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[
Dermatol Clin,
1989]
It is apparent that there are many similarities among the various filariae. Besides a common life cycle, with an arthropod vector and human hosts, there are similarities in the diseases that they produce. This clinical picture takes one of two main courses: (1) characteristic disease produced by the presence of adult nematodes in their target tissue, which distinguishes typical cases for each of the filariae, and (2) the systemic hypersensitivity reactions to the circulating microfilaria, which tend to be similar. The characteristic feature of Wuchereria bancrofti is genital disease with funiculitis and hydrocele and less often elephantiasis. For Brugia malayi it is elephantiasis of the distal leg or arm, usually leaving the knee or elbow uninvolved with normal contours. Brugia timori, restricted to just a few islands of Indonesia, produces elephantiasis similar to that of Brugia malayi, but with its characteristic descending lymphadenitis. Loa loa is best known for the Calabar swelling, or angioedema, that it produces, although other filariae can induce similar reactions. Both Loa loa and Dirofilaria tenuis cause macroscopic, subconjunctival eyeworms. Clinical disease from onchocerciasis takes four predominant forms: eye disease, lymphadenitis, subcutaneous nodules (onchocercomata), and a pruritic, hypopigmented, or hyperpigmented papular dermatitis.
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[
Br J Dermatol,
2020]
Onchocerciasis is a neglected tropical disease caused by a nematode parasite, Onchocerca volvulus, and transmitted by bites of Simulium blackflies which breed near fast-flowing rivers. In humans thousands of microfilariae (immature worms) migrate to the skin and eyes where they cause pathology. Historically, much research was devoted to the serious effect of blindness, from which the disease earns its alternative name of "river blindness". Mapping the burden of onchocercal skin disease (OSD) was expedited by the development of a clinical classification and grading system which facilitated comparison of data from different countries. After successful field-testing in Nigeria, the classification scheme was used in a multicountry study in seven endemic sites, to estimate the true burden of OSD across Africa. High levels of OSD were found, affecting 28% of the population. A new control programme, the African Programme for Onchocerciasis Control (APOC) was launched in 20 countries using annual doses of ivermectin, donated by Merck & Co., Inc. The multicountry study also found a close correlation between the levels of itching and OSD with the level of endemicity, as determined by the prevalence of onchocercal nodules. This enabled APOC to use Rapid Epidemiological Mapping of Onchocerciasis (REMO) which entailed identifying likely vector breeding sites near rivers, then sampling 50 adult males in nearby villages to determine the prevalence of nodules and delineate which villages required treatment. Onchocerciasis is now targeted for elimination in Africa, and the challenge is to complete Onchocerciasis Elimination Mapping (OEM) of hypoendemic areas using serology.
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[
Br J Pharmacol,
2008]
RIC-3 is a transmembrane protein which acts as a molecular chaperone of nicotinic acetylcholine receptors (nAChRs). For some nAChR subtypes (such as homomeric alpha7 neuronal nAChRs), RIC-3 is required for efficient receptor folding, assembly and functional expression. In contrast, for other nAChR subtypes (such as heteromeric alpha4beta2 neuronal nAChRs) there have been reports that RIC-3 can both enhance and reduce levels of functional expression. There is also evidence that RIC-3 can modulate maturation of the closely related 5-hydroxytryptamine (5-HT) receptor (5-HT(3)R). As with heteromeric nAChRs, apparently contradictory results have been reported for the influence of RIC-3 on 5-HT(3)R maturation in different expression systems. Recent evidence indicates that these differences in RIC-3 chaperone activity may be influenced by the host cell, suggesting that other proteins may play an important role in modulating the effects of RIC-3 as a chaperone. RIC-3 was originally identified in the nematode Caenorhabditis elegans as the protein encoded by the gene
ric-3 (resistance to inhibitors of cholinesterase) and has subsequently been cloned and characterized from mammalian and insect species. This review provides a brief history of RIC-3; from the identification of the
ric-3 gene in C. elegans in 1995 to the more recent demonstration of its activity as a nAChR chaperone.British Journal of Pharmacology advance online publication, 4 February 2008; doi:10.1038/sj.bjp.0707661.
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[
Br J Dermatol,
2005]
Summary The nematode Caenorhabditis elegans has proven a robust genetic model for studies of aging and the roles of stress. In this review we focus on the genetics of select long-lived and short-lived mutants of C. elegans that have proven useful in revealing the relationships that exist between oxidative stress and life span. The former are known to be controlled by an insulin/insulin-like signaling pathway, while the latter are affected by mitochondrial functions.
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[
Br J Pharmacol,
2010]
Current high-throughput screening methods for drug discovery rely on the existence of targets. Moreover, most of the hits generated during screenings turn out to be invalid after further testing in animal models. To by-pass these limitations, efforts are now being made to screen chemical libraries on whole animals. One of the most commonly used animal model in biology is the murine model Mus musculus. However, its cost limit its use in large-scale therapeutic screening. In contrast, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the fish Danio rerio are gaining momentum as screening tools. These organisms combine genetic amenability, low cost and culture conditions that are compatible with large-scale screens. Their main advantage is to allow high-throughput screening in a whole-animal context. Moreover, their use is not dependent on the prior identification of a target and permits the selection of compounds with an improved safety profile. This review surveys the versatility of these animal models for drug discovery and discuss the options available at this day.
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[
Br J Pharmacol,
2011]
With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes - which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions.
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[
WormBook,
2014]
Mass spectrometry (MS)-based shotgun proteomics is an enabling technology for the study of C. elegans proteins. When coupled with co-immunoprecipitation (CoIP), new interactions and functions among proteins can be discovered. We provide a general background on protein complexes and methods for their analysis, along with the lifecycle and interaction types of proteins that ultimately define the identifiable components of protein complexes. We highlight traditional biochemical methods to evaluate whether the complexes are sufficiently pure and abundant for analysis with shotgun proteomics. We present two CoIP-MS case studies of protein complexes from C. elegans, using both endogenous and fusion protein antibodies to illustrate the important aspects of their analyses. We discuss results from mass spectrometers with differences in mass accuracy and resolution, along with the relevant information that can be extracted from the data generated, such as protein relative abundance, post-translational modifications, and identification confidence. Finally, we illustrate how comparative analysis can reveal candidate binding partners for biological follow-up and validation. This chapter should act as a complement and extension to the WormBook chapter Biochemistry and molecular biology, which describes tandem affinity purification (TAP) of protein complexes for analysis by mass spectrometry.
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[
FEBS J,
2022]
Amyloid formation is a misfolding process that has been linked to age-related diseases, including Alzheimer's and Huntington's. Understanding how cellular factors affect this process in vivo is vital in realizing the dream of controlling this insidious process that robs so many people of their humanity. SERF (Small EDRK Rich Factor) was initially isolated as a factor that accelerated polyglutamine amyloid formation in a C. elegans model. SERF knockouts inhibit amyloid formation of a number of proteins that include huntingtin, α-synuclein, and β-amyloid which are associated with Huntington's, Parkinson's and Alzheimer's disease, respectively, and purified SERF protein speeds their amyloid formation in vitro. SERF proteins are highly conserved, highly charged and conformationally dynamic proteins that form a fuzzy complex with amyloid precursors. They appear to act by specifically accelerating the primary step of amyloid nucleation. Brain-specific SERF knockout mice, though viable, appear to be more prone to deposition of amyloids, and show modified fibril morphology. Whole-body knockouts are perinatally lethal due to an apparently unrelated developmental issue. Recently, it was found that SERF binds RNA and is localized to nucleic acid rich membraneless compartments. SERF-related sequences are commonly found fused to zinc finger sequences. These results point toward a nucleic acid-binding function. How this function relates to their ability to accelerate amyloid formation is currently obscure. In this review, we discuss the possible biological functions of SERF family proteins in the context of their structural fuzziness, modulation of amyloid pathway, nucleic acid binding and their fusion to folded proteins.
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Sternberg PW, Jex AR, Hofmann A, Deplazes P, Boag PR, Gasser RB, Ansell BR, Schnyder M, Young ND, Mangiola S, Korhonen PK, Hall RS
[
Biotechnol Adv,
2013]
Angiostrongylus vasorum is a metastrongyloid nematode of dogs and other canids of major clinical importance in many countries. In order to gain first insights into the molecular biology of this worm, we conducted the first large-scale exploration of its transcriptome, and predicted essential molecules linked to metabolic and biological processes as well as host immune responses. We also predicted and prioritized drug targets and drug candidates. Following Illumina sequencing (RNA-seq), 52.3 million sequence reads representing adult A. vasorum were assembled and annotated. The assembly yielded 20,033 contigs, which encoded proteins with 11,505 homologues in Caenorhabditis elegans, and additional 2252 homologues in various other parasitic helminths for which curated data sets were publicly available. Functional annotation was achieved for 11,752 (58.6%) proteins predicted for A. vasorum, including peptidases (4.5%) and peptidase inhibitors (1.6%), protein kinases (1.7%), G protein-coupled receptors (GPCRs) (1.5%) and phosphatases (1.2%). Contigs encoding excretory/secretory and immuno-modulatory proteins represented some of the most highly transcribed molecules, and encoded enzymes that digest haemoglobin were conserved between A. vasorum and other blood-feeding nematodes. Using an essentiality-based approach, drug targets, including neurotransmitter receptors, an important chemosensory ion channel and cysteine proteinase-3 were predicted in A. vasorum, as were associated small molecular inhibitors/activators. Future transcriptomic analyses of all developmental stages of A. vasorum should facilitate deep explorations of the molecular biology of this important parasitic nematode and support the sequencing of its genome. These advances will provide a foundation for exploring immuno-molecular aspects of angiostrongylosis and have the potential to underpin the discovery of new methods of intervention.