An integration by parts formula for the bilinear form of the hypersingular boundary integral operator for the transient heat equation in three spatial dimensions

While an integration by parts formula for the bilinear form of the hypersingular boundary integral operator for the transient heat equation in three spatial dimensions is available in the literature, a proof of this formula seems to be missing. Moreover, the available formula contains an integral term including the time derivative of the fundamental solution of the heat equation, whose interpretation is difficult at second glance. To fill these gaps we provide a rigorous proof of a general version of the integration by parts formula and an alternative representation of the mentioned integral term, which is valid for a certain class of functions including the typical tensor-product discretization spaces

Landschaften, die inklusive Gesellschaften ermöglichen / hervorbringen. Eine Reflexion über persönliche Entwicklung und Entwicklungen im Berufsfeld Schule

Zwei mutige Gesetze – die Auflösung aller Sonderschulen und die Schulautonomie – bringen die Bildungslandschaft in Südtirol/Italien in Bewegung. Der Autor, zunächst Grundschullehrer, dann über viele Jahre Schuldirektor, erzählt von seinen Erfahrungen aus der Praxis. Laut denkend versucht er den Essentials nachzuspüren, die inklusive Gesellschaften ermöglichen bzw. hervorbringen. Er reflektiert über die eigene Entwicklung, macht Herausforderungen und Chancen sichtbar, die durch die neuen gesetzlichen Rahmungen entstanden sind und er berichtet anhand von konkreten Beispielen, wie seine Schulen sich aus sich heraus auf den Weg gemacht haben. Seine Aussagen lassen eine Ahnung aufkommen, was wirksam zur Transformation von Individuen und Systemen hin zu gelebten inklusiven Gesellschaften beitragen könnte. (DIPF/Orig.)Two courageous laws – the dissolution of all special schools and school autonomy – set the educational landscape in South Tyrol/Italy in motion. The author, first a primary school teacher, then a school principal for many years, tells of his experiences in practice. Thinking aloud, he tries to trace the essentials that make inclusive societies possible or produce them. He reflects on his development and highlights challenges and opportunities that have arisen due to the new legal frameworks. Therefore he uses concrete examples to report how his schools have set out independently. His statements give a sense of what might be effective in transforming individuals and systems toward living inclusive societies. (DIPF/Orig.

Catalytic residues and a predicted structure of tetrahydrobiopterin-dependent alkylglycerol mono-oxygenase

Alkylglycerol mono-oxygenase (EC 1.14.16.5) forms a third, distinct, class among tetrahydrobiopterin-dependent enzymes in addition to aromatic amino acid hydroxylases and nitric oxide synthases. Its protein sequence contains the fatty acid hydroxylase motif, a signature indicative of a di-iron centre, which contains eight conserved histidine residues. Membrane enzymes containing this motif, including alkylglycerol mono-oxygenase, are especially labile and so far have not been purified to homogeneity in active form. To obtain a first insight into structure–function relationships of this enzyme, we performed site-directed mutagenesis of 26 selected amino acid residues and expressed wild-type and mutant proteins containing a C-terminal Myc tag together with fatty aldehyde dehydrogenase in Chinese-hamster ovary cells. Among all of the acidic residues within the eight-histidine motif, only mutation of Glu137 to alanine led to an 18-fold increase in the Michaelis–Menten constant for tetrahydrobiopterin, suggesting a role in tetrahydrobiopterin interaction. A ninth additional histidine residue essential for activity was also identified. Nine membrane domains were predicted by four programs: ESKW, TMHMM, MEMSAT and Phobius. Prediction of a part of the structure using the Rosetta membrane ab initio method led to a plausible suggestion for a structure of the catalytic site of alkylglycerol mono-oxygenase

Semi-analytic integration for a parallel space-time boundary element method modelling the heat equation

The presented paper concentrates on the boundary element method (BEM) for the heat equation in three spatial dimensions. In particular, we deal with tensor product space-time meshes allowing for quadrature schemes analytic in time and numerical in space. The spatial integrals can be treated by standard BEM techniques known from three dimensional stationary problems. The contribution of the paper is twofold. First, we provide temporal antiderivatives of the heat kernel necessary for the assembly of BEM matrices and the evaluation of the representation formula. Secondly, the presented approach has been implemented in a publicly available library besthea allowing researchers to reuse the formulae and BEM routines straightaway. The results are validated by numerical experiments in an HPC environment.Web of Science10317015

First insights into structure-function relationships of alkylglycerol monooxygenase

Alkylglycerol monooxygenase is a tetrahydrobiopterin-dependent enzyme that cleaves the O-alkyl-bond of alkylglycerols. It is an exceptionally unstable, hydrophobic membrane protein which has never been purified in active form. Recently, we were able to identify the sequence of alkylglycerol monooxygenase. TMEM195, the gene coding for alkylglycerol monooxygenase, belongs to the fatty acid hydroxylases, a family of integral membrane enzymes which have an 8-histidine motif crucial for catalysis. Mutation of each of these residues resulted in a complete loss of activity. We now extended the mutational analysis to another 25 residues and identified three further residues conserved throughout all members of the fatty acid hydroxylases which are essential for alkylglycerol monooxygenase activity. Furthermore, mutation of a specific glutamate resulted in an 18-fold decreased affinity of the protein to tetrahydrobiopterin, strongly indicating a potential important role in cofactor interaction. A glutamate residue in a comparable amino acid surrounding had already been shown to be responsible for tetrahydrobiopterin binding in the aromatic amino acid hydroxylases. Ab initio modelling of the enzyme yielded a structural model for the central part of alkylglycerol monooxygenase where all essential residues identified by mutational analysis are in close spatial vicinity, thereby defining the potential catalytic site of this enzym

Insights from a Murine Aortic Transplantation Model

Transplant vasculopathy (TV) represents a major obstacle to long-term graft survival and correlates with severity of ischemia reperfusion injury (IRI). Donor administration of the nitric oxide synthases (NOS) co-factor tetrahydrobiopterin has been shown to prevent IRI. Herein, we analysed whether tetrahydrobiopterin is also involved in TV development. Using a fully allogeneic mismatched (BALB/c to C57BL/6) murine aortic transplantation model grafts subjected to long cold ischemia time developed severe TV with intimal hyperplasia (α-smooth muscle actin positive cells in the neointima) and endothelial activation (increased P-selectin expression). Donor pretreatment with tetrahydrobiopterin significantly minimised these changes resulting in only marginal TV development. Severe TV observed in the non-treated group was associated with increased protein oxidation and increased occurrence of endothelial NOS monomers in the aortic grafts already during graft procurement. Tetrahydrobiopterin supplementation of the donor prevented all these early oxidative changes in the graft. Non-treated allogeneic grafts without cold ischemia time and syngeneic grafts did not develop any TV. We identified early protein oxidation and impaired endothelial NOS homodimer formation as plausible mechanistic explanation for the crucial role of IRI in triggering TV in transplanted aortic grafts. Therefore, targeting endothelial NOS in the donor represents a promising strategy to minimise TV

The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle. Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80. Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite. In addition, the ability of DCs to initiate T-cell proliferation and to produce the proinflammatory cytokines IL-12 and tumour necrosis factor-α was markedly impaired by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-κB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M. These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of leflunomide in inflammatory diseases, including RA

Pre-existing malignancies in renal transplant candidates-time to reconsider waiting times

Current proposals for waiting times for a renal transplant after malignant disease may not be appropriate. New data on malignancies in end-stage renal disease and recent diagnostic and therapeutic options should lead us to reconsider our current practice