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Biophysical Characterization of Membrane Proteins: External Stimuli as Key Regulators of Ion Channel Activation
No full textThis dissertation explores novel mechanisms underlying ion channel function and regulation by examining three proteins with distinct external stimuli: the mechanosensitive channel of large conductance from Escherichia coli, EcMscL, the voltage-gated proton channel from Karlodinium veneficum, KvHv1, and the cation channel channelrhodopsin-1 from Chlamydomonas augustae, CaChR1.
Initially, we tested the force-from-lipid gating model for EcMscL by incorporating a photoswitchable lipid into artificial membrane. This strategy enabled modulation of channel activity through light-driven manipulation and therefore providing us with support for the lipid-based gating hypothesis while presenting a novel technique for light-controlled ion channel activation. Additionally, chemical activation of the protein provided information about activation in the absence of mechanical stimuli and the gating model of the system.
Furthermore, the structural simplicity of KvHv1, suggests it as a model protein for biophysical studies. Its functional properties and ion selectivity region offers fundamental insights into activation and regulation of voltage-gated proton channels. Mutation studies as well as spectroscopical investigation (in collaborations), shade light to the selectivity filter and its dynamics. Notably, inhibitory studies with the trivalent cation La3+ are suggesting a new model of activation.
Finally, this work also presents for the first time the structural characterization of CaChR1 ground state obtained via CryoEM providing further support to previous spectroscopic results with detailed structural analysis. Comparative studies with a structurally homologous channelrhodopsin provided extra information over key amino acid residues governing its photocycle.
Collectively, the investigation of EcMscL, KvHv1, and CaChR1 presented here enrich our understanding of ion channel’s function and manipulation, while offering substantial groundwork for future studies aimed at elucidating complex molecular mechanisms of channel activation and regulation.Diese Arbeit untersucht neuartige Mechanismen, die der Funktion und Regulation von Ionenkanälen zugrunde liegen, anhand von drei Proteinen mit unterschiedlichen externen Stimuli: dem mechanosensitiven Kanal mit hoher Leitfähigkeit aus Escherichia coli (EcMscL), dem spannungsgesteuerten Proton Kanal aus Karlodinium veneficum (KvHv1) und dem Kationenkanal Channelrhodopsin-1 aus Chlamydomonas augustae (CaChR1).
Zunächst überprüften wir das „Force-from-Lipid“-Modell für die Aktivierung von EcMscL, indem wir ein photoschaltbares Lipid in eine künstliche Membran integrierten. Diese Strategie ermöglichte die Modulation der Kanalaktivität durch lichtinduzierte Steuerung und lieferte somit Unterstützung für die Lipid-basierte Aktivierungshypothese sowie eine neuartige Methode zur lichtgesteuerten Aktivierung von Ionenkanälen. Zusätzlich ermöglichte die chemische Aktivierung des Proteins Einblicke in die Kanalöffnung in Abwesenheit mechanischer Reize sowie in das zugrunde liegende Aktivierungsmodell.
Darüber hinaus legt die strukturelle Einfachheit von KvHv1 nahe, dass es sich um ein geeignetes Modellprotein für biophysikalische Untersuchungen handelt. Seine funktionellen Eigenschaften und die Region der Ionenselektivität liefern grundlegende Erkenntnisse zur Aktivierung und Regulation spannungsgesteuerter Protonenkanäle. Mutationsstudien sowie spektroskopische Untersuchungen (in Zusammenarbeit mit Partnern) warfen neues Licht auf den Selektivitätsfilter und dessen Dynamik. Besonders hervorzuheben sind Inhibitionsstudien mit dem dreiwertigen Kation La³⁺, die auf ein neues Modell der Kanalaktivierung hindeuten.
Abschließend präsentiert diese Arbeit erstmals die strukturelle Charakterisierung des Grundzustands von CaChR1 mittels Kryo-EM und liefert damit durch die detaillierte Strukturanalyse Bestätigung für frühere spektroskopische Ergebnisse. Vergleichende Studien mit einem strukturell homologen Channelrhodopsin lieferten zusätzliche Informationen über Schlüsselasparagine, die den Photozyklus steuern.
Zusammenfassend vertiefen die hier vorgestellten Untersuchungen zu EcMscL, KvHv1 und CaChR1 unser Verständnis der Ionenkanalbiologie und bieten eine solide Grundlage für zukünftige Studien zur Aufklärung komplexer molekularer Mechanismen der Kanalaktivierung und -regulation
Fingerprint-Based Machine Learning for SARS-CoV-2 and MERS-CoV Mpro Inhibition: Highlighting the Potential of Bayesian Neural Networks
No full textSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two important targets in current drug discovery, mainly due to the COVID-19 pandemic and the MERS-CoV outbreaks in recent years. An important target of both SARS-CoV-2 and MERS-CoV is the main protease (Mpro). Recently, the ASAP Discovery Consortium focused on the acceleration of Mpro inhibitors with a part of this initiative being an open blind challenge in collaboration with Valence lab using the Polaris platform, where data sets of previously undisclosed inhibitors of SARS-CoV-2 Mpro and MERS-CoV Mpro were shared with researchers, to allow the development of machine learning and deep learning models for the prediction of the potency. We used this opportunity to evaluate and compare traditional machine learning models consisting of a random forest (RF) and gradient boosting model (XGBoost) with a bayesian neural network (BNN) model. For this purpose, we created single task models for the predictions of each of the targets. The results obtained showed that the BNN model outperformed both traditional machine learning models for both targets, indicating that BNNs are a promising deep learning framework in low-data regimes
Correlative Characterization of Molecular Two-Dimensional van der Waals Material Heterostructures on the Nanometer Scale
No full textIn the design of nanoscale materials, hybrid van der Waals heterostructures that integrate the excitonic landscape of atomically thin transition metal dichalcogenide (TMDC) semiconductors with molecular electric dipoles offer enhanced control over light–matter interactions and charge carrier dynamics. Even minor deviations in homogeneity can profoundly affect their optoelectronic properties and, consequently, device performance, necessitating stringent quality control capable of probing structural and compositional divergences down to the nanoscale. However, the reliable characterization of such complex, multilayered systems remains challenging due to the interplay of chemical, structural, and optical inhomogeneities across different length scales. In this study, we examine a trilayer heterostructure consisting of chemical vapor deposition (CVD) graphene (G), a self-assembled layer of Rhodamine 6G (R6G), and a transferred monolayer MoS₂ (G/R6G/MoS₂), incorporating regions of a tri- and multilayer MoS₂ as well. Comprehensive structural and optical characterization was performed to identify possible inhomogeneities, employing photoluminescence (PL) spectroscopy, Raman spectroscopy, Kelvin probe force microscopy (KPFM), and scattering-type scanning near-field optical microscopy (s-SNOM). Analytical methods indicate that the TMDC layer has almost uniform molecular coverage and preserved crystallinity. Importantly, near-field optical imaging demonstrates the propagation of exciton-polaritons in MoS₂, with a clear redshift of the polariton wavelength upon R6G integration, signifying substantial modulation of the local dielectric environment and excitonic response. These findings underscore the tunability of hybrid 2D molecular–inorganic interfaces and their promise for advanced applications in nanophotonic devices, excitonic circuitry, and quantum optoelectronics
The CHEOPS view of HD 95338b: Refined transit parameters, and a search for exomoons
No full textContext. Despite the ever-increasing number of known exoplanets, no uncontested detections have been made of their satellites, known as exomoons.
Aims. The quest to find exomoons is at the forefront of exoplanetary sciences. Certain space-born instruments are thought to be suitable for this purpose. We show the progress made with the CHaracterising ExOPlanets Satellite (CHEOPS) in this field using the HD 95338 planetary system. We present a novel methodology as an important step in the quest to find exomoons.
Methods. We utilised ground-based spectroscopic data in combination with Gaia observations to obtain precise stellar parameters. These were then used as input in the analysis of the planetary transits observed by CHEOPS and the Transiting Exoplanet Survey Satellite (TESS). In addition, we searched for the signs of satellites primarily in the form of additional transits in the Hill sphere of the eccentric Neptune-sized planet HD 95338b in a sequential approach based on four CHEOPS visits. We also briefly explored the transit timing variations of the planet.
Results. We present refined stellar and planetary parameters, narrowing down the uncertainty on the planet-to-star radius ratio by a factor of ten. We also pin down the ephemeris of HD 95338b. Using injection-and-retrieval tests, we show that a 5σ detection of an exomoon would be possible at RMoon = 0.8 R⊕ with the methodology presented here.
Conclusions. We exclude the transit of an exomoon in the HD 95338 system with RMoon ≈0.6 R⊕ at the 1σ level. The algorithm used for finding the transit-like event can be used as a baseline for other similar targets, observed by CHEOPS or other missions
Prediction of language outcome in brain tumor surgery based on imaging analysis of structural networks
No full textHintergrund
Die neurochirurgische Resektion von links-hemisphärischen Hirntumoren kann postoperativ zu Sprachdefiziten führen. In dieser Dissertation wird die Rolle von nicht-invasiven, bildgebenden Methoden zur Analyse der strukturellen Verbindungen des Sprachnetzwerks für die präoperative Risikoeinschätzung und operative Planung von Hirntumoren in Spracharealen untersucht.
Methoden
In drei Studien wurden Patient*innen mit links-hemisphärischen Hirntumoren (Tuncer et al., 2021: n=50, Silva et al., 2022: n=30, Ntemou et al., 2023: n=52) eingeschlossen. In Tuncer et al., 2021 wurde auf Grundlage der präoperativen Traktografie der fünf Haupt- sprachfasertrakte (Fasciculus arcuatus [AF], Frontal Aslant Tract [FAT], Fasciculus fronto-occipitalis inferior [IFOF], Fasciculus longitudinalis inferior [ILF], Fasciculus uncinatus [UF]) mittels diffusionsgewichteter Magnetresonanztomografie (MRT) in Kombination mit postoperativer MRT-Bildgebung das Ausmaß chirurgischer Traktverletzungen bestimmt. Die Verletzung von Trakten wurde mit der postoperativen Sprachfunktion korreliert und auf dieser Basis Regressions-basierte Risikomodelle errechnet. In Silva et al., 2022 erhielten Patient*innen präoperativ sowohl eine Traktografie der Sprachfasertrakte als auch eine Kartierung der Sprachareale mittels navigierter transkranieller Magnetsti- mulation (nTMS). Auf dieser Basis wurden verschiedene Traktografie-Protokolle (in Kombination mit nTMS) in Hinsicht auf ihre Eignung in der operativen Planung anhand qualitativer Expertenbefragung verglichen. In Ntemou et al., 2023 wurde die Beziehung zwischen der Involvierung von Hirnarealen durch den Tumor und Sprachdefiziten in spezifischen linguistischen Modalitäten aufsteigender Komplexität anhand von Voxel-basiertem Lesion-Symptom-Mapping (VLSM) analysiert.
Ergebnisse
Die chirurgische Verletzung von Knotenpunkten innerhalb der weißen Substanz war mit einem signifikant höheren Risiko einer postoperativen Aphasie assoziiert: die temporo- parieto-okzipitale Übergangszone (temporo-parietales Segment des AF sowie mittleres Segment des IFOF; OR: 23,04) sowie der Temporalstamm (mittlere Segmente des IFOF, ILF und UF; OR: 21,96). Die Anatomie-basierte Darstellung der Sprachfasertrakte erwies sich als geeignetster Ansatz für die operative Planung und Risikoeinschätzung anhand der Expertenbefragung, während nTMS-basierte Traktografie-Methoden als weniger
geeignet eingeschätzt wurden. In der VLSM-Analyse war die Involvierung des AF mit der Benennung von einfachen Objekten und der Benennung von Handlungen assoziiert, während die Involvierung des IFOF mit der Benennung zusammengesetzter Nomina assoziiert war.
Schlussfolgerungen
Das perioperative Risiko von Hirntumorpatienten, ein Sprachdefizit zu erleiden, kann mithilfe der Traktografie des Sprachnetzwerkes abgeschätzt werden. Insbesondere die Anatomie-basierte Darstellung ist geeignet für den Einsatz in der chirurgischen Planung. Zusätzlich konnte gezeigt werden, dass verschiedenen linguistischen Prozessen unterschiedliche Netzwerke innerhalb des Gehirns zugrunde liegen. Zukünftige Risikomodelle sollten für eine ganzheitliche Vorhersage diese Aspekte berücksichtigen.Background
Neurosurgical resection of left-hemispheric brain tumors may lead to postoperative language deficits. This dissertation investigates the role of non-invasive, imaging-based methods to analyze the structural connections of the language network for preoperative risk assessment and surgical planning of brain tumors in language areas.
Methods
Patients with surgically treated left-hemispheric brain tumors were included in three different studies (Tuncer et al., 2021: n=50, Silva et al., 2022: n=30, Ntemou et al., 2023: n=52). In Tuncer et al., 2021 preoperative diffusion MRI-based tractography of the 5 main language-related fiber tracts (Arcuate Fasciculus [AF], Frontal Aslant Tract [FAT], Inferior Fronto-Occipital Fasciculus [IFOF], Inferior Longitudinal Fasciculus [ILF], Uncinate Fasciculus [UF]) combined with postoperative MRI was used to determine the surgical injury of tracts. Tract injury was then correlated with postoperative language function and regression-based models for prediction of postoperative language deficits were calculated. In Silva et al., 2022, patients underwent preoperative tractography of the language network as well as navigated transcranial magnetic stimulation (nTMS)-based mapping of the cortical language areas. On this basis, different tractography protocols (in combination with nTMS) were assessed by experts and compared regarding their usefulness in surgical planning. In Ntemou et al., 2023, the relationship between the tumorous
involvement of brain areas and language deficits in specific linguistic modalities of varying complexity was analyzed using Voxel-based Lesion-Symptom-Mapping (VLSM). Results
Surgical injury to distinct functional nodes within the white matter was associated with a significantly higher risk of postoperative aphasia: the temporo-parieto-occipital junction (temporo-parietal segment of the AF and middle segment of the IFOF; OR: 23.04) and the temporal stem (middle segments of the IFOF, ILF and UF; OR: 21.96). Anatomy- based visualization of the language tracts was found to be the most suitable approach for surgical planning and risk assessment based on expert opinion, while nTMS-based tractography methods were found to be less suitable. In the VLSM analysis, involvement of the AF was associated with naming of simple objects and sentence naming, while involvement of the IFOF was associated with naming of compounds.
Conclusions
The risk of brain tumor patients developing a language deficit can be assessed using tractography-based imaging of the language network. Anatomy-based visualization is particularly suitable for use in surgical planning. In addition, linguistic processes of different complexity are associated with distinct parts of the language network. Future risk models should take these aspects into account for a holistic prediction
Conventional and biodegradable agricultural microplastics: effects on soil properties and microbial functions across a European pedoclimatic gradient
No full textAgricultural plastics like mulching films may become a major source of microplastic (MP) soil contamination during their degradation and fragmentation. This study investigates the effects of agricultural MPs from conventional (linear low-density polyethylene, PE) and biodegradable (starch-blended polybutylene adipate co-terephthalate, PBAT-BD) mulching films on soil physicochemical properties, aggregation, microbial diversity and functions, litter decomposition, and greenhouse gases emissions (GHG). For this purpose, MPs were mixed into soils at realistic MP concentrations of 0.005 % and 0.05 % (w/w) in 2022 on experimental plots in three EU countries representing different pedoclimatic conditions (Finland, Germany and Spain), followed by monitoring of the above-mentioned variables in the subsequent growing seasons 2022 and 2023. We found several significant MP-induced effects for soil properties, aggregation, microbial diversity, litter decomposition, and GHG, but the effect endpoints were less pronounced or varied considerably. Contrarily, microbial activity, contributing to soil functions such as nitrogen cycling, was consistently reduced by both conventional and biodegradable MPs. The reductions were more pronounced after the second season and for the higher MP treatment. As the higher MP concentration (i.e., 0.05 % w/w) is environmentally relevant in Europe, our findings emphasize the potential effects of environmentally relevant MP concentrations on soil health. Furthermore, the effects increased from north to south, probably modulated by varying pedoclimatic conditions, inducing reflection of a need for regionally tailored risk assessment to protect soil from plastic pollution
Unequal Media Worlds: East Berlin Media Criticism after 1990
No full textThis article examines East Berlin media criticism post-1990, focusing on the unequal distribution of symbolic resources between East and West Germans. Utilising Giddens’s structuration and identity theories, we link the discursive side of inequality with media and define media criticism as one response of marginalised groups’ to hegemonic discourses. We conducted 37 biographical interviews with East Berliners to examine their media criticism and experiences of exclusion in media discourse. We found that hegemonic media narratives about East Germany have influenced East Berlin media criticism. This criticism is directed at systemic media biases, particularly in public service broadcasting. The study identified a latent consciousness of structural factors shaping media realities among East Berliners, often linked to their experiences of social declassing and the socioeconomic challenges after reunification. A range of East Berliners criticised the portrayal of German Democratic Republic (GDR) life in the media, particularly the focus on the Stasi and negative stereotypes, which they feel misrepresent their lived experiences. The persistence of these stereotypes has, for some, reinforced an East German identity and fostered media criticism as a form of identity work
Psychosocial functioning in personality disorders
No full textThe present paper takes a broad perspective on the psychosocial functioning in adult patients with personality disorders. We start with a working definition, then we report on psychosocial functioning in personality disorders from both categorical and dimensional perspectives of personality disorder. We add a section on assessment tools which may be used in this context. We then address the question of how problematic psychosocial functioning may be addressed in psychotherapy and other treatment contexts, when it comes to supporting the person’s move towards sustained recovery. We add a lived and living experience perspective to psychosocial functioning and recovery. We end with recommendations for future research in the domain of psychosocial functioning
DEPRISK Deportation Database
No full textThe DEPRISK Deportation Database is part of the research project DEPRISK – Immigration Enforcement across the World: The Drivers and Consequences of Deportation Risk. The DEPRISK project was motivated by the lack of annual, country-level panel data on deportation corridors covering a wide range of country pairs over time. To address this gap, the project aimed to bring different data sources together in one database. The project is hosted at the Institute for Latin American Studies (LAI) of Freie Universität Berlin and was funded by the Fritz Thyssen Foundation from 2022 to 2025.The DEPRISK Deportation Database provides annual indicators related to immigration enforcement and deportation practices, including: "Orders to leave the territory"; "Total reported returns"; "Enforced returns"; "Other reported returns"; and "Refusals of entry at the border".
The database currently includes bilateral data from over 40 deporting countries, including most OECD countries. Data is obtained from administrative sources in deporting countries, either through published government statistics or data requests. For many of the European countries, we rely on data provided by Eurostat
New upper and lower bounds on the smallest singular values of nonsingular lower triangular (0,1)-matrices
No full textLet Kndenote the set of all nonsingular n×nlower triangular (0,1)-matrices. Hong and Loewy (2004) introduced the number sequence
cn=min{λ|λ is an eigenvalue ofXXT, X∈Kn}, n∈Z+.
There have been a number of attempts in the literature to obtain bounds on the numbers cnby Mattila (2015), Altınışık et al. (2016), Kaarnioja (2021), Loewy (2021), and Altınışık (2021). In this paper, improved upper and lower bounds are derived for the numbers cn. By considering the characteristic polynomial corresponding to the matrix Znsatisfying cn=∥Zn∥−12, it is shown that the second largest eigenvalue of Znis bounded from above by 45leading to an improved upper bound on cn. On the other hand, Samuelson’s inequality applied to the roots of the characteristic polynomial of Znyields an improved lower bound. Numerical experiments demonstrate the quality of the new bounds