Mapping Solar System chaos with the Geological Orrery.

The Geological Orrery is a network of geological records of orbitally paced climate designed to address the inherent limitations of solutions for planetary orbits beyond 60 million years ago due to the chaotic nature of Solar System motion. We use results from two scientific coring experiments in Early Mesozoic continental strata: the Newark Basin Coring Project and the Colorado Plateau Coring Project. We precisely and accurately resolve the secular fundamental frequencies of precession of perihelion of the inner planets and Jupiter for the Late Triassic and Early Jurassic epochs (223-199 million years ago) using the lacustrine record of orbital pacing tuned only to one frequency (1/405,000 years) as a geological interferometer. Excepting Jupiter's, these frequencies differ significantly from present values as determined using three independent techniques yielding practically the same results. Estimates for the precession of perihelion of the inner planets are robust, reflecting a zircon U-Pb-based age model and internal checks based on the overdetermined origins of the geologically measured frequencies. Furthermore, although not indicative of a correct solution, one numerical solution closely matches the Geological Orrery, with a very low probability of being due to chance. To determine the secular fundamental frequencies of the precession of the nodes of the planets and the important secular resonances with the precession of perihelion, a contemporaneous high-latitude geological archive recording obliquity pacing of climate is needed. These results form a proof of concept of the Geological Orrery and lay out an empirical framework to map the chaotic evolution of the Solar System.

The revolution of crossdating in marine palaeoecology and palaeoclimatology.

Over the past century, the dendrochronology technique of crossdating has been widely used to generate a global network of tree-ring chronologies that serves as a leading indicator of environmental variability and change. Only recently, however, has this same approach been applied to growth increments in calcified structures of bivalves, fish and corals in the world's oceans. As in trees, these crossdated marine chronologies are well replicated, annually resolved and absolutely dated, providing uninterrupted multi-decadal to millennial histories of ocean palaeoclimatic and palaeoecological processes. Moreover, they span an extensive geographical range, multiple trophic levels, habitats and functional types, and can be readily integrated with observational physical or biological records. Increment width is the most commonly measured parameter and reflects growth or productivity, though isotopic and elemental composition capture complementary aspects of environmental variability. As such, crossdated marine chronologies constitute powerful observational templates to establish climate-biology relationships, test hypotheses of ecosystem functioning, conduct multi-proxy reconstructions, provide constraints for numerical climate models, and evaluate the precise timing and nature of ocean-atmosphere interactions. These 'present-past-future' perspectives provide new insights into the mechanisms and feedbacks between the atmosphere and marine systems while providing indicators relevant to ecosystem-based approaches of fisheries management.

A multifault earthquake threat for the Seattle metropolitan region revealed by mass tree mortality.

Compound earthquakes involving simultaneous ruptures along multiple faults often define a region's upper threshold of maximum magnitude. Yet, the potential for linked faulting remains poorly understood given the infrequency of these events in the historic era. Geological records provide longer perspectives, although temporal uncertainties are too broad to clearly pinpoint single multifault events. Here, we use dendrochronological dating and a cosmogenic radiation pulse to constrain the death dates of earthquake-killed trees along two adjacent fault zones near Seattle, Washington to within a 6-month period between the 923 and 924 CE growing seasons. Our narrow constraints conclusively show linked rupturing that occurred either as a single composite earthquake of estimated magnitude 7.8 or as a closely spaced double earthquake sequence with estimated magnitudes of 7.5 and 7.3. These scenarios, which are not recognized in current hazard models, increase the maximum earthquake size needed for seismic preparedness and engineering design within the Puget Sound region of >4 million residents.

Destabilisation of the Subpolar North Atlantic prior to the Little Ice Age.

The cooling transition into the Little Ice Age was the last notable shift in the climate system prior to anthropogenic global warming. It is hypothesised that sea-ice to ocean feedbacks sustained an initial cooling into the Little Ice Age by weakening the subpolar gyre circulation; a system that has been proposed to exhibit bistability. Empirical evidence for bistability within this transition has however been lacking. Using statistical indicators of resilience in three annually-resolved bivalve proxy records from the North Icelandic shelf, we show that the subpolar North Atlantic climate system destabilised during two episodes prior to the Little Ice Age. This loss of resilience indicates reduced attraction to one stable state, and a system vulnerable to an abrupt transition. The two episodes preceded wider subpolar North Atlantic change, consistent with subpolar gyre destabilisation and the approach of a tipping point, potentially heralding the transition to Little Ice Age conditions.

Natural drivers of multidecadal Arctic sea ice variability over the last millennium.

The climate varies due to human activity, natural climate cycles, and natural events external to the climate system. Understanding the different roles played by these drivers of variability is fundamental to predicting near-term climate change and changing extremes, and to attributing observed change to anthropogenic or natural factors. Natural drivers such as large explosive volcanic eruptions or multidecadal cycles in ocean circulation occur infrequently and are therefore poorly represented within the observational record. Here we turn to the first high-latitude annually-resolved and absolutely dated marine record spanning the last millennium, and the Paleoclimate Modelling Intercomparison Project (PMIP) Phase 3 Last Millennium climate model ensemble spanning the same time period, to examine the influence of natural climate drivers on Arctic sea ice. We show that bivalve oxygen isotope data are recording multidecadal Arctic sea ice variability and through the climate model ensemble demonstrate that external natural drivers explain up to third of this variability. Natural external forcing causes changes in sea-ice mediated export of freshwater into areas of active deep convection, affecting the strength of the Atlantic Meridional Overturning Circulation (AMOC) and thereby northward heat transport to the Arctic. This in turn leads to sustained anomalies in sea ice extent. The models capture these positive feedbacks, giving us improved confidence in their ability to simulate future sea ice in in a rapidly evolving Arctic.

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 2.

HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.

Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1.

GW4511, GW4751, and GW3011 showed IC50 values < or =2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.

Evidence of immediate activation of gender information from a social role name.

Two experiments investigated whether the stereotypical gender of a character is encoded immediately into the discourse representation and influences later comprehension. In Experiment 1 people read, and were confused by, a short story in which an incongruity arises at the end if the gender of a character introduced by a social role name has been inferred. In Experiment 2 online measures confirmed that readers were slower to read the final clause of the passage. In addition, a follow-up verification question revealed that these readers did not immediately resolve the inconsistency by inferring the appropriate gender for the role term. These findings provide strong evidence for gender activation at the time that a role name is encoded. The implications of these results for the mental representation of gender information and for constraints on inference during text comprehension are discussed.

Synthesis and antiviral activities of novel N-alkoxy-arylsulfonamide-based HIV protease inhibitors.

A series of novel N-alkoxy-arylsulfonamide HIV protease inhibitors with low picomolar enzyme activity and single digit nanomolar antiviral activity is disclosed.

Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir.

GW433908 is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of GW433908 is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl(3)) in pyridine. A single-dose pharmacokinetic study of GW433908 sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of GW433908 was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of GW433908 calcium salt in dogs and rats produced portal vein GW433908 concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, GW433908 had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that GW433908 is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, GW433908 was advanced to clinical development.