Ensuring water supply for all towns and villages in the Eastern Cape and Western Cape Provinces of South Africa

The Department of Water Affairs (DWA) has embarked on a nationwide programme to develop water-reconciliation strategies for all towns across the country. Reconciliation strategies for the major metropolitan areas and systems (e.g. Johannesburg/Pretoria, East London, Cape Town and Durban) were developed next. The implementation of these strategies is monitored by strategy steering committees. The approach has now been extended to all other metropolitan areas as well as all towns and villages or clusters of villages. In order to prepare the actual strategies, regardless of the size of the town, thorough documentation, research and analysis of the available information was required, as well as evaluation of projected growth scenarios to assess water requirements over the next 25 years and identification of potential additional sources to meet this growing requirement. It has emerged that the poor operation and maintenance of water supply, treatment and reticulation infrastructure are resulting in significant losses, which, if corrected, can reverse the current water shortages being experienced. Similarly, the generally poor management of effluent remains a threat to surface water and groundwater quality downstream. It appears that many municipalities perceive groundwater as an unreliable resource; however, in general, the issue of staff and skills shortages to manage the resource effectively is the actual problem. This is an operational issue rather than a groundwater-resource-specific issue. This aspect requires special attention for existing groundwater schemes and proposed groundwater development. In most instances water conservation and water-demand management and the development of local surface and groundwater resources are the most feasible options to meet any current or projected future water-supply shortfalls. Any intervention must be combined with a skills-development programme at the operational level to ensure the sustainability of the proposed supply options. This paper is based on the experience gained in the development of reconciliation strategies for the towns and villages in the DWA Southern Planning Region (i.e. surface water drainage areas in the Eastern Cape and Western Cape Provinces), which was carried out by Umvoto Africa in association with engineering consulting practice Aurecon

A. Lincoln Color Engraving

The object is an engraved portrait of Abraham Lincoln from the waist up that has been printed on off-white paper with black ink. It has severe foxing on its recto and verso. The engraving was probably a book illustration.https://scholarsjunction.msstate.edu/fvw-artifacts/1191/thumbnail.jp

A. Lincoln Color Engraving

The object is an engraved portrait of Abraham Lincoln from the waist up that has been printed on off-white paper with black ink. It has severe foxing on its recto and verso. The engraving was probably a book illustration.https://scholarsjunction.msstate.edu/fvw-prints/1114/thumbnail.jp

Ultra-low-dose quadruple combination blood pressure lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of four blood pressure- lowering agents each at a quarter dose may provide a simple, safe and effective blood pressure lowering solution which may also improve long term-adherence. The QUARTET (Quadruple UltrA-low-dose tReaTment for hypErTension) double-blind, active controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline recommended standard care, in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure, either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg and bisoprolol 2.5 mg or to control therapy of a single identical appearing pill containing irbesartan 150 mg. In both arms step up therapy of open-label amlodipine 5mg will be provided if BP is >140/90 at 6weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12weeks follow-up. The primary outcome and some secondary outcomes will be assessed at 12weeks, there is an optional 12months extension phase to assess longer term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects and better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure

Enhanced In Vitro Refolding of Fibroblast Growth Factor 15 with the Assistance of SUMO Fusion Partner

Fibroblast growth factor 15 (Fgf15) is the mouse orthologue of human FGF19. Fgf15 is highly expressed in the ileum and functions as an endocrine signal to regulate liver function, including bile acid synthesis, hepatocyte proliferation and insulin sensitivity. In order to fully understand the function of Fgf15, methods are needed to produce pure Fgf15 protein in the prokaryotic system. However, when expressed in Escherichia coli (E. coli), the recombinant Fgf15 protein was insoluble and found only in inclusion bodies. In the current study, we report a method to produce recombinant Fgf15 protein in E. coli through the use of small ubiquitin-related modifier (SUMO) fusion tag. Even though the SUMO has been shown to strongly improve protein solubility and expression levels, our studies suggest that the SUMO does not improve Fgf15 protein solubility. Instead, proper refolding of Fgf15 protein was achieved when Fgf15 was expressed as a partner protein of the fusion tag SUMO, followed by in vitro dialysis refolding. After refolding, the N-terminal SUMO tag was cleaved from the recombinant Fgf15 fusion protein by ScUlp1 (Ubiquitin-Like Protein-Specific Protease 1 from S. cerevisiae). With or without the SUMO tag, the refolded Fgf15 protein was biologically active, as revealed by its ability to reduce hepatic Cyp7a1 mRNA levels in mice. In addition, recombinant Fgf15 protein suppressed Cyp7a1 mRNA levels in a dose-dependent manner. In summary, we have developed a successful method to express functional Fgf15 protein in prokaryotic cells

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

In vitro susceptibility to pyrimethamine of DHFR I164L single mutant Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>Recently, <it>Plasmodium falciparum </it>parasites bearing <it>Pfdhfr </it>I164L single mutation were found in Madagascar. These new mutants may challenge the use of antifolates for the intermittent preventive treatment of malaria during pregnancy (IPTp). Assays with transgenic bacteria suggested that I164L parasites have a wild-type phenotype for pyrimethamine but it had to be confirmed by testing the parasites themselves.</p> <p>Methods</p> <p>Thirty <it>Plasmodium falciparum </it>clinical isolates were collected in 2008 in the south-east of Madagascar. A part of <it>Pfdhfr </it>gene encompassing codons 6 to 206 was amplified by PCR and the determination of the presence of single nucleotide polymorphisms was performed by DNA sequencing. The multiplicity of infection was estimated by using an allelic family-specific nested PCR. Isolates that appeared monoclonal were submitted to culture adaptation. Determination of IC_50sto pyrimethamine was performed on adapted isolates.</p> <p>Results</p> <p>Four different <it>Pfdhfr </it>alleles were found: the 164L single mutant-type (N = 13), the wild-type (N = 7), the triple mutant-type 51I/59R/108N (N = 9) and the double mutant-type 108N/164L (N = 1). Eleven out 30 (36.7%) of <it>P. falciparum </it>isolates were considered as monoclonal infection. Among them, five isolates were successfully adapted in culture and tested for pyrimethamine <it>in vitro </it>susceptibility. The wild-type allele was the most susceptible with a 50% inhibitory concentration (IC₅₀) < 10 nM. The geometric mean of IC₅₀of the three I164L mutant isolates was 6-fold higher than the wild-type with 61.3 nM (SD = 3.2 nM, CI95%: 53.9-69.7 nM). These values remained largely below the IC₅₀of the triple mutant parasite (13,804 nM).</p> <p>Conclusion</p> <p>The IC₅₀s of the I164L mutant isolates were significantly higher than those of the wild-type (6-fold higher) and close from those usually reported for simple mutants S108N (roughly10-fold higher than wild type). Given the observed values, the determination of IC₅₀s directly on parasites did not confirm what has been found on transgenic bacteria. The prevalence increase of the <it>Pfdhfr </it>I164L single mutant parasite since 2006 could be explained by the selective advantage of this allele under sulphadoxine-pyrimethamine pressure. The emergence of highly resistant alleles should be considered in the future, in particular because an unexpected double mutant-type allele S108N/I164L has been already detected.</p

Molecular signature for receptor engagement in the metabolic peptide hormone amylin

The pancreatic peptide hormone, amylin, plays a critical role in the control of appetite, and synergizes with other key metabolic hormones such as glucagon-like peptide 1 (GLP-1). There is opportunity to develop potent and long-acting analogs of amylin or hybrids between these and GLP-1 mimetics for treating obesity. To achieve this, interrogation of how the 37 amino acid amylin peptide engages with its complex receptor system is required. We synthesized an extensive library of peptides to profile the human amylin sequence, determining the role of its disulfide loop, amidated C-terminus and receptor “capture” and “activation” regions in receptor signaling. We profiled four signaling pathways with different ligands at multiple receptor subtypes, in addition to exploring selectivity determinants between related receptors. Distinct roles for peptide sub-regions in receptor binding and activation were identified, resulting in peptides with greater activity than the native sequence. Enhanced peptide activity was preserved in the brainstem, the major biological target for amylin. Interpretation of our data using full-length active receptor models supported by molecular dynamics, metadynamics and supervised molecular dynamics simulations guided the synthesis of a potent dual agonist of GLP-1 and amylin receptors. The data offer new insights into the function of peptide amidation, how allostery drives peptide-receptor interactions, and provide a valuable resource for the development of novel amylin agonists for treating diabetes and obesity