to include strain-specific utilization of these pathways in the model. We determined experimentally that the Embden-Meyerhof-Parnas pathway carried at most 7% of the total glycolytic flux. Predicted growth rates from Lreuteri_530 were in good agreement with experimentally determined values. To further validate the prediction accuracy of Lreuteri_530, the predicted effects of glycerol addition and adhE gene knock-out, which results in impaired ethanol production, were compared to in vivo data. Examination of both growth rates and uptake- and secretion rates of the main metabolites in central metabolism demonstrated that the model was able to accurately predict the experimentally observed effects. Lastly, the potential of L. reuteri as a cell factory was investigated, resulting in a number of general metabolic engineering strategies. Conclusion: We have constructed a manually curated genome-scale metabolic model of L. reuteri JCM 1112T that has been experimentally parameterized and validated and can accurately predict metabolic behavior of this important platform cell factory. ; This study was supported by the Marine Biotechnology ERA-NET Thermo-Factories project grant number 5178–00003B; the Technology Development fund in Iceland grant number 159004-0612; The Novo Nordisk Foundation in Denmark; and the European Union's Horizon 2020 research and innovation programme under grant agreement No 686070 (DD-DeCaF). ; Peer Reviewed

This article belongs to the Special Issue Plant Respiration. ; The interaction of the alternative oxidase (AOX) pathway with nutrient metabolism is important for understanding how respiration modulates ATP synthesis and carbon economy in plants under nutrient deficiency. Although AOX activity reduces the energy yield of respiration, this enzymatic activity is upregulated under stress conditions to maintain the functioning of primary metabolism. The in vivo metabolic regulation of AOX activity by phosphorus (P) and nitrogen (N) and during plant symbioses with Arbuscular mycorrhizal fungi (AMF) and Rhizobium bacteria is still not fully understood. We highlight several findings and open questions concerning the in vivo regulation of AOX activity and its impact on plant metabolism during P deficiency and symbiosis with AMF. We also highlight the need for the identification of which metabolic regulatory factors of AOX activity are related to N availability and nitrogen-fixing legume-rhizobia symbiosis in order to improve our understanding of N assimilation and biological nitrogen fixation. ; This work was supported by FONDECYT No. 1191118 from National Agency for Research and Development (ANID) and the Chilean Scholarship Program/Becas de doctorado nacional/2017–21180329. I.F.-S. has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 753301. ; Peer reviewed

Il lavoro di tesi consiste nello sviluppo di un modello in silico per la simulazione dell'azione del farmaco all'interno del pathway metabolico scelto e uno studio di docking molecolare. Il farmaco preso in considerazione è il Viagra, che contiene il principio attivo Sildenafil. La sua funzione è il rilassamento della muscolatura liscia. Il linguaggio di programmazione considerato per la modellazione è Python. Il software per effetuare il docking molecolare è AutoDock Vina. Con le informazioni ottenute è possibile verificare l'utilizzo del Sildenafil in altre applicazioni cliniche, diverse da quelle approvate dagli enti governativi. The thesis work consists in the development of an in silico model for the simulation of the drug action within the chosen metabolic pathway and a molecular docking study. The drug under consideration is Viagra, which contains the active ingredient Sildenafil. Its function is the relaxation of smooth muscles. The programming language considered for modeling is Python. The software for molecular docking is AutoDock Vina. With the information obtained, it is possible to verify the use of the Sildenafil in other clinical applications, other than those approved by government bodies.

Bacterial photobiohybrids and photosynthesis: Optimizing energy harvesting with bacterial-semiconductor hybrids
Photosynthesis serves as the primary mechanism for converting solar energy into chemical energy and plays a pivotal role in regulating atmospheric oxygen levels and carbon dioxide concentrations, influencing global climate patterns as a result. Traditional photosynthetic pigments, such as chlorophyll, can only absorb specific regions of the electromagnetic spectrum, leaving a significant span of wavelengths of light unutilized. The solar energy-conversion efficiency of photosynthesis typically reaches a maximum of ~6%; however, some plants exhibit efficiencies lower than 1%, depending on the type of organism, environmental conditions, and the specific metabolic pathway involved. While photosynthesis has relatively low efficiency compared to some human-made solar energy technologies, it plays a crucial role in sustaining life on Earth by providing the primary source of energy for most ecosystems.

AbstractObesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it's effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and interleukin 6 (IL-6). The activation of IκB kinase β (IKKβ) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKβ/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility.

15 pages, 7 figures, supplementary information https://doi.org/10.1038/s42003-021-02112-2.-- All data generated or analyzed during this study are included in this published article (and its supplementary information files). All raw sequences are publicly available at both DOE's JGI Integrated Microbial Genomes and Microbiomes (IMG/MER) and the European Nucleotide Archive (ENA). Individual metagenome assemblies, annotation files, and alignment files can be accessed at IMG/MER. All accession numbers are listed in Supplementary Data 1. The co-assembly for the MAG dataset construction can be found through ENA at https://www.ebi.ac.uk/ena with accession number PRJEB40454, the nucleotide sequence for each MAG and their annotation files can be found through BioStudies at https://www.ebi.ac.uk/biostudies with accession S-BSST457 and also in the companion website to this manuscript at https://malaspina-public.gitlab.io/malaspina-deep-ocean-microbiome/.-- All software used in this work is publicly available distributed by their respective developers, and it is described in "Methods", including the versions and options used. Additional custom scripts to assign taxonomy to the M-geneDB genes and to filter and format FRA results are available through BioStudies at https://www.ebi.ac.uk/biostudies with accession S-BSST457 ; The deep sea, the largest ocean's compartment, drives planetary-scale biogeochemical cycling. Yet, the functional exploration of its microbial communities lags far behind other environments. Here we analyze 58 metagenomes from tropical and subtropical deep oceans to generate the Malaspina Gene Database. Free-living or particle-attached lifestyles drive functional differences in bathypelagic prokaryotic communities, regardless of their biogeography. Ammonia and CO oxidation pathways are enriched in the free-living microbial communities and dissimilatory nitrate reduction to ammonium and H2 oxidation pathways in the particle-attached, while the Calvin Benson-Bassham cycle is the most prevalent inorganic carbon fixation pathway in both size fractions. Reconstruction of the Malaspina Deep Metagenome-Assembled Genomes reveals unique non-cyanobacterial diazotrophic bacteria and chemolithoautotrophic prokaryotes. The widespread potential to grow both autotrophically and heterotrophically suggests that mixotrophy is an ecologically relevant trait in the deep ocean. These results expand our understanding of the functional microbial structure and metabolic capabilities of the largest Earth aquatic ecosystem ; This work was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) through the Consolider-Ingenio program (Malaspina 2010 Expedition, ref. CSD2008-00077). The sequencing of 58 bathypelagic metagenomes was done by the U.S. Department of Energy Joint Genome Institute, supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02 05CH11231 to SGA (CSP 612 "Microbial metagenomics and transcriptomics from a global deep-ocean expedition"). Additional funding was provided by the project MAGGY (CTM2017-87736-R) to S.G.A. from the Spanish Ministry of Economy and Competitiveness, Grup de Recerca 2017SGR/1568 from Generalitat de Catalunya, and King Abdullah University of Science and Technology (KAUST) under contract OSR #3362 and by funding of the EMFF Program of the European Union (MERCLUB project, Grant Agreement 863584). The ICM researchers have had the institutional support of the "Severo Ochoa Centre of Excellence" accreditation (CEX2019-000928-S). High-Performance computing analyses were run at the Marine Bioinformatics Service (MARBITS, https://marbits.icm.csic.es) of the Institut de Ciències del Mar (ICM-CSIC), Barcelona, Supercomputing Center (Grant BCV-2013-2-0001) and KAUST's Ibex HPC ; Peer reviewed

AbstractWinery effluents containing high ethanol concentrations and diverse organic matter are ideal substrates for producing medium-chain carboxylic acids via fermentation and chain elongation. However, the process needs to be better understood. This study presents novel insights into the bioconversion mechanisms of medium-chain carboxylic acids by correlating fermentation and chain elongation kinetic profiles with the study of microbial communities at different pH (5 to 7) conditions and temperatures (30 to 40 °C). It was found that high productivities of MCCA were obtained using a native culture and winery effluents as a natural substrate. Minor pH variations significantly affected the metabolic pathway of the microorganisms for MCCA production. The maximal productivities of hexanoic (715 mg/L/d) and octanoic (350 mg/L/d) acids were found at pH 6 and 35 °C. Results evidence that the presence of Clostridium, Bacteroides, and Negativicutes promotes the high productions of MCCA. The formation of heptanoic acid was favor when Mogibacterium and Burkholderia were present.
Graphical Abstract

Endurance and resistance exercises, alone or in combination, induce metabolic changes that affect tryptophan (Trp) catabolism. The kynurenine pathway (KP) is the main route of Trp degradation, and it is modulated by the inflammatory and redox environments. Previous studies have shown that KP metabolites work as myokines that mediate the positive systemic effects related to exercise. However, it is poorly understood how different exercise modalities and intensities impact the KP. The aim of this study was to characterize the effect of two different exercise modalities, military diving and swimming, on the KP and the redox environment. A total of 34 healthy men from the Mexican Navy were included in the study, 20 divers and 14 swimmers, who started and stayed in military training consistently during the six months of the study; 12 Mexican men without fitness training were used as the control group. Physical fitness was determined at the beginning and after 6 months of training; criteria included body composition; serum levels of Trp, kynurenine (KYN), kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK); the glutathione ratio (GSH/GSSG); and malondialdehyde (MDA). Results showed a significant loss of body fat in both the diver and swimmer groups. Compared with the control group, divers showed a decrease in Trp and 3-HK levels, but no changes were observed in the KYN/Trp, KYNA/Trp or 3-HK/Trp ratios, while swimmers showed a decrease in KYN levels and an increase in the KYNA and 3-HK levels. Additionally, divers showed a decrease in the GSH/GSSG ratio and an increase in MDA levels, in contrast to the swimmers, who showed a decrease in MDA levels and an increase in GSH/GSSG levels. Our findings suggest a differential shift in the KP and redox environment induced by diving and swimming. Swimming promotes an antioxidant environment and a peripheral overactivation of the KP.

Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients ; This work was supported by ''Ministerio de Ciencia e Innovación'' (SAF2010-17833); ''Fondo de Investigaciones Sanitarias'' (PS09/00538 and PI12/00289); ''Red de Investigación de Centros de Enfermedades Tropicales'' (RICET RD12/0018/0004); European Union (HEALTH-FE-2008-22303, ChagasEpiNet); ''Universidad Autónoma de Madrid'' and ''Comunidad de Madrid'' (CC08-UAM/SAL-4440/08); AECID Cooperation with Argentine (A/025417/09 and A/031735/10), Comunidad de Madrid (S-2010/BMD-2332) and ''Fundación Ramón Areces''

© 2014 Gironès et al. Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients. ; Ministerio de Ciencia e Innovación'' (SAF2010-17833); ''Fondo de Investigaciones Sanitarias'' (PS09/00538 and PI12/00289); ''Red de Investigación de Centros de Enfermedades Tropicales'' (RICET RD12/0018/0004); European Union (HEALTH-FE-2008-22303, hagasEpiNet); ''Universidad Autónoma de Madrid'' and ''Comunidad de Madrid'' (CC08-UAM/SAL-4440/08); AECID Cooperation with Argentine (A/025417/09 and A/031735/10), Comunidad de Madrid (S-2010/BMD-2332) and ''Fundación Ramón Areces''. ; Peer Reviewed

Bacteroides is among the most abundant microorganism inhabiting the human intestine. They are saccharolytic bacteria able to use dietary or host-derived glycans as energy sources. Some Bacteroides fragilis strains contribute to the maturation of the immune system but it is also an opportunistic pathogen. The intestine is the habitat of most Bifidobacterium species, some of whose strains are considered probiotics. Bifidobacteria can synthesize exopolysaccharides (EPS), which are complex carbohydrates that may be available in the intestinal environment. We studied the metabolism of B. fragilis when an EPS preparation from bifidobacteria was added to the growth medium compared to its behavior with added glucose. 2D-DIGE coupled with the identification by MALDI-TOF/TOF evidenced proteins that were differentially produced when EPS was added. The results were supported by RT qPCR gene expression analysis. The intracellular and extracellular pattern of certain amino acids, the redox balance and the a-glucosidase activity were differently affected in EPS with respect to glucose. These results allowed us to hypothesize that three general main events, namely the activation of amino acids catabolism, enhancement of the transketolase reaction from the pentose-phosphate cycle, and activation of the succinate-propionate pathway, promote a shift of bacterial metabolism rendering more reducing power and optimizing the energetic yield in the form of ATP when Bacteroides grow with added EPS. Our results expand the knowledge about the capacity of B. fragilis for adapting to complex carbohydrates and amino acids present in the intestinal environment. © 2015 Rios-covian, Sanchez, Salazar, Martinez, Redruello, Gueimonde and De los Reyes-Gavilan. ; This work was financed by projects AGL2010-16525 and AGL2013-43770-R from Plan Nacional/Plan Estatal de I+D+I (Spanish Ministry of Economy and Competitiveness, MINECO). The activity of Probiotics and Prebiotics Group is being partly supported through the Grant GRUPIN14-043 from Plan Regional de Investigación del Principado de Asturias. Both, national and regional grants received cofounding from European Union FEDER funds. DR-C was the recipient of predoctoral FPI fellowship whereas BS enjoys a Ramon and Cajal contract from MINECO. NS benefits from a Clarin post-doctoral contract (Marie Curie European CoFund Program) cofinanced by Plan Regional de Investigación del Principado de Asturias, Spain. We acknowledge the excellent technical assistance of Lidia Alaez, whose technician contract was partially supported by the project AGL2010-16525 and by Plan Regional de Investigación del Principado de Asturias, through the grant COF 13-020. ; Peer Reviewed

The polyphenol resveratrol (3,5,4-trihydroxystilbene) is a well-known plant secondary metabolite, commonly used as a medical ingredient and a nutritional supplement. Due to its health-promoting properties, the demand for resveratrol is expected to continue growing. This stilbene can be found in different plants, including grapes, berries (blackberries, blueberries and raspberries), peanuts and their derived food products, such as wine and juice. The commercially available resveratrol is usually extracted from plants, however this procedure has several drawbacks such as low concentration of the product of interest, seasonal variation, risk of plant diseases and product stability. Alternative production processes are being developed to enable the biotechnological production of resveratrol by genetically engineering several microbial hosts, such as Escherichia coli, Corynebacterium glutamicum, Lactococcus lactis, among others. However, these bacterial species are not able to naturally synthetize resveratrol and therefore genetic modifications have been performed. The application of emerging metabolic engineering offers new possibilities for strain and process optimization. This mini-review will discuss the recent progress on resveratrol biosynthesis in engineered bacteria, with a special focus on the metabolic engineering modifications, as well as the optimization of the production process. These strategies offer new tools to overcome the limitations and challenges for microbial production of resveratrol in industry. ; We would like to thank the European Union Framework Program 7 "BacHBerry" (http://www.bachb erry.eu), Project No. FP7-613793 for financial support, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469 unit, COMPETE 2020 (POCI-01-0145FEDER-006684) and BiotecNorte operation (NORTE-01-0145FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. ...