Mast cell stabilizing compound FPL 55618 reduces right ventricular hypertrophy and lung mast cell hyperplasia in chronically hypoxic rats

Rats treated with chronic hypobaric hypoxia (21 days, 380 Torr) and mast cell stabilizing compound FPL 55618 had significantly less right ventricular hypertrophy and lung mast cell hyperplasia than rats subjected to chronic hypoxia alone. Right ventricular blood pressure was not reduced.     

The European dimension for the mouse genome mutagenesis program

The European Mouse Mutagenesis Consortium is the European initiative contributing to the international effort on functional annotation of the mouse genome. Its objectives are to establish and integrate mutagenesis platforms, gene expression resources, phenotyping units, storage and distribution centers and bioinformatics resources. The combined efforts will accelerate our understanding of gene function and of human health and disease.     

Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR

Many biochemical processes proceed through the formation of functionally significant intermediates. Although the identification and characterization of such species can provide vital clues about the mechanisms of the reactions involved, it is challenging to obtain information of this type in cases where the intermediates are transient or present only at low population. One important example of such a situation involves the folding behaviour of small proteins that represents a model for the acquisition of functional structure in biology. Here we use relaxation dispersion nuclear magnetic resonance (NMR) spectroscopy to identify, for two mutational variants of one such protein, the SH3 domain from Fyn tyrosine kinase, a low-population folding intermediate in equilibrium with its unfolded and fully folded states. By performing the NMR experiments at different temperatures, this approach has enabled characterization of the kinetics and energetics of the folding process as well as providing structures of the intermediates. A general strategy emerges for an experimental determination of the energy landscape of a protein by applying this methodology to a series of mutants whose intermediates have differing degrees of native-like structure.     

Functional interaction of phytochrome B and cryptochrome 2

Light is a crucial environmental signal that controls many photomorphogenic and circadian responses in plants. Perception and transduction of light is achieved by at least two principal groups of photoreceptors, phytochromes and cryptochromes. Phytochromes are red/far-red light-absorbing receptors encoded by a gene family of five members (phyA to phyE) in Arabidopsis. Cryptochrome 1 (cry1), cryptochrome 2 (cry2) and phototropin are the blue/ultraviolet-A light receptors that have been characterized in Arabidopsis. Previous studies showed that modulation of many physiological responses in plants is achieved by genetic interactions between different photoreceptors; however, little is known about the nature of these interactions and their roles in the signal transduction pathway. Here we show the genetic interaction that occurs between the Arabidopsis photoreceptors phyB and cry2 in the control of flowering time, hypocotyl elongation and circadian period by the clock. PhyB interacts directly with cry2 as observed in co-immunoprecipitation experiments with transgenic Arabidopsis plants overexpressing cry2. Using fluorescent resonance energy transfer microscopy, we show that phyB and cry2 interact in nuclear speckles that are formed in a light-dependent fashion.     

A molecular information ratchet

Motor proteins and other biological machines are highly efficient at converting energy into directed motion and driving chemical systems away from thermodynamic equilibrium. But even though these biological structures have inspired the design of many molecules that mimic aspects of their behaviour, artificial nanomachine systems operate almost exclusively by moving towards thermodynamic equilibrium, not away from it. Here we show that information about the location of a macrocycle in a rotaxane-a molecular ring threaded onto a molecular axle-can be used, on the input of light energy, to alter the kinetics of the shuttling of the macrocycle between two compartments on the axle. For an ensemble of such molecular machines, the macrocycle distribution is directionally driven away from its equilibrium value without ever changing the relative binding affinities of the ring for the different parts of the axle. The selective transport of particles between two compartments by brownian motion in this way bears similarities to the hypothetical task performed without an energy input by a 'demon' in Maxwell's famous thought experiment. Our observations demonstrate that synthetic molecular machines can operate by an information ratchet mechanism, in which knowledge of a particle's position is used to control its transport away from equilibrium.     

Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae

The aspergilli comprise a diverse group of filamentous fungi spanning over 200 million years of evolution. Here we report the genome sequence of the model organism Aspergillus nidulans, and a comparative study with Aspergillus fumigatus, a serious human pathogen, and Aspergillus oryzae, used in the production of sake, miso and soy sauce. Our analysis of genome structure provided a quantitative evaluation of forces driving long-term eukaryotic genome evolution. It also led to an experimentally validated model of mating-type locus evolution, suggesting the potential for sexual reproduction in A. fumigatus and A. oryzae. Our analysis of sequence conservation revealed over 5,000 non-coding regions actively conserved across all three species. Within these regions, we identified potential functional elements including a previously uncharacterized TPP riboswitch and motifs suggesting regulation in filamentous fungi by Puf family genes. We further obtained comparative and experimental evidence indicating widespread translational regulation by upstream open reading frames. These results enhance our understanding of these widely studied fungi as well as provide new insight into eukaryotic genome evolution and gene regulation.