Plasmodium falciparum is a protozoan parasite responsible for causing the most severe form of malaria in humans. This species is responsible for over 90% of malaria mortalities which occur predominantly in Africa. An increase in drug resistant parasites in recent years is threatening the progress made against malaria and thus new antimalarial drugs and vaccines are needed to combat this disease. During the intraerythrocytic phase, merozoites egress from mature schizonts to invade new uninfected erythrocytes. Glycophosphatidylinositol (GPI) -anchored proteins cover most of the exterior surface of the merozoite prior to invasion, while other GPI-anchored proteins are released onto the merozoite surface through apical organelle secretions. These proteins are involved in interactions with erythrocytes and are thought to be vital to erythrocyte invasion. GPI-anchored proteins have also been implicated as a cause of pathogenic symptoms and activation of immune components. These proteins are then released or cleaved to enable merozoite entry into the erythrocyte. Several enzymes are thought to be involved in their cleavage including the serine proteases subtilisin-like proteases (SUB) 1 and 2, and phosphatidylinositol-phospholipase C (PIPLC); GPI-anchored proteins are also generally sensitive to phospholipase A2 (PLA2). Cleaved proteins are released into the host blood system, while uncleaved proteins are carried into the erythrocyte during invasion. Merozoites have a limited period in which they retain invasive capacity. A previous lack of available techniques that are specifically adapted to merozoite analysis has resulted in an incomplete understanding of invasion and GPI-anchored protein involvement in invasion. This study aimed to determine how GPI-anchored proteins on the merozoite surface are altered in the invasive phase, and explore the possibility of using merozoite GPI-anchored proteins as potential drug targets to block erythrocyte invasion. Optimised methods of in vitro parasite culturing which produce highly synchronised merozoites was essential to this study. Parasite culturing techniques were optimised by utilising low haematocrit cultures with frequent culture splitting and optimised synchronisation. The “Malarwheel” is a tool that was developed for this research to provide a means for scheduling sorbitol treatments and MACs isolations. This tool and optimised culturing methods enabled large volumes of highly synchronised invasive merozoites to be harvested. Four compounds (vanadate, edelfosine, dioctyl sodium sulfosuccinate (DSS), and gentamicin) suspected to interfere with GPIanchored cleavage or processes were screened on intraerythrocytic stages and merozoites. Antimalarial and anti-invasive properties of these compounds were screened by modified malaria SYBR Green I-based fluorescence (MSF) assay and merozoite invasion assays (MIA) respectively. DSS and gentamicin showed limited potential as antimalarials or as anti-invasive agents. Vanadate and edelfosine both showed antimalarial and anti-invasive activity, while edelfosine was the most potent anti-invasive agent at physiological concentrations. The merozoite GPI-anchored proteome was analysed by sodium dodecyl sulphatepolyacrylamide gel electrophoresis (SDS-PAGE) followed by complete gel lane analyses conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on soluble and pelleted merozoite proteins in samples from either invasive or non-invasive merozoites. Thirteen known or predicted GPI-anchored proteins were identified in samples. Several changes were identified in merozoite GPI-anchored proteins between the invasive phase and after its completion, and minor differences were observed following treatment with edelfosine. Edelfosine showed partial inhibition of erythrocyte invasion, however, the primary cause of inhibition cannot be directly related to interferences with GPI-anchored proteins. These results suggest that GPIanchored proteins are controlled by various complex processes, and are cleaved or processed by diverse mechanisms during the invasive phase. These mechanisms may be controlled by multiple signals which effect proteins or groups of proteins in specific ways. These signals may be influenced by “checkpoints” during invasion processes including the time period after egress from schizonts, and possibly the recognition of erythrocyte targets. These methods and results provide a foundation for future research to enable culturing of P. falciparum parasites specifically for merozoite research, and to identify merozoite proteins active during the invasive phase. These results confirm and challenge previous ideas reported in literature on the GPI-anchored processes of merozoites and further characterise less studied GPIanchored proteins. The results suggest that the processes controlling GPI-anchored proteins may be more complex than previously thought. These results form a basis to further identify and characterise GPI-anchored proteins in the aim to develop antimalarial medications and vaccines that target merozoites and their GPI-anchored processes. / Dissertation (MSc)--University of Pretoria, 2017. / Pharmacology / MSc / Unrestricted

Le placenta humain est un organe indispensable au bon déroulement de la grossesse. La villosité choriale est l’unité structurale et fonctionnelle du placenta. Elle est constituée essentiellement de cellules trophoblastiques. Les cytotrophoblastes extra-villeux (CTEV) présentent des propriétés invasives et assurent l’ancrage du placenta dans l’endomètre maternel. De plus, une apoptose physiologique assure le renouvellement des cytotrophoblastes tout au long de la grossesse.Le Facteur Préimplantatoire (PIF) est un peptide de 15 acides aminés, sécrété par des embryons viables. Le PIF exerce un effet autocrine positif sur le développement embryonnaire. Le PIF est également impliqué dans le contrôle de l’immunité et de l’inflammation dans divers types cellulaires.Au cours de ce travail de thèse, nous nous sommes intéressés aux rôles du PIF dans le développement placentaire humain. Dans un premier temps, nous avons caractérisé l’expression protéique du PIF dans des placentas humains de 1er et 3ème trimestre de grossesse.Nous avons montré que i) l’expression du PIF diminue au cours de la grossesse et ii) le PIF est majoritairement exprimé dans les CTEV.Dans un second temps, nous avons mis en évidence que le PIF i) favorise l’invasion trophoblaste et ii) inhibe l’apoptose des CTEV en régulant la voie de signalisation de p53.Par ailleurs, des altérations de l’invasion et de l’apoptose trophoblastiques sont associées à des pathologies de la grossesse telles que la pré-éclampsie et le retard de croissance intra-utérin. Ainsi, dans un dernier temps nous avons montré que l’expression du PIF est diminuée dans des placentas humains de 3ème trimestre issus de grossesses pathologiques par comparaison avec des grossesses normales.L’ensemble de ces résultats démontrent que le PIF est un nouvel acteur de la placentation humaine. De plus, le PIF pourrait être considéré comme un nouveau biomarqueur des pathologies de la grossesse. / Human placentation is a critical step in the establishment of a successful pregnancy. The chorionic villus constitutes the structural and functional unit of the placenta. The extravillous trophoblast (EVT) is a placental cell type that differentiates from the highly proliferative cytotrophoblast located at the base of the anchoring villous. EVT have invasive properties, essential for placenta anchoring in the endometrium and uterine artery remodeling. Moreover, programmed cell death is an active process required for normal trophoblastic cell turnover during pregnancy.PreImplantation Factor (PIF) is a 15-amino-acid peptide secreted by developing embryos. PIF exerts autotrophic and protective effects on the embryo. PIF is also implicated in the control of immune and inflammatory processes in various cell types.In this work, we aimed to determine the direct effects of PIF on human placental development.In a first part, we characterized PIF protein expression in first and third trimester human placentas. We showed that PIF protein expression i) decreased over the course of the pregnancy and ii) was higher in EVT compared to villous trophoblast.In a second part, we showed that PIF i) enhanced pro-invasive capacities and ii) prevented cell death by regulating p53 signaling pathway in human EVT.Dysregulation of trophoblastic invasion and apoptosis have been associated with pregnancy pathologies. Thereby, in a last part, we showed that PIF protein expression was lower in placentas from preeclampsia and intra-uterine growth restriction as compared with non-pathological placentas. Altogether, we highlighted for the first time, that PIF is a new positive regulator of placental functions. PIF could be considered as a novel biomarker of a favorable outcome of pregnancy.

Sparvugglan (Glaucidium passerinum) är en invasionsfågel som uppvisar årliga fluktuationer i sina invasioner vid Hammarö Fågelstation. Invasioner av denna art utlöses vanligtvis av brist på föda tidigt under hösten, vilket kan orsaka att hundratals fåglar migrerar på ett oförutsägbart sätt. Syftet med denna studie var att undersöka vilka ekologiska faktorer som ligger bakom detta beteende, och om invasioner vid Hammarö Fågelstation sker samtidigt som invasioner i övriga Sverige. Hypoteserna var att 1) sparvugglefångst uppvisar ingen årlig trend vid Hammarö Fågelstation, 2) sparvugglans populationstrender sammanfaller inte med andra ugglors trender, 3) det finns en korrelation mellan sparvugglans populationstrender vid Hammarö Fågelstation och övriga Sverige, och 4) det finns ett samband mellan sparvugglors populationstrender vid Hammarö Fågelstation och årliga fluktueringar i sorkpopulationer samt andra ekologiska faktorer såsom årlig temperatur och snötäcke. Data samlades in från Hammarö Fågelstations årsrapporter över fångst och ringmärkning av migratoriska fågelarter, och data som uppskattar populationstrender över hela Sverige inhämtades från Svensk Fågeltaxering. Korrelationstester utfördes på dessa parametrar mot sorkpopulationer och andra ekologiska faktorer. Studien fann en positiv korrelation mellan sparvugglefångst på Hammarö och populationstrender från hela Sverige under vintermånaderna. Det fanns även en positiv korrelation mellan årliga fluktuationer i sorkpopulationer vid Vindeln och fångst av sparvuggla i Hammarö. Inga korrelationer hittades när sparvugglefångst mättes mot miljömässiga faktorer. Dessa resultat stämmer överens med tidigare litteratur över området, och öppnar för möjligheter till ny forskning gällande miljö- och beteendemässiga aspekter av invasionsmigratoriska mönster, som ännu är en dåligt förstådd aspekt av fågelbeteende. / The Eurasian pygmy owl (Glaucidium passerinum) is an irruptive migrant that shows yearly fluctuations in its invasions at Hammarö Bird Station, Värmland, Sweden. Invasions in this species are usually triggered by a shortage in food supply during early autumn, which can cause hundreds of birds to migrate in an unpredictable manner. The purpose of this study was to explore what ecological factors cause this behaviour, and if invasions at Hammarö Bird Station occur during the same years as invasions in the rest of Sweden. The hypotheses were that: 1) Eurasian pygmy owl captures at Hammarö Bird Station show no inter-annual trend, 2) Eurasian pygmy owl invasions are not correlated with captures of other owl species, 3) there is a correlation between population trends of the Eurasian pygmy owl at Hammarö Bird Station and trends in the rest of Sweden, and 4) there is a correlation between Eurasian pygmy owl captures and annual fluctuations in vole population as well as other environmental factors such as yearly temperature and snow cover. Data was collected from Hammarö Bird Stations annual review of capture and ringing of migratory bird species, and data approximating population trends nationwide were collected from “Svensk Fågeltaxering”. Correlation tests were conducted on these parameters against vole populations and other ecological factors. The study found a positive correlation between owl captures at Hammarö and population trends from all of Sweden during the winter. A positive correlation was also found between annual vole population fluctuations in Vindeln, Västerbotten and owl captures at Hammarö. No correlations were found when measuring owl captures against environmental factors. These results coincide with previous literature on the subject, and open up possibilities for future research regarding the environmental and behavioral aspects of irruptive migration patterns, which is still a poorly-understood aspect of bird behaviour.

No description available.

In this study, we examine the effect of ESG-ranking and strong financial flexibility have on Swedish firms’ stock price during the initial stage of Russia’s invasion of Ukraine. This study is based on examining this theme during Russia's invasion of Ukraine with a time frame that lasts during the first half of 2022. The sample for this study is limited to the large index OMXS30 that is part of the Stockholm Stock Exchange. Moreover, in this paper five portfolios have been formed for this purpose, which are divided into high respectively low ESG ranking and high respectively low financial flexibility in comparison to the markets portfolio. The findings in this paper show that the portfolios with Swedish firms that have strong financial flexibility and low ESG-ranking outperform the market portfolio. Meanwhile the portfolios with Swedish firms that have high ESG-ranking and low financial flexibility underperform the market portfolio. In addition to this, the paper found that the Swedish firms with high ESG-ranking have a stable excess return and they are the safest option in terms of investments. While the Swedish firms with strong financial flexibility have high excess return but they are riskier.

No description available.

The development of several organ systems through modeling and shaping of the tissue structure occurs from signaling through axon guidance molecules. The Slit family of ligands has been shown to regulate branching morphogenesis in mammary gland duct development and loss of Slit gene expression during this time leads to the formation of hyperplastic, disorganized lesions suggesting a potential role for Slits in cancer formation. Characterization of human pancreatic ductal adenocarcinoma cell lines showed a loss of SLIT2 expression in cells that contain activated Kras. Loss of SLIT2 expression was associated with DNA methylation of CpG sites within the SLIT2 core promoter and chromatin enrichment of repressive histone modifications at the SLIT2 transcriptional start site. Additionally, treatment of pancreatic ductal adenocarcinoma cell lines with demethylating agent 5-aza-2'-deoxycytidine led to SLIT2 re-expression while treatment with histone deacetylase inhibitor Trichostatin A did not. Mir-218-1 is an intronic microRNA encoded within intron 15 of the SLIT2 gene. Expression of mir-218-1 does not correlate with SLIT2 mRNA expression suggesting that it is transcribed from a promoter independent of the SLIT2 gene promoter. Pancreatic ductal adenocarcinoma cell lines showed a peak of H3K4me3 chromatin enrichment localized to a 1kb region within intron 4 of the SLIT2 gene denoting a candidate alternative promoter for mir-218-1. A concordant peak of H4ac chromatin enrichment overlapped the peak of H3K4me3 enrichment and transcriptional activity was measured from the 1kb region in all pancreatic ductal adenocarcinoma cell lines. A NF-κB binding site was also predicted to exist within the 1kb region. Transfection with two independent siRNAs to NF-κB led to an increase in both pre-mir-218-1 and mature mir-218-1 while treatment with an inhibitor to IκB kinase led to an increase in pre-mir-218-1 expression. Additionally, the p65 subunit of NF-κB was found to bind to the candidate mir-218-1 alternative promoter in pancreatic ductal adenocarcinoma cell lines that do not contain DNA CpG methylation at the predicted NF-κB binding site. It was discovered that miR-218 is a modulator of ARF6 expression suggesting a role in the inhibition of pancreatic ductal adenocarcinoma cell invasion through modulation of the actin cytoskeleton. Overexpression with a miR-218 precursor showed that miR-218 is an inhibitor of pancreatic ductal adenocarcinoma cell invasion in two dimensions. Additionally, it was found that while miR-218 does not have an affect on the ability of pancreatic ductal adenocarcinoma cells to form functional invadopodia, miR-218 is an inhibitor of the extracellular matrix degradation properties of mature invadopodia. Interestingly, the effect of miR-218 on pancreatic ductal adenocarcinoma cell invasion or extracellular matrix degradation is not reliant on the cell's dependency on Kras signaling for growth and survival. Collectively, these observations indicate that understanding the transcriptional regulation of SLIT2 and mir-218-1 expression as well as their signaling properties may provide a step toward the development of diagnostic tests and therapeutic treatments for patients with invasive or metastatic pancreatic ductal adenocarcinoma.

De longs délais temporels peuvent exister entre les perturbations survenant à un site et les réponses des espèces de la communauté occupant ce site. Ces changements écosystémiques transitoires lents en comparaison d’une vie humaine peuvent être difficiles à détecter ou à comprendre sans la prise en compte du contexte temporel par l’utilisation de données historiques. C’est souvent le cas pour les processus d’invasion de plantes ou d’animaux non-indigènes dans les communautés forestières. Bien que les perturbations anthropiques soient reconnues pour faciliter les invasions dans ce type de communauté, des temps de latence importants peuvent tout de même survenir à chaque étape du processus. On peut donc penser que les patrons d’invasion d’un site représenteraient davantage les legs écologiques des perturbations plus anciennes que ceux des perturbations plus récentes. Ce mémoire vise à évaluer si l’on gagne à tenir compte de l’âge des perturbations pour expliquer les invasions biologiques établies dans les sites environnants. Pour vérifier cela, nous avons inventorié l’abondance et la composition des communautés de plantes et de vers de terre non-indigènes dans 85 parcelles dispersées dans l’ensemble de la Réserve Naturelle Gault. Suite à une reconstitution fouillée de l’historique des perturbations anthropiques, nous avons comparé le pouvoir explicatif des perturbations initiées avant 1910 avec celui des perturbations survenues après 1910. Nous avons aussi pris en compte les variables environnementales reconnues comme importantes. Les résultats suggèrent que dans les forêts de la Réserve Naturelle Gault, la présence et l’intensité des invasions de plantes et de vers de terre non-indigènes sont en premier lieu expliquées par la proximité aux perturbations anthropiques initiées il y a plus d’un siècle. Les conclusions de ce mémoire soulignent l’importance de l’utilisation d’une approche historique pour comprendre pleinement la durée des impacts écologiques des perturbations anthropiques quant à la facilitation des processus d’invasion biologique.

Le glioblastome multiforme est le plus fréquent et le plus agressif des gliomes malins. Suite au diagnostic, la survie médiane des patients est de 12 à 15 mois. Le traitement de première ligne consiste en une chirurgie de résection suivie de chimiothérapie combinée à la radiothérapie. Malgré la combinaison de plusieurs modalités de traitement, la survie des patients n'est prolongée que de quelques mois. Or, plusieurs études ont démontré que les extraits de pelure de pomme peuvent inhiber la prolifération et induire la mort cellulaire de lignées cancéreuses in vitro, dont quelques-unes sur des cellules provenant de gliomes malins. Des propriétés anticancéreuses ont été observées in vivo sur des tumeurs d'hépatome, de cancer du sein et de mélanome. Dans ce contexte, il apparaissait intéressant d'évaluer le potentiel thérapeutique de la pelure de pomme dans le cancer cérébral. Nous avons donc conçu une étude en 2 volets: tout d'abord un volet in vitro impliquant 3 lignées cellulaires de gliomes de haut grade (F98, U-118 MG et U-87 MG) exposées à 0,1, 0,2 et 0,4 mg/mL de PPPS; puis un volet in vivo portant sur des tumeurs développées suite à l'implantation de cellules F98 chez les rats Fischer, qui ont été gavés quotidiennement avec de la PPPS (61,71 mg/kg ou 123,43 mg/kg) ou de l'eau (contrôle) à partir du 10e jour post implantation. Dans les 3 lignées cellulaires, les traitements de PPPS diminuent de façon significative le métabolisme cellulaire et augmentent la proportion de la population hypodiploïde. En présence de PPPS, la croissance et l'invasion des sphéroïdes de F98 et de U-87 MG sont inhibées. La PPPS diminue de moitié la proportion de cellules F98 en phase S, et fait augmenter dans les U-118 MG les deux marqueurs d’autophagie étudiés, soit p62 et LC3-II. Par contre, aucune différence dans la survie des rats Fischer-F98 n'a été observée entre le groupe contrôle et les groupes traités. La taille des tumeurs ainsi que les marqueurs d'apoptose et d'autophagie ne présentaient pas de différence entre les groupes. Les résultats obtenus ouvrent la voie à l'exploration plus approfondie des mécanismes des effets in vitro observés, tout en suggérant d'envisager d'autres voies d'administration de la PPPS in vivo.

Thesis (MSc)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: For solid tumours to grow and metastise, they need to pass through two distinct stages: the avascular growth phase in which the tumour remains in a limited diffusion size and the vascular growth phase where the invasion may take place. In order to accomplish the transition from the former to the latter growth phase, a solid tumour may secrete a substance known as tumour angiogenesis factor (TAF) into the surrounding tissues to stimulate its own blood vessels. Once the tumour has its own blood supply, it can invade other parts of the body destroying healthy tissues organs by secreting the matrix degrading enzymes (MDE). During the invasion, the adhesion both cell-cell and cell-matrix play an extremely important role. In this work, we review some mathematical models dealing with various stages of development of solid tumours and the resulting reaction diffusion equations are solved using the Crank-Nicolson finite differences scheme. We also present a system of reaction-diffusion-taxis partial differential equations, with nonlocal (integral) terms describing the interactions between cancer cells and the host tissue. We then investigate the local and global existence of the solution of the previous model using the semigroup method and Sobolev embeddings. / AFRIKAANSE OPSOMMING: Daar is twee afsonderlike fases nodig vir soliede kanker gewasse om te groei en kwaadaardig te word: die avaskulêre groeifase waarin die gewas tot ’n sekere diffusie grootte beperk word en die vaskulêre groei fase waar die indringing plaasvind. Ten einde die oorgang tussen die twee fases te bewerkstellig, skei die soliede gewas ân stof in die omliggende weefsel af wat bekend staan as âtumor angiogenese factorâ (TAF). Dit stimuleer die vorming van die gewas se eie bloedvate. Wanneer die gewas sy eie bloedtoevoer het, kan dit ander dele van die liggaam indring en gesonde orgaanweefsel vernietig deur die afskeiding van die âmatrix degrading enzymesâ (MDE). Gedurende hierdie proses speel die sel-sel en sel-matriks interaksies ân belangrike rol. In hierdie werk het ons ân paar wiskundige modelle vergelyk wat die verskillende stadiums van die ontwikkeling van soliede gewasse beskryf. Die gevolglike diffusiereaksie vergelykings is opgelos deur gebruik te maak van die âCrank-Nicolson finite differences schemeâ. Ons bied ook ’n stelsel van âreaction-diffusion-taxisâ, met nie-lokale (integrale) terme wat die interaksies tussen kankerselle en die gasheerweefsel beskryf. Ons stel dan ondersoek in na die lokale en globale bestaan van die oplossing van die vorige model, met behulp van die semi-groep metode en die Sobolev ingebeddings.