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Assoziation von Polymorphismen des NRG3-Gens mit der P300-Amplitude im EEG als Endophänotyp der Schizophrenie
Get PDFSchizophrenia is a serious mental illness with enormous consequences for those affected and their families. A multifactorial genesis is assumed. In addition to various risk factors, a polygenetic influence plays a significant role; in the meantime, a large number of genes have been associated with schizophrenia.
Neuregulins are proteins which, as growth factors, lead to the activation of various intracellular signalling pathways by binding to their receptors. Neuregulin 3 is a gene that plays a role in embryonic neuronal development and SNPs in NRG3 have already been associated with schizophrenia in various populations as well as with the expression of delusions. Endophenotypes in psychiatry represent neuronal changes or structures underlying a disorder. The detection of these endophenotypes thus forms the link between genotype and disease and offers the possibility of removing ambiguities in the aetiology of schizophrenia. The P300 wave is an event-correlated potential that can be measured in the EEG. Many studies indicate an amplitude reduction of the P300 wave in schizophrenia patients.
This dissertation investigates whether associations exist between SNPs of the NRG3 gene and an amplitude change of the P300 wave in the EEG as a potential endophenotype of schizophrenic patients. Sample 1 included 116 patients and 256 controls, each of whom underwent an EEG examination with recording of the P300 wave. In sample 2 of 112 patients, the significant SNPs of the EEG examination were examined for an association with clinical phenotypes using the PANSS scale. The SNPs rs2622807 and rs635481 as well as the haplotypes formed from them could be significantly associated with the amplitude level in the patient group in the derivation Pz, whereby the rarer alleles or the corresponding haplotype were more likely to be found at high amplitude. Another association, also in patients and the Pz derivation and additionally via Cz, was recorded with the haplotype GCC, consisting of the minor alleles of the SNP, rs11595793, rs1336290, rs722982. The haplotype was more frequently found at a lower amplitude. In addition, for 2 of the 3 SNPs, an increased incidence of guilt was observed in the presence of the minor allele.
These results indicate an association of polymorphisms of the NRG3 gene and an amplitude change of the P300 wave. However, more research is needed to establish a comparable set of studies and to validate the potential associations between variations in NRG3 and P300 amplitude as an endophenotype.Schizophrenie ist eine gravierende psychische Erkrankung mit enormen Folgen für Betroffene und Angehörige. Es wird von einer multifaktoriellen Genese ausgegangen. Neben unterschiedlichen Risikofaktoren spielt eine polygenetische Einflussnahme eine wesentliche Rolle, inzwischen konnte eine Vielzahl von Genen mit Schizophrenie assoziiert werden.
Neureguline sind Proteine, welche als Wachstumsfaktoren durch Bindung an ihre Rezeptoren zu der Aktivierung unterschiedlicher intrazellulärer Signalwege führen. Neuregulin 3 ist ein Gen, welches in der embryonalen neuronalen Entwicklung eine Rolle spielt und SNPs im NRG3 konnten bereits in verschiedenen Bevölkerungsgruppen mit Schizophrenie sowie mit der Ausprägung von Wahn assoziiert werden. Endophänotypen in der Psychiatrie stellen einer Erkrankung zugrunde liegende neuronale Veränderungen oder Strukturen dar. Die Erfassung dieser Endophänotypen bildet somit das Bindeglied zwischen Genotyp und Erkrankung und bietet die Möglichkeit Unklarheiten in der Ätiologie der Schizophrenie zu beseitigen. Die P300-Welle ist ein im EEG messbares Ereignis-korreliertes Potential. Viele Studien weisen auf eine Amplitudenminderung der P300-Welle bei Schizophreniekranken hin.
Diese Dissertation untersucht, ob Assoziationen zwischen SNPs des NRG3-Gens und einer Amplitudenveränderung der P300-Welle im EEG als potentieller Endophänotyp schizophrener PatientInnen bestehen. In Stichprobe 1 wurden 116 PatientInnen und 256 Kontrollpersonen einbezogen, bei welchen jeweils eine EEG-Untersuchung mit Erfassung der P300-Welle durchgeführt wurde. In Stichprobe 2 aus 112 PatientInnen wurden die signifikanten SNPs der EEG-Untersuchung auf eine Assoziation mit klinischen Phänotypen anhand der PANSS-Skala untersucht. Die SNPs rs2622807 und rs635481 sowie die daraus gebildeten Haplotypen konnten in der PatientInnengruppe bei der Ableitung Pz signifikant mit der Amplitudenhöhe assoziiert werden, wobei die selteneren Allele, bzw. der entsprechende Haplotyp eher bei hoher Amplitude zu finden waren. Eine weitere Assoziation ebenfalls bei PatientInnen und der Pz-Ableitung sowie zusätzlich über Cz wurde mit dem Haplotyp GCC, bestehend aus den minoren Allelen der SNPs rs11595793, rs1336290, rs722982 erfasst. Der Haplotyp war häufiger bei einer niedrigeren Amplitude zu finden. Zusätzlich war für 2 der 3 SNPs bei Vorliegen des minoren Alleles ein verstärktes Auftreten von Schuldgefühlen (PANSS) zu beobachten.
Diese Ergebnisse weisen auf eine Assoziation von Polymorphismen des NRG3-Gens und einer Amplitudenveränderung der P300-Welle hin. Es bedarf jedoch noch vieler weitergehender Untersuchungen, um eine vergleichbare Studienlage zu schaffen und die potentiellen Zusammenhänge zwischen Variationen im NRG3 und der P300-Amplitude als Endophänotyp zu validieren
Therapeutisches Drug Monitoring von Antiinfektiva bei kritisch kranken Patienten auf der Intensivstation
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Vaccine antigen identification against dangerous Gram-positive ESKAPE pathogens
Get PDFEnterococcus faecium and Staphylococcus aureus, the Gram-positive pathogens of the ESKAPE group, are known to represent a great threat to human health, especially due to their presence in the healthcare setting where they often present with high virulence and multiple resistances to antibiotics. Together, S. aureus and E. faecium account for 45% of annual antimicrobial resistance related-deaths in the US.
In this study, we combined several techniques for antigen discovery in an effort to reduce the number of identified proteins to only promising candidates. We used a subtractive proteome analysis that we combined with a false positive analysis of peptides obtained by trypsin shaving. Briefly, the subtractive proteome analysis was conducted on proteins extractions obtained by lysostaphin digestion, SDS boiling or sonication that were run through SDS-PAGE in triplicates. Two of the gels were blotted onto a membrane and detected with either pooled human sera previously tested for the presence of opsonic antibodies, or with the same sera previously depleted of S. aureus-specific antibodies. Bands identified with the pooled sera but not with the depleted one were reported to the remaining gel and matching bands were excised for protein identification by mass spectrometry. The false positive analysis was performed using trypsin shaving: bacteria were incubated with or without trypsin in a hypotonic solution and the resulting supernatant was run through mass spectrometry, leading to a list of proteins enriched by the treatment with the enzyme. Combination of the results obtained with both techniques formed a list of 40 potential antigens which was narrowed down to 10 candidates after removal of already described antigens, cytoplasmic and non-immunogenic proteins. We picked five of them: the DUF5011 domain-containing Fe/B12 transporter, and Fe(3+) dicitrate ABC transporter; and two having an amino acid sequence really close to two already discovered antigens in enterococci: PrsA and AdcAau. Cross-opsonic effect was investigated and showed that antibodies raised against the two enterococcal antigens can mediate the killing of S. aureus. We showed that our selected proteins are able to elicit specific and opsonic antibodies against the S. aureus strain MW2. We also demonstrate that PrsA and AdcAau can cross-bind to their homologs and cross-opsonize several S. aureus, E. faecium and E. faecalis strains.
These findings show that the novel experimental approach for antigen discovery can lead to the identification of promising candidates that can induce the production of opsonic antibodies. We showed that three of the investigated candidates could mediate the killing of S. aureus. Also, two of the identified proteins are antigens that could be considered for vaccine formulation against both Gram-positive ESKAPE pathogens
Synthesis of hypermodified nucleosides and examination of nucleic acid templated stereoselective peptide formation in an RNA-peptide world
Get PDFLife on Earth in its full complexity could not exist without the ability to replicate and maintain its essential genetic and metabolic functions. The question of “how” and “when” life emerged, is one of the biggest unsolved mysteries of humankind. We can follow the evolution of living species by analysing the fossils excavated by scientist around the globe, but tracing back the beginnings of life to understand the transition from abiotic Earth to living matter is a much more difficult riddle to address. Modern life is based on the interactions between the nucleic acids (DNA and RNA) and the proteins, also known as the “central dogma of molecular biology”. One of the most important processes of contemporary biology is the translation, which can be seen as a link between the genotype and phenotype. In this process, the genetic information is decoded and translated into a chain of amino acids, which, upon folding, forms catalytically active proteins. The translation itself poses a chicken-and-egg conundrum, since it involves both nucleic acids and proteins in form of tRNA and the ribosome (a nucleic acid-protein hybrid). The RNA-world hypothesis suggests that initially the RNA molecule carried the dual function of being the keeper of genetic information as well as a catalyst. It is suspected that this versatility was supported by the presence of an extended genetic alphabet of modified nucleosides. Interestingly, a collection of modified nucleosides such as t6A, m6t6A and (m)nm5U, which may be considered to be “molecular fossils”, can be found in close proximity of the anticodon loop of modern tRNA.
Another burning question in the prebiotic science field is the emergence and maintenance of biological homochirality. Modern life, with the complex protein folding and specific interactions, would not be able to maintain its functions if the building blocks were composed of mixed diastereomers. Life requires the molecules of life to be homochiral, with RNA built exclusively out of D-ribose and the proteins out of L-amino acids.
In this work, I address the chicken-and-egg problem, postulating an RNA-peptide world, in which RNA can self-decorate with peptides. I show that the nucleoside-amino acid hybrid structure (m6)aa6A, (analogous to (m6)t6A), can be formed by loading an amino acid onto N6-methylurea adenosine under prebiotically plausible conditions. The modified nucleosides (m6)aa6A and (m)nm5U can be incorporated into RNA, forming strands that can act as a donor and an acceptor, respectively. The complementary oligonucleotides hybridise through hydrogen bonds, which brings the modified nucleosides into close proximity and facilitates peptide bond formation after prior activation of the amino acid. Subsequently, the formed RNA-peptide hairpin strand can be thermally cleaved at the urea moiety, releasing the amino acid-loaded acceptor strand. Upon encounter with another amino acid-carrying donor strand, the cycle can be repeated and the peptide will grow longer. This iterative cycle can be conducted under one-pot conditions, imitating a prebiotic world where the separation of the intermediates was not required. I present results with a range of different amino acid and various activation methods, leading to the formation of up to decapeptides on RNA.
I demonstrate in my thesis that the peptide coupling reaction in RNA, but also in DNA, exhibits high stereoselectivity towards the naturally occurring L-amino acids. I report that the close proximity of the amino acid to RNA has strong influence on the stereoselectivity, which indicates that the D-ribose sugar present in RNA induces the L-homochirality of peptides. This stereochemical preference is based on the kinetic rather than thermodynamic aspects of the reactions, since the rate constants are the highest for the L-L amino acid coupling. The transfer of di- and tri- peptides is also possible with clear preference for homochirality. I also show a temperature-driven one-pot peptide synthesis with clear selectivity to form the homo-L-peptides.
This thesis provides data that suggests a plausible alternative to the RNA world, namely the RNA-peptide world, in which RNA can self-decorate with peptides and these hybrids can then perform a peptide synthesis cycle, selectively transferring L-amino acids. The repetition of this cycle leads to the growth of longer peptides and can be a considered a prototype of a prebiotic, primitive, stereoselective translation mechanism, leading to homochiral peptides
The complexity of treatment failure – prevalence and predictors of dropout and non-response in psychological treatment for traumatized populations
Get PDFThe efficacy of psychological interventions in the treatment of traumatized patients has been widely demonstrated (Martin et al., 2021) and the current evidence shows promising results for specific populations, such as refugees and asylum seekers (e.g., Thompson et al., 2018). However, there is strong evidence that a substantial proportion of patients does not benefit sufficiently from treatment or discontinues treatment prematurely (Schottenbauer et al., 2008; Varker et al., 2021). Treatment failure is a complex construct that can be viewed as an umbrella term encompassing several aspects, such as dropout and non-response (Oasi & Werbart, 2020). The consequences of treatment failure are far-reaching and include negative effects on the patient, the therapist, society, and the healthcare system in general (e.g., Ogrodniczuk et al., 2005; Smith-Apeldoorn et al., 2019; Swift et al., 2012). However, to date there is a significant lack of research on dropout and non-response in the treatment of traumatized patients. In order to gain an in-depth understanding of both aspects, which can later form the basis for deriving preventive measures, it is important to examine the prevalence and identify baseline predictors. Therefore, the overarching aim of this thesis was to fill this gap by providing new evidence on the prevalence and predictors of dropout and non-response in the treatment of traumatized populations. In particular, this thesis covers three publications designed to investigate the prevalence and predictors of dropout in understudied areas, namely the treatment of refugees and treatment of PTSD patients in naturalistic settings. The fourth publication focused on non-response, aiming to investigate its prevalence and predictors in PTSD treatment.
Publication I and Publication II were the first to provide comprehensive evidence on the prevalence and predictors of dropout in the treatment of refugees and asylum seekers. In the absence of previous knowledge, Publication I was designed as a review, synthesizing refugee-specific findings and additionally reviewing existing evidence on treatment dropout in general and applying the findings to the refugee population. Further, we reviewed the current evidence on measures to prevent dropout. The review revealed a significant range of reported dropout rates, varying from 0% to 64.7%. Additionally, the review emphasized the importance of predictors specific to refugees, such as high initial impairment, differing perceptions of mental health, deviating expectations of psychological treatment, and external treatment barriers. To prevent dropout, it is crucial to prioritize the promotion of cultural competencies, cultural adaptation of treatment, and preparation for treatment.
Based on the findings of the review, Publication II aimed to provide the first comprehensive evidence on the prevalence and predictors of dropout in psychological or psychosocial interventions for refugees and asylum seekers. The meta-analytic results of 28 eligible randomized controlled trials (RCTs), with 39 active treatment conditions, and 2,691 participants, revealed a weighted average dropout rate of 19.14%. Dropout was less frequent in the treatment condition compared to the control condition (OR = 0.52). The results revealed no significant predictor of dropout, except the country in which the study was conducted, but showed a potential influence of refugee-specific variables on dropout. Overall, the findings suggest that the dropout rate is comparable to those reported in non-refugee populations. Future research should focus on refugee-specific variables, such as duration of stay in the country of resettlement and asylum status, rather than applying predictors of dropout from Western samples directly to the refugee population.
Publication III examined the dropout rates and predictors of dropout in PTSD treatment in a naturalistic setting. Of the 195 adults diagnosed with PTSD included in the study, 15.38% discontinued trauma-focused cognitive behavioral therapy prematurely, which was provided in three specialized outpatient centers. Dropout rates were higher in younger patients, and lower in patients who lived with their parents compared to living alone. Results showed that the dropout rate found in naturalistic settings was comparable to dropout rates found in RCT studies. Although routinely assessed baseline patient variables were associated with dropout, the results on prediction performance indicate that the overall model, comprising different pretreatment variables, could not predict dropout to a practically useful level.
Publication IV was the first study to provide comprehensive evidence on the prevalence and predictors of non-response to first-line guideline-recommended psychological treatments for PTSD. The meta-analysis employed a methodology similar to Publication II, and meta-analyzed 86 studies, with 117 active treatment conditions, and 7,894 patients. The weighted average non-response rate was 39.23%, and non-response was less frequent in the treatment condition compared to the control condition (OR = 0.22). Higher non-response rates were found to be associated with male gender, older age, and with being a refugee or veteran. Further, higher PTSD symptom severity and the presence of comorbid depressive disorder or higher depressive symptoms was associated with non-response. Treatment type and treatment format were identified as significant treatment-related predictors, with lowest non-response rates in treatments combining prolonged exposure (PE) and cognitive therapy (CT), and in a combination of individual and group therapy. Finally, non-response was significantly higher in studies reporting intention-to-treat (ITT) analysis compared to per-protocol (PP). The findings indicate that treatment modifications should be considered for specific subgroups of PTSD patients characterized by one or more of the identified baseline predictors.
In conclusion, this thesis addresses the lack of research on treatment failure in traumatized populations. The integrated findings of the four publications provide comprehensive knowledge on the prevalence and predictors of dropout and non-response in the treatment of PTSD in general, in specific subpopulations of traumatized patients, and in specific treatment settings. Future research should focus on a wider range of specific predictors and examine underlying mechanisms and process variables beyond pretreatment predictors. In clinical practice, the findings have implications for the derivation of measures to prevent and reduce dropout and non-response in the treatment of traumatized populations
Spectroscopy of spin-valley excitons in two-dimensional semiconductors and heterostructures
Get PDFTransition metal dichalcogenides such as tungsten diselenide (WSe2) and molybdenum diselenide (MoSe2) are two-dimensional semiconductors that exhibit unique optical and electronic properties. In the monolayer limit, they exhibit a direct band gap with optical transitions in the visible to near-infrared spectrum. At the energy minima of the inequivalent K and K' valleys, light-matter interactions couple electrons of the conduction band with empty valence band states. The reduced electrostatic screening due to the two-dimensional nature of the crystal structure leads to the formation of tightly bound excitons. These are energetically degenerate and exhibit valley-index dependent optical selection rules, making them ideal for next generation optoelectronic devices. This thesis focuses on the light-matter interactions in WSe2 mono- and bilayers as well as MoSe2-WSe2 heterobilayers at cryogenic temperatures to add to the understanding of their exciton transitions, phonon interactions and valley polarisation.
The first part of this study investigates the temperature-dependent photoluminescence of WSe2 mono- and bilayer under controlled electrical doping. A pronounced asymmetry in the spectral profile of phonon-assisted luminescence from momentum-indirect exciton reservoirs were observed. In contrast, excitons with direct radiative decay pathways display thermally broadened, symmetric spectral profiles. The photon dispersion relation reduces the number of allowed radiative states due to energy and momentum conservation. This restriction is removed by phonons. The results of this work add to the understanding of phonon-assisted recombination of momentum-dark excitons and, more generally, establish means to access the thermal distribution of finite-momentum excitons in atomically thin semiconductors with indirect bandgaps.
The second part of the thesis explores the spin dynamics of interlayer excitons in MoSe2-WSe2 heterobilayers in spin-triplet configuration. Cryogenic, spectral and time-resolved measurements of the photoluminescence in magnetic field were performed under controlled polarisation. The measured degree of polarisation was decomposed into magnetic and optical contributions and described within a rate equation model. The model includes thermalisation between Zeeman-split reservoirs and dephasing due to long-range Coulomb interactions. Within these minimal assumptions, momentum-indirect interlayer excitons were found as a polarisation-maintaining reservoir. The resulting valley polarisation of interlayer excitons as a function of magnetic field was described for both the steady-state and time-resolved regimes. This work provides an analytical framework applicable to the whole class of interlayer-excitons in heterobilayer systems
Hyperexcitable molecular layer interneurons drive cerebellar circuit dysfunction in spinocerebellar ataxia type I
Get PDFSpinocerebellar ataxia type 1 (Sca1) is an autosomal dominant, neurodegenerative disease, emerging from a CAG repeat expansion mutation in the gene ATXN1. Classical patient symptoms include motor incoordination and abnormal gait, which coincide with the hallmark pathology of atrophy across the cerebellum and brainstem, in particular, degeneration of the cerebellar cortex Purkinje neurons (PN). Given that there are currently no disease modifying treatments for patients, it is imperative to understand the pathogenesis of Sca1. Research has primarily focussed on how the ATXN1 mutation leads to PN dysfunction and ultimately degeneration. However, ATXN1 is ubiquitously expressed, and many cell types other than PNs degenerate, thus are likely also altered in Sca1 (Seidel et al., 2012). Indeed, recent evidence has shown that in the presymptomatic stage of a Sca1 mouse model there is already an increase in synaptic connections from surrounding inhibitory neurons onto PNs (Edamakanti et al., 2018). Despite such findings, early alterations in distinct neuronal populations of the cerebellar cortex, and their interactions as a circuit, are poorly understood. To investigate early cellular and circuit dysfunction in distinct neuronal populations of the cerebellar cortex, I investigated a Sca1 mouse model as symptoms are emerging. Specifically, I utilized in vivo two-photon calcium imaging, simultaneously recording the three primary inhibitory neurons of the cerebellar cortex circuit; PNs, molecular layer interneurons (MLINs) and Golgi cells. In order to unravel alterations in either spontaneous activity or response properties to cerebellum-associated behaviours, we recorded neuronal calcium signals in anesthetised mice and during a range of awake conditions. The most prominent deficits emerged in the MLIN population, which were hyperactive during quiet wakefulness and hyperresponsive to sensorimotor input MLIN dysfunction also appeared to drive a breakdown in the capacity of the cerebellar cortex to encode sensorimotor information. The PN dendrites, which receive extensive input from MLINs, also displayed enhanced calcium signals. To establish the pathophysiological relevance of these findings to Sca1, I used chemogenetic tools to specifically inhibit MLINs. Acute prevention of MLIN hyperactivity in Sca1 mice reduced aberrant PN dendrite calcium signals, restored network encoding, and most importantly, improved motor coordination. Thirty-day chronic inhibition of MLINs induced lasting motor improvements and delayed disease progression. The critical role of hyperactive MLIN in triggering symptoms typical of Sca1, was further corroborated by mimicking the increased MLIN excitability through chemogenetic stimulation of MLINs in healthy mice. Acute stimulation of MLINs disrupted motor function and could drive pathological features in PN dendrites, whilst chronic MLIN stimulation in young healthy mice induced lasting motor impairments and reduction of PN post-synapses reminiscent of Sca1 pathology, detectable over four months after treatment end. These findings together show, for the first time, that aberrant MLIN activity is a clear feature of early Sca1, and can drive neuronal circuit dysfunction. Moreover, our experiments revealed that non-cell autonomous mechanisms are sufficient in driving PN pathology. Crucially, we showed that selectively targeting MLINs in the early stages of the disorder alleviates classical motor symptoms in Sca1 mice, opening up a novel therapeutic avenue
Die Rolle der Eltern bei Schulverweigerung
Get PDFSchulverweigerung stellt ein vielschichtiges Problem dar, das weitreichende Konsequenzen für die Bildungs- und Sozialentwicklung betroffener Kinder und Jugendlicher hat. Während die Ursachen oft in psychischen Belastungen wie Ängstlichkeit und Depression liegen, spielen auch die Eltern eine zentrale Rolle. Ziel der vorliegenden Untersuchung war es, mittels Elterninterviews Motive, Einflussfaktoren und Sinnkonstruktionen der Eltern zu erfassen, die die Erziehungsberechtigten dazu veranlassen, mit legitimierenden Entschuldigungen das Fernbleiben der Kinder von der Schule zu billigen.
Angewandt wurde eine qualitative Forschungsstrategie, die mit semistrukturierten Interviews die Wahrnehmung von 24 Eltern schulverweigernder Kinder und Jugendlicher analysierte. Die Daten wurden mittels qualitativer Inhaltsanalyse ausgewertet, die deduktive und induktive Ansätze kombinierte.
Die Analyse der Daten verdeutlicht, dass sich Schulverweigerung häufig schleichend entwickelt. Betroffene Kinder zeigen bei Schulverweigerung eine Vielzahl an Verhaltensweisen, die Eltern stark belasten. Außerdem sind erzieherische Unsicherheiten, Sorgen und Befürchtungen mit dem elterlichen Verhalten und dem Entschuldigen der Kinder verknüpft, wobei u. a. die Erfahrung eigener Ängste eine Rolle spielt. Zentrale Bedingungsfaktoren für elterliches Entschuldigungsverhalten lassen sich im Bereich elterlichen Belastungserlebens und spezifischer kognitiver Muster finden. Es ist zu vermuten, dass unzureichendes Verständnis für Hintergründe und Dynamik schulverweigernden Verhaltens, (un)begründete Sorgen und Befürchtungen sowie überprotektive Tendenzen der Entwicklung spezifischer Rechtfertigungsstrategien zuträglich sind. Die Covid-19-Pandemie fungierte als zusätzlicher Stressfaktor.
Die Befunde unterstreichen die Notwendigkeit umfassender Interventionen, die Eltern, Schulen und externe Unterstützungssysteme einbeziehen. Frühzeitige Erkennung, koordinierte Zusammenarbeit und Sensibilisierung des Schulpersonals sind essenziell. Schulische Unterstützungsmaßnahmen spielen eine zentrale Rolle, da sie niedrigschwelliger und sozial akzeptierter sind