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Item type:Item, Direct and time-lagged impact of heat stress on primary and functional traits in dairy and dual-purpose cattle at different “omics” levels(2025) Halli, KathrinThis habilitation thesis focuses on the impact of acute and maternal heat stress (HS) on production and functional traits and on metabolism of dairy and dual-purpose cattle and offspring considering the temperature humidity index (THI) as environmental descriptor. In this context, the comprehensive introduction, the discussion and the 10 original research papers address the different “omics” levels “phenomics” (phenotypic association studies), “genomics” (genetic parameters, genome wide association studies, gene annotations), “epigenomics” (DNA methylation profiles), “metabolomics” (metabolite concentrations) and “transcriptomics” (gene expression levels). The original research paper 1 focused on the impact of acute HS during the early life of dual-purpose calves on their weight development and of acute and time-lagged HS on fertility traits of dams under pasture-based conditions. Across-generation effects of maternal HS during late gestation are also content of this paper. Our results indicated acute and time-lagged HS effects and limited acclimatization processes to heat, especially during the cooler spring and autumn months. Similarly, the original research paper 2 focused on across-generation effects of maternal HS during late gestation on production and functional traits, however, in dairy cattle. We found an unfavorable impact of HS from the dry period on time-lagged performances in offspring on most primary and functional traits, even on longevity. Metabolic aspects of acute HS during late gestation on German dairy cows and of across-generation effects of maternal HS on female progeny are content of original research paper 3 and 4. The results showed altered concentrations of different plasma metabolites from different biochemical classes between animals suffering from direct or maternal HS or not with potential to serve as biomarkers for HS. The impact of time-lagged HS during late gestation and postpartum on genetic parameter estimates for birth weight and weight gain in dual-purpose calves is presented in original research paper 5. Additive genetic variances and heritabilities of all traits increased under challenging climatic conditions indicating a higher selection response in beef cattle traits under HS conditions. Genetic correlations substantially smaller than 0.80 indicated genotype by climate interactions, proven by substantial alterations of sire EBVs for production traits in dependency of time-lagged climatic alterations. In a similar context, maternal HS during late gestation was analyzed for its impact on production and functional traits in dairy cattle in the original research paper 6. Birth weights and birth weight genetic parameters of dual-purpose and dairy calves in context of time-lagged effects due to HS during late gestation and genotype by climate interactions for birth weight are also presented in this paper. The results showed detrimental effects of prenatal HS on birth weight in offspring. Direct and maternal heritabilities for calf birth weight were independent from prenatal HS effects. No genotype by climate interactions on calf birth weight were identified for maternal genetic effects. We concluded that the decline in birth weight is more likely caused by maternal permanent environmental effects instead of genetics, why we suggested to avoid HS during the dry period of dams. The original research paper 7 focused on direct and maternal genetic effects and the annotation of potential candidate genes for weight and meat quality traits of dual-purpose cattle, raised under outdoor climatic conditions. For intramuscular fat content (IMF), we estimated quite high heritabilities and we identified a quite strong maternal genetic component on weight traits as well as on IMF. This is probably due to the intensive calf-cow relationship in the outdoor suckler system. We suggest the application of models with maternal genetic effect in genetic evaluations, and we recommended to develop a breeding goal including IMF for the used dual-purpose cattle breed. Direct and maternal genetic effects, and maternal genetic sensitivity on prenatal HS for calf diseases and corresponding genomic loci in German Holsteins were analyzed in the original research paper 8. Genotype by climate interactions for calf diseases in dairy calves, suffering from prenatal HS were analyzed. Our results showed that HS, particularly during the last week of gestation, contributed to increased calf disease incidence. Maternal heritabilities for pneumonia increased with increasing heat. We identified 30 suggestive and 2 significant SNPs from the GWAS and 43 genes, annotated as potential candidate genes. Based on these genes, 3 biological processes were inferred, indicating association between the genetics of prenatal HS mechanisms and immune physiology and disease resistance mechanisms. Original research paper 9 addressed the estimation of genotype by time-lagged HS variance components for milk production traits of the offspring generation, and main and interaction SNP-marker effects for maternal HS during late pregnancy. The results indicated quite small effects of HS during late pregnancy on the test day and lactation milk production traits. Genotype by HS interaction variances varied, depending on the week with in-utero HS. Eight out of 31 suggestive SNPs affect cattle functionality, indicating a possible favorable correlation between functional traits and heat tolerance. Two biological processes contributing to immune response mechanisms, were inferred with suggestive interaction effects. In original research paper 10, we studied HS effects on 3 different “omics features” which were methylations, gene expressions and metabolic pattern from a direct perspective in pregnant cows and from an indirect time-lagged intergenerational perspective in offspring. Differences in DNA methylation between maternally heat stressed and not heat stressed calves were proven in this paper, supporting the hypothesis of an epigenetic percentage, explaining across generation effects of HS. With regard to the intergenerational perspective, transcriptomic and metabolic profiles showed obvious clustering between dams and calves. In the context of HS separation, gene expression and methylation data clearly separated HS and control groups. However, in the multi-omics analysis, methylation information was the least important omics tier to classify dams in terms of direct HS, when compared to the other omics datasets. Overall, the studies of this habilitation thesis present important findings for future research studies regarding heat stress mitigation strategies in cattle under German climatic conditions and breeding programs in context of heat stress resistance.Item type:Item, Operationen bei Kindern mit Aortenbogenpathologien- Ergebnisse einer neuen Operationstechnik mit autologem pulmonalarteriellem Gewebe(2026) Yörüker, UygarFortschritte in der chirurgischen Technik und in perioperative Medizin haben dazu geführt, dass bei der Therapie des unterbrochenen Aortenbogens (IAA) zufriedenstellende Überlebensraten erreicht werden. Allerdings sind die bisher etablierten chirurgischen Verfahren mit den folgenden typischen Komplikationen assoziert: - Anastomosenstenose infolge übermäßiger Spannung im Anastomosenbereich. - Ausbildung eines sogenannten gotischen Bogens, mit nachteiligen Blutflußeigenschaften die zu eine arterielle Hypertonie führen können. - Kompression des linken Hauptbronchus. Um diese Komplikationen zu minimieren, wird seit 2005 am Kinderherzzentrum Giessen bei Patienten mit IAA oder mit ausgeprägter Aortenbogenhypoplasie eine von Prof.Dr.Hakan Akintürk neu entwickelte operative Technik angewendet. Bei dieser Technik wird autologes Gewebe aus dem Stamm der Pulmonalarterie des Patienten entnommen und bei der Rekonstruktion des Aortenbogens als Hinterwand des Aortenbogens verwendet. Für die Vorderwand des Aortenbogens wird ein autologes Perikardgewebe verwendet. Auf diese Weise wird eine breite, spannungsarme und normale Anatomie nahezu entsprechender Aortenbogen geschaffen. Durch die Verwendung körpereigener Gewebe mit Wachstumspotenzial können auch langfristig gute Ergebnisse erzielt werden. Im Rahmen dieser Doktorarbeit wurden, die mit dieser neuen Technik operierten Patienten retrospektiv untersucht um überprüfen, inwieweit die theoretisch zu erwartenden guten Ergebnisse auch in der klinischen Anwendung zu erzielen sind. Die Analyse erfolgte im Hinblick auf die frühe und späte Mortalität sowie die frühe und späte Morbidität. Obwohl die frühe und späte Mortalität vergleichbare Ergebnisse wie andere in der Literatur beschriebene Techniken zeigte, wurden hinsichtlich der frühen und späten Morbidität insgesamt bessere Ergebnisse beobachtet, insbesondere in Bezug auf die Vermeidung von Re-Interventionen am Aortenbogen, die Prävention der Gothic-Arch- Entwicklung sowie das Auftreten von Hypertonie und einer Kompression des linken Hauptbronchus. Zusammenfassend zeigt diese neue Methode sowohl im frühen als auch im Langzeitverlauf vielversprechende Ergebnisse und kann als eine effektive Alternative zu konventionellen Techniken angesehen werden. Vor allem im Hinblick auf eine Vermeidung der „Gothic-Arch-Bildung“ und den damit verbundenen potenziellen Komplikationen sowie auch im Hinblick auf das Wachstumspotential könnte das hier vorgestellte Verfahren vorteilhaft zu sein. Für eine abschließende Beurteilung sind allerdings noch Anwendung in anderen Zentren, eine insgesamt größere Patientenanzahl und weitere Langzeitergebnisse abzuwarten.Item type:Item, Analysis of CXCR4 in microglial pyroptosis after ischemia–reperfusion(2026) Yu, HaiyangCerebral ischemia–reperfusion injury elicits rapid sterile inflammation in which microglia undergo marked state transitions and can contribute to secondary tissue damage. Pyroptosis, executed by gasdermin D cleavage and pore formation, has been implicated in amplification of neuroinflammation, while the chemokine receptor CXCR4 is induced after stroke and may intersect with inflammatory execution pathways. This thesis investigated the role of CXCR4 in microglial pyroptosis after ischemia–reperfusion and evaluated whether pharmacological CXCR4 blockade with AMD3100 attenuates acute pyroptotic execution. Public datasets were reanalyzed, including bulk RNA sequencing of microglia three days after 60-min middle cerebral artery occlusion (MCAO) with reperfusion and brain-wide single-cell RNA sequencing 24 h after MCAO or sham. Bulk RNA-seq identified extensive transcriptional remodeling and significant induction of CXCR4 together with prominent inflammatory, and enrichment analyses mapped CXCR4-containing programs to chemokine signaling, chemotaxis, cytoskeletal remodeling, and receptor trafficking. Single-cell analysis resolved eight microglial states indicating pronounced post-ischemic heterogeneity. Pyroptosis-related module scores were broadly reduced across most MCAO-associated states but increased in the interferon-responsive state. CXCR4-axis activity showed weak yet significant positive associations with pyroptosis composite and execution programs after ischemia–reperfusion, whereas no significant correlations were detected in sham microglia, and a network-based virtual CXCR4 knockout suggested the most coherent attenuation of pyroptosis-related regulation in the interferon-responsive microglial state. For in vitro validation, primary mouse microglia were subjected to oxygen–glucose deprivation followed by reoxygenation (OGD/RO). CXCR4 protein increased transiently and peaked at 6 h OGD with 12 h reoxygenation. Under this condition, AMD3100 treatment reduced the cleaved GSDMD N-terminal fragment without altering full-length GSDMD and was accompanied by reduced membrane-associated GSDMD patterns and partial morphological normalization. Collectively, these findings support a model in which CXCR4 contributes to microglial pyroptotic execution in a time- and state-dependent manner after ischemia–reperfusion and indicate CXCR4 antagonism as a potential strategy to dampen acute inflammatory injury.Item type:Item, Chemosensitivität von cholinergen urethralen Bürstenzellen jenseits der Wahrnehmung von bitter, umami und süß(2026) Galdiga, ChrissyIn dieser Arbeit wurde sich mit Bürstenzellen beschäftigt, welche bereits in verschiedenen Organen von Mäusen nachgewiesen wurden. Bei Bürstenzellen handelt es sich um extraorale chemosensorische Zellen, welche ähnlich wie Geschmackszellen, eine Geschmackssignaltransduktionskaskade beinhalten. Das bedeutet, dass die Aktivierung eines Geschmackrezeptors, wie α-Gustducin, PLCβ2 oder TRPM5 zu einem Anstieg der intrazellulären Calcium-Konzentration führt, was wiederum eine Ausschüttung von Acetylcholin zur Folge hat. Hier wurden speziell die urethralen Bürstenzellen (UBC) und die Wahrnehmung derer auf verschiedene Stimuli betrachtet. Es wurde bereits gezeigt, dass eine bedeutende Anzahl an UBC, welche auf Denatonium reagieren, auch auf Glutamat reagieren (Deckmann et al., 2014). Im Zusammenhang mit oropharyngealer Geschmackswahrnehmung spiegeln diese Substanzen einen aversiven (Denatonium: bitter) und einen “attraktiven” (Glutamat: umami) Stimulus wider und werden durch unterschiedliche Zellpopulationen wahrgenommen, welche als Subtypen der Typ II Geschmackszellen angesehen werden können (Chaudhari and Roper, 2010). Methodisch wurden die UBC isoliert und auf verschiedene Arten verarbeitet, um nachzuweisen, ob Rezeptoren zur Wahrnehmung von sauren (PKD2L1, PDK1L3), fettigen (CD36, GPR120, GPR40) und salzigen Stimuli (ENaC) enthalten sind. Zum einen wurde durch Immunfluoreszenz nachgewiesen, dass o. g. Rezeptoren für saure und fettige Stimuli weder in der Urethra noch in UBC vertreten sind. Zum anderen konnte mittels PCR nachgewiesen werden, dass jedoch die α-Untereinheit des ENaC- Kanals in den UBC vorkommen. Weiterhin wurde, nach Isolation der UBC, unter einem CLSM (Konfokales Laser Scanning Mikroskop) gezeigt, dass die Zellen nach Zugabe von NaCl mit einer Erhöhung der intrazellulären Calcium-Konzentration reagieren. Dass es sich hierbei um einen osmotischen Effekt handelt, wurde durch die Zugabe einer vergleichbaren Konzentration an Mannitol und ausbleibender intrazellulärer Calciumerhöhung nachgewiesen. Amilorid als bekannter Hemmer des ENaCs führte bei simultaner NaCl Gabe ebenfalls zu einem Ausbleiben einer Reaktion der Zelle. Die mit dieser Arbeit erhobenen Daten zeigen, dass es eine noch größere Vielfältigkeit an Subtypen der UBC gibt, bei denen einige auch Funktionen und Merkmale der Typ I Geschmackszellen beinhalten, ENaC (epithelialer Natriumkanal) exprimieren und somit auf NaCl (Natriumchlorid) in Form einer Erhöhung der intrazellulären Calcium-Konzentration reagieren können (Vandenbeuch et al., 2008). Die Untersuchungen untermauern zudem die Vermutung des polymodalen Charakters von UBC. Die multiplen Kombinationen an Reaktionen auf verschiedene chemosensorische Stimuli und die Expression verschiedener Gene, welche für unterschiedliche Signalkaskaden verantwortlich sind, sind eher als phänotypische Variation einer polymodalen chemosensorischen Zelle, anstelle von verschiedenen, klar zu unterscheidenden Zelltypen zu interpretieren.Item type:Item, Recombinant CCL17 Shifts Microglial Phenotype and Protects Neurons from Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) Injury(2025) Luan, TengfeiIschemic stroke is a leading cause of death and disability worldwide, characterized by complex neuroinflammatory processes. Microglia serve as the innate immune cells within the central nervous system and are central mediators of neuroinflammatory responses. We investigated whether recombinant CCL17 (rCCL17) could influence microglial polarization and exert neuroprotective effects under OGD/R-induced injury conditions. Using brain tissue from neonatal mice, primary microglia were obtained and validated through morphological examination and immunofluorescence detection of IBA-1 and CD206. MTT assays revealed that microglial viability decreased significantly following prolonged hypoxia, establishing a 4-hour OGD with 24-hour reoxygenation as the experimental paradigm. Exposure to OGD/R conditions induced a marked increase in M1-associated genes—CD16, CD32, and iNOS—in microglia, whereas M2 markers like CD206, Arg-1, and IL-10 exhibited minimal upregulation. Notably, rCCL17 treatment at 150 ng/mL mitigated this pro-inflammatory response, facilitating a shift toward the M2 phenotype with elevated expression of associated markers. Furthermore, LPS stimulation led to increased M1 marker expression and a reduction in M2 markers, an effect that was reversed by rCCL17 treatment, except for IL-10. To assess the impact of rCCL17 on neuronal survival, primary neurons were subjected to OGD/R, revealing significant cell death after 4 h of hypoxia. rCCL17 at 100 ng/mL and 150 ng/mL significantly improved neuronal viability. When neurons were co-cultured with rCCL17-pretreated microglia, neuronal viability was significantly improved. Western blot analysis further confirmed that rCCL17-pretreated microglia reduced cleaved caspase-3 levels in neurons, indicating an anti-apoptotic effect. These results point to CCL17 as a modulator of microglial polarization, dampening M1-related responses and favoring M2-associated functions, thereby exerting neuroprotective effects under ischemic conditions. Evidence from this work suggests that CCL17 could be developed as an effective treatment for ischemic stroke.