Achukwi MD et al. (2007) Parasite Immunol "Successful vaccination against Onchocerca ochengi infestation in cattle using live Onchocerca volvulus infective larvae."

Enyong P, Renz A, Harnett W, Achukwi MD

[Parasite Immunol, 2007]

Epidemiological evidence has led to the hypothesis that the concurrent and predominant transmission of Onchocerca ochengi by Simulium damnosum s.l. in sub-Saharan Africa could lead to the protection of humans against onchocerciasis caused by Onchocerca volvulus (zooprophylaxis). To gain support for this hypothesis, we investigated whether exposure to O. volvulus could protect cattle from O. ochengi. Gudali calves were vaccinated with live O. volvulus-infective larvae and subsequently challenged with O. ochengi-infective larvae whilst raised in a fly-proof house. Post-challenge adult parasite and microfilaria development, IgG1 and lgG2 subclass antibodies response to Ov10/Ov11 recombinant Onchocerca antigens, and peripheral blood lymphocyte proliferative responses to O. ochengi crude antigens were studied over a 1-year period. The vaccinated-challenged animals had 83-87% less adult O. ochengi parasites than non-vaccinated-challenged animals. IgG1 and lgG2 antibodies to Ov10/Ov11 recombinant Onchocerca antigens were invoked by non-vaccinated-challenged animals but not by most (80%) of the vaccinated-challenged animals. These findings support the idea of cross-protection (zooprophylaxis) due to inoculation of humans with O. ochengi-infective larvae under natural transmission conditions in endemic areas.

Achukwi MD et al. (2004) Vet Parasitol "Onchocerca ochengi acquisition in zebu Gudali cattle exposed to natural transmission: parasite population dynamics and IgG antibody subclass responses to Ov10/Ov11 recombinant antigens."

Renz A, Bradley J, Harnett W, Achukwi MD

[Vet Parasitol, 2004]

Ngaoundere Gudali zebu cattle naturally exposed to Simulium damnosum s.l. and Culicoides spp. bites were examined during 4 years for O. ochengi adult worm acquisition, Onchocerca ochengi and Onchocerca gutturosa skin microfilaria dynamics, and IgG1 and IgG2 antibody subclass responses. Eleven animals acquired a total of 465 O. ochengi nodules (average of 17 per female and 72 per male). The O. ochengi nodule load was highly variable in individual animals and exacerbated in mature male cattle. Three patterns of acquisition of O. ochengi (resistant to new infestation, early susceptibility and late susceptibility), not associated with Simulium biting intensity (P > 0.05), were distinguished. The minimum prepatent periods for O. ochengi nodules, O. ochengi microfilariae and O. gutturosa microfilariae were 10, 20 and 21 months, respectively. The O. ochengi microfilaria density significantly (P < 0.001) increased with age, was higher in young mature bulls than female animals (P < 0.001) and finally reached highest levels (P < 0.005) during the dry season. Antibody responses to Ov10/Ov11 recombinant O. volvulus antigens were predominantly of the IgG1 subclass. High levels of this subclass (not IgG2) observed in new born calves declined to almost zero levels at the age of 5-8 months but IgG1 levels significantly increased (P < 0.05) with age subsequently during patency. Put together the acquisition and accumulation of O. ochengi parasites in zebu cattle, apart from being season, sex (gender) and host age associated, may also suggest a density-dependent regulation of parasite establishment in a proportion of the exposed population.

Eve A (2021) Development "An interview with Swathi Arur."

Eve A

[Development, 2021]

Swathi Arur is an Associate Professor for the Department of Genetics at the MD Anderson Cancer Center, USA, where she uses multidisciplinary approaches to understand female germline development and fertility. She has received numerous accolades, including the MD Anderson Distinguished Research Faculty Mentor Award in 2017. In 2020, she was elected to the American Association for the Advancement of Science (AAAS). Swathi joined the team at Development as an Academic Editor in 2020, and we met with her over Zoom to hear more about her life, her career and her love for <i>C. elegans</i>.

Alvarez LD et al. (2012) Proteins "The Caenorhabditis elegans DAF-12 nuclear receptor: structure, dynamics, and interaction with ligands."

Estrin DA, Burton G, Alvarez LD, Manez PA

[Proteins, 2012]

A structure for the ligand binding domain (LBD) of the DAF-12 receptor from Caenorhabditis elegans was obtained from the X-ray crystal structure of the receptor LBD from Strongyloides stercoralis bound to (25R)-(7)-dafachronic acid (DA) (pdb:3GYU). The model was constructed in the presence of the ligand using a combination of Modeller, Autodock, and molecular dynamics (MD) programs, and then its dynamical behavior was studied by MD. A strong ligand binding mode (LBM) was found, with the three arginines in the ligand binding pocket (LBP) contacting the C-26 carboxylate group of the DA. The quality of the ceDAF-12 model was then evaluated by constructing several ligand systems for which the experimental activity is known. Thus, the dynamical behavior of the ceDAF-12 complex with the more active (25S)-(7)-DA showed two distinct binding modes, one of them being energetically more favorable compared with the 25R isomer. Then the effect of the Arg564Cys and Arg598Met mutations on the (25R)-(7)-DA binding was analyzed. The MD simulations showed that in the first case the complex was unstable, consistent with the lack of transactivation activity of (25R)-(7)-DA in this mutant. Instead, in the case of the Arg598Met mutant, known to produce a partial loss of activity, our model predicted smaller effects on the LBM with a more stable MD trajectory. The model also showed that removal of the C-25 methyl does not impede the simultaneous strong interaction of the carboxylate with the three arginines, predicting that 27-nor-DAs are putative ceDAF-12 ligands.

Eisenbarth A et al. (2013) Acta Trop "Molecular evidence of 'Siisa form', a new genotype related to Onchocerca ochengi in cattle from North Cameroon."

Streit A, Hildebrandt J, Ekale D, Renz A, Eisenbarth A, Achukwi MD

[Acta Trop, 2013]

Onchocerca ochengi, a filarial nematode parasite from African Zebu cattle is considered to be the closest relative of Onchocerca volvulus, the causative agent of river blindness. Both Onchocerca species share the vector, black flies of the Simulium damnosum complex. Correct identification of their infective third-stage larvae in man-biting vectors is crucial to distinguish the transmission of human or animal parasites. In order to identify different closely related Onchocerca species we surveyed the sequences from the three mitochondrial loci 12S rRNA, 16S rRNA and coxI in both adult worms isolated from Onchocerca-induced nodules in cattle and infective third stage larvae isolated from vector flies from North Cameroon. Two distinct groups of mitochondrial haplotypes were found in cattle as well as in flies. One of them has been formerly mentioned in the literature as Onchocerca sp. 'Siisa', a filaria isolated from the vector S. damnosum sensu lato in Uganda with hitherto unknown host. Both variants are found sympatric, also in the same nodule of the animal host and in the vector. In the flies we also found the mitochondrial haplotype that had been described for O. volvulus which is about equally different from the two previously mentioned ones as they are from each other. These results suggest a higher genetic diversification of Onchocerca ochengi than previously reported.

Wang Z et al. (2015) J Phys Chem B "Probing structural determinants of ATP-binding cassette exporter conformational transition using coarse-grained molecular dynamics."

Wang Z, Liao J

[J Phys Chem B, 2015]

ATP-binding cassette (ABC) exporters pump various substrates across the cell membrane by alternating between inward-facing (IF) and outward-facing (OF) conformations of the transmembrane domains (TMDs). However, the structural determinants of the conformational transition and their functional roles are not fully understood. In this study, we carried out coarse-grained molecular dynamics (CG-MD) simulations with umbrella sampling for the multidrug transporter P-glycoprotein from Caenorhabditis elegans in the presence of the membrane and explicit water molecules. The potential of mean force (PMF) is obtained to identify a reliable pathway where the predicted OF and IF structures are in good agreement with available experiments. The CG-MD simulations reveal that the different transmembrane (TM) helices play distinct but highly cooperative roles in the large-scale conformational changes. Most notably, the CG-MD trajectories show that the periplasmic gate is closed before the cytoplasmic gate is opened during the OF to IF conformational transition in response to the dissociation of the nucleotide-binding domains (NBDs), capturing the unidirectional feature of substrate translocation through the exporter. The structural and dynamical analyses identify the structural determinants and their functional roles in the structural transition. The present work sheds light on how the mechanical force generated upon the NBD dissociation is transferred to the periplasmic end at a distance over 70 A to close the gate, and subsequently to open the cytoplasmic gate. These results extend our understanding of the ABC transport mechanism.

Ndjonka D et al. (2014) J Helminthol "Anthelmintic activity of phenolic acids from the axlewood tree Anogeissus leiocarpus on the filarial nematode Onchocerca ochengi and drug-resistant strains of the free-living nematode Caenorhabditis elegans."

Ndjonka D, Djafsia B, Achukwi MD, Liebau E, Abladam ED, Ajonina-Ekoti I

[J Helminthol, 2014]

The effect of three phenols (ellagic, gentisic and gallic acids) from the axlewood tree Anogeissus leiocarpus on Onchocerca ochengi and drug-resistant strains of Caenorhabditis elegans, a model organism for research on nematode parasites, is investigated. Worms were incubated in different concentrations of phenols and their survival was monitored after 48h. Among the three acids, ellagic acid strongly affected the survival of O. ochengi microfilariae, O. ochengi adults, a wild-type C. elegans and anthelmintic-resistant strains of C. elegans, namely albendazole (CB3474), levamisole (CB211, ZZ16) and ivermectin (VC722, DA1316), with LC50 values ranging from 0.03mm to 0.96mm. These results indicate that the binding of ellagic acid in the worm differs from that of resistant strains of C. elegans. The efficacy of both gallic and gentisic acids was not significantly changed in resistant strains of C. elegans treated with levamisole (ZZ16, LC50=9.98mm, with gallic acid), albendazole (CB3474, LC50=7.81mm, with gentisic acid) and ivermectin (DA1316, LC50=10.62mm, with gentisic acid). The efficacy of these three pure compounds is in accordance with the use of A. leiocarpus from its locality of origin. The in vivo toxicity data reveal that the thresholds are up to 200 times higher than the determined LC50 values. Thus, ellagic acid could be a potential option for the treatment of nematode infections, even in cases of drug resistance towards established anthelmintic drugs.

Zou C et al. (2024) iScience "β-chitosan attenuates hepatic macrophage-driven inflammation and reverses aging-related cognitive impairment."

Alitongbieke G, Xue Y, Zhang G, Pan Y, Zhang S, Cai R, Li Y, Zou C

[iScience, 2024]

Recently, increasing evidence has shown the association between liver abnormal inflammation and cognition impairment, yet their age-related pathogenesis remains obscure. Here, our study provides a potential&#xa0;mechanistic link between liver macrophage excessive activation and neuroinflammation in aging progression. In aged and LPS-injected C57BL/6J mice, systemic administration of &#x3b2;-chitosan ameliorates hepatic macrophage-driven inflammation and reduces peripheral accumulations of TNF-&#x3b1; and IL-1&#x3b2;. Downregulation of circulatory pro-inflammatory cytokines then decreases vascular VCAM1 expression and neuroinflammation in the hippocampus, leading to cognitive improvement in aged/LPS-stimulated mice. Interestingly, &#x3b2;-chitosan treatment also exhibits the beneficial effects on the behavioral recovery of aged/LPS-stimulated zebrafish and <i>Caenorhabditis elegans</i>. In our cell culture and molecular docking experiments, we found that &#x3b2;-chitosan prefers shielding the MD-2 pocket, thus blocking the activation of TLR4-MD-2 complex to suppress NF-&#x3ba;B signaling pathway activation. Together, our findings highlight the extensive therapeutic potential of &#x3b2;-chitosan in reversing aged-related/LPS-induced cognitive impairment via the liver-brain axis.

Arya H et al. (2014) J Mol Model "Virtual screening of traditional Chinese medicine (TCM) database: identification of fragment-like lead molecules for filariasis target asparaginyl-tRNA synthetase."

Coumar MS, Arya H

[J Mol Model, 2014]

Lymphatic filariasis (LF) is a vector borne infectious disease caused by the nematode Wuchereria bancrofti, Brugia malayi, and Brugia timori. Over 120 million people are affected by LF in the world, of which two-thirds are in Asia. The infection restricts the normal flow of lymph from the infected area resulting in swelling of the extremities and causing permanent disability. As the available drugs for the treatment of LF are becoming ineffective due to the development of resistance, there is an urgent need to find new leads for drug development. In this study, asparaginyl-tRNA synthetase (AsnRS; PDB ID: 2XGT) essential for the protein bio-synthesis in the filarial nematode was used to carry out virtual screening (VS) of plant constituents from traditional Chinese medicine (TCM) database. Docking as well as E-pharmacophore based VS were carried out to identify the hits. The top scoring hits, Agri 1 (1,3,8-trihydroxy-4,5-dimethoxyxanthen-9-one-3-O-beta-D-glucopyranoside) and Agri 2 (5,7-dihydroxy-2-propylchromone 7-O-beta-D-glucopyranoside), constituents of Agrimonia pilosa, were selected for molecular dynamics (MD) simulation study for 10ns. MD simulation showed that both the glycosides Agri 1 and Agri 2 were forming stable interactions with the target protein. Moreover, docking and MD simulation of the lead A (1,3,8-trihydroxy-4,5-dimethoxyxanthen-9-one; Mol. Wt.: 304.25; CLogP: 3.07) and lead B (5,7-dihydroxy-2-propylchromone; Mol. Wt.: 220.22; CLogP: 3.02), the aglycones of Agri 1 and Agri 2, respectively, were carried out with the target AsnRS. The in silico investigations of the aglycones suggest that the lead B could be a suitable fragment-like lead molecule for anti-filarial drug discovery.

Beyer A et al. (2012) Adv Exp Med Biol "A dynamic physical model of cell migration, differentiation and apoptosis in Caenorhabditis elegans."

Fisher J, Piterman N, Hengartner MO, Hajnal A, Beyer A, Eberhard R

[Adv Exp Med Biol, 2012]

The germ line of the nematode C. elegans provides a paradigm to study essential developmental concepts like stem cell differentiation and apoptosis. Here, we have created a computational model encompassing these developmental landmarks and the resulting movement of germ cells along the gonadal tube. We have used a technique based on molecular dynamics (MD) to model the physical movement of cells solely based on the force that arises from dividing cells. This novel way of using MD to drive the model enables calibration of simulation and experimental time. Based on this calibration, the analysis of our model shows that it is in accordance with experimental observations. In addition, the model provides insights into kinetics of molecular pathways within individual cells as well as into physical aspects like the cell density along the germ line and in local neighbourhoods of individual germ cells. In the future, the presented model can be used to test hypotheses about diverse aspects of development like stem cell division or programmed cell death. An iterative process of evolving this model and experimental testing in the model system C. elegans will provide new insights into key developmental aspects.