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Annu Rev Physiol,
2008]
blacksquare, square, filled Abstract Insulin-like signaling is critical for nutrient homeostasis, growth and survival. However, work with lower metazoans-Caenorhabditis elegans and Drosophila-shows that reduced insulin-like signaling extends life span. In addition, reduced insulin signaling in higher animals-rodents and humans-causes glucose intolerance and hyperinsulinemia that progresses to diabetes and shortens the life span of affected individuals. Hyperinsulinemia usually develops to maintain glucose homeostasis and prevent the progression toward life-threatening type 2 diabetes; however, increased circulating insulin may have negative effects on the brain that promote age-related disease. We discuss the possibility that the brain is the site where reduced insulin-like signaling can consistently extend mammalian life span-just as reduced insulin-like signaling extends the life span of lower metazoans. Expected final online publication date for the Annual Review of Physiology Volume 70 is February 11, 2008. Please see
http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Parasitology,
2000]
This detailed review of the published studies underlying ivermectin's recent registration for use in lymphatic filariasis (LF) demonstrates the drug's single-dose efficacy (over the range of 20-400 microg/kg) in clearing microfilaraemia associated with both Wuchereria bancrofti and Brugia malayi infections of humans. While doses as low as 20 microg/kg could effect transient microfilarial (mf) clearance, higher dosages induced greater and more sustained mf reduction. The single dose of 400 microg/kg yielded maximal responses, but a number of practical considerations suggest that either 400 microg/kg or 200 microg/kg doses would be acceptable for use in LF control programmes. Associated safety assessments indicate that adverse events, which occur commonly following treatment of microfilaraemic individuals, develop not because of drug toxicity but because of host inflammatory responses to dying microfilariae killed by the ivermectin treatment. Ivermectin is, therefore, a highly effective and generally well tolerated microfilaricide that may soon become an essential component of many public health initiatives to interrupt transmission of lymphatic filarial infection in an effort to eliminate LF globally.
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Acta Leiden,
1990]
Community trials were started to address questions concerning the safety of ivermectin during large scale treatment, its potential for transmission control, its effect in preventing ocular onchocercal disease, its acceptability and the organization of large scale treatment. A summary is presented of the major, latest results on the short-term epidemiological impact of large scale ivermectin treatment, as observed in eight community trials undertaken in the Onchocerciasis Control Programme in West Africa (OCP). Ivermectin treatment resulted in a 96%-99% reduction in the mean load of microfilariae (mf) in the skin in treated patients. The subsequent mf-repopulation of the skin was faster than in the clinical trials and after 12 months the mean loads had returned to more than 40% of the pre-treatment load. Ocular mf loads were also greatly reduced and a post-treatment regression of early lesions of the anterior segment of the eye was observed. The transmission of Onchocerca volvulus was reduced by some 60% during the first year after treatment in one trial but no additional reduction was observed after the second treatment round. These results, and other recent research findings, have been used to quantify an epidemiological model for the transmission and control of onchocerciasis. Preliminary results of computer simulations of the predicted long-term epidemiological impact of large scale ivermectin treatment indicate that ivermectin treatment may play a very important role in disease control but that it is unlikely to become a practical tool for transmission control in endemic foci. Ivermectin treatment appears to be the most appropriate method for control of recrudescence of infection in an area where the parasite reservoir has been virtually eliminated by vector control, such as in the core area of the OCP.
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Science,
1994]
In 1967, Sydney Brenner isolated the first behavioral mutants of the nematode Caenorhabditis elegans, and in 1970, John White began the systematic reconstruction of its nervous system. This dual approach of genetics coupled with detailed morphological analysis, now enhanced by the tools of molecular biology and electrophysiology, still dominates the study of the function and development of the C. elegans nervous system. Although Brenner's vision of a comprehensive understanding of this simple animal has taken time to mature, findings of the past few years indicate that the tree is bearing fruit.
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Results Probl Cell Differ,
2000]
Aging can be defined in three ways: (1) as a progressive increase in the probability of dying of nonaccidental causes, (2) as a progressive increase in the probability of being afflicted with a number of specific diseases, such as cancer, cardiovascular diseases, and neurodegenerative diseases, and (3) as a progressive increase in the prevalence of features that are not in themselves pathological, but which are linked to chronological age, like wrinkled skin or white hair. In recent years, several investigators have used definition (1) and the measure of life span in the nematode Caenorhabditis elegans to study genetic, cellular, and molecular mechanisms that might be responsible for the aging process in all organisms.
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Cell,
1996]
Across the animal kingdom, fertilization requires the encounter between a large stationary egg and small motile sperm. To maximize their likelihood of reaching the egg before their competition, sperm are extraordinarily specialized cells, generally consisting of little more than a haploid nucleus, mitochondria to generate energy, and a highly efficient movement engine. Almost all animal sperm are flagellated and seek the egg by swimming quickly through a liquid environment. Nematodes, however, produce sperm that move by crawling along solid substrates. These roundworm sperm extend pseudopods that look and behave like the actin-rich pseudopods of a wide variety of cells ranging from free-living soil amoebae to human white blood cells. The crawling sperm appear by most criteria to be exploiting classic actin-based cell motility, with one important difference: the sperm contain practically no actin (Nelson et al., 1982).
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Philos Trans R Soc Lond B Biol Sci,
2015]
The article 'Structure of the nervous system of the nematode Caenorhabditis elegans' (aka 'The mind of a worm') by White et al., published for the first time the complete set of synaptic connections in the nervous system of an animal. The work was carried out as part of a programme to begin to understand how genes determine the structure of a nervous system and how a nervous system creates behaviour. It became a major stimulus to the field of C. elegans research, which has since contributed insights into all areas of biology. Twenty-six years elapsed before developments, notably more powerful computers, made new studies of this kind possible. It is hoped that one day knowledge of synaptic structure, the connectome, together with results of many other investigations, will lead to an understanding of the human brain. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.
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Front Cell Dev Biol,
2019]
Autophagy as a ubiquitous catabolic process causes degradation of cytoplasmic components and is generally considered to have beneficial effects on health and lifespan. In contrast, inefficient autophagy has been linked with detrimental effects on the organism and various diseases, such as Parkinson's disease. Previous research, however, showed that this paradigm is far from being black and white. For instance, it has been reported that increased levels of autophagy during development can be harmful, but become advantageous in the aging cell or organism, causing enhanced healthspan and even longevity. The antagonistic pleiotropy hypothesis postulates that genes, which control various traits in an organism, can be fitness-promoting in early life, but subsequently trigger aging processes later. Autophagy is controlled by the mechanistic target of rapamycin (mTOR), a key player of nutrient sensing and signaling and classic example of a pleiotropic gene. mTOR acts upstream of transcription factors such as FOXO, NRF, and TFEB, controlling protein synthesis, degradation, and cellular growth, thereby regulating fertility as well as aging. Here, we review recent findings about the pleiotropic role of autophagy during development and aging, examine the upstream factors, and contemplate specific mechanisms leading to disease, especially neurodegeneration.
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Curr Top Dev Biol,
1999]
Wg/Wnt signaling regulates cell proliferation and differentiation in species as divergent as nematodes, flies, frogs, and humans. Many components of this highly conserved process have been characterized and work from a number of laboratories is beginning to elucidate the mechanism by which this class of secreted growth factor triggers cellular decisions. The Wg/Wnt ligand apparently binds to Frizzled family receptor molecules to initiate a signal transduction cascade involving the novel cytosolic protein Dishevelled and the serine/threonine kinase Zeste-white 3/GSK3. Antagonism of Zw3 activity leads to stabilization of Armadillo/beta-catenin, which provides a transactivation domain when complexed with the HMG box transcription factor dTCF/LEF-1 and thereby activates expression of Wg/Wnt-responsive genes. The Wg/Wnt ligands pass through the secretory pathway and associate with extracellular matrix components; recent work shows that sulfated glycosaminoglycans are essential for proper transduction of the signal. Mutant forms of Wg in Drosophila reveal separable aspects of Wg function and suggest that proper transport of the protein across cells is essential for cell fate specification. Complex interactions with the Notch and EGF/Ras signaling pathways also play a role in cell fate decisions during different phases of Drosophila development. These many facets of Wg/Wnt signaling have been elucidated through studies in a variety of species, each with powerful and unique experimental approaches. The remarkable conservation of this pathway suggests that Wg/Wnt signal transduction represents a fundamental mechanism for the generation of diverse cell fates in animal embryos.
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Methods Cell Biol,
1995]
Although Caenorhabditis elegans was originally chosen as a model organism for cell biology with serial section electron microscopy (EM) methods in mind, these methods have remained a daunting challenge. There is an apocryphal story that Nichol Thomson originally advised Sydney Brenner that C. elegans was unsuitable for electron microscopy and that Brenner should choose another species. Other experienced microscopists have probably shared similar dark thoughts from time to time. Nonetheless, the worm's very small size, simple organization, and cablelike nervous system have permitted Brenner's colleagues to characterize every cell and cell contact in the wild-type animal, potentiating the genetic characterization of cellular development in remarkable detail. We attempt to provide an adequate background for anyone to initiate EM studies of C. elegans. Two decades ago, as the first of Brenner's postdoctoral fellows left his laboratory to establish new worm laboratories, it was standard practice to include an EM component in their studies. Their combined efforts to characterize the adult animal's cell types and the essential steps in its development helped to erect a lovely scaffold of key manuscripts, capped by the description of the "Mind of the Worm" in some 600 micrographs and 175 drawings. Many of these works required technical heroics or suffered long delays before publication. Most people later chose to leave electron microscopy behind in pursuit of molecular quarry. The fruits of their molecular and genetic studies should soon stimulate a renewed flowering of electron microscopy. We hope to smooth your entry or reentry into these techniques. We also summarize our methods for three-dimensional (3D) image reconstruction, based largely on film techniques introduced by John White and Randle Ware. Digital imaging techniques seem poised to make 3D reconstruction more accessible, and may simplify the exchange of morphological data between laboratories. We discuss several computer systems that the C. elegans community could adopt for high-resolution studies of structure and function. In addition, we briefly cover several specialized specimen preparation techniques for electron microscopy, including freeze fracture and electron microscopic immunocytochemistry.