Bioscience Horizons - recent issues

Editorial

2009-05-19

Measuring interdisciplinary research: analysis of co-authorship for research staff at the University of York

Bellanca, L. — 2009-05-19

Collaboration allows researchers to combine the strength of different disciplines to undertake research that neither could do individually. Scientific collaboration can be examined by analysing patterns of co-authorship of papers in publication databases (e.g. Web of Science) using methods from Social Network Analysis. In this project, I describe three networks consisting of researchers in the Biology and Chemistry Departments at the University of York to investigate degree, degree distribution, key brokers and preference of researchers for collaborating within or outside their own research field. Clustering (or transitivity) was used to describe whether collaboration is more likely if two researchers have a collaborator in common. To introduce a control and realize the significance of the results produced, a network consisting of 98 researchers from the Chemistry and Biology departments was produced and compared with a distribution of 1000 ER random graphs for degree, transitivity and betweenness. We find that researchers in the Department of Biology (50 researchers) have fewer collaborations with their departmental colleagues than those in the Department of Chemistry (45 researchers): the average number of links each researcher had with others in the Biology collaboration network was 2.6, the corresponding values for Chemistry were 4.8 links per researcher. We also find that researchers within the Chemistry department were more likely than their colleagues in Biology to collaborate with another researcher if they had a collaborator in common. One aim of the study was to characterize the extent of interdisciplinary research within the Department of Biology. Staff in the Biology department were categorized into distinct research foci, indicating the discipline of the researcher. There were many links from the Bioinformatics and Mathematics, and Biophysics and Biochemistry foci, to other foci, implying that staff within these foci were interdisciplinary in their research—indicative of their role in providing techniques or tools that are applicable across discipline boundaries. This sort of analysis provides quantitative evidence to understand the social patterns of scientific collaboration and may be a useful tool in the development of strategies to promote interdisciplinary research within research institutions.

Therapeutic drug monitoring: an e-learning resource

Samani, K. — 2009-05-19

The main aim of this project was to produce an interactive e-learning resource explaining the pharmacokinetic principles related to therapeutic drug monitoring (TDM). The target audience for the resource were scientists at Manchester Royal Infirmary and the intended learning outcome for the users was to improve their understanding of the pharmacology behind the results they generate. The null hypothesis stated that the resource would not cause a significant improvement in the users' understanding of pharmacokinetics. The ADDIE Instructional Design Model was applied to the learning situation. A pre-project questionnaire allowed for a needs analysis to be conducted, determining the current level of knowledge. Design and development involved production of project plans and storyboards and the entire resource was produced using Opus Professional. The resource was distributed via compact discs, along with pre- and post-resource questionnaires to permit analysis. Knowledge was compared before and after using the resource to establish the effectiveness of the resource, and the functionality of the resource was evaluated. The needs questionnaire results outlined the existing level of knowledge as being varied and provided suggestions for possible concepts to include in the resource. A more precise and accurate definition of TDM, why it is carried out, and the pharmacokinetic parameters were apparent in the post-resource questionnaire results. Confidence in the understanding and interpretation of data produce was not significantly improved (Wilcoxon matched pairs signed ranks test, n = 14, P = 0.13), while confidence in the understanding of pharmacokinetic parameters was significantly improved (Wilcoxon matched pairs signed ranks test, n = 16, P = 0.01). About 81% of the audience found the resource very helpful to understanding TDM and all of the users found it either easy to use or very easy to use. The post-resource results showed that confidence in the understanding of pharmacokinetics was improved, indicating that the learning outcomes of the user were achieved thus allowing the null hypothesis to be rejected. However, confidence in understanding the data generated was not improved, suggesting a possible aspect to be developed if the project was to be repeated. Functionality of the resource was successful as users found the resource easy to use and navigate.

The effects of riparian habitat quality and biological water quality on the European Otter (Lutra lutra) in Devon

Bedford, S. J. — 2009-05-19

After a period of decline, European Otter (Lutra lutra) populations are showing signs of recovery throughout the UK. Populations in Devon are thought to be almost fully recovered, although exact numbers are unknown; however, there are still rivers within Devon that do not appear to support Otter populations. The aim of this research was to determine the relationship between environmental condition and the presence of Otters by comparing the quality of riparian habitat of rivers with and without evidence of Otters. The research was undertaken in four rivers in Devon, the Rivers Culm, Ken, Coly and Otter: the first two being river stretches with no documented evidence of Otter populations, and the latter two having documented evidence of Otter populations. Along each of the rivers, 10 sections of 50 m were sampled. In each section, the riparian habitat quality was recorded using the Qualitat del Bosc de Riberia index. The biological water quality was determined by calculating Biological Monitoring Water Party scores, and water chemical concentrations were obtained from Environment Agency data. The riparian habitat quality and biological water quality were found to be of significantly lower quality in the river stretches that did not have evidence of Otter populations when compared with those with Otter populations. The chemical water quality was correlated to biological water quality: the quality being worse in the rivers without evidence of Otter populations. The results of this research suggest that rivers with no evidence of Otter populations are generally of worse riparian quality than those supporting Otter populations.

Optimization of MALDI tissue imaging and correlation with immunohistochemistry in rat kidney sections

Gregson, C. — 2009-05-19

Cancer is responsible for approximately 6.7 million deaths and 10.9 million newly diagnosed cases worldwide per year. Currently, the definitive diagnosis of a tissue or cell sample is determined by molecular pathology and histochemical techniques, which assess tumour type, grade and stage. This information also allows for the diagnosis, prognosis and available treatment options to be established. In addition, immunohistochemistry (IHC) in combination with histochemistry is used to determine the surgical margin status of tumours, which can be correlated to the likelihood of recurrence. Matrix-assisted laser desorption/ionization (MALDI) imaging is a mass spectrometry profiling technique, which can be used to simultaneously identify multiple species within a tissue section. The array format of the acquisition allows for the creation of an image that is viewed in a similar way to an IHC section. MALDI imaging could potentially provide an alternative diagnostic assay that could be used to provide cancer prognosis. To assess the suitability of MALDI imaging for this application, sample preparation and MALDI imaging methodology were developed using _2u-globulin as an example protein. This protein is known to be preferably expressed in the kidneys of male rats allowing a proof-of-principle study to be performed comparing the expression levels and localization between male and female rat kidney sections. The expression of _2u-globulin was localized to the cortex region of the kidney, with the levels of _2u-globulin shown to be significantly higher in the male than the female kidney sections. These findings were validated by comparison with IHC data. The proof-of-principle study therefore demonstrated that MALDI imaging could be a potential alternative to current molecular pathology and histochemical techniques for the determination of tumour type, grade and stage as well as the determination of surgical margin status.

Patterns of genetic diversity in populations of two bat species (Sturnira ludovici and Artibeus toltecus) in Cusuco National Park, Honduras

Asher, C. — 2009-05-19

Habitat loss, disturbance and fragmentation are thought to be major threats to many species, particularly those in habitats that are already rare. In this study, we examined whether habitat disturbance, primarily due to the cultivation of coffee, has had a major impact on populations of two species of bats in a Honduran cloud forest, using genetic diversity as a measure of population health. Bats were selected as the study species because they play a major role in seed dispersal within the tropics. I compared the genetic diversity of two frugivorous bat species, Sturnira ludovici and Artibeus toltecus, between two localities within Cusuco National Park; a buffer zone in which some human activity, including coffee plantations, is allowed, and the core zone in which no disturbance is permitted. Genetic diversity was assessed using intersimple sequence repeats, a technique similar to random amplification of polymorphic DNA (RAPD). I also measured various habitat variables including foliage height diversity (FHD), fruit availability, canopy cover, aspect of slope and angle of slope in the two sites. I found that FHD and fruit availability differed significantly between the two localities, with the buffer zone having higher values for both. Despite these differences in habitat, we found no significant differences in the level of genetic diversity between the two locations for either bat species. This may be because effective population sizes of the bats do not differ significantly between the sites, because of a lag between disturbance and population decline or because migration is sufficiently frequent to homogenize allele frequencies between the localities.

Study of small mammal populations within two Barn owl corridors at Folly Farm

Keene, A. — 2009-05-19

This study examines small mammal populations present within Barn owl corridors on Folly Farm, an Avon Wildlife Trust Reserve located near the village of Bishop Sutton in Bath and North East Somerset. Two corridors were chosen, the primary difference between the two sites being only one has undergone management (grazing). The focus of this study was the Microtus agrestis (Short-tailed field vole) population, the most frequently taken prey item by Barn owls. Apodemus sylvaticus (Wood mice) and Sorex araneus (Common shrew) populations are also discussed as they are frequently taken. Using Longworth live traps, 600 trap-nights data were collected from three sessions in November 2006, February and March 2007. Although M. agrestis was the most abundant species in both corridors, they were more prevalent in the un-grazed corridor (comprising 19 of the 31 individuals). In the corridor that had undergone management, fewer M. agrestis were captured (eight), although a higher species diversity and richness was recorded. Unusually for a grassland habitat, there were nearly as many A. sylvaticus as there were M. agrestis (seven compared with eight) in the grazed corridor. Some small mammal species not usually found in grassland habitats were captured; explanations for these seemingly anomalous results are discussed. Differences in population characteristics between the two corridors are discussed including: sex ratio, weights, seasonal variation and age structure. Pellet analysis from the nearby pair of Barn owls showed that they were preferentially hunting M. agrestis; the pellet data largely mirrored findings of the trapping data.

Pre- and post-copulatory mate choice in Platygryllus primiformis: cryptic female choice and sexual conflict

Parker, D. — 2009-05-19

The effect of sexual conflict upon mating systems is a controversial topic. The aim of this study was to determine whether post-copulatory choice by females (spermatophore removal) reinforces pre-copulatory choice with respect to male body size and fighting ability, and whether such post-copulatory female choice is influenced by post-copulatory mate guarding by males using Platygryllus primiformis (Orthoptera: Gryllidae; Gryllinae). A no-choice test was used to determine the attractiveness of males and spermatophore attachment time was recorded as a measure of cryptic female choice. Females maintained a pre-copulatory mate choice for large males that were more successful in fighting, shown by a shorter latency to copulation. Larger, males that were more successful in fighting were also preferred by post-copulatory cryptic female choice, shown by a longer spermatophore attachment time, reinforcing pre-copulatory mate choice. Males attempted to counter this selection by guarding females, which increased their spermatophore attachment time. Interestingly, spermatophore attachment time increased similarly for all sizes of male as a result of mate guarding, meaning that females maintained their original choice.

The anti-proliferative effect of different tomato varieties on the human colon adenocarcinoma cells

Saunders, C. — 2009-05-19

Epidemiological evidence suggests that diets rich in fruit and vegetables protect against the development of colon cancer, primarily due to their high levels of polyphenols, in particular a group known as flavonoids. Tomatoes contain significant amounts of the glycosides of the flavonoids quercetin and naringenin. Both quercetin and naringenin have been shown to exert anti-proliferative effects on colon cancer cells, although the effects of whole tomato polyphenol extracts are unclear. The aim of this study was to determine the effect of three tomato varieties, with differing levels of flavonoids and total phenolics, on the proliferation of human colon adenocarcinoma cells. We show that all three varieties were able to significantly inhibit the growth of colon cancer cells, although this activity was found not to be linked to the levels of the flavonoids rutin and naringenin in the tomatoes, but rather to their total phenolic content. We show that the mechanism of growth inhibition was linked to the effects of tomato phenolics on the cell cycle, in that exposure of cells to the tomato extract induced a reduction in the percentage of cells in the S-phase, i.e. those actively synthesizing DNA. These data indicate that tomatoes may help to prevent colon cancer but that their flavonoid content does not appear to determine the magnitude of their biological effect.

Human attitudes towards animals in relation to species similarity to humans: a multivariate approach

Batt, S. — 2009-05-19

Human attitudes towards animals are becoming of increasing importance in the areas of conservation and welfare. It has long been taken for granted that our attitudes are influenced by the degree of biological or behavioural similarity between a given species and ourselves. This research investigates whether there is a link between bio-behavioural similarity to humans and preferences for animal species that are obtained when subjects view a set of 40 pictures illustrating a wide diversity of animals. Extensive data regarding the natural history, behaviour and physiology of 40 species of animals from a wide range of taxonomic groups were collected. Bio-behavioural similarity between animal species and humans was formed on the basis of multidimensional analyses, including factors such as size, weight and lifespan among the physical attributes, and reproductive strategy, parental investment and social organization among the behavioural traits. It was found that a clear relationship between similarity and preference exists, suggesting that humans are predisposed to liking species on the basis of shared bio-behavioural traits. These results imply that efforts made in the conservation and welfare of species may be biased more by anthropocentric views than has been previously recognized. It may be important for a new approach to be taken when it comes to determining the targets of conservation.

Characterizing chloroplast sensor kinase

Ibrahim, I. M. — 2009-05-19

In higher plants and green algae, photosynthesis takes place within specialized sub-cellular organelles called chloroplasts. Chloroplasts were once prokaryotes and evolved by endosymbiosis from cyanobacteria. They contain a semi-autonomous genetic system that encodes for core proteins of photosynthetic reaction centres in the energy-transducing membrane known as the chloroplast thylakoid. The photosynthetic apparatus in the thylakoid membrane makes use of excitation energy from sunlight to remove four electrons and protons from two water molecules. The electrons transfer them to the electron acceptor ferredoxin and NADP⁺, respectively. In this system, plastoquinone acts as a mobile electron and proton carrier between Photosystem I and Photosystem II in reduction–oxidation or ‘redox’ reactions. A balanced redox state in the chloroplast is important for efficient energy conversion. However, the slightest error could lead to photo-inactivation as well as DNA mutation. Therefore, photosynthetic enzymes that are involved in photosynthesis are tightly regulated. In this study we analyse the mechanism of redox regulation involved in chloroplast gene expression that requires chloroplast sensor kinase (CSK). CSK is a bacterial-like histidine kinase that functions as a two-component system. Such simple but effective signalling transduction is abundant in prokaryotes, but found less widely in eukaryotic cells. CSK is encoded by the nuclear genomes of all higher plants examined, and the CSK proteins are targeted to chloroplasts where they function as a redox sensor. Through the cloning process, the result expressed the full-length CSK and the putative sensor domain (GAF domain) into a pGEX-6P-2 plasmid containing a GST tag. The construction was over-expressed into Escherichia coli cells. From bioinformatics study, it was found that in higher plants CSK is a modified histidine kinase, whereas in diatoms and red algae it is a typical histidine kinase.

Can ESR be used to assess the levels of oxidative stress in fat-loaded human hepatocytes and hepatic stellate cells?

Wetherill, L. F. — 2009-05-19

Non-alcoholic fatty liver disease (NAFLD) is a growing clinical problem, which manifests itself particularly in obese subjects who may have the metabolic syndrome. A two-hit hypothesis for the pathogenesis of the disease has been proposed. The first hit is the development of insulin resistance leading to fat accumulation specifically in the liver. The second hit involves oxidative damage to the liver when intracellular triglyceride is metabolized by beta-oxidation in the mitochondria to produce harmful reactive oxygen species (ROS) and their hydroperoxide by-products. An in vitro model for NAFLD along with a method to detect the levels of oxidative stress would be useful for testing this hypothesis. Such a model would also allow investigation of the ability of antioxidants such as selenium to prevent oxidative damage. This study aimed to develop a method for assessing the levels of oxidative stress in cultured fat-loaded human hepatocytes (C3A cells) and hepatic stellate cells (LX-2 cells) using electron spin resonance with the spin trap 1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidine (TEMPONE-H). Cells were fat-loaded with either LPON (lactate, pyruvate, octanoate and NH₄⁺) or oleate. Initial experiments showed that the culture media alone generated free radicals but this was minimal when Dulbecco's phosphate-buffered saline was used as the TEMPONE-H carrier. It proved difficult to detect the free radical production by cells cultured in the basal state; however, when marked oxidative stress was induced in the cells by adding tertiary butyl hydroperoxide (t-BuOOH), free radical production by cells could be identified. Pre-treating cells with selenium, to induce the synthesis of selenoenzymes with antioxidant action, protected cells from the harmful effects of t-BuOOH. This supported selenium's role as an antioxidant, which may have the potential to prevent the onset of non-alcoholic steato-hepatitis. The human vascular endothelial cell line EAhy926 also accumulates lipid as triglyceride when pre-treated with oleate but not with LPON. This suggests that the use of LPON rather than oleate may be a more appropriate model of NAFLD.

Differential localization of two plant homologues of Rab5 GTPases in the secretory pathway

Lee, H. — 2009-05-19

Rab5 GTPases are key regulators of vesicular transport. Known plant Rab5 homologues ARA6 and RHA1 have been assigned to the endocytic and/or biosynthetic vesicular trafficking pathway, but conflicting reports in the literature justify further work on these two GTPases. In this project, binary vectors for Agrobacterium-mediated plant transformation were constructed to drive expression in tobacco leaf epidermis of GTP-trapped mutants of ARA6-green fluorescent protein (GFP) and Venus-RHA1. Confocal laser scanning microscopy revealed key differences in the subcellular localization of the two fluorescently tagged GTPase mutants. When present in the GTP-locked configuration ARA6-GFP is primarily found associated with the tonoplast, whereas Venus-RHA1 is significantly cytosolic. Co-expression of the two fluorescently tagged mutant GTPases with the Golgi markers ST-YFP and ST-CFP, respectively, suggest that neither ARA6 nor RHA1 mutants are mis-targeted to the Golgi apparatus and moreover, they do not show any significant colocalization with each other. The results are consistent with the notion that they differ in their roles within the endocytic and biosynthetic vesicular pathway. A future focus to continue this project would be to use GFP-tagged ARA7, the third plant Rab5 homologue, to verify if the high sequence homology between RHA1 and ARA7 warrants overlapping redundant functions or not.

Viral evasion of interferon stimulated genes

Short, J. A.L. — 2009-05-19

Viruses and their hosts since the dawn of time have been battling for supremacy. In recent years, the ‘Interferon Gateway’ encompassing interferon-alpha and -beta (IFN-/β) expression, signalling and antiviral responses, has been uncovered. IFN-/β are cytokines that co-ordinate the innate and adaptive immune responses to eliminate virus infections from the host. Interferon Stimulated Gene (ISG) products, such as protein kinase R, can prevent the translation of viral and cellular mRNAs to limit viral replication and can also initiate apoptosis if the cell is overwhelmed. In order to replicate, viruses have evolved viral evasion proteins that are able to target all aspects of the host response through a variety of sophisticated mechanisms. Viral evasion proteins can encode cellular domains to interact directly with ISGs and neutralize their function, hijack cellular pathways or degrade antiviral components. The high mutation rates associated with viral replication ensure that viruses will continue to adapt to our defences, but equally the viral evasion proteins are novel drug targets for eliminating or managing virus infections.

Editorial & Author biographies

2009-03-18

Outer membrane proteomics of Pasteurella multocida isolates to identify putative host-specificity determinants

Wheeler, R. — 2009-03-18

Pasteurella multocida is a Gram-negative bacterium responsible for diseases affecting a broad range of farm-reared animals. Although there is an association between capsular serotype and disease, the molecular basis of host specificity is poorly understood. Outer membrane proteins (OMPs) are at the interface of bacterium and host and are likely to play important roles in host specificity and disease. Two classes are of particular importance—adhesins that are adapted for colonization of specific host niches and iron-acquisition proteins that allow pathogens to acquire iron from host-specific iron complexes. A comparative analysis of the outer membrane (OM) proteome of eight P. multocida isolates associated with disease of avian, bovine, ovine and porcine species was performed to identify putative host-specificity determinants. Isolates were cultured in iron-replete media, and also in iron-limited conditions to mimic the iron-limited host environment, and induce expression of iron-regulated OMPs expressed in vivo. The OMP-rich sarcosyl-insoluble cell fraction was isolated and the OMPs were separated by SDS-PAGE and identified by matrix-assisted light desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). The expressed proteome was compared with the in silico predicted proteome from the genome sequence of P. multocida strain Pm70, using PSORTb and Proteome Analyst subcellular localization software. In iron-rich conditions isolates were clustered into three groups based on high molecular weight (HMW) OMP similarity. Isolates responsible for invasive disease were clustered into a single group. Putative colonization OMPs were present in isolates recovered from different host species, but showed molecular weight heterogeneity. Such proteins are good candidates for further study as disease or host-specificity determinants, as variation between these proteins may be a consequence of adaptation to different host niches. HMW OMPs were identified as being involved in iron-uptake. However, isolates associated with different diseases and host species expressed different iron-uptake proteins, or regulated expression differently, suggesting adaptation to specific host niches.

ERp57 is involved in the oxidative folding of the low-density lipoprotein receptor in the endoplasmic reticulum

Berry, J.-L., Bulleid, N. J. — 2009-03-18

This work explores the role of the thiol-oxidoreductase ERp57 in the post-translational oxidative folding of the low-density lipoprotein receptor (LDL-R), a cell-surface glycoprotein responsible for the uptake of cholesterol from plasma. The LDL-R provides a general model to analyse oxidative folding of multi-domain proteins in the endoplasmic reticulum; yet its folding pathway is also of specific interest as a high proportion of mutations in disulphide-rich domains of the protein are evident in familial hypercholesterolemia. Previous studies have suggested that the LDL-R forms a set of distinct non-native disulphide intermediates during folding, which are extensively isomerized prior to secretion of the native conformer. In addition, ERp57 has been suggested to be predominantly reduced in vivo and to form a mixed disulphide with the LDL-R. In this study, the LDL-R was expressed in both wild-type cells and those lacking the thiol-oxidoreductase ERp57 under conditions that prevent disulphide formation. The protein was then allowed to fold under oxidizing conditions, and samples taken at various timepoints. The electrophoretic mobility of folding intermediates from knock-out cells was compared with that of wild-type cells. The results show that dissimilar disulphide intermediates form between the two cell types, particularly during early stages of folding. A mutant form of ERp57, able to form but unable to resolve mixed disulphides, was also found to form mixed disulphides with the LDL-R. The results signify the requirement for ERp57 in oxidative folding of the LDL-R and also suggest that non-native disulphide intermediates may be central to the process of multi-domain protein folding.

Enhancer of split-related-2 mRNA shows cyclic expression during somitogenesis in Xenopus laevis

Blewitt, R. — 2009-03-18

Somitogenesis is responsible for production of the segmented body plan typical of vertebrate embryos. The somites are blocks of mesoderm, produced by this process, that give rise to the vertebrae and ribs, the dermis of the skin and all the skeletal muscle of the body. Many genes that regulate somitogenesis have been identified in chick and mouse, whereas considerably fewer are known in Xenopus laevis. The expression of Hairy/Enhancer of split-related genes is known to cycle during somitogenesis and provides a mechanism for the regular formation of somites. In this project, in situ hybridizations were carried out on bowline, Thylacine1, Enhancer of split-related-1 (ESR1), ESR2 and ESR-5 in order to study their expression in relation to somitogenesis. All genes were found to be expressed during somitogenesis, even as early on as late gastrula stages in some cases. In addition, the expression of ESR2 is shown to be oscillating in the presegmented mesoderm of neurula and early-tailbud embryos. This study has identified ESR2 as the second known gene (after esr9) to show periodic oscillations of gene expression which can be considered as cycling during somitogenesis in X. laevis.

The application of social network theory to animal behaviour

Coleing, A. — 2009-03-18

Social network analysis (SNA) is a mathematical technique for analysing social relationships and the patterns and implications of these relationships (Wasserman S, Faust K (1994) Social Network Analysis: Methods and Applications. Cambridge: Cambridge University Press). It has only recently been discovered by behavioural biologists as a useful tool in the study of animal behaviour (Wey T, Blumstein DT, Shen W et al. (2008) Social network analysis of animal behaviour: a promising tool for the study of sociality. Anim Behav 75: 333–344). Video recording over a 2 month period was used to record the behaviour of the elephant group at Chester Zoo. SNA was applied in an investigation of the group structure and interactions of the group. Observations of individual and group behaviour were based upon 40 h of playback of the social interactions were recorded and analysed using AGNA (2003) and Pajek (2005) packages. The analysis showed that the many facets of individual behaviour could be understood in terms of social structure of the group. This study has demonstrated that SNA is a powerful approach to understanding group dynamics and is particularly applicable to the study of obligate social species. In conclusion, it is suggested that SNA is potentially a useful tool in the management of captive animal populations.

The impact of stream support on the hydrology and macrophytes of the upper Bristol Avon

Haley, M. A. — 2009-03-18

Low river flow due to water abstraction has impacted the macrophyte communities on several rivers in England. Stream Support is a method of alleviating low flows by augmenting water supply to the headwater channels of rivers when flow falls below a trigger level. This project has studied that the effect Stream Support has had on the hydrology of the upper Bristol Avon, and the consequent impact these changes have had on the macrophyte communities of the river. The Winterbourne classification methodology was used to investigate hydrological effects on macrophyte communities since the early 1990s. Stream Support was found to have successfully targeted low flow conditions with the annual Q95 measure of low flow closely associated with augmentation (Tetbury: R² = 71%, p < 0.001; Sherston: R² = 78%, p < 0.001). Decade long Q95 (discharge exceeded 95% of the time) measures of low flow on the river were shown to have risen in 1998–2007 by 60% above measures for 1978–1987 and 1988–1997. Aquatic species such as Ranunculus penicillatus pseudofluitans had increased coverage since the 1990s by as much as 40%, but wetland species such as Myosotis scorpioides and Mentha aquatica had marginally lower coverage. These changes may be partly attributable to a reduction in low flow conditions. Stream Support may not be sustainable if global warming leads to annually occurring prolonged periods of summer drought.

An electrophysiological analysis of deep cerebellar nuclei, with particular focus on Kv3 channels

Lamont, M. — 2009-03-18

Deep cerebellar nuclei (DCN) form three symmetrical, bilateral nuclei, deep within the white matter of the cerebellum and represent the sole output of the cerebellum to the central nervous system. Although innervated by spontaneously active inhibitory Purkinje cells, DCN neurons also fire action potentials spontaneously at a relatively high frequency, a property attributed to Kv3 channels. In the present study, an electrophysiological approach was carried out on DCN neurons, the purpose of which was to investigate the properties and elucidate the involvement of Kv3 channels. Using whole-cell patch clamp techniques, electrophysiological recordings from the dentate nucleus were obtained from coronal cerebellar slices of Wistar rats (P ~ 12) in both current and voltage clamp modes. Kv3-mediated currents were investigated in the presence of tetrodotoxin (1 µM), by applying low concentration tetraethyl ammonium (TEA) (100 µM). Current-clamp recordings revealed a population of tonically firing neurons, exhibiting a maximum action potential firing frequency of 18.1 ± 6.9 Hz and a steady firing frequency of 14.2 ± 4.8 Hz (n = 6). These neurons were also shown to exhibit a mean action potential amplitude of 48.7 ± 9.5 mV, mean half-width of 2.9 ± 1 ms and mean afterhyperpolarization amplitude of 19.6 ± 7.5 mV. Depolarizing sag (indicative of the I_h current), followed by rebound depolarization, was observed in all neurons. Voltage-clamped neurons revealed a voltage-dependent slowly inactivating outward current with a peak amplitude of 1538.5 ± 1096.6 pA (n = 10). Application of low concentration TEA (100 µM) reduced the current by a statistically significant 19.4 ± 13.4% (P < 0.05; paired t-test) and this effect was reversible. Application of a Boltzmann function yielded a V_1/2 value of 9.9 mV for the TEA-sensitive current. As Kv3 channels have been previously localized in DCN, the results suggest that the TEA-sensitive current (~20% of the total outward current exhibited) is mediated by Kv3 channels.

Cell-penetrating peptides and their therapeutic applications

Sebbage, V. — 2009-03-18

The process of introducing drugs into cells has always proved a major challenge for research scientists and for the pharmaceutical industry. The cell membrane is selectively permeable and supports no generic mechanism for their uptake. A drug must be either highly lipophilic or very small to stand a chance of cellular internalization. These restrictions mean that the repertoire of possible drug molecules is limited. Similarly, novel therapeutic approaches such as gene and protein therapy also have limited potential due to the cell-impermeable nature of peptides and oligonucleotides. The existing methods for delivery of macromolecules, such as viral vectors and membrane perturbation techniques, can result in high toxicity, immunogenicity and low delivery yield. However, in 1988 the remarkable ability of a peptide to traverse a cell's plasma membrane independent of a membrane receptor was revealed. Known as Tat, the transcription activator of the human immunodeficiency virus type 1 (HIV-1) viral genome was shown to enter cells in a non-toxic and highly efficient manner. In light of such properties Tat became known as the first ‘cell-penetrating peptide’ (CPP). CPPs have demonstrated themselves to be capable of delivering biologically active cargo to the cell interior and the vehicular capabilities of CPPs have already been harnessed for use as laboratory tools. However, it is believed that their true potential lies within the field of therapeutics. Attached to a CPP, therapeutic cargo could be delivered to an intracellular target, thus overcoming the entry restrictions set by the plasma membrane. Since the discovery of Tat, the number of known peptides with cell-penetrating capabilities has grown and in 2003, the first CPP-based drug reached phase II clinical trials. This review discusses the controversial mechanism of entry employed by CPPs, their potential applications in vitro and in vivo, and the ways in which CPP properties have been optimized to maximize their potential as future therapeutics.

Leishmania vaccines: from leishmanization to the era of DNA technology

Dunning, N. — 2009-03-18

Leishmania are obligate intracellular vector-borne parasites that cause significant morbidity and mortality in many countries worldwide. There are several species of the parasite which vary according to geographical location and cause a variety of clinical syndromes ranging from self-limiting cutaneous lesions to potentially fatal infection of the viscera. The disease manifested is dependent on both the species of the parasite and the immune response of the host. Depending on the species of the parasite, resistance to infection is generally associated with a T-helper-1 immune response that activates macrophages to kill intracellular Leishmania in a nitric oxide-dependent manner. Conversely, disease progression is generally associated with a T-helper-2 response that activates humoral immunity. Chemotherapeutic treatments for leishmaniasis exist but are expensive, toxic and ineffective against resistant strains. A vaccine against leishmaniasis is feasible since most individuals that were once infected become resistant to clinical infection when later exposed. However, despite the wealth of information regarding the genetics of the parasite and the experimental immunology of the disease, there is currently no vaccine against Leishmania. A multitude of vaccine strategies have been pursued including the use of killed and genetically modified parasites. Immunization with naked plasmid DNA encoding Leishmania antigens represents a new approach to a Leishmania vaccine and confers several advantages over the more traditional vaccination methods. In order to develop an effective vaccine against leishmaniasis, it is important to understand the mechanisms of the immune response to Leishmania infection. This review discusses such immune mechanisms in detail and also explores several of the Leishmania vaccination strategies employed to date, with particular emphasis on DNA vaccines.

Molecular mechanisms involved in intervertebral disc degeneration and potential new treatment strategies

Ireland, D. — 2009-03-18

Lower back pain (LBP) is a major cause of pain and disability. However, current treatment strategies are focused primarily on relieving its symptoms and have varying degrees of success. For future treatments to be proactive, they must target the underlying pathogenic alterations in cellular biology. Intervertebral disc degeneration (IVDD) has been linked to a high percentage of LBP cases, therefore, inhibition of the processes contributing to IVDD and, regeneration of the intervertebral disc (IVD) matrix lost during IVDD are the primary focuses of current research. Therapies aimed at the inhibition of the cytokine interleukin-1 that is increased during IVDD have been investigated as potential treatments aimed at inhibiting the pathogenic processes of IVDD. In addition, the application of growth factors, such as insulin-like growth factor, transforming growth factor and bone morphogenetic protein or alternatively replacement of abnormal IVD cells, either by injection of mesenchymal stem cells or autologous disc cell transplantation, has been investigated as potential therapeutic agents aimed at regeneration of the IVD matrix. However, for research into these therapeutic techniques to progress, a more detailed knowledge of the complex cellular biology of the IVD is required.

Insights into the development of online plant identification keys based on literature review: an exemplar electronic key to Australian Drosera

Drinkwater, R. E. — 2009-03-18

Keys are traditionally created from data gathered from real observations, which can be a complex and time-consuming process. With a large number of texts containing written descriptions of species, data needed for the creation of a key are already available. A number of published works on Drosera were chosen and the data in these were used to create an interactive, web-based key. The types of data used were evaluated for ease of use and accuracy and the effectiveness of purely literature-based data was tested. The resulting key highlighted a number of problems of using characters and states which have not been observed, as well as showing that literature-based research can lead to a workable key.

Author biographies

2009-03-18

Editorial & Author biographies

2008-05-29

A study into the potential role of Survivin localization in resistance to drug-induced apoptosis

Angell, H. — 2008-05-29

The aim of this study was to test the hypothesis that diverting the cytoplasmic subcellular localization of the anti-apoptotic form of Survivin to the nucleus would sensitize cancer cells to chemotherapeutics. Apoptosis is a morphologically and biochemically distinctive form of cell death, critical in the maintenance of tissue homeostasis. Caspases are a family of cysteine proteases that have a vital role in the implementation of apoptosis, and their activity is regulated by Inhibitors of Apoptosis Proteins. Recent studies indicate that one such inhibitor, Survivin, may have dual functions that are specific to its cellular location, including suppression of apoptotis (cytosolic) and regulation of cell division (nuclear). Since both apoptosis and proliferation are altered in cancer, identifying whether these roles for Survivin are dependent on its subcellular localization will inform future approaches to treat chemotherapeutically resistant tumour cells. After initially confirming the specificity of several Survivin antibodies, the distribution of Survivin was examined by immunofluorescence microscopy and sub-cellular fractionation in breast cancer cell lines. The threshold of drug-induced apoptosis was compared in cells over-expressing either wildtype Survivin or a form of Survivin unable to exit the nucleus due to a mutation in its nuclear export sequence. Endogenous Survivin localized to both nucleus and cytoplasm of breast cancer cell lines. Over-expressed Survivin had an anti-apoptotic, protective function. In contrast, cells expressing Survivin with the mutated nuclear export sequence had a lower apoptotic threshold to chemotherapeutic drugs. These results demonstrate for the first time that Survivin is localized to both the nucleus and cytoplasm of breast cancer cell lines. Importantly, the sensitivity of cells to chemotherapeutic drugs was increased when Survivin's localization was restricted to the nucleus, consistent with cytoplasmic Survivin having the anti-apoptotic role. Since clinical studies have shown that nuclear Survivin is a positive prognostic factor in breast cancer patients, the data suggest that strategies to alter Survivin distribution may be useful in the fight against cancer.

Sphingosine-1-phosphate activation of TRPC5 in vascular smooth muscle cells

Fahy, S. — 2008-05-29

Calcium signalling is a complex and diverse system utilized in many cellular processes and in the transmission of cellular information. A number of transient receptor potential (TRP) proteins have been identified in humans and other mammals; these proteins are implicated as having a role in calcium signalling. TRPC5 is a member of this protein family which combines with TRPC1 to form non-selective cation channels in human saphenous vein cells, a type of smooth muscle cell. The exact function of TRPC5 remains elusive, however, it can be activated by sphingosine-1-phosphate (S1P), an endogenous signalling phospholipid involved in SMC migration.

The aim of these experiments was to investigate the effects of S1P on the intracellular calcium concentration, [Ca²⁺]_i, in HSV cells, utilizing dominant-negative (DN)-TRPC5 transfected cells to establish the role played by TRPC5 in this response. A secondary aim was to establish the effect of SMC migration on the above response parameters to S1P using the HSV scratch assay, where a ~2 mm line of cells was scraped away from the surface of a glass cover slip and the remaining cells incubated for 24 h.

Concurrent with the literature, S1P evoked a significant response in HSV cells (n=23; P=0.001). The baseline was significantly lower in the DN-TRPC5 cells compared with the control cells (P<0.001), and the maximum response in the DN-TRPC5 transfected HSV cells reached only 60% of the maximum response in control cells. This suggested that TRPC5 was involved with maintaining basal [Ca2+]_i levels and indicated the proportion of the response for which TRPC5 was responsible.

The response to S1P was significantly larger in migrated (n=7) compared with static (n=11) HSV cells (P=<0.001) and this response was delayed by ~2.3 min; the baseline was also higher in the latter group. This suggested a functional change in the cell following migration that may have been attributable to TRPC5, for example, channel up-regulation.

In conclusion, TRPC5-like channels are responsible for a proportion of the S1P response and are implicated in SMC migration. This highlights potential pharmacological targets for the treatment of atherosclerosis, neointimal hyperplasia and coronary heart disease.

The potential effect of excessive coffee consumption on nicotine metabolism: CYP2A6 inhibition by caffeic acid and quercetin

Woodward, G. M. — 2008-05-29

Over the past decade interest in the biochemical and biological properties of polyphenols has grown considerably, as epidemiological evidence for their beneficial effects on health continues to increase. Dietary polyphenol antioxidants are reported to have many ‘health promoting’ properties, including anti-inflammatory, vasoprotection, anti-cancer and anti-obesity effects. However, their absorption and metabolism are as yet not fully elucidated, particularly with regard to their interactions with other metabolized compounds, such as nicotine. Epidemiological studies have shown that coffee-drinking cigarette smokers are more likely to smoke less in comparison to non-coffee drinking cigarette smokers. Nicotine is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2A6 and may be inhibited by the metal chelating properties of polyphenols via haem interactions with their hydroxyl groups. To model nicotine metabolism, bovine liver microsomes, shown to suitably represent human CYP2A6 metabolism, were isolated by calcium precipitation and differential centrifugation. Fluorometric analysis of 7-hydroxycoumarin, the CYP2A6 metabolite of coumarin and known probe for CYP2A6 activity, was used to model nicotine metabolism in vitro and to quantify the degree of CYP2A6 inhibition imposed by caffeic acid and quercetin. It was found that both caffeic acid and quercetin, major polyphenolic constituents of caffeine containing beverages, significantly inhibited CYP2A6 activity in vitro by 37.9% (P < 0.05) and 48.2% (P < 0.05), respectively. Thus, this study demonstrates the first reported biochemical evidence in support of previous epidemiological observations, where it is suggested that polyphenol interaction with CYP2A6 prolongs the pharmacological effects of nicotine by decreasing its rate of elimination.

Temperature stress-induced bleaching of the coralline alga Corallina officinalis: a role for the enzyme bromoperoxidase

Latham, H. — 2008-05-29

Coralline algae are important components of coral reefs and are involved in reef building via calcification, cementation, the synthesis of anti-fouling compounds and the synthesis of allochemicals to aid recruitment, settling and metamorphosis of reefs species. Using Corallina officinalis we have shown that these algae undergo temperature-related bleaching at similar temperatures to those known to cause bleaching in corals. The bleaching appears to be associated with considerable increases in the vanadium-containing enzyme bromoperoxidase (VBPO). This enzyme is involved in hydrogen peroxide (H₂O₂) elimination and generates the powerful brominating/oxidizing agent hypobromous acid (HOBr, probably present as Br⁺). This is used to synthesize volatile halogenated organic compounds (VHOCs) from a pool of organic acceptor molecules. Earlier in vitro work has shown this enzyme to be effective in bleaching the phycobilin photosynthetic accessory pigments and to be partly located in chloroplasts. The data presented here supports the suggestion that increases in temperature lead to an increase in the cellular production of H₂O₂ and other reactive oxygen species that result in an increase in VBPO, a subsequent increase in HOBr/Br⁺ followed by pigment bleaching when the capacity to produce VHOCs has been exceeded. Addition of the exogenous antioxidant mannitol decreases both pigment bleaching and VBPO induction. A scheme is presented to illustrate proposals for the involvement of VBPO in the bleaching of coralline algae such as C. officinalis. The importance of these species in reef building and rebuilding is discussed.

Effects of modulators of TASK potassium channels on rat pulmonary artery tone

Shah, S. D. — 2008-05-29

TWIK-related acid-sensitive potassium (TASK) channels have been implicated as having a role in maintaining and mediating the tone of pulmonary arteries by influencing the membrane potential of the smooth muscle cells. Inhibition of these channels would be expected to promote depolarization, calcium influx and contraction. The purpose of this study was to investigate the effects of TASK modulators on rat intrapulmonary artery tone. The modulators included pH, an important physiological TASK modulator, and drugs that inhibit TASK channels, such as bupivacaine, methanandamide and zinc. Small vessel myography was used to measure the tone of both conduit and resistance pulmonary arteries. Cumulative bupivacaine and methanandamide dose–response curves were compared with phenylephrine (a sympathomimetic vasoconstrictor). The effects of pH were investigated on vessel tone and responses to bupivacaine, methanandamide or zinc chloride. Bupivacaine and methanandamide (>10 µM) resulted in increased artery tone, with similar effects seen in conduit and resistance vessels. Zinc had no effect, possibly reflecting an inhibitory action on calcium channels. In the presence of endothelial blockers, methanandamide (100 µM) still resulted in an increase in artery tone, implying an action on smooth muscle. The application of nifedipine resulted in the inhibition of the response seen with bupivacaine (100 µM), implying that voltage-gated calcium entry was involved. Changing the pH from 7.3 to 8.3 resulted in vasoconstriction, and a relaxation was seen in acidic conditions. This is opposite to the result expected for TASK channel modulation, but may reflect the multiple effects of pH on smooth muscle. The contractions seen with bupivacaine and methanandamide were increased at pH 8.3 but inhibited at pH 6.3, consistent with an effect on TASK channels. Responses to bupivacaine and methanandamide were, however, very small, suggesting that currents produced by TASK channels may not be a major factor in contracting intrapulmonary arteries, but may still have a minor role.

The effects of immune challenge on phenoloxidase activity in locust salivary glands in vitro

Wells, K. L. — 2008-05-29

Homogenates of salivary glands from Locusta migratoria possess phenoloxidase (PO) activity. This study investigates the activation of prophenoloxidase (PPO) in these glands in vitro. When freshly dissected salivary glands from L. migratoria are incubated with the immunogen laminarin, and then homogenized, a ~4-fold increase in PO activity (expressed as a percentage of the total PO) can be measured within 20 min. Addition of laminarin to the incubation medium is best made prior to addition of salivary gland tissue, because when laminarin is added 10 min after the addition of tissue, the response to laminarin is reduced by ~50%. When salivary glands are incubated in Ca²⁺-free Ringer, the response to laminarin cannot be demonstrated. Addition of a calcium ionophore to the incubation in normal Ringer does not initiate a response on its own, but does augment the response to laminarin. Addition of phorbol ester to an incubation containing normal Ringer has no effect on PO activity, and does not augment the response to laminarin. In contrast, addition of okadaic acid to normal Ringer has no effect on its own, but does augment the response to laminarin. Activation of PPO in response to laminarin is therefore calcium-dependant, possibly involving an influx of extracellular Ca²⁺, and modulated by protein phosphatases. Future work should aim to clarify the function of salivary glands in the immune defence of the locust and to investigate the exact source of the PO associated with the glands.

Species richness and aggregation effects on the productivity of ruderal plant communities under drought perturbation

Nakamura, N. — 2008-05-29

The effect of species richness and spatial aggregation on the stability of community productivity in response to drought perturbation was investigated with experimental plant communities. Communities comprising all single- and three-species combinations of the ruderal species, Capsella bursa-pastoris, Tripleurospermum inodorum, Poa annua, and Stellaria media, were established in glasshouse. Habitat patchiness was manipulated by applying different seed-sowing patterns, either aggregated or random. After the establishment of communities, 8 days of drought treatment was imposed. Followed by a week of recovery with a regular watering regime, aboveground biomass was harvested. Community biomass was not affected by species richness or by aggregation, but was affected by perturbation. When multi-species community productivity was compared with monocultures in relative terms, species mixtures performed better in drought-induced conditions. This suggests that the positive effect of species richness may be enhanced under the perturbed condition. Sampling effects were evident under perturbation favouring the least productive species, P. annua and drought-tolerant S. media. All species except C. bursa-pastoris showed reduced productivity in species mixtures, but this may be mitigated under perturbed environments by species complementarity. Lack of clear responses to aggregation may suggest that the revealed diversity effect is not related to spatial structure. While competition predominates in communities in the resource-rich environment, drought perturbation enhance overall community productivity via a shift in relative significance of species interactions from competition to sampling and complementarity effects.

Body surface temperature and length in relation to the thermal biology of lizards

Garrick, D. — 2008-05-29

This study investigated body surface temperature (T_bs) in 22 lizards of 18 species. The difference between T_bs and ambient temperature (T_a) was correlated with size. The greater T_bs – T_a differentials, which were recorded in larger lizards, may occur as a result of heat transfer from the core to surface in prevention of overheating. The structure of the integument may contribute to heat dissipation. Heliothermy and thigmothermy as forms of thermoregulation were also incorporated into the data set. Heliothermic lizards showed a positive correlation between length and T_bs – T_a. Thigmothermic lizards, however, exhibited a negative correlation. Differences in size and rate of conductive heat transfer are put forward as possible reasons for the negative correlation.

The importance of birds in the diet of otter Lutra lutra on Shapwick Heath

de la Hey, D. C. — 2008-05-29

This study investigates the importance of avian species in the diet of Shapwick Heath's otter population. The frequency occurrence of prey items was recorded from spraints collected between July 2006 and January 2007. Bird feathers extracted from otter spraints were investigated under a microscope. Where possible, feathers were identified to species level. The presence of fish scales in spraints was recorded, but not quantified. Bird feathers were recorded in 41% of all spraints, compared with 4.6% on Slapton Ley in 1981 and 4.7% on the Somerset Levels in 1975. The highest proportion of bird feathers was recorded in July 2006, at 61%. Ralliformes were more frequently recorded than any other family of birds. Coot Fulica atra L. were more frequently recorded then any other species; 15 spraints were found to contain coot feathers. Mallard Anas platyrhynchos feathers were recorded in six spraints. Cormorant Phalacrocorax carbo feathers were found in three spraints and Water rail Rallus aquaticus feathers were found in two spraints. Pintail Anas acuta, teal Anas creca, moorhen Gallinula chloropus and little grebe Tachybaptus ruficollis feathers were found in one spraint each. Two spraints contained feathers from both mallard and coot, respectively. The high proportion of birds in the otter's diet, in comparison with past studies suggests that otters are substituting birds for part of their traditional diet of fish. It is recommended that studies into the nature of the fish stock and the development of the aquatic ecosystem on Shapwick Heath be undertaken.

The effect and interaction of enhanced nitrogen deposition and reduced light on the growth of woodland ground flora

Andrews, N. R. — 2008-05-29

Woodland ground flora species Geranium robertianum, Prunella vulgaris and Deschampsia caespitosa were grown in greenhouse conditions under various light regimes (100%, 20% and 5% of ambient summer light) and were misted weekly with solutions of ammonium nitrate to simulate increased atmospheric wet and dry deposition of nitrogen (N) due to pollution at 0, 15 and 30 kg ha^–1 year^–1 concentrations. In the last 5 weeks of the study, the photosynthetic rate of G. robertianum was measured weekly. At the end of the 10-week-treatment period, the plants were harvested and growth was recorded using various measurable growth parameters. Growth of the plants and photosynthetic rate of G. robertianum were found to be primarily dependent on light availability, where reduced light levels showed a decrease in overall plant growth, indicating the importance of light in woodlands. N was not found to have an effect on the growth of the plants and thus questions arise over the calculations of critical loads of N deposition for woodland habitats. Five interactions were noted where increased N led to a significant reduction in growth at 20% light, yet a significant increase in growth at 100% light. These interactions were mainly noted for P. vulgaris, which could be explained by relatively large differences between its Ellenberg values for light and N, reflecting a preference for high light conditions and fairly infertile soils. G. robertianum was least affected by a reduction in light, reflecting its preference for semi-shaded conditions.

Has golf-course management had an effect on the plant species composition and character of a calcareous grassland?

Worster, M. P. — 2008-05-29

Lowland calcareous grassland in the UK is a priority habitat designated under the UK Biodiversity Action Plan. Calcareous grasslands used to be common in north-western Europe and were utilized for grazing livestock such as sheep and cows. Many calcareous grasslands in England have been either agriculturally ‘improved’ through the addition of fertilizer and herbicides to increase productivity or have been ploughed up to make way for arable production, which has led to a dramatic decrease in the area of calcareous grassland.

Minchinhampton Common is an area of lowland calcareous grassland located within the English county of Gloucestershire. In 1889, a golf course was laid out on the common for the use and enjoyment of local people.

The first objective of this project was to investigate whether the presence of the golf course on Minchinhampton Common and associated golf-course management activities have had an effect on the composition and character of the calcareous grassland. The second objective was to investigate whether abandoned golf-course features on Minchinhampton Common, such as old fairways and old greens can recover to resemble undisturbed calcareous grassland.

Significant differences were found between the undisturbed calcareous grassland and the fairways, greens and pathways in terms of vegetation height, plant species composition, botanical diversity and soil characteristics. This demonstrates that the presence of the golf course and the management carried out to maintain it has had an effect on the composition and character of the calcareous grassland.

Significant differences were found when the fairways and greens were compared with the abandoned old fairways and old greens. This shows that after 15 years of abandonment the old fairways and old greens are no longer similar to the fairways and greens, but they are still different from the undisturbed calcareous grassland. It is hypothesized that to aid recovery, the abandoned features should be cut annually and the clippings removed. This will decrease the nutrient status of the soil and reduce the competitiveness of grasses, thus providing greater opportunities for the establishment of forb species typical of nutrient poor calcareous grasslands in north-western Europe.

The role of hepatitis C virus in the pathogenesis of hepatocellular carcinoma

Tran, G. — 2008-05-29

Hepatitis C virus (HCV) is a worldwide pandemic, chronically affecting over 170 million people worldwide. It is a major risk factor for the development of hepatocellular carcinoma (HCC) and there is increasing experimental evidence to suggest that the virus plays a direct role in neoplastic transformation. The purpose of this letter is to review the literature regarding two individual proteins of HCV, namely NS5A and core, and their role in the pathogenesis of HCC through perturbations of cellular pathways, in addition to their immunopathological effects of chronic inflammation. A systematic search of MEDLINE in addition to manual searches of citations in key papers was employed to identify relevant studies. There is overwhelming evidence suggesting the direct and indirect roles HCV plays in the pathogenesis of HCC. Recent progress in our understanding of the pathophysiology of HCV coupled with advances in in vitro models will ensure that positive strides are made in the treatment and management of this potentially fatal virus.