Michael WM (2017) MicroPubl Biol "Asymmetric distribution of cyb-3 in 4-cell stage embryos."

Michael WM

[MicroPubl Biol, 2017]

Early embryos were fixed and stained with Mab F2F4 (green), shown to recognize CYB-3 (Michael, 2016), and DAPI, to illuminate the DNA (blue). Either wild type or par-4 mutant embryos were examined, after 24-hour incubation at 25C (the non-permissive temperature for the it47 allele of par-4). Anterior is to the left in all images. The data presented here reveals previously not shown data that depicts CYB-3 as asymmetrically distributed at the 4-cell stage. These data further support reported findings in Michael, 2016. There is more CYB-3 in the AB cell relative to its sister P1. In 4-cell embryos there is more CYB-3 in the EMS cell relative to its sister, P2. Thus, during P-lineage divisions, CYB-3 is asymmetrically distributed such that the somatic precursor receives more than its germline precursor sister cell. This asymmetry is abolished in par-4 mutant embryos, where all blastomeres contain equivalent amounts of CYB-3.

Vairoletti F et al. (2019) Medchemcomm "Synthesis of bicyclic 1,4-thiazepines as novel anti-Trypanosoma brucei brucei agents."

Fontan P, Melendrez J, Medeiros A, Vairoletti F, Salinas G, Saldana J, Mahler G, Jancik V, Tabarez C, Comini MA, Saiz C, Franco J

[Medchemcomm, 2019]

1,4-Thiazepines derivatives are pharmacologically important heterocycles with different applications in medicinal chemistry. In the present work, we describe the preparation of new bicyclic thiazolidinyl-1,4-thiazepines <b>3</b> by reaction between azadithiane compounds and Michael acceptors. The reaction scope was explored and the yields were optimized. The activity of the new compounds was evaluated against <i>Nippostrongylus brasiliensis</i> and <i>Caenorhabditis elegans</i> as anthelmintic models and <i>Trypanosoma brucei brucei.</i> The most active compound was <b>3l</b>, showing an EC₅₀ = 2.8 +/- 0.7 M against <i>T. b. brucei</i> and a selectivity index &gt;71.

Roussell DL et al. (1994) Parasitol Today "Germ-line determination in Caenorhabditis and Ascaris: will a helicase begin to unravel the mystery?"

Bennett KL, Roussell DL, Gruidl ME

[Parasitol Today, 1994]

How cell lineages are established during development in higher eukaryotes is being addressed by geneticists and by developmental and molecular biologists. In Drosophila melanogaster, a gene corresponding to a germ-line-specific RNA helicase, vasa, has been shown to be a component o f the posteriorly localized germ granules o f the developing embryo. A putative RNA helicase, glh-I r which appears germ-line specific in its expression, has recently been reported from the free-living nematode Caenorhabditis elegans. Parasitologists studying the nematode Ascaris lumbricoides var. suum have found it to be a useful complement to Caenorhabditis. Deborah Roussell, Michael Gruidl and Karen Bennett predict that Ascaris will be valuable in determining the role played by germ-line helicases in development.

Zhang M et al. (2018) FEMS Yeast Res "Floricolin C elicits intracellular ROS accumulation and disrupts mitochondria to exert fungicidal action."

Lou H, Shi H, Zhang M, Zheng S, Li W, Li Y, Chang W

[FEMS Yeast Res, 2018]

Candida albicans, one most prevalent fungal pathogen, causes severe mucosal and invasive infections in predisposed individuals. The rise of fungal infection and drug-resistance demands the development of novel antifungal agents. In this study, we observed that floricolin C (FC), a p-terphenyl pigment from an endolichenic fungus, killed C. albicans cells at planktonic state or within biofilms through reactive oxygen species (ROS) accumulation. Further test revealed that FC could directly damage the mitochondria to cause ROS accumulation. In addition, FC can quench thiol-based agents through a Michael reaction involving the ,-unsaturated carbonyl group, whose effect may chelate intracellular thiol-based molecules or proteins in C. albicans, resulting in imbalance of redox homeostasis. Increased ROS generation led to mitochondria dysfunction, nuclear dispersion, and consequently cell death. We further demonstrated that FC could prevent biofilm formation of other Candida species and eradicate their pre-formed biofilms. In vivo study demonstrated that FC prolonged the survival of C. albicans-infected Caenorhabditis elegans. Taken together, our study provides a basis for the application of FC to combat Candida infections.

Brackman G et al. (2011) PLoS One "Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp."

Nelis HJ, Celen S, Cos P, Coenye T, Hillaert U, Maes L, Van Calenbergh S, Brackman G

[PLoS One, 2011]

BACKGROUND: Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. METHODOLOGY/PRINCIPAL FINDINGS: By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an , unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. CONCLUSIONS/SIGNIFICANCE: Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

Garms R (1987) Trop Med Parasitol "Infection rates and parasitic loads of Onchocerca volvulus, and other filariae, in Simulium sanctipauli s.l. and S. yahense in a rain-forest area of Liberia."

Garms R

[Trop Med Parasitol, 1987]

Simulium sanctipauli s.l. and S. yahense are common and widespread in the rain-forest zone of Liberia, but differ with regard to their biting densities and contribution to the transmission of Onchocerca volvulus. Although, in a study area on the St. Pauli River, S. sanctipauli s.l. (presumably S. soubrense in the sense of Post) was the predominant ma-biting species (74.3% of 30,855 females examined), S. yahense was shown to be the important vector. While 1000 biting females of S. yahense carried 96 3rd stage larvae indistinguishable from O. volvulus, only 14 were found per 1000 females of S. sanctipauli s.l. Of the parous females (3135 S. sanctipauli s.l./1621 S. yahense) 23.8/39.9% harboured 1st and/or 2nd stage filarial larvae and 1.9/9.4% 3rd stage larvae of O. volvulus. Animal filariae of unknown origin, indicative of zoophily, were very common in S. sanctipauli s.l. (13.8%) but practically absent from S. yahense (0.5%). In spite of its poorer vectorial performance S. sanctipauli s.l. cannot be neglected as a vector because it may occur in high biting densities and contribute considerably to the transmission, in particular in the vicinity of the St. Paul River. The interplay of two vector species, which develop in different types of water-courses explains the overall high endemicity of onchocerciasis in the study area.

Schwarzbauer JE et al. (1994) Methods Enzymol "Extracellular calcium-binding protein SPARC/osteonectin in Caenorhabditis elegans."

Ryan CS, Mussetbi F, Schwarzbauer JE

[Methods Enzymol, 1994]

The nematode Caenorhabditis elegans is an excellent genetic system for dissecting protein function. Beginning with the pioneering work of Brenner numerous mutations have been generated and characterized phenotypically. Ease of culture, transparency, and small size, (fewer than 1000 nongonadal nuclei), have allowed the determination of a complete cell lineage map by direct observation of living nematodes. Colocalizatioin of genetic and physical loci is made possible by an extensive C. elegans genome map. The ability to identify genes corresponding to particular mutations has ad significantly with the development of methods for transformation of mutants with wild-type genes. The ability to introduce mutations into specific genes is now becoming possible by Tc1 transposon insertion of excision. A comprehensive volume describing all aspects of nematode biology is an excellent resource for anyone studying C. elegans, from novice to expert. In addition, The Worm Breeder's Gazette, published quarterly by the Caenorhabditis Genetics Center (CGC, University of Minnesota, St. Paul, MN), contains short research articles and technical notes contributed by members of the nematode community and represents a unique mechanism for keeping abreast of the latest techniques and the most recent results from other laboratories. The CGC, supported by the NIH National Center for Research Resources, also maintains a large collection of normal and mutant strains for distribution on request.

Levin ED et al. (2009) Neurotoxicology "Genetic aspects of behavioral neurotoxicology."

Welsh-Bohmer KA, Lnenicka G, Corl AB, Page GP, Hirsch HV, Levin ED, Chen L, Kirshner A, Possidente D, Heberlein U, Possidente B, Aschner M, French R, Ruden D, Eddins D, Berger K, Linney E, Hayden KM, Helmcke K, Bartlett S

[Neurotoxicology, 2009]

Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.

Bhoj PS et al. (2019) Parasitol Res "In vitro apoptotic effect on human lymphatic filarial parasite by piperidine derivatives and thymidine reversal study."

Agrawal NR, Bhoj PS, Togre NS, Chandak HS, Goswami K, Bahekar SP, Rao S, Patil MB, Sharma R

[Parasitol Res, 2019]

A novel library of synthetic piperidine derivatives was used to screen against human lymphatic filarial parasite Brugia malayi. Piperidine has earlier been reported to have effect against parasites including rodent filarial nematodes. Compounds with hydroxyl substitutions (4Q and 4H) showed marked antifilarial effect. Molecular docking of 4H derivative showed more favorable thermodynamic parameters against thymidylate synthase of B. malayi than human counterpart. A wide difference between IC₅₀ and LD₅₀ ensured the therapeutic safety of the candidates against the filarial parasites. Addition of thymidine to the treatment regimen led to a significant reversal of antifilarial effect of 4H that confirmed inhibition of thymidylate synthase as pharmacological rationale. Apoptosis induced in the parasite as a consequence of probable inhibition of thymidylate synthase was studied by acridine orange/ethidium bromide fluorescent staining and poly (ADP-ribose) polymerase activity inhibition. Involvement of mitochondria was confirmed by decreased 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) conversion and increased cytosolic cytochrome c level in 4H treated microfilariae, compared with the untreated microfilariae. Moreover, Michael adduct of chalcone targeting dihydrofolate reductase and piperidine targeting thymidylate synthase demonstrated synergistic effect on the parasite, indicating the importance of inhibition of DNA synthesis by combined effect. In conclusion, piperidine derivatives with hydroxyl substitution have a great therapeutic potential with an apoptotic rationale involving mitochondrial pathway, due to possible inhibition of parasitic thymidylate synthase.

Hanneman AJ et al. (2006) Glycobiology "Isomer and glycomer complexities of core GlcNAcs in Caenorhabditis elegans."

Rosa JC, Ashline D, Hanneman AJ, Reinhold VN

[Glycobiology, 2006]

Analysis of protein glycosylation within the nematode Caenorhabditis elegans has revealed an abundant and unreported set of core chitobiose modifications (CCM) to N-linked glycans. With hydrazine release an array of glycomers and isobars were detected with hexose extensions on the 3- and 3,6-positions of the penultimate and reducing terminus, respectively. A full complement of structures includes a range of glycomers posessing a Galss(1-4)Fuc disaccharide at the 3- and 6-positions of the protein-linked GlcNAc. Importantly, enzymatic (PNGase F/A) release failed to liberate many of these extended structures from reduced and alkylated peptides and, as a consequence, such profiles were markedly deficient in a representation of the worm glycome. Moreover, the 3-linked Galss(1-4)Fuc moiety was notably resistant to a range of commercial galactosidases. For identification the fragments were spectrum-matched with synthetic products and library standards using sequential mass spectrometry (MS(n)). A disaccharide observed at the 3-position of penultimate GlcNAc, indicating a Hex-Fuc branch on some structures, was not further characterized due to low ion abundance in MS(n). Additionally, a Hex-Hex-Fuc trisaccharide on the 6-position of proximal GlcNAc was also distinguished on select glycomers. Similar branch extensions on 6-linked core fucosyl residues have recently been reported among other invertebrates. Natural methylation and numerous isobars complement the glycome, which totals well over 100 individual structures. Complex glycans were detected at lower abundance, indicating glucosaminyltransferase (GnT)-I and GnT-II activity. A range of phosphorylcholine (PC) substituted complex glycans was also confirmed following a signature two-stage loss of PC during MS(n) analysis, although the precursor ion was not observed in the mass profiles. In a similar manner numerous other minor glycans may be present but unobserved in hydrazine release profiles dominated by fucosylated structures. All CCM structures, including multiple isomers, were determined without chromatography by gas-phase disassembly, (MS(n)), in Paul and linear ion trap instruments.