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Tracing volatile element fractionations in the early Solar System: Evidence from Ge isotopes in meteorites and planetary bodies
No full textVolatile elements are variably depleted in all meteoritic and planetary materials, including Earth and other terrestrial planets, relative to the bulk solar composition. The origins and underlying mechanisms of these depletions remain highly topical problems in present-day planetary sciences. Much of the debate centers around the question to what extent the depletions among different planetary materials reflect prior nebular fractionations or, alternatively, planetary devolatilization processes during the accretion and the subsequent thermal evolution of planetary bodies. This thesis investigates these issues by determining the concentration and mass-dependent isotopic composition of the moderately volatile element (MVE) Germanium in a range of variably volatile-depleted planetary materials. For this purpose, an analytical Ge double spike routine was developed, which allows for simultaneous high-precision measurements of Ge concentrations and isotopic compositions using multi-collector inductively coupled plasma mass spectrometry (MC-ICPMS).
Nebular fractionation processes were examined by analyzing chondrite meteorites. The volatile element budget and isotopic composition of ‘non-depleted’, primordial material was obtained by analyzing Ivuna-type (CI) chondrites and a sample from the Cb-type asteroid Ryugu. CI chondrites and Ryugu have similar elemental and mass-dependent isotope systematics of the MVEs Ge, Te, and Zn, which are distinct from those of all other carbonaceous chondrites. These results reinforce the notion that CI chondrites and Ryugu formed from the same precursor materials, and indicate that for moderately volatile (and more refractory) elements, their compositions were not significantly modified by processes in the solar protoplanetary disk or on the parent bodies. For these elements, CI chondrites/Ryugu thus likely record the average chemical and mass-dependent isotopic composition of most parts of the disk and the bulk Solar System.
Compared to Ryugu and CI chondrites, other carbonaceous chondrites display group-specific Ge elemental and isotopic variations. In line with observations for other MVEs these correlations are best explained by variable mixing between a volatile-rich, isotopically heavy CI-like matrix and a volatile-poor, isotopically light chondrule (precursor) component common to all carbonaceous chondrite groups. Consistent with their chondrule-rich nature, enstatite and ordinary chondrites have lighter Ge isotope compositions than the more volatile-rich carbonaceous chondrites.
Planetary volatile element fractionation processes—and their delamination from nebular processes—were investigated by analyzing the Ge elemental and isotopic composition of differentiated planetary materials and metal- and sulfide-melt degassing experiments. The experiments reveal that evaporation of Ge increases with increasing temperatures, decreasing pressure, in the presence of S, and is accompanied by a heavy Ge isotope enrichment in the residue. Such features are also seen for non-magmatic iron meteorites, supporting near-surface impact processes as a likely scenario for their formation.
In contrast, the systematic study of variably volatile-depleted magmatic iron meteorites (i.e., those sampling planetary cores) demonstrates that the combined effects of primary nebular, and subsequent planetary volatile element depletions are required to account for their Ge elemental and mass-dependent isotope compositions. In this context, the parent bodies of the magmatic iron meteorites—like the chondrite parent bodies—are inferred to have initially formed as mixtures of volatile-rich and volatile-poor precursor assemblages. Starting from this nebular baseline, evaporation during planetary differentiation and collisional exposure of molten cores then set the final volatile budgets of the iron meteorites.
Finally, the combined Ge elemental and isotopic data of differentiated and undifferentiated meteorites in concert with new Ge data for terrestrial rocks are used to gain insight into the (volatile) accretion history of the Earth. The Ge isotope compositions of the bulk silicate Earth (BSE) is uniform, falls within the chondritic range, and is best accounted for as a 65:35 mixture of CI and enstatite chondrite-derived Ge. This mixing ratio is distinct from the 30:70 ratio inferred for Zn, reflecting the different geochemical behavior of Ge (siderophile) and Zn (lithophile), and indicating the late-stage accretion of volatile-rich CC materials to Earth. On dynamical grounds it has been argued that Earth accreted CC material through a few, Moon-sized embryos, and so the Ge isotope results imply that these objects were volatile-rich, presumably because they were either undifferentiated or accreted volatile-rich objects themselves before being accreted by Earth.2026-02-1
Current supply situation and need for action
No full textAutismus zählt zu den häufigsten Neuroentwicklungsstörungen weltweit. Aktuell geht man von einer Prävalenz von 1% aus. Bezogen auf Niedersachen sind dies ca. 81.000 Betroffene. Menschen mit Autismus weisen eine geringere Lebensqualität und Lebenserwartung auf. Um eine Verbesserung der Lebenssituation von Autist*innen in Niedersachsen zu erreichen, war es zunächst notwendig eine umfangreiche Datenerhebung durchzuführen, um Kenntnis über die aktuelle Versorgung, Lebenssituation und Bedürfnisse zu erlangen.
Mittels eines online Fragebogens wurden 472 Menschen mit Autismus aus Niedersachen zu den Themengebieten: Ablauf der Autismus Diagnostik, Lebenssituation und Lebenszufriedenheit, Versorgungssituation und Finanzierung, aktueller Unterstützung- und Handlungsbedarf befragt.
Das Durchschnittsalter betrug 19,8 Jahre. Die Geschlechtsverteilung war: 71,8% männlich, 25,8% weiblich und 2,1% divers. Die Teilnehmenden erhielten ihre Diagnose im Durchschnitt mit 13,3 Jahren. Bei 64% dauerte es länger als ein Jahr zwischen Verdacht und Diagnosestellung. Bei 70% lag mindestens eine komorbide Störung vor. Zu den häufigsten komorbiden Störungen gehörten: ADHS, Depression, Störung des Sozialverhaltens, Angststörung. Die Lebenszufriedenheit lag mit einem Durchschnittswert von 5,96 (Skala 1-10) unter dem der Allgemeinbevölkerung in Niedersachen (6,6). Weibliche Autistinnen, Erwachsene Autist*innen und Autist*innen mit komorbiden Störungen gaben eine signifikant niedrigere Lebenszufriedenheit an als jeweils ihre Vergleichsgruppe. In den letzten 12 Monaten hatten nur 4,7% der Teilnehmenden keinen Kontakt zum Gesundheits- und Sozialsystem. Das Unterstützungsangebot vor Ort wurde von 47,5 % als unzureichend beschrieben.
Die Diagnose Autismus wurde in Niedersachsen deutlich später gestellt im Vergleich zum Bundesdurchschnitt. Dies weist auf die Notwendigkeit des Ausbaus von spezialisierten Diagnostik Stellen für Autismus, sowie auf den Bedarf nach Schulung von Fachkräften zur besseren Erkennung von autistischen Symptomen. Die hohe Rate an komorbiden Störungen und damit einhergehenden Mehrbelastungen zeigten, dass weitere Unterstützungsangebote sowohl hinsichtlich der gesundheitlichen Versorgung als auch in der Unterstützung im Alltag notwendig sind. Derzeit liegt ein hoher Nutzungsbedarf im Bereich des Gesundheits- und Sozialsystems bei Menschen mit Autismus vor. Dennoch besteht weiterhin Handlungsbedarf, da das aktuelle Angebot als unzureichend angegeben wurde. Aktuelle Daten belegen, dass Lebensqualität positiv mit der wahrgenommenen Unterstützung im Zusammenhang steht. Ein Hauptaugenmerk sollte daher beim Ausbau, laut vorliegender Befragung, vor allem auf weibliche Autistinnen, sowie Erwachsene Autist*innen und Autist*innen mit komorbiden Störungen gelegt werden, da diese eine geringere Lebenszufriedenheit aufwiesen.Autism is one of the most common neurodevelopmental disorders worldwide. Its prevalence is currently estimated at 1%. In Lower Saxony, this equates to approximately 81,000 people affected. People with autism have a lower quality of life and life expectancy. In order to improve the living conditions of people with autism in Lower Saxony, it was first necessary to conduct a comprehensive data collection to gain knowledge about the current care, living conditions and needs.
Using an online questionnaire, 472 people with autism from Lower Saxony were surveyed on the topics: autism diagnosis process, living situation and life satisfaction, care situation and financing, current support and action needs.
The average age was 19.8 years. The gender distribution was: 71.8% male, 25.8% female and 2.1% diverse. Participants received their diagnosis at an average age of 13.3 years. For 64%, it took more than one year between suspicion and diagnosis. Seventy percent had at least one comorbid disorder. The most common comorbid disorders included ADHD, depression, social behaviour disorder and anxiety disorder. Life satisfaction was below that of the general population in Lower Saxony (6.6), with an average score of 5.96 (scale 1-10). Female autistic, autistic adults and autistic with comorbid disorders reported significantly lower life satisfaction than their respective comparison groups. In the last 12 months, only 4.7% of participants had no contact with the health and social services system. Local support services were described as inadequate by 47.5%.
The diagnosis of autism was made significantly later in Lower Saxony than the national average. This points to the need to expand specialized diagnostic centres for autism, as well as the need to train professionals to better recognize autistic symptoms. The high rate of comorbid disorders and the associated additional burdens showed that further support services are necessary, both in terms of health care and support in everyday life. Currently, there is a high demand for health and social services among people with autism. Nevertheless, there is still a need for action, as the current services were described as insufficient. Current data show that quality of life is positively correlated with perceived support. According to the present survey, the main focus should therefore be on expanding support for autistic women, autistic adults and autistic people with comorbid disorders, as they reported lower life satisfaction.2025-09-3
Stellenwert der kardialen Resynchronisationstherapie bei Kindern und Erwachsenen mit einem angeborenen Herzfehler
No full textOwing to advances in medical care, patients with congenital heart disease (CHD) of varying complexity are increasingly surviving into adulthood. This population presents a unique and growing challenge to health care systems, given the heterogeneity of cardiac morphology, the resultant hemodynamics and sequelae of prior surgical interventions. Depending on the underlying CHD and corrective procedures, patients are often confronted with long-term consequences of their pathophysiologic circulation, including progressive structural remodeling of the heart and disturbances of the conduction system that may culminate in dyssynchrony and heart failure. Although the evidence supporting cardiac resynchronization therapy (CRT) in the general heart failure population is robust, data regarding its indications and efficacy in patients with CHD remain limited.
This single-center retrospective study sought to characterize the parameters historically applied for CRT indication in CHD patients, to analyze responders and nonresponders according to clinical endpoints during follow-up and to describe complications. Response was defined as an improvement in ejection fraction (EF) of ≥10%, New York Heart Association (NYHA) functional class ≤I and narrowing of the QRS complex. Nonresponse was defined as a decrease in EF of ≤5%, NYHA class >I and QRS prolongation. From 2003 to 2022, 41 patients with a median age of 38 years were followed for a median of 6.5 years across five intervals extending to ≥60 months. Eighty percent had a systemic left ventricle and twenty percent had a systemic right ventricle. Epicardial lead placement predominated in patients with a systemic right ventricle (83%). Automatic algorithm functions were present in only 20% of systemic right ventricles and 37% of systemic left ventricles. Mean ventricular pacing burden was nearly 99%.
With long observational period reported, our findings corroborate reference literature by demonstrating favorable outcomes, high response rates and low nonresponse rates. EF increased by almost 12% in absolute terms, reaching statistical significance at 12 months. QRS duration decreased progressively, with an absolute reduction of 20 ms, highly significant both at early and late follow-up. Median NYHA class remained II, with a significant one-class improvement at 12 months only. Stratified by systemic ventricle, significant improvements were confined to patients with a systemic left ventricle, consistent with recent meta-analyses. Response rates were 58% for EF, 65% for QRS narrowing and 88% for NYHA class; nonresponse rates were 12%, 19% and 13%, respectively. Response in EF was notably stronger in systemic left ventricles.
Indication criteria were consistent with established guidelines, most commonly NYHA class II–IV, a median EF of 42%, QRS duration of 160 ms and a mean pacing burden of ~60%. More than 90% pacing burden was present in nearly 40% of patients. These findings align with current Heart Rhythm Society recommendations and highlight the importance of proactive functional assessment.
Mortality and heart transplantation rates were also consistent with published reference data. Overall mortality was 12%, with a mean time to death of 8.6 ± 2.97 years. Twelve percent of patients were listed for heart transplantation, a rate that fell by 40% after CRT implantation. Transplant-free survival averaged 15.4 years, though median survival until transplantation was only 9 years in patients with a systemic right ventricle, underscoring earlier CRT exhaustion and transplantation in this subgroup.
Device-related complications—such as lead dysfunction, device- or catheter-associated infections and hematomas—occurred at somewhat higher rates than in reference studies, whereas all other CRT-related complications were at or below published rates for CHD patients.
Given these challenges, further investigation into CRT and emerging conduction system pacing techniques is warranted to meet the complex needs of this expanding population.2025-11-1
a prospective pilot study
No full textHintergrund/Zielsetzung:
Klare Leitlinien für das perioperative Management von Patient*innen unter gerinnungsmodulierenden Medikamenten bei okuloplastischen Eingriffen fehlen bisher. Diese Studie untersucht Risikofaktoren für Blutungskomplikationen und bewertet die Wirksamkeit einer standardisierten Blutungsrisikobewertung bei extraokularen Operationen.
Methoden:
In dieser prospektiven Studie wurde ein standardisierter Fragebogen zur Erhebung der Blutungsvorgeschichte der Patient*innen eingesetzt. Es wurden Zusammenhänge zwischen den Werten des Blutungsanamnesefragebogens und präoperativen/demografischen Faktoren (gerinnungsmodulierende Medikamente, Alter, Geschlecht, Begleiterkrankungen) sowie chirurgischen Faktoren (Blutdruck, Operationsart, primäre vs. Revisionseingriffe, Anästhesieverfahren, Operationsdauer, Schmerztherapie) analysiert. Zwei Blutungsscores quantifizierten die Schwere der Blutungen. Die Patient*innen wurden postoperativ je nach Eingriff 24 Stunden (Lidchirurgie) bis zu drei bis vier Tage (orbitale/nasolakrimale Eingriffe) überwacht.
Ergebnisse:
Insgesamt wurden 324 Patient*innen (Alter 18–92 Jahre) eingeschlossen (252 Lid-, 56 Orbita- und 16 nasolakrimale Eingriffe). 87 Patient*innen nahmen gerinnungsmodulierende Medikamente ein. Relevante Blutungskomplikationen traten bei 35 Patienten auf, bei vier war eine Revisionsoperation erforderlich, niemand erlitt bleibende Schäden. Relevante Blutungskomplikationen waren signifikant mit höheren Blutungsanamnesefragebogenwerten (p = 0,048), der Einnahme von Acetylsalicylsäure (ASS) bei Lidoperationen (p = 0,038), Diabetes mellitus (p = 0,016), Nierenerkrankungen (p = 0,044), Allgemeinanästhesie (p = 0,001) sowie längerer Operationsdauer (p = 0,007) assoziiert. Lokale Infiltration, Antikoagulanzien und systolische Hypertonie zeigten hingegen keine signifikante Assoziation mit dem Blutungsrisiko.
Schlussfolgerung:
Der Blutungsanamnesefragebogen stellt ein nützliches Instrument zur Einschätzung des Blutungsrisikos bei okuloplastischen Patienten dar. Die Ergebnisse legen nahe, dass zukünftige multizentrische Studien erforderlich sind, um evidenzbasierte perioperative Leitlinien zum Umgang mit gerinnungsmodulierenden Medikamenten bei okuloplastischen Eingriffen zu entwickeln. Limitationen der Studie umfassen eine heterogene Patientenkohorte, eine geringe Fallzahl, ein nicht verblindetes Studiendesign sowie subjektive Bewertungen der Blutungsschwere, die die Vergleichbarkeit einschränken.Background/Aims: Clear guidelines for managing patients on antiplatelet (AP) or anticoagulant
(AC) therapy undergoing oculoplastic surgery are lacking. This study investigates bleeding risk
factors and evaluates the effectiveness of a standardized bleeding risk assessment in extraocular
surgery.
Methods: In this prospective study, a standardized questionnaire (SQ) was employed to gather
patients' bleeding histories. Associations between SQ scores and preoperative/demographic
factors (AP/AC use, age, sex, comorbidities), and surgical factors (blood pressure, surgery type,
primary vs. revision surgery, anesthesia type, duration, pain management) were assessed. A
scoring system quantified bleeding severity. Patients were monitored postoperatively for 24
hours (eyelid procedures) to three or four days (orbital/nasolacrimal surgery).
Results: A total of 324 patients (aged 18–92) were included (252 eyelid, 56 orbital, and 16
nasolacrimal surgeries). 87 patients were using AP, AC, and/or herbal supplements. Severe
bleeding occurred in 35 patients, four required revision surgery, though none suffered permanent
damage. Bleeding complications were significantly associated with higher SQ scores (p = .048),
acetylsalicylic acid (ASA) use in eyelid surgery (p = .038), diabetes mellitus (p = .016), renal
disease (p = .044), general anesthesia (p = .001), and longer surgery duration (p = .007). Local
anesthesia, AC use, and systolic hypertension were not significantly associated with bleeding risk.
Conclusion: The SQ is a valuable tool for assessing bleeding risk in oculoplastic patients. Findings
support future multicenter studies to develop evidence-based perioperative guidelines for AP
and AC management. Limitations include cohort heterogeneity, small sample size, non-blinded
design and subjective bleeding scores affecting comparability.2025-11-0
Effect of transcranial magnetic stimulation on somatic symptoms in individuals with depression
No full textDepressionen sind eine häufige psychische Erkrankung, die sowohl für Betroffene als auch für Gesellschaft und Gesundheitssystem eine erhebliche Belastung darstellt. Patient*innen berichten beim medizinischen Erstkontakt oft über somatische Beschwerden wie Schmerzen, Schlaf- oder Appetitstörungen, während psychische Kernsymptome weniger vordergründig sind. Dies erschwert eine frühzeitige Diagnose, verzögert den Therapiebeginn und ist mit schwereren Krankheitsverläufen sowie einer Chronifizierung verbunden. Eine Therapiemethode, die gezielt somatische Symptome behandelt, wäre daher besonders relevant. In dieser Dissertation wurde der Effekt der intermittierenden Theta-Burst-Stimulation (iTBS), einer Form der repetitiven transkraniellen Magnetstimulation, auf somatische Symptome bei Menschen mit Depression untersucht. Die Daten stammen aus der sechswöchigen, randomisierten Crossover-Studie PreNeSt-2. Für diese Dissertation wurden 79 geeignete Proband*innen ausgewählt, die sowohl iTBS- als auch Placebo-Sitzungen erhielten. Depressions- und Somatik-Symptomatik wurden mit HAMD-17, MADRS und einer eigens entwickelten somatischen Subskala erfasst. Vergleichsdaten zur Pharmakotherapie stammen aus der AFFDIS-Studie. Die Ergebnisse der statistischen Analysen zeigten eine Reduktion somatischer Symptome über den Studienverlauf, jedoch keinen signifikanten Unterschied zwischen iTBS und Placebo oder im Vergleich zur medikamentösen Behandlung. Explorative Analysen ergaben, dass die Schwere der somatischen Symptome zu Beginn den iTBS-Effekt nicht beeinflusste. Die Befunde deuten darauf hin, dass iTBS eine antidepressive Wirkung hat, jedoch keine spezifischen Vorteile für somatische Symptome bietet. Weitere Forschung mit validierten Messinstrumenten für somatische Symptome bei Depressionen und mit Patient*innen mit ausgeprägter somatischer Symptomatik ist angezeigt.Depression is one of the most common mental disorders, posing a significant burden on both affected individuals and society. At initial medical contact, patients often report somatic complaints such as pain, sleep, or appetite disturbances, while psychological symptoms may be less prominent. This can delay diagnosis, hinder timely treatment, and is associated with more severe disease courses and increased risk of chronicity. Therapies that specifically target somatic symptoms are therefore of particular interest.
This thesis investigated the effect of intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, on somatic symptoms in individuals with depression. Data were drawn from the six-week randomized crossover study PreNeSt-2. For this thesis, 79 eligible participants were selected, each receiving both iTBS and sham sessions. Depression and somatic symptoms were assessed using the HAMD-17, MADRS, and a self-developed somatic subscale. Pharmacotherapy comparison data were obtained from the AFFDIS study.
Results of statistical analyses indicated a reduction in somatic symptoms over the study period but revealed no significant differences between iTBS and sham, or compared to pharmacological treatment. Baseline severity of somatic symptoms did not influence treatment outcomes.
These findings suggest that iTBS exerts antidepressant effects but does not confer specific benefits for somatic symptoms. Further studies using validated instruments and including participants with pronounced somatic symptomatology are warranted.2026-01-0
“Establishment and characterization of a human cell model to investigate the pathophysiology of alternating hemiplegia of childhood”
No full textDie Alternierende Hemiplegie des Kindesalters (AHC) ist eine seltene, schwerwiegende neurologische Erkrankung, die sich durch transiente Episoden von Hemiplegie in Kombination mit
anderen paroxysmalen Symptomen wie Dystonie, Nystagmus, epileptischen Anfällen und autonomen Störungen auszeichnet. Hervorgerufen wird die Erkrankung durch heterozygote Mutationen im ATP1A3-Gen, die typischerweise de novo als autosomal dominante Mutationen
vorliegen. Das ATP1A3-Gen kodiert die alpha-3-Untereinheit der P-Typ Natrium-Kalium-ATPase, die für den Erhalt und die Wiederherstellung eines elektrochemischen Gradienten der
Plasmamembran verantwortlich ist und Neuronen-spezifisch exprimiert wird. Zur Erforschung
der funktionellen Konsequenzen der Mutationen auf das Genprodukt in humanen Neuronen,
stellt die Generierung von Neuronen aus humanen induzierten pluripotenten Stammzellen
(hiPSCs) aufgrund der fehlenden Verfügbarkeit beim direkten Zugriff auf Patientengewebe
eine elegante Möglichkeit dar.
Ziel dieser Arbeit war die Etablierung und Charakterisierung eines humanen in vitro Zellsystem
zur Erforschung der Pathogenese der AHC. Zu diesem Zweck wurden die aus humanen Fibroblasten durch Re-Programmierung gewonnen hiPSCs von zwei AHC-Patienten mit unter
schiedlichen zugrundeliegenden Missense-Mutationen (Val322Asp und Glu815Lys) und drei
neurologisch gesunden Kontrollpatienten charakterisiert und die Pluripotenz nach heute gängigen Methoden bewiesen. Die Re-Differenzierung der hiPSCs in Neurone über neuronale Vorläuferzellen gelang erfolgreich unter Anwendung zweier unterschiedlicher Protokolle durch duale Smad Inhibierung ausgehend vom feederfreien System sowie durch Co-Kultivierung der hiPSCs mit PA6-Zellen. Es erfolgten Immunfluoreszenzfärbungen zur Überprüfung der verschiedenen Zellstadien sowie Immunfluoreszenz-Cofärbungen gegen ATP1A3, jeweils in Kombination mit einem Membranfarbstoff (membrane-binding flourophore-cysteine-lysine-palmitoyl group, mCling) sowie einem mitochondrialen Antikörper (TOMM20) für die Identifikation der subzellulären Lokalisation von ATP1A3. Unsere mittels Immunfärbungen generierten Ergebnisse suggerieren, dass es sich bei der AHC eher um ein funktionelles Problem, als um ein Lokalisationsproblem von ATP1A3 handelt und reiht sich somit in die Ergebnisse anderer Studien ein. Mittels morphologischer Charakterisierung der Neurone an sich sowie der Lokalisation von ATP1A3 in Bezug auf Zellmembran und Mitochondrien wurde die Voraussetzung für die funktionelle Diagnostik mittels elektrophysiologischer Methoden gegeben. Die Arbeit trägt
somit zur grundlagenwissenschaftlichen Erforschung der seltenen und klinisch komplexen alternierenden Hemiplegie des Kindesalters bei.Alternating hemiplegia of childhood (AHC) is a rare, severe neurological disorder characterized by transient episodes of hemiplegia combined with other paroxysmal symptoms such as dystonia, nystagmus, seizures, and autonomic disturbances. The disease is caused by heterozygous mutations in the ATP1A3 gene which typically occur de novo as autosomal dominant mutations. ATP1A3 encodes the alpha-3 subunit of the P-type sodium-potassium ATPase, which is responsible for maintaining and restoring an electrochemical gradient in the plasma membrane and is exclusively expressed in neurons. To investigate the functional consequences of ATP1A3 mutations on the gene product in human neurons, the generation of neurons from human induced pluripotent stem cells (hiPSCs) represents an elegant option due to the lack of direct access to patient tissue. The aim of this study was to establish and characterize a human in vitro cell system
to investigate the pathogenesis of AHC. For this purpose, hiPSCs derived from human fibroblasts by reprogramming were characterized from two AHC patients with different underlying missense mutations (Val322Asp and Glu815Lys) and three neurologically healthy control patients, and their pluripotency was demonstrated using current methods. The re-differentiation of hiPSCs into neurons via neuronal progenitor cells was successfully achieved using two different protocols by dual Smad inhibition starting from the feeder-free system and by co-cultivation of hiPSCs with PA6 cells. Immunofluorescence staining was performed to verify the different cell stages as well as immunofluorescence co-staining against ATP1A3, each in combination with a membrane dye (membrane-binding fluorophore-cysteine-lysine-palmitoyl group, mCling) and a mitochondrial antibody (TOMM20) to identify the subcellular localization of ATP1A3. Our immunostaining results suggest that AHC is rather a functional problem than a localization problem of ATP1A3 and thus fit in with the results of other studies. By means of morphological characterization of the neurons themselves as well as the localization of ATP1A3 in relation to the cell membrane and mitochondria, the requirement for functional diagnostics using e.g. electrophysiological methods was provided. This work contributes to basic scientific research into the rare and clinically complex alternating hemiplegia of childhood.2025-11-1
Adhesion of Lipid Vesicles on Bio-Inspired Surfaces
No full textMany biological transport processes rely on vesicles composed of a lipid membrane enclosing a fluid volume. Examples are the neurotransmitter release at the synapse or the transport by vesicles in and between cells. The ability to transport cargo makes vesicles a promising tool for targeted drug delivery. The adaptive adhesion and desorption of the vesicles to a biological substrate are key for all these processes. Consequently, it is important to understand the factors determining whether and how a vesicle adsorbs to a substrate and what shape it will adopt. In this thesis, I employ static Fourier-mode-based simulations to systematically study the equilibrium shapes of vesicles adsorbed to planar substrates with short- and long-range interactions, with and without buoyancy. Additionally, we study the dynamics of such a process using coarse-grained Molecular Dynamics simulations.
For the static equilibrium shapes of vesicles, we focus on the shape of adhered vesicles on a substrate with a finite-range membrane–substrate interaction, a relevant experimental characteristic. When comparing our theoretical predictions with the experimental measurements from the Tanaka group, we found a good qualitative agreement in the vesicle shapes. Furthermore, the interaction range of the membrane potential alters the type of the adsorption transition from a second-order transition for a contact potential to a first-order adhesion transition for finite-range potentials. In contrast, the local transversality condition that relates the maximal curvature at the edge of the adhesion zone to the adhesion strength remains rather accurate even for a finite interaction range as long as the vesicle is large compared to the interaction range. Hence, the transversality condition can be utilized to extract the interaction strength between substrate and vesicle from experimental data. We extended our model to incorporate the influence of buoyancy, a factor largely omitted in theoretical investigations. For large vesicles, even minor density differences between the inside and the outside of the vesicle give rise to significant buoyancy effects. Buoyancy leads to an offset in the transversality condition. For upward buoyancy, we find that adsorbed vesicles are at most metastable. We constructed an adsorption diagram summarizing the metastable region of upward buoyant adsorbed vesicles. Lastly, we also investigated how the interface between two vesicles adhered to one another
deforms as a function of their size ratio.
Further, we study permeable vesicles, adapting dynamically to substrates with a finite-range adhesion potential using coarse-grained Molecular Dynamics (MD) simulations. The membrane deforms during adhesion and induces fluid flow inside and outside the vesicle. This complex interaction between membrane deformation and hydrodynamics significantly affects the shapes observed during adhesion. We note that final shapes remain similar in the presence of hydrodynamics, whereas the transient shapes differ significantly. We find that the hydrodynamic coupling seems to set the timescale of the adhesion process. This timescale can be estimated using dimensional analysis and predicts a faster adhesion time for smaller vesicles, whereas larger vesicle adhesion takes longer. Our findings help with the interpretation of experimental data. All the explored effects might help to design optimized artificial vesicles for efficient and targeted drug delivery.2025-10-1
Optimizing phase contrast based virtual histology
No full textDie histologische Analyse von menschlichen und tierischen Geweben ist für die medizinische Diagnostik und biomedizinische Forschung von grundlegender Bedeutung, da sie Einblicke in Krankheitsmechanismen, den Krankheitsverlauf und das Ansprechen auf Behandlungen liefert. Die traditionelle Histologie, bei der gefärbte, mikrometerdünne Gewebeschnitte unter einem Lichtmikroskop untersucht werden, ist seit den 1660er Jahren etabliert. Diese Analysemethode weist jedoch Einschränkungen auf. Zum einen treten Gewebeverformungen durch das Schneiden auf und zum anderen sind aufgrund ihrer inhärenten 2D-Natur 3D-Strukturinformationen limitiert. Um diese Nachteile zu umgehen, werden insbesondere 3D Bildgebungsverfahren angewandt, wie zum Beispiel die Mikro-Computertomographie (μCT), die sich zur hochauflösenden Bildgebung größerer Proben eignet, jedoch in der Regel die Verwendung kontrastverstärkender Färbemittel erfordert. Als weitere zerstörungsfreie 3D-Bildgebungsmodalität steht die Röntgen-Phasenkontrast-Bildgebung in freier Ausbreitung (PBI), wie die Röntgenphasen- Mikro-CT (PCμCT), in Synchrotron-Einrichtungen zur Verfügung. Diese erlaubt die Analyse von ungefärbten Weichgeweben, indem sie zusätzlich zur Abschwächung der Röntgenstrahlen, auch die Unterschiede in ihren Brechungsindizes nutzt. Dadurch wird ein hervorragender Kontrast erzielt undeine innovative virtuelle Histologie ermöglicht.
Um die Vorteile der PCμCT nutzen zu können, ist eine besondere Probenvorbereitung erforderlich, da herkömmliche histologische Protokolle nicht vollständig mit den Anforderungen derPCμCT- Bildgebung kompatibel sind. Die hier vorgestellte Arbeit leistet einen wichtigen Beitrag zur Optimierung der Probenvorbereitungstechniken für diePCμCT-Methode. Dafür haben wir ein optisches Aufklarungsprotokoll angewendet, das die Kompatibilität von Gewebeproben mit den Voraussetzungen des Single- Distance-Phase-Retrieval-Algorithmus erhöht und zu einer verbesserten Rekonstruktion ihrer PCμCT- Scans führt. Da die phasensensitive PBI vielversprechend insbesondere für die hochauflösende Bildgebung der Lunge bei niedrigsten Röntgendosen ist, haben wir eine Formaldehyd-Dampf-Fixierungsmethode etabliert, um die klinische Validierung dieses Ansatzes zu ermöglichen. Hierbei werden Schweinelungen in ihrem physiologischen expandierten Zustand konserviert und anschließend histopathologisch untersucht.
Um die PCμCT-Bildgebung insbesondere von diesem formalinfixierten, in Paraffin eingebetteten (FFPE) Lungengewebe weiter zu verbessern, haben wir einen auf "conditional generative artificial networks" (cGANs) basierenden Ansatz entwickelt. Dieser unterdrückt Artefakte, die durch eingeschlossene Luft in den FFPE-Proben entstehen und häufig die Visualisierung und 3D-Strukturanalyse behindern. Darüber hinaus erwiesen sich herkömmlicheMethoden und Optimierungen zur Berechnung der Phasenverschiebung in den aufgenommenen Daten ("phase retrieval") als begrenzt, insbesondere in ihrer Fähigkeit gleichzeitig unterschiedliche Gewebegrenzflächen auszuwerten. Im Gegensatz dazu ersetzt unsere maßgeschneiderte cGANs-Architektur luftgefüllte Bereiche effektiv durch realistische Gewebestrukturen, die anhand speziell generierter Datensatz-Paare trainiert wurden. Dadurch unterstützt die hier präsentierte Datenaufbereitungs Pipeline nicht nur die Korrektur von Artefakten in PCμCT Daten, sondern hat darüber hinaus Potenzial für die breitere Anwendungen in der medizinischen Bildverarbeitung, einschließlich Rauschunterdrückung und anderer Arten der Artefaktentfernung, bei der annotierte Trainingsdaten in der Regel rar sind.
Ein wichtiger Bestandteil dieser Arbeit ist die Entwicklung einer multimodalen, multiskaligen Gewebeanalyse- Pipeline, die auf PCμCT Bilddaten von FFPE-Lungenproben basiert. Diese Pipeline bewahrt die räumliche Korrelation zwischen verschiedenen Modalitäten und integriert Strukturdaten der PCμCT mit histologischen Schnitten und Messungen mittels Rasterkraftmikroskopie (AFM) Sie, ermöglicht damit eine umfassende Analyse heterogener pathologischer Merkmale, wie zum Beispiel Lungenfibrose. Dieser integrierte Ansatz überwindet die Einschränkungen des unspezifischen Kontrasts der virtuellen Histologie und unterstützt die Validierung von PBI-Befunden durch die Angleichung an bereits etablierte pathologische und bildgebende Standards. Die Pipeline wurde in einem Rattenmodell für beatmungsinduzierte Lungenschäden ("ventilator induced lung injury" - VILI) angewandt, um die strukturellen und mechanischen Auswirkungen von Lungenfibrose zu untersuchen. Durch die Kombination von halbautomatischer Bildanalyse, AFM-basierter Steifigkeitsmessung und histologischer Auswertung konnte die Studie zeigen, dass fibrotische Umbaureaktionen die mechanische Widerstandsfähigkeit gegenüber VILI verbessern können, was auf eine potenziell schützende Rolle der Lungenfibrose unter mechanischer Beatmungsbelastung hindeutet und neue Einblicke in die biomechanischen Grundlagen von Lungenschäden liefert.
Diese Forschungsarbeit stellt insgesamt einen leistungsstarken, integrativen Rahmen vor, der ein hohes Potential besitzt die Bildanalyse der Lunge zu verbessern. Des Weiteren versprechen die entwickeltenMethoden eine zukünftige Translation in die Forschung und klinische Diagnostik, da sie eine hochauflösende, artefaktreduzierte Visualisierung von Lungengewebe, sowohl im physiologischen als auch im pathologischen Zustand, ermöglichen.Histological analysis ofhumanand animal tissues is fundamental tomedical diagnosis and biomedical research, providing insights into disease mechanisms, progression, and treatment response. Traditional histology, involving the examination of stained, micrometer-thin tissue sections under an optical microscope, has been standard practice since the 1660s, but presents limitations, including tissue deformation from sectioning and restricted three-dimensional (3D) structural information due to its inherently two-dimensional (2D) nature. To address these drawbacks, 3D imaging modalities such as micro-CT, in particular, enables high-resolution imaging of larger specimens, however typically requires contrast-enhancing staining agents. In contrary, free propagation based imaging (PBI) technique such asX-ray phase contrast micro-CT (PCμCT), available at synchrotron facilities, offers label-free, non-destructive 3D imaging of soft tissues by exploiting differences in X-ray refractive indices rather than attenuation, providing superior contrast and facilitating advanced virtual histology.
Despite the advantages of PCμCT, optimization of sample preparation remains essential, as conventional histological protocols are not fully compatible with PCμCT imaging requirements. This thesis contributes to the optimization of sample preparation techniques for the PBI method. We proposed an optical clearing protocol which enhances the compatibility of the tissue sample with the property of a single distance phase retrieval algorithm which results in an improved reconstruction of PCμCT scans. Additionally, phase-sensitive PBI, shows promise for high-resolution, low-dose lung imaging. To support clinical validation of this approach, we established a formaldehyde vapor fixation method which essentially preserves the inflated porcine lungs in their physiological state, enabling subsequent histopathological analysis.
To further enhance PCμCT imaging, particularly in formalin-fixed and paraffin-embedded (FFPE) lung tissue, we developed a conditional generative adversarial networks (cGANs)-based approach to suppress air artifacts that commonly hinder visualization and 3D structural analysis. Traditional methods and optimizations of phase retrieval algorithm have shown limitations, especially in resolving overlapping tissue interfaces and preserving structural fidelity. Our tailored cGANs architecture effectively replaces air-filled regions with realistic tissue structures, trained on a custom-generated paired dataset. This data preparation pipeline not only supports artifact correction in PCμCT but also holds potential for broader applications in medical image processing, including denoising and other types of artifact removal, where annotated training data are typically scarce.
A key achievement of this work is the development of a multimodal, multiscale tissue analysis pipeline centered on FFPE lung specimens for PCμCT. This pipeline maintains spatial correlation across modalities and integrates structural data from PCμCT with histological sections and atomic force microscopy(AFM)measurements, enabling comprehensive analysis of heterogeneous pathological features such as fibrosis. Our integrated approach addresses the limitations of non-specific contrast in virtual histology and supports clinical validation of PBI findings through alignment with established pathological and imaging standards. The pipeline was applied in a rat model of ventilator-induced lung injury (VILI) to investigate the structural and mechanical implications of lung fibrosis. By combining semi-automatic image analysis, AFM-based stiffness measurements, and histological evaluation, the study revealed that fibrotic remodeling may enhance mechanical resilience to VILI. These results, suggest a potential protective role of fibrosis under mechanical ventilation stress and providing novel insights into the biomechanical basis of lung injury.
This research collectively introduces a powerful, integrative imaging workflow that represents a significant advancement in the field of pulmonary pathology. The methodologies developed hold significant promise for future translational research and clinical diagnostics by enabling high-resolution, artifact-reduced visualization of lung tissue in both physiological and pathological states.2025-10-3
Selectivity Control in Ruthenium- and Cobalt-Catalysed C–H Activation of Pharmaceuticals
No full textThe construction of C–C bonds is of great significance because C–C bonds are the fundamental linkages and the backbones of pharmaceuticals, agrochemicals, natural products and various materials. Consequently, the chemistry community calls for milder and more sustainable synthetic methodologies for making such bonds, and new strategies to construct previously inaccessible molecules through C–C bond formation. In this thesis, several different transformations to selectively functionalise arenes through new C–C bond formation were investigated, guided by high-throughout experimentation. In each project, late-stage functionalisation was implemented to demonstrate its applicability in medicinal chemistry and drug discovery. In the first project, we developed a redox-neutral, base-free method for the rutheniumcatalysed ortho-C(sp²)−H aminocarbonylation of anthranilamide. The second project explored the possibility of developing a more sustainable and efficient method for the direct alkylation of arenes using earth abundant cobalt catalyst. In the third project, we have developed a strategy for meta-selective C–H methylation and mono-, di-, and trifluoromethylation of arenes, allowing for the rapid access of various C1-substituted compounds from a single parent molecule.2025-12-2
Towards a Dynamic Irrigation Representation in Land Surface Models
No full textIrrigation is crucial for sustaining agricultural productivity and food security, accounting for over 70% of global freshwater withdrawals. Beyond stabilizing crop yields, it increasingly serves as a key climate adaptation strategy in regions facing intensified hydroclimatic stress. By supplementing rainfall, irrigation supports crop growth in marginal areas, modulates land surface energy balance, and buffers agricultural systems against climatic variability. Although traditionally linked to arid and semi-arid zones, irrigation has gained importance in Europe, where climatic conditions range from drought-prone Mediterranean regions to temperate, humid zones. Climate-driven changes such as altered precipitation patterns, more frequent droughts, and intensified heatwaves are reshaping crop water demand and irrigation practices. Consequently, understanding irrigation dynamics in Europe is essential to guide sustainable water management and enhance agricultural resilience across diverse climatic conditions.
The volume of irrigation water use is strongly influenced by the extent of irrigated area. Despite its growing importance, long-term and spatially explicit datasets capturing irrigation area dynamics across Europe remain limited, particularly those disaggregated by crop type. This persistent data gap constrains the assessment of agricultural water demand, the monitoring of adaptation responses, and the design of evidence-based water governance. To address this challenge, this dissertation constructs a suite of consistent, climate-driven, and crop-specific irrigation area datasets covering multiple decades by integrating process-based modeling with multi-source data and spatial disaggregation strategies. The central hypothesis is that drought conditions exert a dominant influence on the actual use of irrigation infrastructure, such that interannual variability in irrigation area can be inferred from drought signals.
This dissertation comprises three interconnected studies that advance the understanding of irrigation dynamics across Europe. Section 2 examines interannual variability in irrigation infrastructure use in response to drought conditions, leading to the reconstruction of the European Long-term Irrigation Area Dataset (ELIAD). Specifically, it reveals that drought tend to stimulate irrigation practices in humid regions such as Western Europe and Northern Europe, whereas in arid areas like Spain in Southern Europe, water scarcity constrains irrigation, resulting in a negative correlation between drought and irrigated area. Historical and socio-economic factors also moderate this relationship, producing weaker responses in Eastern Europe and parts of Central Europe. Furthermore, this study describes the development of the first annual dataset of total irrigable and irrigated areas for 32 European countries from 1990 to 2020, identifying peak irrigation extents during drought years (2003 and 2018, with 11.93 and 11.77 million hectares, respectively) and minima during wet years (2002 and 2014, with 10.71 and 10.31 million hectares). It also analyzes the spatial heterogeneity of irrigation patterns between dry and wet years, revealing distinct regional responses. By characterizing the long-term spatial and temporal variability of irrigation, this work provides a crucial baseline for assessing agricultural water demand and guiding adaptive management under climate variability.
Following this, section 3 describes the development and validation of the European Crop-specific Irrigated Area (ECIRA) dataset. It provides annual growing areas of 16 major irrigated and rainfed crops a 1-km resolution, for 28 European countries from 2010 to 2020. ECIRA disaggregates the subnational total irrigation areas from ELIAD by integrating statistical survey data and gridded information on crop distribution and irrigation infrastructure. It demonstrates high consistency with national census data, LUCAS field surveys, and existing irrigation datasets (i.e., MIRCA-OS, SPAM, and EIM2010), while substantially improving spatial resolution (1 km vs. ~10 km) to better characterize crop-specific irrigation patterns. Despite minor discrepancies in humid regions or for crops with low irrigation prevalence, ECIRA effectively captures spatial hotspots of major irrigated crops, offering a reliable basis for agricultural and hydrological applications across Europe. This enhanced spatial and thematic detail provides a robust foundation for crop water modeling, land surface simulations, and policy-relevant assessments of irrigation.
Section 4 of this thesis presents a comprehensive review of the state of large-scale irrigation area mapping. It first reviews the properties of major global and regional (Europe, India, China, and the United States) irrigation data sets, and highlights their methodological linkages, strengths, and limitations. Using Europe as a case study, it then benchmarks existing datasets alongside the developed ELIAD and ECIRA products, against EUROSTAT 2020 gridded statistics. The evaluation includes visual consistency checks, national-level aggregation comparisons, and 10 km pixel-wise regression analyses. Results show that in humid regions, where irrigation is often supplementary and produces weak spectral and temporal signals, methods supported by ground-truth information (e.g., field and statistical surveys) achieve substantially higher accuracy, whereas datasets lacking such information tend to be less reliable (R² = 0.7 vs. 0.2). Next, the review explores how current irrigation mapping approaches leverage spectral, temporal, and spatial features to identify and characterize irrigation practices. Lastly, it outlines key priorities for future research, emphasizing the role of multi-source data integration and ground-based observations in advancing robust irrigation mapping frameworks. Collectively, this review clarify the current landscape of irrigation data and mapping methodology, and provide a roadmap for advancing data quality and usability in future research and applications.
Sections 2–4 are based on three articles published in (sections 2 and 3) or submitted to (section 4) highly ranked scientific journals. The overall contributions of this thesis can be summarized in three key aspects: (1) irrigation responses to climate variability are elucidated, highlighting contrasting effects of drought stimulation across European climatic zones; (2) an important data gap is addressed through the construction of long-term, high-resolution, crop-specific irrigation datasets for Europe, supported by a scalable framework integrating process-based modeling with multi-source data and spatial disaggregation; (3) existing large-scale irrigation area products are systematically reviewed and evaluated, clarifying their interconnections, strengths, and limitations, thereby deepening the understanding of irrigation mapping principles and providing guidance for future improvements in accuracy and applicability.2025-11-0