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•WEPP modeling was conducted on paired, nested watersheds with forest managements.•WEPP-simulated daily streamflow was in close agreement with observed values.•WEPP captured water and ...sediment yields and changes due to harvesting practices.•Results demonstrated WEPP’s potential as a decision-aid tool in forest management.
The Water Erosion Prediction Project (WEPP) model was applied to seven paired, nested watersheds within the Mica Creek Experimental Watershed located in northern Idaho, USA. The goal was to evaluate the ability of WEPP to simulate the direct and cumulative effects of clear-cutting and partial-cutting (50% canopy removal) on water and sediment yield. WEPP was modified to better represent changes in the Leaf Area Index during post-harvest forest vegetative recovery. Good agreement between simulated and observed streamflow was achieved with minimal to no calibration over a 16-year (1992–2007) period. For the seven watersheds and the entire study period, the overall Nash-Sutcliffe Efficiency (NSE), Kling-Gupta efficiency (KGE), and deviation of runoff volume (DV) between observed and simulated daily streamflow ranged 0.58–0.71, 0.67–0.81, and −4% to 9%, respectively. Good agreement between predicted and observed suspended sediment yield was achieved through the calibration of a single channel critical shear stress parameter. For sediment yield, NSE, KGE, and DV ranged 0.62–0.97, 0.43–0.97, and −2% to 2%, respectively, for the calibration period, and 0.61–0.93, 0.42–0.95, and −24% to 13%, respectively, for the period of model performance assessment. Regression analysis of observed- and WEPP-simulated increase in water and sediment yield following clear-cut treatment was similar; however, the WEPP-simulated increase was lower compared to observations particularly from the partial-cut watershed. The variability in the critical shear parameter for different stream channels in the study watersheds was directly related to the observed mean particle size on the stream bed and suggests that applications of the WEPP model in ungauged basins could potentially set the critical shear parameter based on particle size. Overall, the simulated results demonstrate the potential of WEPP as a modeling tool for forestland watershed management, particularly for estimating the effects of forest harvest on hydrograph fluctuations and consequently, stream sediment transport.
Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. ...Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress.
Natural and constructed wetlands have been successful in remediating municipal and industrial wastewater effluent before it is discharged to downstream watersheds. There are several wetland ecosystem ...processes that can contribute to retention or removal of elements input in wastewater, although their relative importance is uncertain and variable among different wetlands. In this study we combined measurements of plant biomass production, nutrient content and stable nitrogen isotope compositions (δ
15
N) in
Schoenoplectus acutus
to determine the role of these dominant emergent aquatic plants in uptake and removal of wastewater nitrogen input to the Frank Lake (Alberta, Canada) wetland complex. Municipal and industrial wastewater effluent enters Frank Lake in Basin 1 and water flow is directed through Basin 2 and Basin 3 before input to the Little Bow River. Plant and sediment δ
15
N values (> 15 ‰) showed extreme enrichment of
15
N illustrating incorporation of effluent-derived nitrogen in the wetland complex. Nitrogen uptake by emergent plant biomass contributed approximately 8.7% of the total removal of that nutrient from Basin 1, while sequestration of nitrogen in lake sediments (25–50%) was a more important mechanism of nitrogen retention/removal. The relatively high plant δ
15
N values in Basins 1 and 2 were consistent with significant rates of denitrification occurring in those areas of the wetland.
Background KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to ...improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously.
Methods The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets.
Results This resulted not only in improved glycaemic control (HbA1c fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change.
Conclusions This is the first clear report of cognitive function improving in a patient with the neurological features associated with a KATP channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.
Mammary epithelial cells are embedded in a unique extracellular environment to which adipocytes and other stromal cells contribute. Mammary epithelial cells are critically dependent on this milieu ...for survival. However, it remains unknown which adipocyte-secreted factors are required for the survival of the mammary epithelia and what role these adipokines play in the process of ductal carcinoma tumorigenesis. Here, we take a systematic molecular approach to investigate the multiple ways adipocytes and adipokines can uniquely influence the characteristics and phenotypic behavior of malignant breast ductal epithelial cells. Microarray analysis and luciferase reporter assays indicate that adipokines specifically induce several transcriptional programs involved in promoting tumorigenesis, including increased cell proliferation (IGF2, FOS, JUN, cyclin D1), invasive potential (MMP1, ATF3), survival (A20, NFkappaB), and angiogenesis. One of the key changes in the transformed ductal epithelial cells associated with the cell cycle involves the induction of NFkappaB (five-fold) and cyclin D1 (three-fold). We show that by regulating the transcription of these molecules, the synergistic activity of adipocyte-derived factors can potentiate MCF-7 cell proliferation. Furthermore, compared to other stromal cell-secreted factors, the full complement of adipokines shows an unparalleled ability to promote increased cell motility, migration, and the capacity for angiogenesis. Adipocyte-secreted factors can affect tumorigenesis by increasing the stabilization of pro-oncogenic factors such as beta-catenin and CDK6 as a result of a reduction in the gene expression of their inhibitors (i.e. p18). An in vivo coinjection system using 3T3-L1 adipocytes and SUM159PT cells effectively recapitulates the host-tumor interactions in primary tumors. Type VI collagen, a soluble extracellular matrix protein abundantly expressed in adipocytes, is further upregulated in adipocytes during tumorigenesis. It promotes GSK3beta phosphorylation, beta-catenin stabilization, and increased beta-catenin activity in breast cancer cells and may critically contribute towards tumorigenesis when not counterbalanced by other factors.
Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we ...identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
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•Surveys on liver fluke control in sheep were conducted in N. Ireland in 2005 and 2011.•There was a progressive shift away from use of TCBZ; it was replaced largely by ...closantel.•Lowland sheep owners rotated drugs more often in 2011 than 2005.•The timing of treatments moved towards the start of the year.•At both time-points, almost one-third of farmers gave 3 or more treatments per year to ewes.•Few flock owners gave quarantine treatments in 2005. The percentage dropped further in 2011, from 31.0% to 15.2% and 25.9% to 13.9% for lowland and upland flock owners, respectively.
Reports of resistance to triclabendazole (TCBZ) among fluke populations have increased in recent years. Allied to this, there has been a rise in the prevalence of the disease, which has been linked to climate change. Results from questionnaire surveys conducted in Northern Ireland (NI) in 2005 (covering the years 1999–2004) and 2011 (covering the years 2008–2011) have provided an opportunity to examine the extent to which fluke control practices have changed over a prolonged time-frame, in light of these changes.
A number of differences were highlighted. There was a significant shift away from the use of TCBZ over time, with it being replaced largely by closantel. The timing of treatments had moved earlier in the year, perhaps in response to climate change (and an altered pattern of disease). In relation to the frequency of drug treatments, there were no major changes in the overall pattern of drug treatments between the two survey points, although on both occasions approximately one-third of flock owners gave more than 3 treatments per year to ewes. In lowland areas in 2011, flock owners were rotating drug classes more often (each year and at each treatment) than in 2005, whereas in upland areas, flock owners were rotating less often and more were not rotating at all. Between 2005 and 2011, the percentage of flock owners giving quarantine treatments to bought-in stock had halved, to a very low level (approximately 10%).
Using data from a complementary TCBZ resistance survey (Hanna et al., 2015), it has been shown that the way in which data are selected and which efficacy formula is applied can influence the calculation of drug efficiency and impact on diagnosis of resistance.
Background
Fetal growth restriction (FGR) is an obstetric complication associated with adverse perinatal outcomes. Doppler ultrasound can improve perinatal outcomes through monitoring at‐risk fetuses ...and helping time delivery.
Aim
To investigate the prognostic value of different Doppler ultrasound measurements for adverse perinatal outcomes.
Materials
Individual participant data.
Methods
We performed a pooled analysis on individual participant data. We compared six prognostic models using multilevel logistic regression, where each subsequent model added a new variable to a base model that included maternal characteristics. Estimated fetal weight (EFW) and four Doppler ultrasound measurements were added in turn: umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI), cerebroplacental ratio (CPR), and mean uterine artery pulsatility index (mUtA PI). The primary outcome was a composite adverse perinatal outcome, defined as perinatal mortality, emergency caesarean delivery for fetal distress, or neonatal admission. Discriminative ability was quantified with area under the curve (AUC).
Results
Three data sets (N = 3284) were included. Overall, the model that included EFW and UA PI improved AUC from 0.650 (95% CI 0.624–0.676) to 0.673 (95% CI 0.646–0.700). Adding more ultrasound measurements did not improve further the discriminative ability. In subgroup analysis, the addition of EFW and UA PI improved AUC in both preterm (AUC from 0.711 to 0.795) and small for gestational age pregnancies (AUC from 0.729 to 0.770), but they did not improve the models in term delivery or normal growth subgroups.
Conclusions
Umbilical artery pulsatility index added prognostic value for adverse perinatal outcomes to the already available information, but the combination of other Doppler ultrasound measurements (MCA PI, CPR or UtA PI) did not improve further prognostic performance.
A sheep trial was performed to standardise a coproantigen reduction test (CRT) protocol for the diagnosis of resistance to triclabendazole (TCBZ) in
Fasciola hepatica). The CRT employs the BIO K201
...Fasciola coproantigen ELISA (Bio-X Diagnostics, Jemelle, Belgium) to test for the presence of
F. hepatica coproantigens in a faecal sample. If it is coproantigen-positive, the CRT protocol recommends that faecal samples are re-tested for coproantigens at 14 days post-treatment (dpt), with negative testing at this point indicating TCBZ success.
Initial work aimed to confirm the sensitivity of the BIO K201 ELISA for
Fasciola infection and investigate whether coproantigens represent a robust reduction marker of TCBZ efficacy. Thirty-eight, indoor-reared sheep were artificially infected with
F. hepatica isolates known to be susceptible (Cullompton) and resistant (Sligo) to TCBZ action, respectively. Treatment was administered at 12 weeks post-infection (wpi), with 2 sheep groups, infected with each isolate, culled at 2 and 4 weeks post-treatment (wpt), respectively. Necropsy was performed to confirm treatment efficacy. Individual faecal samples were collected twice-weekly throughout the trial period.
Additional work focused on the effect of temperature on faecal sample collection and storage. Faecal samples collected from sheep positive for
F. hepatica infection were sub-sampled and left at room temperature. Individual sub-samples were tested by ELISA on consecutive days and these readings compared to the original test result on the day of collection. In addition, ELISA values were compared between faecal sub-samples prepared on the day of sampling and post storage at −20
°C. Also, an immunocytochemical study was performed to determine the tissue site of origin of the coproantigen protein in the fluke.
Results showed that the BIO K201 ELISA was sensitive for
Fasciola coproantigens, with coproantigens detectable from 5 wpi onwards. The suitability of coproantigens as a diagnostic marker of TCBZ efficacy was supported by the absence and presence of coproantigens in TCBZ-treated Cullompton (TCBZ-susceptible) and Sligo (TCBZ-resistant)
F. hepatica infections at 2 and 4 wpt, respectively. Study results suggest that low to moderate temperature has little, if any, impact on coproantigen stability in faecal samples, but that higher temperatures may have. Immunolabelling for the coproantigen showed that it was specific to the gastrodermal cells of both adult and juvenile flukes.
Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter ...presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θμe mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm241, excluding the 90% C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90% CLs for Δm241 < 13 eV2. Furthermore, the LSND and MiniBooNE 99% C.L. allowed regions are excluded at 99% CLs for Δm241 < 1.6 eV2.
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