Effect of sleep stage on breathing in children with central hypoventilation.

The early literature suggests that hypoventilation in infants with congenital central hypoventilation syndrome (CHS) is less severe during rapid eye movement (REM) than during non-REM (NREM) sleep. However, this supposition has not been rigorously tested, and subjects older than infancy have not been studied. Given the differences in anatomy, physiology, and REM sleep distribution between infants and older children, and the reduced number of limb movements during REM sleep, we hypothesized that older subjects with CHS would have more severe hypoventilation during REM than NREM sleep. Nine subjects with CHS, aged (mean +/- SD) 13 +/- 7 yr, were studied. Spontaneous ventilation was evaluated by briefly disconnecting the ventilator under controlled circumstances. Arousal was common, occurring in 46% of REM vs. 38% of NREM trials [not significant (NS)]. Central apnea occurred during 31% of REM and 54% of NREM trials (NS). Although minute ventilation declined precipitously during both REM and NREM trials, hypoventilation was less severe during REM (drop in minute ventilation of 65 +/- 23%) than NREM (drop of 87 +/- 16%, P = 0.036). Despite large changes in gas exchange during trials, there was no significant change in heart rate during either REM or NREM sleep. We conclude that older patients with CHS frequently have arousal and central apnea, in addition to hypoventilation, when breathing spontaneously during sleep. The hypoventilation in CHS is more severe during NREM than REM sleep. We speculate that this may be due to increased excitatory inputs to the respiratory system during REM sleep.     

Discovery of novel sphingosine kinase-1 inhibitors. Part 2

Building on our initial work, we have identified additional novel inhibitors of sphingosine kinase-1 (SK1). These new analogs address the shortcomings found in our previously reported compounds. Inhibitors 51 and 54 demonstrated oral bioavailability in a rat PK study.     

Towards a biogeographic regionalization of the European biota

Aim To determine if it is possible to generate analytically derived regionalizations for multiple groups of European plants and animals and to explore potential influences on the regions for each taxonomic group. Location Europe. Methods We subjected range maps of trees, butterflies, reptiles, amphibians, birds and mammals to k‐means clustering followed by v‐fold cross‐validation to determine the pattern and number of regions (clusters). We then used the mean range sizes of species in each group as a correlate of the number of regions obtained for each taxon, and climate and species richness gradients as correlates of the spatial arrangement of the group‐specific regions. We also included the pattern of tree clusters as a predictor of animal clusters in order to test the ‘habitat templet’ concept as an explanation of animal distribution patterns. Results Spatially coherent clusters were found for all groups. The number of regions ranged from three to eight and was strongly associated with the mean range sizes of the species in each taxon. The cluster patterns of all groups were associated with various combinations of climate, underlying species richness gradients and, in the case of animals, the arrangement of tree clusters, although the rankings of the correlates differed among groups. In four of five groups the tree pattern was the strongest single predictor of the animal cluster patterns. Main conclusions Despite a long history of human disturbance and habitat modification, the European biota retains a discernable biogeographic structure. The primary driver appears to be aspects of climate related to water–energy balance, which also influence richness gradients. For many animals, the underlying habitat structure, as measured by tree distributions, appears to have a strong influence on their biogeographic structure, highlighting the need to preserve natural forest formations if we want to preserve the historical signal found in geographic distributions.     

Genome-Wide Distribution of Transposed Dissociation Elements in Maize

The maize (Zea mays) transposable element Dissociation (Ds) was mobilized for large-scale genome mutagenesis and to study its endogenous biology. Starting from a single donor locus on chromosome 10, over 1500 elements were distributed throughout the genome and positioned on the maize physical map. Genetic strategies to enrich for both local and unlinked insertions were used to distribute Ds insertions. Global, regional, and local insertion site trends were examined. We show that Ds transposed to both linked and unlinked sites and displayed a nonuniform distribution on the genetic map around the donor r1-sc:m3 locus. Comparison of Ds and Mutator insertions reveals distinct target preferences, which provide functional complementarity of the two elements for gene tagging in maize. In particular, Ds displays a stronger preference for insertions within exons and introns, whereas Mutator insertions are more enriched in promoters and 5′-untranslated regions. Ds has no strong target site consensus sequence, but we identified properties of the DNA molecule inherent to its local structure that may influence Ds target site selection. We discuss the utility of Ds for forward and reverse genetics in maize and provide evidence that genes within a 2- to 3-centimorgan region flanking Ds insertions will serve as optimal targets for regional mutagenesis.     

GO‐At : in silico prediction of gene function in Arabidopsis thaliana by combining heterogeneous data

Despite recent advances, accurate gene function prediction remains an elusive goal, with very few methods directly applicable to the plant Arabidopsis thaliana. In this study, we present GO‐At (gene ontology prediction in A. thaliana), a method that combines five data types (co‐expression, sequence, phylogenetic profile, interaction and gene neighbourhood) to predict gene function in Arabidopsis. Using a simple, yet powerful two‐step approach, GO‐At first generates a list of genes ranked in descending order of probability of functional association with the query gene. Next, a prediction score is automatically assigned to each function in this list based on the assumption that functions appearing most frequently at the top of the list are most likely to represent the function of the query gene. In this way, the second step provides an effective alternative to simply taking the ‘best hit’ from the first list, and achieves success rates of up to 79%. GO‐At is applicable across all three GO categories: molecular function, biological process and cellular component, and can assign functions at multiple levels of annotation detail. Furthermore, we demonstrate GO‐At’s ability to predict functions of uncharacterized genes by identifying ten putative golgins/Golgi‐associated proteins amongst 8219 genes of previously unknown cellular component and present independent evidence to support our predictions. A web‐based implementation of GO‐At ( http://www.bioinformatics.leeds.ac.uk/goat ) is available, providing a unique resource for plant researchers to make predictions for uncharacterized genes and predict novel functions in Arabidopsis.     

Mapping macroecology

Although macroecology arose from geographical ecology, it has diverted from a geographical perspective. At present, most macroecological studies use a statistical approach that adopts an 'individual species focus' and relies on comparisons between species to test for broad-scale ecological patterns. Sometimes, space is included as part of the analysis, but almost always in a single dimension. In both situations, observed relationships are depicted using bivariate scatter-plots. We argue that current macroecological approaches may interfere with our perception of patterns and have important implications for their biological interpretation. We use the literature concerned with spatial variation in the range sizes of species (Rapoport's rule) to illustrate our point of view. Given the current lack of maps actually showing the patterns we are trying to explain, we contend that macroecology could benefit greatly by returning to its geographical roots, at least when data contain spatial structure.     

A catastrophic meltwater flood event and the formation of the Hudson Shelf Valley

The Hudson Shelf Valley (HSV) is the largest physiographic feature on the U.S. mid-Atlantic continental shelf. The 150-km long valley is the submerged extension of the ancestral Hudson River Valley that connects to the Hudson Canyon. Unlike other incised valleys on the mid-Atlantic shelf, it has not been infilled with sediment during the Holocene. Analyses of multibeam bathymetry, acoustic backscatter intensity, and high-resolution seismic reflection profiles reveal morphologic and stratigraphic evidence for a catastrophic meltwater flood event that formed the modern HSV. The valley and its distal deposits record a discrete flood event that carved 15-m high banks, formed a 120-km² field of 3- to 6-m high bedforms, and deposited a subaqueous delta on the outer shelf. The HSV is inferred to have been carved initially by precipitation and meltwater runoff during the advance of the Laurentide Ice Sheet, and later by the drainage of early proglacial lakes through stable spillways. A flood resulting from the failure of the terminal moraine dam at the Narrows between Staten Island and Long Island, New York, allowed glacial lakes in the Hudson and Ontario basins to drain across the continental shelf. Water level changes in the Hudson River basin associated with the catastrophic drainage of glacial lakes Iroquois, Vermont, and Albany around 11,450 ¹⁴C year BP (∼ 13,350 cal BP) may have precipitated dam failure at the Narrows. This 3200 km³ discharge of freshwater entered the North Atlantic proximal to the Gulf Stream and may have affected thermohaline circulation at the onset of the Intra-Allerød Cold Period. Based on bedform characteristics and fluvial morphology in the HSV, the maximum freshwater flux during the flood event is estimated to be ∼ 0.46 Sv for a duration of ∼ 80 days.     

Maspin binds to urokinase-type and tissue-type plasminogen activator through exosite-exosite interactions

Maspin is a member of the serpin family with a reactive center loop that is incompatible with proteinase inhibition by the serpin conformational change mechanism. Despite this there are reports that maspin might regulate uPA-dependent processes in vivo. Using exogenous and endogenous fluorescence, we demonstrate here that maspin can bind uPA and tPA in both single-chain and double-chain forms, with K(d) values between 300 and 600 nM. Binding is at an exosite on maspin close to, but outside of, the reactive center loop and is therefore insensitive to mutation of Arg(340) within the reactive center loop. The binding site on tPA does not involve the proteinase active site, with the result that maspin can bind to S195A tPA that is already complexed to plasminogen activator inhibitor-1. The ability of maspin to bind these proteinases without involvement of the reactive center loop leaves the latter free to engage in additional, as yet unidentified, maspin-protein interactions that may serve to regulate the properties of the exosite-bound proteinase. This may help to reconcile apparently conflicting studies that demonstrate the importance of the reactive center loop in certain maspin functions, despite the inability of maspin to directly inhibit tPA or uPA catalytic activity in in vitro assays through engagement between its reactive center loop and the active site of the proteinase.