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The repurposing of chemical compounds as anti-cryptococcus drugs
No full textThe manifestation of disseminated cryptococcal infection in HIV-infected individual is a life-threatening infection, with 70% mortality rate in sub-Saharan Africa. People are dying because of the complications around the management. Thus, there is a need for alternative drugs for better management of HIV-associated cryptococcal infection. This thesis successfully demonstrated in vitro anti-cryptococcus activity of: 1) anti-inflammatory drugs (aspirin and ibuprofen), 2) aspirinate-metal complex (CAS), and 3) anti-psychotic drugs (quetiapine and olanzapine). In this thesis, EUCAST guidelines were followed closely and this provides a sense of effectiveness, which is very important for improving patient outcomes.
Chapter 2 focused on repurposing aspirin and ibuprofen as alternative anti-cryptococcal drugs. The major findings from this part of the thesis show that, all the tested fungal strains revealed a dose dependent response profile towards aspirin and ibuprofen. Compared to aspirin, ibuprofen exerts greater antimicrobial action. More importantly, the MICs of both drugs did not negatively affect the functioning of macrophages - rather they enhanced the phagocytic capability of macrophages to internalize more cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B at lower concentrations than individual concentrations tested. Our findings revealed the mode of action employed by aspirin and ibuprofen which is via oxidative damage.
Chapter 3 focused on a derivative of aspirin viz. copper acyl salicylate (CAS). CAS possess anti-fungal activity against cryptococcal cells and acted in synergy with fluconazole and amphotericin B at lower concentrations than their individual concentrations tested. CAS also kills cells via reactive oxygen species (ROS)-mediated membrane damage. The effect of CAS did not negatively affect macrophages but rather enhance their phagocytic function. Comparing with aspirin, CAS led to more growth reduction and showed less toxicity.
Today, one of the main challenges in the management of disseminated cryptococcal infections is the secondary complications such as psychosis. Therefore, chapter 4 considers repurposing two anti-psychotic drugs i.e. quetiapine and olanzapine as suitable candidate anti-Cryptococcus drugs. The in vitro susceptibility results revealed that quetiapine and olanzapine have anti-cryptococcus activity and kill cells by compromising their membrane integrity. Importantly, the concentrations of drug tested were within the recommended dosage in the blood. Additionally, they acted in synergy with conventional drugs at concentrations that were lower than their defined MICs. It was also interesting to find that these two drugs chemosensitised macrophages, just like cytokines, which in turn, increase the appetite of macrophages against cryptococcal cells.
The presented data from this thesis has highlighted the potential clinical application of aspirin, ibuprofen, CAS, quetiapine and olanzapine as candidate anti-cryptococcus drugs. More encouragingly, all the drugs were able to effect synergism at reduced concentrations, which in turn can minimize the issues of side effects. These compounds employed a killing mechanism that was efficient against cryptococcal cells, although of lower eukaryotic origin. Therefore, it is important to demonstrate the effectiveness of these drugs in higher eukaryotic host cells. Towards this end, animal studies should be used as model to establish their therapeutic benefits in higher eukaryotic hosts. The duality of these compounds should also be assessed, which may provide additional beneficial therapeutic outcomes such as to manage pathogen-emergent psychosis and out-of-control inflammatory responses. Lastly, it is also important to determine if the antimicrobial activities of these compounds also occurs in other medically important pathogensNational Research Foundatio
Evaluation of the gasification reactivity of highveld coals for application in the coal to liquids process
No full textCoal is a very heterogeneous substance with widely varying properties from one source to another, requiring continuous analysis to determine the properties and reaction behaviour of coals as new sources become mined. There is furthermore a lack of research and understanding of the gasification behaviour of South African coals under elevated pressure conditions, relevant to the industry. This study was endeavoured to analyse and determine the high pressure gasification behaviour of five South African coals, in order to address knowledge shortfalls.
Five coals from three different seams form the Highveld coalfield of South Africa were characterised by routine analysis techniques. The coals were denoted 2C, 2N, 4C, 4N and 5N, the number referring to the seam of origin. Devolatilisation of the coals was performed to prepare chars. These chars were then subjected to CO2 gasification (30% CO2, 70% N2) at a range of temperatures (825 °C to 925 °C) and operating pressures (1 bar, 10 bar and 20 bar). A new fixed-bed high-pressure reactor was developed to conduct the gasification investigation at elevated pressures, ensuring that commercial operations are better emulated in the laboratory-scale experimentation.
The five coals investigated exhibited widely varying characteristic properties. Notable results include the following for coal samples 2C, 2N, 4C, 4N and 5N respectively:
- Ash yield (dry basis) of 15.5%, 19.5%, 24.8%, 26.5%, and 30.5%.
- Calorific value (MJ/kg) of 25.2, 24.1, 22.6, 21.5, and 20.5.
- Total vitrinite (mineral matter free) of 28.9%, 23.5%, 20.8%, 10.5%, and 60.1%.
- Total inertinite (mineral matter free) of 66.3%, 71.6%, 69.9%, 84.4%, and 28.5%.
- Vitrinite mean reflectance of 0.58, 0.55, 0.60, 0.66, and 0.53.
- Char BET surface area (m2/g) of 136, 134, 111, 92, and 106.
Fixed-beds of 500 μm sized char particles were gasified at isothermal conditions. Activation energies observed from the gasification results were within 244 ± 14 kJ/mol for all five chars, exhibiting low variability. The activation energies were also not observed to vary significantly with increasing operating pressure. An increase in operating pressure was observed to significantly increase the char reaction rates. The observed reaction orders with regards to CO2 partial pressure were determined to be within 0.35 ± 0.02 for all five chars, again exhibiting low variability. The reaction orders were also not observed to vary with increasing partial pressures, remaining seemingly constant over the partial pressure range investigated. The observations from the high pressure gasification results suggest that further increases in char reaction rate can be expected at operating pressures greater than 20 bar (corresponding to a CO2 partial pressure of 6 bar).
Char reaction rate, normalised to instantaneous carbon content, is graphically presented as a function of carbon conversion. These visualisations clearly indicate the behaviour of the chars over the entire conversion range. Visual inspection of these results indicates that the char gasification behaviour was significantly different at low pressure, compared to high pressure. As an example, a comparatively slow reacting char (4C) at 1 bar becomes comparatively fast reacting at 20 bar. Different chars also react differently to an increase in operating pressure, for example char 5N conversion rate increased on average by 266% at 20 bar compared to 1 bar, while for char 2C the increase was only 199%. This suggests that gasification results determined at low (near ambient) pressure may be poor predictors of gasification behaviour at higher pressure, as encountered in commercial equipment. It is therefore suggested that laboratory testing of coal gasification behaviour be conducted under conditions, particularly pressure, representative of the commercial operations in question, in order to ensure relevant results. Such empirical testing may provide the only accurate and sensible indication of performance, until predictors of high pressure gasification behaviour are identified and sufficiently studied.
At 1 bar operating pressure the char reactivity was generally in ascending order: 4C < 4N < 2N < 2C < 5N. At 20 bar operating pressure the char reactivity was generally in ascending order: 4N < 2C < 4C < 2N < 5N. The seam 5 char consistently exhibited the fastest char-CO2 reaction. The reaction rates of the other chars differ relative to one another at low pressure compared to high pressure. Generally, the seam 4 chars exhibited the lowest reaction rates, followed by the seam 2 chars.
Coal petrographic properties were determined to be good predictors of the char-CO2 reaction rate at low conversion, after normalising reactivity with regards to operating temperature and CO2 partial pressure. Particularly, the total vitrinite content, detrovitrinite content, and maceral indices were observed to correlate well to the pre-exponential factors of the five chars. Empirical models were proposed which were able to predict the pre-exponential factors to within 33% of experimental values, utilising only a single variable derived from petrographic characteristicsNational Research Foundatio
Antioxidant activity and hepatoprotective potential of leaf extracts from Morella serrata (Lam.) Killick (Myricaceae)
No full textMorella serrata L. Killick (Myricaceae) - is a South African plant finding therapeutic applications in oxidative stress related disorders including asthma, diabetes and male sexual dysfunction. The plant has not been scientifically investigated for its antioxidant and hepatoprotective activity. Thus the present study was aimed at determining the chemical constituents, antioxidant activity of M. serrata leaf extracts (ethanol, hydroalcohol and water) and hepatoprotective potential of aqueous-ethanol extract against carbon tetrachloride-induced liver injury in Wistar rats.
Phytochemical screening coupled with quantification of phenolic compounds was performed in extracts using standard methods. The preliminary screening of M. serrata leaf extracts revealed the presence of flavonoids, tannins, phenols, saponins, steroids, terpenoids and resins whilst alkaloids, phlabotannins as well as cardiac glycosides were not detected. The total phenolic, flavonoid and flavonol content of the extracts ranged from 0.06± 0.01 to 0.24±0.02 mg GAE/g; 1.25± 0.01 to 2.04± 0.03 mg QE/g; and 0.35± 0.01 to 0.50± 0.01 mg QE/g respectively.
The antioxidant activity of the extracts was assessed using DPPH, ABTS, nitric oxide, hydroxyl radical, reducing power, hydrogen peroxide and metal chelating assays using ascorbic acid as reference. Of all the tested extracts, the ethanol extract showed maximum free radical scavenging activity in the DPPH and nitric oxide scavenging activity assays while water extract showed maximum free radical scavenging activity in the ABTS, hydroxyl radical, hydrogen peroxide and metal chelating assay. Hydroalcohol extract showed maximum scavenging activity in the reducing power assay as compared to other extracts.
A 21-day daily double dose protective effect of the graded doses (100, 200, 400 mg/kg body weight) of M. serrata hydro-alcohol extract was tested against CCl4-induced hepatotoxicity in Wistar rats using silymarin as a positive control. The effect of CCl4 was investigated on liver and body weight, feed and water intake, haematological parameters, serum biochemical functions, liver marker enzymes and liver histology. Findings revealed a significant increase in liver weight in CCl4-alone intoxicated rats compared to normal control. All groups intoxicated with CCl4 displayed a loss in appetite after CCl4 administration as compared to normal control. A decrease in body weight was observed in
rats treated with CCl4-alone which was reversed following treatment with extract and silymarin. CCl4 intoxicated rats showed severe liver damage which was indicated by altered haematological parameters and elevated serum activity of ALP, ALT and AST. This was accompanied by a reduction in activity of marker enzyme CAT and a significant rise in TBARS concentration. This was however ameliorated in MSLAEE and silymarin treatments groups. Histopathological micrographs of hepatotoxic group revealed extensive liver damage characterised by severe necrosis, however, such damage was prevented in MSLAEE and silymarin pre-treated groups. The degree of damage in liver tissues was in the order CCl4- alone treated rats > 200 mg/kg b.w MSLAEE treated rats > 400 mg/kg b.w treated rats > 100 mg/kg b.w treated rats > Silyamrin treated rats > Normal control.
Our findings from the research work provide support and evidence on the folkloric use Morella serrata as a potential natural antioxidant in treating oxidative stress induced ailments. The study also diverts from the perception that only the roots can be used to treat such ailments as the leaf extracts also showed effective antioxidant activity, thus contributing to the conservation of the plant. Data emanating from the further indicate that M. serrata was able to protect the liver against CCl4-induced oxidative damage in rats which may be attributed to its antioxidant and free radical scavenging activities.National Research Foundatio
NRF Internal audit: Grant Management & Institutional Visits
No full textThe Grants Management and Systems Administration (GMSA) Directorate hosted its 8th annual Research Administrators Workshop (RAW) from 9 to 11 October 2017 in the Western Cape. The workshop aimed to bring together key stakeholders from universities and science councils across South Africa, including international delegates, to share experiences and best practices in research administration and management
The Role of a DA: Inter-Intra Institutional Processes, Challenges and Bottlenecks
No full textThe Grants Management and Systems Administration (GMSA) Directorate hosted its 8th annual Research Administrators Workshop (RAW) from 9 to 11 October 2017 in the Western Cape. The workshop aimed to bring together key stakeholders from universities and science councils across South Africa, including international delegates, to share experiences and best practices in research administration and management
The proteolytic activity in raw milk and the effect of such activity on the stability of milk proteins
No full textMilk flocculation/age gelation is regarded as a major problem for the dairy industry since it has a
negative impact on milk quality. Flocculation can be observed as a physical change in fresh milk
when milk is exposed to extreme destabilisation conditions such as low storage temperatures and
heat exposure (milk added to boiling water during coffee preparation). The end result is decreased
fluidity and increased viscosity due to the formation of a three-dimensional protein network and the
formation of visible flakes. This type of milk is totally rejected by the consumers.
Flocculation can occur through chemical or enzymatic action. The chemical mechanism is when the
three-dimensional protein network is formed during the storage of milk by the interaction between β-
LG and К-casein within the casein micelle due to heat treatment which eventually results in the
formation of a gel. During this interaction, a complex is formed between β-LG and К-casein. The
enzymatic mechanism involves proteases which are responsible for the release of this βК-complex
which forms a protein network and eventually results in the formation of a gel. The two main
enzymes that play a role in milk flocculation are native plasmin and proteases from psychrotrophic
bacteria.
Detection methods for milk flocculation are needed in order to establish the cause and possibly
combat this problem. The already established milk flocculation detection techniques are the Alizarol
test and the protease assay. The techniques developed in this study to detect milk flocculation/age
gelation included RP-HPLC (MILQC software) and the milk agar plate technique for protease
detection. All the techniques can effectively detect high risk milk prone to flocculation/gelation and
some of the techniques can even distinguish between the proteolytic action of indigenous plasmin
and microbial proteases.National Research Foundatio
Identification of rare gene variants in South African breast cancer families through next generation sequencing
No full textBreast cancer (BC) has become the leading cancer amongst women in South Africa. The
overall life time risk for developing this disease is one in 12 (National Cancer registry, 2000-
2011). A strong family history (≥3 affected) is an important factor for inherited predisposition to
BC that accounts for approximately 10% of cases worldwide. Mutations in several high- and
moderate risk breast cancer genes have been associated with familial BC and includes
BRCA1, BRCA2, TP53, PALB2, and CHEK2. Individuals that carry germline mutations in
BRCA1 and BRCA2 possess an 80% lifetime risk for BC. Mutations in BRCA1 and BRCA2 are
responsible for 29% and 25% of familial BC worldwide. In South Africa BRCA1 mutations
account for 19% and BRCA2 for 47% of familial breast cancer. Mutations associated with a
moderate risk for BC account for ~1% of cases. This data suggests that ~30% of South African
BC families are not characterised by pathogenic mutations in known breast/ovarian (BC/OVC)
genes. The purpose of the present study was to identify gene variants that may predispose to breast
cancer. Next generation sequencing was performed to investigate the germline DNA of highrisk
BC/OVC families that have previously tested negative for premature truncating mutations
in BRCA1/2, PALB2 and RAD51C. Paired-end whole exome sequencing was performed with
nine index cases, selected from six families with a strong background for BC/OVC. This
resulted in the discovery of an average of 26 000 coding variants in index cases. Gene
prioritisation strategies were incorporated to filter all exome variants and identify high-priority
genes for further analysis. After sequence verification, three high-priority genes were selected
for further analysis. The three genes coded for; a novel putative tumour suppressor (TCHP) that is pro-apoptotic;
the XPF-endonuclease homolog, EME2; and a POLQ like helicase enzyme (HELQ). Prioritised
genes were screened in a total of 61 high-risk families and cohorts of patients with BC or OVC
without a family history for their disease. Two potentially damaging variants (stop-gain & inframe
amino acid deletion) were identified in TCHP, four (frameshift, nonsense & two in-frame
deletions) in EME2 and one frameshift mutation in HELQ in high-risk families and cases that
were without a family history for BC/OVC.
The analyses performed in the last section of this project was aimed at identifying other
potential genes of interest by making use of a list of 516 well recognised and putative DNA repair genes. Through this approach, one additional truncating mutation in POLN
(p.Q837SfsX7) was highlighted as a potential gene of interest for future investigation.
Despite the key roles that the high-priority genes play in their respective processes, the
present study could not verify that the potential loss of function variants discovered make an
appreciable contribution towards BC/OVC susceptibility in our setting. Further investigation is
necessary to validate their involvement in breast/ovarian cancer predisposition.National Research Foundatio
The effects of Rooibos (Aspalathus linearis) supplementation on the pancreas, liver, and kidney of male Wistar rats following antiretroviral treatment
No full textNational Research Foundatio
Structural-stratigraphic investigation of an area near Kakamas and environs, Namaqua mobile belt, South Africa
No full textThe study area is near Kakamas in the Northwest Cape and is located in the tectonostratigraphic Grünau Terrane - an accreted crustal fragment associated with the Mesoproterozoic Namaqua Province. The mapping campaign covered an area of some 6,500 km2 comprising of highly deformed and metamorphosed pre-tectonic supracrustals and syntectonic sheet intrusives emplaced and tectonised during the 1.2 to 1 Ga Namaqua Orogeny. The granulite grade Grünau Terrane is juxtaposed against the amphibolite facies Bladgrond Terrane and transported south-westwards along the inter-terrane Hartbees River Thrust (HBRT).
The study area incorporates the north-western section of the Riemvasmaak-Kenhardt Mega Sheath Fold (RK-MS) which contains a series of sheath fold complexes divided into five structural domains. Macroscopic sheath folds have been recognised and documented in the western Namaqua Province for both the ~2Ga Pofadder Terrane and the ~1.6Ma Aggeneys Terrane: this study reports for the first time, the details of large scale sheath fold complexes in the Eastern Namaqua sector. In the Aggeneys Terrane the Aggeneys Mountain consist of a series of stacked sheath folds and Gamsberg Mountain represents a single macroscopic sheath fold formed under a compressive simple shear regime associated with south-west accretion of terranes.
The dominant stratigraphic features are suites of sheeted granitoids interdigitating pre-tectonic supracrustals that consist of metasedimentary and volcaniclastic rocks. The oldest of the supracrustals is the Blouputs Formation with a provenance age of c.1800 Ma. The intrusives are a combination of leucocratic to granodioritic granites and the product of kilometre scale anatexis. Both the supracrustal and intrusive rocks are confined to the five structural domains. The Vaaldrift sheath fold is the only structure (Domain 4) that does not have an inter-sheeted granite associated with the supracrustals. The intrusive rocks has an intrusive age distribution ranging from the oldest, Eendoorn gneiss (1200 Ma) to the youngest, Friersdale charnockite (1080 ±13 Ma).
The sheath fold complexes are bounded by intra-terrane thrusts along which thrust sheets (both supracrustals and granites) are cut out. The boundary of the RK-MS is defined by the Waterval thrust which is the sole thrust to the intra-terrane thrust system. The macroscopic sheath folds which are mapped during this study contains co-linear L-fabrics consisting of meso- and macroscopic fold axes of various fold phases and mineral stretching lineations plunging towards the north-north-east, which indicates a south-south-westerly tectonic transport direction. Three main fabrics are defined during this study, namely: S0 (compositional banding), S1 and the regional S2; both foliations are caused by shear processes and are also recognisable in the sheeted intrusives (e.g. Rooipad, Eendoorn and Harpersputs). The foliation and axial planes of the macroscopic sheath folds have a co-planar relationship and trend north-west. On a mesoscopic scale, two types of folds have been defined as model 1 and model 2 folds, which formed simultaneously during a flow perturbation process. North-west trending shear zones are mapped as the last stage of deformation during which the intra-terrane thrust was reactivated as sub-vertical shear zones.
A progressive shear deformation model is proposed for the structures in the study area. Four deformation phases were recognised with the first of them having two separate sub-phases (D1a and D1b). The initial phase of the first event (D1a) resulted in the mesoscopic model 1 and model 2 folds during terrane assembly. The main deformation event was the second D1 event (D1b), characterised by macroscopic scale sheath folds (F1) formed during flow perturbation under general shear. The D1(b) event consisted of two phases of sheath folds (F1 and F2), the F2 being localised refolding of the F1 structures during a similar process. The D1(b)F1 structures are characterised by folded S0/S1 with S2 as an axial planar cleavage. Two metamorphic events are recorded by previous authors for the area: the first event was during terrane amalgamation at ~1200Ma and the second event during the last stages of deformation (1018±11 to 1024±14Ma; D4 north-west shear event).
The second deformation phase (D2) is characterised by the intrusion of the Oranjekom Complex (~1100Ma) which is simultaneously deformed into a sheath fold; it defined the end of a progressive shear model which initiated at D1a. The Grünau Terrane underwent two phases of kilometre scale anatectic melting producing two of the most prominent lithological units, namely: Eendoorn gneiss (~1200Ma) and Witwater gneiss (~1123±6).
The third deformation phase (D3) resulted in the intrusion of the Friersdale Charnockite into pre-existing macroscopic D1(b)F1 and F2 sheath fold hinge zones. This emplacement resulted in the D3 folds which are associated with D4 shearing. The D4 shear event caused reactivation of intra-terrane thrusts as sub-vertical shear zones and shears such as the Cnydas, Neusberg and Duiwelsnek shear zones along the limbs of the macroscopic sheath folds. The D4 shear zones trend north-westerly with an associated oblique movement resulting in both a lateral and vertical displacement of strata and structures. The dominant lateral displacement is predominantly sinistral with East-up; the sigmoidal rotation (on km-scale) of F1 axial traces of the macroscopic sheath folds are prominent features of this late shear event.
It is concluded that a dynamic model combining progressive shear deformation during flow perturbation (layer-normal differential and layer-parallel shear) from a mesoscopic to a macroscopic scale resulted in the intricate structures mentioned above.National Research Foundation (South Africa