QBF with Soft Variables

QBF formulae are usually considered in prenex form, i.e. the quantifierblock is completely separated from the propositional part of the QBF.Among others, the semantics of the QBF is defined by the sequence ofthe variables within the prefix, where existentially quantifiedvariables depend on all universally quantified variables stated to theleft.In this paper we extend that classical definition and consider a newquantification type which we call soft variable. The idea is toallow a flexible position and quantifier type for these variables.Hence the type of quantifier of the soft variable can also bealtered. Based on this concept, we present an optimization problemseeking an optimal prefix as defined by user-given preferences. We statean algorithm based on MaxQBF, and present several applications – mainlyfrom verification area – which can be naturally translated into theoptimization problem for QBF with soft variables. We further implementeda prototype solver for this formalism, and compare our approach toprevious work, that differently from ours does not guarantee optimalityand completeness

Bioenergetik und Biochemie bei zerebralen Organoazidopathien am Beispiel der Glutaryl-CoA-Dehydrogenase-Defizienz und der Succinat-Semialdehyd-Dehydrogenase-Defizienz

In der vorliegenden Arbeit wurde die Rolle der Biochemie und Bioenergetik bei zerebralen Organoazidopathien am Beispiel der Glutaryl-CoA-Dehydrogenase (GCDH)-Defizienz und der Succinatsemialdehyd-Dehydrogenase (SSADH)-Defizienz untersucht. Die GCDH-Defizienz ist eine erbliche Stoffwechselstörung im Abbau der Aminosäuren L-Lysin, L-Hydroxylysin und L-Tryptophan. Durch einen Defekt der GCDH akkumulieren bei Patienten Glutaryl-CoA, Glutarsäure (GA) und 3-Hydroxyglutarsäure (3-OH-GA) in Geweben und Körperflüssigkeiten. Unbehandelt wird diese Krankheit in der Kindheit zumeist durch eine striatale Degeneration im Rahmen einer enzephalopathischen Krise nach einer katabolen Stoffwechsellage kompliziert. Die SSADH-Defizienz ist eine erbliche Stoffwechselstörung im Abbau des Neurotransmitters gamma-Aminobuttersäure (GABA). Patienten fallen durch eine Akkumulation von GABA, gamma-Hydroxybuttersäure, Succinatsemialdehyd und 4,5-Dihydroxyhexansäure in Geweben und Körperflüssigkeiten infolge einer defekten SSADH auf. Häufige klinische Befunde sind psychomotorische Retardierung, epileptische Krampfanfälle, Bewegungstörungen und Verhaltensauffälligkeiten. Im bioenergetischen Teil der vorliegenden Arbeit wurde untersucht, ob eine mitochondriale, bioenergetische Dysfunktion an der Pathogenese dieser Erkrankungen beteiligt ist. Hierfür wurden endogene Enzymaktivitäten der Atmungskette und der beta-Oxidation in Gewebehomogenaten von Gcdh- und Ssadh-defizienten Mäusen bestimmt. An isolierten Enzymen, Gewebehomogenaten und submitochondrialen Partikeln wurde der Einfluss der akkumulierenden Metabolite auf die Enzyme der Atmungskette, der beta-Oxidation und des Citratzyklusses getestet. Oxidativer Stress wurde über die Glutathion-Konzentrationen in Gewebehomogenaten abgeschätzt. Das wichtigste Ergebnis für die GCDH-Defizienz war eine unkompetitive Hemmung der alpha-Ketosäure-Dehydrogenase-Komplexe - insbesondere des alpha-Ketoglutarat-Dehydrogenase Komplexes - durch Glutaryl-CoA. Es konnte kein weiterer Einfluss akkumulierender Metabolite auf die Enzyme des Citratzyklusses, der Atmungskette und der beta-Oxidation gefunden werden. Bei Gcdh-defizienten Mäusen waren die endogenen Aktivitäten von Enzymen der beta-Oxidation erniedrigt, die Aktivitäten der Atmungskettenkomplexe waren jedoch unverändert. Für die SSADH-Defizienz konnte keine Änderung endogener Enzymaktivitäten der Atmungskette oder ein direkter Einfluss akkumulierender Metabolite auf die Enzyme der Atmungskette oder des Citratzyklusses gefunden werden. Bei beiden Mausmodellen wurden im Gehirn erniedrigte Glutathion-Konzentrationen als Hinweis auf oxidativen Stress nachgewiesen Die biochemischen Eigenschaften (Gewebeverteilung, Bluthirnschranke [BBB]-Permeabilität und Herkunft der zerebralen Konzentrationen) akkumulierender Metabolite sind für die SSADH-Defizienz gut beschrieben. Obwohl GA und 3-OH-GA postulierte Neurotoxine sind, sind diese Faktoren bei der GCDH-Defizienz noch relativ unbekannt. Deshalb wurden diese biochemischen Eigenschaften für GA und 3-OH-GA untersucht. Hierzu wurden die Konzentrationen dieser Dicarbonsäuren in Gcdh-defizienten (Gcdh-/-) Mäusen, hepatozytären Gcdh-/--Mäusen und C57Bl/6-Mäusen nach einer intraperitonealen Injektion von d4-GA und d5-3-OH-GA gemessen. Zusätzlich wurde der Transport von d4-GA und d5-3-OH-GA über kapilläre Endothelzellen aus Schweinehirn, einem in vitro-Modell der BBB, untersucht. Die wichtigsten Ergebnisse waren wie folgt: 1) ein äquimolarer Anstieg zerebraler und hepatischer GA- und 3-OH-GA-Konzentrationen in Gcdh-/--Mäusen, 2) ein unterschiedlicher Anstieg (Leber >> Gehirn) bei hepatozytären Gcdh-/--Mäusen und C57Bl/6-Mäusen nach einer intraperitonealen Injektion von d4-GA und d5-3-OH-GA und 3) eine geringe Permeabilität der BCEC für GA und 3-OH-GA (Efflux > Influx). Diese Ergebnisse weisen auf eine zerebrale de novo-Synthese von GA und 3-OH-GA und anschließendes Trapping durch eine stark limitierte BBB-Permeabilität für diese Dicarbonsäuren hin

A selectively reduced degree basis for efficient mixed nonlinear isogeometric beam formulations with extensible directors

The effect of higher order continuity in the solution field by using NURBS basis function in isogeometric analysis (IGA) is investigated for an efficient mixed finite element formulation for elastostatic beams. It is based on the Hu-Washizu variational principle considering geometrical and material nonlinearities. Here we present a reduced degree of basis functions for the additional fields of the stress resultants and strains of the beam, which are allowed to be discontinuous across elements. This approach turns out to significantly improve the computational efficiency and the accuracy of the results. We consider a beam formulation with extensible directors, where cross-sectional strains are enriched to avoid Poisson locking by an enhanced assumed strain method. In numerical examples, we show the superior per degree-of-freedom accuracy of IGA over conventional finite element analysis, due to the higher order continuity in the displacement field. We further verify the efficient rotational coupling between beams, as well as the path-independence of the results.Comment: 50 pages, 23 figure

A change of the seaward boundary of Goukamma Marine Protected Area could increase conservation and fishery benefits

Goukamma Marine Protected Area (MPA) on the South African temperate South Coast has been shown to be effective in maintaining a spawning stock of roman, Chrysoblephus laticeps (Sparidae). The larval ecology and the oceanographic conditions in the area suggest a good potential for the enhancement of roman stocks outside the reserve through larval dispersal. A high rate of illegal fishing just inside the seaward boundary of the MPA could severely compromise its function.We suggest that a change of the seaward boundary of the reserve to coincide with a latitudinal line could increase its function as a harvest refuge for resident reef fishes such as roman, facilitate voluntary compliance and monitoring and prosecution of illegal fishing without a significant negative impact on the commercial linefishing fleet in the area. Simple adjustments such as the one proposed here could be attempted at a number of South African MPAs as they would be beneficial to achieve fishery and conservation goals alike

A change of the seaward boundary of Goukamma Marine Protected Area could increase conservation and fishery benefits

Goukamma Marine Protected Area (MPA) on the South African temperate South Coast has been shown to be effective in maintaining a spawning stock of roman, Chrysoblephus laticeps (Sparidae). The larval ecology and the oceanographic conditions in the area suggest a good potential for the enhancement of roman stocks outside the reserve through larval dispersal. A high rate of illegal fishing just inside the seaward boundary of the MPA could severely compromise its function. We suggest that a change of the seaward boundary of the reserve to coincide with a latitudinal line could increase its function as a harvest refuge for resident reef fishes such as roman, facilitate voluntary compliance and monitoring and prosecution of illegal fishing without a significant negative impact on the commercial linefishing fleet in the area. Simple adjustments such as the one proposed here could be attempted at a number of South African MPAs as they would be beneficial to achieve fishery and conservation goals alike

Dark-adapted versus bleached state in fluorescence lifetime imaging ophthalmoscopy

Purpose: The (early) detection of diseases based on metabolic changes in the retina is the goal of the novel autofluorescence lifetime ophthalmoscopy (FLIO) technique. These metabolic changes can be detected as alterations in the fundus autofluorescence (FAF) lifetimes. The influences of the photopigment bleaching and photobleaching on the FAF lifetimes are unknown. Thus, we performed a volunteer study to investigate these influences. Methods: In 21 healthy volunteers (23.6±3.8 years) time-resolved FAF was measured with a FLIO device (30° of fundus, excitation at 473nm, detection in two spectral channels: 500-560nm (ch1) and 560-720nm (ch2), time-correlated single photon counting method). All subjects had a crystalline lens. The pupil was dilated with 0.5% Tropicamid. After volunteers adapted to the dark using a custom-made lightproof eyewear over a period of 30 min, the first FLIO measurement was recorded (dark-adapted state). Subsequently, one eye was bleached for 1 min using a luminance of 3200cd/m2, followed by a FLIO measurement (bleached state). The fluorescence lifetimes were estimated from the FAF decays, based on three exponential functions, using the software FLIMX (www.flimx.de). Average values from the central region, and the inner and outer rings of the ETDRS grid were utilized to compare both bleaching states using analysis of variance, Friedman, and post hoc tests. Results : Only ch2 yielded significant changes (p<0.05) for the fluorescence lifetime τ2 from all ETDRS regions (+19-28ps), for the fluorescence lifetime τ1 (+6ps) and the mean fluorescence lifetime (+6ps) in the central area that were less than 10% in magnitude. Additionally, the acquisition time in the bleached state was significantly reduced by approximately 20% on average, compared to the dark-adapted state. The fluorescence lifetime differences caused by bleaching were much smaller than pathological states known from literature. Conclusions: We conclude that bleaching is not relevant for current clinical FLIO applications because of the small magnitude of the elicited fluorescence lifetime changes. Thus, it is advisable to instruct patients to wait in a bright room before FLIO measurements. If the expected changes in the fluorescence lifetime in a specific experimental paradigm are small, FLIO users should follow a strict acquisition protocol in terms of the photopigment bleaching state of the patients to obtain the most reliable results

Severe dysfunction of respiratory chain and cholesterol metabolism in Atp7b−/− mice as a model for Wilson disease

AbstractWilson disease (WD) is caused by mutations of the WD gene ATP7B resulting in copper accumulation in different tissues. WD patients display hepatic and neurological disease with yet poorly understood pathomechanisms. Therefore, we studied age-dependent (3, 6, 47weeks) biochemical and bioenergetical changes in Atp7b−/− mice focusing on liver and brain. Mutant mice showed strongly elevated copper and iron levels. Age-dependently decreasing hepatic reduced glutathione levels along with increasing oxidized to reduced glutathione ratios in liver and brain of 47weeks old mice as well as elevated hepatic and cerebral superoxide dismutase activities in 3weeks old mutant mice highlighted oxidative stress in the investigated tissues. We could not find evidence that amino acid metabolism or beta-oxidation is impaired by deficiency of ATP7B. In contrast, sterol metabolism was severely dysregulated. In brains of 3week old mice cholesterol, 8-dehydrocholesterol, desmosterol, 7-dehydrocholesterol, and lathosterol were all highly increased. These changes reversed age-dependently resulting in reduced levels of all previously increased sterol metabolites in 47weeks old mice. A similar pattern of sterol metabolite changes was found in hepatic tissue, though less pronounced. Moreover, mitochondrial energy production was severely affected. Respiratory chain complex I activity was increased in liver and brain of mutant mice, whereas complex II, III, and IV activities were reduced. In addition, aconitase activity was diminished in brains of Atp7b−/− mice. Summarizing, our study reveals oxidative stress along with severe dysfunction of mitochondrial energy production and of sterol metabolism in Atp7b−/− mice shedding new light on the pathogenesis of WD