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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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[
J Neurogenet
]
John Sulston changed the way we do science, not once, but three times - initially with the complete cell lineage of the nematode <i>Caenorhabditis elegans</i>, next with completion of the genome sequences of the worm and human genomes and finally with his strong and active advocacy for open data sharing. His contributions were widely recognized and in 2002 he received the Nobel Prize in Physiology and Medicine.
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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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[
Pathogens,
2020]
We investigated urinary N-acetyltyramine-O,-glucuronide (NATOG) levels as a biomarker for active <i>Onchocerca volvulus</i> infection in an onchocerciasis-endemic area in the Democratic Republic of Congo with a high epilepsy prevalence. Urinary NATOG was measured in non-epileptic men with and without <i>O. volvulus</i> infection, and in <i>O. volvulus-</i>infected persons with epilepsy (PWE). Urinary NATOG concentration was positively associated with microfilarial density (<i>p</i> < 0.001). The median urinary NATOG concentration was higher in PWE (3.67 M) compared to men without epilepsy (1.74 M), <i>p</i> = 0.017; and was higher in persons with severe (7.62 M) compared to mild epilepsy (2.16 M); <i>p</i> = 0.008. Non-epileptic participants with and without <i>O. volvulus</i> infection had similar NATOG levels (2.23 M and 0.71 M, <i>p</i> = 0.426). In a receiver operating characteristic curve analysis to investigate the diagnostic value of urinary NATOG, the area under the curve was 0.721 (95% CI: 0.633-0.797). Using the previously proposed cut-off value of 13 M to distinguish between an active <i>O. volvulus</i> infection and an uninfected state, the sensitivity was 15.9% and the specificity 95.9%. In conclusion, an <i>O. volvulus</i> infection is associated with an increased urinary NATOG concentration, which correlates with the individual parasitic load. However, the NATOG concentration has a low discriminating power to differentiate between infected and uninfected individuals.
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Raimon S, Yibi Logora M, Kumar-Singh S, Suliman A, Abd-Elfarag G, Y Carter J, Nelson Siewe Fodjo J, Colebunders R, Hotterbeekx A, Sebit W, De Witte P
[
Int J Infect Dis,
2019]
OBJECTIVES: Epidemiological evidence links onchocerciasis with the development of epilepsy. We aimed to detectOnchocerca volvulus microfilariae or its bacterial endosymbiont, Wolbachia, in the cerebrospinal fluid (CSF) of persons with onchocerciasis-associated epilepsy (OAE). METHODS: Thirteen persons with OAE andO. volvulus skin snip densities of >80 microfilatiae were recruited in Maridi County (South Sudan), and their CSF obtained. Cytospin centrifuged preparations of CSF were examined by light microscopy for presence of O. volvulus microfilariae. DNA was extracted from CSF to detect O. volvulus (O-150 repeat) by quantitative real-time PCR, and Wolbachia (FtsZ gene) by standard PCR. To further investigate if CSF from onchocerciasis-infected participants could induce seizures, 3- and 7-days old zebrafish larvae were injected with the CSF intracardially and intraperitoneally, respectively. For other zebrafish larvae, CSF was added directly to the larval medium. RESULTS: No microfilariae, parasite orWolbachia DNA were detected in any of the CSF samples by light microscopy or PCR, respectively. All zebrafish survived the procedures and none developed seizures. CONCLUSION: The absence of O. volvulus in CSF suggests that OAE is likely not caused by direct parasite invasion into the central nervous system, but by another phenomenon triggered by O. volvulus infection.
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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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[
Indian J Med Res,
1982]
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[
Infection,
1977]
Serum samples from persons who lived in areas where onchocerciasis occurred or who had filariasis were examined with the complement fixation test and the indirect hemagglutination test for the presence of antibodies against crude extracts from Dirofilaria immitis, Onchocerca volvulus, Dipetalonema viteae, and Ascaris suum. The results could be interpreted as follows: 1. The indirect hemagglutination test was more sensitive than the complement fixation test for the demonstration of antibodies in sera from European and indigenous inhabitants of endemic areas. 2. There were no differences between the responses to the four crude worm extracts among the groups of 21 patients with Loa loa, 12 patients with Onchocerca volvulus, 11 patients with Dipetalonema perstans, and 22 patients with clinical filariasis in whom no microfilaria had been found. It was concluded that the examination with crude extracts cannot give any information about the antigens that had caused the stimulation of antibodies.