Browsing by Author "Mueller, T."

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P < 0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.

Several tetrasubstituted cyclopropenes have been prepared and their pyrolyses and photolyses have been investigated. Tetrakis(trimethylsilyl)cyclopropene (10), which was obtained in 25% yield from tris(trimethylsilyl) cyclopropenylium hexachloroantimonate (9), gave tetrakis(trimethylsilyl)allene (12) as the sole product both thermally and photochemically. Kinetic studies in [D-8]toluene indicated first-order behavior with Arrhenius parameters log(A/s(-1)) = 11.75 +/- 1.20 and E-a = (37.5 +/- 2.5) kcal mol(-1). All three new 3-alkenyl-1,2,3-tris(trimethylsilyl) cyclopropenes (17a-c, with C-1-, C-2-, and C-3-alkenyl groups as tethers, respectively) gave allenes upon irradiation, but thermally only two (17a, 17c) gave allenes, whilst 17b yielded a bicyclo[4.1.0]hept-3-ene derivative 22 as a result of an intramolecular ene reaction. Photolyses of two further cyclopropenes (33a,b) bearing 1,2-bis(alkenyldimethylsilyl) substituents also gave the corresponding allenes as the sole products. For none of these tethered cyclopropenes was a product found that could have originated from intramolecular trapping of a cyclopropylidene intermediate. Quantum mechanical (ab initio) calculations have been carried out on the silyl-substituted cyclopropene model compounds 3,3-dimethyl-1-silyl- (36a), 3,3-dimethyl-1,2-disilyl-(37), and tetrasilylcyclopropene (38) at the QCISD(T)/G-311G //B3LYP/6311G + ZPVE level of theory, and on 3,3-dimethyl-l- (trimethylsilyl) cyclopropene (36b) at the B3LYP/6-311G //BSLYP/6-311G + ZPVE level. These calculations provided us with detailed energy surfaces for the potential pyrolysis pathways. Although the potential cyclopropylidene species in these rearrangements are significantly stabilized, for none of the systems was this sufficient to permit isomerization via these intermediates. 36b is calculated to rearrange via a vinylidene intermediate to give 3-methyl-1-trimethylsilyl-1-butyne (47), in agreement with experiment. Comparison of the calculations for 36a and 36b shows that H3Si- is a poor model for an Me3Si- substituent in these rearrangements. When an appropriate correction is applied, the calculations on disilyl-(37) and tetrasilylcyclopropenes (38) are consistent with the experimental findings that the trimethylsilyl-substituted cyclopropenes 48 and 10 form allenes 49 and 12, respectively, via vinylcarbene-type intermediates. These findings considerably extend our understanding of silyl group substituent effects on the various intermediates involved in cyclopropene rearrangements.

Including RNA secondary structures improves accuracy and robustness in reconstruction of phylogenetic trees. It is possible to simultaneously infer alignments and phylogenies on the primary sequence and the secondary structure information. For the internal transcribed spacer 2 (ITS2), a phylogenetic RNA transcript marker, two different structure conformations (I or Y shape for helix I) were published for Scenedesmaceae, and a third appeared in the ITS2 database. We contrast the effects on phylogenetic tree reconstruction of different structure sets for a small scenedesmacean subset, using neighbour-joining, maximum parsimony and, for the first time, maximum likelihood, on sequence-structure alignments. Generally our study supports inclusion of secondary structure information. However, we found that any of the three structure conformations is equally fit for phylogenetic studies, but prefer the I shape for helix I. Moreover, our results enable us to give general recommendations on how to build a phylogenetic tree using ITS2 sequencestructure alignments, including different methods to obtain the secondary structures. Thus, we hope to provide a valuable contribution not only for scenedesmacean ITS2 phylogeny, but also for other approaches using RNA transcript markers.