04 Fakultät Energie-, Verfahrens- und Biotechnik

Permanent URI for this collectionhttps://elib.uni-stuttgart.de/handle/11682/5

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Open Access
2-Methoxyestradiol damages DNA in glioblastoma cells by regulating nNOS and heat shock proteins
(2022) Bastian, Paulina Emilia; Daca, Agnieszka; Płoska, Agata; Kuban-Jankowska, Alicja; Kalinowski, Leszek; Gorska-Ponikowska, Magdalena
Gliomas are the most prevalent primary tumors of the central nervous system (CNS), accounting for over fifty percent of all primary intracranial neoplasms. Glioblastoma (GBM) is the most prevalent form of malignant glioma and is often incurable. The main distinguishing trait of GBM is the presence of hypoxic regions accompanied by enhanced angiogenesis. 2-Methoxyestradiol (2-ME) is a well-established antiangiogenic and antiproliferative drug. In current clinical studies, 2-ME, known as Panzem, was examined for breast, ovarian, prostate, and multiple myeloma. The SW1088 grade III glioma cell line was treated with pharmacological and physiological doses of 2-ME. The induction of apoptosis and necrosis, oxidative stress, cell cycle arrest, and mitochondrial membrane potential were established by flow cytometry. Confocal microscopy was used to detect DNA damage. The Western blot technique determined the level of nitric oxide synthase and heat shock proteins. Here, for the first time, 2-ME is shown to induce nitro-oxidative stress with the concomitant modulation of heat shock proteins (HSPs) in the SW1088 grade III glioma cell line. Crucial therapeutic strategies for GMB should address both cell proliferation and angiogenesis, and due to the above, 2-ME seems to be a perfect candidate for GBM therapy.
Open Access
Abschaltung von dezentralen Erzeugungsanlagen infolge von Unterspannungen im Kontext von LFSM-O
(2022) Schöll, Christian; Lehner, Joachim; Weidner, Johannes; Lens, Hendrik
Bei einer Überfrequenz jenseits von 50,2 Hz müssen sämtliche Erzeugungsanlagen ihre in das Netz eingespeiste Wirkleistung reduzieren. In den zumeist resistiv geprägten Verteilungsnetzen der Mittel- und Niederspannung führt diese überfrequenzbedingte Leistungsreduktion zu einer lokalen Absenkung des Spannungsprofils. Unterschreiten die Spannungen die Vorgaben aus den Netzanschlussbedingungen, unter denen dezentrale Erzeugungsanlagen die Verbindung zum Netz aufrechterhalten müssen, kann es zu unterspannungsbedingten Schutzabschaltungen kommen. Theoretisch könnten diese bei großflächigem Auftreten zu einer Umkehr des ursprünglichen Überfrequenzereignisses in ein Unterfrequenzereignis führen. Anhand von simulationsbasierten Untersuchungen wird in diesem Beitrag jedoch aufgezeigt, dass unter realitätsnahen Annahmen und unter Berücksichtigung der nationalen Richtlinien sowie der zugehörigen netzplanerischen Leitplanken kein besonderes Risiko hinsichtlich der Anregung der beschriebenen Wirkungskette vorliegt.
Open Access
Acoustic streaming‐induced multimodal locomotion of bubble‐based microrobots
(2023) Mahkam, Nima; Aghakhani, Amirreza; Sheehan, Devin; Gardi, Gaurav; Katzschmann, Robert; Sitti, Metin
Acoustically‐driven bubbles at the micron scale can generate strong microstreaming flows in its surrounding fluidic medium. The tunable acoustic streaming strength of oscillating microbubbles and the diversity of the generated flow patterns enable the design of fast‐moving microrobots with multimodal locomotion suitable for biomedical applications. The acoustic microrobots holding two coupled microbubbles inside a rigid body are presented; trapped bubbles inside the L‐shaped structure with different orifices generate various streaming flows, thus allowing multiple degrees of freedom in locomotion. The streaming pattern and mean streaming speed depend on the intensity and frequency of the acoustic wave, which can trigger four dominant locomotion modes in the microrobot, denoted as translational and rotational, spinning, rotational, and translational modes. Next, the effect of various geometrical and actuation parameters on the control and navigation of the microrobot is investigated. Furthermore, the surface‐slipping multimodal locomotion, flow mixing, particle manipulation capabilities, the effective interaction of high flow rates with cells, and subsequent cancerous cell lysing abilities of the proposed microrobot are demonstrated. Overall, these results introduce a design toolbox for the next generation of acoustic microrobots with higher degrees of freedom with multimodal locomotion in biomedical applications.
Open Access
Advancement of segmented cell technology in low temperature hydrogen technologies
(2020) Biswas, Indro; Sánchez, Daniel G.; Schulze, Mathias; Mitzel, Jens; Kimmel, Benjamin; Gago, Aldo Saul; Gazdzicki, Pawel; Friedrich, K. Andreas
The durability and performance of electrochemical energy converters, such as fuel cells and electrolysers, are not only dependent on the properties and the quality of the used materials. They strongly depend on the operational conditions. Variations in external parameters, such as flow, pressure, temperature and, obviously, load, can lead to significant local changes in current density, even local transients. Segmented cell technology was developed with the purpose to gain insight into the local operational conditions in electrochemical cells during operation. The operando measurement of the local current density and temperature distribution allows effective improvement of operation conditions, mitigation of potentially critical events and assessment of the performance of new materials. The segmented cell, which can replace a regular bipolar plate in the current state of the technology, can be used as a monitoring tool and for targeted developments. This article gives an overview of the development and applications of this technology, such as for water management or fault recognition. Recent advancements towards locally resolved monitoring of humidity and to current distributions in electrolysers are outlined.
Open Access
Analysis and prediction of electromobility and energy supply by the example of Stuttgart
(2021) Wörner, Ralf; Morozova, Inna; Cao, Danting; Schneider, Daniela; Neuburger, Martin; Mayer, Daniel; Körner, Christian; Kagerbauer, Martin; Kostorz, Nadine; Blesl, Markus; Jochem, Patrick; Märtz, Alexandra
This paper seeks to identify bottlenecks in the energy grid supply regarding different market penetration of battery electric vehicles in Stuttgart, Germany. First, medium-term forecasts of electric and hybrid vehicles and the corresponding charging infrastructure are issued from 2017 to 2030, resulting in a share of 27% electric vehicles by 2030 in the Stuttgart region. Next, interactions between electric vehicles and the local energy system in Stuttgart were examined, comparing different development scenarios in the mobility sector. Further, a travel demand model was used to generate charging profiles of electric vehicles under consideration of mobility patterns. The charging demand was combined with standard household load profiles and a load flow analysis of the peak hour was carried out for a quarter comprising 349 households. The simulation shows that a higher charging capacity can lead to a lower transformer utilization, as charging and household peak load may fall temporally apart. Finally, it was examined whether the existing infrastructure is suitable to meet future demand focusing on the transformer reserve capacity. Overall, the need for action is limited; only 10% of the approximately 560 sub-grids were identified as potential weak points.
Open Access
Analyzing the effects of Cr and Mo on the pearlite formation in hypereutectoid steel using experiments and phase field numerical simulations
(2024) Qayyum, Faisal; Darabi, Ali Cheloee; Guk, Sergey; Guski, Vinzenz; Schmauder, Siegfried; Prahl, Ulrich
In this study, we quantitatively investigate the impact of 1.4 wt.% chromium and 1.4 wt.% molybdenum additions on pearlitic microstructure characteristics in 1 wt.% carbon steels. The study was carried out using a combination of experimental methods and phase field simulations. We utilized MatCalc v5.51 and JMatPro v12 to predict transformation behaviors, and electron microscopy for microstructural examination, focusing on pearlite morphology under varying thermal conditions. Phase field simulations were carried out using MICRESS v7.2 software and, informed by thermodynamic data from MatCalc v5.51 and the literature, were conducted to replicate pearlite formation, demonstrating a good agreement with the experimental observations. In this work, we introduced a semi-automatic reliable microstructural analysis method, quantifying features like lamella dimensions and spacing through image processing by Fiji ImageJ v1.54f. The introduction of Cr resulted in longer, thinner, and more homogeneously distributed cementite lamellae, while Mo led to shorter, thicker lamellae. Phase field simulations accurately predicted these trends and showed that alloying with Cr or Mo increases the density and circularity of the lamellae. Our results demonstrate that Cr stabilizes pearlite formation, promoting a uniform microstructure, whereas Mo affects the morphology without enhancing homogeneity. The phase field model, validated by experimental data, provides insights into the morphological changes induced by these alloying elements, supporting the optimization of steel processing conditions.
Open Access
Anti-adhesive surfaces inspired by bee mandible surfaces
(2023) Saccardi, Leonie; Schiebl, Jonas; Balluff, Franz; Christ, Ulrich; Gorb, Stanislav N.; Kovalev, Alexander; Schwarz, Oliver
Propolis, a naturally sticky substance used by bees to secure their hives and protect the colony from pathogens, presents a fascinating challenge. Despite its adhesive nature, honeybees adeptly handle propolis with their mandibles. Previous research has shown a combination of an anti-adhesive fluid layer and scale-like microstructures on the inner surface of bee mandibles. Our aim was to deepen our understanding of how surface energy and microstructure influence the reduction in adhesion for challenging substances like propolis. To achieve this, we devised surfaces inspired by the intricate microstructure of bee mandibles, employing diverse techniques including roughening steel surfaces, creating lacquer structures using Bénard cells, and moulding resin surfaces with hexagonal patterns. These approaches generated patterns that mimicked the bee mandible structure to varying degrees. Subsequently, we assessed the adhesion of propolis on these bioinspired structured substrates. Our findings revealed that on rough steel and resin surfaces structured with hexagonal dimples, propolis adhesion was significantly reduced by over 40% compared to unstructured control surfaces. However, in the case of the lacquer surface patterned with Bénard cells, we did not observe a significant reduction in adhesion.
Open Access
The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer
(2020) Fullstone, Gavin; Bauer, Tabea L.; Guttà, Cristiano; Salvucci, Manuela; Prehn, Jochen H. M.; Rehm, Markus
The execution phase of apoptosis is a critical process in programmed cell death in response to a multitude of cellular stresses. A crucial component of this pathway is the apoptosome, a platform for the activation of pro-caspase 9 (PC9). Recent findings have shown that autocleavage of PC9 to Caspase 9 (C9) p35/p12 not only permits XIAP-mediated C9 inhibition but also temporally shuts down apoptosome activity, forming a molecular timer. In order to delineate the combined contributions of XIAP and the apoptosome molecular timer to apoptosis execution we utilised a systems modelling approach. We demonstrate that cooperative recruitment of PC9 to the apoptosome, based on existing PC9-apoptosome interaction data, is important for efficient formation of PC9 homodimers, autocatalytic cleavage and dual regulation by XIAP and the molecular timer across biologically relevant PC9 and APAF1 concentrations. Screening physiologically relevant concentration ranges of apoptotic proteins, we discovered that the molecular timer can prevent apoptosis execution in specific scenarios after complete or partial mitochondrial outer membrane permeabilisation (MOMP). Furthermore, its ability to prevent apoptosis is intricately tied to a synergistic combination with XIAP. Finally, we demonstrate that simulations of these processes are prognostic of survival in stage III colorectal cancer and that the molecular timer may promote apoptosis resistance in a subset of patients. Based on our findings, we postulate that the physiological function of the molecular timer is to aid XIAP in the shutdown of caspase-mediated apoptosis execution. This shutdown potentially facilitates switching to pro-inflammatory caspase-independent responses subsequent to Bax/Bak pore formation.
Open Access
Application of ion chromatography for the reliable quantification of ammonium in electrochemical ammonia synthesis experiments : a practical guide
(2023) Bragulla, Sebastian C. H.; Lorenz, Julian; Harms, Corinna; Wark, Michael; Friedrich, K. Andreas
Assessing novel electrocatalysts for the electrochemical ammonia synthesis (EAS) requires reliable quantitative trace analysis of electrochemically produced ammonia to infer activity and selectivity. This study concerns the development of an ion chromatography (IC) method for quantitative trace analysis of ammonium in 0.1 M sulfuric acid electrolyte, which is applied to EAS gas-diffusion electrode (GDE) experiments with commercial chromium nitride as electrocatalyst. The developed IC method is highly sensitive, versatile, and reliable, achieving a limit of quantification (LOQ) of 6 μg l-1 (6 ppbmol) ammonium. The impacts of the sample matrix, dilution, and neutralization, as well as contamination, on the quantitative analysis by IC are analyzed. Experimental constraints result in an effective LOQ including dilution of 60 μg l-1 for the determination of ammonium in 0.1 M sulfuric acid electrolyte, owing to necessary sample dilution. The practical guide presented herein is intended to be very relevant for the field of EAS as a guideline and applicable to a broad range of catalyst systems and ion chromatography devices.
Open Access
Applying a GAN-based classifier to improve transcriptome-based prognostication in breast cancer
(2023) Guttà, Cristiano; Morhard, Christoph; Rehm, Markus
Open Access
An approach to reducing the greenhouse gas footprint in the manufacturing industry: Determinants for an economic assessment of industrial decarbonisation measures
(2022) Buettner, Stefan M.; Wang, Diana
A reduction of the greenhouse gas footprint towards net zero emissions can be achieved with the help of a wide variety of measures. There are three principal approaches (categories): first, reducing greenhouse gases by adjusting the way business is done (efficiency and processes); second, substituting what business is done with (sources of energy and material); and third, offsetting the greenhouse gases emitted. Some measures seem simple and obvious, while others appear complex and demanding. The decisive factor is the respective impact on economic efficiency. Therefore, the authors have identified six types of measures that differ in terms of the impact of investment and operating costs on energy and emission costs. In this report, the authors evaluate these types of measures from an economic perspective and address the limitations and advantages and disadvantages of the different types of measures in terms of emerging needs for action and consequences. Since, for example, on-site measures are often more sensible and also the increase or introduction of emission prices in many countries can have significant cost implications (and subsequently affect global supply chains), an adjustment of the traditional approach to economic valuation seems necessary. On this basis, a novel economic valuation approach for decarbonisation measures is proposed. The approach, illustrated by calculation examples and extensions to dynamically rank, score, and adjust to changing circumstance over time, facilitates an optimal selection of measures to support companies in achieving and sustaining their greenhouse gas reduction goals while maintaining economic efficiency.
Open Access
Assessing fatigue life cycles of material X10CrMoVNb9-1 through a combination of experimental and finite element analysis
(2023) Rahim, Mohammad Ridzwan Bin Abd; Schmauder, Siegfried; Manurung, Yupiter H. P.; Binkele, Peter; Dusza, Ján; Csanádi, Tamás; Ahmad, Meor Iqram Meor; Mat, Muhd Faiz; Dogahe, Kiarash Jamali
This paper uses a two-scale material modeling approach to investigate fatigue crack initiation and propagation of the material X10CrMoVNb9-1 (P91) under cyclic loading at room temperature. The Voronoi tessellation method was implemented to generate an artificial microstructure model at the microstructure level, and then, the finite element (FE) method was applied to identify different stress distributions. The stress distributions for multiple artificial microstructures was analyzed by using the physically based Tanaka-Mura model to estimate the number of cycles for crack initiation. Considering the prediction of macro-scale and long-term crack formation, the Paris law was utilized in this research. Experimental work on fatigue life with this material was performed, and good agreement was found with the results obtained in FE modeling. The number of cycles for fatigue crack propagation attains up to a maximum of 40% of the final fatigue lifetime with a typical value of 15% in many cases. This physically based two-scale technique significantly advances fatigue research, particularly in power plants, and paves the way for rapid and low-cost virtual material analysis and fatigue resistance analysis in the context of environmental fatigue applications.
Open Access
Assessing the application-specific substitutability of lithium-ion battery cathode chemistries based on material criticality, performance, and price
(2021) Kiemel, Steffen; Glöser-Chahoud, Simon; Waltersmann, Lara; Schutzbach, Maximilian; Sauer, Alexander; Miehe, Robert
The material use of lithium-ion batteries (LIBs) is widely discussed in public and scientific discourse. Cathodes of state-of-the-art LIBs are partially comprised of high-priced raw materials mined under alarming ecological and social circumstances. Moreover, battery manufacturers are searching for cathode chemistries that represent a trade-off between low costs and an acceptable material criticality of the comprised elements while fulfilling the performance requirements for the respective application of the LIB. This article provides an assessment of the substitutability of common LIB cathode chemistries (NMC 111, -532, -622, -811, NCA 3%, -9%, LMO, LFP, and LCO) for five major fields of application (traction batteries, stationary energy storage systems, consumer electronics, power-/garden tools, and domestic appliances). Therefore, we provide a tailored methodology for evaluating the substitutability of products or components and critically reflect on the results. Outcomes show that LFP is the preferable cathode chemistry while LCO obtains the worst rating for all fields of application under the assumptions made (as well as the weighting of the considered categories derived from an expert survey). The ranking based on the substitutability score of the other cathode chemistries varies per field of application. NMC 532, -811, -111, and LMO are named recommendable types of cathodes.
Open Access
Azido-functionalized gelatin via direct conversion of lysine amino groups by diazo transfer as a building block for biofunctional hydrogels
(2020) Keller, Silke; Bakker, Tomke; Kimmel, Benjamin; Rebers, Lisa; Götz, Tobias; Tovar, Günter E. M.; Kluger, Petra J.; Southan, Alexander
Gelatin is one of the most prominent biopolymers in biomedical material research and development. It is frequently used in hybrid hydrogels, which combine the advantageous properties of bio-based and synthetic polymers. To prevent the biological component from leaching out of the hydrogel, the biomolecules can be equipped with azides. Those groups can be used to immobilize gelatin covalently in hydrogels by the highly selective and specific azide-alkyne cycloaddition. In this contribution, we functionalized gelatin with azides at its lysine residues by diazo transfer, which offers the great advantage of only minimal side-chain extension. Approximately 84-90% of the amino groups are modified as shown by 1H-NMR spectroscopy, 2,4,6-trinitrobenzenesulfonic acid assay as well as Fourier-transform infrared spectroscopy, rheology, and the determination of the isoelectric point. Furthermore, the azido-functional gelatin is incorporated into hydrogels based on poly(ethylene glycol) diacrylate (PEG-DA) at different concentrations (0.6, 3.0, and 5.5%). All hydrogels were classified as noncyctotoxic with significantly enhanced cell adhesion of human fibroblasts on their surfaces compared to pure PEG-DA hydrogels. Thus, the new gelatin derivative is found to be a very promising building block for tailoring the bioactivity of materials.
Open Access
Balancing glucose and oxygen uptake rates to enable high amorpha‐4,11‐diene production in Escherichia coli via the methylerythritol phosphate pathway
(2021) Patil, Vikas; Santos, Christine N. S.; Ajikumar, Parayil K.; Sarria, Stephen; Takors, Ralf
Amorpha‐4,11‐diene (AMD4,11) is a precursor to artemisinin, a potent antimalarial drug that is traditionally extracted from the shrubs of Artemisia annua. Despite significant prior efforts to produce artemisinin and its precursors through biotechnology, there remains a dire need for more efficient biosynthetic routes for its production. Here, we describe the optimization of key process conditions for an Escherichia coli strain producing AMD4,11 via the native methylerythritol phosphate (MEP) pathway. By studying the interplay between glucose uptake rates and oxygen demand, we were able to identify optimal conditions for increasing carbon flux through the MEP pathway by manipulating the availability of NADPH required for terpenoid production. Installation of an optimal qO2/qglucose led to a 6.7‐fold increase in product titers and a 6.5‐fold increase in carbon yield.
Open Access
Beneficial properties of green tea catechins
(2020) Musial, Claudia; Kuban-Jankowska, Alicja; Gorska-Ponikowska, Magdalena
Green tea (Camellia sinesis) is widely known for its anticancer and anti-inflammatory properties. Among the biologically active compounds contained in Camellia sinesis, the main antioxidant agents are catechins. Recent scientific research indicates that the number of hydroxyl groups and the presence of characteristic structural groups have a major impact on the antioxidant activity of catechins. The best source of these compounds is unfermented green tea. Depending on the type and origin of green tea leaves, their antioxidant properties may be uneven. Catechins exhibit the strong property of neutralizing reactive oxygen and nitrogen species. The group of green tea catechin derivatives includes: epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate. The last of these presents the most potent anti-inflammatory and anticancer potential. Notably, green tea catechins are widely described to be efficient in the prevention of lung cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer and prostate cancer. The current review aims to summarize the potential anticancer effects and molecular signaling pathways of major green tea catechins. It needs to be clearly emphasized that green tea as well as green tea catechols cannot replace the standard chemotherapy. Nonetheless, their beneficial effects may support the standard anticancer approach.
Open Access
Biobased immiscible polylactic acid (PLA) : poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) blends : impact of rheological and non-isothermal crystallization on the bead foaming behavior
(2024) Brütting, Christian; Dreier, Julia; Bonten, Christian; Ruckdäschel, Holger
Nowadays, bead foams are of great interest due to their high lightweight potential. The processing of such foams strongly depends on the crystallization and rheological behavior of the polymers used. By blending polymers, these properties can be tailored to obtain beaded foams with low density, small cell size and high cell density. As a bio-based polymer, PLA is of great interest due to its renewable carbon source. PLA suffers from its low thermal and rheological properties, which can be compensated by using blends. The correlation between the PLA/PHBV ratio and the rheological as well as the crystallization behavior was investigated. The use of PHBV as a minor phase significantly changes the rheological properties and increases the crystallization behavior of PLA. These findings were applied to the foam extrusion process to obtain low density bead foams. Bead foams with densities below 100 kg/m 3 , mean cell sizes below 50 µm and cell densities of 1 × 10 7 cells/cm 3 were obtained.
Open Access
Bottom-up assessment of household electricity consumption in dynamic cities of the Global South : evidence from Kigali, Rwanda
(2023) Vetter-Gindele, Jannik; Bachofer, Felix; Braun, Andreas; Uwayezu, Ernest; Rwanyiziri, Gaspard; Eltrop, Ludger
Data on electricity consumption is crucial for assessing and modeling energy systems, making it a key element of sustainable urban planning. However, many countries in the Global South struggle with a shortage of statistically valid, geocoded, and disaggregated household-level data. This paper aims to develop a generic methodology for the generation of such a database in terms of electricity consumption. The methodology was tested in Kigali, the capital city of Rwanda, with a focus on all single-family residential building types of the inner city. Discrete data on buildings is obtained through combined information products derived from very high resolution (VHR) satellite imagery, field surveys, and computer assisted personal interviewing. In total, 509 valid geocoded survey datasets were used to evaluate and model household electricity consumption, as well as electrical appliance ownership. The study's findings reveal that the arithmetic mean of specific electricity consumption was 3.66 kWh per household per day and 345 kWh per capita per year in 2015. By subdividing the data into distinct building types as well as their spatial location, and weighting the specific values according to their proportion in the study area, a more accurate mean value of 1.88 kWh per household per day and 160 kWh per capita per year was obtained. Applying this weighted mean to extrapolate household electricity consumption for the study area, in conjunction with the sample's precision level, resulted in an estimate of 126-137 GWh for the year 2015. In contrast, using the arithmetic mean would have led to values twice as high, even exceeding the total electricity consumption of the entire city, including multi-family and non-residential buildings. The study highlights the significance of on-site data collection combined with geospatial mapping techniques in enhancing of understanding of residential energy systems. Using building types as indicators to distinguish between households with contrasting electricity consumption and electrical appliance load levels can address the challenges posed by rapid urban growth in the Global South. This proposed method can assist municipal administrations in establishing a database that can be updated resource-efficiently at regular intervals by acquiring new satellite images.
Open Access
Bridging granularity gaps to decarbonize large‐scale energy systems : the case of power system planning
(2021) Cao, Karl‐Kiên; Haas, Jannik; Sperber, Evelyn; Sasanpour, Shima; Sarfarazi, Seyedfarzad; Pregger, Thomas; Alaya, Oussama; Lens, Hendrik; Drauz, Simon R.; Kneiske, Tanja M.
The comprehensive evaluation of strategies for decarbonizing large‐scale energy systems requires insights from many different perspectives. In energy systems analysis, optimization models are widely used for this purpose. However, they are limited in incorporating all crucial aspects of such a complex system to be sustainably transformed. Hence, they differ in terms of their spatial, temporal, technological, and economic perspective and either have a narrow focus with high resolution or a broad scope with little detail. Against this background, we introduce the so‐called granularity gaps and discuss two possibilities to address them: increasing the resolutions of the established optimization models, and the different kinds of model coupling. After laying out open challenges, we propose a novel framework to design power systems in particular. Our exemplary concept exploits the capabilities of power system optimization, transmission network simulation, distribution grid planning, and agent‐based simulation. This integrated framework can serve to study the energy transition with greater comprehensibility and may be a blueprint for similar multimodel analyses.
Open Access
Brought to light: the Bcl-2 transmembrane domain interactome elucidated by a bimolecular split luciferase assay and its impact on apoptosis signalling
(2024) Beigl, Tobias B.; Morrison, Markus (Prof. Dr.)
Apoptose ist eine Form des programmierten Zelltods, die häufig bei verschiedenen Krankheiten wie Krebs gestört ist. Ein Schlüsselereignis der Apoptose ist die Permeabilisierung der äußeren Mitochondrienmembran (MOMP), die von der B-Zell-Lymphom 2 (Bcl-2) Proteinfamilie gesteuert wird. Bcl-2-Proteine bilden ein komplexes Interaktionsnetzwerk, in dem sich pro- und anti-apoptotische Mitglieder gegenseitig zugunsten von Zelltod oder -Überleben hemmen. Das Netzwerk wird durch die Interaktion zwischen dem Bcl-2 Homologie 3 Motiv (BH3) und der hydrophoben Furche definiert. Eine neue Art von niedermolekularen Wirkstoffen, sogenannte BH3-Mimeticka, welche die hydrophobe Furche anti-apoptotischer Bcl-2 Proteine besetzen, ist wirksam in der Krebstherapie. Es verdichten sich jedoch Hinweise darauf, dass die weit weniger untersuchte C-terminale Transmembrandomäne (TMD) von Bcl-2 Proteinen, die traditionell als Membrananker fungiert, ebenfalls als Interaktionsfläche dienen kann. Zur weiteren Aufklärung der Interaktionen in der Bcl-2-Proteinfamilie über die TMD wurde ein zellbasierter Assay entwickelt und validiert, bei dem das mit TMDSequenzen fusionierte bimolekulare Luziferase-System NanoBiT mit gleichzeitiger Expression von Fluorophoren zur Signalnormalisierung kombiniert wird. Eine systematische Analyse der TMD-Interaktionen zwischen pro-apoptotischen Effektor-Bcl-2-Proteinen (BAX, BAK und BOK) und anti-apoptotischen Bcl-2-ähnlichen Proteinen (BCL-2, BCL-XL, BCL-W, MCL-1 und A1) offenbarte homotypische Interaktionen zwischen Effektor-TMDs und Interaktionen von Effektor-TMDs mit BCL-XL-TMD und BCL-W-TMD. Interessanterweise wurde eine bisher unbekannte Interaktion von BOK-TMD und BCL-2-TMD identifiziert. Die subzelluläre Lokalisierung Fluorophor-konjugierter TMD-Peptide verdeutlichte, dass einige TMDs präferentiell in Mitochondrien (BAX, BAK, BCL-XL, BCL-W) lokalisiert sind, während andere (BOK, BCL-2, MCL-1) vorwiegend mit dem endoplasmatischen Retikulum (ER) kolokalisiert sind. TMD-Austausch und Mutation in BAX bestätigten eine wichtige Rolle der BAX-TMD bei der BAX-Inhibition, während der TMD-Austausch in BAK einen vernachlässigbaren Einfluss auf die BAK-Regulierung durch BCL-2 hatte. Darüber hinaus hingen sowohl die Kolokalisierung von BOK und BCL-2 als auch die Hemmung des durch BOK-Überexpression induzierten Zelltods durch BCL-2 von den TMD Sequenzen ab. Dementsprechend modulierte TMD-Mutation von BCL-2 die Interaktion mit BOK-TMD, die subzelluläre Lokalisierung und die anti-apoptotische Kapazität von BCL-2. Letztlich steigerte die Abwesenheit von BCL-2 den BOK-abhängigen ER-Stress-induzierten Zelltod, was auf einen physiologischen Kontext für die funktionelle Bedeutung ihrer TMD-Interaktion hinweist. Somit hebt diese Arbeit hervor, dass die Aufklärung des Bcl-2-TMD-Interaktoms für unser Verständnis der Apoptose-Regulation wichtig ist und ebnet den Weg für zukünftige Untersuchungen der TMD als Ziel für klinische Interventionen.