@techreport{Dandekar2021, type = {Working Paper}, author = {Dandekar, Thomas}, title = {A new cosmology of a crystallization process (decoherence) from the surrounding quantum soup provides heuristics to unify general relativity and quantum physics by solid state physics}, doi = {10.25972/OPUS-23076}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230769}, pages = {42 Seiten}, year = {2021}, abstract = {We explore a cosmology where the Big Bang singularity is replaced by a condensation event of interacting strings. We study the transition from an uncontrolled, chaotic soup ("before") to a clearly interacting "real world". Cosmological inflation scenarios do not fit current observations and are avoided. Instead, long-range interactions inside this crystallization event limit growth and crystal symmetries ensure the same laws of nature and basic symmetries over our domain. Tiny mis-arrangements present nuclei of superclusters and galaxies and crystal structure leads to the arrangement of dark (halo regions) and normal matter (galaxy nuclei) so convenient for galaxy formation. Crystals come and go, allowing an evolutionary cosmology where entropic forces from the quantum soup "outside" of the crystal try to dissolve it. These would correspond to dark energy and leads to a big rip scenario in 70 Gy. Preference of crystals with optimal growth and most condensation nuclei for the next generation of crystals may select for multiple self-organizing processes within the crystal, explaining "fine-tuning" of the local "laws of nature" (the symmetry relations formed within the crystal, its "unit cell") to be particular favorable for self-organizing processes including life or even conscious observers in our universe. Independent of cosmology, a crystallization event may explain quantum-decoherence in general: The fact, that in our macroscopic everyday world we only see one reality. This contrasts strongly with the quantum world where you have coherence, a superposition of all quantum states. We suggest that a "real world" (so our everyday macroscopic world) happens only in our domain, i.e. inside a crystal. "Outside" of our domain and our observable universe there is the quantum soup of boiling quantum foam and superposition of all possibilities. In our crystallized world the vacuum no longer boils but is cooled down by the crystallization event and hence is 10**20 smaller, exactly as observed in our everyday world. As we live in a "solid" state, within a crystal, the different quanta which build our world have all their different states nicely separated. This theory postulates there are only n quanta and m states available for them (there is no Everett-like ever splitting multiverse after each decision). In the solid state we live in, there is decoherence, the states are nicely separated. The arrow of entropy for each edge of the crystal forms one fate, one worldline or clear development of a world, while the layers of the crystal are different system states. Some mathematical leads from loop quantum gravity point to required interactions and potentials. A complete mathematical treatment of this unified theory is far too demanding currently. Interaction potentials for strings or membranes of any dimension allow a solid state of quanta, so allowing decoherence in our observed world are challenging to calculate. However, if we introduce here the heuristic that any type of physical interaction of strings corresponds just to a type of calculation, there is already since 1898 the Hurwitz theorem showing that then only 1D, 2D, 4D and 8D (octonions) allow complex or hypercomplex number calculations. No other hypercomplex numbers and hence dimensions or symmetries are possible to allow calculations without yielding divisions by zero. However, the richest solution allowed by the Hurwitz theorem, octonions, is actually the observed symmetry of our universe, E8.  }, subject = {Kosmologie}, language = {en} } @article{KuehnemundtLeifeldSchergetal.2021, author = {K{\"u}hnemundt, Johanna and Leifeld, Heidi and Scherg, Florian and Schmitt, Matthias and Nelke, Lena C. and Schmitt, Tina and Bauer, Florentin and G{\"o}ttlich, Claudia and Fuchs, Maximilian and Kunz, Meik and Peindl, Matthias and Br{\"a}hler, Caroline and Kronenthaler, Corinna and Wischhusen, J{\"o}rg and Prelog, Martina and Walles, Heike and Dandekar, Thomas and Dandekar, Gudrun and Nietzer, Sarah L.}, title = {Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing}, series = {ALTEX}, volume = {38}, journal = {ALTEX}, doi = {10.14573/altex.2008141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231465}, pages = {289-306}, year = {2021}, abstract = {High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.}, language = {en} } @article{SchererFleishmanJonesetal.2021, author = {Scherer, Marc and Fleishman, Sarel J. and Jones, Patrik R. and Dandekar, Thomas and Bencurova, Elena}, title = {Computational Enzyme Engineering Pipelines for Optimized Production of Renewable Chemicals}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {9}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2021.673005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240598}, year = {2021}, abstract = {To enable a sustainable supply of chemicals, novel biotechnological solutions are required that replace the reliance on fossil resources. One potential solution is to utilize tailored biosynthetic modules for the metabolic conversion of CO2 or organic waste to chemicals and fuel by microorganisms. Currently, it is challenging to commercialize biotechnological processes for renewable chemical biomanufacturing because of a lack of highly active and specific biocatalysts. As experimental methods to engineer biocatalysts are time- and cost-intensive, it is important to establish efficient and reliable computational tools that can speed up the identification or optimization of selective, highly active, and stable enzyme variants for utilization in the biotechnological industry. Here, we review and suggest combinations of effective state-of-the-art software and online tools available for computational enzyme engineering pipelines to optimize metabolic pathways for the biosynthesis of renewable chemicals. Using examples relevant for biotechnology, we explain the underlying principles of enzyme engineering and design and illuminate future directions for automated optimization of biocatalysts for the assembly of synthetic metabolic pathways.}, language = {en} } @article{OsmanogluKhaledAlSeiariAlKhoorietal.2021, author = {Osmanoglu, {\"O}zge and Khaled AlSeiari, Mariam and AlKhoori, Hasa Abduljaleel and Shams, Shabana and Bencurova, Elena and Dandekar, Thomas and Naseem, Muhammad}, title = {Topological Analysis of the Carbon-Concentrating CETCH Cycle and a Photorespiratory Bypass Reveals Boosted CO\(_2\)-Sequestration by Plants}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {9}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2021.708417}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249260}, year = {2021}, abstract = {Synthetically designed alternative photorespiratory pathways increase the biomass of tobacco and rice plants. Likewise, some in planta-tested synthetic carbon-concentrating cycles (CCCs) hold promise to increase plant biomass while diminishing atmospheric carbon dioxide burden. Taking these individual contributions into account, we hypothesize that the integration of bypasses and CCCs will further increase plant productivity. To test this in silico, we reconstructed a metabolic model by integrating photorespiration and photosynthesis with the synthetically designed alternative pathway 3 (AP3) enzymes and transporters. We calculated fluxes of the native plant system and those of AP3 combined with the inhibition of the glycolate/glycerate transporter by using the YANAsquare package. The activity values corresponding to each enzyme in photosynthesis, photorespiration, and for synthetically designed alternative pathways were estimated. Next, we modeled the effect of the crotonyl-CoA/ethylmalonyl-CoA/hydroxybutyryl-CoA cycle (CETCH), which is a set of natural and synthetically designed enzymes that fix CO₂ manifold more than the native Calvin-Benson-Bassham (CBB) cycle. We compared estimated fluxes across various pathways in the native model and under an introduced CETCH cycle. Moreover, we combined CETCH and AP3-w/plgg1RNAi, and calculated the fluxes. We anticipate higher carbon dioxide-harvesting potential in plants with an AP3 bypass and CETCH-AP3 combination. We discuss the in vivo implementation of these strategies for the improvement of C3 plants and in natural high carbon harvesters.}, language = {en} } @article{OthmanBekhitAnanyetal.2021, author = {Othman, Eman M. and Bekhit, Amany A. and Anany, Mohamed A. and Dandekar, Thomas and Ragab, Hanan M. and Wahid, Ahmed}, title = {Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines}, series = {Molecules}, volume = {26}, journal = {Molecules}, number = {10}, issn = {1420-3049}, doi = {10.3390/molecules26102961}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239734}, year = {2021}, abstract = {The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.}, language = {en} } @article{LiPradaDaminelietal.2021, author = {Li, Kunkun and Prada, Juan and Damineli, Daniel S. C. and Liese, Anja and Romeis, Tina and Dandekar, Thomas and Feij{\´o}, Jos{\´e} A. and Hedrich, Rainer and Konrad, Kai Robert}, title = {An optimized genetically encoded dual reporter for simultaneous ratio imaging of Ca\(^{2+}\) and H\(^{+}\) reveals new insights into ion signaling in plants}, series = {New Phytologist}, volume = {230}, journal = {New Phytologist}, number = {6}, doi = {10.1111/nph.17202}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239847}, pages = {2292 -- 2310}, year = {2021}, abstract = {Whereas the role of calcium ions (Ca\(^{2+}\)) in plant signaling is well studied, the physiological significance of pH-changes remains largely undefined. Here we developed CapHensor, an optimized dual-reporter for simultaneous Ca\(^{2+}\) and pH ratio-imaging and studied signaling events in pollen tubes (PTs), guard cells (GCs), and mesophyll cells (MCs). Monitoring spatio-temporal relationships between membrane voltage, Ca\(^{2+}\)- and pH-dynamics revealed interconnections previously not described. In tobacco PTs, we demonstrated Ca\(^{2+}\)-dynamics lag behind pH-dynamics during oscillatory growth, and pH correlates more with growth than Ca\(^{2+}\). In GCs, we demonstrated abscisic acid (ABA) to initiate stomatal closure via rapid cytosolic alkalization followed by Ca2+ elevation. Preventing the alkalization blocked GC ABA-responses and even opened stomata in the presence of ABA, disclosing an important pH-dependent GC signaling node. In MCs, a flg22-induced membrane depolarization preceded Ca2+-increases and cytosolic acidification by c. 2 min, suggesting a Ca\(^{2+}\)/pH-independent early pathogen signaling step. Imaging Ca2+ and pH resolved similar cytosol and nuclear signals and demonstrated flg22, but not ABA and hydrogen peroxide to initiate rapid membrane voltage-, Ca\(^{2+}\)- and pH-responses. We propose close interrelation in Ca\(^{2+}\)- and pH-signaling that is cell type- and stimulus-specific and the pH having crucial roles in regulating PT growth and stomata movement.}, language = {en} } @article{BreitenbachHelfrichFoersterDandekar2021, author = {Breitenbach, Tim and Helfrich-F{\"o}rster, Charlotte and Dandekar, Thomas}, title = {An effective model of endogenous clocks and external stimuli determining circadian rhythms}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-95391-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261655}, pages = {16165}, year = {2021}, abstract = {Circadian endogenous clocks of eukaryotic organisms are an established and rapidly developing research field. To investigate and simulate in an effective model the effect of external stimuli on such clocks and their components we developed a software framework for download and simulation. The application is useful to understand the different involved effects in a mathematical simple and effective model. This concerns the effects of Zeitgebers, feedback loops and further modifying components. We start from a known mathematical oscillator model, which is based on experimental molecular findings. This is extended with an effective framework that includes the impact of external stimuli on the circadian oscillations including high dose pharmacological treatment. In particular, the external stimuli framework defines a systematic procedure by input-output-interfaces to couple different oscillators. The framework is validated by providing phase response curves and ranges of entrainment. Furthermore, Aschoffs rule is computationally investigated. It is shown how the external stimuli framework can be used to study biological effects like points of singularity or oscillators integrating different signals at once. The mathematical framework and formalism is generic and allows to study in general the effect of external stimuli on oscillators and other biological processes. For an easy replication of each numerical experiment presented in this work and an easy implementation of the framework the corresponding Mathematica files are fully made available. They can be downloaded at the following link: https://www.biozentrum.uni-wuerzburg.de/bioinfo/computing/circadian/.}, language = {en} } @article{ShityakovSkorbFoersteretal.2021, author = {Shityakov, Sergey and Skorb, Ekaterina V. and F{\"o}rster, Carola Y. and Dandekar, Thomas}, title = {Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer's Disease}, series = {Frontiers in Chemistry}, volume = {9}, journal = {Frontiers in Chemistry}, issn = {2296-2646}, doi = {10.3389/fchem.2021.736509}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248703}, year = {2021}, abstract = {Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial.}, language = {en} } @article{LiangBencurovaPsotaetal.2021, author = {Liang, Chunguang and Bencurova, Elena and Psota, Eric and Neurgaonkar, Priya and Prelog, Martina and Scheller, Carsten and Dandekar, Thomas}, title = {Population-predicted MHC class II epitope presentation of SARS-CoV-2 structural proteins correlates to the case fatality rates of COVID-19 in different countries}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms22052630}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258936}, year = {2021}, abstract = {We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions.}, language = {en} } @article{DandekarBencurovaOsmanogluetal.2021, author = {Dandekar, Thomas and Bencurova, Elena and Osmanoglu, {\"O}zge and Naseem, Muhammad}, title = {Klimapflanzen und biologische Wege zu negativen Kohlendioxidemissionen}, series = {BIOspektrum}, volume = {27}, journal = {BIOspektrum}, number = {7}, issn = {1868-6249}, doi = {10.1007/s12268-021-1677-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270067}, pages = {769-772}, year = {2021}, abstract = {Climate plants are critical to prevent global warming as all efforts to save carbon dioxide are too slow and climate disasters on the rise. For best carbon dioxide harvesting we compare algae, trees and crop plants and use metagenomic analysis of environmental samples. We compare different pathways, carbon harvesting potentials of different plants as well as synthetic modifications including carbon dioxide flux balance analysis. For implementation, agriculture and modern forestry are important.}, language = {de} } @article{OthmanFathyBekhitetal.2021, author = {Othman, Eman M. and Fathy, Moustafa and Bekhit, Amany Abdlrehim and Abdel-Razik, Abdel-Razik H. and Jamal, Arshad and Nazzal, Yousef and Shams, Shabana and Dandekar, Thomas and Naseem, Muhammad}, title = {Modulatory and toxicological perspectives on the effects of the small molecule kinetin}, series = {Molecules}, volume = {26}, journal = {Molecules}, number = {3}, issn = {1420-3049}, doi = {10.3390/molecules26030670}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223064}, year = {2021}, abstract = {Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.}, language = {en} } @article{AudretschGrataniWolzetal.2021, author = {Audretsch, Christof and Gratani, Fabio and Wolz, Christiane and Dandekar, Thomas}, title = {Modeling of stringent-response reflects nutrient stress induced growth impairment and essential amino acids in different Staphylococcus aureus mutants}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-88646-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260313}, year = {2021}, abstract = {Stapylococcus aureus colonises the nose of healthy individuals but can also cause a wide range of infections. Amino acid (AA) synthesis and their availability is crucial to adapt to conditions encountered in vivo. Most S. aureus genomes comprise all genes required for AA biosynthesis. Nevertheless, different strains require specific sets of AAs for growth. In this study we show that regulation inactivates pathways under certain conditions which result in these observed auxotrophies. We analyzed in vitro and modeled in silico in a Boolean semiquantitative model (195 nodes, 320 edges) the regulatory impact of stringent response (SR) on AA requirement in S. aureus HG001 (wild-type) and in mutant strains lacking the metabolic regulators RSH, CodY and CcpA, respectively. Growth in medium lacking single AAs was analyzed. Results correlated qualitatively to the in silico predictions of the final model in 92\% and quantitatively in 81\%. Remaining gaps in our knowledge are evaluated and discussed. This in silico model is made fully available and explains how integration of different inputs is achieved in SR and AA metabolism of S. aureus. The in vitro data and in silico modeling stress the role of SR and central regulators such as CodY for AA metabolisms in S. aureus.}, language = {en} } @article{BalkenholKaltdorfMammadovaBachetal.2020, author = {Balkenhol, Johannes and Kaltdorf, Kristin V. and Mammadova-Bach, Elmina and Braun, Attila and Nieswandt, Bernhard and Dittrich, Marcus and Dandekar, Thomas}, title = {Comparison of the central human and mouse platelet signaling cascade by systems biological analysis}, series = {BMC Genomics}, volume = {21}, journal = {BMC Genomics}, doi = {10.1186/s12864-020-07215-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230377}, year = {2020}, abstract = {Background Understanding the molecular mechanisms of platelet activation and aggregation is of high interest for basic and clinical hemostasis and thrombosis research. The central platelet protein interaction network is involved in major responses to exogenous factors. This is defined by systemsbiological pathway analysis as the central regulating signaling cascade of platelets (CC). Results The CC is systematically compared here between mouse and human and major differences were found. Genetic differences were analysed comparing orthologous human and mouse genes. We next analyzed different expression levels of mRNAs. Considering 4 mouse and 7 human high-quality proteome data sets, we identified then those major mRNA expression differences (81\%) which were supported by proteome data. CC is conserved regarding genetic completeness, but we observed major differences in mRNA and protein levels between both species. Looking at central interactors, human PLCB2, MMP9, BDNF, ITPR3 and SLC25A6 (always Entrez notation) show absence in all murine datasets. CC interactors GNG12, PRKCE and ADCY9 occur only in mice. Looking at the common proteins, TLN1, CALM3, PRKCB, APP, SOD2 and TIMP1 are higher abundant in human, whereas RASGRP2, ITGB2, MYL9, EIF4EBP1, ADAM17, ARRB2, CD9 and ZYX are higher abundant in mouse. Pivotal kinase SRC shows different regulation on mRNA and protein level as well as ADP receptor P2RY12. Conclusions Our results highlight species-specific differences in platelet signaling and points of specific fine-tuning in human platelets as well as murine-specific signaling differences.}, language = {en} } @article{NaseemOsmanoğluKaltdorfetal.2020, author = {Naseem, Muhammad and Osmanoğlu, {\"O}zge and Kaltdorf, Martin and Alblooshi, Afnan Ali M. A. and Iqbal, Jibran and Howari, Fares M. and Srivastava, Mugdha and Dandekar, Thomas}, title = {Integrated framework of the immune-defense transcriptional signatures in the Arabidopsis shoot apical meristem}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms21165745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285730}, year = {2020}, abstract = {The growing tips of plants grow sterile; therefore, disease-free plants can be generated from them. How plants safeguard growing apices from pathogen infection is still a mystery. The shoot apical meristem (SAM) is one of the three stem cells niches that give rise to the above ground plant organs. This is very well explored; however, how signaling networks orchestrate immune responses against pathogen infections in the SAM remains unclear. To reconstruct a transcriptional framework of the differentially expressed genes (DEGs) pertaining to various SAM cellular populations, we acquired large-scale transcriptome datasets from the public repository Gene Expression Omnibus (GEO). We identify here distinct sets of genes for various SAM cellular populations that are enriched in immune functions, such as immune defense, pathogen infection, biotic stress, and response to salicylic acid and jasmonic acid and their biosynthetic pathways in the SAM. We further linked those immune genes to their respective proteins and identify interactions among them by mapping a transcriptome-guided SAM-interactome. Furthermore, we compared stem-cells regulated transcriptome with innate immune responses in plants showing transcriptional separation among their DEGs in Arabidopsis. Besides unleashing a repertoire of immune-related genes in the SAM, our analysis provides a SAM-interactome that will help the community in designing functional experiments to study the specific defense dynamics of the SAM-cellular populations. Moreover, our study promotes the essence of large-scale omics data re-analysis, allowing a fresh look at the SAM-cellular transcriptome repurposing data-sets for new questions.}, language = {en} } @article{BaurNietzerKunzetal.2020, author = {Baur, Florentin and Nietzer, Sarah L. and Kunz, Meik and Saal, Fabian and Jeromin, Julian and Matschos, Stephanie and Linnebacher, Michael and Walles, Heike and Dandekar, Thomas and Dandekar, Gudrun}, title = {Connecting cancer pathways to tumor engines: a stratification tool for colorectal cancer combining human in vitro tissue models with boolean in silico models}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {1}, issn = {2072-6694}, doi = {10.3390/cancers12010028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193798}, pages = {28}, year = {2020}, abstract = {To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.}, language = {en} } @article{KannKunzHansenetal.2020, author = {Kann, Simone and Kunz, Meik and Hansen, Jessica and Sievertsen, J{\"u}rgen and Crespo, Jose J. and Loperena, Aristides and Arriens, Sandra and Dandekar, Thomas}, title = {Chagas disease: detection of Trypanosoma cruzi by a new, high-specific real time PCR}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {5}, issn = {2077-0383}, doi = {10.3390/jcm9051517}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205746}, year = {2020}, abstract = {Background: Chagas disease (CD) is a major burden in Latin America, expanding also to non-endemic countries. A gold standard to detect the CD causing pathogen Trypanosoma cruzi is currently not available. Existing real time polymerase chain reactions (RT-PCRs) lack sensitivity and/or specificity. We present a new, highly specific RT-PCR for the diagnosis and monitoring of CD. Material and Methods: We analyzed 352 serum samples from Indigenous people living in high endemic CD areas of Colombia using three leading RT-PCRs (k-DNA-, TCZ-, 18S rRNA-PCR), the newly developed one (NDO-PCR), a Rapid Test/enzyme-linked immuno sorbent assay (ELISA), and immunofluorescence. Eighty-seven PCR-products were verified by sequence analysis after plasmid vector preparation. Results: The NDO-PCR showed the highest sensitivity (92.3\%), specificity (100\%), and accuracy (94.3\%) for T. cruzi detection in the 87 sequenced samples. Sensitivities and specificities of the kDNA-PCR were 89.2\%/22.7\%, 20.5\%/100\% for TCZ-PCR, and 1.5\%/100\% for the 18S rRNA-PCR. The kDNA-PCR revealed a 77.3\% false positive rate, mostly due to cross-reactions with T. rangeli (NDO-PCR 0\%). TCZ- and 18S rRNA-PCR showed a false negative rate of 79.5\% and 98.5\% (NDO-PCR 7.7\%), respectively. Conclusions: The NDO-PCR demonstrated the highest specificity, sensitivity, and accuracy compared to leading PCRs. Together with serologic tests, it can be considered as a reliable tool for CD detection and can improve CD management significantly.}, language = {en} } @article{ShityakovBencurovaFoersteretal.2020, author = {Shityakov, Sergey and Bencurova, Elena and F{\"o}rster, Carola and Dandekar, Thomas}, title = {Modeling of shotgun sequencing of DNA plasmids using experimental and theoretical approaches}, series = {BMC Bioinformatics}, volume = {2020}, journal = {BMC Bioinformatics}, doi = {10.1186/s12859-020-3461-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229169}, year = {2020}, abstract = {Background Processing and analysis of DNA sequences obtained from next-generation sequencing (NGS) face some difficulties in terms of the correct prediction of DNA sequencing outcomes without the implementation of bioinformatics approaches. However, algorithms based on NGS perform inefficiently due to the generation of long DNA fragments, the difficulty of assembling them and the complexity of the used genomes. On the other hand, the Sanger DNA sequencing method is still considered to be the most reliable; it is a reliable choice for virtual modeling to build all possible consensus sequences from smaller DNA fragments. Results In silico and in vitro experiments were conducted: (1) to implement and test our novel sequencing algorithm, using the standard cloning vectors of different length and (2) to validate experimentally virtual shotgun sequencing using the PCR technique with the number of cycles from 1 to 9 for each reaction. Conclusions We applied a novel algorithm based on Sanger methodology to correctly predict and emphasize the performance of DNA sequencing techniques as well as in de novo DNA sequencing and its further application in synthetic biology. We demonstrate the statistical significance of our results.}, language = {en} } @article{GuptaSrivastavaOsmanogluetal.2020, author = {Gupta, Shishir K. and Srivastava, Mugdha and Osmanoglu, Oezge and Dandekar, Thomas}, title = {Genome-wide inference of the Camponotus floridanus protein-protein interaction network using homologous mapping and interacting domain profile pairs}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-020-59344-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229406}, year = {2020}, abstract = {Apart from some model organisms, the interactome of most organisms is largely unidentified. High-throughput experimental techniques to determine protein-protein interactions (PPIs) are resource intensive and highly susceptible to noise. Computational methods of PPI determination can accelerate biological discovery by identifying the most promising interacting pairs of proteins and by assessing the reliability of identified PPIs. Here we present a first in-depth study describing a global view of the ant Camponotus floridanus interactome. Although several ant genomes have been sequenced in the last eight years, studies exploring and investigating PPIs in ants are lacking. Our study attempts to fill this gap and the presented interactome will also serve as a template for determining PPIs in other ants in future. Our C. floridanus interactome covers 51,866 non-redundant PPIs among 6,274 proteins, including 20,544 interactions supported by domain-domain interactions (DDIs), 13,640 interactions supported by DDIs and subcellular localization, and 10,834 high confidence interactions mediated by 3,289 proteins. These interactions involve and cover 30.6\% of the entire C. floridanus proteome.}, language = {en} } @article{StelznerWinklerLiangetal.2020, author = {Stelzner, Kathrin and Winkler, Ann-Cathrin and Liang, Chunguang and Boyny, Aziza and Ade, Carsten P. and Dandekar, Thomas and Fraunholz, Martin J. and Rudel, Thomas}, title = {Intracellular Staphylococcus aureus Perturbs the Host Cell Ca\(^{2+}\) Homeostasis To Promote Cell Death}, series = {mBio}, volume = {11}, journal = {mBio}, doi = {10.1128/mBio.02250-20}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231448}, year = {2020}, abstract = {The opportunistic human pathogen Staphylococcus aureus causes serious infectious diseases that range from superficial skin and soft tissue infections to necrotizing pneumonia and sepsis. While classically regarded as an extracellular pathogen, S. aureus is able to invade and survive within human cells. Host cell exit is associated with cell death, tissue destruction, and the spread of infection. The exact molecular mechanism employed by S. aureus to escape the host cell is still unclear. In this study, we performed a genome-wide small hairpin RNA (shRNA) screen and identified the calcium signaling pathway as being involved in intracellular infection. S. aureus induced a massive cytosolic Ca\(^{2+}\) increase in epithelial host cells after invasion and intracellular replication of the pathogen. This was paralleled by a decrease in endoplasmic reticulum Ca\(^{2+}\) concentration. Additionally, calcium ions from the extracellular space contributed to the cytosolic Ca2+ increase. As a consequence, we observed that the cytoplasmic Ca\(^{2+}\) rise led to an increase in mitochondrial Ca\(^{2+}\) concentration, the activation of calpains and caspases, and eventually to cell lysis of S. aureus-infected cells. Our study therefore suggests that intracellular S. aureus disturbs the host cell Ca\(^{2+}\) homeostasis and induces cytoplasmic Ca\(^{2+}\) overload, which results in both apoptotic and necrotic cell death in parallel or succession. IMPORTANCE Despite being regarded as an extracellular bacterium, the pathogen Staphylococcus aureus can invade and survive within human cells. The intracellular niche is considered a hideout from the host immune system and antibiotic treatment and allows bacterial proliferation. Subsequently, the intracellular bacterium induces host cell death, which may facilitate the spread of infection and tissue destruction. So far, host cell factors exploited by intracellular S. aureus to promote cell death are only poorly characterized. We performed a genome-wide screen and found the calcium signaling pathway to play a role in S. aureus invasion and cytotoxicity. The intracellular bacterium induces a cytoplasmic and mitochondrial Ca\(^{2+}\) overload, which results in host cell death. Thus, this study first showed how an intracellular bacterium perturbs the host cell Ca\(^{2+}\) homeostasis."}, language = {en} } @article{SarukhanyanShityakovDandekar2020, author = {Sarukhanyan, Edita and Shityakov, Sergey and Dandekar, Thomas}, title = {Rational drug design of Axl tyrosine kinase type I inhibitors as promising candidates against cancer}, series = {Frontiers in Chemistry}, volume = {7}, journal = {Frontiers in Chemistry}, number = {920}, issn = {2296-2646}, doi = {10.3389/fchem.2019.00920}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199505}, year = {2020}, abstract = {The high level of Axl tyrosine kinase expression in various cancer cell lines makes it an attractive target for the development of anti-cancer drugs. In this study, we carried out several sets of in silico screening for the ATP-competitive Axl kinase inhibitors based on different molecular docking protocols. The best drug-like candidates were identified, after parental structure modifications, by their highest affinity to the target protein. We found that our newly designed compound R5, a derivative of the R428 patented analog, is the most promising inhibitor of the Axl kinase according to the three molecular docking algorithms applied in the study. The molecular docking results are in agreement with the molecular dynamics simulations using the MM-PBSA/GBSA implicit solvation models, which confirm the high affinity of R5 toward the protein receptor. Additionally, the selectivity test against other kinases also reveals a high affinity of R5 toward ABL1 and Tyro3 kinases, emphasizing its promising potential for the treatment of malignant tumors.}, language = {en} }