Search

The endothelium is an attractive drug target and an important site of adverse drug reactions. Endothelial dysfunction is strongly associated with inflammation and contributes to drug-induced cardiovascular toxicity. Endothelial cells in the circulation are exposed to haemodynamic forces including shear stress. Including shear stress may improve future endothelial cell drug discovery or toxicity screening. Piezo-1 is required for endothelial cells to respond to shear stress. In this study, we investigated whether a small molecule activator of Piezo-1, Yoda-1, can mimic the effect of laminar flow-induced shear stress on endothelial cell inflammation, and endothelial cytotoxicity in response to the chemotherapy agent, doxorubicin. First, we tested whether Yoda-1 could mimic the effects of shear stress of expression of the endothelial adhesion molecules, ICAM-1 and VCAM-1. Human umbilical vein endothelial cells (HUVEC) were cultured in static conditions (with or without Yoda-1) or under laminar flow-induced shear stress (5 dyn/cm2). Yoda-1 and laminar flow had similar anti-inflammatory effects, reducing the ability of TNF-α to induce ICAM-1 and VCAM-1 expression. We then tested whether Yoda-1 could mimic the effect of shear stress on doxorubicin-induced cytotoxicity. Both laminar flow and Yoda-1 treatment of static cultures increased the cytotoxicity of doxorubicin. These findings show that Piezo-1 activation with Yoda-1 in static culture leads to an endothelial cell phenotype that mimics endothelial cells under laminar flow. Pharmacological activation of Piezo-1 may be a useful approach to mimic constant shear stress in static cultures, which may improve endothelial drug discovery and toxicity testing. [ABSTRACT FROM AUTHOR]

HMGB1 and HMGB2 are DNA-interacting proteins but can also have extracellular actions during inflammation. Despite their relatively high homology, they may have distinct roles, making it essential to be able to differentiate between the two. Here we examine the specificity of five commercially-available anti-HMGB1 antibodies. By Western blotting of recombinant proteins and HMGB1−/− mouse embryonic fibroblasts, we identified only one HMGB1 antibody that, under our experimental conditions, did not also detect HMGB2. Selecting specific antibodies for HMGB1 and HMGB2 allowed identification of distinct HMGB1 and HMGB2 subcellular pools in primary neutrophils. [ABSTRACT FROM AUTHOR]

Background The African continent has the greatest burden of surgical disability-adjusted life years, yet the least is known about operative care here. This analysis describes the surgical patients admitted to 7 hospitals supported by the Médécins Sans Frontières (MSF) over 3 years in 3 conflict-affected countries—Eastern Democratic Republic of Congo, Central African Republic, and South Sudan. Methods A standardized operative data collection tool was used for routine collection of operative inpatient data between 2011 and 2013 at 7 MSF surgical facilities. Surgical records of 14,482 patients were analyzed to describe surgical epidemiology, major procedures, and perioperative mortality. The perioperative mortality rate (POMR) was calculated within 2 days of admission (POMR2) and within 30 days from admission (POMR30). The POMR is used as a marker of quality of operative care. Results Caesarean delivery was the most common major procedure performed and had a POMR30 of 5.28 per 1,000 admissions. The overall inpatient mortality was 19.67 per 1,000 admissions. Children had greater POMR than adults for the same procedure types (47.97 vs 15.89 deaths per 1,000 admissions, P < .001); 85.1% of all major procedures were emergency procedures and between 3 and 30% of admissions were related to violence. After adjustment, perioperative death was associated with emergency surgery, violence, and age younger than 15 years. Conclusion POMRs varied by age group and type of major procedure performed. Collecting surgical data is achievable and can inform future planning and support for national surgical programs. More information is needed on operative outcomes in adults and children in low-resource settings to improve quality and access to care. [ABSTRACT FROM AUTHOR]

The effects of atmospheric pollution on plant species richness (n sp) are of widespread concern. We carried out a modelling exercise to estimate how n sp in British semi-natural ecosystems responded to atmospheric deposition of nitrogen (N dep) and sulphur (S dep) between 1800 and 2010. We derived a simple four-parameter equation relating n sp to measured soil pH, and to net primary productivity (NPP), calculated with the N14CP ecosystem model. Parameters were estimated from a large data set (n = 1156) of species richness in four vegetation classes, unimproved grassland, dwarf shrub heath, peatland, and broadleaved woodland, obtained in 2007. The equation performed reasonably well in comparisons with independent observations of n sp. We used the equation, in combination with modelled estimates of NPP (from N14CP) and soil pH (from the CHUM-AM hydrochemical model), to calculate changes in average n sp over time at seven sites across Britain, assuming that variations in n sp were due only to variations in atmospheric deposition. At two of the sites, two vegetation classes were present, making a total of nine site/vegetation combinations. In four cases, n sp was affected about equally by pH and NPP, while in another four the effect of pH was dominant. The ninth site, a chalk grassland, was affected only by NPP, since soil pH was assumed constant. Our analysis suggests that the combination of increased NPP, due to fertilization by N dep , and decreased soil pH, primarily due to S dep , caused an average species loss of 39% (range 23–100%) between 1800 and the late 20th Century. The modelling suggests that in recent years n sp has begun to increase, almost entirely due to reductions in S dep and consequent increases in soil pH, but there are also indications of recent slight recovery from the eutrophying effects of N dep. [Display omitted] • Semi-natural plant species richness depends on soil pH and net primary productivity. • Parameterized model fitted to field richness data for four vegetation types. • Richness 1800–2010 predicted from measured soil pH and modelled productivity. • Calculated richness reduced by nitrogen and sulphur atmospheric pollution. • Recent recovery in richness, owing to declines in sulphur pollution. Capsule: Modelling the long-term effects of atmospheric deposition indicates that both nutrient enrichment and soil acidification reduced plant species richness, which is now recovering from acidification. [ABSTRACT FROM AUTHOR]

Understanding how agricultural practices alter biogeochemical cycles is vital for maintaining land productivity, food security, and other ecosystem services such as carbon sequestration. However, these are complex, highly coupled long-term processes that are difficult to observe or explore through empirical science alone. Models are required that capture the main anthropogenic disturbances, whilst operating across regions and long timescales, simulating both natural and agricultural environments, and shifts among these. Many biogeochemical models neglect agriculture or interactions between carbon and nutrient cycles, which is surprising given the scale of intervention in nitrogen and phosphorus cycles introduced by agriculture. This gap is addressed here, using a plant-soil model that simulates integrated soil carbon, nitrogen and phosphorus (CNP) cycling across natural, semi-natural and agricultural environments. The model is rigorously tested both spatially and temporally using data from long-term agricultural experiments across temperate environments. The model proved capable of reproducing the magnitude of and trends in soil nutrient stocks, and yield responses to nutrient addition. The model has potential to simulate anthropogenic effects on biogeochemical cycles across northern Europe, for long timescales (centuries) without site-specific calibration, using easily accessible input data. The results demonstrate that weatherable P from parent material has a considerable effect on modern pools of soil C and N, despite significant perturbation of nutrient cycling from agricultural practices, highlighting the need to integrate both geological and agricultural processes to understand effects of land-use change on food security, C storage and nutrient sustainability. The results suggest that an important process or source of P is currently missing in our understanding of agricultural biogeochemical cycles. The model could not explain how yields were sustained in plots with low P fertiliser addition. We suggest that plant access to organic P is a key uncertainty warranting further research, particularly given sustainability concerns surrounding rock sources of P fertiliser. Unlabelled Image • A C-N-P model simulating transition from natural to agricultural land-use • The model is compared with data from long-term experimental plots in Europe. • Agriculture causes significant changes to nutrient cycling. • Modern C and N stocks remain strongly influenced by initial weatherable P. • Results indicate a missing process or source of P in current understanding. [ABSTRACT FROM AUTHOR]

Evaluating distributed soil erosion models is challenging because of the uncertainty in models and measurements of system responses. Here, we present an approach to evaluate soil erosion and sediment delivery models, which incorporates sediment source fingerprinting and sediment-rating curve uncertainty into model testing. We applied the Generalized Likelihood Uncertainty Estimation (GLUE) methodology to the Sediment Delivery Distributed model (SEDD) for a large catchment in Southeast Brazil. The model was not rejected, as 23.4% of model realizations were considered behavioral. Fingerprinting results and SEDD simulations showed a partial agreement regarding the identification of the main sediment sources in the catchment. However, grid-based estimates of soil erosion and sediment delivery rates were highly uncertain, which restricted the model's usefulness for quantifying sediment dynamics. Although our results are case-specific, similar levels of error might be expected in erosion models elsewhere. The representation of such errors should be standard practice. • GLUE was applied to an erosion and sediment delivery model. • Models were conditioned according to sediment load measurements. • Behavioral simulations were tested against sediment fingerprinting apportionments. • Forcing and testing data were highly uncertain, as well as model outputs. • Better observational data is needed to reject non-behavioral models. [ABSTRACT FROM AUTHOR]

This paper describes an agricultural model (Roth-CNP) that estimates carbon (C), nitrogen (N) and phosphorus (P) pools, pool changes, their balance and the nutrient fluxes exported from arable and grassland systems in the UK during 1800–2010. The Roth-CNP model was developed as part of an Integrated Model (IM) to simulate C, N and P cycling for the whole of UK, by loosely coupling terrestrial, hydrological and hydro-chemical models. The model was calibrated and tested using long term experiment (LTE) data from Broadbalk (1843) and Park Grass (1856) at Rothamsted. We estimated C, N and P balance and their fluxes exported from arable and grassland systems on a 5 km × 5 km grid across the whole of UK by using the area of arable of crops and livestock numbers in each grid and their management. The model estimated crop and grass yields, soil organic carbon (SOC) stocks and nutrient fluxes in the form of NH 4 -N, NO 3 -N and PO 4 -P. The simulated crop yields were compared to that reported by national agricultural statistics for the historical to the current period. Overall, arable land in the UK have lost SOC by −0.18, −0.25 and −0.08 Mg C ha −1 y −1 whereas land under improved grassland SOC stock has increased by 0.20, 0.47 and 0.24 Mg C ha −1 y −1 during 1800–1950, 1950–1970 and 1970–2010 simulated in this study. Simulated N loss (by leaching, runoff, soil erosion and denitrification) increased both under arable (−15, −18 and −53 kg N ha −1 y −1 ) and grass (−18, −22 and −36 kg N ha −1 y −1 ) during different time periods. Simulated P surplus increased from 2.6, 10.8 and 18.1 kg P ha −1 y −1 under arable and 2.8, 11.3 and 3.6 kg P ha −1 y −1 under grass lands 1800–1950, 1950–1970 and 1970–2010. [ABSTRACT FROM AUTHOR]

Water erosion negatively affects soil fertility, soil structure, and water availability to plants. Moreover, off-site erosion effects contribute to the sedimentation and eutrophication of water courses. The Grande River is one of the main tributaries of the Paraná River, and an important source of hydroelectric power in Brazil. The Upper Grande River Basin covers an area of 15,705 km 2 , mostly occupied by rangelands. Shallow and little permeable Cambisols are the predominant soil class in the basin, which, combined with the intensive and highly concentrated summer rainfall, characterize an erosion-prone scenario. The aim of this study was to model the soil losses and the sediment yield in the Upper Grande River Basin. It also sought to quantify the sediment delivery to the two main hydroelectric power plant reservoirs in the basin: Camargos/Itutinga and Funil. Geographical Information Systems (GIS) were used to apply the Revised Universal Soil Loss Equation (RUSLE) and the Sediment Delivery Distributed model (SEDD) in the study area. The models were calibrated using sediment transport data obtained from a river gauging station located in a subwatershed. RUSLE predictions estimated that the average soil losses in the Upper Grande River Basin were of 22.35 t ha − 1 yr − 1 , and that bare soils, eucalypt and agriculture suffered the highest erosion rates among the identified land use classes. The average specific sediment yield in the basin was of 1.93 t ha − 1 yr − 1 . According to the model calibration, the specific sediment yield predictions showed an error of 0.01 t ha − 1 yr − 1 , or 0.6%. Agriculture and eucalypt forests, which compose approximately 10% of the study area, contribute to more than 40% of the sediment yield in the basin. The model predictions estimated that 1.45 million t yr − 1 of sediments are delivered to the Camargos/Itutinga power plant reservoir, whereas the Funil power plant reservoir receives a sediment input of 1.68 million t yr − 1 . Although model calibration yielded small errors in relation to the observed sediment measurements, the relative lack of available data has impaired a more thorough validation of the employed models. Nevertheless, the results indicate that the RUSLE/SEDD approach may be useful for analyzing sediment transport in Brazilian watersheds, where limited input data is available. [ABSTRACT FROM AUTHOR]