TY - JOUR A1 - Zavorka, Libor A1 - Blanco, Andreu A1 - Chaguaceda, Fernando A1 - Cucherousset, Julien A1 - Killen, Shaun S. A1 - Lienart, Camilla A1 - Mathieu-Resuge, Margaux A1 - Nemec, Pavel A1 - Pilecky, Matthias A1 - Scharnweber, Inga Kristin A1 - Twining, Cornelia W. A1 - Kainz, Martin J. T1 - The role of vital dietary biomolecules in eco-evo-devo dynamics JF - Trends in ecology and evolution N2 - The physiological dependence of animals on dietary intake of vitamins, amino acids, and fatty acids is ubiquitous. Sharp differences in the availability of these vital dietary biomolecules among different resources mean that consumers must adopt a range of strategies to meet their physiological needs. We review the emerging work on omega-3 long-chain polyunsaturated fatty acids, focusing predominantly on predator-prey interactions, to illustrate that trade-off between capacities to consume resources rich in vital biomolecules and internal synthesis capacity drives differences in phenotype and fitness of consumers. This can then feedback to impact ecosystem functioning. We outline how focus on vital dietary biomolecules in eco-eco-devo dynamics can improve our understanding of anthropogenic changes across multiple levels of biological organization. Y1 - 2023 U6 - https://doi.org/10.1016/j.tree.2022.08.010 SN - 0169-5347 SN - 1872-8383 VL - 38 IS - 1 SP - 72 EP - 84 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Grdseloff, Nastasja A1 - Boulday, Gwenola A1 - Roedel, Claudia J. A1 - Otten, Cecile A1 - Vannier, Daphne Raphaelle A1 - Cardoso, Cecile A1 - Faurobert, Eva A1 - Dogra, Deepika A1 - Tournier-Lasserve, Elisabeth A1 - Abdelilah-Seyfried, Salim T1 - Impaired retinoic acid signaling in cerebral cavernous malformations JF - Scientific reports N2 - The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were drug regiment-sensitive, possibly due to adverse developmental effects of this hormone. A treatment with high doses of retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of retinoic acid levels can alleviate CCM phenotypes. KW - Developmental biology KW - Molecular medicine Y1 - 2023 U6 - https://doi.org/10.1038/s41598-023-31905-0 SN - 2045-2322 VL - 13 IS - 1 PB - Nature Portfolio CY - Berlin ER - TY - JOUR A1 - Stübler, Sabine A1 - Kloft, Charlotte A1 - Huisinga, Wilhelm T1 - Cell-level systems biology model to study inflammatory bowel diseases and their treatment options JF - CPT: pharmacometrics & systems pharmacology N2 - To help understand the complex and therapeutically challenging inflammatory bowel diseases (IBDs), we developed a systems biology model of the intestinal immune system that is able to describe main aspects of IBD and different treatment modalities thereof. The model, including key cell types and processes of the mucosal immune response, compiles a large amount of isolated experimental findings from literature into a larger context and allows for simulations of different inflammation scenarios based on the underlying data and assumptions. In the context of a large and diverse virtual IBD population, we characterized the patients based on their phenotype (in contrast to healthy individuals, they developed persistent inflammation after a trigger event) rather than on a priori assumptions on parameter differences to a healthy individual. This allowed to reproduce the enormous diversity of predispositions known to lead to IBD. Analyzing different treatment effects, the model provides insight into characteristics of individual drug therapy. We illustrate for anti-TNF-alpha therapy, how the model can be used (i) to decide for alternative treatments with best prospects in the case of nonresponse, and (ii) to identify promising combination therapies with other available treatment options. Y1 - 2023 U6 - https://doi.org/10.1002/psp4.12932 SN - 2163-8306 VL - 12 IS - 5 SP - 690 EP - 705 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Derežanin, Lorena A1 - Blažytė, Asta A1 - Dobrynin, Pavel A1 - Duchêne, David A. A1 - Grau, José Horacio A1 - Jeon, Sungwon A1 - Kliver, Sergei A1 - Koepfli, Klaus-Peter A1 - Meneghini, Dorina A1 - Preick, Michaela A1 - Tomarovsky, Andrey A1 - Totikov, Azamat A1 - Fickel, Jörns A1 - Förster, Daniel W. T1 - Multiple types of genomic variation contribute to adaptive traits in the mustelid subfamily Guloninae JF - Molecular ecology N2 - Species of the mustelid subfamily Guloninae inhabit diverse habitats on multiple continents, and occupy a variety of ecological niches. They differ in feeding ecologies, reproductive strategies and morphological adaptations. To identify candidate loci associated with adaptations to their respective environments, we generated a de novo assembly of the tayra (Eira barbara), the earliest diverging species in the subfamily, and compared this with the genomes available for the wolverine (Gulo gulo) and the sable (Martes zibellina). Our comparative genomic analyses included searching for signs of positive selection, examining changes in gene family sizes and searching for species-specific structural variants. Among candidate loci associated with phenotypic traits, we observed many related to diet, body condition and reproduction. For example, for the tayra, which has an atypical gulonine reproductive strategy of aseasonal breeding, we observed species-specific changes in many pregnancy-related genes. For the wolverine, a circumpolar hypercarnivore that must cope with seasonal food scarcity, we observed many changes in genes associated with diet and body condition. All types of genomic variation examined (single nucleotide polymorphisms, gene family expansions, structural variants) contributed substantially to the identification of candidate loci. This argues strongly for consideration of variation other than single nucleotide polymorphisms in comparative genomics studies aiming to identify loci of adaptive significance. KW - adaptation KW - gene family evolution KW - genomics KW - mustelids KW - positive KW - selection KW - structural variation Y1 - 2022 U6 - https://doi.org/10.1111/mec.16443 SN - 0962-1083 SN - 1365-294X VL - 31 IS - 10 SP - 2898 EP - 2919 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Abdelilah-Seyfried, Salim A1 - Iruela-Arispe, M. Luisa A1 - Penninger, Josef M. A1 - Tournier-Lasserve, Elisabeth A1 - Vikkula, Miikka A1 - Cleaver, Ondine T1 - Recalibrating vascular malformations and mechanotransduction by pharmacological intervention JF - Journal of clinical investigation Y1 - 2022 U6 - https://doi.org/10.1172/JCI160227 SN - 0021-9738 SN - 1558-8238 VL - 132 IS - 8 PB - American Society for Clinical Investigation CY - Ann Arbor ER - TY - JOUR A1 - Cao, Xianyong A1 - Tian, Fang A1 - Herzschuh, Ulrike A1 - Ni, Jian A1 - Xu, Qinghai A1 - Li, Wenjia A1 - Zhang, Yanrong A1 - Luo, Mingyu A1 - Chen, Fahu T1 - Human activities have reduced plant diversity in eastern China over the last two millennia JF - Global change biology N2 - Understanding the history and regional singularities of human impact on vegetation is key to developing strategies for sustainable ecosystem management. In this study, fossil and modern pollen datasets from China are employed to investigate temporal changes in pollen composition, analogue quality, and pollen diversity during the Holocene. Anthropogenic disturbance and vegetation's responses are also assessed. Results reveal that pollen assemblages from non-forest communities fail to provide evidence of human impact for the western part of China (annual precipitation less than 400 mm and/or elevation more than 3000 m.a.s.l.), as inferred from the stable quality of modern analogues, principal components, and diversity of species and communities throughout the Holocene. For the eastern part of China, the proportion of fossil pollen spectra with good modern analogues increases from ca. 50% to ca. 80% during the last 2 millennia, indicating an enhanced intensity of anthropogenic disturbance on vegetation. This disturbance has caused the pollen spectra to become taxonomically less diverse over space (reduced abundances of arboreal taxa and increased abundances of herbaceous taxa), highlighting a reduced south-north differentiation and divergence from past vegetation between regions in the eastern part of China. We recommend that care is taken in eastern China when basing the development of ecosystem management strategies on vegetation changes in the region during the last 2000 years, since humans have significantly disturbed the vegetation during this period. KW - analogue quality KW - human-vegetation interaction KW - land use KW - latitudinal KW - zonation KW - plant diversity KW - pollen Y1 - 2022 U6 - https://doi.org/10.1111/gcb.16274 SN - 1354-1013 SN - 1365-2486 VL - 28 IS - 16 SP - 4962 EP - 4976 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Córdoba, Sandra Correa A1 - Tong, Hao A1 - Burgos, Asdrubal A1 - Zhu, Feng A1 - Alseekh, Saleh A1 - Fernie, Alisdair A1 - Nikoloski, Zoran T1 - Identification of gene function based on models capturing natural variability of Arabidopsis thaliana lipid metabolism JF - Nature Communications N2 - The use of automated tools to reconstruct lipid metabolic pathways is not warranted in plants. Here, the authors construct Plant Lipid Module for Arabidopsis rosette using constraint-based modeling, demonstrate its integration in other plant metabolic models, and use it to dissect the genetic architecture of lipid metabolism. Lipids play fundamental roles in regulating agronomically important traits. Advances in plant lipid metabolism have until recently largely been based on reductionist approaches, although modulation of its components can have system-wide effects. However, existing models of plant lipid metabolism provide lumped representations, hindering detailed study of component modulation. Here, we present the Plant Lipid Module (PLM) which provides a mechanistic description of lipid metabolism in the Arabidopsis thaliana rosette. We demonstrate that the PLM can be readily integrated in models of A. thaliana Col-0 metabolism, yielding accurate predictions (83%) of single lethal knock-outs and 75% concordance between measured transcript and predicted flux changes under extended darkness. Genome-wide associations with fluxes obtained by integrating the PLM in diel condition- and accession-specific models identify up to 65 candidate genes modulating A. thaliana lipid metabolism. Using mutant lines, we validate up to 40% of the candidates, paving the way for identification of metabolic gene function based on models capturing natural variability in metabolism. KW - Biochemical networks KW - Biochemical reaction networks KW - Genetic models KW - Plant molecular biology Y1 - 2023 U6 - https://doi.org/10.1038/s41467-023-40644-9 SN - 2041-1723 VL - 14 IS - 1 PB - Springer Nature CY - London ER - TY - JOUR A1 - Cheng, Feng A1 - Dennis, Alice B. A1 - Osuoha, Josephine Ijeoma A1 - Canitz, Julia A1 - Kirschbaum, Frank A1 - Tiedemann, Ralph T1 - A new genome assembly of an African weakly electric fish (Campylomormyrus compressirostris, Mormyridae) indicates rapid gene family evolution in Osteoglossomorpha JF - BMC genomics N2 - Background Teleost fishes comprise more than half of the vertebrate species. Within teleosts, most phylogenies consider the split between Osteoglossomorpha and Euteleosteomorpha/Otomorpha as basal, preceded only by the derivation of the most primitive group of teleosts, the Elopomorpha. While Osteoglossomorpha are generally species poor, the taxon contains the African weakly electric fish (Mormyroidei), which have radiated into numerous species. Within the mormyrids, the genus Campylomormyrus is mostly endemic to the Congo Basin. Campylomormyrus serves as a model to understand mechanisms of adaptive radiation and ecological speciation, especially with regard to its highly diverse species-specific electric organ discharges (EOD). Currently, there are few well-annotated genomes available for electric fish in general and mormyrids in particular. Our study aims at producing a high-quality genome assembly and to use this to examine genome evolution in relation to other teleosts. This will facilitate further understanding of the evolution of the osteoglossomorpha fish in general and of electric fish in particular. Results A high-quality weakly electric fish (C. compressirostris) genome was produced from a single individual with a genome size of 862 Mb, consisting of 1,497 contigs with an N50 of 1,399 kb and a GC-content of 43.69%. Gene predictions identified 34,492 protein-coding genes, which is a higher number than in the two other available Osteoglossomorpha genomes of Paramormyrops kingsleyae and Scleropages formosus. A Computational Analysis of gene Family Evolution (CAFE5) comparing 33 teleost fish genomes suggests an overall faster gene family turnover rate in Osteoglossomorpha than in Otomorpha and Euteleosteomorpha. Moreover, the ratios of expanded/contracted gene family numbers in Osteoglossomorpha are significantly higher than in the other two taxa, except for species that had undergone an additional genome duplication (Cyprinus carpio and Oncorhynchus mykiss). As potassium channel proteins are hypothesized to play a key role in EOD diversity among species, we put a special focus on them, and manually curated 16 Kv1 genes. We identified a tandem duplication in the KCNA7a gene in the genome of C. compressirostris. Conclusions We present the fourth genome of an electric fish and the third well-annotated genome for Osteoglossomorpha, enabling us to compare gene family evolution among major teleost lineages. Osteoglossomorpha appear to exhibit rapid gene family evolution, with more gene family expansions than contractions. The curated Kv1 gene family showed seven gene clusters, which is more than in other analyzed fish genomes outside Osteoglossomorpha. The KCNA7a, encoding for a potassium channel central for EOD production and modulation, is tandemly duplicated which may related to the diverse EOD observed among Campylomormyrus species. KW - Campylomormyrus KW - Pacbio sequencing KW - Gene family KW - Osteoglossomorpha KW - Kv1 Y1 - 2023 U6 - https://doi.org/10.1186/s12864-023-09196-6 SN - 1471-2164 VL - 24 IS - 1 PB - BMC CY - London ER - TY - JOUR A1 - Peter, Lena A1 - Wendering, Désirée Jacqueline A1 - Schlickeiser, Stephan A1 - Hoffmann, Henrike A1 - Noster, Rebecca A1 - Wagner, Dimitrios Laurin A1 - Zarrinrad, Ghazaleh A1 - Münch, Sandra A1 - Picht, Samira A1 - Schulenberg, Sarah A1 - Moradian, Hanieh A1 - Mashreghi, Mir-Farzin A1 - Klein, Oliver A1 - Gossen, Manfred A1 - Roch, Toralf A1 - Babel, Nina A1 - Reinke, Petra A1 - Volk, Hans-Dieter A1 - Amini, Leila A1 - Schmueck-Henneresse, Michael T1 - Tacrolimus-resistant SARS-CoV-2-specific T cell products to prevent and treat severe COVID-19 in immunosuppressed patients JF - Molecular therapy methods and clinical development N2 - Solid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cell receptor (TCR) sequencing analyses. Based on the promising results, we aim for clinical validation of this approach in transplant recipients. Additionally, we propose a combinatory approach with tacrolimus, to prevent an overshooting immune response manifested as bystander T cell activation in the setting of severe COVID-19 immunopathology, and tacrolimus-resistant SARS-CoV-2-specific T cell products, allowing for efficient clearance of viral infection. Our strategy has the potential to prevent severe COVID-19 courses in SOT or autoimmunity settings and to prevent immunopathology while providing viral clearance in severe non-transplant COVID-19 cases. Y1 - 2022 U6 - https://doi.org/10.1016/j.omtm.2022.02.012 SN - 2329-0501 VL - 25 SP - 52 EP - 73 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Tomowski, Maxi A1 - Lozada-Gobilard, Sissi Donna A1 - Jeltsch, Florian A1 - Tiedemann, Ralph T1 - Recruitment and migration patterns reveal a key role for seed banks in the meta-population dynamics of an aquatic plant JF - Scientific reports N2 - Progressive habitat fragmentation threatens plant species with narrow habitat requirements. While local environmental conditions define population growth rates and recruitment success at the patch level, dispersal is critical for population viability at the landscape scale. Identifying the dynamics of plant meta-populations is often confounded by the uncertainty about soil-stored population compartments. We combined a landscape-scale assessment of an amphibious plant's population structure with measurements of dispersal complexity in time to track dispersal and putative shifts in functional connectivity. Using 13 microsatellite markers, we analyzed the genetic structure of extant Oenanthe aquatica populations and their soil seed banks in a kettle hole system to uncover hidden connectivity among populations in time and space. Considerable spatial genetic structure and isolation-by-distance suggest limited gene flow between sites. Spatial isolation and patch size showed minor effects on genetic diversity. Genetic similarity found among extant populations and their seed banks suggests increased local recruitment, despite some evidence of migration and recent colonization. Results indicate stepping-stone dispersal across adjacent populations. Among permanent and ephemeral demes the resulting meta-population demography could be determined by source-sink dynamics. Overall, these spatiotemporal connectivity patterns support mainland-island dynamics in our system, highlighting the importance of persistent seed banks as enduring sources of genetic diversity. Y1 - 2023 U6 - https://doi.org/10.1038/s41598-023-37974-5 SN - 2045-2322 VL - 13 IS - 1 PB - Springer Nature CY - London ER -