MSUIR Collection:

Proceedings of meeting of the World NCD Federation, Africa Region: Framing the noncommunicable diseases response and realizing sustainable development goals for the African region; December 12–14, 2018

Davison Munodawafa — Tue, 01 Jan 2019 00:00:00 GMT

Title: Proceedings of meeting of the World NCD Federation, Africa Region: Framing the noncommunicable diseases response and realizing sustainable development goals for the African region; December 12–14, 2018 Authors: Davison Munodawafa Abstract: As noncommunicable disease (NCD) burden continues to grow globally as well as in low‑ and middle‑income countries, there is an imperative to pursue opportunities and solutions that lead to risk mitigation, health promotion, and health system strengthening through integrated services for NCDs. The primary aim of integration is to reduce cost, improve efficiency, and achieve better health outcomes in relation to NCDs. The momentum around Sustainable Development Goals (SDG) and Universal Health Coverage (UHC) provides an opportunity to shift focus away from vertical health programs toward an integrated approach, particularly at primary healthcare level. The World Health Organization (WHO) 13th General Programme of Work (GPW13) sets out WHO’s strategic direction – strategic priorities, goals/impacts and outcomes, and strategic and organizational shifts for 2019–2023. Under the outcome 1.1, 1.2, and 1.3, of the GPW13, the WHO will efficiently and effectively increase coverage of essential health services by providing guidance and technical assistance to enable countries to strengthen their health systems and establish a strong foundation for integrated primary healthcare. This will help scale up context appropriate interventions that include prevention, early detection, treatment, and rehabilitation, with a view of achieving a 20% reduction in premature NCD death by 2023. Further, the 2011 UN Political Declaration on NCDs provides the mandate for multisectoral action and whole‑of‑government and whole‑of‑society responses. It mandates governments to work across sectors, including industries as broad as health, education, agriculture, sports, and environment; it also calls for intersectoral cooperation between UN agencies, governments, nongovernmental organizations, and the private sector. Pursuant of the above, this meeting was planned as a joint collaboration between the World NCD Federation (WNCDF), Chandigarh, India, and the WHO, Regional Office for Africa, NCD Directorate, together with the University of Botswana [Figure 1]. The specific objectives of the meeting were: (1) to discuss the latest advances and trends in detection, prevention, management, and surveillance of NCDs in Africa region within the context and framework of health system strengthening, UHC, and the SDG target on NCDs; (2) to share experiences, best practices, challenges, and bottlenecks of establishment and implementation of high‑level multisectoral coordination mechanism for NCDs within the framework of an overarching multisectoral coordination mechanism for health in Africa; (3) to discuss opportunities and challenges for scale‑up of NCD best buys within the African context and come up with recommendations on best practices; (4) to discuss how NCD prevention and control interventions can be accelerated in the region to meet the SDG of one‑third reduction in premature mortality.

A Dimeric Calcium-modulated GC-linked Receptor Kinase, PSKR1

Muleya, Victor — Tue, 01 Jan 2013 00:00:00 GMT

Title: A Dimeric Calcium-modulated GC-linked Receptor Kinase, PSKR1 Authors: Muleya, Victor; Wheeler, Janet I; Ruzvidzo, Oziniel; Kwezi, Lusisizwe; Thomas, Ludivine; Marondedze, Claudius; Gehring, Christoph; Irving, Helen R Abstract: The phytosulfokine receptor 1, PSKR1 is a membrane-localised leucine-rich repeat receptor-like kinase that also possesses intrinsic guanylate cyclase (GC) activity. The GC activity is conferred, in part, by the presence of a GC catalytic centre that is embedded within its kinase domain. This unusual domain architecture represents a novel class of GC-linked receptor kinases. This novel class of kinases was unearthed using sequence homology-guided bioinformatic data mining tools. Only four members of this new class of kinases have been shown to possess both kinase and GC activity. Currently, there is a paucity of information as to how this dual catalytic activity is regulated in these molecules; therefore we set out to explore the regulatory factors that modulate the dual catalysis in this unusual family of receptor kinases. Our functional studies on PSKR1 demonstrate that calcium acts as a molecular switch regulating this dual catalysis. Functional analysis of PSKR1 at different calcium concentrations showed that calcium inhibits the kinase activity of PSKR1 in a concentration dependant manner whilst on the other hand, enhancing the GC activity of PSKR1. Our previous studies have also demonstrated that, cyclicGMP (a product of GC activity) inhibits the kinase activity of PSKR1. Taken together, our observations indicate that calcium and cyclicGMP act as molecular switches of PSKR1-mediated signalling. Furthermore, our structural analysis of the cytoplasmic domain of PSKR1 suggests that it exists as a reversible dimer in solution. This observation may represent a physiological conformation of PSKR1. In a separate experiment, using tandem mass spectrometry, we have mapped out the phosphorylation pattern of the cytoplasmic domain of PSKR1. Our findings show that the cytoplasmic domain of PSKR1 has 14 phosphorylation sites in its cytoplasmic domain including 3 phospho-tyrosines. This current study presents a mechanistic model of how calcium and phosphorylation act as bimodal switches regulating the dual catalysis in PSKR1. Description: Abstract

Calcium is the molecular switch shifting the phytosulfokine receptor 1 (PSKR1) from kinase to guanylate cyclase activity

Muleya, Victor — Tue, 01 Jan 2013 00:00:00 GMT

Title: Calcium is the molecular switch shifting the phytosulfokine receptor 1 (PSKR1) from kinase to guanylate cyclase activity Authors: Muleya, Victor; Wheeler, J. I.; Freihat, L.; Thomas, L.; Marondedze, C.; Manallack, D. T.; Ruzvidzo, O.; Kwezi, L.; Gehring, C.; Irving, H. R. Abstract: Many plant responses are mediated by interactions between intracellular calcium and the second messenger cGMP formed by guanylate cyclases (GCs). Previously we identified a novel class of receptor-GCs containing the GC catalytic center embedded within the kinase domain and showed that the recombinant cytoplasmic domain of phytosulfokine receptor AtPSKR1 has both guanylate cyclase and kinase activity in vitro (Kwezi et al. 2011 J Biol Chem 286: 22580-8). We now show that physiological increases in calcium levels enhance GC activity of AtPSKR1 whereas these calcium levels reversibly inhibit kinase activity. In addition PSKR1 kinase activity is reduced in the presence of the GC product cGMP. Recombinant AtPSKR1 can undergo in vitro autophosphorylation and we have confirmed it has 14 phosphorylation sites in its cytoplasmic domain including 8 serine, 3 threonine and 3 tyrosine residues. Three phospho-serine residues at the juxta-membrane position were mutated to either mimic phosphorylation on or off states. Kinase activity was enhanced in the on mutant and suppressed in the off mutant while GC activity was unaffected suggesting calcium acts as a molecular switch of PSKR1- mediated signalling that can be modulated by the phosphorylation state. The challenge now lies in understanding how molecular interactions between the GC and kinase domains are capitalized on in the plant. Description: Conference presentation

Estimated glomerular filtration rate and C-reactive protein measures enhance the specificity for left ventricular hypertrophy detection using electrocardiographic criteria: paper presented at the 4th Congress of the African Federation of Clinical Chemists; Zimbabwe: 28-30 April 2015

Maunganidze, Fabian — Thu, 01 Jan 2015 00:00:00 GMT

Title: Estimated glomerular filtration rate and C-reactive protein measures enhance the specificity for left ventricular hypertrophy detection using electrocardiographic criteria: paper presented at the 4th Congress of the African Federation of Clinical Chemists; Zimbabwe: 28-30 April 2015 Authors: Maunganidze, Fabian; Woodiwiss, Angela J.; Maseko, Muzi; Libhaber, Carlos; Majane, Olebogeng HI; Norton, Gavin R. Abstract: Introduction: Left ventricular hypertrophy (LVH), the detection of which is recommended for routine risk prediction by all guidelines, is more prevalent in groups of African ancestry. This is in-part attributed to higher prevalence rates of obesity. The detection of LVH using standard electrocardiographic (ECG) criteria (ECG-LVH) has poor sensitivity and specificity and therefore needs modification in groups of African ancestry. Aim: To assess the usefulness of independent associations between Left Ventricular Mass Index (LVMI) and estimated glomerular filtration rate (eGFR) or serum C-reactive protein (CRP) concentrations to complement ECG criteria for LVH detection in predominantly obese African populations. Method: LVH determined by ECG using at least 12 different criteria (formulae) was compared to LVH determined by echocardiography (LV mass index>51g/m2.7) in a random sample of 358 participants from a prospective cohort from an urban, developing community of African ancestry in South Africa (41% obese) and used together with CRP concentrations and eGFR above or below the median for the sample. Results: A combination of CRP concentrations and eGFR above or below the median for the sample respectively showed significant performance (AUC=0.61±0.03, p<0.0005), but a low specificity (ability to report negative results as negative) for LVH detection (77%). When eGFR and CRP concentrations were employed to complement the R wave amplitude of the electrocardiographic lead aVL (RaVL)the specificity increased (93%), although the overall performance did not improve (AUC=0.71±0.03, p<0.0005, RaVL alone: AUC=0.70±0.03). The sensitivity (ability to report positive results as positive) of 25% was however in-line with previously reported sensitivities for LVH detection using ECG criteria in alternative population samples. However, without changing overall performance, eGFR together with RaVL increased the specificity to 88% and CRP concentrations when considered together with RaVL increased the specificity to 87%. Summary: Routine measurements of CRP and GFR can be used to enhance the specificity of electrocardiographic tests for LVH (especially the RaVL criterion) in obese African patients since these exhibit poor results from ECG alone. Conclusion: In groups of African ancestry, obesity contributes toward a poor validity and performance of all voltage criteria for the detection of LVH, but the use of eGFR and/or CRP concentrations to complement ECG criteria increases the specificity without altering the overall performance. Learning Outcomes: This study reveals the extra importance and usefulness of routine clinical laboratory tests in enhancing specialist diagnostic procedures.