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Biogerontology,
2002]
This is a personal account of the early days in the genetic analysis of aging when it was difficult to persuade the world that there were genes that specified life prolongation. I describe the situation in 1980 and briefly describe the background of early work on the nematode Caenorhabditis elegans and my role in the revolution in aging research that has occurred in the last 20 years.
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Adv Exp Med Biol,
2010]
Latrophilin, a neuronal "adhesion-G protein-coupled receptor", is the major brain receptor for alpha-latrotoxin, a black widow spidertoxin which stimulates strong neuronal exocytosis in vertebrates. Latrophilin has an unusual structure consisting of two fragments that are produced by the proteolytic cleavage of the parental molecule and that behave independently in the plasma membrane. On binding an agonist, the fragments reassociate and send an intracellular signal. This signal, transduced by a heterotrimeric G protein, causes release of calcium from intracellular stores and massive release of neurotransmitters. Latrophilin represents a phylogenetically conserved family of receptors, with orthologues found in all animals and up to three homologues present in most chordate species. From mammalian homologues, latrophilins 1 and 3 are expressed in neurons, while latrophilin 2 is ubiquitous. Latrophilin 1 may control synapse maturation and exocytosis, whereas latrophilin 2 may be involved in breast cancer. Latrophilins may play different roles during development and in adult animals: thus, LAT-1 determines cell fate in early embryogenesis in Caenorhabditis elegans and controls neurotransmitter release in adult nematodes. This diversity suggests that the functions of latrophilins may be determined by their interactions with respective ligands. The finding of the ligand of latrophilin 1, the large postsynaptic protein lasso, is the first step in the quest for the physiological functions of latrophilins.
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J Mol Biol,
2021]
The COVID-19 pandemic entered its third and most intense to date wave of infections in November 2020. This perspective article describes how combination therapies (polytherapeutics) are a needed focus for helping battle the severity of complications from SARS-CoV-2 infection. It outlines the types of humanized systems that are needed for fast and efficient combinatorial assessment of therapeutic candidates. Proposed are micro-physiological systems using human iPSC as a format for tissue specific infection modeling, the use of gene-humanized zebrafish and C. elegans for combinatorial drug screens due to the animals being addressable in liquid multi-well formats, and the use of engineered pseudo-typing systems to safely model infection in the transgenic animals and engineered tissue systems.
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Mol Aspects Med,
2022]
Precision medicine strives for highly individualized treatments for disease under the notion that each individual's unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In the realm of rare disorders, genetic predisposition is often the predominant mechanism driving disease presentation. For such, mostly, monogenic disorders, a causal gene to phenotype association is likely. As a result, it becomes important to query the patient's genome for the presence of pathogenic variations that are likely to cause the disease. Determining whether a variant is pathogenic or not is critical to these analyses and can be challenging, as many disease-causing variants are novel and, ergo, have no available functional data to help categorize them. This problem is exacerbated by the need for rapid evaluation of pathogenicity, since many genetic diseases present in young children who will experience increased morbidity and mortality without rapid diagnosis and therapeutics. Here, we discuss the utility of animal models, with a focus mainly on C. elegans, as a contrast to tissue culture and in silico approaches, with emphasis on how these systems are used in determining pathogenicity of variants with uncertain significance and then used to screen for novel therapeutics.
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Neuropharmacology,
2004]
Genetic analysis in the nematode C. elegans has provided important insights into many aspects of neuronal cell biology, including functions related to addiction. Specifically, genetic and molecular screens to have been used to identify molecules involved in long-term responses to drugs of abuse and to analyze the mechanisms underlying their effects on nervous system development, plasticity, and behavior. This review presents a personal view of addiction-related research in C. elegans, and includes a discussion of technical innovations that have facilitated neurobiological analyses in C. elegans and a look at future prospects drug addiction research in simple animal models.
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Trends Cogn Sci,
2017]
At the centenary of D'Arcy Thompson's seminal work 'On Growth and Form', pioneering the description of principles of morphological changes during development and evolution, recent experimental advances allow us to study change in anatomical brain networks. Here, we outline potential principles for connectome development. We will describe recent results on how spatial and temporal factors shape connectome development in health and disease. Understanding the developmental origins of brain diseases in individuals will be crucial for deciding on personalized treatment options. We argue that longitudinal studies, experimentally derived parameters for connection formation, and biologically realistic computational models are needed to better understand the link between brain network development, network structure, and network function.
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[
1983]
In 1974, Sydney Brenner published an elegant paper that described the genetic system of Caenorhabditis elegans and led to its use in research on a wide variety of topics, including aging (Brenner, 1974). Its small size (1mm as an adult) and determinate cell lineage has allowed a description of the entire somatic cell lineage from the one-cell stage to the adult (Sulston and Horvitz, 1977; Deppe et al., 1978; Kimble and Hirsh, 1979; Suslton et al., personal communication). Its ease of culture makes it an organism of choice for studies of various aspects of anatomy and physiology, including muscle formation and function (Zengel and Epstein, 1980; Mackenzie and Epstein, 1980), cuticle formation (Cox et al, 1981), neuroanatomy (Ward et al, 1975; Ware et al, 1975; Sulston et al, 1975), and behavior (Dusenbery, 1980). Several genes have been cloned by recombinant DNA techniques ablation (Kimble, 1981; Laufer and von Ehrenstin, 1981) procedures, as well as most of the modern molecular techniques, are in use.
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Lancet,
1998]
An estimated 17.7 million persons, most of them in Africa, are infected with the parasite Onchocerca volvulus. Onchocerciasis has caused blindness in 270,000 and left another 500,000 with severe visual impairment. Onchocerciasis also can cause disfiguring skin changes, musculoskeletal complaints, weight loss, changes in immune function, epilepsy, and growth arrest. The development of ivermectin and its donation by the manufacturer has reduced transmission in many parts of Africa and Latin America. Progress in developing a drug that can destroy adult worms has been slow, however. The immediate need is to extend ivermectin mass distribution to as many endemic areas as possible on a continuing basis, with steps toward community ownership of such programs. This article presents a comprehensive review of the literature on the epidemiology, parasitology, vector, symptoms, diagnosis, and treatment and control of onchocerciasis. Future research aims include fuller understanding of the parasite and its relationship with the host, the nature of the systemic effects of O. volvulus infection, the natural history of skin disease, and a better appreciation of the social and economic consequences of this parasitic disease.
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Acta Trop,
2020]
This review summarises more than a century of research on onchocerciasis, also known as river blindness, and its control. River blindness is an infection caused by the tissue filaria Onchocerca volvulus affecting the skin, subcutaneous tissue and eyes and leading to blindness in a minority of infected persons. The parasite is transmitted by its intermediate hosts Simulium spp. which breed in rivers. Featured are history and milestones in onchocerciasis research and control, state-of-the-art data on the parasite, its endobacteria Wolbachia, on the vectors, previous and current prevalence of the infection, its diagnostics, the interaction between the parasite and its host, immune responses and the pathology of onchocerciasis. Detailed information is documented on the time course of control programmes in the afflicted countries in Africa and the Americas, a long road from previous programmes to current successes in control of the transmission of this infectious disease. By development, adjustment and optimization of the control measures, transmission by the vector has been interrupted in foci of countries in the Americas, in Uganda, in Sudan and elsewhere, followed by onchocerciasis eliminations. The current state and future perspectives for control, elimination and eradication within the next 20-30 years are described and discussed. This review contributes to a deeper comprehension of this disease by a tissue-dwelling filaria and it will be helpful in efforts to control and eliminate other filarial infections.
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East Afr Med J,
1994]
The nematode parasites Wuchereria bancrofti, Brugia malayi and B. timori are the causative agents of human lymphatic filariasis. Of the estimated 90 million infections world-wide, W. bancrofti is responsible for over 80 million cases and is the only known aetiologic agent in the African Region. Numbers of infected persons are on the increase world-wide due to rural-urban migrations which result in mushrooming of shanty towns often encouraging formation of favourable mosquito breeding-sites. Development of insecticide resistance by the vector mosquitoes; the toxicity and high cost of available effective formulations, and the deteriorating global economy aggravate this situation. Human lymphatic filariasis is more of a morbidity than a mortality-causing disease but can be devastating and crippling at both the individual and community levels. Unlike many parasitic infections, lymphatic filariasis can easily be controlled. The success of any control programme depends on sensitive diagnostic techniques and this is the challenge. Identification of all true positive individuals in an endemic community can be problematic since filariasis is spectral and no single diagnostic technique can be expected to be uniformly sensitive in all situations. Availability of new biotechnologies has given impetus to formulations of several diagnostic tools. New diagnostic methods and improvements on the traditional ones is the topic of this review. Recommendations in view of their field applications are also discussed.