Recent Advances in Catalytic Asymmetric Synthesis

The rapid development in the genomics and proteomics research has brought about an unprecedented number of potential new drug targets, which translates into an ever-increasing need to rapidly assemble highly pure small molecules （MRS850） with an increased structural complexity ＇to identify a small molecule partner for every gene product＇. Simultaneously, our increasing awareness of environmental aspects of synthesis places a nearly orthogonal set of requirements for the kinds of syntheses admissible in the future which can be expressed as a rule of 6S＇ s： selectivity and speed of the syntheses;     

Demonstration of vitamin D3 metabolism inmytilus edulis

Summary Radiolabeled vitamin D₃ was converted into several polar metabolites upon incubation with tissue homogenates from the common musselMytilus edulis. Chromatographic analysis indicated that the metabolites have chromatographic mobilities different from those of known standards. The results suggest that vitamin D₃ is metabolized in mussels via pathways that differ from the vertebrate systems.Acknowledgments. The authors thank Dr Pirjo Rantamäki for the mussels and F. Hoffmann-La Roche & Co. for supplying the vitamin D₃ metabolite standards. This work was supported by a grant from the Magnus Ehrnrooth Foundation to T. K.     

Steroid metabolism by mouse preimplantation embryos in vitro.

Mouse preimplantation embryos were incubated with radioactive pregnenolone, progesterone or dehydroepiandrosterone for various periods of time. These substrates were not converted to metabolites even after incubation of 120 h. We suggest that preimplantation mouse embryo does not possess enzyme activities for steroid metabolism.     

Contemporary fisherian life-history evolution in small salmonid populations

The relative importance of natural selection and random drift in phenotypic evolution has been discussed since the introduction of the first population genetic models. The empirical evidence used to evaluate the evolutionary theories of Fisher and Wright remains obscure because formal tests for neutral divergence or sensitive attempts to separate the effects of selection and drift are scarce, subject to error, and have not been interpreted in the light of well-known population demography. We combined quantitative genetic and microsatellite DNA analyses to investigate the determinants of contemporary life-history evolution in isolated populations of grayling (Thymallus thymallus, Salmonidae) that originated from a common source 80-120 years ago. Here we show that natural selection was the dominant diversifying agent in the evolution of the quantitative traits. However, the populations were founded by a small number of individuals, exhibit very low microsatellite-based effective sizes and show genetic imprints of severe 'bottlenecks'; which are conditions often suggested to constrain selection and favour drift. This study demonstrates a very clear case of fisherian evolution in small natural populations across a contemporary timescale.     

The loss of ions from Venus through the plasma wake

Venus, unlike Earth, is an extremely dry planet although both began with similar masses, distances from the Sun, and presumably water inventories. The high deuterium-to-hydrogen ratio in the venusian atmosphere relative to Earth's also indicates that the atmosphere has undergone significantly different evolution over the age of the Solar System. Present-day thermal escape is low for all atmospheric species. However, hydrogen can escape by means of collisions with hot atoms from ionospheric photochemistry, and although the bulk of O and O2 are gravitationally bound, heavy ions have been observed to escape through interaction with the solar wind. Nevertheless, their relative rates of escape, spatial distribution, and composition could not be determined from these previous measurements. Here we report Venus Express measurements showing that the dominant escaping ions are O+, He+ and H+. The escaping ions leave Venus through the plasma sheet (a central portion of the plasma wake) and in a boundary layer of the induced magnetosphere. The escape rate ratios are Q(H+)/Q(O+) = 1.9; Q(He+)/Q(O+) = 0.07. The first of these implies that the escape of H+ and O+, together with the estimated escape of neutral hydrogen and oxygen, currently takes place near the stoichometric ratio corresponding to water.     

A classifying procedure for signalling turning points

A Hidden Markov Model (HMM) is used to classify an out‐of‐sample observation vector into either of two regimes. This leads to a procedure for making probability forecasts for changes of regimes in a time series, i.e. for turning points. Instead of estimating past turning points using maximum likelihood, the model is estimated with respect to known past regimes. This makes it possible to perform feature extraction and estimation for different forecasting horizons. The inference aspect is emphasized by including a penalty for a wrong decision in the cost function. The method, here called a ‘Markov Bayesian Classifier (MBC)’, is tested by forecasting turning points in the Swedish and US economies, using leading data. Clear and early turning point signals are obtained, contrasting favourably with earlier HMM studies. Some theoretical arguments for this are given. Copyright © 2004 John Wiley & Sons, Ltd.     

Structural basis for messenger RNA movement on the ribosome

Translation initiation is a major determinant of the overall expression level of a gene. The translation of functionally active protein requires the messenger RNA to be positioned on the ribosome such that the start/initiation codon will be read first and in the correct frame. Little is known about the molecular basis for the interaction of mRNA with the ribosome at different states of translation. Recent crystal structures of the ribosomal subunits, the empty 70S ribosome and the 70S ribosome containing functional ligands have provided information about the general organization of the ribosome and its functional centres. Here we compare the X-ray structures of eight ribosome complexes modelling the translation initiation, post-initiation and elongation states. In the initiation and post-initiation complexes, the presence of the Shine-Dalgarno (SD) duplex causes strong anchoring of the 5'-end of mRNA onto the platform of the 30S subunit, with numerous interactions between mRNA and the ribosome. Conversely, the 5' end of the 'elongator' mRNA lacking SD interactions is flexible, suggesting a different exit path for mRNA during elongation. After the initiation of translation, but while an SD interaction is still present, mRNA moves in the 3'-->5' direction with simultaneous clockwise rotation and lengthening of the SD duplex, bringing it into contact with ribosomal protein S2.     

Steroid metabolism by mouse preimplantation embryos in vitro

Summary Mouse preimplantation embryos were incubated with radioactive pregnenolone, progesterone or dehydroepiandrosterone for various periods of time. These substrates were not converted to metabolites even after incubation of 120 h. We suggest that preimplantation mouse embryo does not possess enzyme activities for steroid metabolism.Acknowledgments. The authors would like to thank Prof. L. Saxén for giving the animals and the facilities of his tissue culture laboratory.     

A new understanding of the decoding principle on the ribosome

During protein synthesis, the ribosome accurately selects transfer RNAs (tRNAs) in accordance with the messenger RNA (mRNA) triplet in the decoding centre. tRNA selection is initiated by elongation factor Tu, which delivers tRNA to the aminoacyl tRNA-binding site (A site) and hydrolyses GTP upon establishing codon-anticodon interactions in the decoding centre. At the following proofreading step the ribosome re-examines the tRNA and rejects it if it does not match the A codon. It was suggested that universally conserved G530, A1492 and A1493 of 16S ribosomal RNA, critical for tRNA binding in the A site, actively monitor cognate tRNA, and that recognition of the correct codon-anticodon duplex induces an overall ribosome conformational change (domain closure). Here we propose an integrated mechanism for decoding based on six X-ray structures of the 70S ribosome determined at 3.1-3.4?? resolution, modelling cognate or near-cognate states of the decoding centre at the proofreading step. We show that the 30S subunit undergoes an identical domain closure upon binding of either cognate or near-cognate tRNA. This conformational change of the 30S subunit forms a decoding centre that constrains the mRNA in such a way that the first two nucleotides of the A codon are limited to form Watson-Crick base pairs. When U·G and G·U mismatches, generally considered to form wobble base pairs, are at the first or second codon-anticodon position, the decoding centre forces this pair to adopt the geometry close to that of a canonical C·G pair. This by itself, or with distortions in the codon-anticodon mini-helix and the anticodon loop, causes the near-cognate tRNA to dissociate from the ribosome.