Herstellung hochgenauer Prototypen mittels Fräsen als quasi-generativem Rapid-Prototyping-Verfahren

Die Entwicklung neuer Produkte in möglichst kurzen Zeiträumen verlangt nach Werkzeugen, die den Entwicklungsprozess beschleunigen. In der Praxis hat sich das Rapid Prototyping (RP) als eine Methode etabliert, die grundsätzlich eine Verkürzung der Produktentwicklungsprozesse ermöglicht. Beim Rapid Prototyping steht das schnelle Erstellen von physischen Prototypen im Fokus. Grund-sätzlich erfolgt der Aufbau von Prototypen mittels RP durch das Fügen von konturierten Bauteil-schichten. Während im Zusammenhang mit RP häufig nur die sogenannten generativen RP-Verfahren betrachtet werden, tritt das Fräsen als RP-Verfahren gegenwärtig nur als Randerschei-nung auf. Bei einer Bewertung der einzelnen generativen RP-Verfahren haben sich eine Reihe von techni-schen Schwierigkeiten sowie einzelne Nachteile herausgestellt. Diese betreffen u.a. die geforderte Werkstoffvielfalt sowie Anforderungen an die Bauteilgenauigkeit und die Oberflächengüte. Mit einer Nutzung von Fräsen als RP-Verfahren könnten diese Nachteile umgangen werden. Im ersten Schritt wurden Anforderungen für einen optimalen Prototyping-Prozess mittels Fräsen ausgearbeitet und formuliert. Im einzelnen zählte dazu eine Vermeidung von Ungenauigkeiten in der Bauteilgeometriebeschreibung, sowie eine verbesserte Datenaufbereitung der zu fertigenden Bauteilschichten. Ferner mussten im Hinblick auf eine Prototypenfertigung mittels Fräsen Lösungs-ansätze für spanntechnische Probleme entwickelt werden. Abschließend sollte die Forderung nach einer alternativen, reversiblen Verbindung der Bauteilschichten erfüllt werden. Im Rahmen der vorliegenden Arbeit wurden folgende Lösungsansätze entwickelt: Eine werkzeugo-rientierte Schnittstrategie minimiert die notwendige Anzahl an Bauteilschichten sowie die erforder-lichen Fügevorgänge. Die Entwicklung von inneren Hilfsgeometrien in Form einer Bohrung-Zapfen-Kombination lässt eine zweiseitige Bauteilbearbeitung ohne Beeinflussung der äußeren Bauteilgeometrie zu. Durch eine Auslegung dieser Bohrung-Zapfen-Kombination als Pressverbin-dung ist ein Fügen mit einer definierbaren Festigkeit gegeben. Die entwickelten Ansätze wurden anhand eines Industriebeispiels überprüft und verifiziert. Die Geometrie des untersuchten Bauteils (Miniaturturbine) war hinreichend komplex und stellte weit-reichende Anforderungen an die Fertigungsgenauigkeit. Die Ergebnisse wurden in Form einer Struktur- und Genauigkeitsanalyse der gefertigten Bauteile festgehalten. Durch einen direkten Vergleich mit lasergesinterten Bauteilen konnte die grundsätzliche Eignung der hier entwickelten Ansätze zur Herstellung von hochgenauen Prototypen festgestellt werden

Corrigendum: Valenced action/inhibition learning in humans is modulated by a genetic variant linked to dopamine D2 receptor expression

Motivational salience plays an important role in shaping human behavior, but recent studies demonstrate that human performance is not uniformly improved by motivation. Instead, action has been shown to dominate valence in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward, but the neural mechanism behind this behavioral specificity is yet unclear. In all mammals, including humans, the monoamine neurotransmitter dopamine is particularly important in the neural manifestation of appetitively motivated behavior, and the human dopamine system is subject to considerable genetic variability. The well-studied TaqIA restriction fragment length polymorphism (rs1800497) has previously been shown to affect striatal dopamine metabolism. In this study we investigated a potential effect of this genetic variation on motivated action/inhibition learning. Two independent cohorts consisting of 87 and 95 healthy participants, respectively, were tested using the previously described valenced go/no-go learning paradigm in which participants learned the reward-associated no-go condition significantly worse than all other conditions. This effect was modulated by the TaqIA polymorphism, with carriers of the A1 allele showing a diminished learning-related performance enhancement in the rewarded no-go condition compared to the A2 homozygotes. This result highlights a modulatory role for genetic variability of the dopaminergic system in individual learning differences of action-valence interaction

Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.Peer Reviewe

A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803–814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE-SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust agegroup-related differences for the subsequent memory contrast, and the FADE-SAME score additionally exhibited age-group-related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single-value scores of memory-related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Applications of Lie methods to computations with polycyclic groups

In this thesis we demonstrate the algorithmic usefulness of the so-called Mal'cev correspondence for computations with infinite polycyclic groups. This correspondence between Q-powered nilpotent groups and rational nilpotent Lie algebras was discovered by Anatoly Mal'cev in 1951. We show how the Mal'cev correspondence can be realized on a computer. We explore two possibilities for this purpose and compare them: the first one uses matrix embeddings and the second the Baker-Campbell-Hausdorff formula. Then, we describe a new collection algorithm for polycyclically presented groups, which we call Mal'cev collection. Algorithms for collection lie at the heart of most methods dealing with polycyclically presented groups. The current state of the art is "collection from the left" as recently studied by Gebhardt, Leedham-Green/Soicher and Vaughan-Lee. Mal'cev collection is in some cases dramatically faster than collection from the left, while using less memory. Further, we explore how the Mal'cev correspondence can be used to describe symbolically the collection process in polycyclically presented groups. In particular, we describe an algorithm that computes the collection functions for splittable polycyclic groups. This algorithm is based on work by du Sautoy. We apply it to the computation of pro-p-completions of polycyclic groups. Finally we describe a practical algorithm for testing polycyclicity of finitely generated rational matrix groups. Previously, not only did no such method exist but it was not clear whether this question was decidable at all. Most of the methods described in this thesis are implemented in the computer algebra system GAP and publicly available as part of the GAP packages Guarana and Polenta. Reports on the implementation including runtimes for some examples are given at the appropriate places