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[
J Parasitol,
2004]
The nematode parasites Wuchereria bancrofti, Brugia malayi, and B. timori cause a human disease known as lymphatic filariasis, which afflicts approximately 120 million people worldwide. The parasites enter the human host from the mosquito as L3 or infective larvae and subsequently differentiate through 2 molts. In this communication, I report that B. malayi and B. pahangi depend on an exogenous source of at least 1 purine and 1 pyrimidine nucleoside to complete the L3 to L4 molt. The requirement for exogenous nucleosides opens the door for possible chemotherapeutic intervention.
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[
J Parasitol,
1992]
Onchocerca volvulus is an obligate human parasite, and its study has been difficult due to an inability to maintain it outside the human host. We report the successful transplantation of onchocercomata containing living adult O. volvulus worms into immunodeficient C.B.-17.scid/scid (scid) mice or athymic rnu/rnu (nude) rats. Living, motile worms containing viable microfilariae were present in onchocercomata recovered from scid mice or nude rats for up to 20 wk, establishing a novel animal model for future investigation of O. volvulus.
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[
J Parasitol,
1995]
Immunocompetent mice are resistant to the growth and development of human lymphatic filarial parasites, including the aperiodic strain of Brugia malayi. We have recently established that mice homozygous for the severe combined immunodeficiency (scid) mutation, and therefore deficient in both T and B lymphocytes, are permissive for infection. This observation suggests that components of the adaptive (antigen-specific) immune system are obligate requirements for murine resistance to B. malayi. In order to determine more precisely the component of the immune system that mediates murine resistance to B. malayi, we have used mouse strains in which individual genes involved in the maturation of specific components of the immune system have been disrupted by homologous recombination. In previous studies, we demonstrated that mice that lack either major histocompatibility (MHC) class I restricted, CD8+ T lymphocytes (beta 2-microglobulin knockout mice; beta 2M-/-) or CD4+ T lymphocytes (CD4 knockout mice; CD4-/-) are as resistant to B. malayi as intact mice. In the current study, we have used mice in which the membrane exon of the immunoglobulin (Ig) mu (heavy chain) constant region gene segment has been disrupted by homologous recombination. These mice cannot develop mature B lymphocytes and lack serum Ig. We demonstrate that such "B-less" mice are completely resistant to B. malayi. These data, taken in combination with the observation that T-cell-deficient athymic mice homozygous for the nu (nude) mutation are fully permissive for infection, suggest that B lymphocytes and their products are neither required nor sufficient to mediate resistance to B. malayi.
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[
J Parasitol,
2003]
The nematode parasites Wuchereria bancrofti, Brugia malayi, and B. timori cause a disease in humans known as lymphatic filariasis, which afflicts approximately 120 million people worldwide. The parasites enter the human host from the mosquito either as L3 or as infective larvae and subsequently differentiate through 2 molts. In this article, we show that B. malayi depends on an exogenous source of vitamin C to complete the L3 to L4 molt, a critical morphogenic step in its life cycle. Brugia malayi apparently belongs to a small group of living organisms that depend on an exogenous source of vitamin C. This group includes only primates (including man) and guinea pigs among mammals.
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[
Am J Trop Med Hyg,
2004]
The nematode parasites Wuchereria bancrofti, Brugia malayi, and B. timori cause a human disease known as lymphatic filariasis, which afflicts approximately 120 million people worldwide. These organisms are known to contain endosymbiotic bacteria (Wolbachia) that are related to rickettsiae. It has been previously reported that tetracycline blocks the L3 to L4 molt of the filarial parasite B. malayi, and suggested that this was related to their known anti-rickettsial activity. However, this interpretation was tempered by several observations. First, Wolbachia DNA could still be detected in nematodes from tetracycline-treated cultures. In addition, chloramphenicol, which has anti-rickettsial and anti-chlamydial activity, failed to inhibit the molt. These observations could not rule out the possibility that the anti-molting activity of tetracycline is due to pharmacologic activities unrelated to its anti-rickettsial functions. This study shows that chemically modified tetracycline, which does not to have anti-microbial activity, also blocks molting.
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[
Biochemistry,
1987]
The major intestinal esterase from the nematode Caenorhabditis elegans has been purified to essential homogeneity. Starting from whole worms, the overall purification is 9000-fold with a 10% recovery of activity. The esterase is a single polypeptide chain of Mr 60,000 and is stoichiometrically inhibited by organophosphates. Substrate preferences and inhibition patterns classify the enzyme as a carboxylesterase (EC 3.1.1.1), but the physiological function is unknown. The sequence of 13 amino acid residues at the esterase N- terminus has been determined. This partial sequence shows a surprisingly high degree of similarity to the N-terminal sequence of two carboxylesterases recently isolated from Drosophila mojavensis [Pen, J., van Beeumen, J., & Beintema, J. J. (1986) Biochem. J. 238, 691-699].
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[
Genome Res,
2005]
The Hedgehog (Hh) signaling pathway promotes pattern formation and cell proliferation in Drosophila and vertebrates. Hh is a ligand that binds and represses the Patched (Ptc) receptor and thereby releases the latent activity of the multipass membrane protein Smoothened (Smo), which is essential for transducing the Hh signal. In Caenorhabditis elegans, the Hh signaling pathway has undergone considerable divergence. Surprisingly, obvious Smo and Hh homologs are absent whereas PTC, PTC-related (PTR), and a large family of nematode Hh-related (Hh-r) proteins are present. We find that the number of PTC-related and Hh-r proteins has expanded in C. elegans, and that this expansion occurred early in Nematoda. Moreover, the function of these proteins appears to be conserved in Caenorhabditis briggsae. Given our present understanding of the Hh signaling pathway, the absence of Hh and Smo raises many questions about the evolution and the function of the PTC, PTR, and Hh-r proteins in C. elegans. To gain insights into their roles, we performed a global survey of the phenotypes produced by RNA-mediated interference (RNAi). Our study reveals that these genes do not require Smo for activity and that they function in multiple aspects of C. elegans development, including molting, cytokinesis, growth, and pattern formation. Moreover, a subset of the PTC, PTR, and Hh-r proteins have the same RNAi phenotypes, indicating that they have the potential to participate in the same processes.
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Berynskyy M, Morimoto RI, Bukau B, Stengel F, Kirstein J, Szlachcic A, Arnsburg K, Stank A, Scior A, Nillegoda NB, Gao X, Guilbride DL, Aebersold R, Wade RC, Mayer MP
[
Nature,
2015]
Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.
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[
Mol Immunol,
1999]
Invertebrate cells lack the
p53 recombination checkpoint but contain mobile DNA sequences that transpose by a mechanism in part shared with excision of the V(D)J recombination signal sequences (RSS). In this work, inversion, deletion, and duplication of sequences associated with an invertebrate C. elegans Tc6 element is described. The structure of this C. elegans sequence and other dispersed Tc6 elements suggests that covalently closed 'hairpin' structures are not unique to excision of the V(D)J RSS by the RAG proteins, but rather can be generated by transposases at transposon termini leading to characteristic inversion and duplication events. Comparative analysis of recombination events at invertebrate sequences resembling the vertebrate V(D)J RSS may be useful in understanding V(D)J recombination-mediated recombination events in malignant vertebrate cells or genetic diseases such as ataxia telangectasia, in which the
p53 recombination checkpoint is defective.
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[
Phytother Res,
2008]
A bioassay-guided fractionation of Juniperus procera berries yielded antiparasitic, nematicidal and antifouling constituents, including a wide range of known abietane, pimarane and labdane diterpenes. Among these, abieta-7,13-diene (1) demonstrated in vitro antimalarial activity against Plasmodium falciparum D6 and W2 strains (IC(50) = 1.9 and 2.0 microg/mL, respectively), while totarol (6), ferruginol (7) and 7beta-hydroxyabieta-8,13-diene-11,12-dione (8) inhibited Leishmania donovani promastigotes with IC(50) values of 3.5-4.6 microg/mL. In addition, totarol demonstrated nematicidal and antifouling activities against Caenorhabditis elegans and Artemia salina at a concentration of 80 microg/mL and 1 microg/mL, respectively. The resinous exudate of J. virginiana afforded known antibacterial E-communic acid (4) and 4-epi-abietic acid (5), while the volatile oil from its trunk wood revealed large quantities of cedrol (9). Using GC/MS, the two known abietanes totarol (6) and ferruginol (7) were identified from the berries of J. procera, J. excelsa and J. phoenicea.