Fasciola hepatica cathepsin L-like proteases: biology, function and potential in the development of first generation liver fluke vaccines.

Fasciola hepatica secretes cathepsin L proteases that facilitate the penetration of the parasite through the tissues of its host, and also participate in functions such as feeding and immune evasion. The major proteases, cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) are members of a lineage that gave rise to the human cathepsin Ls, Ks and Ss, but while they exhibit similarities in their substrate specificities to these enzymes they differ in having a wider pH range for activity and an enhanced stability at neutral pH. There are presently 13 Fasciola cathepsin L cDNAs deposited in the public databases representing a gene family of at least seven distinct members, although the temporal and spatial expression of each of these members in the developmental stage of F. hepatica remains unclear. Immunolocalisation and in situ hybridisation studies, using antibody and DNA probes, respectively, show that the vast majority of cathepsin L gene expression is carried out in the epithelial cells lining the parasite gut. Within these cells the enzyme is packaged into secretory vesicles that release their contents into the gut lumen for the purpose of degrading ingested host tissue and blood. Liver flukes also express a novel multi-domain cystatin that may be involved in the regulation of cathepsin L activity. Vaccine trials in both sheep and cattle with purified native FheCL1 and FheCL2 have shown that these enzymes can induce protection, ranging from 33 to 79%, to experimental challenge with metacercariae of F. hepatica, and very potent anti-embryonation/hatch rate effects that would block parasite transmission. In this article we review the vaccine trials carried out over the past 8 years, the role of antibody and T cell responses in mediating protection and discuss the prospects of the cathepsin Ls in the development of first generation recombinant liver fluke vaccines. Author Keywords: Helminths; Trematodes; Parasites; Cathepsins; Proteases; Vaccines; Immunology; Biochemistry

Isotope Hydrology of the Oldman River basin, southern Alberta, Canada

The partially semi-arid Oldman River basin (OMRB), located in southern Alberta (Canada), has an area of 28 200 km2, is forested in its western headwater part, and is used for agriculture in its eastern part. Hydrometric measurements indicate that flow in the Oldman River has decreased by ~34% between 1913 and 2003, and it is predicted that water withdrawals will increase in the next 20 years. The objective of this study was to determine whether isotope ratio measurements can provide further insight into the water dynamics of the Oldman River and its tributaries. Surface water samples were collected monthly between December 2000 and March 2003. Groundwater samples were taken from 58 wells during one-time sampling trips. Runoff within the OMRB is currently about 70 mm year-1, with a corresponding runoff ratio of 0Ð18. Seasonal flow characteristics are markedly different upstream and downstream of the Oldman River reservoir. Upstream, sharp increases in flow in late spring and early summer are followed by a rapid decrease to base flow levels. Downstream, a prolonged high flow peak is observed due to the storage effect of the Oldman River reservoir. The seasonal variation in the isotopic composition of surface water from upstream sites is small. This suggests that peak runoff is not predominantly generated by melting snow accumulated during the preceding winter, but mainly by relatively well-mixed young groundwater. A significant increase in the d18O and d2H values in the downstream part of the basin was observed. The increase in the isotopic values is partly due to surface water and groundwater influx with progressively higher d18O and d2H values in the eastern part, and partly due to evaporation. Hence, the combination of hydrometric data with isotope measurements yields valuable insights into the water dynamics in the OMRB that may be further refined with more intensive measurement programmes in the future.

The pathogenesis of venous thromboembolism in cancer: emerging links with tumour biology.

Venous thromboembolism (VTE) is a frequent complication in individuals with cancer and is considered to be a cause of substantial mortality. Epidemiological studies identify malignancy as an independent VTE risk factor and show that cancer patients are at increased risk of both initial and recurrent VTE events. The risk due to cancer is compounded by the effects of chemotherapy and other treatments. The pathogenesis of cancer-associated VTE is complex involving multiple interactions between tumours and various components of haemostasis. The development of a systemic hypercoagulable state is considered a key pathogenetic feature and is attributed to tumour expression of tissue factor and other procoagulants, activation of vascular cells by tumour-derived cytokines and adhesive interactions between tumour cells and host cells. An increasing body of evidence indicates that the activation of haemostasis in malignant disease contributes to tumour growth and progression by stimulation of intracellular signalling pathways. The interaction of tissue factor, thrombin and other coagulation factors with protease activated receptor (PAR) proteins expressed by tumour cells and host vascular cells leads to the induction of genes related to the processes of angiogenesis, cell survival and cell adhesion and migration.