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Parasitology,
2012]
Despite the utility of RNAi for defining gene function in Caenorhabditis elegans and early successes reported in parasitic nematodes, RNAi has proven to be stubbornly inconsistent or ineffective in the animal parasitic nematodes examined to date. Here, we summarise some of our experiences with RNAi in parasitic nematodes affecting animals and discuss the available data in the context of our own unpublished work, taking account of mode of delivery, larval activation, site of gene transcription and the presence/absence of essential RNAi pathway genes as defined by comparisons to C. elegans. We discuss future directions briefly including the evaluation of nanoparticles as a means to enhance delivery of interfering RNA to the target worm tissue.
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Biochem Soc Symp,
1987]
Human lymphatic filariasis is a chronic, potentially debilitating disease caused by Brugia and Wuchereria species of parasitic nematodes. The spectrum of clinical manifestations appears to be related to the immune response of individuals to invasive larvae, adult worms and circulating first-stage larvae (microfilariae). Potential immunopathological outcomes place constraints on vaccine development, emphasizing the need to understand the basis of immunity and pathology. Clones coding for a number of distinct antigenic proteins of Brugia pahangi and Brugia malayi have been isolated via immunological screening of a cDNA expression library. A small number of these expressed peptides show exclusive reactivity with antibody from amicrofilaraemic, potentially immune individuals. Surprisingly, a dominant immunogen isolated with human antibody is the filarial parasite homologue of heat shock protein (hsp) 70. This protein is constitutively expressed in both insect- and mammalian-dwelling parasitic stages, but does not appear to presented to the host immune system in intact worms.
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Int J Parasitol,
1998]
All filariae examined to date express a comprehensive repertoire of both cytoplasmic and secreted anti-oxidant enzymes, although significant differences exist between species and life-cycle stages. Adult Brugia malayi, Dirofilaria immitis and Onchocerca volvulus secrete CuZn superoxide dismutases, and the former two species also secrete a selenocysteine-independent glutathione peroxidase. This enzyme has been localised to the cuticular matrix of B. malayi, and the preferential reduction of fatty acid- and phospholipid hydroperoxides suggests that it may protect cuticular membranes from oxidative damage rather than directly metabolise hydrogen peroxide. Adult O. volvulus may compensate for an apparent deficiency in expression of this enzyme via a secreted variant of glutathione S-transferase. Recent studies have identified a highly expressed family of enzymes collectively termed peroxiredoxins, which most probably play an essential role in reduction of hydroperoxides. Data from cDNA cloning exercises indicate that all filarial species examined thus far express at least two peroxiredoxin variants which have been localised to diverse tissues. In-vitro studies have shown that B. malayi are particularly resistant to oxidative stress, and that the parasites do not rely solely on enzymatic mechanisms of defence. Cuticular lipids are relatively resistant to lipid peroxidation due to the low unsaturation indices of the constituent fatty acyl residues, but complete protection is afforded by the presence of alpha-tocopherol, presumably assimilated from host extracellular fluids. Brugia malayi are also relatively resistant to nitric oxide-mediated toxicity, and this may be due in part to incomplete dependence on aerobic metabolism. Little is known of potential mechanisms for detoxification of nitric oxide derivatives and adaptive responses to oxidative stress in general, and these represent goals for future research.
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Experimental Parasitology,
1993]
Nematodes possess biologically unusual surfaces. The dominant feature is the cuticle, a collagen-rich extracellular matrix which acts as the exoskeleton and is synthesized in the outermost tissue layer of the organism, the epidermis or hypodermis. The cuticle, which may be 1 um or more in depth, has on its external face a lipid-rich epicuticle which in some species resembles a unit membrane. There may be an additional envelope, loosely attached and distal to the epicuticle, in the form of a surface coat or glycocalyx, or as a thin sheath retained by some larval nematodes from previous developmental stages. The organisation of these components is depicted in Fig. 1. Detailed studies of these structures are now becoming available in both parasitic and free-living nematodes such as Caenorhabditis elegans...
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Cancer Research,
1999]
It is an honor and a great pleasure to introduce Dr. Robert Horvitz to you as the 1998 recipient of the Alfred Sloan Prize of the General Motors Cancer Research Foundation. Let me begin by telling you a little bit about Bob's
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Chembiochem,
2003]
I never expected to spend most of my life studying worms. However, when the time came for me to choose an area for my postdoctoral research, I was intrigued both with the problems of neurobiology and with the approaches of genetics. Having heard that a new "genetic organism" with a remarkably simple nervous system was being explored by Sydney Brenner - the microscopic soil nematode Caenorhabditis elegans - I decided to join Sydney in his efforts.
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Biochem Biophys Res Commun,
2017]
Programmed cell clearance is a highly regulated physiological process of elimination of dying cells that occurs rapidly and efficiently in healthy organisms. It thus ensures proper development as well as homeostasis. Recent studies have disclosed a considerable degree of conservation of cell clearance pathways between nematodes and higher organisms. The externalization of the anionic phospholipid phosphatidylserine (PS) has emerged as an important "eat-me" signal for phagocytes and its exposition on apoptotic cells is controlled by phospholipid translocases and scramblases. However, there is mounting evidence that PS exposure occurs not only in apoptosis, but may also be actively expressed on the surface of cells undergoing other forms of cell death including necrosis; PS is also expressed on the surface of engulfing cells. Additionally, PS may act as a "save-me" signal during axonal regeneration. Here we discuss mechanisms of PS exposure and its recognition by phagocytes as well as the consequences of PS signaling in nematodes and in mammals.
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Front Cell Dev Biol,
2023]
Phosphatidylserine (PS) is a lipid component of the plasma membrane. It is asymmetrically distributed to the inner leaflet in live cells. In cells undergoing apoptosis, phosphatidylserine is exposed to the outer surfaces. The exposed phosphatidylserine acts as an evolutionarily conserved "eat-me" signal that attracts neighboring engulfing cells in metazoan organisms, including the nematode <i>Caenorhabditis elegans</i>, the fruit fly <i>Drosophila melanogaster</i>, and mammals. During apoptosis, the exposure of phosphatidylserine to the outer surface of a cell is driven by the membrane scramblases and flippases, the activities of which are regulated by caspases. Cells undergoing necrosis, a kind of cell death frequently associated with cellular injuries and morphologically distinct from apoptosis, were initially believed to allow passive exposure of phosphatidylserine through membrane rupture. Later studies revealed that necrotic cells actively expose phosphatidylserine before any rupture occurs. A recent study in <i>C. elegans</i> further reported that the calcium ion (Ca<sup>2+</sup>) plays an essential role in promoting the exposure of phosphatidylserine on the surfaces of necrotic cells. These findings indicate that necrotic and apoptotic cells, which die through different molecular mechanisms, use common and unique mechanisms for promoting the exposure of the same "eat me" signal. This article will review the mechanisms regulating the exposure of phosphatidylserine on the surfaces of necrotic and apoptotic cells and highlight their similarities and differences.
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Cell Mol Life Sci,
2016]
Programmed cell death is critical to the development of diverse animal species from C. elegans to humans. In C. elegans, the cell death program has three genetically distinguishable phases. During the cell suicide phase, the core cell death machinery is activated through a protein interaction cascade. This activates the caspase CED-3, which promotes numerous pro-apoptotic activities including DNA degradation and exposure of the phosphatidylserine "eat me" signal on the cell corpse surface. Specification of the cell death fate involves transcriptional activation of the cell death initiator EGL-1 or the caspase CED-3 by coordinated actions of specific transcription factors in distinct cell types. In the cell corpse clearance stage, recognition of cell corpses by phagocytes triggers several signaling pathways to induce phagocytosis of apoptotic cell corpses. Cell corpse-enclosing phagosomes ultimately fuse with lysosomes for digestion of phagosomal contents. This article summarizes our current knowledge about programmed cell death and clearance of cell corpses in C. elegans.
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Mech Ageing Dev,
2002]
It strikes me that among our relatively small community of gerontologists concerned with genetic approaches to our science, there is somewhat of a dichotomization. On the one hand, there are those of us, like myself, who tend to be dour ''complificationists''. Journalists talk to us, but are usually disappointed by the encounter. We are perhaps too impressed with the enormous diversity of genetic modulations of human senescence and with our interpretations of the implications of the evolutionary biological theory of senescence, namely that senescent phenotypes per se are non-adaptive, non-determinative, subject to stochastic events as well as highly polygenic modulations, with resulting wide variability in mechanisms of senescence among and within species. Quite happily, however, there are wonderful optimists among us. They seem to be convinced that there are likely to be a rather small number of major gene effects for a few major mechanisms. They include most Saccharomyces cerevisiae and Caenorhabditis elegans geneticists, some Drosophila melanogaster geneticists, and some mouse geneticists. They also include caloric restriction enthusiasts. Let''s call these colleagues ''simplificationists''. Journalists and friends generally find them to be delightful companions. Where does the truth lie? Perhaps the truth lies somewhere between these two extremes and is largely dependent upon the organisms and the range of environments being investigated.