TY - GEN A1 - Send, T. S. A1 - Gilles, M. A1 - Codd, V. A1 - Wolf, I. A. C. A1 - Bardtke, S. A1 - Streit, Fabian A1 - Strohmaier, Jana A1 - Frank, Josef A1 - Schendel, D. A1 - Sutterlin, M. W. A1 - Denniff, M. A1 - Laucht, Manfred A1 - Samani, N. J. A1 - Deuschle, Michael A1 - Rietschel, Marcella A1 - Witt, Stephanie H. T1 - Telomere length in newborns is related to maternal stress during pregnancy Response T2 - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology KW - Predictive markers KW - Risk factors Y1 - 2018 U6 - https://doi.org/10.1038/s41386-018-0079-8 SN - 0893-133X SN - 1740-634X VL - 43 IS - 11 SP - 2164 EP - 2164 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Witt, Stephanie H. A1 - Frank, Josef A1 - Gilles, Maria A1 - Lang, Maren A1 - Treutlein, Jens A1 - Streit, Fabian A1 - Wolf, Isabell A. C. A1 - Peus, Verena A1 - Scharnholz, Barbara A1 - Send, Tabea S. A1 - Heilmann-Heimbach, Stefanie A1 - Sivalingam, Sugirthan A1 - Dukal, Helene A1 - Strohmaier, Jana A1 - Sütterlin, Marc A1 - Arloth, Janine A1 - Laucht, Manfred A1 - Nöthen, Markus M. A1 - Deuschle, Michael A1 - Rietschel, Marcella T1 - Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation JF - BMC genomics N2 - Background: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. Methods: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. Results: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. Conclusion: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight. KW - DNA methylation KW - Smoking KW - Birth weight KW - Mediation analysis Y1 - 2018 U6 - https://doi.org/10.1186/s12864-018-4652-7 SN - 1471-2164 VL - 19 PB - BMC CY - London ER - TY - GEN A1 - Hartung, Niklas A1 - Benary, Uwe A1 - Wolf, Jana A1 - Kofahl, Bente T1 - Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background Cells are able to communicate and coordinate their function within tissues via secreted factors. Aberrant secretion by cancer cells can modulate this intercellular communication, in particular in highly organised tissues such as the liver. Hepatocytes, the major cell type of the liver, secrete Dickkopf (Dkk), which inhibits Wnt/ β-catenin signalling in an autocrine and paracrine manner. Consequently, Dkk modulates the expression of Wnt/ β-catenin target genes. We present a mathematical model that describes the autocrine and paracrine regulation of hepatic gene expression by Dkk under wild-type conditions as well as in the presence of mutant cells. Results Our spatial model describes the competition of Dkk and Wnt at receptor level, intra-cellular Wnt/ β-catenin signalling, and the regulation of target gene expression for 21 individual hepatocytes. Autocrine and paracrine regulation is mediated through a feedback mechanism via Dkk and Dkk diffusion along the porto-central axis. Along this axis an APC concentration gradient is modelled as experimentally detected in liver. Simulations of mutant cells demonstrate that already a single mutant cell increases overall Dkk concentration. The influence of the mutant cell on gene expression of surrounding wild-type hepatocytes is limited in magnitude and restricted to hepatocytes in close proximity. To explore the underlying molecular mechanisms, we perform a comprehensive analysis of the model parameters such as diffusion coefficient, mutation strength and feedback strength. Conclusions Our simulations show that Dkk concentration is elevated in the presence of a mutant cell. However, the impact of these elevated Dkk levels on wild-type hepatocytes is confined in space and magnitude. The combination of inter- and intracellular processes, such as Dkk feedback, diffusion and Wnt/ β-catenin signal transduction, allow wild-type hepatocytes to largely maintain their gene expression. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 886 KW - Wnt/ β-catenin signalling pathway KW - Dickkopf diffusion and feedback regulation KW - APC concentration gradient KW - mathematical model KW - paracrine and autocrine regulation KW - reaction-diffusion system Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-430778 SN - 1866-8372 IS - 886 ER - TY - JOUR A1 - Dschietzig, Thomas Bernd A1 - Krause-Relle, Katharina A1 - Hennequin, Maud A1 - von Websky, Karoline A1 - Rahnenfuhrer, Jan A1 - Ruppert, Jana A1 - Groena, Hans Juergen A1 - Armbruster, Franz Paul A1 - Bathgate, Ross A. D. A1 - Aschenbach, Joerg R. A1 - Forssmann, Wolf-Georg A1 - Hocher, Berthold T1 - Relaxin-2 does not Ameliorate Nephropathy in an experimental model of Type-1 Diabetes JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background/Aims: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Methods: Low-dose (32 mu g/kg/day) and high-dose (320 mu g/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Results: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-beta pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. Conclusions: We investigated a model showing early DN without overt tubulo-interstitial fibrosis and activation of the TGF-beta-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes. KW - Diabetic nephropathy KW - Diabetic cardiomyopathy KW - Fibrosis KW - Inflammation KW - Relaxin Y1 - 2015 U6 - https://doi.org/10.1159/000368484 SN - 1420-4096 SN - 1423-0143 VL - 40 IS - 1 SP - 77 EP - 88 PB - Karger CY - Basel ER - TY - JOUR A1 - Send, Tabea Sarah A1 - Gilles, Maria A1 - Codd, Veryan A1 - Wolf, Isabell A1 - Bardtke, Svenja A1 - Streit, Fabian A1 - Strohmaier, Jana A1 - Frank, Josef A1 - Schendel, Darja A1 - Suetterlin, Mark W. A1 - Denniff, Matthew A1 - Laucht, Manfred A1 - Samani, Nilesh J. A1 - Deuschle, Michael A1 - Rietschel, Marcella A1 - Witt, Stephanie H. T1 - Telomere Length in Newborns is Related to Maternal Stress During Pregnancy JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology N2 - Telomere length (TL) is a marker of biological aging, and numerous studies have shown associations between TL and somatic or psychiatric disorders. Research also indicates an association between maternal stress during pregnancy and TL in the offspring. The present study investigated possible associations between TL and: (1) maternal perceived stress during pregnancy; (2) a maternal lifetime history of psychiatric disorder (lifetime PD); and (3) paternal age. TL was analyzed in 319 newborns and 318 mothers from a predominantly Caucasian sample (n= 273 Caucasian newborns and n= 274 Caucasian mothers). Two key findings were observed. First, maternal perceived stress during pregnancy was associated with shorter telomeres in newborns but not with maternal TL. Second, maternal lifetime PD was associated with shorter maternal telomeres, but not with TL in newborns. Paternal age was not associated with TL in newborns. The finding that maternal stress during pregnancy is associated with shorter telomeres in newborns supports the results of smaller previous studies. The fact that a relation between maternal prenatal stress and TL was observed in the offspring but not in mothers may be attributable to a high vulnerability to stress during intrauterine development of a maturing organism. To our knowledge, this is the largest study to date to show that maternal stress during pregnancy but not maternal lifetime PD is associated with shorter telomeres in the offspring. Y1 - 2017 U6 - https://doi.org/10.1038/npp.2017.73 SN - 0893-133X SN - 1740-634X VL - 42 SP - 2407 EP - 2413 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Hartung, Niklas A1 - Benary, Uwe A1 - Wolf, Jana A1 - Kofahl, Bente T1 - Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes JF - BMC systems biology N2 - Background: Cells are able to communicate and coordinate their function within tissues via secreted factors. Aberrant secretion by cancer cells can modulate this intercellular communication, in particular in highly organised tissues such as the liver. Hepatocytes, the major cell type of the liver, secrete Dickkopf (Dkk), which inhibits Wnt/beta-catenin signalling in an autocrine and paracrine manner. Consequently, Dkk modulates the expression of Wnt/beta-catenin target genes. We present a mathematical model that describes the autocrine and paracrine regulation of hepatic gene expression by Dkk under wild-type conditions as well as in the presence of mutant cells. Results: Our spatial model describes the competition of Dkk and Wnt at receptor level, intra-cellular Wnt/beta-catenin signalling, and the regulation of target gene expression for 21 individual hepatocytes. Autocrine and paracrine regulation is mediated through a feedback mechanism via Dkk and Dkk diffusion along the porto-central axis. Along this axis an APC concentration gradient is modelled as experimentally detected in liver. Simulations of mutant cells demonstrate that already a single mutant cell increases overall Dkk concentration. The influence of the mutant cell on gene expression of surrounding wild-type hepatocytes is limited in magnitude and restricted to hepatocytes in close proximity. To explore the underlying molecular mechanisms, we perform a comprehensive analysis of the model parameters such as diffusion coefficient, mutation strength and feedback strength. Conclusions: Our simulations show that Dkk concentration is elevated in the presence of a mutant cell. However, the impact of these elevated Dkk levels on wild-type hepatocytes is confined in space and magnitude. The combination of inter-and intracellular processes, such as Dkk feedback, diffusion and Wnt/beta-catenin signal transduction, allow wild-type hepatocytes to largely maintain their gene expression. KW - Wnt/beta-catenin signalling pathway KW - Dickkopf diffusion and feedback regulation KW - APC concentration gradient KW - Mathematical model KW - Paracrine and autocrine regulation KW - Reaction-diffusion system Y1 - 2017 U6 - https://doi.org/10.1186/s12918-017-0470-9 SN - 1752-0509 VL - 11 PB - BioMed Central CY - London ER - TY - JOUR A1 - Eccard, Jana A1 - Wolf, Jochen B. W. T1 - Effects of brood size on multiple-paternity rates : a case for 'paternity share' as an offspring- based estimate Y1 - 2009 UR - http://www.sciencedirect.com/science/journal/00033472 U6 - https://doi.org/10.1016/j.anbehav.2009.04.008 SN - 0003-3472 ER - TY - JOUR A1 - Schmidt, Sabrina A1 - Saxenhofer, Moritz A1 - Drewes, Stephan A1 - Schlegel, Mathias A1 - Wanka, Konrad M. A1 - Frank, Raphael A1 - Klimpel, Sven A1 - von Blanckenhagen, Felix A1 - Maaz, Denny A1 - Herden, Christiane A1 - Freise, Jona A1 - Wolf, Ronny A1 - Stubbe, Michael A1 - Borkenhagen, Peter A1 - Ansorge, Hermann A1 - Eccard, Jana A1 - Lang, Johannes A1 - Jourdain, Elsa A1 - Jacob, Jens A1 - Marianneau, Philippe A1 - Heckel, Gerald A1 - Ulrich, Rainer Günter T1 - High genetic structuring of Tula hantavirus JF - Archives of virology N2 - Tula virus (TULV) is a vole-associated hantavirus with low or no pathogenicity to humans. In the present study, 686 common voles (Microtus arvalis), 249 field voles (Microtus agrestis) and 30 water voles (Arvicola spec.) were collected at 79 sites in Germany, Luxembourg and France and screened by RT-PCR and TULV-IgG ELISA. TULV-specific RNA and/or antibodies were detected at 43 of the sites, demonstrating a geographically widespread distribution of the virus in the studied area. The TULV prevalence in common voles (16.7 %) was higher than that in field voles (9.2 %) and water voles (10.0 %). Time series data at ten trapping sites showed evidence of a lasting presence of TULV RNA within common vole populations for up to 34 months, although usually at low prevalence. Phylogenetic analysis demonstrated a strong genetic structuring of TULV sequences according to geography and independent of the rodent species, confirming the common vole as the preferential host, with spillover infections to co-occurring field and water voles. TULV phylogenetic clades showed a general association with evolutionary lineages in the common vole as assessed by mitochondrial DNA sequences on a large geographical scale, but with local-scale discrepancies in the contact areas. Y1 - 2016 U6 - https://doi.org/10.1007/s00705-016-2762-6 SN - 0304-8608 SN - 1432-8798 VL - 161 SP - 1135 EP - 1149 PB - Springer CY - Wien ER - TY - JOUR A1 - Heger, Tina A1 - Bernard-Verdier, Maud A1 - Gessler, Arthur A1 - Greenwood, Alex D. A1 - Grossart, Hans-Peter A1 - Hilker, Monika A1 - Keinath, Silvia A1 - Kowarik, Ingo A1 - Küffer, Christoph A1 - Marquard, Elisabeth A1 - Mueller, Johannes A1 - Niemeier, Stephanie A1 - Onandia, Gabriela A1 - Petermann, Jana S. A1 - Rillig, Matthias C. A1 - Rodel, Mark-Oliver A1 - Saul, Wolf-Christian A1 - Schittko, Conrad A1 - Tockner, Klement A1 - Joshi, Jasmin Radha A1 - Jeschke, Jonathan M. T1 - Towards an Integrative, Eco-Evolutionary Understanding of Ecological Novelty: Studying and Communicating Interlinked Effects of Global Change JF - Bioscience N2 - Global change has complex eco-evolutionary consequences for organisms and ecosystems, but related concepts (e.g., novel ecosystems) do not cover their full range. Here we propose an umbrella concept of "ecological novelty" comprising (1) a site-specific and (2) an organism-centered, eco-evolutionary perspective. Under this umbrella, complementary options for studying and communicating effects of global change on organisms, ecosystems, and landscapes can be included in a toolbox. This allows researchers to address ecological novelty from different perspectives, e.g., by defining it based on (a) categorical or continuous measures, (b) reference conditions related to sites or organisms, and (c) types of human activities. We suggest striving for a descriptive, non-normative usage of the term "ecological novelty" in science. Normative evaluations and decisions about conservation policies or management are important, but require additional societal processes and engagement with multiple stakeholders. KW - Anthropocene KW - eco-evolutionary experience KW - global change KW - novel ecosystems KW - shifting baselines Y1 - 2019 U6 - https://doi.org/10.1093/biosci/biz095 SN - 0006-3568 SN - 1525-3244 VL - 69 IS - 11 SP - 888 EP - 899 PB - Oxford Univ. Press CY - Oxford ER -