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Floods are the largest natural disaster currently facing the UK, whilst the incidents of droughts have increased in recent years. Floods and droughts can have devastating consequences on society, resulting in significant financial damage to the economy. Climate models suggest that precipitation and temperature changes will exacerbate future hydrological extremes (i.e., floods and droughts). Such events are likely to become more frequent and intense in the future; thus to develop adaptation plans climate model projections feed hydrological models to provide future water resource projections. ‘eFLaG’ is one set of future river flow projections produced for the UK driven by UKCP18 climate projections from the UK Met Office. The UKCP18-derived eFLaG dataset provides state-of-the-art projections for a single GCM driven by RCP 8.5 across the entire UK. A QE-ANOVA approach has been used to partition contributing sources of uncertainty for two flow quantiles (Q5 high flows and Q95 low flows), at near and far future time scales, for each of the 186 GB catchments in the eFLaG dataset. Results suggest a larger hydrological model uncertainty associated with low flows and greater regional climate model uncertainty for high flows which remains stationary between flow indicators. Total uncertainty increases from near to far future and highly uncertain catchments have been identified with a high concentration in South-East England. [ABSTRACT FROM AUTHOR]

The article reports that Barbara Van Dyck was fired from her post at the University of Leuven in Belgium on June 3, 2011 and her supports for the anti-GMO (Genetically Modified Organism) activist group called Field Liberation Movement (FLM) is cited as reason. The friction between science and policy making and Amateur science are discussed.

There are numerous anecdotal examples of drought terminations documented throughout the historical record on most continents. The end of a drought is the critical time during which water resource managers urgently require information on the replenishment of supplies. Yet this phase has been relatively neglected by the academic community, with much of the existing body of research on drought termination assessing the likelihood of droughts ending rather than its temporal profile. In particular, there has been little effort to characterise drought termination events themselves. This is partly explained by existing definitions of drought termination as a specific point in time when drought is considered to have finished, rather than a more holistic consideration based on approaches developed within biological sciences. There is also a lack of understanding about how drought termination propagates through the hydrological cycle. This paper specifically examines and reviews available research on drought termination, highlighting limitations associated with current definitions and offering suggestions for characterising the temporal stages of drought. An alternative definition of drought termination is proposed: a period between the maximum negative anomaly and a return to above-average conditions. Once this phase has been delineated, the duration, rate and seasonality of drought termination can be derived. The utility of these metrics is illustrated through a case study of the 2010-2012 drought in the UK, and the propagation of drought termination between river flows and groundwater levels. [ABSTRACT FROM AUTHOR]

This article examines the global phenomenon of the Critical Mass Cycle Ride, mass cycling protests that take place in many different cities around the world but follow similar patterns of spontaneous (dis)organisation and regular but shifting rhythms. It explores the theatricality of the cycle rides as a form of protest, arguing that this theatricality is central to understanding their gestural politics. The article focuses in particular on the London ride discussing the debates (2005–08) that culminated in a House of Lords ruling on their legal status. A critical account of these debates suggests that the rides employ a mode of ‘sly civility’ (Bhabha) to register what the geographer Doreen Massey has called a relational politics of place: a local practice of citizenship beyond the local. [ABSTRACT FROM AUTHOR]

The article introduces the topics of the August 2015 issue of the theater periodical "Contemporary Theatre Review" including third wave feminist protest performances, the Critical Mass cycling protest as performance, and Laila Soliman's performance piece "No Time for Art".

Volumetric absorptive microsampling (VAMS) is a simple intuitive technique for collecting and quantitative analysis of dried blood samples. It enables the collection of an accurate blood volume (approximately 10 μL) regardless of blood hematocrit. A bioanalytical method for the determination of paracetamol in dried blood supported on VAMS samplers has been validated and used to support a toxicokinetic (TK) study in rat. The calculated TK parameters were comparable to those obtained from blood–water (1:1, v/v) samples. VAMS is demonstrated to be a robust method that simplifies both the blood sample collection and bioanalytical laboratory procedures and generates high quality quantitative data. However, problems were encountered with controlling the bleed rate during sample collection, resulting in the VAMS tips being flooded and highlighting the need for bleeding methods to be compatible with microsampling techniques to avoid wasting blood. Alternative sample collection procedures are discussed that minimize these issues. [ABSTRACT FROM AUTHOR]

This paper reports on a study which seeks to evaluate the role of small business rates relief as a means of government support for small businesses, in terms of both the financial benefit for recipient businesses and the symbolic significance of rates relief as a form of state support for the small business community in general. In doing so, the paper engages with the theoretical debate regarding the effectiveness and targeting of support to small businesses and how best to achieve this. The paper is based upon a survey of 391 small businesses receiving rates relief in Wales. The study contributes to the literature by filling a gap in our knowledge of business perception of the impact of rates relief and identifying some of the positive and negative aspects of such support mechanisms. [ABSTRACT FROM AUTHOR]

This article examines youth theatre as a mode of promoting public dialogue within situations of political tension or conflict. It reflects on the author's own experience of trying unsuccessfully to find a framework to evaluate an European Union supported theatre project, youth/art/peace/network, which took place in Austria, Israel and Palestine in the late 1990s. In the context of this reflection and the author's attempts to address the challenge of finding an evaluative framework and mode of analysis, the article combines a critical account of Habermas' notion of communicative reason inspired by Iris Marion Young with Lefebvre's rhythmanalysis. It argues that understanding drama practices in rhythmic terms provides potential for evaluating the complex spatio-temporal relationships the practices might have with everyday life. Through focusing on the presences and absences of particular people and things, such evaluation shows up the risks of performing a misleading or coerced state of health. The article suggests that the problem in this case was underpinned by a restrictive or exclusionary understanding of constructive dialogue at odds with participants' daily experience. However, the analysis also points more optimistically towards the potential of monologue and particular proxemics of co-presence in finding modes of performance to represent such experience. [ABSTRACT FROM AUTHOR]

The article discusses the pattern of drought and floods in England and Wales in 2012. It states that the month of March is one of the most important droughts for a century observed in the regions. According to the author, the droughts have caused exceptionally depressed groundwater levels as well as spring river flows in both areas.

Whilst hydrological systems can show resilience to short-term streamflow deficiencies during within-year droughts, prolonged deficits during multi-year droughts are a significant threat to water resources security in Europe. This study uses a threshold-based objective classification of regional hydrological drought to qualitatively examine the characteristics, spatio-temporal evolution and synoptic climatic drivers of multi-year drought events in 1962-64,1975-76 and 1995-97, on a European scale but with particular focus on the UK. Whilst all three events are multi-year, pan-European phenomena, their development and causes can be contrasted. The critical factor in explaining the unprecedented severity of the 1975-76 event is the consecutive occurrence of winter and summer drought. In contrast, 1962-64 was a succession of dry winters, mitigated by quiescent summers, whilst 1995-97 lacked spatial coherence and was interrupted by wet interludes. Synoptic climatic conditions vary within and between multi-year droughts, suggesting that regional factors modulate the climate signal in streamflow drought occurrence. Despite being underpinned by qualitatively similar climatic conditions and commonalities in evolution and characteristics, each of the three droughts has a unique spatio-temporal signature. An improved understanding of the spatio-temporal evolution and characteristics of multi-year droughts has much to contribute to monitoring and forecasting capability, and to improved mitigation strategies. [ABSTRACT FROM AUTHOR]

This paper presents a new methodology for assessing the ability of gridded hydrological models to reproduce large-scale hydrological high and low flow events (as a proxy for hydrological extremes) as described by catalogues of historical droughts [using the regional deficiency index (RDI)] and high flows [regional flood index (RFI)] previously derived from river flow measurements across Europe. Using the same methods, total runoff simulated by three global hydrological models from the Water Model Intercomparison Project (WaterMIP) [Joint U.K. Land Environment Simulator (JULES), Water Global Assessment and Prognosis (WaterGAP), and Max Planck Institute Hydrological Model (MPI-HM)] run with the same meteorological input (watch forcing data) at the same spatial 0.5° grid was used to calculate simulated RDI and RFI for the period 1963-2001 in the same European regions, directly comparable with the observed catalogues. Observed and simulated RDI and RFI time series were compared using three performance measures: the relative mean error, the ratio between the standard deviation of simulated over observed series, and the Spearman correlation coefficient. Results show that all models can broadly reproduce the spatiotemporal evolution of hydrological extremes in Europe to varying degrees. JULES tends to produce prolonged, highly spatially coherent events for both high and low flows, with events developing more slowly and reaching and sustaining greater spatial coherence than observed-this could be due to runoff being dominated by slow-responding subsurface flow. In contrast, MPI-HM shows very high variability in the simulated RDI and RFI time series and a more rapid onset of extreme events than observed, in particular for regions with significant water storage capacity-this could be due to possible underrepresentation of infiltration and groundwater storage, with soil saturation reached too quickly. WaterGAP shares some of the issues of variability with MPI-HM-also attributed to insufficient soil storage capacity and surplus effective precipitation being generated as surface runoff-and some strong spatial coherence of simulated events with JULES, but neither of these are dominant. Of the three global models considered here, WaterGAP is arguably best suited to reproduce most regional characteristics of large-scale high and low flow events in Europe. Some systematic weaknesses emerge in all models, in particular for high flows, which could be a product of poor spatial resolution of the input climate data (e.g., where extreme precipitation is driven by local convective storms) or topography. Overall, this study has demonstrated that RDI and RFI are powerful tools that can be used to assess how well large-scale hydrological models reproduce large-scale hydrological extremes-an exercise rarely undertaken in model intercomparisons. [ABSTRACT FROM AUTHOR]

Abstract: Protein C inhibitor (PCI) is a 57-kDa glycoprotein that exists in many tissues and secretions in human. As a member of the serpin superfamily of proteins it displays unusually broad protease specificity. PCI is implicated in the regulation of a wide range of processes, including blood coagulation, fertilization, prevention of tumors and pathogen defence. It has been reported that PCI isolated from human blood plasma is highly heterogeneous, and that this heterogeneity is caused by differences in N-glycan structures, N-glycosylation occupancy, and the presence of two forms that differ by the presence or absence of 6 amino acids at the amino-terminus. In this study we have verified that such heterogeneity exists in PCI purified from single individuals, and that individuals of two different ethnicities possess a similar PCI pattern, verifying that the micro-heterogeneity is conserved among humans. Furthermore, we have provided experimental evidence that PCI in both individuals is O-glycosylated on Thr20 with a core type 1 O-glycan, which is mostly NeuAcGalGalNAc. Modeling suggested that the O-glycan attachment site is located in proximity to several ligand-binding sites of the inhibitor. [ABSTRACT FROM AUTHOR]

The hyaluronic acid receptor for endocytosis (HARE)/Stabilin-2 is the primary systemic scavenger receptor for 13 ligands including hyaluronan (HA), heparin and chondroitin sulfates. Most ligand-binding sites are within the 190 kDa isoform, which contains ∼25 kDa of N-glycans and is the C-terminal half of the full-length 315 kDa HARE. Glycoproteomic analyses of purified recombinant human 190-HARE ecto-domain identified a diverse population of glycans at 10 of 17 consensus sites. The most diversity (and the only sialylated structures) occurred at N2280, within the HA-binding Link domain. To determine if these N-glycans are required for HA binding, we created human Flp-In 293 cell lines expressing membrane-bound or soluble ecto-domain variants of 190-HARE(N2280A). Membrane-bound HARE lacking Link domain N-glycans mediated rapid HA endocytosis, but purified 190-HARE(N2280A) ecto-domain showed little or no HA binding in ELISA-like, HA-HARE pull-down assays or by surface plasmon resonance analysis (which detected very high apparent affinity for 190-HARE ecto-domain binding to HA; Kd = 5.2 nM). The results indicate that Link domain N-glycans stabilize interactions that facilitate HA binding to HARE. [ABSTRACT FROM PUBLISHER]

How do you stage the world? This article reviews how a series of performance installations by the theatre company Stan's Cafe have approached global space. It examines the way Plague Nation and Of All the People in All the World tackle national and global scale through the representation of populations. Drawing on a discussion of cosmopolitanism by the geographer, David Harvey, the paper argues that the school versions of Plague Nation point towards a geographically rooted drama pedagogy for global citizenship. This pedagogy displays political and aesthetic features in common with Baz Kershaw's theorisation of 'spectacles of deconstruction'. The article concludes by exploring how the installations' own global travels might be understood as a practice of global citizenship. [ABSTRACT FROM AUTHOR]

CD52 is composed of a 12 amino acid peptide with N-linked glycans bound to the single potential glycosylation site at position 3, and a glycosylphosphatidylinositol-anchor attached at the C-terminus. Some glycoforms of this molecule expressed in the male reproductive tract are recognized by complement-dependent sperm-immobilizing antibodies in infertile patients making this antigen an important target for immunocontraception and fertility studies. Although the amount of posttranslational modification is already remarkable for such a small polypeptide, O-glycosylation of CD52 has additionally been implicated by several studies, but never rigorously characterized. In this report, we show clear evidence for the presence of O-glycans in CD52 preparations immunopurified using the murine S19 monoclonal antibody generated against sperm agglutination antigen-1 (SAGA-1), a male reproductive tract specific form of CD52. The O-glycans have been characterized by MALDI-TOF and tandem mass spectrometry after reductive elimination and permethylation. The data indicate that the major SAGA-1 O-glycans are core 1 and 2 mucin-type structures, with and without sialic acid (NeuAc0−2Hex1−3HexNAc1−2HexNAcitol). Minor fucosy- lated O-glycans are also present including some struc- tures with putative Ley epitopes (NeuAc0−1Fuc1−3Hex1−2 HexNAc0−1HexNAcitol). Analysis of O-glycopeptides by tandem mass spectrometry provided an additional level of support for the O-glycosylation of SAGA-1. Elucidation of the O-glycosylation of SAGA-1 adds to the complexity of this molecule and may help to explain its biological activity. [ABSTRACT FROM PUBLISHER]

Abstract: Defects in glycosylation are becoming increasingly associated with a range of human diseases. In some cases, the disease is caused by the glycosylation defect, whereas in others, the aberrant glycosylation may be a consequence of the disease. The implementation of highly sensitive and rapid mass spectrometric screening strategies for profiling the glycans present in model biological systems is revealing valuable insights into disease phenotypes. In addition, glycan screening is proving useful in the analysis of knock-out mice where it is possible to assess the role of glycosyltransferases and glycosidases and what function they have at the cellular and whole organism level. In this study, we analysed the effect of insulin on the glycosylation of 3T3-L1 cells and the effect of insulin resistance on glycosylation in a mouse model. Transcription profiling of 3T3-L1 cells treated with and without insulin revealed expression changes of several glycogenes. In contrast, mass spectrometric screening analysis of the glycans from these cells revealed very similar profiles suggesting that any changes in glycosylation were most likely on specific proteins rather than a global phenomenon. A fat-fed versus carbohydrate-fed mouse insulin resistant model was analysed to test the consequences of chronic insulin resistance. Muscle and liver N-glycosylation profiles from these mice are reported. [Copyright &y& Elsevier]

Abstract: The MUC6 mucin was originally isolated from stomach mucus and is one of the major secreted mucins of the digestive tract. A full-length cDNA has not been isolated for this large molecule (greater than 15 kb) and it remains poorly studied. To circumvent the lack of reagents for investigating MUC6, we isolated a cDNA clone from a human fetal pancreatic duct cDNA library that encodes 282 amino acids of the MUC6 tandem repeat. A blast search with the sequence of this cDNA clone showed 90% homology with the original MUC6 (L07517) derived from a human stomach cDNA library and 95% homology both with AK096772, a MUC6-related protein isolated from a human prostate cDNA library and the human genome project clone AC083984. The MUC6 partial cDNA clone isolated from fetal pancreas was inserted into an epitope-tagged MUC1 mucin molecule in place of the native tandem repeat. This chimeric mucin was expressed in human pancreatic (Panc1) and colon (Caco2) carcinoma cell lines and purified for analysis of O-glycosylation by fast atom bombardment mass spectrometry (FAB-MS). The FAB-MS spectra showed O-glycans that had been detected previously on chimeric mucins carrying different tandem repeats, though the spectra for MUC1F/6TR mucins expressed in the Panc1 and Caco2 cells were very different. There was a paucity of O-glycosylation in Panc1 cells in comparison to Caco2 cells where many more structures were evident, and the most abundant glycans in Panc1 cells were sialylated. [Copyright &y& Elsevier]

The summer of 2022 was particularly notable for the prolonged and extensive hot and dry conditions experienced across the UK. The resultant 2022 drought had widespread impacts and prompted much discussion about the continuing vulnerability of the UK to drought, particularly in the context of anthropogenic warming. Here, we briefly describe the evolution of the drought before focusing on the severity of rainfall, river flow, soil moisture and groundwater level deficits from summer 2022, placing the event into a historical context and addressing the impacts of the drought. We also consider whether the 2022 drought is part of a long‐term trend towards increasing drought severity. [ABSTRACT FROM AUTHOR]

Long-term planning of water resources has been a key requirement of the providers of water supplies, and this is extremely important nowadays. There are multiple competing demands on public water supplies due to increasing populations, climate change and the need to protect the environment. In the UK, public water supply is provided by around 25 water companies. The regulators require water companies to produce management plans on a five-year cycle, ensuring that the companies have given the necessary consideration of how to manage the supply-demand balance at present and future. It has recently been necessary to test water supply systems against the 'worst historical' drought event and consider those 'beyond historical' that might occur in future. However, this event varies by region. There is also no agreed methodology for determining this worst historical event, and each water company may use different datasets to reach an answer. Given this lack of consistency at a national scale, there is considerable interest in rationalising the approach to help answer questions relating to drought affecting multiple neighbouring water companies and around the feasibility of large-scale water transfers.This need is addressed by the UK Droughts & Water Scarcity Programme, which supports improved decision-making and communication in relation to droughts and water scarcity for a range of sectors. Capitalising on new improved national-scale data for extensive historical and future timeframes, consistently derived 'drought libraries' are developed. These drought libraries are sets of drought events across a range of durations and severities. They have been produced for a range of spatial domains, facilitating the exploration of questions around the spatial coherence of drought. Due to the extended historic period, the libraries incorporate information about droughts events back to the second half of the 19th century and provide the opportunity to characterise the recent events in their wider historical context. Moreover, the information about possible realisations of the future droughts, with climate model projections up to 2099, can inform stakeholders on the expected severity of future events. These can be used by the water industry for stress testing water supply systems and quantification of the probable future drought hazard.This study demonstrates the applicability of the drought libraries and utility to the water industry through a number of case study catchments in southern England. Based on the results, the severity of a specific historical drought event varies notably across different rainfall accumulation periods, showing that the reference events should be carefully selected for the various durations. Moreover, the future projections indicate that the drought hazard will be intensified in this part of the UK. Events of a certain severity in historical datasets are expected to increase in frequency in the future. The application of nationally consistent drought libraries in assessments of resilience to past, present and future droughts will maximise the benefit in managing the UK's national water resources, and begin to address some of the critical questions around how to reconcile the often competing demands from society, economy and environment. [ABSTRACT FROM AUTHOR]

Studies of the behaviour of hydrological state along intermittent rivers and through time are required to fully characterise their behaviour and assess their response to climatic and anthropogenic drivers. However, long term, spatially distributed datasets, and therefore opportunities to conduct such analyses, are rare. Monthly observations of flowing, ponded and dry states at multiple sites along ten Chalk rivers in the south east of England are used to demonstrate one method of characterisation (longitudinal permanence) and one of assessing response to a climatic driver (drought tracking).The behaviour of the rivers is characterised using long term permanence of hydrological state for each site, integrated temporally across all months in a ten-year period. Charted longitudinally, hydrological state permanence thus reveals spatial variability in intermittence, and by extension regime, along a river. Conversely, by spatially integrating all sites on a given river, the monthly composition of hydrological state allows comparison of the development and extent of drought events. Charts of flow, ponded and dry permanence reveal both broad shapes, as their relative permanences alter incrementally downstream, and localised augmentations from natural and artificial sources. Similarities and differences along and across the rivers are revealed. In the tracking of drought development, contraction of the network increases the proportion of dry state each month on groundwater-dominated rivers, whilst the proportion of ponding is more variable in time and space. The response of the rivers to recent dry winters is compared with that of drought events from the last two decades.The appraisal of a developing drought against previous dry years and long-term average conditions illustrates the importance of such datasets with good temporal resolution and extent in assessing the response of intermittent rivers to climatic and anthropogenic drivers. The equal importance of good spatial resolution is demonstrated in the characterisation of the rivers. The techniques demonstrate the potential for spatial zoning of intermittent river regime and subsequent assessment of the vulnerability of river zones to drought and artificial influences. [ABSTRACT FROM AUTHOR]

Aims: To examine the role of ex vivo oxytocin metabolism in post‐dose peptide measurements. Methods: The stability of oxytocin (Study 1) and oxytocinase activity (Study 2) in late‐stage pregnancy blood was quantified using liquid‐chromatography tandem mass‐spectrometry (LC–MS/MS) and a fluorogenic assay, respectively. Analyses were conducted using blood from pregnant women (>36 weeks gestation) evaluated in lithium heparin (LH), ethylenediaminetetraacetic acid (EDTA) and BD P100 blood collection tubes with or without protease inhibitors. In addition, plasma oxytocin concentrations following administration of oxytocin 240 IU inhaled, 5 IU intravenous or 10 IU intramuscular in women in third stage of labour (TSL) were analysed using enzyme‐linked immunosorbent assay (ELISA) and LC–MS/MS to understand how quantified peptide concentrations differ between these analytical methods (Study 3). Results: Study 1: Oxytocin was stable in blood collected into EDTA tubes with or without protease inhibitors but not in LH tubes. Study 2: Blood collected into all EDTA‐containing collection tubes led to near‐complete inhibition of oxytocinase (≤100 min). In plasma, a 35% reduction in oxytocinase activity was observed in LH tubes with EDTA added. In plasma from late‐stage pregnancy compared to nonpregnant participants, the oxytocinase activity was approximately 11‐fold higher. Study 3: Plasma oxytocin concentrations from nonpregnant or women in TSL following exogenous oxytocin administration were ≤33 times higher when analysed using ELISA vs. LC–MS/MS methods. Conclusions: Collection of blood from late‐stage pregnant women into tubes containing EDTA inhibits oxytocinase effectively stabilizing oxytocin, suggesting low concentrations of oxytocin after dose administration reflect rapid in vivo metabolism. [ABSTRACT FROM AUTHOR]

Aims: To compare pharmacokinetics (PK) and safety of heat‐stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety. Methods: A phase 1, randomized, cross‐over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception). Participants were randomized 1:1 to: Group 1, oxytocin 10 IU (17 μg) IM or oxytocin 240 IU (400 μg) IH immediately after delivery; Group 2, oxytocin 5 IU (8.5 μg) intravenously and oxytocin 240 IU (400 μg) IH at 2 separate dosing sessions. Results: Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomized; received either IH (n = 9) or IM (n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 (n = 14), oxytocin IH concentrations remained quantifiable ≤3 h postdose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%); Group 2, n = 14 (100%). Conclusion: Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay. [ABSTRACT FROM AUTHOR]

A correction is presented to the website location for Critical Mass London which appeared in the article "A Theatrical Gesture of Disavowal: The Civility of the Critical Mass Cycle Ride" by Simon Parry, which appeared in the 25(3) 2015 issue.

This paper details the development and evaluation of the enhanced future FLows and Groundwater (eFLaG) dataset of nationally consistent hydrological projections for the UK, based on the latest UK Climate Projections (UKCP18). The projections are derived from a range of hydrological models. For river flows, multiple models (Grid-to-Grid, PDM (Probability Distributed Model) and GR (Génie Rural; both four- and six-parameter versions, GR4J and GR6J)) are used to provide an indication of hydrological model uncertainty. For groundwater, two models are used, a groundwater level model (AquiMod) and a groundwater recharge model (ZOODRM: zooming object-oriented distributed-recharge model). A 12-member ensemble of transient projections of present and future (up to 2080) daily river flows, groundwater levels and groundwater recharge was produced using bias-corrected data from the UKCP18 regional (12 km) climate ensemble. Projections are provided for 200 river catchments, 54 groundwater level boreholes and 558 groundwater bodies, all sampling across the diverse hydrological and geological conditions of the UK. An evaluation was carried out to appraise the quality of hydrological model simulations against observations and also to appraise the reliability of hydrological models driven by the regional climate model (RCM) ensemble in terms of their capacity to reproduce hydrological regimes in the current period. The dataset was originally conceived as a prototype climate service for drought planning for the UK water sector and so has been developed with drought, low river flow and low groundwater level applications as the primary objectives. The evaluation metrics show that river flows and groundwater levels are, for the majority of catchments and boreholes, well simulated across the flow and level regime, meaning that the eFLaG dataset could be applied to a wider range of water resources research and management contexts, pending a full evaluation for the designated purpose. Only a single climate model and one emissions scenario are used, so any applications should ideally contextualise the outcomes with other climate model–scenario combinations. The dataset can be accessed in Hannaford et al. (2022): 10.5285/1bb90673-ad37-4679-90b9-0126109639a9. [ABSTRACT FROM AUTHOR]

This paper presents an 'enhanced future FLows and Groundwater' (eFLaG) dataset of nationally consistent hydrological projections for the UK, based on the latest UK Climate Projections (UKCP18). The hydrological projections are derived from a range of river flow models (Grid-to-Grid, PDM, GR4J and GR6J), to provide an indication of hydrological model uncertainty, as well as groundwater level (Aquimod) and groundwater recharge (ZOODRM) models. A 12-member ensemble of transient projections of present and future (up to 2080) daily river flows, groundwater levels and groundwater recharge were produced using bias corrected data from the UKCP18 Regional (12 km) climate ensemble. Projections are provided for 200 river catchments, 54 groundwater level boreholes and 558 groundwater bodies, all sampling across the diverse hydrological and geological conditions of the UK. An evaluation was carried out, to appraise the quality of hydrological model simulations against observations and also to appraise the reliability of hydrological models driven by the RCM ensemble, in terms of their capacity to reproduce hydrological regimes in the current period. The dataset was originally conceived as a prototype climate service for drought planning for the UK water sector, so has been developed with drought, low river flow and low groundwater level applications as the primary focus. The evaluation metrics show that river flows and groundwater levels are, for the majority of catchments and boreholes, well simulated across the flow and level regime, meaning that the eFLaG dataset could be applied to a wider range of water resources research and management contexts, pending a full evaluation for the designated purpose. [ABSTRACT FROM AUTHOR]

The inherent variability of the UK's climate achieved an extreme expression in 2012 when one of the most significant prolonged droughts for a century was dramatically terminated by the wettest April to July over England and Wales in almost 250 years. Through late spring and summer, runoff and aquifer recharge rates increased steeply and there were numerous instances of flooding, underlining a hydrological transformation with no close modern parallel at this time of year. This paper reviews the development, severity and impacts of the 2010-2012 drought. It is intended that a companion paper will examine the exceptionally wet conditions which began in April 2012 and resulted in runoff and aquifer recharge patterns very rarely experienced during the summer half-year. [ABSTRACT FROM AUTHOR]

Dried bloodspot (DBS) technology has been available for many decades but only in the last five years has it been considered for routine bioanalysis of blood samples collected on preclinical and clinical studies as part of a drug development programme. Advantages of using DBS versus typical plasma samples include smaller blood volumes, less processing of the samples (e.g. no centrifugation) and no requirement for storing or shipping of the samples at frozen temperatures. The current study compared blood concentrations (AUC0-t and Cmax) from rats given an oral dose of acetaminophen (APAP) using two different sampling sites (caudal venepuncture versus tail snip), two different collection methods (3 separate 15 µL ethylenediaminetetraacetic acid [EDTA]-coated capillary tubes versus an EDTA integrated capillary blood collection system) and variability between blood spots on one card. There were no noteworthy differences (i.e. two-fold or greater) in blood concentrations of APAP using the different sites or methods. Furthermore, comparisons of the APAP blood concentrations in the original spot to a duplicate bloodspot from the same bloodspot card were within 12% of the original concentration. [ABSTRACT FROM AUTHOR]

Ecological communities can remain stable in the face of disturbance if their constituent species have different resistance and resilience strategies. In turn, local stability scales up regionally if heterogeneous landscapes maintain spatial asynchrony across discrete populations—but not if large‐scale stressors synchronize environmental conditions and biological responses. Here, we hypothesized that droughts could drastically decrease the stability of invertebrate metapopulations both by filtering out poorly adapted species locally, and by synchronizing their dynamics across a river network. We tested this hypothesis via multivariate autoregressive state‐space (MARSS) models on spatially replicated, long‐term data describing aquatic invertebrate communities and hydrological conditions in a set of temperate, lowland streams subject to seasonal and supraseasonal drying events. This quantitative approach allowed us to assess the influence of local (flow magnitude) and network‐scale (hydrological connectivity) drivers on invertebrate long‐term trajectories, and to simulate near‐future responses to a range of drought scenarios. We found that fluctuations in species abundances were heterogeneous across communities and driven by a combination of hydrological and stochastic drivers. Among metapopulations, increasing extent of dry reaches reduced the abundance of functional groups with low resistance or resilience capacities (i.e. low ability to persist in situ or recolonize from elsewhere, respectively). Our simulations revealed that metapopulation quasi‐extinction risk for taxa vulnerable to drought increased exponentially as flowing habitats contracted within the river network, whereas the risk for taxa with resistance and resilience traits remained stable. Our results suggest that drought can be a synchronizing agent in riverscapes, potentially leading to regional quasi‐extinction of species with lower resistance and resilience abilities. Better recognition of drought‐driven synchronization may increase realism in species extinction forecasts as hydroclimatic extremes continue to intensify worldwide. [ABSTRACT FROM AUTHOR]

Disturbance events govern how the biodiversity of ecological communities varies in both space and time. In freshwater ecosystems, there is evidence that local and regional‐scale drivers interact to influence ecological responses to drying disturbances. However, most research provides temporal snapshots at the local scale, whereas few studies encompass a gradient of drying severity spanning multiple years. Using a dataset of rare spatiotemporal extent and detail, we demonstrate how independent and interacting local and regional‐scale factors drive shifts in the α and β diversities of communities in dynamic river ecosystems. We examined aquatic invertebrate assemblage responses to hydrological variability (as characterized by monthly observations of instream conditions) at 30 sites over a 12‐year period encompassing typical years and two severe drought disturbances. Sites varied in their disturbance regimes and hydrological connectivity at both local (i.e. site‐specific) and regional (i.e. river catchment) scales. Whereas α diversity was mainly influenced by local factors including flow permanence and the temporal extent of ponded and dry conditions, both temporal and spatial β diversities also responded to regional‐scale metrics such as the spatial extent of flow and hydrological connectivity. We observed stronger local negative responses for taxa with lower capacities to tolerate drying (i.e. resistance) and/or to recover after flow resumes (i.e. resilience), whereas taxa with functional traits promoting resilience made an increasing contribution to spatial β diversity as hydrological connectivity declined. As droughts increase in extent and severity across global regions, our findings highlight the functional basis of taxonomic responses to disturbance and connectivity, and thus advance understanding of how drying disturbances shape biodiversity in river networks. Our identification of the role of regional hydrological factors could inform catchment‐scale management strategies that support ecosystem resilience in a context of global change. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF.Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%.Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination.Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug.Trial Registration: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017. [ABSTRACT FROM AUTHOR]

Drought can occur in any climate zone (including the UK), and studies aiming to characterise and understand hydrological drought should utilise appropriate hydrological data (rather than, for example, rainfall data which best characterises meteorological drought). Although the UK has a dense flow gauging network, the majority of the river flow records begin in the 1960s. Yet, we know from individual long river flow records, regional reconstructions and qualitative data that severe hydrological droughts occurred in the late 19th and early 20th century. Until recently, it has not been possible to identify and characterise these hydrological droughts at the national scale.Using a new dataset of daily river flow reconstructions dating back to 1891, it has been possible to identify, characterise and rank hydrological drought events nationally. Drought events were systematically identified using the Standardised Streamflow Index (using accumulation periods of 3 and 12 months) for 108 near-natural catchments across the UK from 1891 to 2015. Events were then characterised and ranked according to four characteristics: duration, accumulated deficit, mean deficit and maximum intensity. The results provide an unparalleled account of hydrological droughts in the UK, their characteristics according to different measures of severity and their relative ranking. This enables a comparison of recent events to those outside of the observed record, as well as shedding light on the poorly documented events of the late 19th and early 20th century. This extended understanding based on an objective identification protocol over ~125 years, provides vital information: informing the planning and management of future events; aiding the development of scenarios beyond those observed; and providing benchmarks against which current and future events can be compared. [ABSTRACT FROM AUTHOR]

Purpose: Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants.Methods: Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1-3000 mcg given by nebulisation.Results: A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100-3000 mcg). Dose normalised geometric mean Cmax increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety.Conclusions: In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300-3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF. [ABSTRACT FROM AUTHOR]

This paper describes the development of the first operational seasonal hydrological forecasting service for the UK, the Hydrological Outlook UK (HOUK). Since June 2013, this service has delivered monthly forecasts of streamflow and groundwater levels, with an emphasis on forecasting hydrological conditions over the next three months, accompanied by outlooks over longer time horizons. This system is based on three complementary approaches combined to produce the outlooks: (i) national-scale modelling of streamflow and groundwater levels based on dynamic seasonal rainfall forecasts, (ii) catchment-scale modelling where streamflow and groundwater level models are driven by historical meteorological forcings (i.e. the Ensemble Streamflow Prediction, ESP, approach), and (iii) a catchment-scale statistical method based on persistence and historical analogues. This paper provides the background to the Hydrological Outlook, describes the various component methods in detail and then considers the impact and usefulness of the product. As an example of a multi-method, operational seasonal hydrological forecasting system, it is hoped that this overview provides useful information and context for other forecasting initiatives around the world. [ABSTRACT FROM AUTHOR]

Sound water policy and management rests on sound hydrometeorological and ecological data. Conversely, unrepresentative, poorly collected, or erroneously archived data introduce uncertainty regarding the magnitude, rate, and direction of environmental change, in addition to undermining confidence in decision-making processes. Unfortunately, data biases and errors can enter the information flow at various stages, starting with site selection, instrumentation, sampling/measurement procedures, postprocessing and ending with archiving systems. Techniques such as visual inspection of raw data, graphical representation, and comparison between sites, outlier, and trend detection, and referral to metadata can all help uncover spurious data. Tell-tale signs of ambiguous and/or anomalous data are highlighted using 12 carefully chosen cases drawn mainly from hydrology ('the dirty dozen'). These include evidence of changes in site or local conditions (due to land management, river regulation, or urbanization); modifications to instrumentation or inconsistent observer behavior; mismatched or misrepresentative sampling in space and time; treatment of missing values, postprocessing and data storage errors. Also for raising awareness of pitfalls, recommendations are provided for uncovering lapses in data quality after the information has been gathered. It is noted that error detection and attribution are more problematic for very large data sets, where observation networks are automated, or when various information sources have been combined. In these cases, more holistic indicators of data integrity are needed that reflect the overall information life-cycle and application(s) of the hydrological data. WIREs Water 2017, 4:e1209. doi: 10.1002/wat2.1209 For further resources related to this article, please visit the . [ABSTRACT FROM AUTHOR]

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB- DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM. [ABSTRACT FROM AUTHOR]

The article focuses on the impact of winter storms in Great Britain during 2013-2014. It states that heavy rainfall, along with strong winds, high tides and storm surge conditions resulted in groundwater and coastal flooding in many parts of the nation. By the end of November 2013, groundwater levels across Great Britain were generally in normal range, but levels still declined in some boreholes.

Abstract: Toxicokinetic (TK) information can substantially enhance the value of the data generated from toxicity testing, and is an integral part of pharmaceutical safety assessment. It is less widely used in the chemical, agrochemical and consumer products industries, but recognition of its value is growing, as reflected by increased reference to the use of TK information in new and draft OECD test guidelines. To help promote increased consideration of the important role TK can play in chemical risk assessment, we have gathered practical examples from the peer-reviewed literature, as well as in-house industry data, that highlight opportunities for the use of TK in the selection of dose levels. Use of TK can help to ensure studies are designed to be of most relevance to assessing potential risk in humans, and avoid the use of excessively high doses that could result in unnecessary suffering in experimental animals. Greater emphasis on the potential contribution of TK in guiding study design and interpretation should be incorporated in regulatory data requirements and associated guidance. [Copyright &y& Elsevier]

Abstract: Engineered receptor fragments and glycoprotein ligands employed in different assay formats have been used to dissect the basis for the dramatic enhancement of binding of two model membrane receptors, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and the macrophage galactose lectin, to glycoprotein ligands compared to simple sugars. These approaches make it possible to quantify the importance of two major factors that combine to enhance the affinity of single carbohydrate-recognition domains (CRDs) for glycoprotein ligands by 100-to 300-fold. First, the presence of extended binding sites within a single CRD can enhance interaction with branched glycans, resulting in increases of fivefold to 20-fold in affinity. Second, presentation of glycans on a glycoprotein surface increases affinity by 15-to 20-fold, possibly due to low-specificity interactions with the surface of the protein or restriction in the conformation of the glycans. In contrast, when solution-phase networking is avoided, enhancement due to binding of multiple branches of a glycan to multiple CRDs in the oligomeric forms of these receptors is minimal and binding of a receptor oligomer to multiple glycans on a single glycoprotein makes only a twofold contribution to overall affinity. Thus, in these cases, multivalent interactions of individual glycoproteins with individual receptor oligomers have a limited role in achieving high affinity. These findings, combined with considerations of membrane receptor geometry, are consistent with the idea that further enhancement of the binding to multivalent glycoprotein ligands requires interaction of multiple receptor oligomers with the ligands. [Copyright &y& Elsevier]

Abstract: While toxicokinetics has become an integral part of pharmaceutical safety assessment over the last two decades, its use in the chemical industry is relatively new. However, it is recognised as a potentially important tool in human health risk assessment and recent initiatives have advocated greater application of toxicokinetics as part of an improved assessment strategy for crop protection chemicals that could offer greater efficiency, use fewer animals and provide better data for risk assessment purposes. To explore the potential scientific and animal welfare benefits of increased use of toxicokinetic data across the chemical industry, an international workshop was held in 2008. Experts from a wide range of chemical industry sectors, including industrial chemicals, agrochemicals and consumer products, participated in the meeting as well as representatives from relevant regulatory authorities. Pharmaceutical industry experts were also invited, in order to share experiences from the extensive use of toxicokinetics in drug development. Given that increased generation of toxicokinetic data could potentially result in an increased number of animals undergoing testing, technologies and strategies to reduce and refine animal use for this purpose were also considered. This paper outlines and expands upon the key themes that emerged from the workshop. [Copyright &y& Elsevier]

Abstract: A reversed phase HPLC-MS/MS method has been developed and validated for the quantitative bioanalysis of acetaminophen in dried blood spots (DBS) prepared from small volumes (15μL) of dog blood. Samples were extracted for analysis with methanol. Detection was by positive ion TurboIonSpray™ ionisation combined with selected reaction monitoring MS. The analytical concentration range was 0.1–50μg/mL. The intra-day precision and bias values were both less than 15%. Acetaminophen was stable in DBS stored at room temperature for at least 10 days. The methodology was applied in a toxicokinetic (TK) study where the data obtained from DBS samples was physiologically comparable with results from duplicate blood samples (diluted 1:1 (v/v) with water) analysed using identical HPLC-MS/MS conditions. This work demonstrates that quantitative analysis of a drug extracted from DBS can provide high quality TK data while minimising the volume of blood withdrawn from experimental animals, to an order of magnitude lower than is current practice in the pharmaceutical industry. This is the first reported application of DBS analysis to a TK study in support of a safety assessment study. The success of this and similar, related studies has led to the intent to apply DBS technology as the recommended analytical approach for the assessment of pharmacokinetics (PK)/TK for all new oral small molecule drug candidates, which have previously demonstrated a successful bioanalytical validation. [Copyright &y& Elsevier]