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- http://www.scopus.com/inward/authorDetails.url?authorID=6602108113&partnerID=MN8TOARS (1)
The present work deals with the preparation of hydrogels in different size scales for various applications. Thus, macroscopic bulk hydrogels were prepared from differently modified pig gastric mucin (PGM), microgels were made from PGM in combination with hyaluronic acid (HA), as well as from gelatin in combination with poly(ethylene glycol) (PEG), and nanogels were fabricated from poly(glycidol) (PG). According to their size, each hydrogels have different applications. First, it was investigated whether previously existing studies involving the preparation of covalently crosslinked hydrogels via free radical polymerization from bovine submaxillary gland mucin (BSM) could also be carried out with the much cheaper alternative PGM. After this was successfully demonstrated and the hydrogels were systematically investigated for their mechanical properties and biocompatibility, a second hydrogel system was established. Here, PGM was functionalized with allyl glycidyl ether (AGE) and crosslinked in combination with thiolated HA via thiol-ene reaction. These hydrogels were also systematically evaluated and compared with the hydrogels prepared via free radical polymerization. It was confirmed that the more random free radical polymerization leads to more disordered networks than the thiol-ene reaction. In both systems, biocompatibility was demonstrated with both L929 CCL1 murine fibroblasts and human mesenchymal stem cells (hMSCs). Using this knowledge as background and the request to make mucin printable, microgels were prepared via the emulsion technique using the previously established thiol-ene hydrogel precursor solution. Here, applying the recently used photoinitiator 2-hydroxy-4-(2-hydroxyethoxy)-2- methylpropiophenone (Irgacure 2959), which is more soluble in oil than in water, was challenging and did not result in well-crosslinked microgels. Therefore, a third hydrogel system was established, which was based on thiol-ene crosslinked AGE functionalized pig gastric mucin (PGM-AGE)-thiolated hyaluronic acid (HASH) hydrogels and with lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) being used as photoinitiator. Hereby, stably crosslinked microgels could be prepared via the emulsion technique. After the jamming process, which means the extraction of the microgel solution by vacuum, the resulting so-called granular ink could be successfully printed via extrusion-based printing. The widely known challenge of printing living cells was also successfully managed. Cells were encapsulated in the microgels during microgel synthesis. Here, the stirring velocity had to be adjusted to avoid harming the cells during the manufacturing process. The cell-loaded microgels were successfully printed in the same way as the empty microgels in multiple layers resulting in dimensionally stable constructs. Live/dead experiments verified that many viable cells were printable after 24 hours. In the next part of this thesis, microgels were prepared from AGE-functionalized gelatin and thiol-functionalized PEG by the same procedure. Again, cells were incorporated and printed by extrusion-based printing. After the addition of hydroxypropyl-methylcellulose, the right conditions for viable cells and stable constructs were found. The printed constructs were further secondarily crosslinked by immersion in initiator solution after the printing process followed by re-irradiating with light. Hereafter, a strongly increased stability of the constructs could be observed. Microgels for use as cell sensor particles were produced as part of this thesis. Here, microfluidic was applied to prepare microgels with a monodisperse size distribution. After adjusting the oil phase, as well as optimizing the manufacturing parameters to the mucin hydrogel system, the microfluidic setup established by Ilona Paulus in this research group could be used. By setting very fast flow rates, microgels in the size range of cells could be obtained. Furthermore, various parameters affecting the stiffness of the particles were varied. This laid the foundation for follow-up studies within the framework of the SFB TRR225 to be able to produce cellmimicking particles. Further follow-up experiments could include the investigation of hydrogels being based only on mucin, like a crosslinking of thiolated mucin and mucin modified with an allyl function such as the PGM-AGE. Furthermore, the granular mucin ink could serve as a supporting material for other microgels or less stable inks during the printing process and thus expand the field of applicable materials for three dimensional (3D) printing.
Höhergradige Gliome gehören zu den häufigsten malignen Hirntumoren bei
Erwachsenen und gehen mit einer sehr schlechten Prognose einher. Die Patientinnen
und Patienten leiden häufig unter kognitiven Einschränkungen, welche auch auf einen
Integritätsverlust der Weißen Substanz zurückzuführen sind und die Lebensqualität der
Betroffenen stark beeinträchtigen. Um in Zukunft eine Behandlung zu gewährleisten, die
nicht nur das Überleben verlängert, sondern auch den Erhalt der neurokognitiven
Funktionen verbessert, sind zuverlässige Methoden zur Messung von Veränderungen
der neurokognitiven Fähigkeiten in einem frühen Stadium erforderlich. Der direkteste
Weg zur Objektivierung neurokognitiver Eigenschaften sind neuropsychologische Tests.
Wir betrachten das Corpus callosum als eine zuverlässige Struktur zur Identifizierung
der Verschlechterung der Integrität der weißen Substanz. Wir stellten die Hypothese auf,
dass ein Zusammenhang zwischen einer beeinträchtigten strukturellen Integrität in
bestimmten Regionen des Corpus Callosum und neurokognitiven Defiziten bei
Patientinnen und Patienten mit höhergradigem Gliom besteht.
Wir schlossen 25 Patientinnen und Patienten mit höhergradigem Gliom in unsere Studie
ein, die sich präoperativ einer neuropsychologischen Testbatterie und einer MRT mit DTI
Sequenzen unterzogen. Die MRT-Daten wurden mit der Software fsl, Oxford,
verarbeitet. Neuropsychologische Parameter wurden mit der FA in drei Teilen des
Corpus Callosum korreliert: Rostrum bzw. Genu, Truncus und Splenium.
Präoperativ korrelierten die meisten neuropsychologischen Parameter signifikant mit der
FA von mindestens einem Bereich des Corpus Callosum. Höhere FA-Werte wurden mit
besserer Konzentration, Gedächtnis, Schnelligkeit und flüssigem Sprechen in
Verbindung gebracht. Verschiedene Tests untersuchten den gleichen
neuropsychologischen Parameter und korrelierten dann mit der gleichen Region des
Corpus Callosum. So konnten das lexikalische und visuelle Gedächtnis mit dem Genu
und Rostrum in Verbindung gebracht werden, exekutive Funktionen und das
Arbeitsgedächtnis korrelierten mit dem Truncus und die Verarbeitungsgeschwindigkeit
mit dem Splenium. Darüber hinaus stimmte diese Zuordnung mit den Ergebnissen
vorangegangener Studien überein. Wir betrachten Veränderungen der
mikrostrukturellen Integrität der Corpus Callosum als robustes morphologisches Korrelat
für die Untersuchung des neurokognitiven Zustands von Patientinnen und Patienten mit
höhergradigem Gliom.
Cardio- and cerebrovascular diseases (CVDs), such as myocardial infarction and ischemic stroke, are the leading cause of death worldwide, caused by overshooting platelet activation and subsequent thrombus formation. However, at sites of vascular injury this tightly-regulated, multi¬step process is critical to limit blood loss and to prevent bleeding. Anti-platelet agents, such as aspirin or clopidogrel, have been proven to be beneficial in prevention of CVDs, but are associated with an elevated bleeding risk and therefore are often contraindicative.
In recent years, the (hem)ITAM-bearing receptors GPVI and CLEC-2 have been identified as critical regulators of platelet activation and thrombus formation, rendering them promising targets for novel anti-platelet drugs. Yet, they are also involved in a plethora of (patho)physiological processes. Consequently, interference with the (hem)ITAM signaling cascade may lead to severe side-effects. In this context, GPV has previously been identified as a mediator of thrombotic and hemostatic function, while its mode of action remains elusive. Therefore, this thesis focused on the function of GPV in thrombotic and hemostatic processes.
Extensive characterization of GPV-deficient mice as well as generation and analysis of anti-GPV antibodies and mice with a mutation rendering GPV uncleavable by thrombin (Gp5Kin/Kin) revealed an unexpected role of GPV as a central modulator of platelet activation and thrombus formation. Gp5-/- as well as Gp5Kin/Kin mice restored the thrombotic and hemostatic defect in the absence of both (hem)ITAM receptors. The in-house generated monoclonal anti-GPV antibodies 89F12 and 5G2 were found to reproduce the knockout phenotype and extended the thrombus-modulatory role of GPV beyond (hem)ITAM receptors, pointing to a critical role of thrombin-cleaved soluble GPV (sGPV). Surprisingly, recombinant sGPV had a strong antithrombotic effect in in vivo throm¬bosis models as well as in in vitro flow adhesion assays using human or murine blood, without affecting hemostasis. These data establish GPV as a key player in platelet physiology. Although data gained from studies using genetically modified mice cannot always directly be transferred to humans, the findings presented in this thesis may serve as basis for the generation of novel treatment options for bleeding complications (anti-GPV antibodies) and thrombotic diseases (sGPV) with a good safety profile. The newly generated humanized GPV mouse provides a valuable tool to study human GPV in vivo.
A second part of this thesis focused on the analysis of protein kinase C (PKC) ι/λ. PKC family of serine/threonine kinases is involved in several physiological processes regulating platelet activation. However, little is known about atypical PKC isoforms and particularly PKCι/λ has never been studied before in platelets. Therefore, platelet- and megakaryocyte-specific PKCι/λ knockout mice were used to assess its role in platelet function in vitro and in vivo. Surprisingly, PKCι/λ was found to be dispensable for platelet function in thrombosis and hemostasis.
Background
A significant number of oncological patients are heavily burdened by psychosocial stress. Doctors recommending or referring their patients to psycho-oncologists in the course of routine consultations can positively influence psycho-oncological care. The aim of this study was to analyze the frequency and predictors of such recommendations and to examine the use of these services by patients.
Methods
4,020 cancer patients (mean age 58 years; 51% women) were evaluated in a multicenter, cross-sectional study in Germany. Data was gathered about doctors’ referral practices, patients’ utilization of psycho-oncological care services, and disease-related symptoms. The PHQ-9 depression scale and the GAD-7 anxiety scale were used to measure psychological burden. Descriptive data analysis was conducted on the basis of subgroup comparisons and multivariable analysis was done using binary logistical regression.
Results
21.9% of the respondents reported having been given a recommendation or referral for psycho-oncological care by a doctor within the course of their cancer diagnosis and treatment. This comprises 29.5% of the patients identified by screening as being psychologically burdened. Nearly half of the patients who received a recommendation or referral (49.8%) acted on it. Predictors for seeking out psycho-oncological care included: patient desire (OR = 2.0), previous experience with psycho-oncological care (OR = 1.59), and female gender (OR = 1.57). Multivariable analysis indicated that patients’ level of psychological burden (depression, anxiety) had no effect on whether doctors gave them a recommendation or referral.
Conclusions
Along with examining the degree to which patients are burdened (e.g. using screening instruments), determining whether or not patients would like to receive psycho-oncological care is an important aspect of improving referral practices and, by extension, will allow important progress in the field of psycho-oncological care to be made.
Hematopoietic stem cell transplantation (HSCT) has been an effective method for treating a wide range of malignant or non-malignant disorders. In case of an autologous HSCT, patients receive their own stem cells after myeloablation before extraction. Allogeneic HSCT uses stem cells derived from a donor. Despite being associated with a high risk of early and long-term complications, it is often the last curative option. 229 pediatric patients, who between 1 January 2005 and 31 December 2015 received an HSCT at the University Children’s Hospital Wuerzburg, were studied. Correlations between two groups were calculated with the Chi square test or with a 2x2-contingency table. To calculate metric variables, the Mann-Whitney-U-test was used. Survival curves were calculated according to Kaplan and Meier. Significance was assumed for results with a p-value <0.05 (CI (Confident Interval) 95%). We retrospectively analyzed 229 pediatric patients (105 females, 124 males) for early and late complications of allogeneic and autologous hematopoietic stem cell transplantation. Median age at HSCT was seven years. Underlying diseases were leukemia (n = 73), lymphoma (n = 22), solid tumor (n = 65), CNS (central nervous system)- tumor (n = 41), and “other diseases” (n = 28). Survival times, overall survival, and event-free survival were calculated. Of all patients, 80.8% experienced complications of some degree, including mild and transient complications. Allo-HSCT (allogeneic HSCT) carried a significantly higher risk of complications than auto-HSCT (autologous HSCT) (n = 118 vs. n = 67; p = < .001) and the remission rate after allo-HSCT was also higher (58.7% vs. 44,7%; p = .032). Especially infection rates and pulmonary complications are different between auto- and allo-HSCT. Leukemia patients had the highest risk of early and late complications (95,0%; p < .001). Complications within HSCT are major risk factors following morbidity and mortality. In order to detect complications and risk factors early, strict recordings are needed to reduce the rate of complication by recognition and prevention of triggering factors. In the future, these factors should receive greater attention in the planning of HSCT post-transplantation care in order to improve the results of the transplantation and establish protocols to prevent their occurrence.
Objective
Recent preliminary studies indicated a seasonal association of BMI at admission to inpatient treatment for anorexia nervosa (AN), indicating lower BMI in the cold season for restrictive AN. An impaired thermoregulation was proposed as the causal factor, based on findings in animal models of AN. However, findings regarding seasonality of BMI and physical activity levels in the general population indicate lower BMI and higher physical activity in summer than in winter. Therefore, we aimed to thoroughly replicate the findings regarding seasonality of BMI at admission in patients with AN in this study.
Method
AN subtype, age- and gender-standardized BMI scores (BMI-SDS) at admission, mean daily sunshine duration and ambient temperature at the residency of 304 adolescent inpatients with AN of the multi-center German AN registry were analyzed.
Results
A main effect of DSM-5 AN subtype was found (F(2,298) = 6.630, p = .002), indicating differences in BMI-SDS at admission between restrictive, binge/purge and subclinical AN. No main effect of season on BMI-SDS at admission was found (F(1,298) = 4.723, p = .025), but an interaction effect of DSM-5 subtype and season was obtained (F(2,298) = 6.625, p = .001). Post-hoc group analyses revealed a lower BMI-SDS in the warm season for restrictive AN with a non-significant small effect size (t(203.16) = 2.140, p = .033; Hedges′g = 0.28). Small correlations of mean ambient temperature (r = −.16) and daily sunshine duration (r = −.22) with BMI-SDS in restrictive AN were found. However, the data were widely scattered.
Conclusions
Our findings are contrary to previous studies and question the thermoregulatory hypothesis, indicating that seasonality in AN is more complex and might be subject to other biological or psychological factors, for example physical activity or body dissatisfaction. Our results indicate only a small clinical relevance of seasonal associations of BMI-SDS merely at admission. Longitudinal studies investigating within-subject seasonal changes might be more promising to assess seasonality in AN and of higher clinical relevance.
It was previously shown that the estrogen-receptor negative breast cancer cell line MBA-MD-231 expresses high levels of A2B adenosine receptors as the sole adenosine receptor subtype. These receptors couple to both, stimulation of adenylyl cyclase and a Ca2+ signal. In order to establish a potential role of A2B adenosine receptors in tumor growth and development MAPK signaling was investigated in these breast cancer cells. Although it is known that A2B adenosine receptors may stimulate MAPK it was found that in MBA-MD-231 cells ERK1/2 phosphorylation is reduced upon agonist-stimulation of A2B adenosine receptors. This reduction is also triggered by forskolin, but abolished by the PKA inhibitor H89, suggesting an important role for the cAMP-PKA pathway. Likewise, a role for intracellular Ca2+ was established as the Ca2+ chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM) abolished the reduction of ERK1/2 phosphorylation triggered by A2B stimulation. It was shown that various pathways downstream from A2B adenosine receptors resulted in a stimulation of MAPK phosphatase-1 (MKP-1) which dephosphorylates phospho ERK1/2, and thus plays a critical role in the regulation of the phosphorylation state of ERK1/2. The reduction of ERK1/2 phosphorylation mediated by A2B adenosine receptors might provide an interesting approach for adjuvant treatment leading to reduced growth of certain tumors expressing the A2B subtype.
We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30–60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.
Exploratory behavior of re-orienting foragers differs from other flight patterns of honeybees
(2018)
Honeybees, Apis mellifera, perform re-orientation flights to learn about the new surroundings of the hive when their hive is transported to a new location. Since the pattern of re-orientation flights has not yet been studied, we asked whether this form of exploratory behavior differs from the well described exploratory orientation flights performed by young honeybees before they start foraging. We also investigated whether the exploratory components of re-orientation flights differ from foraging flights and if so how. We recorded re-orientation flights using harmonic radar technology and compared the patterns and flight parameters of these flights with the first exploratory orientation flights of young honeybees and foraging flights of experienced foragers. Just as exploratory orientation flights of young honeybees, re-orientation flights can be classified into short- and long-range flights, and most short-range re-orientation flights were performed under unfavorable weather conditions. This indicates that bees adapt the flight pattern of their re-orientation and orientation flights to changing weather conditions in a similar way. Unlike exploratory orientation flights, more than one sector of the landscape was explored during a long-range re-orientation flight, and significantly longer flight durations and flight distances were observed. Thus, re-orienting bees explored a larger terrain than bees performing their first exploratory orientation flight. By displacing some bees after their first re-orientation flight, we could demonstrate that a single re-orientation flight seems to be sufficient to learn the new location of the hive. The flight patterns of re-orientation flights differed clearly from those of foraging flights. Thus, re-orientation flights represent a special exploratory behavior that is triggered by a change in the location of the hive.
Effect of progesterone on Smad signaling and TGF-β/Smad-regulated genes in lung epithelial cells
(2018)
The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone’s effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.
The role of the subthalamic nucleus in human locomotion is unclear although relevant, given the troublesome management of gait disturbances with subthalamic deep brain stimulation in patients with Parkinson’s disease. We investigated the subthalamic activity and inter-hemispheric connectivity during walking in eight freely-moving subjects with Parkinson’s disease and bilateral deep brain stimulation. In particular, we compared the subthalamic power spectral densities and coherence, amplitude cross-correlation and phase locking value between resting state, upright standing, and steady forward walking. We observed a phase locking value drop in the β-frequency band (≈13-35Hz) during walking with respect to resting and standing. This modulation was not accompanied by specific changes in subthalamic power spectral densities, which was not related to gait phases or to striatal dopamine loss measured with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane and single-photon computed tomography. We speculate that the subthalamic inter-hemispheric desynchronization in the β-frequency band reflects the information processing of each body side separately, which may support linear walking. This study also suggests that in some cases (i.e. gait) the brain signal, which could allow feedback-controlled stimulation, might derive from network activity.
Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer’s disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF.
Living beings evolved in an environment with cyclic changing conditions where a variety of factors such as light, temperature, or food availability oscillate in a daily 24-h rhythm. Endogenous circadian clocks in addition to controlling daily rhythms, are also thought to serve as an internal reference for measuring day length. This allows animals to adapt to seasonal changes through photoperiodic responses. While these responses are well-documented in insects, the underlying timing mechanisms for day-length discrimination remain incompletely understood. This thesis aimed at the characterization of the circadian clock of a strongly photoperiodic insect, the pea aphid Acyrthosiphon pisum, that allowed us to find putative neuronal connection between the circadian clock and the photoperiodic system of this insect. In the first chapter, we characterized the neuronal organization of aphid clock clusters using antibodies against the clock proteins Period and Cryptochrome. These clusters were found in the dorsal and lateral protocerebrum, and in the lamina and exhibited daily oscillations. Notably, the clusters expressing Cryptochrome showed light-dependent oscillations, indicating their potential role as clock photoreceptors. These Cryptochrome-positive clusters projected towards the pars intercerebralis, a region crucial for photoperiodism in aphids. In the second chapter, we focused on the Pigment-dispersing factor (PDF), the most important clock neuropeptide in insects. We discovered significant changes in the, otherwise highly conserved, insect C-terminal amino acid sequence of the newly identified pdf gene. PDF was identified in the lateral clock neurons, and their terminals in the dorsal protocerebrum close to the insulin-producing cells located in the pars intercerebralis. These terminals showed daily and seasonal variations, suggesting PDF’s involvement in regulating neurohormone release. To further explore the neuroanatomy of the aphid circadian clock and identify clock-related neuropeptides, we conducted transcriptomic analysis, mass spectrometry, and fluorescent immunohistochemistry. We found that the lateral clock neurons expressed various neuropeptides (in particular Allatotropin, FMRFamide, Orcokinin-A and PDF), similar to those in cockroaches involved in light input pathways. The dorsal clock neurons also exhibit neuropeptide immunoreactivity (precisely of Allatostatin A, Diuretic Hormone31, FMRFamide and Myoinhibitory Peptide), supporting their involvement in modulating circadian and seasonal neurohormonal rhythms. Finally, in the fourth chapter, we provide an overview of the putative mechanisms of photoperiodic control in aphids, from the photoreceptors involved in this process to the circadian clock and the neuroendocrine system.
Patients diagnosed with the rare autoimmune disease of Stiff Person Syndrome (SPS) suffer from varying motor symptoms mainly characterized by painful spasms and muscle stiffness. Among patients suffering from Stiff Person spectrum, clinical presentation, course of disease and treatment responses also differ. Regardless of disease severity, which ranges from mild and intermittent motor impairments to the most severe form progressive encephalomyelitis with rigidity and myoclonus (PERM), autoantibodies are the underlying cause. One of the autoantibody targets associated with SPS is the glycine receptor (GlyR). Functional impairment of this protein interferes with inhibitory signal transmission in the central nervous system and subsequently causes motor symptoms. Similar to functional alterations of the GlyR upon autoantibody binding, GlyR function can be altered in patients with mutations in genes encoding GlyR subunits. Such mutations underlie hereditary hyperekplexia. Understanding the GlyR physiology and how different molecular mechanisms contribute to disease pathology is crucial for development of more targeted and effective disease options.
Therefore, novel GlyR β subunit mutations identified in hyperekplexia patients were investigated towards their expression, trafficking and receptor function. The findings suggest that impaired recruitment into functional receptors at the synapses might underlie the functional alterations revealed by electrophysiological recordings for most cases.
To unravel the autoantibody-related pathology causing the highly diverse clinical appearance of the Stiff Person spectrum, antibody binding abilities were studied. Neutralization assays confirmed that presence of the entire target protein, a sub-domain or a short peptide eliminates the autoantibodies from patient samples. Epitope characterization using residue exchanges within the GlyR in cell-based assays uncovered that GlyR autoantibody epitopes are polyclonal and their combination is patient-specific. Tissue-based binding assays emphasized the high variability in autoantibody distribution within spinal cord and brain sections regardless of the patients’ primary diagnosis. The irregular binding patterns among the patient groups of SPS, PERM, epilepsy and ‘others’ reflected the variation in the symptomatic arrangement. Passive transfer of GlyR autoantibodies from patients with different courses and severity of disease similarly revealed variable effects on murine motor and anxiety-related behavior. The detected small effects on motor function and post-mortem analyses indicate glycinergic disorganization and a possible onset of compensatory mechanisms.
Altogether, this study demonstrates that GlyR impairment is patient-specific and of greater variability than expected.
Within this PhD thesis, starting from simple alkene precursors a series of novel boron-doped PAHs were successfully in a sequential one-pot synthetic approach, comprising a hydroboration/borylation cascade as the key step. By applying different postsynthetic reactions, the properties of these boron-doped PAHs were further adjusted, aiming for appealing packing motifs, strong electron-acceptors, and NIR-emitters. The thesis thereby focussed on the synthesis of tailor-made molecules, the investigation of their optical and electronic properties and the discussion on the influence of various factors, e.g. doping pattern, size, shape, and substituents, on these properties.
Fear and anxiety are fundamental emotional states that are critical for survival. These states are characterized by a variety of coordinated responses, including behavioral and autonomic changes, that need to be properly integrated. For the past decades, most studies have separated the behavioral and autonomic elements, generating a gap in understanding their integrative nature. In this thesis, a framework analysis is presented that allows for the integration of cardiac, behavioral, and neuronal readouts in freely moving mice during different emotional states. Furthermore, a growing body of evidence demonstrates that a vital component of these states is the physiological report of bodily states, or interoception, which allows for quick adaptation to changing situations. A set of distinctive interoceptive pathways has been described from the periphery to the brainstem; however, the circuits that process and integrate cardiac interoceptive signals in higher orders are poorly understood. The midbrain periaqueductal gray (PAG) is a region crucially involved in defensive states through its modulation of both, cardiac and behavioral components. Preliminary studies demonstrate an anatomical connection between the major cardiac interoception brainstem area, the nucleus of the solitary tract, and the PAG; however, the functional characterization and the specific neuronal substrates responsible for interoception in this area have not been described. An interesting particularity of the PAG is that the ventro-lateral subcolumn is the highest order of the neuraxis where inhibitory neurons that express the glycine can be found. In the lower brainstem and spinal cord, glycinergic inhibitory neurons have demonstrated a role in processing sensory and autonomic signals from the periphery, raising the question of whether the PAG glycinergic neurons could be involved in integrating cardiac interoceptive signals as part of a defensive state. In this thesis, using virally mediated trans-synaptic retrograde tracing, I showed that glycinergic PAG neurons receive inputs from cardiac regulatory areas in the brainstem and project massively to forebrain and midbrain regions. By employing advanced techniques such as deep brain calcium imaging with a miniaturized microscope and optogenetics, this study provides compelling evidence for the involvement of glycinergic PAG neurons in controlling heart rate and maintaining cardiac macrostate dynamics within physiological levels. The results of the optogenetic manipulation further revealed that a change in the heart rate macrostate caused by the glycinergic PAG neurons leads to anxiety-like behaviors, providing further evidence for the role of these neurons in regulating defensive states. Overall, by unraveling the neural circuitry underlying interoception in the PAG, our study paves the way to better understand fear and anxiety disorders.
This thesis focusses on the synthesis of functional chiral molecules using carbo- or hetero[7]helicenes as a chiral element, combined with multiple helicenes, phthalocyanines, and 1,4-azaborine units. The objective is to achieve properties that surpass those of the parent compounds.
In the first project, an enantiopure, propeller-shaped multi-helicene polycyclic aromatic hydrocarbon containing three (P)-[7]helicene units and three (M)-[5]helicene units was stereospecifically synthesized and can be obtained in gram quantities. Leveraging the configurational stability of [7]helicene and the configurational instability of [5]helicene, we exclusively obtained the most thermodynamically stable enantiomer out of 10 possible enantiomeric pairs. The effects of the multi-helicene structure on optical rotation, UVVis absorption, fluorescence, and electronic circular dichroism (CD) spectroscopy were investigated.1
Building on the success of the first project, the second project used the configurationally stable [7]helicene again. Zinc-[7]helicenocyanine (Zn-7HPc) was stereospecifically synthesized by directly conjugating [7]helicenes with a phthalocyanine (Pc) core. Zn-7HPc demonstrates a CD signal in the near-infrared region, indicating efficient chirality transfer from the helicenes to the Pc core. Zn-7HPc forms stable, discrete homochiral dimers over a wide range of concentrations in tetrahydrofuran and dimethyl sulfoxide, as well as in the solid state. These homochiral dimers are formed even within the racemic mixture due to the interlocking of two homochiral monomers. The large comproportionation constant and the observed intervalence charge transfer band that appeared in spectroelectrochemistry experiments indicate strong communication between the two Pc monomers in the dimer.2
In the third project, aza[7]helicenes were incorporated with a 1,4-azaborine unit, which exhibits a multiple-resonance effect, to achieve narrow-band emission, high fluorescence quantum yield (FL), and a small Stokes shift. These properties are essential for ultrahigh-definition organic light-emitting diodes that emit circularly polarized light (CP-OLEDs). The synthesized series of molecules demonstrate small Stokes shifts (0.06–0.07 eV), exceptionally narrow fluorescence and circularly polarized luminescence bands with small full width at half maximum (FWHM, 17–28 nm, 0.07–0.13 eV), and high FL (72–85%).3
In conclusion, the synthesis of functional chiral molecules based on carbo- or hetero[7]helicenes was successfully achieved. The efficient synthetic strategies and improved properties of these molecules provide valuable insights for further investigations into helicenes with advanced structures and enhanced properties.
Um Schüler:innen mit komplexen Kommunikationsbedürfnissen und sonderpädagogischem Unterstützungsbedarf im Schwerpunkt Geistige Entwicklung in ihrer Kommunikationsentwicklung unterstützen zu können, müssen zunächst ihre kommunikativen Kompetenzen eingeschätzt werden. Diese Kompetenzen können jedoch je nach Kommunikationspartner:in und Kontext erheblich variieren. Die Umweltabhängigkeit kommunikativer Kompetenzen sowie methodische Herausforderungen bei der Diagnostik kommunikativer Kompetenzen führen zu der Frage, wie Eltern, Lehrkräfte und andere Kommunikationspartner:innen die kommunikativen Kompetenzen dieser Schüler:innen einschätzen, welche Gemeinsamkeiten und Unterschiede zwischen den Einschätzungen bestehen und wie diese erklärt werden können.
Mittels empirischer Daten eines mehrperspektivisch angelegten Fragebogens (N = 357) im Kontext des Forschungsprojektes SFGE II (Baumann et al., 2021) konnten signifikante Unterschiede zwischen der Einschätzung der Eltern und der Lehrkräfte bei vier der acht untersuchten Items zur Einschätzung der kommunikativen Kompetenzen nachgewiesen werden. Die unjustierte Interraterreliabilitätsanalyse konnte einen Einfluss der Familiensprache, der Diagnose sowie des Grades der Intelligenzminderung auf die Höhe der Reliabilität zwischen Eltern und Lehrkräften nachweisen. Die deskriptive Analyse von fünf Fallbeispielen aus zwei weiteren bayerischen Schulen mit sonderpädagogischem Schwerpunkt Geistige Entwicklung untersuchte die Einschätzungen weiterer Kommunikationspartner:innen und betonte vor allem die Bedeutung der UK-Expertise der Kommunikationspartner:innen sowie den Einfluss der aktuell genutzten Kommunikationsformen der Schüler:innen.
Mit den Ergebnissen dieser Studie liegt erstmals ein empirischer Beleg für die unterschiedlichen Einschätzungen kommunikativer Kompetenzen zwischen Eltern und Lehrkräften von kaum und nicht lautsprachlich kommunizierenden Schüler:innen im sonderpädagogischen Schwerpunkt Geistige Entwicklung vor. Die umfassenden Analysen ermöglichen differenzierte Einblicke in das Einschätzungsverhalten verschiedener Kommunikationspartner:innen, liefern Hinweise zur Erklärung übereinstimmender sowie unterschiedlicher Einschätzungen und verweisen auf die Bedeutung von Mehrperspektivität im Kontext von UK-Diagnostik.
Axon growth, a fundamental process of neuron development, is regulated by both intrinsic and external guidance signals. Impairment of axon growth and maintenance is implicated in the pathogenesis of neurodegenerative disorders such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease (AD). Axon growth is driven by several post-transcriptional RNA processing mechanisms, including alternative splicing, polyadenylation, subcellular localization, and translation. These mechanisms are controlled by RNA-binding proteins (RBPs) through interacting with their target RNAs in a sequence-dependent manner. In this study, we investigate the cytosolic functions of two neuronal RBPs, Ptbp2 and hnRNP R, which are essential for axon growth in motoneurons.
Polypyrimidine tract binding protein 2 (Ptbp2) contributes to neuronal differentiation and axonogenesis by modulating different splicing programs to adjust the level of proteins involved in these processes. While the nuclear functions of Ptbp2 in alternative splicing have been studied in more detail, the cytosolic roles of Ptbp2 associated with axon growth have remained elusive. In the first part of the study, we show that Ptbp2 is present in cytosolic fractions of motoneurons including axons and axon terminals. Depletion of Ptbp2 impairs axon growth and growth cone maturation in cultured embryonic mouse motoneurons. Moreover, Ptbp2 knockdown affects the level of piccolo protein in the growth cone of cultured motoneurons. We detect Ptbp2 as a top interactor of the 3' UTR of the Hnrnpr transcript encoding the RBP hnRNP R. This interaction results in axonal localization of and thereby local translation of Hnrnpr mRNA in motoneurons. Consequently, axonal synthesis of hnRNP R was diminished upon depletion of Ptbp2 in motoneurons. We present evidence that Ptbp2 through cooperation with translation factor eIF5A2 controls hnRNP R synthesis. Additionally, we observe that re-expression of hnRNP R in Ptbp2-deficient motoneurons rescued axon growth defect while Ptbp2 overexpression failed to normalize the axon elongation defect observed in hnRNP R-deficient motoneurons. Our findings pinpoint axonal synthesized hnRNP R as a mediator of Ptbp2 functions in axon growth.
In the second part of this study, we identify hnRNP R binds to the 3' UTR of microtubule-associated tau (Mapt) transcript encoding tau protein and regulates the axonal translocation and translation of Mapt mRNA. Tau protein has a central role in neuronal microtubule assembly and stability. However, in AD, the accumulation of abnormally hyperphosphorylated tau protein leads to axon outgrowth defects. Loss of hnRNP R reduces axonal tau protein but not the total level of tau. We observe that the brains of 5xFAD mice, as a mouse model of AD, deficient for hnRNP R contain lower phospho-tau and amyloid-β plaques. Likewise, Neurons treated with blocking antisense oligonucleotides (ASO) to prevent binding of hnRNP R to Mapt mRNA show reduced axonal Mapt mRNA and consequently newly synthesized tau protein levels. We show that blocking Mapt mRNA transport to axons impairs axon elongation. Our data thus suggest that reducing tau levels selectively in axons, a major subcellular site of tangle formation, might represent a novel therapeutic approach for the treatment of AD.
In this work, two techniques, based on the established method of pump--probe spectroscopy were used to investigate the properties of molecular systems in the liquid phase within the visible spectral wavelength range.
The first technique is standard transient absorption (TA) spectroscopy which was applied to a diazo-precursor to identify the formation of a biradical in an inert solvent after UV excitation. With the combination of EPR spectroscopy and quantum chemical calculations, the formation of a biradical in an unpolar and non-protic solvent was proven. Besides, in the presence of air or a polar and protic solvent, the biradical reacts ultrafast to various side products.
The second technique is time-resolved circular dichroism (TRCD) spectroscopy, which was performed in two different ways. The first approach based on a pulse-enantiomer (PE) setup, where an initially circularly polarized pulse was split into two pulses, of which one was mirrored under normal incidence, to flip its polarization. The result was two pulses with mirrored polarization states that propagate collinearly to the sample as left and right circularly polarized probe pulses. The alignment procedure as well as the drawbacks of this setup are described in detail.
However, a new TRCD setup was built that used a polarization grating to get left and right circularly polarized pulses. With the experiences of working with the PE setup, the new TRCD setup could be optimized so that TRCD spectra of a chiral squaraine polymer could be measured. With the help of quantum chemical calculations, the signals were assigned to exciton dynamics that describe spatial and energetic rearrangements of the excitation energy. The alignment and the measurement procedures to perform TRCD spectroscopy with the new setup are described in detail for future experiments.