Neue lokalanästhetisch wirksame basische Cycloalkylester von substituierten Carbanilsäuren

Summary Highly active local anaesthetics from the group of basic substituted cyclohexylesters of 2-chloro-, 2, 6-dichloro-, 2-chloro-6-methyl-, 2-methyl-, 2, 6-dimethyl-and 2,4,6-trimethylcarbanilic acid were developed. The substances were tested for local anaesthetic activity in surface anaesthesia.     

Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast

Under laboratory conditions 80% of yeast genes seem not to be essential for viability. This raises the question of what the mechanistic basis for dispensability is, and whether it is the result of selection for buffering or an incidental side product. Here we analyse these issues using an in silico flux model of the yeast metabolic network. The model correctly predicts the knockout fitness effects in 88% of the genes studied and in vivo fluxes. Dispensable genes might be important, but under conditions not yet examined in the laboratory. Our model indicates that this is the dominant explanation for apparent dispensability, accounting for 37-68% of dispensable genes, whereas 15-28% of them are compensated by a duplicate, and only 4-17% are buffered by metabolic network flux reorganization. For over one-half of those not important under nutrient-rich conditions, we can predict conditions when they will be important. As expected, such condition-specific genes have a more restricted phylogenetic distribution. Gene duplicates catalysing the same reaction are not more common for indispensable reactions, suggesting that the reason for their retention is not to provide compensation. Instead their presence is better explained by selection for high enzymatic flux.     

Disposable-soma senescence mediated by sexual selection in an ungulate

Senescence may result from an optimal balance between current reproductive investment and bodily repair processes required for future reproduction, a theoretical prediction difficult to prove especially in large, long-lived animals. Here we propose that teeth that have fixed dimensions early in life, but that wear during chewing, can be taken as a measure of total lifetime 'repair', and their wear rate as a measure of current expenditure in performance. Our approach also considers the sexual selection process to investigate the advance of senescence in males compared with females, when selection favouring competition over mates reduces the reproductive lifespan of males. We studied carcasses of 2,141 male and 739 female red deer (Cervus elaphus) of different ages, finding that male molariform teeth emerged at a far smaller size than expected from body size dimorphism. This led to higher workload, steeper wear rate and earlier depletion of male teeth than in females, in concordance with sex-specific patterns of lifetime performance and reproduction. These findings provide the empirical support for the disposable-soma hypothesis of senescence, which predicts that investment in bodily repair will decrease when the return from this investment may not be realized as a result of other causes that limit survival or reproduction.     

Insights into assembly from structural analysis of bacteriophage PRD1

The structure of the membrane-containing bacteriophage PRD1 has been determined by X-ray crystallography at about 4 A resolution. Here we describe the structure and location of proteins P3, P16, P30 and P31. Different structural proteins seem to have specialist roles in controlling virus assembly. The linearly extended P30 appears to nucleate the formation of the icosahedral facets (composed of trimers of the major capsid protein, P3) and acts as a molecular tape-measure, defining the size of the virus and cementing the facets together. Pentamers of P31 form the vertex base, interlocking with subunits of P3 and interacting with the membrane protein P16. The architectural similarities with adenovirus and one of the largest known virus particles PBCV-1 support the notion that the mechanism of assembly of PRD1 is scaleable and applies across the major viral lineage formed by these viruses.     

Tungsten isotope evidence that mantle plumes contain no contribution from the Earth's core

Osmium isotope ratios provide important constraints on the sources of ocean-island basalts, but two very different models have been put forward to explain such data. One model interprets (187)Os-enrichments in terms of a component of recycled oceanic crust within the source material. The other model infers that interaction of the mantle with the Earth's outer core produces the isotope anomalies and, as a result of coupled (186)Os-(187)Os anomalies, put time constraints on inner-core formation. Like osmium, tungsten is a siderophile ('iron-loving') element that preferentially partitioned into the Earth's core during core formation but is also 'incompatible' during mantle melting (it preferentially enters the melt phase), which makes it further depleted in the mantle. Tungsten should therefore be a sensitive tracer of core contributions in the source of mantle melts. Here we present high-precision tungsten isotope data from the same set of Hawaiian rocks used to establish the previously interpreted (186)Os-(187)Os anomalies and on selected South African rocks, which have also been proposed to contain a core contribution. None of the samples that we have analysed have a negative tungsten isotope value, as predicted from the core-contribution model. This rules out a simple core-mantle mixing scenario and suggests that the radiogenic osmium in ocean-island basalts can better be explained by the source of such basalts containing a component of recycled crust.     

Differential distribution of TASK-1, TASK-2 and TASK-3 immunoreactivities in the rat and human cerebellum

In this work, the distributions of some acid-sensitive two-pore-domain K⁺ channels (TASK-1, TASK-2 and TASK-3) were investigated in the rat and human cerebellum. Astrocytes situated in rat cerebellar tissue sections were positive for TASK-2 channels. Purkinje cells were strongly stained and granule cells and astrocytes were moderately positive for TASK-3. Astrocytes isolated from the hippocampus, cerebellum and cochlear nucleus expressed TASK channels in a primary tissue culture. Our results suggest that TASK channel expression may be significant in the endoplasmic reticulum of the astrocytes. The human cerebellum showed weak TASK-2 immunolabelling. The pia mater, astrocytes, Purkinje and granule cells demonstrated strong TASK-1 and TASK-3 positivities. The TASK-3 labelling was stronger in general, but it was particularly intense in the Purkinje cells and pia mater.Received 25 February 2004; received after revision 19 April 2004; accepted 28 April 2004