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Implementation of a plasmodesmata gatekeeper system, and its effect on intercellular transport
(2016)
Personal fabrication tools, such as 3D printers, are on the way of enabling a future in which non-technical users will be able to create custom objects. However, while the hardware is there, the current interaction model behind existing design tools is not suitable for non-technical users. Today, 3D printers are operated by fabricating the object in one go, which tends to take overnight due to the slow 3D printing technology. Consequently, the current interaction model requires users to think carefully before printing as every mistake may imply another overnight print. Planning every step ahead, however, is not feasible for non-technical users as they lack the experience to reason about the consequences of their design decisions.
In this dissertation, we propose changing the interaction model around personal fabrication tools to better serve this user group. We draw inspiration from personal computing and argue that the evolution of personal fabrication may resemble the evolution of personal computing: Computing started with machines that executed a program in one go before returning the result to the user. By decreasing the interaction unit to single requests, turn-taking systems such as the command line evolved, which provided users with feedback after every input. Finally, with the introduction of direct-manipulation interfaces, users continuously interacted with a program receiving feedback about every action in real-time. In this dissertation, we explore whether these interaction concepts can be applied to personal fabrication as well.
We start with fabricating an object in one go and investigate how to tighten the feedback-cycle on an object-level: We contribute a method called low-fidelity fabrication, which saves up to 90% fabrication time by creating objects as fast low-fidelity previews, which are sufficient to evaluate key design aspects. Depending on what is currently being tested, we propose different conversions that enable users to focus on different parts: faBrickator allows for a modular design in the early stages of prototyping; when users move on WirePrint allows quickly testing an object's shape, while Platener allows testing an object's technical function. We present an interactive editor for each technique and explain the underlying conversion algorithms.
By interacting on smaller units, such as a single element of an object, we explore what it means to transition from systems that fabricate objects in one go to turn-taking systems. We start with a 2D system called constructable: Users draw with a laser pointer onto the workpiece inside a laser cutter. The drawing is captured with an overhead camera. As soon as the the user finishes drawing an element, such as a line, the constructable system beautifies the path and cuts it--resulting in physical output after every editing step. We extend constructable towards 3D editing by developing a novel laser-cutting technique for 3D objects called LaserOrigami that works by heating up the workpiece with the defocused laser until the material becomes compliant and bends down under gravity. While constructable and LaserOrigami allow for fast physical feedback, the interaction is still best described as turn-taking since it consists of two discrete steps: users first create an input and afterwards the system provides physical output.
By decreasing the interaction unit even further to a single feature, we can achieve real-time physical feedback: Input by the user and output by the fabrication device are so tightly coupled that no visible lag exists. This allows us to explore what it means to transition from turn-taking interfaces, which only allow exploring one option at a time, to direct manipulation interfaces with real-time physical feedback, which allow users to explore the entire space of options continuously with a single interaction. We present a system called FormFab, which allows for such direct control. FormFab is based on the same principle as LaserOrigami: It uses a workpiece that when warmed up becomes compliant and can be reshaped. However, FormFab achieves the reshaping not based on gravity, but through a pneumatic system that users can control interactively. As users interact, they see the shape change in real-time.
We conclude this dissertation by extrapolating the current evolution into a future in which large numbers of people use the new technology to create objects. We see two additional challenges on the horizon: sustainability and intellectual property. We investigate sustainability by demonstrating how to print less and instead patch physical objects. We explore questions around intellectual property with a system called Scotty that transfers objects without creating duplicates, thereby preserving the designer's copyright.
The human immunodeficiency virus (HIV) has resisted nearly three decades of efforts targeting a cure. Sustained suppression of the virus has remained a challenge, mainly due
to the remarkable evolutionary adaptation that the virus exhibits by the accumulation of drug-resistant mutations in its genome. Current therapeutic strategies aim at achieving and maintaining a low viral burden and typically involve multiple drugs. The choice of optimal combinations of these drugs is crucial, particularly in the background of treatment failure having occurred previously with certain other drugs. An understanding of the dynamics of viral mutant genotypes aids in the assessment of treatment failure with a certain drug
combination, and exploring potential salvage treatment regimens.
Mathematical models of viral dynamics have proved invaluable in understanding the viral life cycle and the impact of antiretroviral drugs. However, such models typically use simplified and coarse-grained mutation schemes, that curbs the extent of their application to drug-specific clinical mutation data, in order to assess potential next-line therapies. Statistical
models of mutation accumulation have served well in dissecting mechanisms of resistance evolution by reconstructing mutation pathways under different drug-environments. While these models perform well in predicting treatment outcomes by statistical learning, they do not incorporate drug effect mechanistically. Additionally, due to an inherent lack of
temporal features in such models, they are less informative on aspects such as predicting mutational abundance at treatment failure. This limits their application in analyzing the
pharmacology of antiretroviral drugs, in particular, time-dependent characteristics of HIV therapy such as pharmacokinetics and pharmacodynamics, and also in understanding the impact of drug efficacy on mutation dynamics.
In this thesis, we develop an integrated model of in vivo viral dynamics incorporating drug-specific mutation schemes learned from clinical data. Our combined modelling
approach enables us to study the dynamics of different mutant genotypes and assess mutational abundance at virological failure. As an application of our model, we estimate in vivo
fitness characteristics of viral mutants under different drug environments. Our approach also extends naturally to multiple-drug therapies. Further, we demonstrate the versatility of our model by showing how it can be modified to incorporate recently elucidated mechanisms of drug action including molecules that target host factors.
Additionally, we address another important aspect in the clinical management of HIV disease, namely drug pharmacokinetics. It is clear that time-dependent changes in in vivo
drug concentration could have an impact on the antiviral effect, and also influence decisions on dosing intervals. We present a framework that provides an integrated understanding
of key characteristics of multiple-dosing regimens including drug accumulation ratios and half-lifes, and then explore the impact of drug pharmacokinetics on viral suppression.
Finally, parameter identifiability in such nonlinear models of viral dynamics is always a concern, and we investigate techniques that alleviate this issue in our setting.
The horse is a fascinating animal symbolizing power, beauty, strength and grace. Among all the animal species domesticated the horse had the largest impact on the course of human history due to its importance for warfare and transportation. Studying the process of horse domestication contributes to the knowledge about the history of horses and even of our own species.
Research based on molecular methods has increasingly focused on the genetic basis of horse domestication. Mitochondrial DNA (mtDNA) analyses of modern and ancient horses detected immense maternal diversity, probably due to many mares that contributed to the domestic population. However, mtDNA does not provide an informative phylogeographic structure. In contrast, Y chromosome analyses displayed almost complete uniformity in modern stallions but relatively high diversity in a few ancient horses. Further molecular markers that seem to be well suited to infer the domestication history of horses or genetic and phenotypic changes during this process are loci associated with phenotypic traits.
This doctoral thesis consists of three different parts for which I analyzed various single nucleotide polymorphisms (SNPs) associated with coat color, locomotion or Y chromosomal variation of horses. These SNPs were genotyped in 350 ancient horses from the Chalcolithic (5,000 BC) to the Middle Ages (11th century). The distribution of the samples ranges from China to the Iberian Peninsula and Iceland. By applying multiplexed next-generation sequencing (NGS) I sequenced short amplicons covering the relevant positions: i) eight coat-color-associated mutations in six genes to deduce the coat color phenotype; ii) the so-called ’Gait-keeper’ SNP in the DMRT3 gene to screen for the ability to amble; iii) 16 SNPs previously detected in ancient horses to infer the corresponding haplotype. Based on these data I investigated the occurrence and frequencies of alleles underlying the respective phenotypes as well as Y chromosome haplotypes at different times and regions. Also, selection coefficients for several Y chromosome lineages or phenotypes were estimated.
Concerning coat color differences in ancient horses my work constitutes the most comprehensive study to date. I detected an increase of chestnut horses in the Middle Ages as well as differential selection for spotted and solid phenotypes over time which reflects changing human preferences.
With regard to ambling horses, the corresponding allele was present in medieval English and Icelandic horses. Based on these results I argue that Norse settlers, who frequently invaded parts of Britain, brought ambling individuals to Iceland from the British Isles which can be regarded the origin of this trait. Moreover, these settlers appear to have selected for ambling in Icelandic horses.
Relating to the third trait, the paternal diversity, these findings represent the largest ancient dataset of Y chromosome variation in non-humans. I proved the existence of several Y chromosome haplotypes in early domestic horses. The decline of Y chromosome variation coincides with the movement of nomadic peoples from the Eurasian steppes and later with different breeding practices in the Roman period.
In conclusion, positive selection was estimated for several phenotypes/lineages
in different regions or times which indicates that these were preferred by humans. Furthermore, I could successfully infer the distribution and dispersal of horses in association with human movements and actions. Thereby, a better understanding of the influence of people on the changing appearance and genetic diversity of domestic horses could be gained. My results also emphasize the close relationship of ancient genetics and archeology or history and that only in combination well-founded conclusions can be reached.