Willkommen bei JLUpub

JLUpub ist das institutionelle Repositorium der Justus-Liebig-Universität.

JLUpub bietet Mitgliedern und Angehörigen der Universität die Möglichkeit neben wissenschaftlichen Dokumenten auch Forschungsdaten elektronisch zu veröffentlichen und dauerhaft zugänglich zu machen. Alle Veröffentlichungen erhalten einen Digital Object Identifier (DOI) und werden über nationale und internationale Bibliothekskataloge sowie Suchmaschinen nachgewiesen und auffindbar.

Photo by B. Zimmermann

Hauptbereiche in JLUpub

Wählen Sie einen Bereich, um dessen Inhalt anzusehen.

Gerade angezeigt 1 - 2 von 2

JLUdata
Forschungsdatenrepositorium
JLUdocs
Schriftenrepositorium

Neue Veröffentlichungen:

Moderne Verfahren zur Charakterisierung und effektiven interventionellen Behandlung von Vorhofflimmern und komplexen atrialen Tachykardien
(2024) Gunawardene, Melanie Anuscha
Ziel der vorliegenden Habilitationsschrift ist es, den Stellenwert hochauflösender dreidimensionaler Mappingverfahren, innovativer Katheterdesigns und neuer Energieformen zur interventionellen Behandlung von VHF und komplexen AT im Kontext der Effizienz und Sicherheit zu evaluieren. Die Katheterablation hat sich in der Behandlung symptomatischen VHF und konsekutiver AT etabliert. Um die Effektivität und Sicherheit zu steigern, wurden die Ablationsmethoden der invasiven Elektrophysiologie in den letzten Jahren kontinuierlich verbessert. Ebenso wurde das Management rund um die Prozedur, insbesondere in Bezug auf die periprozedurale Gabe der oralen Antikoagulation weiter optimiert. Es ist Gegenstand aktueller wissenschaftlicher Bemühungen diese optimierten Methoden im klinischen Einsatz zu evaluieren. Vor diesem Hintergrund wurden folgende Themenbereiche in der vorliegenden Habilitationsschrift behandelt: 1. Der Einfluss verschiedener periprozeduraler Antikoagulationsstrategien auf Komplikationsraten und Krankenhausaufenthaltsdauer bei der Katheterablation von persistierendem Vorhofflimmern 2. Die initiale Anwendung eines Ablationskatheters mit lokaler Impedanzmessung während der Katheterablation von Vorhofflimmern – Vergleich zwischen lokaler und Generator-Impedanz 3. Auftreten komplexer atrialer Tachykardien und die Charakterisierung von Leitungslücken in den initialen Ablationslinien um die Pulmonalvenen nach initialer Hochfrequenzstrom- und Cryoablation unter Verwendung eines ultra-hochauflösenden Mappingssystems 4. Pulsed Field Ablation unter Verwendung eines ultra-hochauflösenden Mappingssystems – Elektrophysiologische Charakteristika und praktische Herangehensweise 5. Pulsed Field Ablation in Kombination mit einem ultra-hochauflösenden Mappingssystem zur interventionellen Behandlung komplexer konsekutiver linksatrialer Tachykardien
Development of Antibody-Based Approaches for Specific Detection and Treatment of Triple Negative Breast and Ovarian Cancers
(2024) Hussain, Ahmad Fawzi
The hypothesis of a ‘‘one pill fits all’’ limits the success of cancer treatments and it is now acknowledged that no single therapeutic agent has the same effect on all patients with the same diagnosis. Precision medicine is a promising paradigm, mainly in cancer treatment, and it is widely believed that precision medicine will have a revolutionary impact on healthcare before, during and after disease by specifically targeting disease cells to ensure maximal efficacy and safety. However, the heterogeneity and complexity of tumors, along the development of different metastases set a countless challenge for cancer targeting therapies. The considerable increase in understanding molecular processes led to identification of numerous biomarkers for cancer detection and treatment. These biomarkers have paved the way for developing several tumor targeting therapies in recent years. It is now becoming increasingly clear that corresponding therapies have a great chance in improving cancer care by selectively targeting tumor cells and concomitantly reducing adverse side effects. Despite recent reduction in breast cancer mortality, breast cancer remains the leading cause of cancer-related death among women worldwide. Breast cancer targeted therapies that rely on tumor cell expression of estrogen (ER), progesterone (PgR) and HER2 receptors can be effective in the treatment of luminal and HER2-positive breast cancers. However, TNBC presents a challenge as it is characterized by the absence of ER, PgR and HER2 receptors. TNBC patients are generally young premenopausal women accounting for up to 20% of breast cancer cases. Moreover, TNBC is associated with unfavorable outcome with decreased disease free and overall survival rates. Ovarian cancer is one of the most common gynecological tumors worldwide. The gold standard therapy for ovarian cancer involves an intensive surgical cytoreduction, followed by a platinum and taxane-based cytostatic treatment. The antiangiogenetic bevacizumab and / or the novel drug class of PARP inhibitors – both effective in some high-grade serous cancers – have improved the progression-free survival as well as the overall survival. Nevertheless, the prognosis of ovarian cancer is poor and new therapeutic approaches warranted. The fatality rate of ovarian cancer is high because the available therapeutic modalities have failed to treat ovarian cancer patients with advanced disease, who are representing more than 70% of patents with ovarian cancer. For these patients, the five-year survival rates are ranging from 20% to 30%, in some settings up to 50%, compared to cure rates of 70% to 90 cure rates for those diagnosed with the disease is confined to the ovary. This is mainly due to the spreading of ovarian tumors into the peritoneum, retroperitoneal space and the serosa layer of the gut, which is one of the major limitations preventing the removal and / or treatment of poor-vascularized macro-metastasis, local and/or long distant micro-metastases as well as non-resectable macro-metastasis during cytoreductive surgery. These untreated tumor tissues usually cause tumor relapse, reducing the median survival rate from ~99 months for the patient with no residual disease to ~36 months if residual tumors are present. The high inter- and intra-tumor heterogeneity of TNBC and ovarian cancer associated with different histopathological features and clinical behaviors that influence differentially the therapeutic outcome of surgery and/or chemotherapy and associated with inherent and acquired drug resistance. Therefore, there is there is an urgent, and till now unmet, medical need for new treatment options for TNBC and ovarian cancer. This work represents the attempts to refine the methods for generating cancer targeting therapy and to overcome the shortcomings of the available therapeutic modalities of TNBC and ovarian cancer, such as tumor heterogeneity, low efficiency, and drug resistance. This is mainly achieved by using SNAP-tag technology as a site-specific conjugation method for arming antibody with therapeutic and / or imaging agents. Moreover, applying different therapeutic strategies (near infrared photo-immunotheranostics (NIR-PIT), antibody drug conjugate (ADC), and immunotoxin) as well as targeting different highly expressed cell surface receptor (EGFR, EpCam and CSPG4) on TNBC and ovarian cancer cells. SNAP-tag technology allows to site-specifically conjugate a wide range of effector molecules rapidly and efficiently under physiological conditions with 1:1 conjugation stoichiometry. The different mechanism of actions can overcome the limitation of cancer cell acquired and inherited drug resistance of TNBC and ovarian cancer, while targeting a set of different cell surface receptor can overcome the inter- and intra-tumor heterogeneity of TNBC and ovarian cancer. The developed NIR-PIT and ADC reagents demonstrated strong imaging properties and / or potent therapeutic activity in combination and / or individually against different TNBC and ovarian cancer cells in vitro. Despite the impressive results, additional experiments are undoubtedly required to determine the pharmacokinetic properties and to verify the imaging and / or the therapeutic activity in vivo. In another therapeutic approach, two human-based immunotoxins, scFv-CSPG4-MAP and GbR201K-scFvEpCam (full human immunotoxin), were generated and evaluated. Both in vitro and in vivo results showed that the immunotoxins have a high translational potential for targeted elimination of TNBC. The impact of developing antibody-based recombinant proteins, the use of SNAP-Tag technology for conjugating effector molecules, targeting three cell surface receptors (EGFR, EpCam and CSPG4) in combination and / or individually and the exploiting of different therapeutic strategies (NIR-PIT, ADC, and immunotoxin) for targeting TNBC and ovarian cancer were investigated and discussed in this work.
cAMP als protektiver Faktor bei der desmosomalen Adhäsion in Keratinozyten: Bedeutung von Flotillinen
(2025) Pilz, Lisa
Pemphigus vulgaris ist eine seltene Autoimmunerkrankung, die durch IgG-Autoantikörper gegen desmosomale Proteine, hauptsächlich Desmoglein (Dsg) 3 und Dsg1, verursacht wird. Dies führt zu Blasenbildung in der Epidermis und/oder der Schleimhaut. Die Lipid-Raft-assoziierten Flotilline, zentrale Regulatoren der Signaltransduktion, interagieren direkt mit Dsg1 und Dsg3. Die Depletion von Flotillinen beeinträchtigt die desmosomale Adhäsion und führt zu einer PV-ähnlichen Dsg3-Lokalisation in Keratinozyten. Kürzlich wurde gezeigt, dass ein erhöhter cAMP-Spiegel vor der induzierten desmosomalen Dissoziation durch pathogene Antikörper schützen kann. In der vorliegenden Arbeit war es ein Ziel zu analysieren, ob Flotilline an dem cAMP vermittelten Schutzmechanismus beteiligt sind. Zunächst zeigte ich, dass die Behandlung von hTert- und HaCaT-Keratinozyten mit Forskolin/Rolipram den intrazellulären cAMP-Spiegel erhöhen und die Zellmonolayer vor der induzierten Dissoziation durch mAK23, ein pathogener anti-Dsg3-Antikörper, schützt. Interessanterweise verhinderte die Behandlung mit Forskolin/Rolipram nicht den durch mAK23 induzierten Verlust der Dsg3-Expression in hTert-Zellen. Zur Aufklärung der Rolle der Flotilline im cAMP-vermittelten Schutzmechanismus wurden hTert-Zelllinien mit fehlender Flotillin(Flot)1- oder Flot2-Expression generiert. In den Flot1- und Flot2-Knockout-Zelllinien war die Monolayer-Dissoziation verstärkt. Auch ohne pathogene Antikörper reduzierte das erhöhte cAMP die Fragmentierung unabhängig von der Flotillin-Expression. Nach mAK23-Stimulation war der schützende Effekt nur in WT- und Flot1-, nicht jedoch in Flot2-defizienten Zellen nachweisbar. Auch Flot2-defiziente HaCaT-Zellen zeigten eine beeinträchtigte Zelladhäsion, die nur ohne mAK23 durch Forskolin/Rolipram teilweise wiederhergestellt werden konnte. Die Überexpression des Flot2-Tyr163Phe-Mutanten in HaCaT-Zellen zeigte einen dominant-negativen Effekt. Dies spricht für die Bedeutung der Flot2-Phosphorylierung bei der cAMP-abhängigen Stabilisierung der Zelladhäsion. Diese Ergebnisse unterstreichen die zentrale Rolle von Flot2 im cAMP-abhängigen Schutz der Keratinozytenadhäsion. Mutationen in Flot2 können diesen Mechanismus stören. Zukünftige Studien sollten die molekularen Interaktionen zwischen Flot2, dem cAMP-Signalweg und desmosomalen Komponenten weiter aufklären, um therapeutische Ansätze für PV und andere Erkrankungen mit gestörter Zelladhäsion zu entwickeln.
Establishing pangenome graph as a framework for the analysis of the impact of structural variation on gene expression
(2025) Yildiz, Gözde
This thesis addresses key challenges and opportunities in structural variation (SV) detection, genotyping, and downstream analyses using pangenome variation graphs for Brassica napus. By integrating different sequencing technologies and available bioinformatics tools, it demonstrates strategies to optimize the analysis of complex plant genomes, which are typically large, repetitive, and polyploid. Popular mapping and SV calling pipelines were evaluated using both simulated and real datasets from major crops, including rapeseed, tomato, maize, and soybean, across low to medium sequencing depths. The results demonstrate the feasibility of cost-effective SV detection, identifying the most efficient aligners and callers that achieve robust performance even at low coverage (≥5×). These findings provide a practical framework for population-scale crop studies, where sequencing costs and coverages are often a limiting factor. A graph-based pangenome approach was developed by combining long-read SV discovery with pangenome reference, allowing comparison with existing references to assess and reduce reference bias. This strategy enabled the identification of SVs, the construction of graph-based pangenomes, and subsequent SV genotyping in larger populations using short-read data, eliminating the need for costly de novo assemblies. The approach is therefore scalable, accessible, and suitable for high-throughput crop genomics. Importantly, integration with gene expression data revealed that many SVs, particularly those linked to transposable elements, significantly affect gene regulation and may underlie key agronomic traits. Overall, this thesis demonstrates that SVs are not only a major source of genetic diversity but also critical drivers of gene regulatory variation in crops. By providing benchmarking guidelines, novel graph-based pipelines, and functional insights into SVs, it lays the foundation for incorporating structural variation into future genome-informed breeding and trait discovery, ultimately supporting the development of more resilient and productive crop varieties.
Effects of Polyamide Microplastic Particles on Aquatic Outdoor Ecosystems - A Mesocosm Study
(2026) Kruckenfellner, Lukas
The protection and preservation of ecosystems, their biodiversity and the inherent ecosystem services should be a central goal of current scientific efforts. Not only the increasing chemical pollution, but also the increased occurrence of plastic is putting constant stress on ecosystems and individuals. There are many regulations and standardized procedures to assess the potential risk that chemical substances can have on the environment. This is not the case for particles such as microplastic. Although the uptake and transfer of microplastic particles along the food chain has already been proven, it is difficult to obtain a comparative overview of the ecotoxicological risk due to the large number of different parent substances, sizes, shapes and chemical additives. Standing water bodies such as lakes or reservoirs are a potential sink for such particles due to the lack of hydrodynamic pressure. This can lead to strong accumulations compared to the lotic inflows. The plastic particles, some of which are colonized by biofilms, can be mistaken for food or ingested unselectively by the organisms. This leads potentially to biomagnification in natural systems.<br> Since this can only be inadequately reproduced in classical laboratory studies, an aquatic field model ecosystem study was carried out in this project to investigate the influence of polyamide particles on aquatic biocoenosis. Particles with a size range of 5-50 µm were applied to the model ecosystems in three concentrations four times over a period of ten days in order to simulate a continuous influx of particles. In addition, a particulate control was used in the experiment to compare the potential effects of pure particles with those of the polyamide microplastic. Abiotic parameters and representatives of all trophic levels were regularly sampled and evaluated over a period of more than 100 days. The primary producers were represented by the chlorophyll a content in free-floating algae and the consumers and decomposers by animal plankton and larger invertebrates. The concentrations used in the approximately 1000 L systems were 1.5 mg L⁻¹, 15 mg L⁻¹ and 150 mg L⁻¹. In addition to pure abundance counts, the biovolume of adult and larval macroinvertebrates was also recorded and emergence time was established as a new endpoint for higher-tier studies.<br> The analysis of the samples revealed effects on the abundance of seed shrimps (Ostracoda). All polyamide treatments showed significant reductions compared to the control, with the effects at the highest concentration being the most long-term. No effects were observed in the particle control. A significantly earlier Emergence mean Time was observed in the emerged individuals of a subfamily of non-biting midges (Orthocladiinae). With a duration of 114 days this study is one of few to include long exposure, a particulate treated control and an environmentally realistic concentration of polyamide particles and gives important information for the risk assessment of microplastic under near-natural conditions.