Speleothem U-series constraints on scarp retreat rates and landscape evolution: an example from the Severn valley and Cotswold Hills gull-caves, UK

Modelling landscape evolution requires quantitative estimates of erosional processes. Dating erosional landscape features such as escarpments is usually difficult because of the lack of datable deposits. Some escarpments and valley margins are associated with the formation of mass-movement caves, sometimes known as ‘gull’ or ‘crevice’ caves, which are typically restricted to within 0.5 km of the valley margin or scarp edge. As in other caves, these mass-movement cavities may host speleothems. As gull-caves develop only after valley incision, uranium-series dating of speleothems within them can provide a minimum age for the timing of valley excavation and scarp formation. Here we present data from several gull-caves in the Cotswold Hills, which form the eastern flank of the Severn valley in southern England. U-series ages from these gull-caves yield estimates for both the minimum age of the Cotswold escarpment and the maximum scarp retreat rate. This is combined with data from geological modelling to propose a model for the evolution of the Severn valley and the Cotswold Hills. The data suggest that the location of the escarpment and regional topography is determined not by valley widening and scarp retreat, but by the in situ generation of relief by differential erosion

Millennial scale control of European climate by the North Atlantic Oscillation from 12,500 BP: the Asiul speleothem record

Contemporary climate in Europe is strongly influenced by the North Atlantic Oscillation (NAO), the atmospheric pressure dipole between Iceland and the Azores1. Under positive NAO conditions winter storm tracks associated with the Atlantic Westerly Jet (AWJ) migrate northwards, leading to wetter and warmer winter conditions in north-western Europe and dry conditions in southern Europe; including the Iberian Peninsula. Under the negative NAO phase, storm tracks weaken and shift southwards reversing the pattern1. Existing proxy records of the NAO suggest that this atmospheric process only began to dominate European climate at approximately 8000 years BP, related to the final breakup of the Laurentide ice shelf2. However, here we present evidence of precipitation changes from a high-resolution speleothem δ18O record from northern Iberia, which indicates NAO-like forcing extending throughout the Holocene and into the Younger Dryas (YD) at 12,500 years BP. These variations in precipitation delivery relate to an underlying millennial scale cycle in NAO dynamics. The speleothem δ18O is strongly correlated to existing records of North Atlantic Ocean ice rafted debris (IRD)3, indicating an NAO-like connection with oceanic circulation during the Holocene2. These large-scale atmospheric processes have dramatically influenced the delivery of precipitation to northern Iberia and may have played a decisive role in environmental and human development in the region, throughout the Holocene

North Atlantic forcing of moisture delivery to Europe throughout the Holocene

Century-to-millennial scale fluctuations in precipitation and temperature are an established feature of European Holocene climates. Changes in moisture delivery are driven by complex interactions between ocean moisture sources and atmospheric circulation modes, making it difficult to resolve the drivers behind millennial scale variability in European precipitation. Here, we present two overlapping decadal resolution speleothem oxygen isotope (δ18O) records from a cave on the Atlantic coastline of northern Iberia, covering the period 12.1–0 ka. Speleothem δ18O reveals nine quasi-cyclical events of relatively wet-to-dry climatic conditions during the Holocene. Dynamic Harmonic Regression modelling indicates that changes in precipitation occurred with a ~1500 year frequency during the late Holocene and at a shorter length during the early Holocene. The timing of these cycles coincides with changes in North Atlantic Ocean conditions, indicating a connectivity between ocean conditions and Holocene moisture delivery. Early Holocene climate is potentially dominated by freshwater outburst events, whilst ~1500 year cycles in the late Holocene are more likely driven by changes internal to the ocean system. This is the first continental record of its type that clearly demonstrates millennial scale connectivity between the pulse of the ocean and precipitation over Europe through the entirety of the Holocene

Identification and characterization of an irreversible inhibitor of CDK2

Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)- 9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds

Roles of key active-site residues in flavocytochrome P450 BM3

Abbreviations used: P450, cytochrome P450 mono-oxygenase; ImC12, 12-(imidazolyl)dodecanoic acid; 1-PIM, 1-phenylimidazole.The effects of mutation of key active-site residues (Arg-47, Tyr-51, Phe-42 and Phe-87) in Bacillus megaterium flavocytochrome P450 BM3 were investigated. Kinetic studies on the oxidation of laurate and arachidonate showed that the side chain of Arg-47 contributes more significantly to stabilization of the fatty acid carboxylate than does that of Tyr-51 (kinetic parameters for oxidation of laurate: R47A mutant, Km 859 µM, kcat 3960 min-1; Y51F mutant, Km 432 µM, kcat 6140 min-1; wild-type, Km 288 µM, kcat 5140 min-1). A slightly increased kcat for the Y51F-catalysed oxidation of laurate is probably due to decreased activation energy (DG‡) resulting from a smaller DG of substrate binding. The side chain of Phe-42 acts as a phenyl 'cap' over the mouth of the substrate-binding channel. With mutant F42A, Km is massively increased and kcat is decreased for oxidation of both laurate (Km 2.08 mM, kcat 2450 min-1) and arachidonate (Km 34.9 µM, kcat 14620 min-1; compared with values of 4.7 µM and 17100 min-1 respectively for wild-type). Amino acid Phe-87 is critical for efficient catalysis. Mutants F87G and F87Y not only exhibit increased Km and decreased kcat values for fatty acid oxidation, but also undergo an irreversible conversion process from a 'fast' to a 'slow' rate of substrate turnover [for F87G (F87Y)-catalysed laurate oxidation: kcat 'fast', 760 (1620) min-1; kcat 'slow', 48.0 (44.6) min-1; kconv (rate of conversion from fast to slow form), 4.9 (23.8) min-1]. All mutants showed less than 10% uncoupling of NADPH oxidation from fatty acid oxidation. The rate of FMN-to-haem electron transfer was shown to become rate-limiting in all mutants analysed. For wild-type P450 BM3, the rate of FMN-to-haem electron transfer (8340 min-1) is twice the steady-state rate of oxidation (4100 min-1), indicating that other steps contribute to rate limitation. Active-site structures of the mutants were probed with the inhibitors 12-(imidazolyl)dodecanoic acid and 1-phenylimidazole. Mutant F87G binds 1-phenylimidazole > 10-fold more tightly than does the wild-type, whereas mutant Y51F binds the haem-co-ordinating fatty acid analogue 12-(imidazolyl)dodecanoic acid > 30-fold more tightly than wild-type

Isotopic composition ( 238 U/ 235 U) of some commonly used uranium reference materials

Abstract We have determined 238 U/ 235 U ratios for a suite of commonly used natural (CRM 112a, SRM 950a, and HU-1) and synthetic (IRMM 184 and CRM U500) uranium reference materials by thermal ionisation mass-spectrometry (TIMS) using the IRMM 3636 233 U-236 U double spike to accurately correct for mass fractionation. Total uncertainty on the 238 U/ 235 U determinations is estimated to be <0.02% (2r). These natural 238 U/ 235 U values are different from the widely used 'consensus' value (137.88), with each standard having lower 238 U/ 235 U values by up to 0.08%. The 238 U/ 235 U ratio determined for CRM U500 and IRMM 184 are within error of their certified values; however, the total uncertainty for CRM U500 is substantially reduced (from 0.1% to 0.02%). These reference materials are commonly used to assess mass-spectrometer performance and accuracy, calibrate isotope tracers employed in U, U-Th and U-Pb isotopic studies, and as a reference for terrestrial and meteoritic 238 U/ 235 U variations. These new 238 U/ 235 U values will thus provide greater accuracy and reduced uncertainty for a wide variety of isotopic determinations

Application of high-resolution telemetered sensor technology to develop conceptual models of catchment hydrogeological processes

Mitigating agricultural water pollution requires changes in land management practices and the implementation of on-farm measures to tackle the principal reasons for water quality failure. However, a paucity of robust empirical evidence on the hydrological functioning of river catchments can be a major constraint on the design of effective pollution mitigation strategies at the catchment-scale. In this regard, in 2010 the UK government established the Demonstration Test Catchment (DTC) initiative to evaluate the extent to which on-farm mitigation measures can cost-effectively reduce the impacts of agricultural water pollution on river ecology while maintaining food production capacity. A central component of the DTC platform has been the establishment of a comprehensive network of automated, web-based sensor technologies to generate high-temporal resolution empirical datasets of surface water, soil water, groundwater and meteorological parameters. In this paper, we demonstrate how this high-resolution telemetry can be used to improve our understanding of hydrological functioning and the dynamics of pollutant mobilisation and transport under a range of hydrometerological and hydrogeological conditions. Furthermore, we demonstrate how these data can be used to develop conceptual models of catchment hydrogeological processes and consider the implications of variable hydrological functioning on the performance of land management changes aimed at reducing agricultural water pollution

The place of strategic environmental assessment in the privatised electricity industry

The private sector has given relatively little attention to the emergence of strategic environmental assessment (SEA); even recently privatised utilities, where SEA might be deemed particularly appropriate, and whose activities are likely to fall within the scope of the European Union SEA Directive, have shown less interest than might be expected. However, the global trend towards the privatisation of state-owned enterprises makes the adaptation of SEA towards these industries all the more pressing. This paper addresses the place that SEA might take within the electricity sector, taking the privatised UK electricity industry as an example. Particular challenges are posed by the radical restructuring of the industry, designed to introduce competitive behaviour, making the development of comprehensive SEA processes problematic, and requiring SEA to be placed in the context of corporate environmental policy and objectives.</p

Analysis of brainstem activitywith fMRI during low-level of pain- a feasibility study with innocuous cold stimuli

Background: In functional magnetic resonance imaging (fMRI)studies, there are limitedpublished data on the functional map of the human brainstem. Objective: The primary goals of this pilot study were to assess the feasibility and  to map  the  neural activity in the human brainstem with fMRIby equal intensity by low-level of thermal stimuli on the peripheral sensors of the skin. Patients and Methods: FMRI studies of the brainstem were carried out on 6healthyindividuals in a 3T MRI machine. Noxious thermal stimuli was applied on the peripheral sensitisation nerves on the arm. FMRI data spanned from the brainstem location by a 32-head channel and analysed using a fixed-effects General Linear Model to discriminate signal intensity changes from physiological motion. The results were normalised and combined to show the activity at each location on a voxel-by-voxel basis. Areas of physiological activity were recognisedwith comparison to the  number of atlases. Results: Noxious and innocuous related activation clusters were approved in thisapplied method. There were considerable activity in the midbrain, pons, medulla and reticular formation. The results  of this pilot study are similar and in some anatomical regions even better with head coils than obtained with previous fMRI spinal coil studies.We obtained evidence of localization of the following nuclei by using this method, asfollows: major activities in the inferior anterior parts of pons and the junction with medulla includes the (olive and pyramids),superior cerebella pundicle, rostral portion of medulla (RMV), Broadmann areas  [5,2] touch and temperature sensation  areas with the innocuous stimuli; activation in the left side of the medulla the (olive and pyramids), the left side of pons, the left side of midbrain, Broadmann area [5,7] pain and temperature sensation areas with noxious stimuli. Conclusion:This pilotstudy provides useful evidenceoflow-painful and innocuous information transmitted  between the peripheral nervous system and the central nervous system in healthy participants.It also demonstrates how peripheral sensitisation induces physiological changes in the brainstem  correlates with noxious and innocuous thermal transmission

Isotopic composition (238U/235U) of some commonly used uranium reference materials

We have determined 238U/235U ratios for a suite of commonly used natural (CRM 112a, SRM 950a, and HU-1) and synthetic (IRMM 184 and CRM U500) uranium reference materials by thermal ionisation mass-spectrometry (TIMS) using the IRMM 3636 233U-236U double spike to accurately correct for mass fractionation. Total uncertainty on the 238U/235U determinations is estimated to be < 0.02% (2σ). These natural 238U/235U values are different from the widely used ‘consensus’ value (137.88), with each standard having lower 238U/235U values by up to 0.08%. The 238U/235U ratio determined for CRM U500 and IRMM 184 are within error of their certified values; however, the total uncertainty for CRM U500 is substantially reduced (from 0.1% to 0.02%). These reference materials are commonly used to assess mass spectrometer performance and accuracy, calibrate isotope tracers employed in U, U-Th and U-Pb isotopic studies, and as a reference for terrestrial and meteoritic 238U/235U variations. These new 238U/235U values will thus provide greater accuracy and reduced uncertainty for a wide variety of isotopic determinations