What drives change? A framework to observe and understand broad-­‐ scale change in river basins

Development in river basins is strongly influenced by a range of non-­‐random factors, called global drivers. These can present a bewildering array of effects that confound concerted action. This report summarizes these effects with the CPWF’s six basins and presents a method of visualizing them together within a process of scenario visualization

Numerical continuation methods: a perspective

AbstractIn this historical perspective the principal numerical approaches to continuation methods are outlined in the framework of the mathematical sources that contributed to their development, notably homotopy and degree theory, simplicial complexes and mappings, submanifolds defined by submersions, and singularity and foldpoint theory

Analysis of Heme Iron Coordination in DGCR8: The Heme-Binding Component of the Microprocessor Complex

DGCR8 is the RNA-binding partner of the nuclease Drosha. Their complex (the “Microprocessor”) is essential for processing of long, primary microRNAs (pri-miRNAs) in the nucleus. Binding of heme to DGCR8 is essential for pri-miRNA processing. On the basis of the split Soret ultraviolet–visible (UV–vis) spectrum of ferric DGCR8, bis-thiolate sulfur (cysteinate, Cys–) heme iron coordination of DGCR8 heme iron was proposed. We have characterized DGCR8 heme ligation using the Δ276 DGCR8 variant and combined electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD), electron nuclear double resonance, resonance Raman, and electronic absorption spectroscopy. These studies indicate DGCR8 bis-Cys heme iron ligation, with conversion from bis-thiolate (Cys–/Cys–) axial coordination in ferric DGCR8 to bis-thiol (CysH/CysH) coordination in ferrous DGCR8. Pri-miRNA binding does not perturb ferric DGCR8’s optical spectrum, consistent with the axial ligand environment being separated from the substrate-binding site. UV–vis absorption spectra of the FeII and FeII–CO forms indicate discrete species exhibiting peaks with absorption coefficients substantially larger than those for ferric DGCR8 and that previously reported for a ferrous form of DGCR8. Electron–nuclear double resonance spectroscopy data exclude histidine or water as axial ligands for ferric DGCR8 and favor bis-thiolate coordination in this form. UV–vis MCD and near-infrared MCD provide data consistent with this conclusion. UV–vis MCD data for ferrous DGCR8 reveal features consistent with bis-thiol heme iron coordination, and resonance Raman data for the ferrous–CO form are consistent with a thiol ligand trans to the CO. These studies support retention of DGCR8 cysteine coordination upon reduction, a conclusion distinct from those of previous studies of a different ferrous DGCR8 isoform

IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Increased numbers of innate lymphoid cells in patients with inflammatory bowel disease

Learning to look : evaluating the student experience of an interactive image appraisal activity

Introduction: Student radiographers have expressed difficulty in performing image appraisal tasks. The purpose of this study was to investigate the value of a workshop delivered to level 4 undergraduate students. All students completed an image appraisal activity, inputting their appraisal into software that displayed their response alongside an expert opinion. They were asked to identify and discuss any discrepancy. Methods: All Level 4 students participated in an image appraisal workshop and were subsequently invited to take part in a focus group immediately after the activity. Twenty-three students took part in three focus groups (n = 7; n = 8; n = 8). A thematic analysis of transcripts was performed alongside validation from observations during the image appraisal activity. Results: Findings demonstrate that despite teaching and resources being available, students had focused on learning a generic checklist for image appraisal, had not appreciated the application of projection specific criteria and felt underprepared. The use of specific criteria and repetition within the task was considered useful. They identified learning needs and misconceptions through peer discussion and via the expert opinion, highlighting the value of feedback. Students enjoyed the workshop and made suggestions for implementation into the curriculum. Conclusion: Educators must not assume that the provision of resources will result in students developing deep knowledge. Teaching and learning strategies that are task specific are recommended to avoid a surface approach to learning. Time, repetition and appropriate feedback are essential to enable learners to develop competence and confidence for complex visual tasks, such as image appraisal

Distinct Genetic Architectures for Male and Female Inflorescence Traits of Maize

We compared the genetic architecture of thirteen maize morphological traits in a large population of recombinant inbred lines. Four traits from the male inflorescence (tassel) and three traits from the female inflorescence (ear) were measured and studied using linkage and genome-wide association analyses and compared to three flowering and three leaf traits previously studied in the same population. Inflorescence loci have larger effects than flowering and leaf loci, and ear effects are larger than tassel effects. Ear trait models also have lower predictive ability than tassel, flowering, or leaf trait models. Pleiotropic loci were identified that control elongation of ear and tassel, consistent with their common developmental origin. For these pleiotropic loci, the ear effects are larger than tassel effects even though the same causal polymorphisms are likely involved. This implies that the observed differences in genetic architecture are not due to distinct features of the underlying polymorphisms. Our results support the hypothesis that genetic architecture is a function of trait stability over evolutionary time, since the traits that changed most during the relatively recent domestication of maize have the largest effects

Simultaneous Inhibition of Ceramide Hydrolysis and Glycosylation Synergizes to Corrupt Mitochondrial Respiration and Signal Caspase Driven Cell Death in Drug-Resistant Acute Myeloid Leukemia

Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a “reset” would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3β, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an in vivo model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists