Burchard GD et al. (1979) Tropenmed Parasitol "Electron microscopical studies on onchocerciasis. III. The onchocerca-nodule."

Bierther M, Burchard GD, Buttner DW

[Tropenmed Parasitol, 1979]

Six onchocerca-nodules from five Liberian patients were examined by electron microscopy. The bulk of cells in the centre of the nodules consists of lymphocytes and macrophages. The lymphocytes can be observed in various stages of differentiation. A major part of the macrophages shows degenerative changes with decrease of lysosomes and increase of fatty vacuoles. Near the worms epithelioid cells and giant cells can be found. Other cells in the nodule include polymorphonuclear neutrophils, eosinophils, plasma cells, and mast cells. Adult Onchocerca volvulus show the basic nematode body plan. The cuticle is subdivided into cortex and two layers with differently arranged fibrillar structures. The characteristics of the hypodermal cells are best seen in the lateral chords, in the interchordal regions the hypodermis is flattened by a muscle layer. The intestine typically contains pigment granules, the cells of the epithelium have folds of their cell membranes forming a basal labyrinth. The uterus consists of two tubes in which the development of the microfilariae from the early embryonic forms to the mature stages is examined.

Burchard GD et al. Trans R Soc Trop Med Hyg "Delayed-type hypersensitivity reactions to Onchocerca volvulus antigens in exposed and non-exposed African individuals."

Horstmann RD, Burchard GD, Brattig NW, Kruppa TF

[Trans R Soc Trop Med Hyg]

Although considered of critical importance, the mode of helper T-lymphocyte function in Onchocerca volvulus infection is still unclear including the role of the Th1/Th2 dichotomy. We studied the delayed-type hypersensitivity (DTH) reaction, which is the classical Th1 response, to O. volvulus antigens in Africans exposed and not exposed to the infection. DTH reactions were found in a small percentage of patients with generalized onchocerciasis, but in a high percentage of patients with localized onchocerciasis, in putatively immune subjects, and also in non-exposed individuals, which may be due to cross-reactivity with other nematodes. These findings support the notions of (i) prenatal influence of maternal O. volvulus infection preventing development of Th1 responses and/or (ii) suppression of Th1 responses by the infection itself.

Kruppa TF et al. Trans R Soc Trop Med Hyg "Similar blackfly attraction by onchocerciasis patients and individuals putatively immune to Onchocerca volvulus."

Kruppa TF, Burchard GD

[Trans R Soc Trop Med Hyg]

In areas endemic for onchocerciasis, a small number of individuals show no detectable infection with Onchocerca volvulus despite an apparently similar exposure to the transmitting blackflies. Such individuals have been termed putatively immune. Since several studies have indicated marked host differences in attractiveness for blood-seeking insects, putative immunity in O. volvulus infection may result, at least in part, from low vector attractiveness of the respective individuals. In an area hyperendemic for onchocerciasis (Guinea), where Simulium yahense is the predominant vector, we organized fly catches by putatively immune individuals and individuals with moderate-to-high worm counts. No differences were found between the 2 groups with respect to (i) the attraction of blackflies, (ii) the attraction of blackflies infected with O. volvulus, or (iii) the numbers of O. volvulus larvae carried by the attracted blackflies.

Zhang W et al. (2011) Nanoscale "Biosafety assessment of Gd@C82(OH)22 nanoparticles on Caenorhabditis elegans."

Zhang L, Zhao B, Zhang W, Nie G, Sun B, Zhao Y

[Nanoscale, 2011]

Gd@C(82)(OH)(22), a water-soluble endohedral metallofullerene derivative, has been proven to possess significant antineoplastic activity in mice. Toxicity studies of the nanoparticle have shown some evidence of low or non toxicity in mice and cell models. Here we employed Caenorhabditis elegans (C. elegans) as a model organism to further evaluate the short- and long-term toxicity of Gd@C(82)(OH)(22) and possible behavior changes under normal and stress culture conditions. With treatment of Gd@C(82)(OH)(22) at 0.01, 0.1, 1.0 and 10 g ml(-1) within one generation (short-term), C. elegans showed no significant decrease in longevity or thermotolerance compared to the controls. Furthermore, when Gd@C(82)(OH)(22) treatment was extended up to six generations (long-term), non-toxic effects to the nematodes were found. In addition, data from body length measurement, feeding rate and egg-laying assays with short-term treatment demonstrated that the nanoparticles have no significant impact on the individual growth, feeding behavior and reproductive ability, respectively. In summary, this work has shown that Gd@C(82)(OH)(22) is tolerated well by worms and it has no apparent toxic effects on longevity, stress resistance, growth and behaviors that were observed in both adult and young worms. Our work lays the foundations for further developments of this anti-neoplastic agent for clinical applications.

Van Brempt N et al. (2023) Biochim Biophys Acta Proteins Proteom "The effect of pH and nitrite on the haem pocket of GLB-33, a globin-coupled neuronal transmembrane receptor of Caenorhabditis elegans."

Johannessen C, Sgammato R, Herrebout W, Van Doorslaer S, Dewilde S, Van Brempt N, Hammerschmid D, Beirinckx Q, Sobott F, Moens L

[Biochim Biophys Acta Proteins Proteom, 2023]

Out of the 34 globins in Caenorhabditis elegans, GLB-33 is a putative globin-coupled transmembrane receptor with a yet unknown function. The globin domain (GD) contains a particularly hydrophobic haem pocket, that rapidly oxidizes to a low-spin hydroxide ligated haem state at physiological pH. Moreover, the GD has one of the fastest nitrite reductase activity ever reported for globins. Here, we use a combination of electronic circular dichroism, resonance Raman and electron paramagnetic resonance (EPR) spectroscopy with mass spectrometry to study the pH dependence of the ferric form of the recombinantly over-expressed GD in the presence and absence of nitrite. The competitive binding of nitrite and hydroxide is examined as well as nitrite-induced haem modifications at acidic pH. Comparison of the spectroscopic results with data from other haem proteins allows to deduce the important effect of Arg at position E10 in stabilization of exogenous ligands. Furthermore, continuous-wave and pulsed EPR indicate that ligation of nitrite occurs in a nitrito mode at pH 5.0 and above. At pH 4.0, an additional formation of a nitro-bound haem form is observed along with fast formation of a nitri-globin.

Tilleman L et al. (2015) J Biol Chem "A globin domain in a neuronal transmembrane receptor of Caenorhabditis elegans and Ascaris suum: molecular modeling and functional properties."

Dewilde S, Hoogewijs D, Germani F, De Henau S, Berghmans H, Helbo S, Desmet F, Fago A, Moens L, Schoofs L, Van Doorslaer S, Tilleman L, Braeckman BP

[J Biol Chem, 2015]

We report the structural and biochemical characterization of GLB-33, a putative neuropeptide receptor that is exclusively expressed in the nervous system of the nematode Caenorhabditis elegans. This unique chimeric protein is composed of a 7-transmembrane domain (7TM), GLB-33 7TM, typical of a G-protein-coupled receptor, and of a globin domain (GD), GLB-33 GD. Comprehensive sequence similarity searches in the genome of the parasitic nematode, Ascaris suum, revealed a chimeric protein that is similar to a Phe-Met-Arg-Phe-amide neuropeptide receptor. The three-dimensional structures of the separate domains of both species and of the full-length proteins were modeled. The 7TM domains of both proteins appeared very similar, but the globin domain of the A. suum receptor surprisingly seemed to lack several helices, suggesting a novel truncated globin fold. The globin domain of C. elegans GLB-33, however, was very similar to a genuine myoglobin-type molecule. Spectroscopic analysis of the recombinant GLB-33 GD showed that the heme is pentacoordinate when ferrous and in the hydroxide-ligated form when ferric, even at neutral pH. Flash-photolysis experiments showed overall fast biphasic CO rebinding kinetics. In its ferrous deoxy form, GLB-33 GD is capable of reversibly binding O2 with a very high affinity and of reducing nitrite to nitric oxide faster than other globins. Collectively, these properties suggest that the globin domain of GLB-33 may serve as a highly sensitive oxygen sensor and/or as a nitrite reductase. Both properties are potentially able to modulate the neuropeptide sensitivity of the neuronal transmembrane receptor.

Mazzulli JR et al. (2011) Cell "Gaucher disease glucocerebrosidase and -synuclein form a bidirectional pathogenic loop in synucleinopathies."

Caldwell GA, McLean PJ, Xu YH, Sidransky E, Grabowski GA, Mazzulli JR, Krainc D, Knight AL, Sun Y

[Cell, 2011]

Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of -synuclein (-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified -syn by stabilizing soluble oligomeric intermediates. We further demonstrate that -syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of -syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.

Tischendorf FW et al. (1999) Acta Trop "Eosinophils, eosinophil cationic protein and eosinophil-derived neurotoxin in serum and urine of patients with onchocerciasis coinfected with intestinal nematodes and in urinary schistosomiasis."

Kubica T, Kreuzpaintner G, Burchard GD, Tischendorf FW, Lintzel M, Brattig NW

[Acta Trop, 1999]

Eosinophils, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN/EPX), myeloperoxidase (MPO) and IgE were measured in blood, serum and/or urine in Schistosoma haematobium- and Onchocerca volvulus-infected Guineans and O. volvulus- and S. haematobium-negative Guineans coinfected or infected with intestinal nematodes. The number of eosinophils and levels of eosinophil granule proteins but not of MPO were found to be strongly elevated in all Africans as compared to European controls. The highest serum ECP and serum and urinary EDN/EPX levels were observed in the hyperreactive form of onchocerciasis (sowda). Onchocerciasis patients and O. volvulus-negative Africans coinfected or infected with intestinal nematodes (hookworm and/or Ascaris lumbricoides) revealed higher serum granule protein concentrations and/or absolute eosinophil counts and urinary ECP than those without nematode infections. Statistical differences between both sections were found for the absolute eosinophil counts and for serum EDN/EPX and IgE in generalized onchocerciasis, and for urinary ECP in sowda, indicating stimulation of the eosinophil potential of O. volvulus-positive patients by coexistent hookworm infection. This worm species, in contrast to A. lumbricoides, causes especially high eosinophil counts and EDN/EPX and IgE levels. From these results it is concluded that in nematode diseases, ECP and EDN/EPX levels reflect the degree of antigenic stimulation, eosinophil activation and eosinophil turnover rates. Serum ECP and serum and urinary EDN/EPX may, therefore, serve as parameters to monitor helminth infection. Urinary ECP may be a marker of eosinophiluria secondary to urogenital manifestation of S. haematobium. It is elevated in hyperreactive onchocerciasis activated by intestinal nematodes.

Peng H et al. (2010) Bioinformatics "Automatic reconstruction of 3D neuron structures using a graph-augmented deformable model."

Atasoy D, Peng H, Sternson S, Ruan Z

[Bioinformatics, 2010]

MOTIVATION: Digital reconstruction of 3D neuron structures is an important step toward reverse engineering the wiring and functions of a brain. However, despite a number of existing studies, this task is still challenging, especially when a 3D microscopic image has low single-to-noise ratio and discontinued segments of neurite patterns. RESULTS: We developed a graph-augmented deformable model (GD) to reconstruct (trace) the 3D structure of a neuron when it has a broken structure and/or fuzzy boundary. We formulated a variational problem using the geodesic shortest path, which is defined as a combination of Euclidean distance, exponent of inverse intensity of pixels along the path and closeness to local centers of image intensity distribution. We solved it in two steps. We first used a shortest path graph algorithm to guarantee that we find the global optimal solution of this step. Then we optimized a discrete deformable curve model to achieve visually more satisfactory reconstructions. Within our framework, it is also easy to define an optional prior curve that reflects the domain knowledge of a user. We investigated the performance of our method using a number of challenging 3D neuronal image datasets of different model organisms including fruit fly, Caenorhabditis elegans, and mouse. In our experiments, the GD method outperformed several comparison methods in reconstruction accuracy, consistency, robustness and speed. We further used GD in two real applications, namely cataloging neurite morphology of fruit fly to build a 3D 'standard' digital neurite atlas, and estimating the synaptic bouton density along the axons for a mouse brain. AVAILABILITY: The software is provided as part of the V3D-Neuron 1.0 package freely available at http://penglab.janelia.org/proj/v3d.

chen, Y. et al. (2013) International Worm Meeting "The Effect of Hydrolysable Tannins from Eucalyptus Leaves on C. elegans Lifespan."

Driscoll, M., Onken, B., Chen, Y., Xiao, S., Cao, Y., Huang, Q., Chen, H.

[International Worm Meeting, 2013]

To identify potential pharmacological compounds that delay the progression of age-related degenerative changes and illness, we monitored the effects of six hydrolysable tannins with high antioxidant activities isolated from Eucalyptus leaves (Oenothein B (OEB), 1,2,3,4,6-penta-O-galloyl-b-D-glucose (PGG), Tellimagrandin I (T1), Tellimagrandin II(T2), Pedunculagin (Ped) and Gemin D (GD) ) on C. elegans lifespan at four different concentrations. We found that of the six, OEB and PGG extended lifespan in a dose-dependent manner and increased median lifespan by up to 22%. OEB significantly prolonged youthful locomotory ability. We also found that the survival curves of T1-treated animals at all tested concentrations were significantly increased, although median lifespan was not significantly improved. OEB, PGG and T1 did not significantly affect the age-associated physiological functions of reproduction, pharyngeal pumping rate, or age pigment accumulation. Animals treated with 40 mM Ped significantly extended median lifespan by 11%, but we did not observe any significant benefits at other Ped concentrations. T2 and GD did not cause significant lifespan extension at any tested concentration. To further determine how OEB and PGG prolong C. elegans lifespan, we investigated the genetic requirements for these benefits. Strikingly, we found that lifespan extension with OEB and PGG treatment was driven by the insulin signaling, dietary restriction, and mitochondrial function pathways, indicating that these compounds target multiple longevity mechanisms to promote lifespan. Together, our results demonstrate broad-based aging benefits with these botanical compounds, which may be exploited in novel therapies to promote healthy aging.