846 research outputs found
The role of Plasmodium falciparum var genes in malaria in pregnancy
No full textSequestration of Plasmodium falciparum-infected erythrocytes in the placenta is responsible for many of the harmful effects of malaria during pregnancy. Sequestration occurs as a result of parasite adhesion molecules expressed on the surface of infected erythrocytes binding to host receptors in the placenta such as chondroitin sulphate A (CSA). Identification of the parasite ligand(s) responsible for placental adhesion could lead to the development of a vaccine to induce antibodies to prevent placental sequestration. Such a vaccine would reduce the maternal anaemia and infant deaths that are associated with malaria in pregnancy. Current research indicates that the parasite ligands mediating placental adhesion may be members of the P. falciparum variant surface antigen family PfEMP1, encoded by var genes. Two relatively well-conserved subfamilies of var genes have been implicated in placental adhesion, however, their role remains controversial. This review examines the evidence for and against the involvement of var genes in placental adhesion, and considers whether the most appropriate vaccine candidates have yet been identified
Remembering David J. Rowe
No full textInternational audienceDavid Rowe was a highly respected theoretical physicist who made seminal contributions that improved our understanding of the atomic nucleus, in particular of the collective behaviour of its constituent nucleons - results he often obtained with the use of sophisticated group-theoretical methods. He will also be remembered as the (co-)author of monographs on nuclear physics, written with the scientific rigour that was characteristic of his research
Remembering David J. Rowe
No full textDavid Rowe was a highly respected theoretical physicist who made seminal contributions that improved our understanding of the atomic nucleus, in particular of the collective behaviour of its constituent nucleons - results he often obtained with the use of sophisticated group-theoretical methods. He will also be remembered as the (co-)author of monographs on nuclear physics, written with the scientific rigour that was characteristic of his research
Erythrocyte complement receptor 1 (CR1) expression level is not associated with polymorphisms in the promoter or 3' untranslated regions of the CR1 gene
No full textComplement receptor 1 (CR1) expression level on erythrocytes is genetically determined and is associated with high (H) and low (L) expression alleles identified by a HindIII restriction fragment-length polymorphism (RFLP) in intron 27 of the CR1 gene. The L allele confers protection against severe malaria in Papua New Guinea, probably because erythrocytes with low CR1 expression, are less able to form pathogenic rosettes with Plasmodium falciparum-infected erythrocytes. Despite the biological importance of erythrocyte CR1, the genetic mutation controlling CR1 expression level remains unknown. We investigated the possibility that mutations in the upstream or 3' untranslated regions of the CR1 gene could control erythrocyte CR1 level. We identified several novel polymorphisms; however, the mutations did not segregate with erythrocyte CR1 expression level or the H and L alleles. Therefore, high and low erythrocyte CR1 levels cannot be explained by polymorphisms in transcriptional control elements in the upstream or 3' untranslated regions of the CR1 gene
The role of the Swain-Langley and McCoy polymorphisms in complement receptor 1 in cerebral malaria
No full textMalaria has been a major driving force in the evolution of the human genome. In
sub-Saharan African populations, two neighbouring polymorphisms in the
Complement Receptor 1 (CR1) gene, named Swain-Langley (Sl2) and McCoy (McCb),
occur at high frequencies, consistent with selection by malaria. This thesis
investigates the association between these two polymorphisms and severe malaria.
Previous studies into this area have produced conflicting findings.
Using a large case-control study of severe malaria in Kenyan children and statistical
models adjusted for confounders, I found that the Sl2 polymorphism was associated
with markedly reduced odds of cerebral malaria and death, while the McCb
polymorphism was associated with increased odds of cerebral malaria. I also
identified an interaction between Sl2 and α+thalassaemia, with the protective
association of Sl2 greatest in children with normal α-globin.
Following these epidemiological findings, I explored potential biological hypotheses
which might explain them. The first approach examined whether the Sl2 and McCb
polymorphisms affected how CR1 forms clusters on erythrocyte membranes, a
process which is key in the binding and transfer of immune complexes from
erythrocytes to macrophages. Using erythrocytes from Kenyan children, I
performed immunofluorescence assays (IFAs) with confocal microscopy to quantify
CR1 cluster number and volume. I found no association between the Sl2 and McCb
polymorphisms and either the number or volume of CR1 clusters formed.
The second approach investigated whether the cerebral malaria-specific
associations seen with Sl2 and McCb might be due to expression of CR1 by human
brain endothelial cells (HBEC). The immortalised cell line HBEC-5i was investigated
for expression of CR1 using IFA, flow cytometry, western blotting, functional C3b
degradation assays, mass spectrometry, immunoprecipitation and siRNA
knockdown experiments. A pool of α-CR1 monoclonal antibodies recognised an
intracellular antigen in permeabilised HBEC-5i cells which was a similar molecular
weight to CR1 on western blotting. However, when the α-CR1 monoclonal
antibodies were tested individually, only E11 recognised an HBEC-5i antigen.
Further investigative approaches did not support the presence of CR1 on HBEC-5i
cells, instead suggesting that E11 was not specific for CR1 and was instead
recognising a protein in the Golgi apparatus.
The final approach was to examine whether the Sl2 and McCb polymorphisms might
influence the binding of the complement components mannose binding lectin, C1q
and L-ficolin to the LHR-D region of CR1. I aimed to generate recombinant proteins
of the LHR-D region which included the polymorphisms. Site-directed mutagenesis
of the region was successful and subcloning and expression of the mutant
amplicons will be performed at a later date.
In summary, I have identified opposing associations between the Sl2 and McCb
polymorphisms and cerebral malaria, which do not appear to be due to differences
in CR1 clustering or expression of CR1 by human brain endothelial cells. My
investigation into whether the polymorphisms might influence complement
component binding is ongoing
Plasmodium falciparum:Rosettes do not protect merozoites from invasion-inhibitory antibodies
No full textRosetting is a parasite adhesion phenotype associated with severe malaria in African children. Why parasites form rosettes is unknown, although enhanced invasion or immune evasion have been suggested as possible functions. Previous work showed that rosetting does not enhance parasite invasion under standard in vitro conditions. We hypothesised that rosetting might promote invasion in the presence of host invasion-inhibitory antibodies, by allowing merozoites direct entry into the erythrocytes in the rosette and so minimising exposure to plasma antibodies. We therefore investigated whether rosetting influences invasion in the presence of invasion-inhibitory antibodies to MSP-1. We found no difference in invasion rates between isogenic rosetting and non-rosetting lines from two parasite strains, R29 and TM284, in the presence of MSP-1 antibodies (P = 0.62 and P = 0.63, Student's t test, TM284 and R29, respectively). These results do not support the hypothesis that rosettes protect merozoites from inhibitory antibodies during invasion. The biological function of rosetting remains unknown
Behaviour of buried pipelines subjected to external loading.
No full textThe research presented in this Thesis was carried out at the University of Sheffield under
the supervision of Dr I. C. Pyrah and Dr W. F. Anderson, and Mr G. Leach at British Gas
Engineering Research Station (ERS). The research was financially supported by a British
Gas Research Scholarship and by the Overseas Research Students Awards Scheme.
The Author would like to express his sincere gratitude to his supervisors for their invaluable
help, guidance and encouragement during the development of the research.
The Author is also grateful to Dr S. R. Mi for his interest and assistance throughout the
research. Special thanks also go to Dr S. J. Wheeler for his supervision during the first year
of the research and sound advice in the initial stage of the work.
The Author would like to express his gratitude to all members of the geotechnics group at
the University of Sheffield for the useful discussions and comments. Special thanks and
appreciation are extended to the staff at the ERS, particularly Mr E. Middleton for
providing the data of the field tests and constructive comments.
The laboratory tests were performed at ERS Soils Laboratory for which the Author is
thankful to the laboratory staff. The Author must also thank British Gas for providing the
computer hardware and software for performing the numerical analyses, and the printing
facilities to produce the Thesis. Thanks also go to Mr D. Reay and Mr B. Bellwood at the
Gas Research Centre of British Gas for ensuring continuous financial support throughout
the award period.
Finally, the Author wishes to thank his family and friends for their endless support and
encouragement throughout the period of study in the UK. Without them, this Thesis may
never have been completed
CR1 Knops blood group alleles are not associated with severe malaria in the Gambia
No full textThe Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-valu
The Kepler-454 system : A small, not-rocky inner planet, a Jovian world, and a distant companion
No full textKepler-454 (KOI-273) is a relatively bright (V = 11.69 mag), Sun-like starthat hosts a transiting planet candidate in a 10.6 d orbit. From spectroscopy, we estimate the stellar temperature to be 5687 +/- 50 K, its metallicity to be [m/H] = 0.32 +/- 0.08, and the projected rotational velocity to be v sin i 10 years and mass >12.1M_J . The twelve exoplanets with radii <2.7 R_Earth and precise mass measurements appear to fall into two populations, with those <1.6 R_Earth following an Earth-like composition curve and larger planets requiring a significant fraction of volatiles. With a density of 2.76 +/- 0.73 g cm-3, Kepler-454b lies near the mass transition between these two populations and requires the presence of volatiles and/or H/He gas.Peer reviewe
Identification of Plasmodium falciparum var1CSA and var2CSA domains that bind IgM natural antibodies
No full textMalaria in pregnancy is responsible for maternal anaemia, low-birth-weight babies and infant deaths. Plasmodium falciparum infected erythrocytes are thought to cause placental pathology by adhering to host receptors such as chondroitin sulphate A (CSA). CSA binding infected erythrocytes also bind IgM natural antibodies from normal human serum, a process that may facilitate placental adhesion or promote immune evasion. The parasite ligands that mediate placental adhesion are thought to be members of the variant erythrocyte surface antigen family P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var genes. Two var gene sub-families, var1CSA and var2CSA, have been identified as parasite CSA binding ligands and are leading candidates for a vaccine to prevent pregnancy-associated malaria. We investigated whether these two var gene subfamilies implicated in CSA binding are also the molecules responsible for IgM natural antibody binding. By heterologous expression of domains in COS-7 cells, we found that both var1CSA and var2CSA PfEMP1 variants bound IgM, and in both cases the binding region was a DBL epsilon domain occurring proximal to the membrane. None of the domains from a control non-IgM-binding parasite (R29) bound IgM when expressed in COS-7 cells. These results show that PfEMP1 is a parasite ligand for non-immune IgM and are the first demonstration of a specific adhesive function for PfEMP1 epsilon type domains
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