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Trends and ecological consequences of phosphorus (P) decline and increasing nitrogen (N) to phosphorus (N:P) ratios in rivers and estuaries are reviewed and discussed. Results suggest that re-oligotrophication is a dominant trend in rivers and estuaries of high-income countries in the last two-three decades, while in low-income countries widespread eutrophication occurs. The decline in P is well documented in hundreds of rivers of United States and the European Union, but the biotic response of rivers and estuaries besides hytoplankton decline such as trends in phytoplankton composition, changes in primary production, ecosystem shifts, cascading effects, changes in ecosystem metabolism, etc., have not been sufficiently monitored and investigated, neither the effects of N:P imbalance. N:P imbalance has significant ecological effects that need to be further investigated. There is a growing number of cases in which phytoplankton biomass have been shown to decrease due to re-oligotrophication, but the potential regime shift from phytoplankton to macrophyte dominance described in shallow lakes has been documented only in a few rivers and estuaries yet. The main reasons why regime shifts are rarely described in rivers and estuaries are, from one hand the scarcity of data on macrophyte cover trends, and from the otherhand physical factors such as peak flows or high turbidity that could prevent a general spread of submerged macrophytes as observed in shallow lakes. Moreover, re-oligotrophication effects on rivers may be different compared to lakes (e.g., lower dominance of macrophytes) or estuaries (e.g., limitation of primary production by N instead of P) or may be dependent on river/estuary type. We conclude that river and estuary re-oligotrophication effects are complex, diverse and still little known, and in some cases are equivalent to those described in shallow lakes, but the regime shift is more likely to occur in mid to high-order rivers and shallow estuaries. This work was supported by a grant from the U.S. National Science Foundation (#DBI-1639145) to the National Socio-Environmental Synthesis Center (Rivershift Project). The work was also financially supported by the Catalan Government through the funding grant ACCIÓ-Eurecat (Project AquaSCI-2022).

Despite improved knowledge regarding disease causality, new drug targets, and enabling technologies, the attrition rate for compounds entering clinical trials has remained consistently high for several decades, with an average 90% failure rate. These failures are manifested in an inability to reproduce efficacy findings from animal models in humans and/or the occurrence of unexpected safety issues, and reflect failures in T1 translation. Similarly, an inability to sequentially demonstrate compound efficacy and safety in Phase IIa, IIb, and III clinical trials represents failures in T2 translation. Accordingly, T1 and T2 translation are colloquially termed 'valleys of death'. Since T2 translation dealt almost exclusively with clinical trials, T3 and T4 translational steps were added, with the former focused on facilitating interactions between laboratory- and population-based research and the latter on 'real world' health outcomes. Factors that potentially lead to T1/T2 compound attrition include: the absence of biomarkers to allow compound effects to be consistently tracked through development; a lack of integration/'de-siloing' of the diverse discipline-based and technical skill sets involved in drug discovery; the industrialization of drug discovery, which via volume-based goals often results in quantity being prioritized over quality; inadequate project governance and strategic oversight; and flawed decision making based on unreliable/irreproducible or incomplete data. A variety of initiatives have addressed this problem, including the NIH National Center for Advancing Translational Sciences (NCATS), which has focused on bringing an unbiased academic perspective to translation, to potentially revitalize the process. This commentary provides an overview of the basic concepts involved in translation, along with suggested changes in the conduct of biomedical research to avoid valleys of death, including the use of Translational Scoring as a tool to avoid translational attrition and the impact of the FDA Accelerated Approval Pathway in lowering the hurdle for drug approval. © 2021 Wiley Periodicals LLC.

Soil compaction is an important concern for surface mine operations that require heavy equipment for land reclamation. Excessive use of rubber-tired equipment, such as scraper pans, may cause mine soil compaction and hinder the success of revegetation efforts. However, information is limited on management strategies for ameliorating the potential compacting effects of scraper pans, particularly during site preparation for loblolly pine (Pinus taeda L.) plantations. Three forms of tillage and one control were replicated five times on surface mined land in the west Gulf Coastal Plain: no tillage (NT), disking (D), single-ripping + disking (R+D), and cross-ripping + disking (CR+D). Mine soil physical properties were investigated at 0 to 30, 30 to 60, and 60 to 90 cm. Percent cover and aboveground biomass of an herbaceous winter cover crop, and survival and growth of loblolly pine seedlings were assessed after one growing season. Herbaceous species biomass was highest on the R+D and CR+D plots and lowest on the NT control. Pine seedling survival was highest on the tilled plots (>90%) compared to NT (85%). The highest intensity combination tillage treatment (CR+D) was superior in terms of lowering soil bulk density (mean 1.36 Mg m–³) and soil strength (mean 2220 kPa) and increasing pine seedling volume index growth (mean 32 cm³). Surface tillage (D) alone improved herbaceous cover and pine seedling survival, while CR+D provided the most favorable responses in mine soil physical properties and vegetative growth.

We report a redox-neutral formylation of aryl chlorides that proceeds through selective 2-functionalization of 1,3-dioxolane through nickel and photoredox catalysis. This scalable benchtop approach provides a distinct advantage over traditional reductive carbonylation in that no carbon monoxide, pressurized gas, or stoichiometric reductant is employed. The mild conditions give unprecedented scope from abundant and complex aryl chloride starting materials.

This paper describes the development of New Zealand's Earth System Model (NZESM) and evaluates its performance against its parent model (United Kingdom Earth System Model, UKESM) and observations. The main difference between the two earth system models is an embedded high‐resolution (1/5°) nested region over the oceans around New Zealand in the NZESM. Due to this finer ocean model mesh, currents such as the East Australian Current, East Australian Current Extension, Tasman Front, and Tasman Leakage, and their volume and heat transports are better simulated in the NZESM. The improved oceanic transports have led to a reduction in upper ocean temperature and salinity biases over the nested region. In addition, net transports through the Tasman Sea of volume, heat and salt in the NZESM agree better with previously reported estimates. A consequence of the increased cross‐Tasman Sea transports in the NZESM is increased temperatures and salinity west of Australia and in the Southern Ocean reducing the meridional sea surface temperature gradient between the subtropics and sub‐Antarctic. This also leads to a weakening of the westerly winds between 60°S and 45°S over large parts of the Southern Ocean, which reduces the northward Ekman transport, reduces the formation of Antarctic Intermediate Water, and allows for a southward expansion of the Super‐Gyre in all ocean basins. Connecting an improved oceanic circulation around New Zealand to a basin‐wide Super‐Gyre response is an important step forward in our current understanding of how local scales can influence global scales in a fully coupled earth system model.

INTRODUCTION:Cerebral small-vessel disease has been implicated in the development of Alzheimer’sdisease (AD). The retinal microvasculature enables non-invasive visualization andevaluation of the systemic microcirculation. We evaluated retinal microvascular parametersin a case-control study of AD patients and cognitively-normal controls. METHODS:Retinal images were computationally analyzed and quantitative retinal parameters (caliber,fractal dimension, tortuosity, and bifurcation) measured. Regression models were used tocompute odds ratios (OR) and confidence intervals (CI) for AD with adjustment forconfounders. RESULTS:Retinal images were available in 213 AD participants and 294 cognitively-normal controls.Persons with lower venular fractal dimension (OR per standard deviation [SD] increase, 0.77[CI: 0.62–0.97]) and lower arteriolar tortuosity (OR per SD increase, 0.78 [CI: 0.63–0.97])were more likely to have AD following appropriate adjustment. DISCUSSION:Patients with AD have a sparser retinal microvascular network and retinal microvascularvariation may represent similar pathophysiological events within the cerebralmicrovasculature of patients with AD.

This study explores communications experienced by Aboriginal people in health care encounters about pain. It examines barriers that can impact upon effective pain management for Aboriginal patients. (This article refers to Aboriginal people, as these were the study participants. It is not intended to exclude Torres Strait Islander people.) A qualitative study using focus groups. Two Aboriginal communities in South East Queensland. The participants were 20 men and 20 women who identified a health condition with associated pain for which they had sought health care, including pain relief. Their conditions included arthritis, orthopaedic injuries, back pain and coronary artery disease. Physical pains associated with participants' health conditions were accorded a second place to deep emotional pain attributed to dispossession, dislocation and loss. At health facilities, prominent perceptions were that health professionals held a negative attitude towards them, and lacked respect and caring. Participants experienced that the language used by health professionals in consultations was complex. Aboriginal people often do not report pain, on the basis of previous negative encounters with the health system. Other perceived barriers to effective pain management included discriminatory attitudes of health professionals and communication problems.

Three trials investigated the pharmacokinetics (PK) of recombinant factor XIII (rFXIII) A-subunit. To compare the PK characteristics of rFXIII among trials and different age groups of patients. Dosing with rFXIII 35 IU kg(-1) every 4th week. Blood samples for PK assessments were collected regularly throughout the dosing interval from a total of 68 individual patients with FXIII congenital deficiency. The mean PK parameters were similar across the three age groups, and for the three trials, as well as constant over time based on results from patients participating in both mentor 1 and mentor 2 trials. The geometric mean half-life ranged from 11.6 to 15.0 days, and the trough FXIII activity levels ranged from 0.15 to 0.21 IU mL(-1) . The population PK model identified body weight as a statistically significant covariate influencing clearance (CL) and volume of distribution (Vd ), with a similar increase in both parameters with increased body weight. The half-life was not affected by body weight. Gender (females vs. males) and age category (paediatric vs. adult) did not affect CL. The PK profile of rFXIII, after dosing with 35 IU kg(-1) of rFXIII, was independent of age and comparable between trials and FXIII trough activity levels were constant. Despite rather large individual variation in the maximal FXIII activity levels, all individual mean trough activity levels were above 0.1 IU mL(-1) during the entire duration of the trials. The results support that monthly dosing with 35 IU kg(-1) of rFXIII to patients with FXIII A-subunit deficiency, regardless of age, is adequate for prophylaxis.

Summary Although it has been suggested that switching of factor VIII (FVIII) products may increase inhibitor formation this is disputed. Half of UK patients changed rFVIII brands because of national contracting in 2010, presenting an opportunity to compare inhibitor incidence of switchers with non-switchers. Centres were requested to test all the patients for inhibitors prior to the switching date and 6-monthly thereafter. Positive and negative inhibitor test data were also collected to analyse for testing bias. A total of 1198 patients with severe haemophilia A and treated with Advate, Kogenate/Helixate or Refacto AF preswitch were included in the analysis, of whom 516 switched to Refacto-AF and 682 did not switch products. Five new inhibitors were reported amongst previously treated patients (>50 exposure days) with a median titre at the time of detection of 1.25 BU mL−1 (IQR 0.7–23.05). One inhibitor occurred in a non-switcher using Kogenate, an incidence of 1.5 per 1000 treatment-years (95% CI 0.2–10.5). Four inhibitors arose in patients who had switched from Kogenate (two) or Advate (two) to ReFacto-AF, an incidence of 7.8 per 1000 treatment-years (95% CI 2.9–20.8). These incidence rates did not differ significantly from one another (incidence rate ratio 5.3 (95% CI 0.5–260.3) or from the historical rate of 6.05 inhibitors/1000 treatment-years (95% CI 5.18–7.06). Only one inhibitor (non-switcher) persisted. Non-switchers were significantly older (P = 0.03), and used significantly less FVIII per year (P = 0.005) prior to switching. Following switching, factor usage increased similarly (P = 0.53) in both groups. Switching from FLRFVIII to Refacto-AF (BDDRFVIII) was not associated with an increased inhibitor development.

Masked hypertension (MH), the presence of normal office blood pressure (BP) with elevated ambulatory pressure, has been shown to correlate with organ damage. Population-based studies from Europe and Asia estimate a prevalence of 8.5% to 15.8%. Two small studies in African Americans estimate a prevalence40%. Therefore, the authors utilized ambulatory BP monitoring (ABPM) to identify the prevalence of MH in our African American population. Pressure was recorded every 30 minutes while awake and every 60 minutes while asleep. Patients with 24-hour average BP ≥ 135/85 mm Hg, awake average BP ≥ 140/90 mm Hg, or asleep average BP ≥ 125/75 mm Hg had MH. Seventy-three participates had valid data. The mean age of the patients was 49.8 years, mean body mass index was 31.1, and 39 patients (53%) were women. Thirty-three patients (45.2%) had MH. Patients with MH had higher clinic systolic BP and trended toward higher BMI values. The authors corroborated the high prevalence of MH in African Americans. ABPM is critical to diagnose hypertension in African Americans, particularly in those with high-normal clinic pressure and obesity.

Commercial swine waste lagoons are regarded as a major reservoir of natural estrogens, which have the potential to produce adverse physiological effects on exposed aquatic organisms and wildlife. However, there remains limited understanding of the complex mechanisms of physical, chemical, and biological processes that govern the fate and transport of natural estrogens within an anaerobic swine lagoon. To improve lagoon management and ultimately help control the offsite transport of these compounds from swine operations, a probabilistic Bayesian network model was developed to assess natural estrogen fate and budget and then compared against data collected from a commercial swine field site. In general, the model was able to describe the estrogen fate and budget in both the slurry and sludge stores within the swine lagoon. Sensitivity analysis within the model demonstrated that the estrogen input loading from the associated barn facility was the most important factor in controlling estrogen concentrations within the lagoon slurry storage, whereas the settling rate was the most significant factor in the lagoon sludge storage. The degradation reactions were shown to be minor in both stores based on prediction of average total estrogen concentrations. Management scenario evaluations demonstrated that the best possible management options to reduce estrogen levels in the lagoon are either to adjust the estrogen input loading from swine barn facilities or to effectively enhance estrogen bonding with suspended solids through the use of organic polymers or inorganic coagulants. Integr Environ Assess Manag 2014;10:511–521. © 2014 SETAC

In Drosophila, serotonin (5-HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12-family of proteins, which have been shown to modify G-protein-coupled receptor (GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5-HT receptor signalling. The KCTD12-family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12-like (Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5-HT receptor 5-HT7, and we observed that both Ktl and the 5-HT1A receptor are required in insulin-producing cells (IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5-HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin-hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5-HT1A receptor. Similar to what was observed with mammalian KCTD12-family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5-HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour.

Exposure to bisphenol A (BPA) in rodents was shown to induce obesity, yet the mechanism by which BPA might induce obesity is still unclear. We employed the genetically tractable model organism, Drosophila melanogaster, to test the effects of raising them on food containing various concentrations of BPA. Of note, raising males on food containing BPA were susceptible to starvation, possibly by inhibiting their ability to perform lipolysis during starvation, leading to significantly increased lipid content after 24 hr of fasting. Furthermore, feeding males with BPA significantly inhibited the expression of insulin-like peptides. From these results, we conclude that BPA may inhibit lipid recruitment during starvation in Drosophila.

Truncated receptor ectodomains have been described for several classes of cell surface receptors, including those that bind to growth factors, cytokines, immunoglobulins, and adhesion molecules. Soluble receptor isoforms are typically generated by proteolytic cleavage of the cell surface receptor or by alternative splicing of RNA transcripts arising from the same gene encoding the full-length receptor. Both the epidermal growth factor receptor (EGFR) and the insulin receptor (INSR) families produce soluble receptor splice variants in vertebrates and truncated forms of insulin receptor-like sequences have previously been described in Drosophila. The EGFR and INSR ectodomains share significant sequence homology with each other suggestive of a common evolutionary origin. We discovered novel truncated insulin receptor-like variants in several arthropod species. We carried out a phylogenetic analysis of the conserved extracellular receptor L1 and L2 subdomains in invertebrate species. Although the segregation of insulin receptor-like L1 and L2 domains indicated that an internal domain duplication had occurred only once, the generation of truncated insulin receptor-like sequences has occurred multiple times. The significance of this work is the previously unknown and widespread occurrence of truncated isoforms in arthropods, signifying that these isoforms play an important functional role, potentially related to such isoforms in mammals.

Using intraday data, we find unidirectional causality from commodity index-linked futures to nonindex-linked commodity futures for up to one hour which disappears when using daily data. Also, the economic significance of index-linked to nonindex commodity transmission declines to zero within about an hour. Finally, we find that the magnitude of index-linked to nonindex return transmission is positively related to the amount of speculation, both long and short, in S&P GSCI commodity index futures. We conclude that speculative pressures exerted by commodity index futures can impact nonindex commodities, mainly through the activity of uninformed, positive feedback traders.

Olefin metathesis (OM) is a reliable and practical synthetic methodology for challenging carbon–carbon bond formations. While existing catalysts can effect many of these transformations, the synthesis and development of new catalysts is essential to increase the application breadth of OM and to achieve improved catalyst activity. The unexpected initial discovery of a novel olefin metathesis catalyst derived from synthetic efforts toward the HCV therapeutic agent grazoprevir (MK-5172) is described. This initial finding has evolved into a class of tunable, shelf-stable ruthenium OM catalysts that are easily prepared and exhibit unique catalytic activity.

The People's Bank of China (PBC) lifted yuan trading restrictions in July of 2010 that led to offshore yuan spot trading in Hong Kong. Based on causality analyses, we find that price discovery is absent between the onshore and offshore spot markets. However, we document the presence of price discovery between onshore spot and offshore nondeliverable forward (NDF) rates. These seemingly inconsistent results present a puzzle wherein one offshore market appears to be more informationally integrated with the onshore market than another. We conclude that price discovery differences in the offshore markets stem from the offshore spot and forward contracts tracking different aspects of yuan rates (e.g., the offshore nondeliverable rate tracks onshore spot rates whereas the offshore spot rate tracks onshore interest rates). Moreover, the introduction of offshore spot trading in Hong Kong has led to an increase in cross-market price discovery between onshore spot and offshore NDF rates. © 2012 Wiley Periodicals, Inc. Jrl Fut Mark 34:103–123, 2014

Summary We studied the relative importance of the magnitude and duration of the shear stimulus to induce flow-mediated dilation (FMD) in the brachial artery of 10 healthy men by ultrasound imaging. The shear stress stimulus was induced by different durations of reactive hyperaemia following 15-min forearm occlusion. The control condition of continuous postocclusion hyperaemia was compared to 20, 40 and 60 s of reactive hyperaemia followed by reapplication of circulatory arrest for 2 min and a second cuff release. In response to the first cuff release, peak shear rate was not different between conditions; total shear during the first minute was reduced in the 40 s and further reduced in the 20 s conditions. FMD in control (10·0 ± 3·0%), 60 s (10·5 ± 3·2%) and 40 s (7·8 ± 3·6%) were greater than the 20-s condition (2·9 ± 2·8%). At second cuff release, peak shear of the 20-s condition was slightly reduced from the first release, but 40 and 60-s conditions were progressively reduced. Total shear to peak dilation was reduced after the second cuff release for the 20 and 40-s conditions and further after the 60-s condition. FMD was maintained in the 20-s condition (8·3 ± 3·7%) but reduced in the 40-s (3·7 ± 1·7%) and 60-s conditions (1·5 ± 2·6%). FMD was not related to peak shear rate after the first occlusion (r = 0·003) but was after the second cuff release (r = 0·32, P = 0·004). The FMD response was correlated with the total shear to time of peak diameter after the first (r = 0·35, P

Summary Venous thrombo-embolism (VTE) is increasingly recognized in paediatric practice. Few clinical trials have been performed in this area in children and management is largely extrapolated from adult practice where there is a considerable evidence base. This is likely to be unsatisfactory for a number of reasons. Firstly, there are significant differences in epidemiology and potential differences in the mechanisms for VTE in this age group. Secondly, many aspects of haemostasis are agedependant, which has implications for the use of anticoagulants in the paediatric population. Thirdly, there are very limited data available on the safety and efficacy of anticoagulants to manage specific indications in paediatric practice, often with limited paediatric formulations available. In addition, children may survive for a prolonged period following these events so that long-term consequences may be highly significant in this age group. The aim of this guideline is to provide a rational basis for the investigation and management of children aged 1 month‐16 years with VTE, including cerebral venous thrombosis (CVT). The guideline is targeted at healthcare professionals involved in the management of children and adolescents with VTE, particularly paediatric haematologists.

Evidence-based guidelines are presented for the management of haemophilia in the fetus and neonate. This includes information regarding the management of pregnancy and delivery as well as aspects of management during the early neonatal period. Specific issues regarding the mode of delivery and the risk of intra-cranial and extra-cranial haemorrhage are discussed.

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Characterizing, modeling, and monitoring the distribution and condition of the Earth’s biodiversity and ecosystems has a long history of being aided by Earth Observation data and the models and derivative products that they support. At the global scale, there need to be more coordinated efforts to acquire, process, analyze, and make available these observation data across all disciplines, particularly since many applications use the same primary and derived data. Towards that end, the Group on Earth Observations (GEO) is implementing the Global Earth Observing System of Systems. The purpose of this article is to provide information on GEO’s goals and activities relevant to biodiversity and ecosystems. The article also describes the data that would best serve as a year 2010 baseline in order to support the objectives of the Convention on Biological Diversity (CBD) as well as many other international agreements, programs, and activities. Indeed, an assessment of existing biodiversity observations with a concomitant recognition of the remaining gaps will promote the establishment of an integrated framework for biodiversity observations in support of the CBD’s efforts.

Consensus-based guidelines supported by the literature are presented on the role of prophylactic administration of factor VIII concentrate in children and adults with severe haemophilia A. The timing of initiation of prophylaxis, the choice of prophylactic regimen, monitoring, management of breakthrough bleeding and education of the patient and family are discussed.

Thrombosis in children may result in vascular occlusion and a potential loss of viability in skin, limbs or organs, or lead to the development of post thrombotic syndrome. Thrombolysis may prevent such complications, and the use of thrombolytics in children has increased in the last three decades. Despite this, optimum paediatric treatment regimens for these drugs remain uncertain, and accurate efficacy and safety profiles for thrombolytics are limited by the lack of controlled, prospective studies in well-defined patient populations. Restoration of vessel patency has often been achieved but the risk of intracranial and other major haemorrhage secondary to thrombolysis continues to be a significant concern for the clinician deciding on such treatment. This review summarises the use of thrombolytic treatment in children and describes outcome data and adverse events following treatment, as well as the limitations of published studies on paediatric thrombolysis.

Nitrous oxide (N2O) emissions from grazed pastures constitute approximately 28% of total global anthropogenic N2O emissions. The aims of this study were to investigate the effect of inorganic N fertilizer application on fluxes of N2O, quantify the emission factors (EFs) for a sandy loam soil which is typical of large areas in Ireland and to investigate denitrification sensitivity to temperature. Nitrous oxide flux measurements from a cut and grazed pasture field for 1 year and denitrification laboratory incubation were carried out. The soil pH was 7.3 and had a mean organic C and N content at 0–20 cm of 44.1 and 4.4 g/kg dry weight, respectively. The highest observed peaks of N2O fluxes of 67 and 38.7 g N2O-N per hectare per day were associated with times of application of inorganic N fertilizer. Annual fluxes of N2O from control and fertilized treatments were 1 and 2.4 kg N2O-N per hectare, respectively. Approximately 63% of the annual flux was associated with N fertilizer application. Multiple regression analysis revealed that soil nitrate and the interaction between soil nitrate and soil water content were the main factors controlling N2O flux from the soil. The derived EF of 0.83% was approximately 66% of the IPCC default EF value of 1.25% as used by the Irish EPA to estimate greenhouse gases (GHGs) in Ireland. The IPCC-revised EF value is 0.9%. A highly significant exponential regression (r2 = 0.98) was found between denitrification and incubation temperature. The calculated Q10 ranged from 4.4 to 6.2 for a temperature range of 10–25 °C and the activation energy was 47 kJ/mol. Our results show that denitrification is very sensitive to increasing temperature, suggesting that future global warming could lead to a significant increase in soil denitrification and consequently N2O fluxes from soils.

The studies described here are the first to evaluate the in vitro and in vivo properties of (111)In-CHX-A''-panitumumab for radioimmunotherapy (alpha- and beta(-)-emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography).Twenty-seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX-A''-DTPA (diethylenetriamine-pentaacetic acid) and radiolabelled with (111)In. Immunoreactivity of the CHX-A''-DTPA-panitumumab and (111)In-CHX-A''-DTPA-panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by gamma-scintigraphy.For 26 of 27 human tumour cell lines, 95% of the cells expressed epidermal growth factor receptors over a range of intensity. Immunoreactivity of panitumumab was retained after modification with CHX-A''-DTPA. Radiolabelling of the immunoconjugate with (111)In was efficient with a specific activity of 19.5 +/- 8.9 mCi.mg(-1) obtained. Immunoreactivity and specificity of binding of the (111)In-panitumumab was shown with A431 cells. Tumour targeting by (111)In-panitumumab was demonstrated in athymic mice bearing A431, HT-29, LS-174T, SHAW or SKOV-3 s.c. xenografts with little uptake observed in normal tissues. The (111)In-panitumumab was also evaluated in non-tumour-bearing mice. Pharmacokinetic studies compared the plasma retention time of the (111)In-panitumumab in both non-tumour-bearing and A431 tumour-bearing mice. Tumour targeting was also visualized by gamma-scintigraphy.Panitumumab can be efficiently radiolabelled with (111)In with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications.

The Lough Muck Formation (Wenlock) is part of the Silurian succession of North Galway, western Ireland. The formation had originally been interpreted as a transitional sequence between shelf and basinal facies in the succession. Its three members (1, 2, and 3 of Laird and McKerrow 1970) were envisaged as representing deposits of the continental rise, slope, and shelf respectively. A subsequent interpretation suggested that the two upper members were of shallow marine origin and that the proposed major Wenlock regressive event was already extant by the time of deposition of Member 2. In this paper we examine Member 1 to ascertain its environment of deposition and thus refine the sea level curve for this element of the Silurian. Member 1 may be divided into five lithofacies A to E. Facies A comprises amalgamated sandstones with low-angle cross-stratification. Facies B consists of couplets of erosively based coquinas containing a low-diversity parautochthonous fauna and graded, laminated sandstones. These couplets are interbedded with thin laminated siltstones. Facies C is characterized by parallel laminated siltstones and discontinuous, erosively based sandstones. Facies D consists of fossiliferous siltstone and Facies E of thin sandstones with low-angle cross-lamination. Facies A and B are interpreted as shoreline deposits based upon comparison with published descriptions of such deposits elsewhere. Facies, C, D, and E, lateral equivalents of the first two facies, are interpreted as deposits which accumulated further offshore. The presence of couplets consisting of a coquina and overlying laminated sandstone, and fossil distribution, the presence of amalgamated beds and low-angle cross-stratification suggest the influence of storms on this shallow-water sequence. A palaeoreconstruction is proposed which envisages a shelf deepening to the southeast off a shoreline which had an approximately northeasterly orientation.

Adenine nucleotides displace the binding of the selective adenosine A-1 receptor ligand [3H]cyclopentyladenosine (CPA) to rat brain membranes in a concentration-dependent manner, with the rank order of activity being ATP greater than ADP greater than AMP. Binding was also displaced by GTP, ITP, adenylylimidodiphosphate (AppNHp), 2-methylthioATP, and the beta-gamma-methylene isostere of ATP, but was unaffected by the alpha-beta-methylene isosteres of ADP and ATP, and UTP. At ATP concentrations greater than 100 microM, the inhibitory effects on CPA binding were reversed, until at 2 mM ATP, specific binding of CPA was identical to that seen in controls. Concentrations of ATP greater than 10 mM totally inhibited specific binding. Inclusion of the catabolic enzyme adenosine deaminase in the incubation medium abolished the inhibitory effects of ATP, indicating that these were due to adenosine formation, presumably due to ectonucleotidase activity. The inhibitory effects were also attenuated by the alpha-beta-methylene isostere of ATP, an ectonucleotidase inhibitor. Adenosine deaminase, alpha-beta-methylene ATP (100 microM), and beta-gamma-methylene ATP (100 microM) had no effect on the "stimulatory" phase of binding, although GTP (100 microM) slightly attenuated it. Comparison of the binding of [3H]CPA in the absence and presence of 2 mM ATP by saturation analysis showed that the KD and apparent Bmax values were identical. Examination of the pharmacology of the control and "ATP-dependent" CPA binding sites showed slight changes in binding of adenosine agonists and antagonists. The responses observed with high concentrations of ATP were not observed with GTP, AppNHp, the chelating agents EDTA and EGTA, or inorganic phosphate. The divalent cations Mg2+ and Ca2+ at 10 mM attenuated the stimulatory actions of high (2 mM) concentrations of ATP, whereas EGTA and EDTA (10 mM) enhanced the "stimulatory" actions of ATP. EDTA (10 mM) abolished the inhibitory effects of ATP, indicating a specific dependence on Mg2+ for the inhibitory response. The effects of ATP on [3H]CPA binding were reversible for antagonists but not agonists. The mechanism by which ATP reverses its own inhibitory action on adenosine A-1 radioligand binding is unclear, and from the observed actions of the divalent cations and chelating agents probably does not involve a phosphorylation-dependent process.

Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (

It has been reported that during Drosophila embryonic development, and in cell culture, that the Rac GTPases are redundant. To better elucidate Rac function in Drosophila, we decided to study the role of Rac2 in larval cellular defense reactions against the parasitiod Leptopilina boulardi. Here we show a dramatic effect in the context of cellular immunity where, unlike embryonic development, Rac2 appears to have a non-redundant function. When an invading parasitoid is recognized as foreign, circulating hemocytes (blood cells) should recognize and attach to the egg chorion. After attachment the hemocytes should then spread to form a multilayered capsule surrounding the invader. In Rac2 mutants this process is disrupted. Immune surveillance cells, known as plasmatocytes, adhere to the parasitoid egg but fail to spread, and septate junctions do not assemble, possibly due to mislocalization of the Protein 4.1 homolog Coracle. Finally, larger cells known as lamellocytes attach to the capsule but also fail to spread, and there is a lack of melanization. From these results it appears that Rac2 is necessary for the larval cellular immune response.