Evidence for Training-Induced Changes in miRNA Levels in the Skeletal Muscle of Patients With Type 2 Diabetes Mellitus

Durch körperliche Aktivität kann bei PatientInnen mit Diabetes mellitus Typ II (DM Typ II) die glykämische Kontrolle positiv beeinflusst werden. Die dieser Verbesserung zugrunde liegenden molekularen Mechanismen sind jedoch noch nicht vollständig erforscht. MicroRNAs (miRNAs), bekannt als wichtige Regulatoren der Proteinexpression, könnten hier einen neuen Ansatzpunkt darstellen. Einige miRNAs wurden bereits sowohl mit einer reduzierten glykämischen Kontrolle (nachgewiesen bei in vivo und/ oder in vitro Studien) als auch mit einer veränderten Regulation in der Skelettmuskulatur bei DM Typ II PatientInnen in Zusammenhang gebracht. In der nachfolgenden Pilotstudie wurde untersucht, ob durch körperliche Aktivität (dreimonatiges Ausdauertraining, drei Mal pro Woche bei einer Herzfrequenz von 70-80% der maximalen Herzfrequenz) bei männlichen DM Typ II Patienten (n=7) diese muskulären miRNAs eine Veränderung in ihrer Menge erfahren. Den Patienten wurde eine Muskelbiopsie aus dem Musculus vastus lateralis zu drei verschiedenen Zeitpunkten entnommen (T1= sechs Wochen vor Trainingsbeginn; T2= eine Woche vor Trainingsbeginn, T3= drei bis vier Tage nach der Trainingsphase). Mittels Echtzeit-PCR wurden die Level von miRNA-27a-3p, -29a-3p, -29b-3p, -29c-3p, -106b-5p, -135a-5p, -143-3p, -144-3p, -194-5p und -206 analysiert. Nach statistischer Analyse durch Friedman Test mit Post-hoc-Tests zeigten die Ergebnisse, dass die Level von miRNA-29b-3p, -29c-3p und -135a-5p nach dem Training signifikant reduziert waren (T3 gegenüber T2 und/ oder T1). Beim glykierten Hämoglobin (HbA1c) sowie dem HOMA Index kam es zu keinen signifikanten Veränderungen, jedoch zeigte sich nach dem Training eine Reduktion des HbA1c Wertes bei sechs von sieben Patienten. Der Rangkorrelationskoeffizient nach Spearman zeigte signifikante negative Korrelationen zwischen den Leveln von miRNA-29c-3p, -106b-5p, -144-3p und -194-5p und der kardiorespiratorischen Fitness (VO2peak). Die Ergebnisse implizieren, dass körperliche Aktivität einen Effekt auf die Regulation der miRNAs im Skelettmuskel bei DM Typ II Patienten haben kann. Inwiefern hierdurch auch eine tatsächliche Veränderung der klinischen Situation bei DM Typ II Patienten erzielt werden kann, erfordert weitere Forschung

Disordered System Approaches to the Yang-Mills Vacuum

Two novel dual descriptions of d = 4 U(Nc) Yang-Mills theory (YM) are constructed and studied in this dissertation. We consider a network theory inspired by Budczies-Zirnbauer model (BZ), which will be abbreviated as BZN, and a continuum field theory, Dirac-Yang- Mills model (DYM). In either BZN or DYM, the dual theory is obtained by integrating out the original gluon degrees of freedom, which leads to a strongly-disordered system of some auxiliary matter fields. We examine the possibilities of applying a modern method, superbosonization (SuB) formula for disordered systems, in the investigation of the dual theories. In the first project, we reformulate BZN using Gaussian integral representation, and derive a master action for gluons and auxiliary matter fields, both of which live on the links of a lattice. The dual description, dual-BZN, is derived using Cayley parametrisation and a gauge-averaging trick, and the resulting dual action is a large−Nc series of color-neutral composite operators. However, using SuB for a direct replacement of these operators by some supermatrix-valued fields is not possible due to the rank-deficiency in the boson-boson sector of the supermatrix. The rank-deficiency is a result of the universality condition Nf ≥ Nc, which is necessary for BZN to flow to YM in its continuum-limit. In the second project, we study both sides of DYM: the induced Yang-Mills (IYM) and its dual (dual-IYM). The theory of dual-IYM describes a system of massive Dirac bosons and Dirac fermions constrained by a zero-current condition (ZC). A beautiful connection between gluon condensates in IYM and matter condensates in dual-IYM inspires a low-energy effective theory (dual-EFT). We discover the relevant dual symmetry groups and assemble a Lagrangian for dual-EFT in analogy with the chiral perturbation theory. Furthermore, we explore the ZC solution space and find out dual-IYM contains all Lorentz-types components, which suggests an energy- hierarchy scheme where dual-EFT is included as the low-energy sector of dual-IYM. Dual-IYM is color gauge-invariant. However, Witten’s bosonization method leads to a divergent effective action for the external field, and hence it is difficult to derive an action for some color-neutral dual-field. An attempt to directly transform the composite super-meson to the dual-field by SuB also fails because of rank-deficiency. In the absence of successful color-neutralisation, we proceed to explore some physical aspects of dual-BZN and dual-IYM. For dual-BZN, the masses and interaction strength of the composite operators are identified. We briefly examine the dual symmetry group and the saddle-point solutions, and point out a challenge to a semi-classical approximation due to the universality condition. For dual-IYM, we present two possible applications for YM mass gap and quark confinement. Furthermore, we explain a possibility of a large−Nc analysis, which might lead to a description of dual-IYM as a gravitational theory and/or a nonlinear sigma model

Transcriptional Regulation and Single Cell Damage Score in Podocytes

It is estimated that around 10% of the global population is affected by chronic kidney disease (CKD), placing a significant burden on healthcare systems worldwide (Francis et al. 2024). Among the causes of CKD, 90% are attributed to glomerular diseases, in which podocytes are damaged and lost (Wiggins 2007). Podocytes are terminally differentiated visceral epithelial cells, which play a crucial role in establishing the selective permeability in the glomerulus. Recent large-scale transcriptomic approaches in mice and humans have demonstrated that alterations in the glomerular transcriptional program are a pivotal feature of numerous diseases affecting podocytes. In this thesis, I investigate the transcriptional regulation of healthy and damaged podocytes through multiple approaches. First, I analyzed novel bulk RNA sequencing data from glomeruli to characterize transcriptional changes resulting from perturbation of the Wt1 transcription factor, a critical regulator of podocyte biology. I then leveraged novel ChIP-seq data to explore how podocyte damage rewires the transcriptional network, focusing on interactions regulated by Wt1 and co-regulated by Tead1. Second, using single-nucleus RNA sequencing (snRNA-seq), I distinguished podocyte-specific transcriptional changes from shifts in cellular composition induced by podocyte injury. Third, I developed a universal metric of podocyte health, termed the podocyte damage score (PDS), using transcriptomic data from published sources. Applying the PDS to single-cell RNA sequencing datasets from various podocyte damage models allowed us to identify both universal and model-specific features of the transcriptional response to injury. Additionally, by integrating these findings with a podocyte transcriptional regulatory network (TRN) constructed from podocyte-specific ATAC-seq data and transcription factor motifs, I characterized the transcriptional regulators involved in podocyte transcriptome rewiring under damage conditions. In conclusion, this research advances our understanding of gene regulation in healthy and damaged podocytes and establishes methodologies for studying cell-specific mechanisms of disease at the single-cell level. It is my hope that these findings will contribute to the development of new therapeutic strategies for CKD

Bedeutung des Monitorings audiologischer, kind- sowie umweltbezogener Einflussfaktoren für die Entwicklung von Kindern nach Versorgung mit Cochlea-Implantat

Integraler Bestandteil der kindlichen Versorgung mit Cochlea Implantat (CI) ist eine multidisziplinäre familienzentrierte Intervention im Rahmen einer CI-Folgetherapie. Gegenstand der vorliegenden Arbeit ist das Monitoring unterschiedlicher Faktoren, die erwiesenermaßen die Entwicklung von CI-versorgten Kindern beeinflussen. Es konnte gezeigt werden, dass der LittlEARS® Hörfragebogen (LEAQ) zur Beurteilung der präverbalen Entwicklung früh bilateral CI-versorgter Kinder sehr gut geeignet ist. Dabei sollte bei früher CI-Versorgung das Lebensalter als Bezugsmaß in der Diagnostik herangezogen werden. Kinder mit schweren zusätzlichen Behinderungen und CI (CAD) weisen Unterschiede in der technischen Versorgung im Vergleich zu Kindern mit CI ohne zusätzliche schwere Behinderungen (CnonAD) auf. Es ist von hoher Bedeutung, die tägliche CI-Tragedauer der CAD zu optimieren, um auch die T- und MC-Level als Basis für eine erfolgreiche Hör- und Kommunikationsentwicklung individuell bestmöglich einzustellen. Sowohl objektive als auch subjektive Verfahren haben in dem CI-Anpassprozess ihre Berechtigung und sollten standardmäßig zum Einsatz kommen. Eine Einschätzung der elterlichen kindgerichteten Sprache (KGS) mittels der an die Bedürfnisse CI-versorgter Kinder adaptierten EKIE-hör ist möglich ist und kann als Grundlage für eine Elternberatung zur Optimierung der Eltern-Kind-Interaktion dienen. Aufgrund der Zeitökonomie lässt sich das Verfahren gut in den klinischen Alltag integrieren. Insbesondere im Hinblick auf eine individuell bestmögliche Chance auf gelingende Teilhabe ist das frühe Monitoring von diversen Einflussfaktoren sinnvoll und anhand diverser Methoden umsetzbar. Die Ergebnisse dieser Studien sollen therapeutisch/pädagogischen sowie audiologischen Fachkräften mehr Sicherheit in der Versorgung der vulnerablen Gruppe sehr junger Kinder mit CI - mit und ohne zusätzliche schwere Behinderungen - geben und dadurch den CI-Versorgungsprozess optimieren. Des Weiteren können die Ergebnisse herangezogen werden, um die individuellen Interventionsprogramme auf Basis der Internationalen Klassifikation der Funktionsfähigkeit, Behinderung und Gesundheit bei Kindern und Jugendlichen (ICF-CY) zu evaluieren und bei Bedarf möglichst frühzeitig anzupassen

Interdisziplinäre Zusammenarbeit zur Verbesserung der Versorgung junger Menschen in psychischen Krisen. Eine Evaluation der Inanspruchnahme des niedrigschwelligen Kontakt- und Beratungsangebots soulspace in Berlin-Kreuzberg

Eine Vielzahl psychischer Erkrankungen manifestiert sich im Jugend- oder jungen Erwachsenenalter. Doch gerade diese Altersgruppe weist besonders geringe Inanspruchnahme- und Behandlungszahlen auf. Zudem sind therapeutische Interventionen in diesem Alter von starker Diskontinuität geprägt. Dazu tragen u.a. die eher unstete, teils durch Instabilität gekennzeichnete Lebensphase der Adoleszenz sowie die defizitäre Versorgungslage alters- und zielgruppenspezifischer Angebote bei. Angesichts langfristiger und gravierender persönlicher sowie gesamtgesellschaftlicher Folgen einer verzögerten Behandlung psychischer Krisen und Erkrankungen besteht demnach Handlungsbedarf. Vor diesem Hintergrund wurde 2018 das multidisziplinär geführte Früherkennungs- und Interventionszentrum soulspace in Berlin-Kreuzberg gegründet. In einer Kooperation bestehend aus der lokalen Kontakt- und Beratungsstelle transit und dem Vivantes Klinikum Am Urban (KAU) arbeiten im soulspace Psycholog*innen, Sozialarbeiter*innen und Fachärzt*innen unter einem Dach. Im Sinne der Niedrigschwelligkeit und zugunsten der Entstigmatisierung erfolgte die Verortung bewusst abseits des Klinikgeländes in einem neutralen Gebäude ohne „Krankenhaus-Charakter“. Für eine erste Evaluation der Inanspruchnahme wurden in zwei Angeboten des soulspace (transit, FIT) die dortigen Erstkontakte analysiert. Ziel der Untersuchung war die Auswertung soziodemografischer und erkrankungsbezogener Daten der Klient*innen beider Angebote sowie von Daten zu dem Erstkontakt folgenden Prozedere. Die Ergebnisse dieser Evaluation wurden in der vorliegenden Arbeit deskriptiv analysiert und angebotsspezifisch miteinander verglichen. Im Untersuchungszeitraum (transit: Juni 2018 – Dezember 2021; FIT: Januar 2016 – Dezember 2021) nutzten 899 Personen den transit-Erstkontakt (MAlter = 24,74 ± 5,06) und 592 Personen die FIT-Sprechstunde (MAlter = 23,51 ± 4,79). Nach dem Erstkontakt wurden vor allem weiterführende interne Angebote häufig genutzt, was auf eine erfolgreiche Annahme des Angebots hindeutet. Im transit-Erstkontakt vorstellige Klient*innen waren mehrheitlich nicht vorbehandelt (53,5 %; n = 347). Dem gegenüber steht, dass die deutliche Mehrheit der Klient*innen der FIT-Sprechstunde zu einem früheren Zeitpunkt bereits Versorgungsangebote genutzt hatten (85,4 %; n = 437) und überwiegend zur Diagnostik in die FIT-Sprechstunde vermittelt wurde (92 %; n = 183). Durch seine gute Zugänglichkeit konnte der transit-Erstkontakt den niedrigschwelligen Charakter des soulspace somit stärken und fungierte dabei wie intendiert als Bindeglied in der Versorgungsstruktur. Neben einem hohen Anteil bereits manifester Diagnosen konnte in der FIT-Sprechstunde bei 110 Personen (71,4 %) eine Hochrisikokonstellation festgestellt werden. Somit wurde die angestrebte Zielgruppe mehrheitlich erreicht. Um bereits erreichte Erfolge in der Versorgung synergistisch zu nutzen, sind weitere Kooperationen mit bereits bestehenden Angeboten anzustreben. Grundsätzlich sollte der Aufbau weiterer Früherkennungszentren und niedrigschwelliger Präventionsangebote mit Nachdruck vorangetrieben werden

Individualizing Management Practices

Firm performance relies heavily on employee motivation, yet individuals differ significantly in what motivates them. A substantial body of literature in economics, management, and management accounting explores the impact of management practices on firm performance and employee outcomes, revealing heterogeneity in employee responses based on characteristics such as gender, social preferences, and personality. This dissertation examines two approaches to individualizing management practices: (1) a centralized approach, using AI for tailored assignments, and (2) a decentralized approach, leveraging managerial discretion. Empirical evidence is drawn from proprietary firm data, surveys, field experiments, and online experiments. Chapter 1 explores the centralized approach, applying machine learning to assign incentives based on worker characteristics. Experiments with gig workers reveal that targeted assignments improve performance compared to assigning a single best incentive scheme. The findings underline the importance of reliably measuring worker characteristics for ensuring algorithmic assignment quality. Chapter 2 studies a decentralized approach in a spot bonus system where managers decide bonus timing. Analyses show that managers award a large portion of bonuses at year-end, reflecting a need for better information on performance. However, timely bonuses are associated with higher employee recognition, suggesting that managers face a trade-off. Chapter 3 examines non-monetary practices, testing how highlighting flexibility in job ads affects applications. A field experiment with 176 job ads shows that emphasizing remote work or flexible work hours increases the number of applications, with the improvement partly varying by job characteristics. Overall, the dissertation demonstrates the advantages and challenges of centralized and decentralized approaches, offering insights for academics and practitioners

Investigation of current and future anthropogenic chemical regimes in simulation chamber experiments

Air pollution is a societal challenge, affecting millions of people world-wide living in urban conglomerates. In cities, emissions are mostly from anthropogenic activities such as traffic, industry, cooking, and use of volatile care products. These emissions are not only hazardous for human health, they also undergo chemical degradation driven by oxidants, forming secondary pollutants such as ozone (O3) and particles. Main tropospheric oxidants are the hydroxyl radical (OH), dominating oxidation processes during the day, the nitrate radical (NO3), predominantly available during the night, and ozone. In the reaction chain of the atmospheric oxidation of volatile organic compounds (VOCs), peroxy (RO2) and hydroperoxy (HO2) radicals are formed, which oxidise nitric oxide (NO) to nitrogen dioxide (NO2), the latter being the main tropospheric source of ozone following its photolysis. Understanding atmospheric oxidation processes is crucial for mitigating air pollution and tackling current and future air quality challenges. In many different field studies, performed in or close to urban areas, measured HO2 and/or RO2 radical concentrations could not be reproduced by chemical model calculations, which represent the current understanding of the atmospheric chemistry. Even though chemical models carry uncertainties, the observed discrepancies in particular for RO2 radicals often exceeded a factor of three, making air quality prediction challenging. Data collected during field campaigns are very valuable in highlighting where our gap of knowledge for atmospheric chemical processes lies. Laboratory studies and experiments in atmospheric simulation chambers can then focus on investigating such processes in a confined and controlled environment. In this thesis, first the performance and comparability of several different atmospheric simulation chambers were studied. Oxidation experiments of alpha-pinene were performed in nine different simulation chambers, which are part of the EUROCHAMP-2020 consortium. Chamber effects, such as the release of small oxygenated compounds from the chamber wall or the loss of trace gases or particles on the chamber wall were characterised. Furthermore, yields of pinonaldehyde, formaldehyde, and acetone, which are products from the oxidation of alpha-pinene by OH, could be derived for experiments in five different chambers. A high variability of the yields of pinonaldehyde and formaldehyde was observed, which is also reflected in the available data from the literature. In contrast, obtained acetone yields agree within the combined uncertainties for the different chambers and within the uncertainties with reported literature values. Overall, well-characterised simulation chambers offer a great opportunity to investigate atmospheric chemistry in a controlled environment. The goal is to simplify the complexity of field studies while still keeping the conditions comparable to the real atmosphere. The main part of the thesis is on the investigation of the daytime and nighttime oxidation of anthropogenic VOCs in the atmospheric simulation chamber SAPHIR at Forschungszentrum Jülich, Germany. Measured trace gas and radical concentrations were compared to zero-dimensional box model calculations, based on the Master Chemical Mechanism (MCM) and complemented by an updated ozonolysis scheme for alkenes, and by state-of-the-art peroxy and alkoxy chemistry from structure-activity relationships (SAR). Photooxidation experiments were performed for a variety of anthropogenic VOCs at different levels of NO, mimicking current (high NO) and future (low NO) chemical regimes. The VOCs investigated were chosen according to their alkoxy chemistry, forming HO2 either in a single-step reaction (propane, propene, trans-2-hexene) or in a multi-step reaction involving the regeneration of RO2 (iso-pentane, n-hexane), which results in a different number of ozone molecules produced per oxidised VOC molecule. A comparison between measured trace gases and radicals with results from the MCM showed overall a good agreement (within 17 %) for most VOCs. An improved agreement of HO2 and RO2 radical concentrations, in experiments with n-hexane, was found for the MCM complemented by SAR, assuming a factor of ~ 1.4 higher organic nitrate yields for first-generation RO2 and RO2 isomerisation reactions. HO2/RO2 ratios were derived from measured and modelled radical concentrations, showing a 20 % smaller ratio for the VOCs forming HO2 in a multi-step reaction compared to VOCs forming HO2 in a single-step reaction. The production of odd oxygen (Ox = O3 + NO2) was calculated from modelled radical concentrations and from measured Ox for 3 < NO < 6 ppbv and for NO < 1 ppbv, where the Ox formation could additionally be determined from measured radical concentrations. Overall, a good agreement was found for the different approaches. In agreement with the observations of the HO2/RO2 ratio, a 20 % higher Ox production was observed for species, regenerating another RO2 radical before eventually forming HO2. Overall, the model-measurement discrepancies of the Ox production rates, as found in urban areas, were not observed in the performed chamber experiments. The nighttime oxidation of cis-2-butene and trans-2-hexene was tested in the presence of NO2 at different temperatures (from 3 °C to 32 °C). At low temperatures, time profiles of measured RO2 radical concentrations were significantly delayed and lower peak concentrations were reached than observed in the modelled RO2 radical time series. The model-measurement agreement could be significantly improved by including the formation of non-acyl peroxynitrates (RO2NO2) from the reaction of RO2 with NO2 in the chemical model for all formed non-acyl peroxy radicals. The formation of non-acyl RO2NO2, with the exception of methyl peroxynitrate, is not implemented in commonly used chemical mechanisms, such as the MCM, as it is thought to be negligible due to the short lifetime of alkyl (non-acyl) RO2NO2 of less than 1 s at 298 K. This study suggests that at 10 °C, 60 % of RO2 radicals are stored as corresponding peroxynitrates in the presence of only few ppbv of NO2, which may impact ambient RO2 and NOx (= NO + NO2) concentrations. In addition, a recent model study found an increase of NOx of up to 25 % on the ground, when including the formation of non-acyl RO2NO2. This suggests that these reactions should be included in chemical mechanisms for a better representation of the underlying chemistry

Importance of dendritic cells in pathogenesis and therapy of conjunctival melanoma

Conjunctival melanoma is a very rare malignant tumor, which occurs in less than 5 % of ocular melanomas. Because of the high recurrence rate of CM, current therapy options are insufficient and, for advanced CM, no standardized therapy is available. The immunological principles, especially the composition of dendritic cell subsets and their functions, are almost completely unknown in CM. DCs are antigen-presenting cells and link the innate and the adaptive immune system. In this dissertation, we investigated the immune cell composition in the physiological conjunctiva, CM and in the draining lymph nodes, the lymph- and hemangiogenic profile and the effect of local injection of non-activated classical DCs on survival, metastases and tumor progression in vivo in immunocompetent C57BL/6N mice using a HGF-Cdk4R24C CM model. DCs can be subclassified into cDC₁, cDC₂, plasmacytoid and monocyte derived DCs. Subclassification showed that CD103- cDC₂ are the most common DC subset in healthy conjunctiva and that CD103- cDC₂, CD103+ cDC₁, moDCs and pDCs are significantly increased in CM. A local injection of non-activated cDC₂ showed neither positive nor negative effects. Furthermore, the angiogenic factors expressed by cDCs and tumor cells were verified in vitro and identified Osteopontin as the most relevant cytokine expressed by the tumor cells, which actually interacts with DCs. We evaluated a combined therapy strategy for CM by subconjunctival OPN blockade and activated cDC vaccination. The combined therapy slowed down tumor progression and inhibited tumor growth completely in 35 % of cases. To better understand the mode of action of the OPN blockade, tumor cells and cDCs, the effect on blood- and lymphatic endothelial cells was studied in co-culture with the supernatant of DCs and tumor cells in combination with an OPN blocking antibody or additional OPN protein in vitro. The results of this thesis will help to get a better understanding of the immunological principles in the development of CM and the influence of the tumor microenvironment on the activity of DCs and on blood- and lymhangiogenesis