Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations.

Defective function of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) causes CF, the most frequent lethal inherited disease among the Caucasian population. The structure of this chloride ion channel includes two nucleotide-binding domains (NBDs), whose ATPase activity controls channel gating. Recently, the experimental structures of mouse and human CFTR NBD1 and our model of the human CFTR NBD1/NBD2 heterodimer have provided new insights into specific structural features of the CFTR NBD dimer. In the present work, we provide a structural classification of CF-causing mutations which may complement the existing functional classification. Our analysis also identified amino acid residues which may play a critical role in interdomain interaction and are located at the NBD1-NBD2 interface or on the surface of the dimer. In particular, a cluster of aromatic amino acids, which includes F508 and straddles the two NBDs, might be directly involved in the interaction of the NBD1/NBD2 heterodimer with the channel-forming membrane-spanning domains.Received 24 May 2005; received after revision 13 June 2005; accepted 18 June 2005     

A novel pattern of fast calcium oscillations points to calcium and electrical activity cross-talk in rat chromaffin cells

Slow oscillations of cytosolic calcium ion concentration – – typically originate from release by intracellular stores, but in some cell types can be triggered and sustained by Ca²⁺ influx as well. In this study we simultaneously monitored changes in and in the electrical activity of the cell membrane by combining indo-1 and patch-clamp measurements in single rat chromaffin cells. By this approach we observed a novel type of spontaneous oscillations, much faster than those previously described in these cells. These oscillations are triggered and sustained by complex electrical activity (slow action potentials and spike bursts), require Ca²⁺ influx and do not involve release from intracellular stores. The possible physiological implications of this new pathway of intracellular signalling are discussed.Received 30 July 2004; received after revision 14 October 2004; accepted 1 November 2004     

An Earth-like correspondence between Saturn's auroral features and radio emission

Saturn is a source of intense kilometre-wavelength radio emissions that are believed to be associated with its polar aurorae, and which provide an important remote diagnostic of its magnetospheric activity. Previous observations implied that the radio emission originated in the polar regions, and indicated a strong correlation with solar wind dynamic pressure. The radio source also appeared to be fixed near local noon and at the latitude of the ultraviolet aurora. There have, however, been no observations relating the radio emissions to detailed auroral structures. Here we report measurements of the radio emissions, which, along with high-resolution images of Saturn's ultraviolet auroral emissions, suggest that although there are differences in the global morphology of the aurorae, Saturn's radio emissions exhibit an Earth-like correspondence between bright auroral features and the radio emissions. This demonstrates the universality of the mechanism that results in emissions near the electron cyclotron frequency narrowly beamed at large angles to the magnetic field.     

A late Eemian aridity pulse in central Europe during the last glacial inception

Investigating the processes that led to the end of the last interglacial period is relevant for understanding how our ongoing interglacial will end, which has been a matter of much debate (see, for example, refs 1, 2). A recent ice core from Greenland demonstrates climate cooling from 122,000 years ago driven by orbitally controlled insolation, with glacial inception at 118,000 years ago. Here we present an annually resolved, layer-counted record of varve thickness, quartz grain size and pollen assemblages from a maar lake in the Eifel (Germany), which documents a late Eemian aridity pulse lasting 468 years with dust storms, aridity, bushfire and a decline of thermophilous trees at the time of glacial inception. We interpret the decrease in both precipitation and temperature as an indication of a close link of this extreme climate event to a sudden southward shift of the position of the North Atlantic drift, the ocean current that brings warm surface waters to the northern European region. The late Eemian aridity pulse occurred at a 65 degrees N July insolation of 416 W m(-2), close to today's value of 428 W m(-2) (ref. 9), and may therefore be relevant for the interpretation of present-day climate variability.     

Generation and annotation of the DNA sequences of human chromosomes 2 and 4

Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.     

Fractures as the main pathways of water flow in temperate glaciers

Understanding the flow of water through the body of a glacier is important, because the spatial distribution of water and the rate of infiltration to the glacier bottom is one control on water storage and pressure, glacier sliding and surging, and the release of glacial outburst floods. According to the prevailing hypothesis, this water flow takes place in a network of tubular conduits. Here we analyse video images from 48 boreholes drilled into the small Swedish glacier Storglaci?ren, showing that the glacier's hydrological system is instead dominated by fractures that convey water at slow speeds. We detected hydraulically connected fractures at all depths, including near the glacier bottom. Our observations indicate that fractures provide the main pathways for surface water to reach deep within the glacier, whereas tubular conduits probably form only in special circumstances. A network of hydraulically linked fractures offers a simple explanation for the origin and evolution of the englacial water flow system and its seasonal regeneration. Such a fracture network also explains radar observations that reveal a complex pattern of echoes rather than a system of conduits. Our findings may be important in understanding the catastrophic collapse of ice shelves and rapid hydraulic connection between the surface and bed of an ice sheet.     

Environmental policy: regional commitment to reducing emissions

The non-participation of the United States in the recently ratified Kyoto Protocol is a matter for global concern because it is estimated that the country produces 24% of all greenhouse-gas emissions worldwide. Here we analyse the commitment of individual states and municipalities to addressing this problem and find that, despite the federal policy, between 24 and 35% of the US population are currently (or soon will be) engaged in policies directed towards significantly reducing anthropogenic climate change. The importance of this sub-national effort, which we estimate corresponds to 27-49% of the gross domestic product, will depend--like the targets adopted in Kyoto--on the real reductions achieved in greenhouse-gas emissions.