Dissertations / Theses on the topic 'Rhens'

Rhes (Ras homolog enriched in striatum) has been identified as a novel monomeric G-protein involved in dopaminergic and other signaling in the striatum. Given the many effects of opioids that involve striatal circuitry, genetically engineered mice that are incapable of making Rhes (rhes-/-) and their control littermates (rhes+/+) were subjected to behavioral tests to determine if any differences existed in opioid analgesia, tolerance, withdrawal, reward, and locomotion. Rhes-/- mice showed an increased opioid mediated analgesia, along with an absence of tolerance and decrease in withdrawal when compared with rhes+/+ littermates. However, no significant changes were seen in opioid induced locomotor activation or conditioned place preference. These results provide strong evidence for the implication of Rhes in opioid signaling.

Purpose: In this study, areas of use of blockchain technology in transportation management will be discussed. The purpose is to contribute with theoretical research of advantages and disadvantages of blockchain technology in transportation management before an implementation at Rhenus Logistics.   Methodology: Through interviews and literature, ways of using blockchain in transportation management is researched. A case study is set up, to further analyze the research topic from the view of an individual third-party logistic company.  Findings: Results showed that for a third-party logistic provider to successfully use blockchain technology within transportation management, it is important to have the entire network onboard in the process. If so, functionalities such as track and trace, digital handling of paperwork and smart contracts could be used. The advantages of using blockchain technology for transportation management at Rhenus Logistics were found to be trust, transparency, traceability, efficiency, cost-saving opportunities and the use of smart contacts. Identified disadvantages for Rhenus Logistics was that blockchain is costly, stakeholders are hesitant to get involved, smart contracts are not considerate of blurry lines in real life practice and there is a challenge in finding an accurate blockchain design for their business model.

Die vorliegende Arbeit 'Abflußentwicklung in Teileinzugsgebieten des Rheins - Simulationen für den Ist-Zustand und für Klimaszenarien' untersucht Auswirkungen möglicher zukünftiger Klimaänderungen auf das Abflußgeschehen in ausgewählten, durch Mittelgebirge geprägten Teileinzugsgebieten des Rheins: Mosel (bis Pegel Cochem); Sieg (bis Pegel Menden 1) und Main (bis Pegel Kemmern).

In einem ersten Schritt werden unter Verwendung des hydrologischen Modells HBV-D wichtige Modellprozesse entsprechend der Einzugsgebietscharakteristik parametrisiert und ein Abbild der Gebietshydrologie erzeugt, das mit Zeitreihen gemessener Tageswerte (Temperatur, Niederschlag) eine Zeitreihe der Pegeldurchflüsse simulieren kann. Die Güte der Simulation des Ist-Zustandes (Standard-Meßzeitraum 1.1.1961-31.12.1999) ist für die Kalibrierungs- und Validierungszeiträume in allen Untersuchungsgebieten gut bis sehr gut.
Zur Erleichterung der umfangreichen, zeitaufwendigen einzugsgebietsbezogenen Datenaufbereitung für das hydrologische Modell HBV-D wurde eine Arbeitsumgebung auf Basis von Programmerweiterungen des Geoinformationssystems ArcView und zusätzlichen Hilfsprogrammen entwickelt. Die Arbeitsumgebung HBV-Params enthält eine graphische Benutzeroberfläche und räumt sowohl erfahrenen Hydrologen als auch hydrologisch geschulten Anwendern, z.B. Studenten der Vertiefungsrichtung Hydrologie, Flexibilität und vollständige Kontrolle bei der Ableitung von Parameterwerten und der Editierung von Parameter- und Steuerdateien ein. Somit ist HBV-D im Gegensatz zu Vorläuferversionen mit rudimentären Arbeitsumgebungen auch außerhalb der Forschung für Lehr- und Übungszwecke einsetzbar.

In einem zweiten Schritt werden Gebietsniederschlagssummen, Gebietstemperaturen und simulierte Mittelwerte des Durchflusses (MQ) des Ist-Zustandes mit den Zuständen zweier Klimaszenarien für den Szenarienzeitraum 100 Jahre später (2061-2099) verglichen. Die Klimaszenarien beruhen auf simulierten Zirkulationsmustern je eines Modellaufes zweier Globaler Zirkulationsmodelle (GCM), die mit einem statistischen Regionalisierungsverfahren in Tageswertszenarien (Temperatur, Niederschlag) an Meßstationen in den Untersuchungsgebieten überführt wurden und als Eingangsdaten des hydrologischen Modells verwendet werden.
Für die zweite Hälfte des 21. Jahrhunderts weisen beide regionalisierten Klimaszenarien eine Zunahme der Jahresmittel der Gebietstemperatur sowie eine Zunahme der Jahressummen der Gebietsniederschläge auf, die mit einer hohen Variabilität einhergeht. Eine Betrachtung der saisonalen (monatlichen) Änderungsbeträge von Temperatur, Niederschlag und mittlerem Durchfluß zwischen Szenarienzeitraum (2061-2099) und Ist-Zustand ergibt in allen Untersuchungsgebieten eine Temperaturzunahme (höher im Sommer als im Winter) und eine generelle Zunahme der Niederschlagssummen (mit starken Schwankungen zwischen den Einzelmonaten), die bei der hydrologischen Simulation zu deutlich höheren mittleren Durchflüssen von November bis März und leicht erhöhten mittleren Durchflüssen in den restlichen Monaten führen. Die Stärke der Durchflußerhöhung ist nach den individuellen Klimaszenarien unterschiedlich und im Sommer- bzw. Winterhalbjahr gegenläufig ausgeprägt. Hauptursache für die simulierte starke Zunahme der mittleren Durchflüsse im Winterhalbjahr ist die trotz Temperaturerhöhung der Klimaszenarien winterlich niedrige Evapotranspiration, so daß erhöhte Niederschläge direkt in erhöhten Durchfluß transformiert werden können.
Der Vergleich der Untersuchungsgebiete zeigt in Einzelmonaten von West nach Ost abnehmende Änderungsbeträge der Niederschlagssummen, die als Hinweis auf die Bedeutung der Kontinentalitätseinflüsse auch unter geänderten klimatischen Bedingungen in Südwestdeutschland aufgefaßt werden könnten.
Aus den regionalisierten Klimaszenarien werden Änderungsbeträge für die Modulation gemessener Zeitreihen mittels synthetischer Szenarien abgeleitet, die mit einem geringen Rechenaufwand in hydrologische Modellantworten überführt werden können. Die direkte Ableitung synthetischer Szenarien aus GCM-Ergebniswerten (bodennahe Temperatur und Gesamtniederschlag) an einzelnen GCM-Gitterpunkten erbrachte unbefriedigende Ergebnisse.
Ob, in welcher Höhe und zeitlichen Verteilung die in den (synthetischen) Szenarien verwendeten Niederschlags- und Temperaturänderungen eintreten werden, kann nur die Zukunft zeigen. Eine Abschätzung, wie sich die Abflußverhältnisse und insbesondere die mittleren Durchflüsse der Untersuchungsgebiete bei möglichen Änderungen entwickeln würden, kann jedoch heute schon vorgenommen werden.

Simulationen auf Szenariogrundlagen sind ein Weg, unbekannte zukünftige Randbedingungen sowie regionale Auswirkungen möglicher Änderungen des Klimasystems ausschnittsweise abzuschätzen und entsprechende Risikominderungsstrategien zu entwickeln. Jegliche Modellierung und Simulation natürlicher Systeme ist jedoch mit beträchtlichen Unsicherheiten verknüpft. Vergleichsweise große Unsicherheiten sind mit der zukünftigen Entwicklung des sozioökonomischen Systems und der Komplexität des Klimasystems verbunden. Weiterhin haben Unsicherheiten der einzelnen Modellbausteine der Modellkette Emissionsszenarien/Gaszyklusmodelle - Globale Zirkulationsmodelle/Regionalisierung - hydrologisches Modell, die eine Kaskade der Unsicherheiten ergeben, neben Datenunsicherheiten bei der Erfassung hydrometeorologischer Meßgrößen einen erheblichen Einfluß auf die Vertrauenswürdigkeit der Simulationsergebnisse, die als ein dargestellter Wert eines Ergebnisbandes zu interpretieren sind.

Der Einsatz
(1) robuster hydrologischer Modelle, die insbesondere temperaturbeeinflußte Prozesse adäquat beschreiben,
(2) die Verwendung langer Zeitreihen (wenigsten 30 Jahre) von Meßwerten und
(3) die gleichzeitige vergleichende Betrachtung von Klimaszenarien, die auf unterschiedlichen GCMs beruhen (und wenn möglich, verschiedene Emissionsszenarien berücksichtigen),
sollte aus Gründen der wissenschaftlichen Sorgfalt, aber auch der besseren Vergleichbarkeit der Ergebnisse von Regionalstudien im noch jungen Forschungsfeld der Klimafolgenforschung beachtet werden.
This thesis 'Development of runoff in subcatchments of the River Rhine - simulations of the current state and for climate change scenarios' investigates the impacts of possible future climate changes on runoff and runoff regime in selected subcatchments of the River Rhine. The regional climate in the selected subcatchments Mosel (up to gauge Cochem), Sieg (gauge Menden 1) and Main (gauge Kemmern) is affected by the middle mountain ranges.

In a first step, important model processes are parameterized according to catchment characteristics. A representation of the regional hydrology is then produced by using the hydrological model HBV-D. Based on time series of daily measurements (temperature, precipitation) at stations within the catchment, this representation can be used to realistically simulate time series of runoff and discharge.
In all examined areas, the quality of simulations of the calibration and validation periods for the current state (standard period of measurements 01/01/1961-12/31/1999) can be regarded as good to excellent.
To aid the catchment-specific, extensive and time-consuming data processing, a working environment for the hydrological model HBV-D has been developed. It is based on program extensions of the geographical information system ArcView and further programs. The working environment HBV-Params contains a graphical interface that gives both experienced hydrologists and students full control and enables them to flexibly derive parameter values and edit parameter and control files. In contrast to previous versions with only rudimentary working environments, HBV-D can therefore be utilized for research as well as for educational purposes.

In a second step, the current states of areal precipitation, areal temperature and simulated mean discharge (MQ) are compared to the corresponding states for two scenarios of future climate changes (100 years later, 2061-2099). These scenarios are based on simulated global circulations of one model run for each of two global circulation models (GCM). These global circulations are regionalized (downscaled) using a statistical approach into scenario time series of daily values (temperature, precipitation - input for the hydrological model) at control stations within the individual catchments.
For the second half of the 21st century, both regionalized climate change scenarios indicate increases in the mean annual areal temperature and mean annual sum of precipitation, along with a high variability of the latter. The seasonal (monthly) changes in temperature, precipitation and mean discharge between scenario state (2061-2099) and current state indicate increases in temperature (higher in summer than in winter) as well as a general increase in precipitation sums (strong fluctuations between individual months). In the hydrological simulations for all investigated catchments, this results in considerably higher mean discharges from November to March and small increases in mean discharge for the other months. The magnitude of the increases in discharge depends on the individual climate change scenario, one showing higher increases than the other during the summer half-year and vice versa for the winter half-year. The main reason for the simulated strong increase in mean discharge during winter half-year is, in spite of higher temperatures, the still relatively low evapotranspiration which allows higher precipitation to be directly transformed into higher discharges.
The comparison of the investigated catchments shows decreasing amounts of changes in the sum of precipitation from West to East in individual months. This indicates the importance of continentality under changed climatic conditions in Southwest Germany.
For the modification of measured time series (temperature, precipitation), which can be easily converted as synthetic scenarios into simulated hydrological results, amounts of change are derived from regionalized (downscaled) climate change scenarios. The derivation of synthetic scenarios directly from GCM output at individual GCM gridpoints yielded unsatisfactory results.
Only the future itself can show whether the timing and amount of changes in temperature and precipitation used in (synthetic) climate change scenarios come close to reality. An assessment of possible developments in runoff regime and specifically mean discharge under possible changed climatic conditions in the investigated catchments is already feasible today.

Simulations based on scenarios are one way to establish unknown future boundary conditions for the estimation of regional impacts of possible changes of the climate system. Nevertheless, all types of modeling and simulation of natural systems are linked with uncertainties. Rather large uncertainties persist regarding the future development of the socio-economic system and the complexity of the climate system and earth system. Furthermore, besides data uncertainties associated with the measurement of hydro-meteorological values, uncertainties associated with individual components of the model chain emission scenarios/gas cycle model - GCM/regionalization - hydrological model, which form a cascade of uncertainty, have a great influence on the trustworthiness of the simulation results (which are understood as one shown value within a range of results).

In the young field of climate impact research the use of
(1) robust hydrological models that adequately describe temperature-dependent processes,
(2) long time series (at least 30 years long) of measurements,
(3) concurrent comparisons of climate change scenarios, based on different GCMs (and, if possible, different emission scenarios)
should be considered for reasons of scientific thoroughness and to improve comparability of regional impact studies.

Mice that are incapable of expressing the small G protein Rhes have been generated and have shown to have abnormalities in behaviors mediated by the striatum, a region in which Rhes is highly expressed. Moreover, conditions that result in dopamine supersensitivity and a breakdown in D1/D2 synergism in rodents, consistently decrease rhes mRNA in striatum. Thus, Rhes may play have relevance in dopamine signal modulation. For evaluating the role of Rhes in anxiety, stereotypy and basal motor activity, adult male and female wild-type (WT) mice, Rhes knockout (KO) mice, and mice heterozygous for the KO and WT alleles (Het) were tested. There was no genotype differences in the distance traveled in the open field. However, female KO mice showed lower anxiety than either WTs or Hets, based on the quantity of time spent in the periphery vs. the central area of the open field (p<0.05). With respect to striatally-mediated motor stereotypy, the mixed D1/D2 agonist apomorphine elicited a significant greater response in male KO and Het compared to WTs (p<0.05). In previous studies of D1/D2 synergism, it has been consistently found in rats and mice that when D2 receptors alone are stimulated, there is an early and brief, D1 independent peak in stereotypy that disappears by 20 minutes. In the present study, this effect was more intense in male KO mice compared to the other two genotypes during the interval between 5 and 10 minutes (p<0.05). The current findings favor the hypothesis that the GTP-binding protein Rhes interacts with as yet unidentified cellular proteins to buffer the transduction of synaptic dopamine signals into intracellular responses. Decreased or loss of Rhes therefore results in increased DA signal transduction.

Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is untreatable, incurable, and ultimately fatal. HD is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein (mHtt) is ubiquitously expressed in HD patients, cellular degeneration occurs only in neurons within the striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent work using cultured cells suggests that Rhes may be a co-factor with mHtt in cell death. However, there is controversy as to whether cell death underlies the symptoms of HD. We used a validated transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD/Rhes-/- mice showed greatly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. The progressive disease is caused by an unstable CAG expansion within the gene that normally encodes for the huntingtin protein (Htt). The expanded mutant form of Htt (mHtt) is expressed ubiquitously throughout patients’ bodies; however, neuronal degeneration is prominent only in the corpus striatum and, to a lesser extent, the cortex. The Ras homolog Rhes is also preferentially localized to the striatum. The putative co-factor Rhes has been shown to act with mHtt to cause neuronal death. Simvastatin, a lipid lowering drug, and zoledronate, a nitrogen bisphosphonate, act on the mevalonate pathway, which gives both Rhes and its target cells, binding sites. The current study aimed to interrupt the mevalonate pathway and inactivate, via de-prenylation, Rhes in CD-1 mice exposed to 3-nitroproprionic acid, a neurotoxin that mimics HD mitochondrial dysfunction and striatal degeneration. Results suggest that drug treatment does not rescue motor impairments and may potentiate 3-NP damage. The persistent motor deficits are discussed in relation to possible Rhes de-prenylation.

Located on the short arm of chromosome 4, there exists a gene, IT15, responsible for the trinucleotide CAG expansion involved in the autosomal dominant neurodegenerative disorder known as Huntington’s disease (HD). The brain region associated with the most atrophy, the striatum, leads to expression of severe motor dysfunction, the hallmark feature of HD. To a lesser degree, the cortex and hippocampus show earlier deterioration indicative of the cognitive deficits that occur prior to motor symptom onset. The brain regions associated with HD-induced neuronal death additionally selectively express the protein Rhes - the combination of Rhes and mutant huntingtin being cytotoxic. Using a 3-nitropropionic acid animal model of HD, we hypothesized that animals with preserved prenylation of Rhes would display cognitive and motor symptomology similar to genetic models of HD while animals administered statins or bisphosphonates would show inhibited Rhes prenylation and delayed cognitive symptoms. Experimental animals, however, did not perform differently than control animals on shallow water variants of the t-maze and MWM.

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. An unstable CAG expansion within the gene normally encoding for the Huntingtin protein is responsible. The expanded mutant form of Huntingtin and the putative protein co-factor Rhes interact and cause cell death within the striatum. We hypothesized chronic treatment with simvastatin, a cholesterol lowering drug, would disrupt the biosynthetical pathway which gives both Rhes and its target cells binding sites and render Rhes inactive. Healthy and HD mice were treated with simvastatin or a vehicle. Animals’ motor behavior was assessed with three separate tests over the first four months of life. No significant differences were found between the HD groups; however, the HD treated animals’ performance on the rotarod test, at month 4, was intermediate between healthy mice and HD vehicle treated mice. The results hint at simvastatin’s therapeutic potential, but are interpreted cautiously.

Huntington’s disease is an incurable, progressive neurological disorder characterized by loss of motor control, psychiatric dysfunction, and eventual dystonia leading to death. Despite the fact that this disorder is caused by a mutation in one single gene, there is no cure. The mutant Huntingtin (mHtt) protein is expressed ubiquitously throughout the brain but frank cell death is limited to the striatum. Recent work has suggested that Rhes, Ras homolog enriched in striatum, which is selectively expressed in the striatum, may play a role in Huntington’s disease neuropathology. In vitro studies have shown Rhes to be an E3 ligase for the post-translational modification protein SUMO. Rhes increases binding of SUMO to mHtt which competes for the same binding site as Ubiquitin. SUMOylation of mHtt leads to disaggregation and cellular death, whereas ubiquitination leads to aggregation and cellular protection. In a previous study we showed that deletion of Rhes caused a decrease in the Huntington’s disease phenotype in mice. We hypothesized that mice lacking Rhes would also show increased aggregation in the striatum and this increased aggregation would correlate in a rescue of behavioral symptoms. Despite the prior in vitro and in vivo evidence, deletion of Rhes in vivo did not alter the aggregation of mHtt in the striatum of mice however deletion of Rhes still showed a rescue from the diseased phenotype. This result would indicate that deletion of Rhes alters the neurobehavioral phenotype of Huntington’s disease through a different pathway than promoting aggregation in striatal cells.

This bachelor thesis engages in a quest to understand the concepts of necessity and grace in Simone Weils thinking. The question in play, in which many more questions lie hidden, reads as follows: How does Weil understand the operations of grace in relation to the ”blind necessity” of the natural world, and what are the philosophical implications of this concept of grace? What are, for instance, given her understanding of the world as God’s creation, the metaphysical grounds for a basic human activitiy such as thinking or reflexion? A reading of Simone Weils works on necessity, grace, affliction and attention is contrasted with her thoughts on science, method and truth. The concept of necessity is compared to the one of Spinoza, especially on the subject of how the good or the just relates to the true and the necessary: it shows there are interesting similarities and illuminating differences between the two philosophers’ lines of thought. Here, the concept of attention becomes central to the image: the idea of a cultivated mode of reception of the world and of the Other. Attention is analogously understood as a method of prayer and a cultivated ethical attitude towards other human beings – and an ideal scientific state of mind. In the final chapter of the analytic part of the composition, Weils concept of grace is investigated in regard to concepts of thinking and understanding. Here, Leibniz idea of the divine world and the divine mind plays a concise but important role on the matter of a tentative metaphysical grounding of thinking as such – how this can be thought and how it reflects and deepens Simone Weils metaphysics, especially her understanding of the highest states of insight into the nature of the world as partly a work of divine grace. In the last chapter Walter Benjamins vision of the coming philosophy as a consolidation between Immanuel Kants transcendental philosophy and religious experience – and religious thought – show the way for further investigation into the field, a field that the thesis has outlined at the same time as it has attempted to answer some specific questions that seems to be the most urgent ones.

This thesis explores reasons and disagreement in ethics, and their connection to personal identity. I begin by arguing that reasons are open; what gives them direction is how they feature in my life and weigh with me. Of course, this does not tell us what reasons are available to a person when they act. In this connection I argue against Bernard Williams’ internal reasons thesis, showing that there are occasions when we will want to say someone has a reason to act even though they are unable to see it. Continuing with Williams, I explore moral necessity, drawing also on the works of Winch, Rhees and Cordner, arguing that Williams too readily conflates psychological with ethical limits. In particular, the possibility of recanting what we took to be necessary should inform our view of moral necessity, since it can show that I had misconstrued the nature of the limits I took myself to have reached. Following this use of recantation, I explore narrative in detail, arguing that my narrative is partly constitutive of who I am. My agency is therefore interpretive. This has ramifications for thinkers such as Christine Korsgaard and Jonathan Dancy, whose work I explore in two excursuses. In different ways, both fail to appreciate the significance of our interpretive identities.