Synthesis of unsaturated aminopyranosides as possible transition state mimics for glycosidases

Four unsaturated aminopyranosides have been prepared as possible transition-state mimics targeted towards carbohydrate processing enzymes. The conformations of the protonated aminosugars have been investigated by molecular modelling and their ability to inhibit alpha- and beta-glucosidases and an a-mannosidase have been probed. Two targets proved moderate inhibitors of alpha-glucosidases from Brewer's yeast and Bacillus stearothennophilus.

Quercetin inhibits collagen-stimulated platelet activation through inhibition of multiple components of the glycoprotein VI signaling pathway

Background: The regulation of platelet function by pharmacological agents that modulate platelet signaling haspharmacolo proven a successful approach to the prevention of thrombosis. A variety of molecules present in the diet have been shown to inhibit platelet activation, including the antioxidant quercetin. Objectives: In this report we investigate the molecular mechanisms through which quercetin inhibits collagen-stimulated platelet aggregation. Methods: The effect of quercetin on platelet aggregation, intracellular calcium release, whole cell tyrosine phosphorylation and intracellular signaling events including tyrosine phosphorylation and kinase activity of proteins involved in the collagen-stimulated glycoprotein (GP) signaling pathway were investigated. Results: We report that quercetin inhibits collagen-stimulated whole cell protein tyrosine phosphorylation and intracellular mobilization of calcium, in a concentration-dependent manner. Quercetin was also found to inhibit various events in signaling generated by the collagen receptor GPVI. This includes collagen-stimulated tyrosine phosphorylation of the Fc receptor gamma-chain, Syk, LAT and phospholipase Cgamma2. Inhibition of phosphorylation of the Fc receptor gamma-chain suggests that quercetin inhibits early signaling events following stimulation of platelets with collagen. The activity of the kinases that phosphorylate the Fc receptor gamma-chain, Fyn and Lyn, as well as the tyrosine kinase Syk and phosphoinositide 3-kinase was also inhibited by quercetin in a concentration-dependent manner, both in whole cells and in isolation. Conclusions: The present results provide a molecular basis for the inhibition by quercetin of collagen-stimulated platelet activation, through inhibition of multiple components of the GPVI signaling pathway, and may begin to explain the proposed health benefits of high quercetin intake.

A new method for the determination of Holocene palaeohydrology

This paper describes a new method for the assessment of palaeohydrology through the Holocene. A palaeoclimate model was linked with a hydrological model, using a weather generator to correct bias in the rainfall estimates, to simulate the changes in the flood frequency and the groundwater response through the late Pleistocene and Holocene for the Wadi Faynan in southern Jordan, a site considered internationally important due to its rich archaeological heritage spanning the Pleistocene and Holocene. This is the first study to describe the hydrological functioning of the Wadi Faynan, a meso-scale (241 km2) semi-arid catchment, setting this description within the framework of contemporary archaeological investigations. Historic meteorological records were collated and supplemented with new hydrological and water quality data. The modelled outcomes indicate that environmental changes, such as deforestation, had a major impact on the local water cycle and this amplified the effect of the prevailing climate on the flow regime. The results also show that increased rainfall alone does not necessarily imply better conditions for farming and highlight the importance of groundwater. The discussion focuses on the utility of the method and the importance of the local hydrology to the sustained settlement of the Wadi Faynan through pre-history and history.

On the edge: Southern Levantine Epipalaeolithic–Neolithic chronological succession

The broad picture of the cultural and chronological succession from the Epipalaeolithic to the Neolithic in the southern Levant is generally well understood. However, at a more detailed, local level, many questions remain unanswered. In this paper we examine the archaeological record of cultural developments in southern Jordan and the Negev. Focusing on a series of 14C dates from the early occupation of the PPNA site of WF16, we provide a critical review of dating evidence for the region. This review suggests that while the 14C chronology is ambiguous and problematic there is good evidence for a local historical development from the Harifian variant of the Natufian to the early PPNA, well to the south of any core Mediterranean woodland zone. This stresses the importance of considering developments at local scales of analysis, and that the Neolithic transition occurred within a framework of many interacting sub-regional provinces.

The maximum rate of mammal evolution

How fast can a mammal evolve from the size of a mouse to the size of an elephant? Achieving such a large transformation calls for major biological reorganization. Thus, the speed at which this occurs has important implications for extensive faunal changes, including adaptive radiations and recovery from mass extinctions. To quantify the pace of large-scale evolution we developed a metric, clade maximum rate, which represents the maximum evolutionary rate of a trait within a clade. We applied this metric to body mass evolution in mammals over the last 70 million years, during which multiple large evolutionary transitions occurred in oceans and on continents and islands. Our computations suggest that it took a minimum of 1.6, 5.1, and 10 million generations for terrestrial mammal mass to increase 100-, and 1,000-, and 5,000- fold, respectively. Values for whales were down to half the length (i.e., 1.1, 3, and 5 million generations), perhaps due to the reduced mechanical constraints of living in an aquatic environment. When differences in generation time are considered, we find an exponential increase in maximum mammal body mass during the 35 million years following the Cretaceous–Paleogene (K–Pg) extinction event. Our results also indicate a basic asymmetry in macroevolution: very large decreases (such as extreme insular dwarfism) can happen at more than 10 times the rate of increases. Our findings allow more rigorous comparisons of microevolutionary and macroevolutionary patterns and processes. Keywords: haldanes, biological time, scaling, pedomorphosis

Lessons from the private finance initiative in the UK: benefits, problems and critical success factors

Purpose – This paper summarises the main research findings from a detailed, qualitative set of structured interviews and case studies of private finance initiative (PFI) schemes in the UK, which involve the construction of built facilities. The research, which was funded by the Foundation for the Built Environment, examines the emergence of PFI in the UK. Benefits and problems in the PFI process are investigated. Best practice, the key critical factors for success, and lessons for the future are also analysed. Design/methodology/approach – The research is based around 11 semi-structured interviews conducted with stakeholders in key PFI projects in the UK. Findings – The research demonstrates that value for money and risk transfer are key success criteria. High procurement and transaction costs are a feature of PFI projects, and the large-scale nature of PFI projects frequently acts as barrier to entry. Research limitations/implications – The research is based on a limited number of in-depth case study interviews. The paper also shows that further research is needed to find better ways to measure these concepts empirically. Practical implications – The paper is important in highlighting four main areas of practical improvement in the PFI process: value for money assessment; establishing end-user needs; developing competitive markets and developing appropriate skills in the public sector. Originality/value – The paper examines the drivers, barriers and critical success factors for PFI in the UK for the first time in detail and will be of value to property investors, financiers, and others involved in the PFI process.