This collection of publications can be considered under three main headings: I. Life cycle and developmental studies on strigeoid trematodes, 2. A study of the host-parasite interface. 3. The reproductive biology of Schistosoma mansoni. The main theme throughout these papers is the study of the host-parasite relationship emphasising selected aspects of parasite biology, structure and histochemical characteristics which are significant to this relationship. The early studies on the strigeoid trematodes drew my attention to the very intimate attachment of these parasites to host tissue via the very specialised adhesive organ. This close physical relationship emphasised the importance of the host-parasite interface in the interaction between two genetically different organisms. This interface, through which all biologically important substances, of both host and parasite origin, must pass, can be regarded as comprising not only the external surfaces but also the lining of the gut, when present. Several examples of trematodes, cestodes and nematodes have been investigated on a multi-disciplined basis using light microscopy, transmission and stereoscan electron microscopy combined with histochemical techniques wherever appropriate. In the strigeoid trematodes in particular, considerable surface specialisation can be associated with the secretory and absorptive processes of the parasite. Similarly, in the cestode Moniezia, surface differentiation in relation to secretion was observed and in Taenia it was found that the phosphatase characteristics of the tegument varied along the length of the worm. In the nematodes, considerable contracts were revealed between the intestinal epithelium and the rest of the gut. This information has been useful in understanding the nature of the host-parasite interface and its function in the host-parasite relationship. In Schistosoma mansoni, a different aspect of the relationship is being studied. The accumulation of eggs laid by the female in host tissues is a stimulus for a delayed hypersensitivity response by the host. and this produces considerable damage to the host tissues. The functioning and co-ordination of the female reproductive system of this parasite is poorly understood and initial studies have been directed at elucidating basic structure and investigating the subcellular effects of known egg-laying inhibitors eg. schistosomicidal drugs on the reproductive system. These studies have produced interesting information on the differential susceptibility of the cells of the reproductive system to drug action, evidence of drug resistance by some cells and the relationship between cytosegresome formation and drug sequestration by others. It is hoped that these studies will provide a basis for the development of more specific inhibitors of egg production and so remove a major cause of host pathology. In the study of some aspects of the host-parasite relationship it is essential that the contact between both organisms remains undisturbed. This poses considerable technical problems in studying the more dynamic aspects of the relationship particularly when these occur at a sub-cellular level. Consequently, rather indirect methods as electron microscopy coupled to autoradiographic and histochemical techniques have to be used. Very recently new approach has become available which will permit the detection of biologically important elements in situ at an ultrastructural level. Introduced foreign elements can also be detected. The technique is the X-ray analysis of ultrathin sections in the transmission electron microscope. - Many problems remain to be overcome in the application of this technique, but some progress has been Made and its initial application has been to a study of drug distribution in Schistosoma mansoni. It will have also considerable value in the study of the host-parasite interface, providing a completely new dimension to the multidisciplined investigations.

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The communication between neurons and other cells at chemical synapses, via the release of neurotransmitters, is a tightly regulated process. Regulation of the synaptic vesicle cycle, responsible for the release of neurotransmitters, controls the level of synaptic transmission. The identities of proteins involved in this regulation are gradually being elucidated using both in vitro and in vivo systems. In C. elegans adults the single Rho GTPase orthologue, RHO-1, stimulates neurotransmitter release at excitatory synapses at the neuromuscular junction. Expression of constitutively active RHO-1 increases release, whilst inhibition of endogenous RHO-1 by C3 transferase decreases release. RHO-1 stimulates release via two pathways, one that is dependent upon the diacylglycerol binding protein UNC-13 and the other that is independent of UNC-13. This thesis explores the upstream regulation of RHO-1. Data presented here suggests that one of the pathways acting upstream of RHO-1 in acetylcholine-releasing motor neurons depends upon Gcn2 (GPA-12), which acts via the single C. elegans RGS RhoGEF, (RHGF-1). Constitutively active GPA-12 has the same effect as constitutively active RHO-1, inducing the accumulation of diacylglycerol and the neuromodulator UNC-13 at release sites, and increased ACh release. All these effects are suppressed by mutation of RHGF-1. GPA-12 acts entirely in an UNC-13 dependent manner, suggesting the probability of other upstream pathways also stimulating RHO-1 to control neurotransmitter release.

There is increasing evidence suggesting that heterotrophic marine organisms could also be potential sources of polyunsaturated fatty acids (PUFAs), in addition to marine bacteria and microalgae, including two polychaete species such as the lugworm (Arenicola marina) and the ragworm (Nereis virens). The capacity for PUFAs production by these species is, therefore, essential to understand the roles of polychaetes in relation to PUFA fluxes in an estuarine food web. Two methods were adopted to study fatty acid biosynthesis by the worms: i) quantifying of PUFA fluxes in closed system (A. marina and N. virens) and ii) stable isotope labelling and mass spectrometry to investigate possible pathway (N. virens only). In the first method, the controlled amount of fatty acid inputs and outputs in the culture worms was determined together with GC/GC-MS analysis to calculate the amount of fatty acid gained per system box after subtracting food given fatty acids. Palmitic acid (C16:0) and monoenoic acids e.g. palmitoleic acid (C16:1n7), oleic acid (C18:1n9) and vaccenic acid (C18:1n7) were prominent fatty acids in the system. EPA was found to be accumulated over the period of experiment in both species. In the stable isotope experiment, 13C-labelled palmitic acid (C16:0) was incorporated into the feed pellets and used to trace the changes in the 13C/12C ratio in characteristic peaks of mass spectra. Significant changes in the 13C/12C ratio of key peaks in the spectra compared with the controlled start samples: palmitic acid (C16:0), stearic acid (C18:0), arachidonic acid (ARA: C20:4n6) and EPA (C20:5n3) within the 7 days period of experiment revealed a pathway for EPA production in N. virens. These findings would therefore corroborate of the concept that some marine animals are able to generate long-chain PUFAs such as ARA, EPA and DHA. N. virens and A. marina could be one of the very important PUFA sources within estuarine marine ecosystem.

Our knowledge of adult stage of helminths is undoubtedly far more comprehensive than that of the larval stages. This is due not merely to the fact hat a larger number of workers has studied adult helminths but rather to the possession by the latter of more easily distinguishable characters. In comparison, larval helminths are difficult to study and identify owing to their small size and to the consequent obscurity of their structural details. It is, therefore, not surprising to find in the literature that the descriptions of larval helminths are sometime very brief and incomplete and this adds greatly to difficulties of their proper identification. Although much useful work has been done on larval helminths in Great Britain, our knowledge concerning them is still very inadequate. A majority of the investigators in Great Britain have concentrated on larval Nematoda, a few have studied larval Cestoda and larval Nematoda, but none, so far as the writer is aware, appears to have described larval Acanthocephala.

Since the discovery of sporocysts and rediae by Steenstrup in 1842, the study of the life histories of different Trematodes has received much attention by investigators, for instance Wagener in 1857, Leuckart in 1882, Thomas in 1883, Heckert in 1889, Creutzberg in 1890 and Looss in recent times. It was from the observations of these workers that the life cycle of Trematodes was put on a firm basis. But no real importance was attached to the study of miracidia, sporocysts, rediaeand corcariae until after the classical work of Thomas in 1883, which resulted in-a thorough explanation of the life history of the liver fluke and its transmission from sheep to sheep. Since'1883 numerous investigations have been carried out from the economical and medical point of view, and the bulk of the contributions*to the knowledge of cercariae consists of the results of observations and experiments on the cercariae of the Trematodes infecting man and the domestic animals Particular attention was paid to the different intermediate hosts and the conditions under which they are capable of causing the infection of the definitive hosts. A serious study of the organisation of cercariae was long neglected and in spite of the numerous cercariae described by many investigators, it is impossible to identify many of the species correctly. It was only after the study of the cercariae of the Schistosomidae infecting man that the study of the morphology and histology of other cercariae was adequately undertaken, and authors began to attach importance to features of the internal organisation, which may throw light on the structure of the adult. The systems which have been carefully studied are the alimentary tract, the excretory and genital systems, and specific differences were observed even among cercariae closely resembling one another. Certain glands in the body have also been observed, and have proved in many cases to play an important part in the process of infection of the definitive host.

Ageing research in model organisms has accomplished great strides in finding genes and pathways that modulate the ageing process. However, the mechanism through which organisms age still remains a mystery. An influential ageing theory views ageing as the result of damage accumulation throughout an organism’s lifespan, which eventually accumulates to noxious levels causing death. In this thesis we will explore an alternative theory proposed by M. Blagosklonny. The hyperfunction theory postulates that ageing is the result of the non-adaptive continuation of developmental and reproductive programmes in late adulthood. Thus, programmes that promote growth and reproductive fitness become quasi-programmes in later life that result in age-related pathologies, some of which cause death. In this thesis we examined two reproductive pathologies, yolk accumulation and gonad degeneration, to try to understand their causes and to test their role in age-related mortality. A clear example of a quasi-programme in ageing worms is the run-on of yolk production in post-reproductive worms. During reproduction yolk is synthesized in the intestine to be transported to oocytes and provision embryogenesis. After reproduction ceases yolk protein accumulates in the body cavity of the worm. We found that yolk proteins accumulate to high levels during ageing. However, RNAi abrogation of vitellogenesis did not increase lifespan, implying that yolk protein accumulation does not cause mortality. Gonad disintegration provides an intriguing example of how quasi-programmes can cause pathology via atrophy. We found that gonad disintegration, which occurs in post-reproductive hermaphrodite worms, is apoptosis dependant. At least half of all germ cells undergo “physiological” programmed cell death. Our results imply that the apoptotic program that ensures reproductive fitness to support oocyte growth continues in older worms giving rise to pathology.

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