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Boron in marine biogenic carbonates as a proxy for the carbonate system
No full textThis thesis has two focus points in the framework of boron in marine biogenic calcium carbonates and its potential as a proxy. Focus point one deals with potential factors, which might influence the boron isotopic composition and boron concentration in marine biogenic calcium carbonates. Since boron in marine biogenic calcium carbonates serves as a proxy for the reconstruction of the carbonate system, the awareness and characterization of potential impacts is of great importance. For that purpose investigations on 1) the effects of temperature and growth rate on the boron concentration and isotopic composition in calcium carbonate were investigated and 2) the potential carbonate system parameters controlling boron incorporation into shells of foraminifers have been determined.
The second focus point introduces a new analytical technique which for the first time allows to determine the boron isotopic composition and boron concentration simultaneously in marine biogenic calcium carbonates. This is a great opportunity for applications in the field of paleoceanography and paleoclimatology since the determination of the boron isotopic composition and boron concentration provides two parameters of the carbonate system which are at least required to reconstruct it
The role of beta two microglobulin in the endocytosis of MHC class I molecules
No full textThe purpose of this work is to establish a correlation between the biochemistry (i.e., the protein structure) and the cell biology (i.e., the intracellular transport and modification) of MHC class I endocytosis. I present some experimental evidence about the role of beta 2 microglobulin (β2m) in the endocytic destruction of the MHC class I allotype H 2Kb. The most important conclusion of my work is that the dissociation of β2m from the heavy chain of H 2Kb is the key requirement for the endocytic destruction of the complex. My experiments suggest that the dissociation of β2m from the heavy chain occurs mostly inside the cell, that is, in an endosomal compartment. I show here that in a fibroblast cell line, there are very few MHC class I free heavy chains (FHC) at steady state at the surface. This is somewhat unexpected, given the wealth of literature describing the presence of FHC at the cell surface of different cell lines, but the apparent discrepancy could be resolved. I have also corroborated that an effect known in the MHC class I field as “empty molecules coming out in the cold” is not correctly named. Rather, the statement should be that “reduced endocytosis causes the low-temperature cell surface accumulation of suboptimally loaded MHC class I molecules”. This accumulation is due to the increased affinity of β2m for the heavy chain of Kb at low temperature.
Finally, I present a different but related on the structural features of β2m by fluorescence spectroscopy. In this part of the work, I provide experimental evidence, using the small molecule reducing agent TCEP, that β2m is a flexible protein. The work can be a starting point for a more detailed investigation on protein folding in general and especially the potential to correlate in vitro experiments with in silico molecular dynamics simulations
Sea-Ice Mass Balance Influenced by Ice Shelves
No full textIce shelves strongly impact coastal Antarctic sea ice through the formation of a sub-ice platelet layer. This matrix of intertwined individual ice crystals influences sea-ice properties, mass- and energy balance, and represents an important habitat for a unique ecosystem. A comprehensive understanding of this system and associated processes is still not well established due to logistical and methodological difficulties.
The main aim of this thesis was to overcome these limitations by the detailed investigation of a sea-ice regime heavily influenced by a nearby ice shelf. An ongoing monitoring program was developed and realized on the landfast sea ice of Atka Bay, a small embayment in front of the Ekström Ice Shelf in the eastern Weddell Sea, Antarctica. By combining measurements of sea ice, ocean and atmosphere over a period of five years, this work revealed important information about the seasonal cycle of the sea ice, its properties, and how it is influenced by the presence of thick snow on the surface and a several meter thick platelet layer underneath.
This study showed that the contribution of ocean/ice-shelf interaction dominated the total sea-ice production at Atka Bay, effectively accounting for up to 70 % of annual sea-ice growth. The total annual ice-platelet volume underlying Atka Bay fast ice was equivalent to more than one fifth of the annual basal melt volume under the Ekström Ice Shelf.
This work also contributed to the advance of several innovative methodological approaches, which are expected to facilitate sea-ice research in the future: 1) thermistor chains with active heating to investigate sea-ice evolution and to identify the governing factors; 2) multi-frequency electromagnetic induction sounding for the retrieval of platelet-layer properties on a larger scale and 3) high-resolution X-band synthetic aperture radar imagery to investigate snow physical properties
Synthesis of Chromium-Containing and Some Other Heteropolytungstates and Study of Their Magnetic, Electrochemical, and Biological Properties
No full textDiscrete metal-oxides, also known as polyoxometalates (POMs), possess a large structural and compositional variety, and a unique range of associated physicochemical properties, leading to applications in many different areas such as catalysis, materials science, and medicine. Transition metal-substituted POMs are an important subclass, and many derivatives of 3d metal ions are known, but to date only a handful of Cr-containing POMs has been reported.
In the course of this work a novel synthetic strategy has been developed which has led to the discovery of six novel CrIII-containing POMs 1a – 6a. The two polyanions [CrIII(HXVW7O28)2]13− (X = P (1a), As (2a)) are the first examples of mononuclear Cr-containing heteropolytungstates, and they exhibit an exceptionally large magnetic anisotropy. Systematic evolution of this structural family by heteroatom substitution has resulted in the two di-CrIII-containing heteropolytungstates, [CrIII2(B-β-SiW8O31)2]14- (3a) and [CrIII2(B-β-GeW8O31)2]14- (4a). Polyanions 3a and 4a represent the first examples of sandwich-type POMs comprising two {XW8O31} (X = Si, Ge) units, and they are stable in solution from pH 1 – 7. Biological studies on 3a and 4a demonstrated interesting antidiabetic and anticancer activity. The polyanion [CrIII2(AsIIIW6O23)2(AsIIIO3)2]14- (5a) exhibits the first example of a di-CrIII-containing tungstoarsenate(III) and comprises two {(AsW6O21)(AsO3)2} units linked by two CrIII centers. The preparation of 1a - 5a demonstrates a remarkable heteroatom template effect in the formation of new POM archetypes. The CrIII-containing hexatungstate [H3CrIIIW6O24]6- (6a) reveals the first chromium derivative of this large Anderson-Evans-type structural heteropolytungstate family.
Following the newly developed synthetic strategy it was possible to isolate another 14 novel polyanions 7a – 20a comprising hexa-, hepta-, and octa-heteropolytungstates, which are all described in Chapter 4. For example, the iron(III)-containing [FeIII(HPW7O28)2]13- (7a) and the high-valent manganese(III)-containing [MnIII(HPW7O28)2]13- (8a) were prepared, and shown to possess interesting magnetic properties. The di-manganese(II)-containing [H3MnII2(AsIIIW6O21)2(AsIIIO3)4]11- (14a) is composed of two equivalent {(AsW6O21)(AsO3)2} units with four terminal arsenate groups. By a slightly modified synthetic procedure the nickel(II)- and manganese(II)-containing polyanions [{Na(H2O)MII(P4W6O34)}2]18- (M = NiII (19a), MnII (20a)) could be prepared, which have a sandwich-type structure capped by three phosphate groups on either side
A Query Language for Scientific Meshes
No full textSeveral scientific domains store their data in unstructured meshes. Due to the complexity of modeling and querying meshes, the database community has neglected the need for a dedicated database model and query language for scientific meshes. Thus, the scientists either use existing databases to model meshes or develop their own technologies to address mesh specific functionalities. Although relational databases can be adapted to store and query meshes, they lack sufficient abstraction for modeling and querying meshes. Scientists develop their own in-house technologies using general-purpose programming languages. Such implementations provide no high-level query language interface, require deep programming knowledge, and are tightly coupled with dataset characteristics and thus are less reusable, their maintenance cost is high, and their performance is limited to memory size.
The thesis addresses the problem of designing a high-level query language for meshes which can express essential mesh processing requirements in the literature. Previous research shows that the concept of iteration (i.e., iteration over cells, topology, geometry) is at the heart of many mesh queries. The thesis starts off by proposing a graph-based mesh data model which represents cells as nodes and topological relations as links. Each node and link act as property containers which can be used to store data fields and geometric information. The thesis shows how to verify several mesh constraints on the model. This includes properties which ensure structural validity of meshes. The semantics of a set of algebraic mesh operators based on the proposed graph model have been described. The set of operators consists of several new operators which are designed to express the mesh processing requirements and in particular the concept of iteration. MQuery has been introduced as a high-level mesh query language w.r.t. the data model and the algebraic operators which enables the user to express the mesh processing requirements. MQuery captures general mesh query processing abstraction by treating meshes and cells as first-class citizens. The iteration introduced by MQuery can be computed in finite time and thus is safe in evaluation. The language has been implemented on top of two database back-ends, namely, Neo4j graph database and PostgreSQL relational database by translating queries to Cypher (Neo4j graph query language) and SQL queries. The performance of the implementations have been compared to a mesh library using five example queries and three datasets and the results are reported
Ocean Acidification vs. Reproduction: What we learned from the past and what we left for the future
No full textOcean Acidification (OA) is the result of the dissolution of carbon dioxide (CO2) into the ocean with a high contribution from anthropogenic activities. OA impairs physiological processes of exposed organisms and most calcifying phyla are sensitive. Many of them belong to important food webs, play key roles at ecosystem level and have economical relevance. In aquatic environments fertilization is frequently external and gametes are released into the water column in massive external spawning events being threatened by natural and artificially created factors. The comprehension of OA effects on crucial steps of fertilization and development becomes essential for assessing the real impact on population sustainability and species survivorship.
In the current study, the effects of CO2-simulated OA on the fertilization success of the sea urchin species Strongylocentrotus droebachiensis were analysed using preindustrial-actual atmospheric CO2 concentrations and levels expected to occur by the end of the century and beyond. The impact of long exposure periods (simulating asynchronous spawning) on fertilization success and the pHi changes of spawned eggs exposed to acidified scenarios before fertilization were assessed. The impact of OA on cytoskeleton in the actin-rich cortex region was examined during the first hours after fertilization. There was a delayed development and an increased polyspermy risk evidenced by the presence of sperm in the perivitelline space under acidified conditions. This might be related to alterations in pHi and actin polymerization of the exposed eggs that could synergically influence the formation of the fertilization envelope and hyaline layer. These structures are required for protecting the eggs from polyspermy. Cytoskeleton disruptions negatively influence the gamete interaction and cellular division, as found in this study. Disruptions on calcium signalling cannot be excluded. Despite being not in the scope of the current study, the relation of the Ca2+signalling pathway with the pHi homeostasis under acidified conditions was discussed
Interaction and toxicological studies of compounds on membrane models, cell cultures and 3D tissue models
No full textThe first part of the study introduces two biotechnologically produced in vitro human cell based 3D hemi-cornea test systems, which aim at the complete replacement of the Draize Eye Irritation test. These test systems allow the assessment of chemicals of any physical-chemical properties and their proper categorization in different GHS categories.
The second part of the thesis describes the protective effect of brilliant blue G (BBG) on the cytotoxicity of trypan blue (TB), octenidine (Oct) and benzalkonium chloride (BAK). In the presence of TB, BBG significantly increased the cell survival of human retinal pigment epithelium cells, whereas at the same concentrations TB alone led to considerable cell damage. In the mixture with BAK, a widely used preservative in ophthalmologic solutions, or Oct, an antiseptic used for skin and wound disinfection, BBG decreased the cytotoxic effects of the two compounds on human corneal epithelial cells.
A third part of the present work includes two closely related studies. The first study describes the interaction of halogenated dodecaborate clusters with liposomal membranes, characterized by using different biophysical techniques. The measurements show a strong interaction of the cluster molecules with the liposomes, which led to morphological changes of the lipids and leakage of the liposomal content. As the toxicity of the clusters on mammalian cells was not significantly high, the use of these molecules is proposed for the targeted release of drugs from liposomes used in cancer therapy.
In a second study the association and uptake of liposomes containing the dodecaborate cluster lipid in endothelial and cancer cell lines is described. The association was cell type dependent and HUVEC (endothelial) cells showed the strongest uptake of lipids. The fluorescent microscopy images showed uptake for both boron-lipid and fluorescent marker lipid, even when the liposomes were sterically stabilized by pegylation
Development of a Physiologically-based Model with a regulatory and excitable cardiovascular system
No full textThe cardiovascular system (CVS) is an organ system that is often considered to be a closed loop system. Closed loop systems have the blood closed at all times within vessels of different size and wall thickness. The CVS consists of the heart (cardio) and the blood vessels (vascular). The CVS is responsible for the supplementation of all organs with for example nutrients and oxygen and also for the distribution of drugs throughout the body. Biological processes in the CVS are responsible for the regulation of temperature, nutrient transport, detoxification, supply with oxygen, regulation of acidity and the transport of proteins and cells of the immune system. With an impairment of this organ not only the whole CVS is disturbed, but all organs will be affected.
The development of drugs, regulating the cardiovascular system (CVS) by the pharmaceutical industry is of high relevance, because cardiovascular disease (CVD) is a global epidemic [1]. There is a need for development of effective drugs in a cost reducing manner and a need to increase clinical development success rates. “Approximately one development path in ten (10.4%) that enters clinical development in phase 1 is expected to advance to FDA approval”. Especially “cardiovascular drugs had the lowest LOA (likelihood of approval) from phase 1 at 8.7% (n = 318)” [2]. To get a better knowledge about relevant processes and to support decision making in drug development, modeling and simulation techniques are well accepted and very potent methods. One of these methods is the use of physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) models. The pharmacokinetics describes the time course of drug absorption, distribution, metabolism, and excretion, while pharmacodynamics refers to the relationship between drug concentration at the site of action and the resulting effect. In the field of cardiovascular modeling, the PD effects can be biochemical and physiological effects like changes in hormone and enzyme levels, blood pressure or heart rate changes. PBPK models are based on a mechanistic understanding of processes, physiology and drug properties. That enables it to assess and predict the drug concentration profiles in plasma and in different organs. This knowledge is essential for an efficient drug development, because it supports a detailed understanding where the drug reaches therapeutically or even toxically concentrations. Or in other terms that is essential to understand the efficacy and risk for adverse effects of the drug in the body. PBPK models are recently used to address both, the distribution of the drug after administration, the targeted effect and all related processes.
The current state of research in CV modeling reveals several approaches for this field of interest. On the one hand, there exist models describing the CVS in terms of blood flow and blood pressure and their regulation by hormonal systems like the renin-angiotensin- aldosterone system (RAAS). On the other hand there are PBPK models describing the PK of drugs all over the body. Nevertheless there is a lack of mechanistic models coupling both approaches to show the effects of PK and PD on the CVS. Up to now PBPK models representing the blood flow for the different organs are available, but no relation to blood pressure and its regulatory processes have been made.
The outline and workflow of this thesis is shown in Figure 1. The thesis integrates a cardiovascular model into a whole body (wb) PBPK model to establish a mechanistic representation of the regulatory character of CVS under different physiological and pathological conditions. A main regulator of the CVS, the renin-angiotensin-aldosterone system (RAAS) was developed and coupled to the CVS to show its effects on the blood pressure. Furthermore, the coupling of the CVS to the RAAS led to a mechanistic representation of the PBPK-PD relationship. Two PBPK models for the exemplary drugs enalapril (Ena) and amlodipine have been established and the effect of these drugs on the RAAS and the CVS could be shown. Both drugs validate the PK and PD relationship within this unistructural model.
Figure 1 represents an overview of the workflow. First a PBPK model for intravenous Enaat was established. This model includes physicochemical and physiological data and was evaluated with human PK-data. Then a PBPK-PO (peroral) model for Ena was created, including the respective physiological and physicochemical properties. After an evaluation with experimental PK-profiles, those two models were coupled to one model that is able to represent the PK-profile on Enaat after an oral Ena administration. Represent in a consistent manner. Then a RAAS-PD model for healthy individuals was established in a second step. After validation of the RAAS model by human data it was coupled to the Ena-Enaat model. A full PD model for the regulation of CVS was developed. It includes physiological and physical information about the CVS and represents the dynamic behavior of the blood pressure, heart rate and blood flow in a detailed organ structure. This model is a full PBPK-model and includes physiological data about hormone levels, enzyme kinetics and physicochemical properties of hormones.
A PD model for the human CVS was developed, including physiological and physical information about the CVS.
It was tested for some pathological states like hypertension and the Irukandji syndrome, which are indicated in Figure 1 by their own orange boxes. The CVS was evaluated with experimental PD-profiles (for the heart rate, the blood pressure or the pressure-volume relationship) for healthy individuals and then coupled to the full Ena-Enaat-RAAS-model. Finally an IV model for amlodipine was created with physicochemical and physiological data concerning amlodipine. From this a PO model for amlodipine could be evaluated, by including the respective data for amlodipine absorption, distribution, metabolism and excretion (ADME). The PO model for amlodipine was then coupled to the CV-model for healthy and also foe hypertensive individuals. Models are checked for consistency amongst each other several times.
The pathogenic state of hypertension can be shown by the CV model. Finally the condition of Carukia Barnesi envenomation has been tested. The physiologically based PD model of the CVS is able to represent the basic behavior for an envenomation sufficiently well, indicating a reasonable description of the underlying physiological processes. Furthermore, a first concept for the changes in blood pressure (BP), heart rate (HR) and activity of the autonomic nervous system are shown.
This model allows a more systematic approach of the CVS. This model allows for a better and more comprehensive understanding of the pharmacokinetic and the pharmacodynamics behavior of a drug acting on the CVS. Since there are no modeling approaches combining full PBPK models with full mechanistic approaches including RAAS and related effects on the CVS, this model provides a significant step further towards a better prediction of pharmacokinetic (PK) and pharmacodynamic (PD) simulations and would allow predictions in healthy and impaired conditions. It reveals the effects of blood pressure modulating drug treatments on the CVS and their own PK and PD. Thereby this model provides a further step to contribution in the process of target validation, proof of concept, dose finding and personalization of medicine
Efficient Advanced Indoor Localization: Analysis and Algorithms
No full textWireless localization is a very mature area of research, with plenty of work done in recent years both in academia and industry. Despite the amount of effort put into this problem, wireless positioning systems are still far off their potential as a real time locating technology (which requires automatic identification and tracking). It is commonly known that wireless localization systems are still inaccurate and unreliable in indoor environment, as a result indoor positioning systems are still quite frail and under-deployed.
One possible reason for this is that numerous constituents are available in the literature to solve parts of this problem, but still do not collectively combine to provide a complete solution. To qualify the above, two very important problems within the area of wireless localization have been treated as separate challenges. These problems are ranging (as defined by the process of estimating distances from physical quantities) and trilateration (as defined by the process of estimating the absolute location of sources given their distances to a set of references).
This is rationalized by the fact that the fundamental tools required to design accurate distance estimators and positioning algorithms are clearly distinct. From an error analysis point of view, these problems are intrinsically interdependent, by the reason of the fundamental limits on the root mean square error on the corresponding estimates (both distances and locations) being governed by the same likelihood function given as the product of the ranging error distributions. Therefore, an attempt at the unification of these problems, with the aim at improving the accuracy, precision, complexity and robustness of wireless localization for indoor positioning systems is reasonable.
During the course of this thesis, we provided estimation and reconstruction analyses on the statistics of the ranging error distributions, we then refrained from pursuing further positioning algorithms as both ranging and trilateration are governed by the same likelihood function, but rather presented efficient ranging and multipoint ranging techniques through the efficient collection of ranging information using Sparse and Golomb rulers obtained utilizing evolutionary genetic techniques, with the adjustment of the ranging techniques to provide highly accurate solutions which aim at improving the quality of distance estimation. We then pursued effective trilateration techniques which allow results and information typically restricted to the ranging problem, to inform positioning algorithms, thereby conditioning results in light of knowledge extracted from ranging information in order to provide accurate wireless localization. Therefore, we bridged and inter-connected both ranging and trilateration methods, which resulted in efficient, robust, accurate, precise and low-complex ranging and trilateration techniques for advanced indoor localization
Objectified humans and humanized objects: Perceived humanness of real and artificial representations of in-group and out-group members
No full textThe primary purpose of this dissertation is to investigate how basic perceptual processes responsible for the evaluations of humanness are influenced by the top- down motivation of ethnic group belonging. Chapter 1 begins with positioning the current work in the broader context of social psychological research and provides an introductory overview of the planned studies. The attribution of human qualities as shaped by the in-group/ out-group divide is then examined with reference to humans in Chapters 2 and 3, and to objects in Chapters 4 and 5. Experiments described in Chapters 2 and 3 are based on rating tasks to respectively assess animacy and mental capacities, and personality features and emotions of natural and artificial faces. The results show animacy to be reserved for faces that can be unambiguously categorized as the in-group. Moreover, although the ascription of aliveness and mental states gradually decreases as the faces attain the more synthetic appearance, these perceptions do not vary as a function of group membership. The assignment of personality traits and emotions evidences in-group favoritism and subtle out-group derogation, and is similar for both types of faces. Subsequently, the artificial versions of the facial stimuli are used to embody anthropomorphic agents in the setting of human-computer interaction. Experiments reported in Chapters 4 and 5 adopt a bargaining game and on-line conversations to explore the reception of machines fulfilling roles once designated only for humans. The results reveal that on the behavioral level, the computer triggers social responses comparable in their nature to the responses typically elicited by human companions, but the emotional reactions to the violations of social norms enacted by the computer seem to be attenuated. Finally, Chapter 6 concludes with a synopsis of the findings and their interpretation in relation to a well-established mind perception framework as demonstrating the entities under scrutiny to be imputed experience and denied agency. In sum, the thesis aims to contribute to the understanding of the social impact the computers have on the user and to in turn inform the design of realistic computer-based characters for contemporary applications