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Fluorescence-lifetime image scanning microscopy
No full textImproving optical resolution and image quality has always been an
important goal in the field of microscopy. One technique that histori-
cally played a major role in the optimization of image quality has been
confocal microscopy. With the ability to remove out of focus contribu-
tion to the final image it has revolutionized the field. Especially for
dense and highly inhomogeneous samples, it is highly important to
separate foreground from background light.
An additional benefit of Confocal Laser Scanning Microscopy
(CLSM) is the possibility to combine it with Fluorescence-Lifetime
Imaging Microscopy (FLIM). Gaining access to a whole new dimen-
sion of information. Because fluorescence lifetime can be influenced
by the surrounding of the specimen. In addition, it can also be used to
differentiate between different fluorescent labels.
By integrating an array detector in a confocal laser scanning mi-
croscope, it is possible to double the spatial resolution with Image
Scanning Microscopy (ISM). This requires no further adjustments to
the microscope, the measurement procedure or the sample prepara-
tion. On the contrary, this technique does no longer require a confocal
pinhole. Thus increasing the light detection efficiency dramatically.
Hence, with the introduction of Single Photon Avalanche Diode-arrays
the full potential of FLIM could also be applied to ISM.
In this thesis, I will introduce a novel and unique combination of
Image Scanning Microscopy and Single-Molecule Localization. That
brings this resolution doubling to the world of single-molecule mi-
croscopy. We achieved a localization precision in the single digit
nanometre range. And with the addition of a multichannel high-speed
Time-Correlated Single Photon Counting (TCSPC) electronics we im-
plemented chromatic aberration free fluorescence-lifetime multiplex-
ing.
I also present a new and straightforward method to determine the
optimal Optical Transfer Function (OTF) for any bandwidth limited
imaging method. This is relevant in all areas of microscopy to correct
aberration or other imaging artefacts. And due to its fundamental
nature, this method can be applied to all forms of imaging processes
and not only to light microscopy.
In addition, I will discuss many of my unpublished contributions.
Such as the development of an open-source focus hold system that
works for a wide verity of microscopy methods and implementa-
tions. And the upgrade to an already existing single partial tracking
framework to include Image Scanning Microscopy with single photon
sensitive array detectors.2025-03-2
Association between cardiovascular risk factors and the duration and number of hospitalizations in patients with schizophrenia
No full textIn den letzten Jahren wurde in mehreren Studien ein Zusammenhang zwischen dem metabolischen Syndrom und der Schizophrenie deutlich. Schizophrenie-Erkrankte haben eine um etwa zehn bis fünfzehn Jahre verkürzte Lebenserwartung im Vergleich zur Allgemeinbevölkerung. Dabei wird das erhöhte Risiko für kardiovaskuläre Erkrankungen als Hauptursache für die verfrühte Mortalität angesehen. Diese retrospektive Studie untersucht den Zusammenhang zwischen kardiovaskulären Risikofaktoren und der Hospitalisierungsdauer und -anzahl bei Patienten mit einer Schizophrenie.
Die Studie umfasst Daten von 736 Patienten (356 Frauen und 380 Männer), die aufgrund ihrer Schizophrenie in der Klinik für Psychiatrie und Psychotherapie der Universitätsmedizin Göttingen oder in der Klinik für Psychiatrie und Psychotherapie des Zentralinstituts für Seelische Gesundheit der Medizinischen Fakultät Mannheim stationär aufgenommen wurden. Ab dem Zeitpunkt der ersten Aufnahme wurden über einen Zeitraum von zehn Jahren die Anzahl als auch die Dauer der Hospitalisierungen erhoben, sowie das Vorliegen der kardiovaskulären Risikofaktoren „arterielle Hypertonie“, „Diabetes mellitus Typ 2“ und „Dyslipidämie“ erfasst. Mittels einer einfaktoriellen Analysis of Variance (ANOVA) wurde die Assoziation zwischen den kardiovaskulären Risikofaktoren mit der Anzahl und der Dauer der Aufenthalte untersucht (Signifikanzniveau von <0,05).
In Hinblick auf die Aufenthaltsdauer zeigte sich, dass die arterielle Hypertonie, sowohl als isolierter Risikofaktor als auch unabhängig vom Vorliegen anderer Risikofaktoren, einen mindestens hochsignifikanten Zusammenhang mit der Aufenthaltsdauer aufwies. Zudem bestand eine signifikante Assoziation zwischen der Aufenthaltsdauer und der Kombination der beiden Risikofaktoren Diabetes mellitus Typ 2 und arterielle Hypertonie sowie der Kombination aller drei Risikofaktoren.
Hinsichtlich der Aufenthaltsanzahl wurde ebenfalls ein höchstsignifikanter Zusammenhang mit dem Risikofaktor der arteriellen Hypertonie, unabhängig vom Vorliegen anderer Risikofaktoren, deutlich. Ebenfalls war die Aufenthaltsanzahl hochsignifikant mit der Kombination von arterieller Hypertonie und Diabetes mellitus Typ 2 als auch mit der Kombination von arterieller Hypertonie und Dyslipidämie assoziiert. Des Weiteren zeigte sich in der Gruppe der Patienten mit einem Diabetes mellitus Typ 2 unabhängig vom Vorliegen anderer Risikofaktoren ein signifikanter Zusammenhang mit der Aufenthaltsanzahl.
Bei allen signifikanten Zusammenhängen stellte sich eine längere Aufenthaltsdauer bzw. höhere Aufenthaltsanzahl als die durchschnittliche Aufenthaltsdauer/-anzahl bzw. als die Aufenthaltsdauer/-anzahl der Referenzgruppe dar. Eine lange Aufenthaltsdauer als auch häufige Rehospitalisierungen deuten auf eine Gruppe besonders kranker und behandlungsbedürftiger Patienten hin.
Die Ergebnisse der weiblichen Patienten ähnelten denen der Gesamtgruppe, indem sich in der Gruppe der Frauen ebenfalls eine signifikante Assoziation mit der Aufenthaltsdauer und -anzahl in der Gruppe der „arteriellen Hypertonie“ darstellte. Dies kann darauf hindeuten, dass das Vorliegen von kardiovaskulären Risikofaktoren, insbesondere der arteriellen Hypertonie, bei Frauen einen negativen Einfluss auf den Krankheitsverlauf der Schizophrenie haben kann.
Der in dieser Studie deutliche Zusammenhang der arteriellen Hypertonie mit der Hospitalisierung könnte durch die erhöhte Stressantwort unter Schizophrenen erklärt werden. Beide Erkrankungen sind durch akuten und chronischen Stress auslösbar und weisen einen erhöhten Cortison-Spiegel vor.
Angesichts der Ergebnisse dieser Studie und den der aktuellen Studien, die einen Zusammenhang der Schizophrenie mit dem metabolischen Syndrom belegen, ist es von großer Wichtigkeit, bereits frühzeitig mit einem Screening und einer Therapie der kardiovaskulären Risikofaktoren bei Schizophrenie-Erkrankten zu beginnen. Zudem sollte ein Hauptaugenmerk auf Stressbewältigungs-Modelle gelegt werden. Durch diese Maßnahmen könnte eine Reduktion der Hospitalisierungsdauer und -anzahl als auch auf eine Reduktion der erhöhten Mortalität dieser Patientengruppe angestrebt werden.In recent years, several studies have shown a link between metabolic syndrome and schizophrenia. People with schizophrenia have a shortened life expectancy of around ten to fifteen years compared to the general population. The increased risk of cardiovascular diseases is considered the main cause of premature mortality. This retrospective study examines the association between cardiovascular risk factors and the duration and number of hospitalizations in patients with schizophrenia.
The study includes data from 736 patients (356 female and 380 male) who were hospitalized because of their schizophrenia in the Clinic for Psychiatry and Psychotherapy at the University Medical Center Göttingen or in the Clinic for Psychiatry and Psychotherapy at the Central Institute for Mental Health at the Mannheim Medical Faculty. From the time of the first admission, the number and duration of hospitalizations were recorded over a period of ten years, and the presence of the cardiovascular risk factors “arterial hypertension”, “type 2 diabetes mellitus” and “dyslipidemia” were documented. Using a one-factor analysis of variance (ANOVA), the association between the cardiovascular risk factors and the number and duration of stays was examined (significance level of <0.05).
It was shown that arterial hypertension, both as an isolated risk factor and independently of the presence of other risk factors, had at least a highly significant association with the duration of the hospitalization. There was also a significant association between the length of stay and the combination of the two risk factors type 2 diabetes mellitus and arterial hypertension as well as the combination of all three risk factors.
Regarding the hospitalization rate, there was a highly significant connection with the risk factor of arterial hypertension regardless of the presence of other risk factors. The number of hospitalizations was also highly significantly associated with the combination of arterial hypertension and type 2 diabetes mellitus as well as with the combination of arterial hypertension and dyslipidemia. There was also a significant connection between the hospitalization rate and the group of patients with type 2 diabetes mellitus, regardless of the presence of other risk factors.
In case of these correlations, there were a higher hospitalization duration as well as rate than the average duration/rate or than the duration/rate of the reference group without any risk factors. A long hospital stay as well as frequent rehospitalizations indicate a group of particularly sick patients in need of treatment.
The results of the female patients were similar to those of the overall group, in that there was also a significant association with the length and number of hospital stays in the “arterial hypertension” group. This may indicate that the presence of cardiovascular risk factors, particularly arterial hypertension, in women may have a negative influence on the course of schizophrenia.
The clear association of arterial hypertension with the duration and number of hospitalizations in this study could be explained by the increased stress response among schizophrenics. Both diseases can be triggered by acute and chronic stress and have an increased cortisone level.
In view of the results of this study and those of the current studies that show a connection between schizophrenia and the metabolic syndrome, it is of great importance to start early with screening and treatment of cardiovascular risk factors in schizophrenia sufferers. In addition, a focus on stress management models should be established. These actions could aim to reduce the duration and number of hospitalizations as well as reduce the increased mortality in this group of patients.2025-05-1
Characterization and Engineering of the 'Biocatalytic' Transketolase from Geobacillus stearothermophilus
No full textBiocatalysis is the use of living organisms or their components to speed up chemical reactions,
and is a powerful tool to enhance efficiency and sustainability in manufacturing processes.
Carboligation, the formation of carbon-carbon bonds, is a critical but challenging reaction to
achieve. To date, carboligating enzymes remain underrepresented among commercially employed
biocatalysts. Enzymes utilizing the organic cofactor thiamine diphosphate (ThDP) are particularly
promising for addressing this gap and have been extensively investigated. The specific chemistry
they catalyze, in fact, enables the coupling of two carbon atoms with similar polarity, in particular
when both are electrophilic in nature. Transketolases are members of the superfamily of ThDPdependent
enzymes. Their physiological substrates are phosphorylated sugars, but they have
been widely engineered to expand their substrate scope to include non-phosphorylated sugars, as
well as aliphatic and aromatic compounds.
The transketolase from Geobacillus stearothermophilus (GstTK) was the first thermostable
transketolase to be cloned and evaluated for its synthetic potential. In this work, we present
a comprehensive characterization of the wild type enzyme to assess and improve its industrial
applicability. Our analysis encompasses the elucidation of the structure and the investigation
of the origins of the enzyme’s thermostability. In particular, we uncover the presence of higher
oligomeric states beyond the functional dimer observed in most transketolases. We report the
negative correlation of the larger oligomers with both activity and thermostability, thus suggesting
that strategies aimed at reducing or eliminating these oligomers could enhance the overall enzyme
performance.
We conducted several biophysical experiments, including the development of a novel protocol to
quantify the cofactor binding affinity using isothermal titration calorimetry (ITC). These studies
reveal an unprecedented degree of cooperativity in GstTK compared to other transketolases and
provide evidence for semi-holo forms of the enzyme, where only one of the two active sites of the
functional dimer is occupied by the cofactor. These findings contribute to challenge the broader
understanding of cooperativity, a complex phenomenon observed in all ThDP-dependent enzymes
but varying in magnitude across enzyme families.
Finally, we characterize and newly identify several GstTK variants, along with their counterparts
from the Escherichia coli orthologue, building on previously reported mutations. Using structural
information, we discuss the role of these mutations in altering the substrate specificity, particularly
towards aliphatic donors and rare deoxy and/or non-phosphorylated sugars. Notably, we highlight
the L118I mutation as potentially beneficial regardless of the substrates used, due to its ability
to induce the cofactor into a more catalytically active conformation. Lastly, we propose future
directions for the engineering of GstTK, emphasizing a focus on rare sugars, for which the enzyme
demonstrates good specific activities.
This work advances the understanding of GstTK’s structure, function, and mutability, providing
a foundation for its optimization in industrial applications.2025-05-0
Faktoren, die Studierende im Praktischen Jahr bei der zukünftigen Facharztwahl beeinflussen
No full textThe following dissertation shows factors that influence students in choosing their future specialty in medicine. Qualitative content analysis can be chosen as a form of analysis of interviews. Referring to the elaborated influencing factors, practical experience plays a major role for students. By knowing the other factors it can be possible to counteract the shortage of doctors in the future.2025-06-1
The Effect of Erythropoietin on the Survival of Brain Neurons of Locusta migratoria after Damage by UV Radiation
No full textErythropoetin ist aufgrund seines anti-apoptotischen Potenzials ein vielversprechender
Kandidat für Neuroprotektion. Ein limitierender Faktor in Studien sind bisher unter
anderem thromboembolische Nebenwirkungen. Es wurden verschiedene Rezeptoren und
Signalwege identifiziert, über die Erythropoetin und seine natürliche Splice-Variante EV-3
(teilweise selektiv) Zellprotektion vermitteln. Einer dieser Rezeptoren ist der bisher kaum
charakterisierte CRLF3 Rezeptor. Das Erythropoetin/CRLF3 Signalsystem ist ein
vermutlich phylogenetisch sehr altes, gut konserviertes und allgemein zellprotektives
Signalsystem, das in dieser Studie an Hirnnervenzellen der L. migratoria näher untersucht
wurde.
Erythropoetin wirkt bei Hypoxie zuverlässig anti-apoptotisch. Wenige Studien an
Säugetierzellen zeigen, dass Erythropoetin bei UV-geschädigten Zellen zellprotektiv wirken
kann. Diese Arbeit hat das anti-apoptotische Potential des Epo/CRLF3 Signalsystems
erstmals bei einer Schädigung durch UVC-Strahlung getestet. UVC-Strahlung induziert vor
allem über eine DNA-Schädigung Apoptose, unterscheidet sich demnach grundlegend von
einer Zellschädigung durch Hypoxie. Dadurch lassen sich potenzielle Anhaltspunkte zum
Wirkmechanismus des Epo/CRLF3 Zellschutz gewinnen.
Zudem wurde erstmalig die anti-apoptotische Wirkung AChE-Inhibitoren bei einer UVC-
Schädigung untersucht. AChE-Inhibitoren wirken bei Insekten und Säugetieren über andere
Mechanismen als Epo anti-apoptotisch, was bisher überwiegend im Zusammenhang mit
Hypoxie-bedingten Zellschäden untersucht wurde.
Die Experimente wurden an primären Nervenzellkulturen aus Gehirnen der
Wanderheuschrecke L. migratoria durchgeführt. Nach Kultivierung, Behandlung mit rhEpo
und AChE-Inhibitoren (NSB und TRB), anschließender Schädigung mit UVC-Strahlung
wurden die Zellen erneut inkubiert (Post-Stimulus-Inkubationsdauer) und dann mit DAPI
gefärbt. Abschließend wurde die Zellviabilität verblindet anhand der Zellkernmorphologie
bestimmt.
Weder Erythropoetin noch AChE-Inhibitoren hatten einen anti-apoptotischen oder
zellprotektiven Effekt auf das Überleben der Zellen nach einer Zellschädigung durch UVC-
Bestrahlung (p < 0,05). In den Experimenten mit Erythropoetin wurden sowohl lange (30
min) als auch kurze (3 und 5 min) UV-Bestrahlungszeiten getestet, sowie unterschiedlich
lange Post-Stimulus-Inkubationszeiten (5 und 24 h). Bei allen Experimenten konnte kein
anti-apoptotischer Effekt auf die Insektenneuronen gezeigt werden.
Ob das Ausbleiben des protektiven Effekts an der DNA-schädigenden UVC-Bestrahlung,
an der Zellart oder den intrazellulären Signalwegen welche durch CRLF3 angeschaltet
werden liegt, bleibt bisher unbeantwortet und bedarf weiterer Untersuchungen.Erythropoietin (Epo) is a well-known candidate for neuroprotection due to its anti-apoptotic properties.
One limiting factor in previous studies has been thromboembolic side effects. Various receptors and signaling pathways have been identified through which erythropoietin and its naturally occurring splice variant EV-3 (partially selectively) mediate cell protection. One of these receptors is the CRLF3 receptor, which has been scarcely characterized to date. The erythropoietin/CRLF3 signaling system is presumed to be a phylogenetically ancient, well-conserved, and broadly cytoprotective pathway, which was examined in this study using brain neurons of Locusta migratoria.
Erythropoietin reliably exhibits anti-apoptotic effects under hypoxic conditions. A few studies in mammalian cells have shown that erythropoietin may also exert cytoprotective effects in UV-damaged cells. This study is the first to investigate the anti-apoptotic potential of the Epo/CRLF3 signaling system following damage induced by UVC radiation. Since UVC primarily induces apoptosis through DNA damage, this mechanism is fundamentally different from hypoxia-induced cellular damage. As such, the study may provide new insights into the underlying mechanisms of Epo/CRLF3-mediated cell protection.
In addition, the anti-apoptotic effects of AChE inhibitors in the context of UVC-induced damage were investigated for the first time. In both insects and mammals, AChE inhibitors act via different mechanisms than erythropoietin, and their protective effects have so far been studied mostly in relation to hypoxia-induced cell damage.
Experiments were conducted using primary neuronal cultures from the brains of L. migratoria. After culturing, cells were treated with recombinant human Epo (rhEpo) and AChE inhibitors (NSB and TRB), then exposed to UVC radiation. Following post-stimulus incubation, the cells were stained with DAPI, and cell viability was assessed in a blinded manner based on nuclear morphology.
Neither erythropoietin nor the AChE inhibitors showed anti-apoptotic or cytoprotective effects on cell survival after UVC-induced damage (p < 0.05). In the erythropoietin experiments, both long (30 min) and short (3 and 5 min) UVC exposure durations, as well as different post-stimulus incubation times (5 and 24 hours), were tested. None of these conditions revealed an anti-apoptotic effect on insect neurons.
Whether the absence of a protective effect is due to the DNA-damaging nature of UVC exposure, the specific cell type, or the intracellular signaling pathways activated by CRLF3 remains unclear and requires further investigation.2025-06-0
Protein Mobility in the Complex Physical Environment of the Synapse
Get PDFRobust signal transmission between cells is vital for our daily lives. It relies on fine
orchestration of many processes, particularly taking place at chemical synapses. Here,
chemical reactions occur in precise order, guiding synaptic vesicles (SV) to release their
neurotransmitters upon incoming stimulation. The involved processes host a multitude of
different proteins each performing crucial, specific functions. Despite signal transmission
being one of the best studied cellular pathways, the mobility of involved proteins only
recently has gained increased attention albeit it is expected to have a large impact.
In this thesis, I employed computational simulations to validate, refine and identify over-
arching, physical principals governing protein mobility. To achieve this, I compared sim-
ulations to experimental data, gathered in synapses in neuronal cultures or reconstituted
systems.
Overall, I set up two distinct sets of simulations. In the first one, I investigated protein
mobility at the scale of the entire presynaptic bouton. Here, we used a kinetic Monte
Carlo algorithm, the next subvolume method, to examine the influence of the synaptic
geometry and binding to synaptic vesicles on protein mobility. We fitted fluorescence
recovery after photobleaching experiments with these simulations to identify diffusion
coefficients, SV-binding and SV-unbinding rates of 40 different synaptic proteins. Our
approach revealed a length scale governing protein concentrating recovery. It is set by the
interplay of the proteins mobility parameters and the geometry of the synaptic bouton
itself.
In the second project, I explored the temporal spatial organisation of the synaptic vesicle
cluster (SVC). Using patchy particles we examined the role of short interactions of intrin-
sically disordered regions of proteins and their interplay between different constituents of
the SVC. We first modified to the existing model from the literature enabling simulations
equilibrating an order of magnitude faster, which makes larger system sizes accessible.
Subsequently, we used these modifications to successively implement different features of
molecular design of key constituents of the SVC, such as interaction strength or size dif-
ferences. Using this approach, we dissected the individual contributions of these features
and of different types of proteins seen in experiments. We identified, how dimerization can
effectively increase diffusion, by allowing higher temperatures of droplet formation and
how α-Synuclein changes the density of the SVC by reducing connectivity and increasing
solubility of Synapsin 1. Additionally, SVs can increase the stability of bonds with their
vicinity creating a nucleation point for condensation.2025-05-2
Auswirkungen der linksseitigen kardialen sympathischen Denervation auf die Arrhythmielast und das vegetative Nervensystem bei jungen Patienten mit therapierefraktären ventrikulären Tachyarrhythmien bei LQTS und CPVT
No full textDie Effektivität der LCSD bezüglich der Kontrolle von therapierefraktären ventrikulären Tachyarrhythmien und der Reduktion des Risikos des plötzlichen Herztodes bei LQTS und CPVT wurde bereits in mehreren Studien gezeigt. Da diese Intervention in das sympatho-vagale Gleichgewicht eingreift, sind vegetative Effekte zu erwarten.
Ziel dieser Arbeit war es, in einer retrospektiven Analyse anhand von Daten aus der Patientenakte und einem Fragebogen die Effektivität der LCSD zur Reduktion für kardiale Ereignisse aufzuzeigen. Zudem sollten die Veränderungen des sympathischen und parasympathischen Gleichgewicht nach LCSD untersucht werden. Zusätzlich sollten die Veränderungen im EKG und Langzeit-EKG, der HRV sowie des Blutdrucks nach der LCSD analysiert werden. Weiterhin sollten potentielle Komplikationen nach der LCSD erfaßt werden.
Es konnten die Daten von 27 Patienten analysiert werden, die in dem Zeitraum von Mai 2003 bis April 2019 in der UMG eine LCSD bei LQTS und CPVT erhalten hatten. Es wurden die biometrischen Daten, EKGs, Langzeit-EKG und Blutdruckmessungen analysiert. Um die Langzeitfolgen der LCSD zu erfassen, wurden die Patienten gebeten, beim Hausarzt oder in der UMG ein erneutes LZ-EKG, LZ-RR, eine spontane Blutdruckmessung und ein 12-Kanal-EKG anfertigen zu lassen sowie einen Fragebogen zu beantworten. Die statistische Analyse erfolgte mit dem Wilcoxon Test mittels eines nicht parametrischen Tests von 2 verbundenen Stichproben. Es wurde ein Signifikanzniveau von p < 0,05 angenommen.
Von den 27 Patienten waren zwölf (44,4 %) männlich und fünfzehn (55,6 %) weiblich. Elf Patienten hatte eine CPVT und 16 Patienten ein Long-QT-Syndrom. Zum Zeitpunkt der LCSD betrug das mediane Alter 14,5 (± 11 SD) Jahre, das mediane Gewicht lag bei 46 kg. Die Ergebnisse der vorliegenden Arbeit zeigten, dass es bei 24/27 Patienten nach LCSD zu einer signifikanten Reduktion der kardialen Ereignisse gekommen ist. Lediglich 3 Patienten zeigten nach LSCD persistierende Symptome, wobei hier eine unzureichende Compliance vorlag. Schwerwiegende peri- und postoperative Komplikationen nach LCSD lagen nicht vor. Eine häufige Komplikation war das Horner-Syndrom. Ein transientes Horner-Syndrom lag postoperativ bei 5 Patienten vor, ein persistierendes Horner-Syndrom bei 10 von 21 (48%) Patienten.
Nach LCSD zeigte sich im 12-Kanal-EKG im gesamten Kollektiv eine signifikante Reduktion QT-Zeit (p=0,003) ohne signifikante Beeinflussung der korrigierten QTc-Zeit (p=0,09). Bei den LQT-Patienten zeigte sich eine Reduktion der QTc-Zeit um 22,5 ± 11,7 ms. Bei den CPVT-Patienten lag keine Veränderung vor.
Die Herzfrequenzvariabilität im 24-h-EKG zeigte eine Reduktion des Magid-Index von 90,5 ms auf 63,5 ms (p=0,033), einen Abfall der SDNN von 155 ms auf 112,2 ms (p=0,002) und eine Zunahme der rMSSD (p=0,001) und pNN>50 % (p=0,003).
In der Langzeit-Blutdruckmessung im gesamten Patientenkollektiv konnte ein signifikanter Anstieg des minimalen systolischen Blutdrucks (p=0,018), der minimalen Diastole (p=0,018), der mittleren Diastole (p=0,012) und der maximalen Diastole (p=0,012) festgestellt werden.
Der Patientenfragebogen legte den Fokus auf die vegetativen Begleiterscheinungen nach LCSD. Bei 7 Patienten (33%) kam es zu einer Anhidrosis auf der Seite der LCSD, 16 Patienten (76%) eine Hyperhidrosis auf der Gegenseite. Des weiteren zeigte sich ein Harlequin-Syndrom bei 23%, rezedivierende Schmerzen bei 28%, Parästhesien bei 76%, ein Taubheitsgefühl bei 42% sowie Temperaturempfindungsstörungen bzw. Temperaturegulationsstörungen bei 76 % der Patienten. Psychische Aspekte wie eine gesteigerte Schreckempfindlichkeit lagen bei 14% und ein erhöhtes Angstgefühl bei 28% der Patienten vor.
Abschließend lässt sich sagen, dass die LCSD bei jungen Patienten mit therapierefraktären ventrikulären Tachyarrhythmien mit LQTS sowie CPVT zu einer signifikanten Reduktion der Arrhythmielast geführt hat. Die vorliegende Studie erfaßte deutliche Nebenwirkungen, welche bis dato als gering eingestuft wurde.The effectiveness of LCSD (left cardiac sympathetic denervation) in controlling therapy-refractory ventricular tachyarrhythmias and reducing the risk of sudden cardiac death in LQTS (Long QT Syndrome) and CPVT (Catecholaminergic Polymorphic Ventricular Tachycardia) has already been demonstrated in several studies. Since this intervention affects the sympatho-vagal balance, vegetative effects are expected.
The aim of this study was to retrospectively analyze data from patient records and questionnaires to assess the effectiveness of LCSD in reducing cardiac events. Additionally, changes in the sympathetic and parasympathetic balance after LCSD were to be examined. Furthermore, alterations in ECG and Holter monitoring, HRV (heart rate variability), and blood pressure following LCSD were to be analyzed. Potential complications after LCSD were also to be documented.
Data from 27 patients were analyzed, who received LCSD for LQTS and CPVT at UMG (University Medical Center) between May 2003 and April 2019. Biometric data, ECGs, Holter recordings, and blood pressure measurements were evaluated. To assess long-term effects, patients were asked to have a repeat Holter ECG, 24-hour blood pressure measurement, and a 12-lead ECG performed by their general practitioner or at UMG, and to complete a questionnaire. Statistical analysis was conducted using the Wilcoxon test, a non-parametric test for two related samples. A significance level of p < 0.05 was assumed.
Of the 27 patients, 12 (44.4%) were male and 15 (55.6%) female. Eleven patients had CPVT, and 16 had Long QT Syndrome. At the time of LCSD, the median age was 14.5 years (± 11 SD), and the median weight was 46 kg. The results showed that in 24 out of 27 patients, there was a significant reduction in cardiac events after LCSD. Only 3 patients exhibited persistent symptoms post-LCSD, which was attributed to inadequate compliance. No severe peri- or postoperative complications were observed. A common complication was Horner's syndrome. Transient Horner's syndrome occurred postoperatively in 5 patients, while 10 of 21 (48%) patients had persistent Horner's syndrome.
Post-LCSD, the 12-lead ECG showed a significant reduction in QT interval across the entire cohort (p=0.003), without a significant effect on the corrected QTc interval (p=0.09). In LQTS patients, QTc was reduced by an average of 22.5 ± 11.7 ms. No change was observed in CPVT patients.
Heart rate variability (HRV) analysis from 24-hour Holter recordings revealed a reduction in the Magid index from 90.5 ms to 63.5 ms (p=0.033), a decrease in SDNN from 155 ms to 112.2 ms (p=0.002), and significant increases in rMSSD (p=0.001) and pNN>50% (p=0.003).
Long-term blood pressure measurements showed a significant increase in the minimum systolic blood pressure (p=0.018), minimum diastolic blood pressure (p=0.018), mean diastolic blood pressure (p=0.012), and maximum diastolic blood pressure (p=0.012).
The patient questionnaire focused on vegetative symptoms following LCSD. In 7 patients (33%), anhidrosis occurred on the side of the denervation, while 16 patients (76%) experienced hyperhidrosis on the opposite side. Additionally, Harlequin syndrome was observed in 23%, recurrent pain in 28%, paresthesias in 76%, numbness in 42%, and temperature or thermoregulatory disturbances in 76% of the patients. Psychological aspects such as increased startle sensitivity were reported by 14%, and heightened anxiety levels by 28%.
In conclusion, it can be said that LCSD in young patients with therapy-refractory ventricular tachyarrhythmias due to LQTS and CPVT led to a significant reduction in arrhythmia burden. The present study documented notable side effects, which have previously been considered minor.2025-07-0
Nanoscale optoelectronic characterization of graphene-based heterostructures
No full textThe ongoing downscaling of electronic devices requires innovative approaches to probe and manipulate electronic behavior at the nanoscale. Two-dimensional (2D) materials offer a remarkable opportunity to directly explore transport processes at this scale and to precisely modify their optoelectronic properties by changing their environment. In particular, graphene is an ideal candidate for such applications due to its remarkable optoelectronic properties, which can be directly tuned by external parameters (i.e. gating), and its combination with other 2D materials to form so-called van der Waals (vdW) heterostructures (HSs). In this thesis, we studied different types of graphene-based HSs with two purposes: to investigate the origin of the resistivity on a nanoscopic level and to manipulate the properties of graphene by combining it in HSs with a new class of materials, known as covalent-organic frameworks (COFs) and metal-organic frameworks (MOFs). These materials are crystalline polymers with customizable structure and electronic properties.
In the first part of the thesis, we investigated the mechanisms dominating the Ohmic resistance on a nanoscopic level. The theoretical framework addressing this topic was developed by Landauer in 1957. Landauer predicted that the voltage drop across a conductor would not be uniform. Instead, it would be localized around fixed scatterers due to a dipolar charge distribution that forms around defects as electronic flow occurs, known as Landauer resistivity dipoles (LRDs). The long-range dipolar charge distribution is too weak to be probed in 3D, thus the first experimental evidence was observed only after the isolation of graphene and other 2D materials. However, only a few experimental studies are available due to the need for a non-invasive local probe. In our study, we utilize the nanometer lateral resolution of near-field photocurrent imaging to thoroughly analyze the formation of LRDs in terms of total carrier density and drain current at a monolayer-bilayer graphene interface, which constitutes an ideal one-dimensional defect. We observed that the photocurrent at the interface has the same polarity as the applied drain current for Fermi energy values close to the charge neutrality point (i.e., at low hole or electron doping). This signature is consistent with the carrier accumulation induced by the LRDs and disappears at higher carrier densities, in agreement with the numerical calculations performed. We could thus demonstrate that photocurrent nanoscopy can be used as a non-invasive technique to study local dissipation at hidden interfaces, and we foresee that this method can be applied to study the electronic flow of other 2D systems.
In the second part of the thesis, we investigated the combination of graphene in vdW HSs with 2D COFs/MOFs. The integration of these novel 2D materials with vdW crystals remains mainly unexplored, although it could be a fruitful avenue of exploration. COFs/MOFs offer highly tunable chemical and electrical properties, as they can be synthesized in all mathematically possible Bravais lattices. In a first study, we thoroughly investigated the optoelectronic properties of HSs composed of graphene and an insulating rectangular 2D polyimide (2DPI). Using theoretical density functional theory calculations and several experimental techniques, we found an interlayer charge exchange between the 2DPI and graphene, which induces hole doping in the graphene layer. This interlayer charge exchange can be tuned with the thickness of the 2DPI layer. In particular, the doping increases with polymer thickness. In a second study, aimed at increasing the interlayer interaction, we investigated the magnetotransport properties of an HS composed of graphene and a 2D MOF with paramagnetic copper. While we observed intriguing behaviors in magnetic fields and resistance, further investigation is needed to understand their origin. In general, the findings of these works highlight the unique ability to tailor functionalities in 2D COF/MOF-based HSs. This could open avenues for the development of optoelectronic devices with precisely engineered properties and stimulate further exploration of the diverse phenomena accessible through tailored designs of the 2D COFs/MOFs.
In conclusion, we analyzed different types of graphene-based HSs. The low-disorder graphene hBN encapsulated HSs allowed us to gain valuable insights into fundamental aspects of electronic transport, while the COF/MOF-graphene HSs enabled us to tailor the graphene's properties. Thus, twenty years after its isolation, graphene continues to serve as an extraordinary platform for understanding fundamental transport
mechanisms and remains a possible key component for modern electronics due to the great tunability of its properties.2025-06-1
Bis(amidophenolate)-supported Pnictogen Complexes: Redox Activity, Cooperativity and Electromerism
No full textThis thesis describes the synthesis, characterization and reactivity of pnictogen compounds derived from the tetradentate, redox-active bis(amidophenolate) ligand, N,N′-bis(3,5-di-tert-butyl-2-phenoxy)-1,2-phenylenediamide.
Initially, the synthesis of the complete series of 10-Pn-4 (Pn: P, As, Sb, Bi) pnictoranide anions is reported. Coordination of these anions to the cyclopentadienyliron(II) dicarbonyl fragment delivers the corresponding 10-Pn-5 complexes for P, As and Sb, while in the case of Bi an electron redistribution takes place: The corresponding 12-Bi-5 compound was isolated featuring a two-electron oxidized bis(amidophenolate) scaffold. This case of Lewis acid-induced electromerism was experimentally confirmed through X-ray diffraction analyses as well as IR, UV-Vis and Mössbauer spectroscopy.
Furthermore, an electrophilic chlorophosphorane derived from the same ligand was synthesized. Substitution of the chloride with 1,2-diphenylhydrazine results in its organocatalytic disproportionation into azobenzene and aniline. Mechanistic studies, spectroscopic analyses and DFT calculations suggest that this unprecedented reactivity mode for P(V)-centers is induced by the high electrophilicity at the P(V)-center combined with the ability of the bis(amidophenolate) ligand to act as an electron reservoir.
The same chlorophosphorane reacts with ketones and aldehydes in a fundamentally different manner. A phosphorus-ligand cooperative pathway gives rise to iminio phosphoramidate species. The amphiphilic nature of these products enables the selective reductive coupling of aldehydes to ethers under catalytic conditions.
Finally, the synthesis and structural characterization of a slightly distorted square pyramidal arsenium cation is described. Spectroscopic, crystallographic, and computational evidence indicate that coordination of typical Lewis bases to the As(III)-center induces its oxidation to As(V) with concomitant reduction of the supporting, redox-active bis(amidophenolate) ligand. That reaction is reversible and represents a well-defined example of base-induced electromerism in an As-complex. Single electron reduction of the same As(III) species generates an As(III)/As(V) heterodimer by redox-induced electron transfer.2025-12-0
Bioinformatic analyses of complex genomic regions in non-human primate genomes
No full textThis PhD thesis investigates the application of bioinformatics techniques to annotate and explore complex genomic regions, with an emphasis on the immune-related Natural Killer Group 2 (NKG2) genes in non-human primates. NKG2 genes are receptors of NK cells with a crucial role in identifying and eliminating infected, cancerous or foreign cells. These receptors are regulated through their interaction with Major Histocompatibility Complex (MHC) class I proteins, which are part of a highly polymorphic, gene-rich region governing both innate and adaptive immune responses. The highly repetitive nature of these complex genomic regions pose significant challenges in their study and require ongoing improvements in sequencing technologies to increase assembly quality and bioinformatic tools to analyze the resulting assemblies. This project aims to further contribute to the characterization of these regions with the development of a bioinformatics annotation pipeline, AnnCX, specialized for complex regions. This pipeline, through the implementation of multiple individual annotation tools, is shown to overall increase annotation accuracy over the widely used MAKER annotation pipeline in our benchmarking study. AnnCX was used to unravel the NKG2 genomic diversity in the latest high-quality whole-genome assemblies of non-human primates produced with third-generation sequencing technologies, kindly provided by the authors of the Primate Genome Project (Wu et al., 2022). For many of these primates, this represented the first time that these complex regions have been sequenced and, therefore, explored. Our results revealed that the 36 species studied possessed single NKG2A and F genes flanking a species-specific variable number of NKG2C, CE and/or E genes, with only NKG2A predicted to have an inhibitory function. NKG2F, which has so far been conceived as a pseudogene or truncated protein, here we predicted as a potential full-length receptor, with a putative C-type lectin-like domain, in 14 species of non-human primates. In Macaca mulatta, we predicted intra-species allelic variation in the length of its NKG2F and the potential interaction between its full-length variant and the binding partners of most NKG2 receptors, CD94 and Mamu-E. The findings from this study hopefully contribute to generate a more comprehensive phylogenetic overview of NKG2 genes and provide improved annotation templates to be used in research in biomedicine and evolutionary biology.2025-12-1