Secondary education reform in Lesotho and Zimbabwe and the needs of rural girls: Pronouncements, policy and practice

Analysis of the educational needs of rural girls in Lesotho and Zimbabwe suggests a number of shortcomings in the current form of secondary education, and ways in which it might be modified so as to serve this sizeable group of students better. Several of the shortcomings, notably in relation to curricular irrelevance and excessive focus on examinations, have long been recognised, including by politicians. Yet political pronouncements are seldom translated into policy, and even where policy is formulated, reforms are seldom implemented in schools. This paper makes use of interviews with educational decision-makers in the two southern African countries and a range of documentary sources to explore why, despite the considerable differences between the two contexts, much needed educational reforms have been implemented in neither

Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors.

The calcitonin gene-related peptide (CGRP) family of G protein-coupled receptors (GPCRs) is formed through the association of the calcitonin receptor-like receptor (CLR) and one of three receptor activity-modifying proteins (RAMPs). Binding of one of the three peptide ligands, CGRP, adrenomedullin (AM), and intermedin/adrenomedullin 2 (AM2), is well known to result in a Gαs-mediated increase in cAMP. Here we used modified yeast strains that couple receptor activation to cell growth, via chimeric yeast/Gα subunits, and HEK-293 cells to characterize the effect of different RAMP and ligand combinations on this pathway. We not only demonstrate functional couplings to both Gαs and Gαq but also identify a Gαi component to CLR signaling in both yeast and HEK-293 cells, which is absent in HEK-293S cells. We show that the CGRP family of receptors displays both ligand- and RAMP-dependent signaling bias among the Gαs, Gαi, and Gαq/11 pathways. The results are discussed in the context of RAMP interactions probed through molecular modeling and molecular dynamics simulations of the RAMP-GPCR-G protein complexes. This study further highlights the importance of RAMPs to CLR pharmacology and to bias in general, as well as identifying the importance of choosing an appropriate model system for the study of GPCR pharmacology.This work was supported by the National Heart Foundation of New Zealand (H.W.), the School of Biological Sciences, University of Auckland seed fund (H.W.), the BBSRC (G.L. - BB/M00015X/1), (D.P. - BB/M000176/1), (C.A.R. - BB/M006883/1), a BBSRC Doctoral Training Partnership (M.H. – BB/JO14540/1), an MRC Doctoral Training Partnership (I.W. - MR/J003964/1), a Warwick Impact Fund (C.W., G.L.), a Warwick Research Development Fund (C.W., G.L.) grant number (RD13301) and the Warwick Undergraduate Research Scholarship Scheme (A.S and R.H).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the American Society for Biochemistry and Molecular Biology

Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy.

Class B peptide hormone GPCRs are targets for the treatment of major chronic disease. Peptide ligands of these receptors display biased agonism and this may provide future therapeutic advantage. Recent active structures of the calcitonin (CT) and glucagon-like peptide-1 (GLP-1) receptors reveal distinct engagement of peptides with extracellular loops (ECLs) 2 and 3, and mutagenesis of the GLP-1R has implicated these loops in dynamics of receptor activation. In the current study, we have mutated ECLs 2 and 3 of the human CT receptor (CTR), to interrogate receptor expression, peptide affinity and efficacy. Integration of these data with insights from the CTR and GLP-1R active structures, revealed marked diversity in mechanisms of peptide engagement and receptor activation between the CTR and GLP-1R. While the CTR ECL2 played a key role in conformational propagation linked to Gs/cAMP signalling this was mechanistically distinct from that of GLP-1R ECL2. Moreover, ECL3 was a hotspot for distinct ligand- and pathway- specific effects, and this has implications for the future design of biased agonists of class B GPCRs

Prevalence of type R virus-like particles in clones of BHK-21 cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32926/1/0000308.pd

Pediatric Phantom Dosimetry of Kodak 9000 Cone-beam Computed Tomography

Purpose: The purpose of the study was to evaluate the radiation dose of the Kodak 9000 cone-beam computed tomography (CBCT) device for different anatomical areas using a pediatric phantom. Methods: Absorbed doses resulting from maxillary and mandibular region three by five cm CBCT volumes of an anthropomorphic 10-year-old child phantom were acquired using optical stimulated dosimetry. Equivalent doses were calculated for radiosensitive tissues in the head and neck area, and effective dose for maxillary and mandibular examinations were calculated following the 2007 recommendations of the International Commission on Radiological Protection (ICRP). Results: Of the mandibular scans, the salivary glands had the highest equivalent dose (1,598 microsieverts [μSv]), followed by oral mucosa (1,263 μSv), extrathoracic airway (pharynx, larynx, and trachea; 859 μSv), and thyroid gland (578 μSv). For the maxilla, the salivary glands had the highest equivalent dose (1,847 μSv), followed closely by oral mucosa (1,673 μSv), followed by the extrathoracic airway (pharynx, larynx, and trachea; 1,011 μSv) and lens of the eye (202 μSv). Conclusion: Compared to previous research of the Kodak 9000, completed with the adult phantom, a child receives one to three times more radiation for mandibular scans and two to 10 times more radiation for maxillary scans

Las conexiones de la enfermedad de Alzheimer: ¿Dónde están? Análisis desde la Proteómica cuantitativa

In this review we present the basic concepts that define the pathology of Alzheimer Disease (AD) and the fundamental methods used in Neuroproteomics for its study. Some results in the analysis of this disease are discussed and their relationship with the APOE4 allele of APOE, the gene coding for the APOE4 genotype of the Apolipoprotein E (ApoE). Finally we present some general considerations on AD, how to avoid the progression and we discuss briefly about the future of research in this area.En el presente artículo se presentan los conceptos básicos que definen la patología de la enfermedad de Alzheimer (EA) y los métodos fundamentales utilizados en Neuroproteómica para su estudio. De igual manera, se discuten algunos resultados en el análisis de esta enfermedad y su relación con el genotipo APOE4 de APOE, el gen que codifica la Apolipoproteína E (ApoE). Finalmente se hacen algunas consideraciones generales sobre la EA, cómo evitar su progresión y se discute brevemente el futuro de la investigación en esta área

Calcitonin receptor N-glycosylation enhances peptide hormone affinity by controlling receptor dynamics

The class B G protein-coupled receptor (GPCR) calcitonin receptor (CTR) is a drug target for osteoporosis and diabetes. N-glycosylation of asparagine 130 in its extracellular domain (ECD) enhances calcitonin hormone affinity with the proximal GlcNAc residue mediating this effect through an unknown mechanism. Here, we present two crystal structures of salmon calcitonin-bound, GlcNAc-bearing CTR ECD at 1.78 and 2.85 Å resolutions and analyze the mechanism of the glycan effect. The N130 GlcNAc does not contact the hormone. Surprisingly, the structures are nearly identical to a structure of hormone-bound, N-glycan-free ECD, which suggested that the GlcNAc might affect CTR dynamics not observed in the static crystallographic snapshots. Hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations revealed that glycosylation stabilized a β-sheet adjacent to the N130 GlcNAc and the N-terminal α-helix near the peptide-binding site, while increasing flexibility of the peptide-binding site turret loop. These changes due to N-glycosylation increased the ligand on-rate and decreased its off rate. The glycan effect extended to RAMP-CTR amylin receptor complexes and was also conserved in the related CGRP receptor. These results reveal that N-glycosylation can modulate GPCR function by altering receptor dynamics

Towards an Understanding of the Interactions between Freshwater Inflows and Phytoplankton Communities in a Subtropical Estuary in the Gulf of Mexico

Subtropical estuaries worldwide face increased pressure on their ecosystem health and services due to increasing human population growth and associated land use/land cover changes, expansion of ports, and climate change. We investigated freshwater inflows (river discharge) and the physico-chemical characteristics of Galveston Bay (Texas, USA) as mechanisms driving variability in phytoplankton biomass and community composition between February 2008 and December 2009. Results of multivariate analyses (hierarchical cluster analysis, PERMANOVA, Mantel test, and nMDS ordination coupled to environmental vector fitting) revealed that temporal and spatial differences in phytoplankton community structure correlate to differences in hydrographic and water quality parameters. Spatially, phytoplankton biomass and community composition responded to nutrient loading from the San Jacinto River in the northwest region of the bay (consistent with nutrient limitation) while hydraulic displacement (and perhaps other processes) resulted in overall lower biomass in the Trinity River delta (northeast region). The influence of inflows on phytoplankton diminished along a north to south gradient in the bay. Temporally, temperature and variables associated with freshwater inflow (discharge volume, salinity, inorganic nitrogen and phosphorus concentrations) were major influences on phytoplankton dynamics. Dissolved inorganic nitrogen: phosphorus (DIN:DIP) ratios suggest that phytoplankton communities will be predominately nitrogen limited. Diatoms dominated during periods of moderate to high freshwater inflows in winter/spring and were more abundant in the upper bay while cyanobacteria dominated during summer/fall when inflow was low. Given the differential influences of freshwater inflow on the phytoplankton communities of Galveston Bay, alterations upstream (magnitude, timing, frequency) will likely have a profound effect on downstream ecological processes and corresponding ecosystem services

Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes