Persistent multi-scale fluctuations shift European hydroclimate to its millennial boundaries.

In recent years, there has been growing concern about the effect of global warming on water resources, especially at regional and continental scales. The last IPCC report on extremes states that there is medium confidence about an increase on European drought frequency during twentieth century. Here we use the Old World Drought Atlas palaeoclimatic reconstruction to show that when Europe's hydroclimate is examined under a millennial, multi-scale perspective, a significant decrease in dryness can be observed since 1920 over most of central and northern Europe. On the contrary, in the south, drying conditions have prevailed, creating an intense north-to-south dipole. In both cases, hydroclimatic conditions have shifted to, and in some regions exceeded, their millennial boundaries, remaining at these extreme levels for the longest period of the 1000-year-long record.

European and Mediterranean hydroclimate responses to tropical volcanic forcing over the last millennium.

Volcanic eruptions have global climate impacts, but their effect on the hydrologic cycle is poorly understood. We use a modified version of superposed epoch analysis, an eruption year list collated from multiple datasets, and seasonal paleoclimate reconstructions (soil moisture, precipitation, geopotential heights, and temperature) to investigate volcanic forcing of spring and summer hydroclimate over Europe and the Mediterranean over the last millennium. In the western Mediterranean, wet conditions occur in the eruption year and the following 3 years. Conversely, northwestern Europe and the British Isles experience dry conditions in response to volcanic eruptions, with the largest moisture deficits in post-eruption years 2 and 3. The precipitation response occurs primarily in late spring and early summer (April-July), a pattern that strongly resembles the negative phase of the East Atlantic Pattern. Modulated by this mode of climate variability, eruptions force significant, widespread, and heterogeneous hydroclimate responses across Europe and the Mediterranean.

Internal ocean-atmosphere variability drives megadroughts in Western North America.

Multidecadal droughts that occurred during the Medieval Climate Anomaly represent an important target for validating the ability of climate models to adequately characterize drought risk over the near-term future. A prominent hypothesis is that these megadroughts were driven by a centuries-long radiatively forced shift in the mean state of the tropical Pacific Ocean. Here we use a novel combination of spatiotemporal tree-ring reconstructions of Northern Hemisphere hydroclimate to infer the atmosphere-ocean dynamics that coincide with megadroughts over the American West, and find that these features are consistently associated with ten-to-thirty year periods of frequent cold El Niño Southern Oscillation conditions and not a centuries-long shift in the mean of the tropical Pacific Ocean. These results suggest an important role for internal variability in driving past megadroughts. State-of-the art climate models from the Coupled Model Intercomparison Project phase 5, however, do not simulate a consistent association between megadroughts and internal variability of the tropical Pacific Ocean, with implications for our confidence in megadrought risk projections.

Discovery of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility.

Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.

Variability in the El Niño-Southern Oscillation through a glacial-interglacial cycle.

The El Niño-Southern Oscillation (ENSO) is the most potent source of interannual climate variability. Uncertainty surrounding the impact of greenhouse warming on ENSO strength and frequency has stimulated efforts to develop a better understanding of the sensitivity of ENSO to climate change. Here we use annually banded corals from Papua New Guinea to show that ENSO has existed for the past 130,000 years, operating even during "glacial" times of substantially reduced regional and global temperature and changed solar forcing. However, we also find that during the 20th century ENSO has been strong compared with ENSO of previous cool (glacial) and warm (interglacial) times. The observed pattern of change in amplitude may be due to the combined effects of ENSO dampening during cool glacial conditions and ENSO forcing by precessional orbital variations.

Assignments and structure determination of the catalytic domain of human fibroblast collagenase using 3D double and triple resonance NMR spectroscopy.

We report here the backbone 1HN, 15N, 13C alpha, 13CO, and 1H alpha NMR assignments for the catalytic domain of human fibroblast collagenase (HFC). Three independent assignment pathways (matching 1H, 13C alpha, and 13CO resonances) were used to establish sequential connections. The connections using 13C alpha resonances were obtained from HNCOCA and HNCA experiments; 13CO connections were obtained from HNCO and HNCACO experiments. The sequential proton assignment pathway was established from a 3D (1H/15N) NOESY-HSQC experiment. Amino acid typing was accomplished using 13C and 15N chemical shifts, specific labeling of 15N-Leu, and spin pattern recognition from DQF-COSY. The secondary structure was determined by analyzing the 3D (1H/15N) NOESY-HSQC. A preliminary NMR structure calculation of HFC was found to be in agreement with recent X-ray structures of human fibroblast collagenase and human neutrophil collagenase as well as similar to recent NMR structures of a highly homologous protein, stromelysin. All three helices were located; a five-stranded beta-sheet (four parallel strands, one antiparallel strand) was also determined. beta-Sheet regions were identified by cross-strand d alpha N and d NN connections and by strong intraresidue d alpha N correlations, and were corroborated by observing slow amide proton exchange. Chemical shift changes in a selectively 15N-labeled sample suggest that substantial structural changes occur in the active site cleft on the binding of an inhibitor.

Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1' group.

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' butyramide group resulted in a nanomolar potent and selective HNC inhibitor as well as a dual HFS/HNC inhibitor. Benzylic ethers with a four- or five-carbon methylene linker in the P1' position also produced nanomolar potent HFS/HNC inhibition and micromolar potent HFC inhibition as expected. Surprisingly, the phenolic ethers of the same overall length as the benzylic ethers showed nanomolar potencies against HFC, as well as HFS and HNC. The potency profile of the phenolic ethers was optimized by structure-activity relationships of the phenolic group and the C-terminal amide. These inhibitors may help elucidate the in vivo roles of matrix metalloproteinases in normal and disease states.

1.56 A structure of mature truncated human fibroblast collagenase.

The X-ray crystal structure of a 19 kDa active fragment of human fibroblast collagenase has been determined by the multiple isomorphous replacement method and refined at 1.56 A resolution to an R-factor of 17.4%. The current structure includes a bound hydroxamate inhibitor, 88 waters and three metal atoms (two zincs and a calcium). The overall topology of the enzyme, comprised of a five stranded beta-sheet and three alpha-helices, is similar to the thermolysin-like metalloproteinases. There are some important differences between the collagenase and thermolysin families of enzymes. The active site zinc ligands are all histidines (His-218, His-222, and His-228). The presence of a second zinc ion in a structural role is a unique feature of the matrix metalloproteinases. The binding properties of the active site cleft are more dependent on the main chain conformation of the enzyme (and substrate) compared with thermolysin. A mechanism of action for peptide cleavage similar to that of thermolysin is proposed for fibroblast collagenase.

Activation of polyomavirus DNA replication by yeast GAL4 is dependent on its transcriptional activation domains.

The polyomavirus replication origin contains transcriptional regulatory sequences. To determine how these elements function in DNA replication, and to learn whether a common mechanism underlies the activation of transcription and DNA replication, we tested whether a well-characterized transcriptional activator, yeast GAL4, was capable of stimulating DNA replication and transcription in the same mammalian cell line. We observed that GAL4 activated polyomavirus DNA replication in mouse cells when its binding site was juxtaposed to the late border of the polyomavirus origin core. Synergistic activation of DNA replication was achieved by multimerization of the GAL4 binding site. Analysis of GAL4 mutant proteins, GAL4 hybrid proteins and mutants of the latter revealed that the activation domains of these transcriptional activators were required to stimulate DNA replication. In agreement with previously published data, the activation domains of GAL4 were also required to enhance transcription in the same mouse cell line. These observations implicate transcriptional activators in Py DNA replication and suggest that similar mechanisms govern the activation of transcription and DNA replication.

Climate and red spruce growth and decline in the northern Appalachians.

Between the mid-1960s and mid-1980s, red spruce (Picea rubens Sarg.) died at unusual rates on the mountains of New York and western New England. We determined the relationship between standardized tree ring widths and monthly climate data for calibration and verification periods from 1856 to 1981 and found that after about 1960, there was a distinct shift in the temperature variables related to standardized ring widths in vigorous spruce. The beginning of widespread spruce mortality, regionwide growth decreases, and the shift in response to climate in the early 1960s corresponds to the onset of a decade of unusually cold winters and several consecutive years when severe winter damage was noted across the Northeast in this species. We suggest that the episodes of winter damage are an important initiating and synchronizing factor in the red spruce decline.

Forest decline: modeling the effect of climate in tree rings.

Tree rings provide an historical record of forest growth that reflects changes with time in site factors including, competition, tree and stand age, fire and other disturbances, and climate. Statistical methods can be used to factor out climatic influences on radial growth to yield a climate response model that can indicate whether declines in forest productivity are related to the modeled climatic variables or to other influences such as atmospheric pollutants. A general method, based on ordinary least squares, is presented for creating climatic response models for forest decline studies. The crux of the method is model verification, whereby the time-stability of the model is tested before it is used to forecast tree-ring variations during a period of decline. Three studies are described that employ monthly mean temperatures to predict tree-ring indices in declining red spruce (Picea rubens Sarg.) stands in the Appalachian Mountains of North America. The results indicate that, since 1960, red spruce trees at most of the sites sampled have undergone a period of growth decline that is unrelated to changes in mean monthly temperature. However, an association between annual ring width and unusual departures from the mean summer and winter temperatures during both present and past periods of decline suggests that climatic effects are implicated to some degree in the current decline.

An analysis of climate and competition as contributors to decline of red spruce in high elevation Appalachian forests of the Eastern United states.

Long-term growth patterns of red spruce (Picea rubens Sarg.) were analyzed from increment cores collected from over 1000 trees at 48 sites in the eastern United States. Principal objectives were the evaluation of the distribution, timing, and uniqueness of observed patterns of decreasing radial growth during the past 25 years and the examination of stand competition and climate as factors contributing to observed changes.Our analyses focused on historical records of spruce mortality and approximately 200 years of radial growth data to search for historical precedents for current trends. In this work we have used time series analysis to detect the temporal frequency of significant negative or positive shifts in radial growth rates, an analysis of relationships between a stand competition index and observed changes in growth and mortality, and modeling of past growth-climate relationships to determine whether recent growth changes could be predicted based on climate.Collectively, these analyses indicate that the observed growth decreases of surviving red spruce trees at northeastern sites with high mortality have been anomalous during the past 20 to 25 years with respect to both historical annual growth patterns and past relationships to climate or stand development at these sites. In general, reductions in radial increment that have also been noted at southern high elevation sites but not at low elevations occurred 5 to 10 years later than at northern sites and represent less substantive departures from growth trends predicted by linear climate models.These results suggest that regional and not local stresses have triggered the observed decline in radial growth of red spruce at these sites. While climatic change may have contributed to observed changes, the degree of radial growth suppression observed is greater than would be expected based on past growth-climate relationships. This unique relationship of growth to climate suggests the influences of either recent, unique combinations of climatic stresses or the possibly interactive intervention of other regional-scale stresses, such as atmospheric pollution.

Tree-ring-drought relationships in the hudson valley, new york.

Annual tree-ring chronologies from certain well-drained sites in the Hudson Valley of New York record past changes in temperature and precipitation. This information accounts for much of the July variation in Palmer drought severity indices during the period 1931 to 1970 and is used to develop a preliminary reconstruction of drought as long ago as 1728.