Publications

573 Publications visible to you, out of a total of 573

Abstract (Expand)

There are two major problems that we are facing currently. Firstly, a growing human population continues to contribute to the increased food demand. Secondly, the volume of organic waste produced will threaten human health and the quality of the environment. Recently, there is an increasing number of efforts placed into farming insect biomass to produce alternative feed ingredients. Black soldier fly larvae (BSFL), Hermetia illucens have proven to convert organic waste into high-quality nutrients for pet foods, fish and poultry feeds, as well as residue fertilizer for soil amendment. However, better BSFL feed formulation and feeding approaches are necessary for yielding a higher nutrient content of the insect body, and if performed efficiently, whilst converting waste into higher value biomass. Lastly, this paper reveals that BSFL, in fact, thrives in various ranges of organic matter composition and with simple rearing systems.

Authors: S. A. Siddiqui, B. Ristow, T. Rahayu, N. S. Putra, N. Widya Yuwono, K. Nisa', B. Mategeko, S. Smetana, M. Saki, A. Nawaz, A. Nagdalian

Date Published: 1st Mar 2022

Publication Type: Journal

Abstract (Expand)

Abstract ICAM-1 is critical for interactions between cells. Previous studies have suggested that ICAM-1 triggers cell-to-cell transmission of HIV-1 or HTLV-1. SARS-CoV-2 shares several features with these viruses in interactions between cells, and SARS-CoV-2 cell-to-cell transmission is associated with COVID-19 severity. However, ICAM-1 and its associated pathways are not identified as essential factors in interactions between cells in COVID-19. For example, the current COVID-19 Disease Map has no entry for those pathways. Therefore, discovering unknown ICAM-1 pathways will be indispensable for clarifying the mechanism of COVID-19. This study builds ICAM1-associated pathways by gene network inference from single-cell omics data and multiple knowledge bases. First, data analyses extracted coexpressed genes with significant differences in expression levels with spurious correlations removed. Second, knowledge bases validate models. Finally, mapping the models onto existing pathways identifies new ICAM1-associated pathways. These pathways indicate that (1) upstream pathways include proteins in noncanonical NF-kappaB pathway and that (2) downstream pathways contain integrins and cytoskeleton or motor proteins for cell transformation. In this way, data-driven and knowledge-based approaches are integrated into gene network inference for ICAM1-associated pathway construction. The results can contribute to repairing and completing the COVID-19 Disease Map, thereby improving our understanding of the mechanisms of COVID-19.

Authors: Mitsuhiro Odaka, Morgan Magnin, Katsumi Inoue

Date Published: 11th Feb 2022

Publication Type: Journal

Abstract (Expand)

Graphite oxide (GO) has been used for the immobilization of several classes of enzymes, exhibiting very interesting properties as immobilization matrix. However, the effect the nanomaterial has on the enzyme cannot be predicted. Herein, the effect GO has on the catalytic behavior of several (S)-selective amine transaminases ((S)-ATAs) has been investigated. These enzymes were the focus of this work as they are homodimers with pyridoxal 5’-phosphate in their active site, significantly more complex systems than other enzymes previously studied. Addition of GO (up to 0.1 mg/mL) in the reaction medium leads to activation (up to 50% improved activity) for most enzymes studied, while they maintain their temperature profile (they perform better between 40-45ºC), and their stability. However, the effect is not universal and there are enzymes that are negatively influenced by the presence of the nanomaterial. More profound is the effect on the (S)-ATA from Chromobacterium violaceum which loses almost 50% of its activity in the presence of 0.1 mg/mL GO, while the stability was significantly decreased, losing its activity after 2 h incubation at 40°C, in the presence of 25 μg/mL GO. This negative effect seems to rise from minor secondary structure alterations; namely, a loss of α-helices and subsequent increase in random coil (~3% in the presence of 25 μg/mL GO). We hypothesize that the effect the GO has on (S)-ATAs is correlated to the surface chemistry of the enzymes; the less negatively-charged enzymes are deactivated from the interaction with GO. This insight will aid the rationalization of ATA immobilization onto carbon-based nanomaterials.

Authors: Nikolaos Kaloudis, Panagiota Zygouri, Nikolaos Chalmpes, Konstantinos Spyrou, Dimitrios Gournis, Ioannis Pavlidis

Date Published: 6th Dec 2021

Publication Type: Journal

Abstract (Expand)

How an organism copes with chemicals is largely determined by the genes and proteins that collectively function to defend against, detoxify and eliminate chemical stressors. This integrative network includes receptors and transcription factors, biotransformation enzymes, transporters, antioxidants, and metal- and heat-responsive genes, and is collectively known as the chemical defensome. Teleost fish is the largest group of vertebrate species and can provide valuable insights into the evolution and functional diversity of defensome genes. We have previously shown that the xenosensing pregnane x receptor (pxr, nr1i2) is lost in many teleost species, including Atlantic cod (Gadus morhua) and three-spined stickleback (Gasterosteus aculeatus), but it is not known if compensatory mechanisms or signaling pathways have evolved in its absence. In this study, we compared the genes comprising the chemical defensome of five fish species that span the teleosteii evolutionary branch often used as model species in toxicological studies and environmental monitoring programs: zebrafish (Danio rerio), medaka (Oryzias latipes), Atlantic killifish (Fundulus heteroclitus), Atlantic cod, and three-spined stickleback. Genome mining revealed evolved differences in the number and composition of defensome genes that can have implication for how these species sense and respond to environmental pollutants, but we did not observe any candidates of compensatory mechanisms or pathways in cod and stickleback in the absence of pxr. The results indicate that knowledge regarding the diversity and function of the defensome will be important for toxicological testing and risk assessment studies.

Authors: Marta Eide, Xiaokang Zhang, Odd André Karlsen, Jared V. Goldstone, John Stegeman, Inge Jonassen, Anders Goksøyr

Date Published: 1st Dec 2021

Publication Type: Journal

Abstract (Expand)

Structure-based antiviral developments in the past two years have been dominated by the structure determination and inhibition of SARS-CoV-2 proteins and new lead molecules for picornaviruses. The SARS-CoV-2 spike protein has been targeted successfully with antibodies, nanobodies, and receptor protein mimics effectively blocking receptor binding or fusion. The two most promising non-structural proteins sharing strong structural and functional conservation across virus families are the main protease and the RNA-dependent RNA polymerase, for which design and reuse of broad range inhibitors already approved for use has been an attractive avenue. For picornaviruses, the increasing recognition of the transient expansion of the capsid as a critical transition towards RNA release has been targeted through a newly identified, apparently widely conserved, druggable, interprotomer pocket preventing viral entry. We summarize some of the key papers in these areas and ponder the practical uses and contributions of molecular modeling alongside empirical structure determination.

Authors: Zlatka Plavec, Ina Pöhner, Antti Poso, Sarah J Butcher

Date Published: 1st Dec 2021

Publication Type: Journal

Abstract (Expand)

Abstract Stable isotope labelling in combination with high-resolution mass spectrometry approaches are increasingly used to analyze both metabolite and protein modification dynamics. To enable correctynamics. To enable correct estimation of the resulting dynamics, it is critical to correct the measured values for naturally occurring stable isotopes, a process commonly called isotopologue correction or deconvolution. While the importance of isotopologue correction is well recognized in metabolomics, it has received far less attention in proteomics approaches. Although several tools exist that enable isotopologue correction of mass spectrometry data, the majority is tailored for the analysis of low molecular weight metabolites. We here present PICor which has been developed for isotopologue correction of complex isotope labelling experiments in proteomics or metabolomics and demonstrate the importance of appropriate correction for accurate determination of protein modifications dynamics, using histone acetylation as an example.

Authors: Jörn Dietze, Alienke van Pijkeren, Anna-Sophia Egger, Mathias Ziegler, Marcel Kwiatkowski, Ines Heiland

Date Published: 1st Dec 2021

Publication Type: Journal

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. We performed network analysis to investigate the dysregulated biological processes in the disease progression and revealed the molecular mechanism underlying NAFLD. Based on network analysis, we identified a highly conserved disease-associated gene module across three different NAFLD cohorts and highlighted the predominant role of key transcriptional regulators associated with lipid and cholesterol metabolism. In addition, we revealed the detailed metabolic differences between heterogeneous NAFLD patients through integrative systems analysis of transcriptomic data and liver-specific genome-scale metabolic model. Furthermore, we identified transcription factors (TFs), including SREBF2, HNF4A, SREBF1, YY1, and KLF13, showing regulation of hepatic expression of genes in the NAFLD-associated modules and validated the TFs using data generated from a mouse NAFLD model. In conclusion, our integrative analysis facilitates the understanding of the regulatory mechanism of these perturbed TFs and their associated biological processes.

Authors: H. Yang, M. Arif, M. Yuan, X. Li, K. Shong, H. Turkez, J. Nielsen, M. Uhlen, J. Boren, C. Zhang, A. Mardinoglu

Date Published: 19th Nov 2021

Publication Type: Journal

Abstract (Expand)

Chemical named entity recognition (NER) is a significant step for many downstream applications like entity linking for the chemical text-mining pipeline. However, the identification of chemical entities in a biomedical text is a challenging task due to the diverse morphology of chemical entities and the different types of chemical nomenclature. In this work, we describe our approach that was submitted for BioCreative version 7 challenge Track 2, focusing on the ‘Chemical Identification’ task for identifying chemical entities and entity linking, using MeSH. For this purpose, we have applied a two-stage approach as follows (a) usage of fine-tuned BioBERT for identification of chemical entities (b) semantic approximate search in MeSH and PubChem databases for entity linking. There was some friction between the two approaches, as our rule-based approach did not harmonise optimally with partially recognized words forwarded by the BERT component. For our future work, we aim to resolve the issue of the artefacts arising from BERT tokenizers and develop joint learning of chemical named entity recognition and entity linking using pre-trained transformer-based models and compare their performance with our preliminary approach. Next, we will improve the efficiency of our approximate search in reference databases during entity linking. This task is non-trivial as it entails determining similarity scores of large sets of trees with respect to a query tree. Ideally, this will enable flexible parametrization and rule selection for the entity linking search.

Authors: Ghadeer Mobasher, Lukrécia Mertová, Sucheta Ghosh, Olga Krebs, Bettina Heinlein, Wolfgang Müller

Date Published: 11th Nov 2021

Publication Type: Proceedings

Abstract (Expand)

Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2–host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP-MS) and the complementary proximity-based labeling MS method (BioID-MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS-CoV-2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image-based drug screen with infectious SARS-CoV-2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein-protein interactions.

Authors: Xiaonan Liu, Sini Huuskonen, Tuomo Laitinen, Taras Redchuk, Mariia Bogacheva, Kari Salokas, Ina Pöhner, Tiina Öhman, Arun Kumar Tonduru, Antti Hassinen, Lisa Gawriyski, Salla Keskitalo, Maria K Vartiainen, Vilja Pietiäinen, Antti Poso, Markku Varjosalo

Date Published: 1st Nov 2021

Publication Type: Journal

Abstract (Expand)

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

Authors: M. Ostaszewski, A. Niarakis, A. Mazein, I. Kuperstein, R. Phair, A. Orta-Resendiz, V. Singh, S. S. Aghamiri, M. L. Acencio, E. Glaab, A. Ruepp, G. Fobo, C. Montrone, B. Brauner, G. Frishman, L. C. Monraz Gomez, J. Somers, M. Hoch, S. Kumar Gupta, J. Scheel, H. Borlinghaus, T. Czauderna, F. Schreiber, A. Montagud, M. Ponce de Leon, A. Funahashi, Y. Hiki, N. Hiroi, T. G. Yamada, A. Drager, A. Renz, M. Naveez, Z. Bocskei, F. Messina, D. Bornigen, L. Fergusson, M. Conti, M. Rameil, V. Nakonecnij, J. Vanhoefer, L. Schmiester, M. Wang, E. E. Ackerman, J. E. Shoemaker, J. Zucker, K. Oxford, J. Teuton, E. Kocakaya, G. Y. Summak, K. Hanspers, M. Kutmon, S. Coort, L. Eijssen, F. Ehrhart, D. A. B. Rex, D. Slenter, M. Martens, N. Pham, R. Haw, B. Jassal, L. Matthews, M. Orlic-Milacic, A. Senff Ribeiro, K. Rothfels, V. Shamovsky, R. Stephan, C. Sevilla, T. Varusai, J. M. Ravel, R. Fraser, V. Ortseifen, S. Marchesi, P. Gawron, E. Smula, L. Heirendt, V. Satagopam, G. Wu, A. Riutta, M. Golebiewski, S. Owen, C. Goble, X. Hu, R. W. Overall, D. Maier, A. Bauch, B. M. Gyori, J. A. Bachman, C. Vega, V. Groues, M. Vazquez, P. Porras, L. Licata, M. Iannuccelli, F. Sacco, A. Nesterova, A. Yuryev, A. de Waard, D. Turei, A. Luna, O. Babur, S. Soliman, A. Valdeolivas, M. Esteban-Medina, M. Pena-Chilet, K. Rian, T. Helikar, B. L. Puniya, D. Modos, A. Treveil, M. Olbei, B. De Meulder, S. Ballereau, A. Dugourd, A. Naldi, V. Noel, L. Calzone, C. Sander, E. Demir, T. Korcsmaros, T. C. Freeman, F. Auge, J. S. Beckmann, J. Hasenauer, O. Wolkenhauer, E. L. Wilighagen, A. R. Pico, C. T. Evelo, M. E. Gillespie, L. D. Stein, H. Hermjakob, P. D'Eustachio, J. Saez-Rodriguez, J. Dopazo, A. Valencia, H. Kitano, E. Barillot, C. Auffray, R. Balling, R. Schneider

Date Published: 19th Oct 2021

Publication Type: Journal

Abstract

Not specified

Authors: Marek Ostaszewski, Anna Niarakis, Alexander Mazein, Inna Kuperstein, Robert Phair, Aurelio Orta‐Resendiz, Vidisha Singh, Sara Sadat Aghamiri, Marcio Luis Acencio, Enrico Glaab, Andreas Ruepp, Gisela Fobo, Corinna Montrone, Barbara Brauner, Goar Frishman, Luis Cristóbal Monraz Gómez, Julia Somers, Matti Hoch, Shailendra Kumar Gupta, Julia Scheel, Hanna Borlinghaus, Tobias Czauderna, Falk Schreiber, Arnau Montagud, Miguel Ponce de Leon, Akira Funahashi, Yusuke Hiki, Noriko Hiroi, Takahiro G Yamada, Andreas Dräger, Alina Renz, Muhammad Naveez, Zsolt Bocskei, Francesco Messina, Daniela Börnigen, Liam Fergusson, Marta Conti, Marius Rameil, Vanessa Nakonecnij, Jakob Vanhoefer, Leonard Schmiester, Muying Wang, Emily E Ackerman, Jason E Shoemaker, Jeremy Zucker, Kristie Oxford, Jeremy Teuton, Ebru Kocakaya, Gökçe Yağmur Summak, Kristina Hanspers, Martina Kutmon, Susan Coort, Lars Eijssen, Friederike Ehrhart, Devasahayam Arokia Balaya Rex, Denise Slenter, Marvin Martens, Nhung Pham, Robin Haw, Bijay Jassal, Lisa Matthews, Marija Orlic‐Milacic, Andrea Senff Ribeiro, Karen Rothfels, Veronica Shamovsky, Ralf Stephan, Cristoffer Sevilla, Thawfeek Varusai, Jean‐Marie Ravel, Rupsha Fraser, Vera Ortseifen, Silvia Marchesi, Piotr Gawron, Ewa Smula, Laurent Heirendt, Venkata Satagopam, Guanming Wu, Anders Riutta, Martin Golebiewski, Stuart Owen, Carole Goble, Xiaoming Hu, Rupert W Overall, Dieter Maier, Angela Bauch, Benjamin M Gyori, John A Bachman, Carlos Vega, Valentin Grouès, Miguel Vazquez, Pablo Porras, Luana Licata, Marta Iannuccelli, Francesca Sacco, Anastasia Nesterova, Anton Yuryev, Anita de Waard, Denes Turei, Augustin Luna, Ozgun Babur, Sylvain Soliman, Alberto Valdeolivas, Marina Esteban‐Medina, Maria Peña‐Chilet, Kinza Rian, Tomáš Helikar, Bhanwar Lal Puniya, Dezso Modos, Agatha Treveil, Marton Olbei, Bertrand De Meulder, Stephane Ballereau, Aurélien Dugourd, Aurélien Naldi, Vincent Noël, Laurence Calzone, Chris Sander, Emek Demir, Tamas Korcsmaros, Tom C Freeman, Franck Augé, Jacques S Beckmann, Jan Hasenauer, Olaf Wolkenhauer, Egon L Wilighagen, Alexander R Pico, Chris T Evelo, Marc E Gillespie, Lincoln D Stein, Henning Hermjakob, Peter D'Eustachio, Julio Saez‐Rodriguez, Joaquin Dopazo, Alfonso Valencia, Hiroaki Kitano, Emmanuel Barillot, Charles Auffray, Rudi Balling, Reinhard Schneider

Date Published: 1st Oct 2021

Publication Type: Journal

Abstract (Expand)

To apply enzymes in technical processes, a detailed understanding of the molecular mechanisms is required. Kinetic and thermodynamic parameters of enzyme catalysis are crucial to plan, model, and implement biocatalytic processes more efficiently. While the kinetic parameters, Km and kcat, are often accessible by optical methods, the determination of thermodynamic parameters requires more sophisticated methods. Isothermal titration calorimetry (ITC) allows the label-free and highly sensitive analysis of kinetic and thermodynamic parameters of individual steps in the catalytic cycle of an enzyme reaction. However, since ITC is susceptible to interferences due to denaturation or agglomeration of the enzymes, the homogeneity of the enzyme sample must always be considered, and this can be accomplished by means of dynamic light scattering (DLS) analysis. We here report on the use of an ITC-dependent work flow to determine both the kinetic and the thermodynamic data for a cofactor-dependent enzyme. Using a standardized approach with the implementation of sample quality control by DLS, we obtain high-quality data suitable for the advanced modeling of the enzyme reaction mechanism. Specifically, we investigated stereoselective reactions catalyzed by the NADPH-dependent ketoreductase Gre2p under different reaction conditions. The results revealed that this enzyme operates with an ordered sequential mechanism and is affected by substrate or product inhibition depending on the reaction buffer. Data reproducibility is ensured by specifying standard operating procedures, using programmed workflows for data analysis, and storing all data in a F.A.I.R. (findable, accessible, interoperable, and reusable) repository (https://doi.org/10.15490/fairdomhub.1.investigation.464.1). Our work highlights the utility for combined binding and kinetic studies for such complex multisubstrate reactions.

Authors: Felix Ott, Kersten S. Rabe, Christof M. Niemeyer, Gudrun Gygli

Date Published: 3rd Sep 2021

Publication Type: Journal

Abstract (Expand)

Single-cell RNA-sequencing (scRNA-seq) provides high-resolution insights into complex tissues. Cardiac tissue, however, poses a major challenge due to the delicate isolation process and the large size of mature cardiomyocytes. Regardless of the experimental technique, captured cells are often impaired and some capture sites may contain multiple or no cells at all. All this refers to "low quality" potentially leading to data misinterpretation. Common standard quality control parameters involve the number of detected genes, transcripts per cell, and the fraction of transcripts from mitochondrial genes. While cutoffs for transcripts and genes per cell are usually user-defined for each experiment or individually calculated, a fixed threshold of 5% mitochondrial transcripts is standard and often set as default in scRNA-seq software. However, this parameter is highly dependent on the tissue type. In the heart, mitochondrial transcripts comprise almost 30% of total mRNA due to high energy demands. Here, we demonstrate that a 5%-threshold not only causes an unacceptable exclusion of cardiomyocytes but also introduces a bias that particularly discriminates pacemaker cells. This effect is apparent for our in vitro generated induced-sinoatrial-bodies (iSABs; highly enriched physiologically functional pacemaker cells), and also evident in a public data set of cells isolated from embryonal murine sinoatrial node tissue (Goodyer William et al. in Circ Res 125:379-397, 2019). Taken together, we recommend omitting this filtering parameter for scRNA-seq in cardiovascular applications whenever possible.

Authors: A. M. Galow, S. Kussauer, M. Wolfien, R. M. Brunner, T. Goldammer, R. David, A. Hoeflich

Date Published: 24th Aug 2021

Publication Type: Manual

Abstract (Expand)

In this study we demonstrated through analytic considerations and numerical studies that the mitochondrial fatty-acid beta-oxidation can exhibit bistable-hysteresis behavior. In an experimentally validated computational model we identified a specific region in the parameter space in which two distinct stable and one unstable steady state could be attained with different fluxes. The two stable states were referred to as low-flux (disease) and high-flux (healthy) state. By a modular kinetic approach we traced the origin and causes of the bistability back to the distributive kinetics and the conservation of CoA, in particular in the last rounds of the beta-oxidation. We then extended the model to investigate various interventions that may confer health benefits by activating the pathway, including (i) activation of the last enzyme MCKAT via its endogenous regulator p46-SHC protein, (ii) addition of a thioesterase (an acyl-CoA hydrolysing enzyme) as a safety valve, and (iii) concomitant activation of a number of upstream and downstream enzymes by short-chain fatty-acids (SCFA), metabolites that are produced from nutritional fibers in the gut. A high concentration of SCFAs, thioesterase activity, and inhibition of the p46Shc protein led to a disappearance of the bistability, leaving only the high-flux state. A better understanding of the switch behavior of the mitochondrial fatty-acid oxidation process between a low- and a high-flux state may lead to dietary and pharmacological intervention in the treatment or prevention of obesity and or non-alcoholic fatty-liver disease.

Authors: F. Abegaz, A. M. F. Martines, M. A. Vieira-Lara, M. Rios-Morales, D. J. Reijngoud, E. C. Wit, B. M. Bakker

Date Published: 13th Aug 2021

Publication Type: Journal

Abstract (Expand)

The circadian clock coordinates plant physiology and development. Mathematical clock models have provided a rigorous framework to understand how the observed rhythms emerge from disparate, molecular processes. However, models of the plant clock have largely been built and tested against RNA timeseries data in arbitrary, relative units. This limits model transferability, refinement from biochemical data and applications in synthetic biology. Here, we incorporate absolute mass units into a detailed model of the clock gene network in Arabidopsis thaliana. We re-interpret the established P2011 model, highlighting a transcriptional activator that overlaps the function of REVEILLE 8/LHY-CCA1-LIKE 5. The U2020 model incorporates the repressive regulation of PRR genes, a key feature of the most detailed clock model KF2014, without greatly increasing model complexity. We tested the experimental error distributions of qRT-PCR data calibrated for units of RNA transcripts/cell and of circadian period estimates, in order to link the models to data more appropriately. U2019 and U2020 models were constrained using these data types, recreating previously-described circadian behaviours with RNA metabolic processes in absolute units. To test their inferred rates, we estimated a distribution of observed, transcriptome-wide transcription rates (Plant Empirical Transcription Rates, PETR) in units of transcripts/cell/hour. The PETR distribution and the equivalent degradation rates indicated that the models’ predicted rates are biologically plausible, with individual exceptions. In addition to updated clock models, FAIR data resources and a software environment in Docker, this validation process represents an advance in biochemical realism for models of plant gene regulation.

Authors: Uriel Urquiza Garcia, Andrew J Millar

Date Published: 5th Aug 2021

Publication Type: Journal

Abstract (Expand)

There is an overarching theme in Science Education to integrate in the school and university curriculum interdisciplinary state-of-art innovations. The field of Nanotechnology is such an example, because it combines the aforementioned interdisciplinarity and novelty with a well-documented educational value. Herein, a novel teaching approach concerning size-dependent properties at the nanoscale for chemistry and physics undergraduate students is proposed. The analysis of the scientific content and its following reconstruction for teaching purposes is based on the theoretical framework of the Model of Educational Reconstruction (MER). This analysis yielded two fundamental concepts and a series of activities that can be the main core of teaching Nanotechnology at a university level.

Authors: Ioannis Metaxas, Emily Michailidi, Dimitris Stavrou, Ioannis V. Pavlidis

Date Published: 13th Jul 2021

Publication Type: Journal

Abstract (Expand)

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD(+) had long remained obscure. Only just recently, the existence of a human mitochondrial NAD(+) carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD(+) carrier in mammals, a long-standing mystery in NAD(+) biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.

Authors: M. Ziegler, M. Monne, A. Nikiforov, G. Agrimi, I. Heiland, F. Palmieri

Date Published: 14th Jun 2021

Publication Type: Journal

Abstract (Expand)

Regulation of glycogen metabolism is of vital importance in organisms of all three kingdoms of life. Although the pathways involved in glycogen synthesis and degradation are well known, many regulatory aspects around the metabolism of this polysaccharide remain undeciphered. Here, we used the unicellular cyanobacterium Synechocystis as a model to investigate how glycogen metabolism is regulated in dormant nitrogen-starved cells, which entirely rely on glycogen catabolism to restore growth. We found that the activity of the enzymes involved in glycogen synthesis and degradation is tightly controlled at different levels via post-translational modifications. Phosphorylation of phosphoglucomutase 1 (Pgm1) on a peripheral residue (Ser63) regulates Pgm1 activity and controls the mobilization of the glycogen stores. Inhibition of Pgm1 activity via phosphorylation on Ser63 appears essential for survival of Synechocystis in the dormant state. Remarkably, this regulatory mechanism seems to be conserved from bacteria to humans. Moreover, phosphorylation of Pgm1 influences the formation of a metabolon, which includes Pgm1, oxidative pentose phosphate cycle protein (OpcA) and glucose-6-phosphate dehydrogenase (G6PDH). Analysis of the steady-state levels of the metabolic products of glycogen degradation together with protein-protein interaction studies revealed that the activity of G6PDH and the formation of this metabolon are under additional redox control, likely to ensure metabolic channeling of glucose-6-phosphate to the required pathways for each developmental stage.

Authors: Sofía Doello, Niels Neumann, Philipp Spät, Boris Maček, Karl Forchhammer

Date Published: 15th Apr 2021

Publication Type: Unpublished

Abstract (Expand)

The circadian clock coordinates plant physiology and development. Mathematical clock models have provided a rigorous framework to understand how the observed rhythms emerge from disparate, molecular processes. However, models of the plant clock have largely been built and tested against RNA timeseries data in arbitrary, relative units. This limits model transferability, refinement from biochemical data and applications in synthetic biology. Here, we incorporate absolute mass units into a detailed, gene circuit model of the clock in Arabidopsis thaliana. We re-interpret the established P2011 model, highlighting a transcriptional activator that overlaps the function of REVEILLE 8/LHY-CCA1-LIKE 5, and refactor dynamic equations for the Evening Complex. The U2020 model incorporates the repressive regulation of PRR genes, a key feature of the most detailed clock model F2014, without greatly increasing model complexity. We tested the experimental error distributions of qRT-PCR data calibrated for units of RNA transcripts/cell and of circadian period estimates, in order to link the models to data more appropriately. U2019 and U2020 models were constrained using these data types, recreating previously-described circadian behaviours with RNA metabolic processes in absolute units. To test their inferred rates, we estimated a distribution of observed, transcriptome-wide transcription rates (Plant Empirical Transcription Rates, PETR) in units of transcripts/cell/hour. The PETR distribution and the equivalent degradation rates indicated that the models’ predicted rates are biologically plausible, with individual exceptions. In addition to updated, explanatory models of the plant clock, this validation process represents an advance in biochemical realism for models of plant gene regulation.

Authors: Uriel Urquiza-Garcia, Andrew J Millar

Date Published: 20th Mar 2021

Publication Type: Tech report

Abstract (Expand)

The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

Authors: S. R. Mohapatra, A. Sadik, S. Sharma, G. Poschet, H. M. Gegner, T. V. Lanz, P. Lucarelli, U. Klingmuller, M. Platten, I. Heiland, C. A. Opitz

Date Published: 8th Mar 2021

Publication Type: Journal

Abstract

Not specified

Authors: Jennifer E. Kay, Joshua J. Corrigan, Amanda L. Armijo, Ilana S. Nazari, Ishwar N. Kohale, Dorothea K. Torous, Svetlana L. Avlasevich, Robert G. Croy, Dushan N. Wadduwage, Sebastian E. Carrasco, Stephen D. Dertinger, Forest M. White, John M. Essigmann, Leona D. Samson, Bevin P. Engelward

Date Published: 1st Mar 2021

Publication Type: Journal

Abstract (Expand)

The enzymatic degradation of polyethylene terephthalate (PET) results in a hydrolysate consisting almost exclusively of its two monomers, ethylene glycol and terephthalate. To biologically valorize the PET hydrolysate, microbial upcycling into high-value products is proposed. Fatty acid derivatives hydroxyalkanoyloxy alkanoates (HAAs) represent such valuable target molecules. HAAs exhibit surface-active properties and can be exploited in the catalytical conversion to drop-in biofuels as well as in the polymerization to bio-based poly(amide urethane). This chapter presents the genetic engineering methods of pseudomonads for the metabolization of PET monomers and the biosynthesis of HAAs with detailed protocols concerning product purification.

Authors: Gina Welsing, Birger Wolter, Henric M.T. Hintzen, Till Tiso, Lars M. Blank

Date Published: 2021

Publication Type: Book

Abstract (Expand)

Despite the plethora of information on (S)-selective amine transaminases, the (R)-selective ones are still not well-studied; only a few structures are known to the day, and their substrate scope is limited, apart from a few stellar works on the field. Herein, Luminiphilus syltensis (R)-selective amine transaminase’s structure was elucidated to facilitate the engineering towards variants active on bulkier substrates. V37A variant led to increased activity towards 1-phenylpropylamine and to activity against 1-butylamine. On the contrary, S248 and T249 positions, located on the β-turn in P-pocket, seem crucial for maintaining enzyme’s activity.

Authors: Eleni Konia, Konstantinos Chatzicharalampous, Athina Drakonaki, Cornelia Muenke, Ulrich Ermler, Georgios Tsiotis, Ioannis V. Pavlidis

Date Published: 2021

Publication Type: Journal

Abstract (Expand)

The oxidative Weimberg pathway for the five-step pentose degradation to α-ketoglutarate is a key route for sustainable bioconversion of lignocellulosic biomass to added-value products and biofuels. The oxidative pathway from Caulobacter crescentus has been employed in in-vivo metabolic engineering with intact cells and in in-vitro enzyme cascades. The performance of such engineering approaches is often hampered by systems complexity, caused by non-linear kinetics and allosteric regulatory mechanisms. Here we report an iterative approach to construct and validate a quantitative model for the Weimberg pathway. Two sensitive points in pathway performance have been identified as follows: (1) product inhibition of the dehydrogenases (particularly in the absence of an efficient NAD+ recycling mechanism) and (2) balancing the activities of the dehydratases. The resulting model is utilized to design enzyme cascades for optimized conversion and to analyse pathway performance in C. cresensus cell- free extracts.

Authors: Lu Shen, Martha Kohlhaas, Junichi Enoki, Roland Meier, Bernhard Schönenberger, Roland Wohlgemuth, Robert Kourist, Felix Niemeyer, David van Niekerk, Christopher Bräsen, Jochen Niemeyer, Jacky Snoep, Bettina Siebers

Date Published: 1st Dec 2020

Publication Type: Not specified

Abstract

Not specified

Authors: Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin, Feixiong Cheng

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract (Expand)

Using standard systems biology methodologies a 14-compartment dynamic model was developed for the Corona virus epidemic. The model predicts that: (i) it will be impossible to limit lockdown intensity such that sufficient herd immunity develops for this epidemic to die down, (ii) the death toll from the SARS-CoV-2 virus decreases very strongly with increasing intensity of the lockdown, but (iii) the duration of the epidemic increases at first with that intensity and then decreases again, such that (iv) it may be best to begin with selecting a lockdown intensity beyond the intensity that leads to the maximum duration, (v) an intermittent lockdown strategy should also work and might be more acceptable socially and economically, (vi) an initially intensive but adaptive lockdown strategy should be most efficient, both in terms of its low number of casualties and shorter duration, (vii) such an adaptive lockdown strategy offers the advantage of being robust to unexpected imports of the virus, e.g. due to international travel, (viii) the eradication strategy may still be superior as it leads to even fewer deaths and a shorter period of economic downturn, but should have the adaptive strategy as backup in case of unexpected infection imports, (ix) earlier detection of infections is the most effective way in which the epidemic can be controlled, whilst waiting for vaccines.

Authors: Hans V. Westerhoff, Alexey N. Kolodkin

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract

Not specified

Authors: Tatjana Walter, Kareen H. Veldmann, Susanne Götker, Tobias Busche, Christian Rückert, Arman Beyraghdar Kashkooli, Jannik Paulus, Katarina Cankar, Volker F. Wendisch

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract (Expand)

The availability of genome sequences, annotations, and knowledge of the biochemistry underlying metabolic transformations has led to the generation of metabolic network reconstructions for a wide range of organisms in bacteria, archaea, and eukaryotes. When modeled using mathematical representations, a reconstruction can simulate underlying genotype-phenotype relationships. Accordingly, genome-scale metabolic models (GEMs) can be used to predict the response of organisms to genetic and environmental variations. A bottom-up reconstruction procedure typically starts by generating a draft model from existing annotation data on a target organism. For model species, this part of the process can be straightforward, due to the abundant organism-specific biochemical data. However, the process becomes complicated for non-model less-annotated species. In this paper, we present a draft liver reconstruction, ReCodLiver0.9, of Atlantic cod (Gadus morhua), a non-model teleost fish, as a practicable guide for cases with comparably few resources. Although the reconstruction is considered a draft version, we show that it already has utility in elucidating metabolic response mechanisms to environmental toxicants by mapping gene expression data of exposure experiments to the resulting model.

Authors: Eileen Marie Hanna, Xiaokang Zhang, Marta Eide, Shirin Fallahi, Tomasz Furmanek, Fekadu Yadetie, Daniel Craig Zielinski, Anders Goksøyr, Inge Jonassen

Date Published: 26th Nov 2020

Publication Type: Journal

Abstract (Expand)

The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.

Authors: Roser Marín-Valls, Karel Hernández, Michael Bolte, Teodor Parella, Jesús Joglar, Jordi Bujons, Pere Clapés

Date Published: 18th Nov 2020

Publication Type: Journal

Abstract (Expand)

How the network around ROS protects against oxidative stress and Parkinson's disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased alpha-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for "life-extending interventions": mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.

Authors: A. N Kolodkin, R. P. Sharma, A. M. Colangelo, A. Ignatenko, F. Martorana, D. Jennen, J. J. Briede, N. Brady, M. Barberis, T. D. G. A. Mondeel, M. Papa, V. Kumar, B. Peters, A. Skupin, L. Alberghina, R. Balling, H. V. Westerhoff

Date Published: 26th Oct 2020

Publication Type: Journal

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