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Einfluss eines Erste-Hilfe-Kurses für Medizinstudierende auf notfallmedizinische Basiskompetenzen
(2021)
Medizinstudierende sind bereits in der Vorklinik häufig mit Situationen konfrontiert, in denen medizinische Notfälle passieren, die unter anderem wegen der Lage des Universitätscampus und den damit verbundenen Kontakt zu Patientinnen und Patienten oder in den Pflegepraktika. Tritt in diesen Situationen ein medizinischer Notfall ein, müssen sie Erste Hilfe leisten können. Das Ziel der vorliegenden Arbeit ist daher die Erfassung notfallmedizinischer Basiskompetenzen von Medizinstudierenden der Vorklinik und die Frage, ob diese ausreichend sind, um den Anforderungen ihres Umfeldes gerecht zu werden. Des Weiteren wurde ein Erste-Hilfe-Kurs speziell für Vorklinikstudierende basierend auf dem ABCDE-Schema konzipiert, implementiert und evaluiert, ob die erfassten Kompetenzdefizite behoben werden konnten.
In einem Pre-Post-Design wurde die theoretische Kompetenz anhand eines 10 Items Multiple-Choice-Tests und die praktischen Kompetenzen anhand von 3 OSCE-/OSPE-Stationen (je 5 min) erfasst. Sowohl der MC-Test als auch die OSCE-/OSPE-Stationen wurden in Probeläufen getestet und überarbeitet. Soziodemographische Daten wurden mittels Fragebogen erhoben. Der entwickelte Kurs umfasst 9 UE (davon 6 UE praktische Übungen) in denen die zu erlernenden Erste-Hilfe-Maßnahmen strukturiert und in logischer Reihenfolge anhand des etablierten ABCDE-Schemas vermittelt werden. Jeweils 8 Teilnehmende werden von zwei geschulten Peer-Dozierenden unterrichtet. Im Anschluss an das Training erfolgte eine erneute Erhebung der theoretischen und praktischen Kompetenzen. Die Eingabe der Rohdaten erfolgte in Microsoft Excel (Microsoft Inc., Redmond, WA, USA). Die weitere Auswertung erfolgte mittels SPSS (SPSS Inc., Chicago, IL, USA).
160 Studierende aus den ersten beiden Studienjahren konnten in die Studie eingeschlossen werden. Im Basis-Assessment demonstrierten nur 25% der Studierenden zwei Minuten lang eine suffiziente Kompression mit richtiger Frequenz und Drucktiefe, nur 29% überstreckten am Ende der Seitenlage den Kopf des Patienten und öffneten den Mund. Im Anschluss an das Training erzielten die Studierenden an allen OSCE/OSPE-Stationen signifikant bessere Ergebnisse: Bei der stabilen Seitenlage steigerten sie sich durchschnittlich um 5,3 Punkte (max. 14), bei der Reanimation um 6,8 Punkte (max. 18). Während sich vor dem Kurs 33% der Studierenden in der Lage fühlten, Wiederbelebungsmaßnahmen durchzuführen, waren dies nach dem Kurs 98%. Die Kursevaluation war durchweg positiv.
Die Erfassung notfallmedizinischer Basiskompetenzen von Medizinstudierenden der Vorklinik zeigte, dass diese nicht ausreichend geschult sind, um Notfallsituationen adäquat zu bewältigen. Vor diesem Hintergrund muss eine dem Anforderungsprofil entsprechende Ausbildung in Erster Hilfe bereits in der Vorklinik an der Universität gewährleistet werden. Die vorliegenden Ergebnisse zeigen, dass mithilfe eines speziell auf Medizinstudierende ausgerichteten Erste-Hilfe-Kurs eine deutliche Steigerung notfallmedizinischer Basiskompetenzen erfolgen kann.
This thesis explores the phase diagrams of the Nambu--Jona-Lasinio (NJL) and quark-meson (QM) model in the mean-field approximation and beyond. The focus lies in the investigation of the interplay between inhomogeneous chiral condensates and two-flavor color superconductivity.
In the first part of this thesis, we study the NJL model with 2SC diquarks in the mean-field approximation and determine the dispersion relations for quasiparticle excitations for generic spatial modulations of the chiral condensate in the presence of a homogeneous 2SC-diquark condensate, provided that the dispersion relations in the absence of color superconductivity are known. We then compare two different Ansätze for the chiral order parameter, the chiral density wave (CDW) and the real-kink crystal (RKC). For both Ansätze we find for specific diquark couplings a so-called coexistence phase where both the inhomogeneous chiral condensate and the diquark condensate coexist. Increasing the diquark coupling disfavors the coexistence phase in favor of a pure diquark phase.
On the other hand, decreasing the diquark coupling favors the inhomogeneous phase over the coexistence phase.
In the second part of this thesis the functional renormalization group is employed to study the phase diagram of the quark-meson-diquark model. We observe that the region of the phase diagram found in previous studies, where the entropy density takes on unphysical negative values, vanishes when including diquark degrees of freedom. Furthermore, we perform a stability analysis of the homogeneous phase and compare the results with those of previous studies. We find that an increasing diquark coupling leads to a smaller region of instability as the 2SC phase extends to a smaller chemical potential. We also find a region where simultaneously an instability occurs and a non-vanishing diquark condensate forms, which is an indication of the existence of a coexistence phase in accordance with the results of the first part of this work.
Bohmian mechanics as formulated originally in 1952, has been useful in the implementation of numerical methods applied to quantum mechanics. The scientific community though has had ever since a critical thought about it. Therefore, there are still points to be clarified and rectified. The two main problems are basically: Bohmian mechanics gives a privilege role to the position representation. Secondly, the current interpretation of Bohmian trajectories has been recently proven wrong.
In this context, in Chapter 2, new complex Bohmian quantities are defined; so that they allow the capacity to formulate Bohmian mechanics in any arbitrary continuous representation, for instance, the momentum representation. This Chapter is fully based on two articles, regarding the proposed complex Bohmian formulation and its extension into momentum space.
Chapter 3 deals with a redefinition and reinterpretation of the Bohmian trajectories from the handling of the continuity equation, this is done without any need of additional postulates or interpretations. Also, it is proved that Bohmian mechanics is actually more than a projective aspect of the Wigner function.
As a third point, Chapter 4 presents a sytematic treatment of the hydrodynamic scheme of Bohmian mechanics. Then, a brief summary of the transport equations in Bohmian mechanics is done. Next, a unified hydrodynamic treatment is found for the Bohmian mechanics. This treatment is useful to sketch, a Bohmian treatment to efficiently find the steady value of the transmission integral.
In Chapter 5 conclusions of this thesis are drawn.
Endolysosomal effectors and their relevance for antiviral activity against the Hepatitis E virus
(2021)
Mit über 20 Millionen registrierter Fälle pro Jahr, repräsentiert das Hepatitis-E-Virus (HEV) eine Hauptursache einer viralen Hepatitis weltweit und stellt ein erhebliches Risiko insbesondere für Schwangere und Immunsupprimierte dar. Jedoch sind Behandlungsoptionen stark limitiert und mit teils schweren Nebenwirkungen verbunden. Neue Erkenntnisse des Wechselspiels zwischen Wirtszelle und HEV werden deshalb benötigt, um neue antivirale Wirkstoffe zu entwickeln. Der Fokus der Arbeit wurde hierbei auf Effektoren des endosomalen Systems gesetzt, welches von HEV zur Freisetzung von Virionen genutzt wird.
Eine virale Infektion führt in der Zelle zur Produktion von Interferonen (IFNs) und weiters zu einer IFN-Antwort. Ein essenzielles Effektormolekül, welches HEV nachweislich effizient repressiert, ist die GTPase guanylate binding protein 1 (GBP1). In dieser Studie wurde beleuchtet, dass Letztere durch eine HEV-Infektion induziert wird. Zusätzlich reduziert die ektopische Expression von GBP1 sowohl die intrazelluläre Menge des HEV Kapsidproteins als auch die Menge freigesetzter Virionen. Mechanistisch liegt diesem Sachverhalt die GBP1-induzierte Inkorporation von Virionen in Lysosomen zugrunde, was schlussendlich deren Abbau nach sich zieht. Erkenntnisse über die Rolle verschiedener GBP1 Proteindomänen innerhalb des Mechanismus wurden unter Verwendung ektopischer Expression von GBP1-Mutanten erlangt. Inkorporation der Mutation R48A führt zum Verlust der GTPase-Aktivität. Andererseits führt eine Inkorporation der Mutation S73A zum Verlust der Homodimerisierung, was die nachfolgende Farnesylierung und gekoppelte Membranassoziation reduziert. Hierbei behält GBP1-R48A Fähigkeiten zur Induktion lysosomalen Abbaus von HEV bei, GBP1-S73A jedoch nicht. Dies wiederum bedeutet, dass eine GBP1 Homodimerisierung notwendig für den antiviralen Mechanismus ist, was eine Adapterfunktion des Moleküls für lysosomale Inkorporation nahelegt. Die Relevanz von GBP1 während einer IFNγ-Antwort wurde deshalb mittels siRNA-basiertem Silencing untersucht. Ähnlich der ektopischen Expression von GBP1 induziert IFNγ die lysosomale Degradation von HEV. In Abwesenheit von GBP1 jedoch, ist dieser Effekt signifikant geringer ausgeprägt, was zu einem Effizienzverlust von IFNy in Bezug auf dessen antiviralen Effekt bedeutet. Dies führte schlussendlich zur Identifizierung von GBP1 als essenziellen Restriktionsfaktor gegen HEV, was seine Rolle in Abhängigkeit seiner Homodimerisierung via Induktion lysosomalen Abbaus erfüllt.
Nebst der Induktion von GBP1, konnte eine Akkumulation von Cholesterin in Lysosomen durch IFNy nachgewiesen werden. Da dieses Lipid einen essenziellen Faktor für endosomale Reifung, Transport und Funktionalität darstellt, wurden Cholesterinspiegel und verbundene transkriptionelle Fußabdrücke im Kontext einer HEV Infektion untersucht. Letztere führt zu einer Dysregulation Cholesterin-assoziierter Genexpression, was eine Reduktion intrazellulären Cholesterins nach sich zieht. Auch in HEV infizierten Patienten liegt eine Abnahme des Serumcholesterins vor. Unter Modulation intrazellulären Cholesterins, wurde deutlich, dass die Inhibition der Cholesterinsynthese durch Simvastatin eine verstärkte Freisetzung von Virionen nach sich zieht, was ebenso in HEV infizierten Patienten nachweisbar war. Im Gegensatz hierzu zieht eine Erhöhung intrazellulären Cholesterins via Supplementierung von Lipoproteinpartikeln niedriger Dichte (LDL) oder 25-Hydroxycholesterin eine signifikante Reduktion des viralen Kapsidproteins und freigesetzter Virionen nach sich. Dem liegt eine verstärkte Inkorporation von HEV in Lysosomen mit anschließender Degradation zugrunde. Ob dieser Mechanismus pharmakologisch nutzbar ist, wurde mittels eines Screenings Lipid modulatorischer Medikamente untersucht. Der p-Glykoprotein Inhibitor PSC833 und besonders der PPARα-Agonist Fenofibrat stellten sich als äußerst effiziente Inhibitoren des HEV heraus. Beide führen zu einer Erhöhung und Akkumulation zellulären Cholesterins in vesikulären Strukturen. Dies zieht eine dramatische Erhöhung lysosomaler Lokalisation von HEV nach sich und führt letzten Endes zu einer signifikanten Reduktion freigesetzter Virionen.
Zusammenfassend konnten in dieser Studie essenzielle Funktionen von GBP1 in Bezug auf dessen restriktiven Effekt gegen HEV identifiziert werden. Weiters wurde dieses als entscheidender Wirtsfaktor für die IFNγ-Antwort gegen das Virus identifiziert. Andererseits legt diese Studie nahe, dass HEV niedrige Cholesterinspiegel innerhalb infizierter Zellen für die Freisetzung von Virionen benötigt. Andererseits sind erhöhte intrazelluläre Cholesterinspiegel schädlich für die virale Freisetzung, da der lysosomale Abbau von Virionen induziert wird. Dies führte zur erfolgreichen Entdeckung eines neuartigen antiviralen Wirkstoffes, welcher diesen cholesterinabhängigen Effekt effizient induziert: Fenofibrat.
Deep learning with neural networks seems to have largely replaced traditional design of computer vision systems. Automated methods to learn a plethora of parameters are now used in favor of previously practiced selection of explicit mathematical operators for a specific task. The entailed promise is that practitioners no longer need to take care of every individual step, but rather focus on gathering big amounts of data for neural network training. As a consequence, both a shift in mindset towards a focus on big datasets, as well as a wave of conceivable applications based exclusively on deep learning can be observed.
This PhD dissertation aims to uncover some of the only implicitly mentioned or overlooked deep learning aspects, highlight unmentioned assumptions, and finally introduce methods to address respective immediate weaknesses. In the author’s humble opinion, these prevalent shortcomings can be tied to the fact that the involved steps in the machine learning workflow are frequently decoupled. Success is predominantly measured based on accuracy measures designed for evaluation with static benchmark test sets. Individual machine learning workflow components are assessed in isolation with respect to available data, choice of neural network architecture, and a particular learning algorithm, rather than viewing the machine learning system as a whole in context of a particular application. Correspondingly, in this dissertation, three key challenges have been identified: 1. Choice and flexibility of a neural network architecture. 2. Identification and rejection of unseen unknown data to avoid false predictions. 3. Continual learning without forgetting of already learned information. These latter challenges have already been crucial topics in older literature, alas, seem to require a renaissance in modern deep learning literature. Initially, it may appear that they pose independent research questions, however, the thesis posits that the aspects are intertwined and require a joint perspective in machine learning based systems. In summary, the essential question is thus how to pick a suitable neural network architecture for a specific task, how to recognize which data inputs belong to this context, which ones originate from potential other tasks, and ultimately how to continuously include such identified novel data in neural network training over time without overwriting existing knowledge.
Thus, the central emphasis of this dissertation is to build on top of existing deep learning strengths, yet also acknowledge mentioned weaknesses, in an effort to establish a deeper understanding of interdependencies and synergies towards the development of unified solution mechanisms. For this purpose, the main portion of the thesis is in cumulative form. The respective publications can be grouped according to the three challenges outlined above. Correspondingly, chapter 1 is focused on choice and extendability of neural network architectures, analyzed in context of popular image classification tasks. An algorithm to automatically determine neural network layer width is introduced and is first contrasted with static architectures found in the literature. The importance of neural architecture design is then further showcased on a real-world application of defect detection in concrete bridges. Chapter 2 is comprised of the complementary ensuing questions of how to identify unknown concepts and subsequently incorporate them into continual learning. A joint central mechanism to distinguish unseen concepts from what is known in classification tasks, while enabling consecutive training without forgetting or revisiting older classes, is proposed. Once more, the role of the chosen neural network architecture is quantitatively reassessed. Finally, chapter 3 culminates in an overarching view, where developed parts are connected. Here, an extensive survey further serves the purpose to embed the gained insights in the broader literature landscape and emphasizes the importance of a common frame of thought. The ultimately presented approach thus reflects the overall thesis’ contribution to advance neural network based machine learning towards a unified solution that ties together choice of neural architecture with the ability to learn continually and the capability to automatically separate known from unknown data.
The project investigates how economic paradigm shifts that occur at the beginning of the 1970s (primarily the abandonment of the gold standard and the endlessly increasing pool of capital awaiting investment that succeeded it) led to the emergence of a unique building type: the high-altitude observation deck. Part investment vehicle, part iteration of an ongoing fascination with the view from above, the project presents the observation deck as the point where three distinct paradigms intersect: observation, speculation and spectacle. Tracing the emergence of the observation deck through a series of case studies (Top of the World atop the World Trade Center (NYC), One World Observatory (NYC), The Tulip (London) the project enriches its interdisciplinary approach with archival research and fieldwork. Re-telling the complicated collaboration between architect Warren Platner and graphic designer Milton Glaser at the end of the 1960s, the project lays out how the observation deck is conceived at a time when the perceived “crisis” of New York results in a rapidly accelerating neoliberalization of urban space. An avatar of this emerging ideology the observation deck is heavily invested in making the city visually comprehensible. Incorporating a sort of neoliberalist geometry, the deck transforms the city into a product to be consumed instead of a reality to live in and thus paves the way for other ventures of what has been called the “experience economy.” Thus, it signals the ongoing shift away from an architecture that possesses any use value, towards one that, as Barthes put it with regards to Eiffel Tower, is centered only on viewing and being viewed. A speculative machine, the observation deck renders the city into a product.
The oleochemical and petrochemical industries provide diverse chemicals used in personal care products, food and pharmaceutical industries or as fuels, oils, polymers and others. However, fossil resources are dwindling and concerns about these conventional production methods have risen due to their strong negative impact on the environment and contribution to climate change.
Therefore, alternative, sustainable and environmentally friendly production methods for oleochemical compounds such as fatty acids, fatty alcohols, hydroxy fatty acids and dicarboxylic acids are desired. The biotechnological production by engineered microorganism could fulfill these requirements. The concept of metabolic engineering, which is the modification of metabolic pathways of a host organism for increased production of a target compound, is a widely used strategy in biotechnology to generate cell factories or chassis strains for robust, efficient and high production. In this work, the versatile model and industrial yeast Saccharomyces cerevisiae was manipulated by metabolic engineering strategies for increased production of the medium-chain fatty acid octanoic acid and de novo production the derived 8-hydroxyoctanoic acid.
Octanoic acid production was enabled by the fatty acid biosynthesis pathway by use of a mutated fatty acid synthase (FASRK) in a wild type FAS deficient strain. The yeast fatty acid synthase (FAS) consists of two polypeptides, α and β, which assemble to a α6β6 complex in a co-translational manner by interaction of the subunits. Because this step might be subject to cellular regulation, the α- and β- subunits of fatty acid synthase were fused to form a single-chain construct (fusFASRK), which displayed superior octanoic acid production compared with split FASRK. Thus, FASRK expression was identified as a limiting step of octanoic acid production. But the strains that produce octanoic acid have a severe growth defect that is undesirable for biotechnological applications and could lead to lower production titers. One reason is the strong
inhibitory effect of octanoic acid. Another possibility is that the mutant FAS no longer produces enough essential long-chain fatty acids. To compensate for this, the mutated split and fused FAS variants were co-expressed individually in a strain harboring genomic wild type FAS alleles. In
addition, mutant and wild type variants of fused and split FAS were co-expressed together in a FAS deficient strain. However, both cases resulted in decreased octanoic acid titers potentially by physical and/or metabolic crosstalk of the FAS variants.
The fatty acid biosynthesis relies on cytosolic acetyl-CoA for initiation and derived malonyl-CoA for elongation and requires NADPH for reductive power. To increase production of octanoic acid, engineering strategies for increased acetyl-CoA and NADHP supply were investigated. First, the flux through the native cytosolic acetyl-CoA and NADPH providing pyruvate dehydrogenase bypass was enhanced by overexpression of the target genes ADH2, ALD6 and ACSL461P from Salmonella enterica in combination or individually. Next, the acety-CoA forming heterologous phosphoketolase/phosphotransacetylase pathway was expressed and NADPH formation was increased by redirecting the flux of glucose-6-phosphate into the NADPH producing oxidative branch of the pentose phosphate pathway. In particular, the flux through glycolysis and pyruvate dehydrogenase bypass was reduced by downregulating the expression of the phosphoglucose isomerase PGI1 and deleting the acetaldehyde dehydrogenase ALD6. Glucose-6-phosphate was guided into the pentose phosphate pathway by overexpressing the glucose-6-phosphate dehydrogenase ZWF1. The first approach did not influence octanoic acid production but the latter increased yields in the glucose consumption phase by 65 %. However,
combining the superior fusFASRK with acetyl-CoA and NADPH supply engineering strategies did not result in additive production effects, indicating that other limitations hinder high octanoic acid accumulation. Limitations could be caused in particular by the strong inhibitory effects of octanoic acid or by intrinsic limitations of the FASRK mutant. To enlarge the octanoic acid production platform towards other derived valuable oleochemical compounds the de novo production of 8-hydroxyoctanoic acid was targeted. Since short- and medium-chain fatty acids have a strong inhibitory effect on Saccharomyces cerevisiae, the inhibitory effect of hydroxy fatty acid and dicarboxylic with eight or ten carbon atoms were compared and revealed only little or no growth impairment. Subsequently, the formation of 8-hydroxyoctanoic acid was targeted by a terminal hydroxylation of externally supplied octanoic acid in a bioconversion. For that, three heterologous genes, encoding for cytochromes P450 enzymes and their cognate cytochrome P450 reductases were expressed and 8-hydroxyoctanoic acid production was compared. In addition, the use of different carbon sources was compared.
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This dissertation investigates several aspects of nominal modification in Ògè, an understudied language of Benue-congo spoken in Àkókó Northwest in Nigeria. The study focuses on two areas of nominal modification namely, Nominal Attributive Modifiers (NAMs) and the strategies of number marking.
The discussion and analysis of NAMs in the language reveal that Ògè belongs to the group of languages which lacks adjectives as a lexical category. NAMs are nominal and they
are derived from an existing lexical category namely, verbs. Predicative modifiers and NAMs have forms that are similar to the long and short forms (LF & SF) of adjectives in languages in which adjectives form an open class, for example, Russian, SerBoCroatian (BCS) and German.
Based on the Minimalist program, the dissertation reveals that unlike Russian, BCS, and German in which the discrepancies between the two forms of adjectives are related to definiteness (as in the case of BCS) and Agree, the discrepancies in the two forms of modifiers in Ògè are related to the fact that Ògè lacks adjectives and resorts into the nominalization of stative verbs in order to derive attributive forms. Using the analyses of adjuncts according to Truswell (2004) and Zeijlstra (2020), the dissertation proposes that NAMs are adjuncts in a modification structure while they are heads in possessive and genitive constructions. In addition, I propose that NAMs are attributive-only modifiers which modify the NP rather than
the DP.
The dissertation also investigates the strategies of number marking in Ògè. Unlike languages in which number marking is obligatory in the nominal domain (Hebrew, German, English),
nouns in Ògè are not always marked for number. This means that nouns in Ògè have general number. The general number nature of nouns in Ògè is like that of the nouns in modifying plural marking languages namely, Halkomelem, Korean, Yucatec Maya and Yorùbá. However, I argue that unlike the modifying plural marking languages in which the Number Phrase (NumP) is not projected, NumP is projected in the nominal spine of Ògè, claiming that NumP bears an
interpretable number feature which values the uninterpretable number feature in D. Argument in support of this comes from the interpretation of the noun in the presence of òtúro (an element which translates to the plural definite interpretation of the noun). I analyze òtúro as a plural determiner which occupies the D-head in the syntax of Ògè. The dissertation argues following Alexiadou (2019) that the locus of the occurrence of the marker of plurality in the nominal spine does not depend on its interpretation as a plural morpheme, rather, the locus of the occurrence of the element that is sensitive to the plural interpretation of the noun depends on other parameters which are definiteness, specificity and animacy.
Exploring the in vivo subthreshold membrane activity of phasic firing in midbrain dopamine neurons
(2021)
Dopamine is a key neurotransmitter that serves several essential functions in daily behaviors such as locomotion, motivation, stimulus coding, and learning. Disrupted dopamine circuits can result in altered functions of these behaviors which can lead to motor and psychiatric symptoms and diseases. In the central nervous system, dopamine is primarily released by dopamine neurons located in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) within the midbrain, where they signal behaviorally-relevant information to downstream structures by altering their firing patterns. Their “pacemaker” firing maintains baseline dopamine levels at projection sites, whereas phasic “burst” firing transiently elevates dopamine concentrations. Firing activity of dopamine neurons projecting to different brain regions controls the activation of distinct dopamine pathways and circuits. Therefore, characterization of how distinct firing patterns are generated in dopamine neuron populations will be necessary to further advance our understanding of dopamine circuits that encode environmental information and facilitate a behavior.
However, there is currently a large gap in the knowledge of biophysical mechanisms of phasic firing in dopamine neurons, as spontaneous burst firing is only observed in the intact brain, where access to intrinsic neuronal activity remains a challenge. So far, a series of highly-influential studies published in the 1980s by Grace and Bunney is the only available source of information on the intrinsic activity of midbrain dopamine neurons in vivo, in which sharp electrodes were used to penetrate dopamine neurons to record their intracellular activity. A novel approach is thus needed to fill in the gap. In vivo whole-cell patch-clamp method is a tool that enables access to a neuron’s intrinsic activity and subthreshold membrane potential dynamics in the intact brain. It has been used to record from neurons in superficial brain regions such as the cortex and hippocampus, and more recently in deeper regions such as the amygdala and brainstem, but has not yet been performed on midbrain dopamine neurons. Thus, the deep brain in vivo patch-clamp recording method was established in the lab in an attempt to investigate the subthreshold membrane potential dynamics of tonic and phasic firing in dopamine neurons in vivo.
The use of this method allowed the first in-depth examination of burst firing and its subthreshold membrane potential activity of in vivo midbrain dopamine neurons, which illuminated that firing activity and subthreshold membrane activity of dopamine neurons are very closely related. Furthermore, systematic characterization of subthreshold membrane patterns revealed that tonic and phasic firing patterns of in vivo dopamine neurons can be classified based on three distinct subthreshold membrane signatures: 1) tonic firing, characterized by stable, non-fluctuating subthreshold membrane potentials; 2) rebound bursting, characterized by prominent hyperpolarizations that initiate bursting; and 3) plateau bursting, characterized by transient, depolarized plateaus on which bursting terminates. The results thus demonstrated that different types of phasic firing are driven by distinct patterns of subthreshold membrane activity, which may potentially signal distinct types of information. Taken together, the deep brain in vivo patch-clamp technique can be used for the investigation of firing mechanisms of dopamine neurons in the intact brain and will help address open questions in the dopamine field, particularly regarding the biophysical mechanisms of burst firing in dopamine neurons that control behavior.
Plastics contain a complex mixture of chemicals including polymers, additives, starting substances and side-products of processing. These plastic chemicals are prone to leach into the packaged goods, in the case of food contact materials (FCMs), or into the natural environment, in the case of plastic debris. Thus, plastics represent an exposure source of chemicals for humans and wildlife alike. While it is widely known that individual plastic chemicals, such as bisphenol A and phthalates, are hazardous, little is known on the overall chemical composition and toxicity of plastics. When fragmented into smaller particles, referred to as microplastics (< 5 mm), the plastic itself can be ingested by many species. It is well established that microplastic ingestion can have negative consequences for a wide range of organisms including invertebrates, but the contribution of plastic chemicals to the toxicity of microplastics is unclear.
Given the above, the present thesis aimed at a comprehensive toxicological, ecotoxicological and chemical characterization of everyday plastics. For a comparative evaluation, 77 plastic products were selected covering 16 material types (e.g., polyethylene) made from petroleum or renewable feedstocks. These products included biodegradable products, FCMs and non-FCMs, as well as raw materials and final products, respectively. In the first two studies, the chemical mixtures contained in the 77 products were extracted with methanol and extracts were analyzed in a set of four in vitro bioassays and by non-target high-resolution gas or liquid chromatography mass spectrometry. Since an exposure only occurs if chemicals actually leach under realistic conditions, in a third study migration experiments with water were conducted for 24 out of the 77 products. The aqueous migrates were assessed in the same way as the methanolic extracts. In addition, the freshwater invertebrate Daphnia magna was exposed chronically to microplastics made of polyvinylchloride (PVC), polyurethane (PUR) and polylactic acid (PLA) to investigate the contribution of chemicals in microplastic toxicity, in a fourth study.
The experimental findings demonstrate that a wide variety of chemicals is present in plastics. A single plastic product can contain up to several thousand chemical features, most of which unique to that product and at the same time unknown. The results also indicate that the majority of these chemical mixtures are toxic in vitro. Accordingly, 65% of the plastic extracts induced baseline toxicity and 42% an oxidative stress response, while 25% had an antiandrogenic and 6% an estrogenic activity. This implies that chemicals causing unspecific toxicity are more prevalent in plastics than such with endocrine effects. These chemicals can also leach from plastics under realistic conditions. Between 17 and 8936 chemical features were detected in a single migrate sample and all 24 tested migrates induced in vitro toxicity. This means that humans and wildlife can actually be exposed to toxic plastic chemicals under realistic conditions. Generally, each product has its individual toxicological and chemical fingerprint. Thus, neither material type, feedstock, biodegradability nor the food contact suitability of a product can serve as a predictor for the toxicity, the chemical composition or complexity of a product. Likewise, this means that bio-based and biodegradable materials are not superior to their petroleum-based counterparts from a toxicological perspective despite being promoted as sustainable alternatives to conventional plastics.
Moreover, the present thesis demonstrates that plastic chemicals can be the main driver for microplastic toxicity. Irregular microplastics made of PVC, PUR and PLA adversely affected life-history traits of D. magna in a polymer type- and endpoint-dependent manner at concentrations between 100 and 500 mg L-1 and with a higher efficiency than natural kaolin particles. While the toxicity of PVC was triggered by the chemicals used in the material, the effects of PUR and PLA were induced by the physical properties of the particle.
In addition, in the fifth study, results and observations made during this thesis were integrated inter- and transdisciplinarily with the perspectives of a social scientist and a product manufacturer. This elucidated that knowledge on plastic ingredients is often concealed, is lacking or not applicable in practice. These intransparencies hinder the safety evaluation of plastic products as well as the choice and sale of the least toxic packaging material.
Overall, the present thesis highlights that the chemical safety of plastics and their bio-based and biodegradable alternatives is currently not ensured. Thus, chemicals require more consideration in the toxicity and risk assessment of plastics and microplastics. Product-specific and complex chemical compositions, including unknown compounds, pose a challenge here. Two essential steps towards non-toxic products are to increase transparency along the product life cycle and to reduce the chemical complexity of plastics by communication and regulation. The results of the present thesis indicate that products exist which do not contain toxic chemicals. These can serve to direct the design of safer plastics. Since toxicity and chemical complexity seem to increase with processing, the integration of toxicity testing during the production steps would further support the safe and sustainable production and use of plastic products.