Michalski AI et al. (2001) Biogerontology "Heating stress patterns in Caenorhabditis elegans longevity and survivorship."

Yashin AI, Cypser JR, Michalski AI, Johnson TE

[Biogerontology, 2001]

Survival data from Caenorhabditis elegans strain TJ1060 (spe-9; fer-15) following brief exposure to 35 degrees C have been investigated. Three experiments with 3-day-old worms were conducted with heat duration ranging between 0 and 12 hours. A statistically significant increase in life expectancy was observed in the groups heated for less than 2 hours, as compared to the unheated control groups. In different experiments P-values for the observed life spans under the hypothesis that heating has no influence on longevity were P < 0.004 after 0.5 hour heat, P < 0.012 after 1 hour heat and P < 0.055 after 2 hours of heating. A biphasic survival model with Gamma distributed frailty has been constructed to describe the survival of worms after heating. The increase in the remaining life expectancy is determined by more effective protection by heat-induced substances in the ages yanger than 27 days. The unheated control group demonstrated acquired heterogeneity of frailty with chronological age while the heat-induced substances defend the worms in a universal way and protect against the development of frailty.

Kawanabe M et al. (1988) Parasitol Res "Transmammary transmission of Strongyloides ratti."

Uchikawa R, Kawanabe M, Nojima H

[Parasitol Res, 1988]

The rate of transmammary transmission of Stronglyloides ratti was examined in albino rats in terms of the route of subcutaneous (s.c.) migration from the infection site (the skin) to the cranium. Inoculation sites nearer the cranium resulted in less frequent transmammary infection. The maximum number of adult worms was recovered from the sucklings when the mother was inoculated in her hindquarter and sucklings were allowed to feed for 30-36 h after inoculation (AI). Few worms were recovered from sucklings when they were allowed to nurse during periods of less than 24 h AI or greater than 42 h AI. In lactating mothers, larval infection of the mammary glands was commonly observed, and these larvae showed an increased esophagus length. In nonlactating mothers, most larvae completed their migration to the cranium within 36 h AI.

Wang R et al. (2013) ACS Chem Biol "In vitro and in vivo characterization of a tunable dual-reactivity probe of the Nrf2-ARE pathway."

Luesch H, Peters EC, Choe KP, Lewin AS, Wang R, Mason DE

[ACS Chem Biol, 2013]

The cell utilizes the Keap1/Nrf2-ARE signaling pathway to detoxify harmful chemicals in order to protect itself from oxidative stress and to maintain its reducing environment. When exposed to oxidative stress and xenobiotic inducers, the redox sensitive Keap1 is covalently modified at specific cysteine residues. Consequently, the latent transcription factor Nrf2 is stabilized and translocates into the nucleus, where it transactivates the expression of detoxification genes through binding to the antioxidant response element (ARE). In the pursuit of potent and bioavailable activators of the ARE, we validated hits from a pathway-directed high-throughput screening campaign by testing them in cell culture and a reporter strain of a whole animal model, Caenorhabditis elegans. These studies allowed us to identify AI-3 as an ARE activator that induces cytoprotective genes in human cells and in worms, which also translated into in vivo activity in mice. AI-3 is an electrophilic ARE activator with two thiol sensitive sites toward a nucleophilic aromatic substitution, and SAR studies indicated the tunability of the system. Tandem LC-MS analysis revealed that AI-3 alkylates Keap1 primarily at Cys151, while AI-3 is reactive toward additional cysteine residues at higher doses in vitro and in vivo. The immediate effects of such alkylation included the disruption of Keap1-Cul3 (low [AI-3]) and/or Keap1-Nrf2 (high [AI-3]) interactions that both led to the stabilization of Nrf2. This further translated into the downstream Nrf2-ARE regulated cytoprotective gene activation. Collectively, AI-3 may become a valuable biological tool and may even provide therapeutic benefits in oxidative stress related diseases.

Joseph A. Ross et al. (2010) Evolutionary Biology of Caenorhabditis and Other Nematodes "High-density genotyping in Caenorhabditis briggsae advanced-intercross recombinant inbred lines reveals unexpected inter-strain genomic incompatibilities"

Julia E. Staisch, Daniel C. Koboldt, Joseph A. Ross, Bhagwati P. Gupta, Scott E. Baird, Raymond D. Miller, Helen M. Chamberlin, Eric S. Haag

[Evolutionary Biology of Caenorhabditis and Other Nematodes, 2010]

Caenorhabditis briggsae is a useful species with which to pursue evolutionary and genomic questions by comparison with C. elegans. However, in C. briggsae the genetic maps and genome assembly necessary for robustly conducting experiments, such as mapping mutations, are not of comparable quality to those available for C. elegans. To improve the genetic map and genome assembly of C. briggsae, 180 AF16xHK104 and HK104xAF16 advanced-intercross recombinant inbred lines (AI-RIL) were genotyped at 1,536 single nucleotide polymorphism (SNP) markers using the Illumina GoldenGate platform. Following quality control, the final dataset comprised 167 AI-RIL typed at 1,034 markers. Employing AI-RIL increased the number and decreased the size of haplotype blocks per chromosome, and the dense panel of genetic markers allowed most previously unplaced sequence contigs to be ordered within chromosome assemblies. Additional issues with the present genome assembly, including contig misassignment to chromosomes, have been resolved to produce a new genome assembly (cb4). Our genotyping data also reveal interesting population genetic phenomena. Analysis of parental allele fraction of the AI-RIL reveals strong bias of three autosomes in favor of the HK104 parental allele. The bias of one autosome is independent of cross direction and due to a slow-growth phenotype elicited in a hybrid genome. The bias of the other two autosomes is strongly dependent on cross direction. Comparison of inter-chromosomal linkage disequilibrium (LD) in the AI-RIL also reveals the presence of cross-direction-specific LD. Together, the genome-wide study of marker segregation in C. briggsae AI-RIL reveals evidence of inter-strain genomic incompatibilities that suggest the onset of genomic divergence and potentially incipient speciation. Efforts are currently under way to identify the incompatibility loci involved.

Lee KM et al. (2011) FEMS Microbiol Lett "Inhibitory effects of broccoli extract on Escherichia coli O157:H7 quorum sensing and in vivo virulence."

Lee KM, Park S, Yoon SS, Jung BY, Yoon MY, Lim J, Park Y, Kwon YK, Nam S

[FEMS Microbiol Lett, 2011]

Broccoli extract (BE) has numerous beneficial effects on human health including anticancer activity. Quorum sensing (QS), mediated by self-produced autoinducer (AI) molecules, is a key process for the production of virulence determinants in pathogenic bacteria. BE suppressed AI-2 synthesis and AI-2-mediated bacterial motility in a dose-dependent manner in Escherichia coli O157:H7. In addition, expression of the ler gene that regulates AI-3 QS system was also diminished in response to treatment with BE. Furthermore, in an in vivo efficacy test using Caenorhabditis elegans as a host organism, C. elegans fed on E. coli O157:H7 in the presence of BE survived longer than those fed solely on the pathogenic bacteria. Quantitative real-time PCR analysis indicated that quercetin was the most active among the tested broccoli-derived compounds in downregulating virulence gene expression, while treatment with myricetin significantly suppressed the expression of the eae gene involved in type III secretion system. These data suggest that BE and its flavonoid constituents can inhibit expression of QS-associated genes, thereby downregulating the virulence attributes of E. coli O157:H7 both in vitro and in vivo. This study clearly elucidates BE's QS-inhibitory activity and suggests that BE has the potential to be developed as an anti-infective agent.

Jiang K et al. (2022) Front Microbiol "Effect of Autoinducer-2 Quorum Sensing Inhibitor on Interspecies Quorum Sensing."

Xiao J, Zhao M, Zhang Y, Jiang K, Luo R, Lin F, Wang L, Yue Y, Wu H, Yuan B, Xu Y

[Front Microbiol, 2022]

Bacterial drug resistance caused by overuse and misuse of antibiotics is common, especially in clinical multispecies infections. It is of great significance to discover novel agents to treat clinical bacterial infections. Studies have demonstrated that autoinducer-2 (AI-2), a signal molecule in quorum sensing (QS), plays an important role in communication among multiple bacterial species and bacterial drug-resistance. Previously, 14 AI-2 inhibited compounds were selected through virtual screening by using the AI-2 receptor protein LuxP as a target. Here, we used Vibrio harveyi BB170 as a reporter strain for the preliminary screening of 14 inhibitors and compound Str7410 had higher AI-2 QS inhibition activity (IC50 = 0.3724 +/- 0.1091 &#956;M). Then, co-culture of Pseudomonas aeruginosa PAO1 with Staphylococcus aureus ATCC 25923 was used to evaluate the inhibitory effects of Str7410 on multispecies infection in vitro and in vivo. In vitro, Str7410 significantly inhibited the formation of mixed bacterial biofilms. Meanwhile, the combination of Str7410 with meropenem trihydrate (MEPM) significantly improved the susceptibility of mixed-species-biofilm cells to the antibiotic. In vivo, Str7410 significantly increased the survival rate of wild-type Caenorhabditis elegans N2 co-infected by P. aeruginosa PAO1 and S. aureus ATCC 25923. Real-time quantitative PCR analysis showed that Str7410 reduced virulence factor (pyocyanin and elastase) production and swarming motility of P. aeruginosa PAO1 by downregulating the expression of QS-related genes in strain PAO1 in co-culture with S. aureus ATCC 25923. Compound Str7410 is a candidate agent for treating drug-resistant multispecies infections. The work described here provides a strategy for discovering novel antibacterial drugs.

Lee MB et al. (2023) Geroscience "The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery."

Kaeberlein M, Blue B, Lee MB, Muir M

[Geroscience, 2023]

Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the "million-molecule challenge", an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.

Yashin AI et al. (2002) J Gerontol A Biol Sci Med Sci "Heat shock changes the heterogeneity distribution in populations of Caenorhabditis elegans: does it tell us anything about the biological mechanism of stress response?"

Yashin AI, Michalski AI, Boyko SI, Johnson TE, Cypser JW, Novoseltsev VN

[J Gerontol A Biol Sci Med Sci, 2002]

In this paper we analyze Survival data of populations of sterilized nematodes. Caenorhabditis elegans. exposed to heat shocks of different duration at the beginning of their adult lives. There are clear hormesis effects after short exposure to heat and clear debilitation effects after long exposure. Intermediate durations result in a mixture of these two effects. In this latter case. the survival curves for the control and experimental populations intersect. We show that observed effects may be explained by using a model of discrete heterogeneity. According to this model. each Population of worms in the experiment is a mixture of subcohorts of frail, normal. and robust individuals: exposure to heat changes the initial proportion of worms in the subcohorts (heterogeneity distribution): and these changes depend on the duration Of exposure. In other words, exposure to heat does not influence mortality rates (survival functions) in the subcohorts but does cause individuals to move from one subcohort to another. In a biological interpretation of this finding we hypothesize that. when coping with stress. the organisms of storms use several lines of defense. Switching these lines of ana off in response to stress in individual organisms Generates the spectrum of observed survival effects at the population level. We discuss possible molecular biological mechanisms of stress response and directions for further research.

Yashin AI et al. (2001) Mech Ageing Dev "Ageing and survival after different doses of heat shock: the results of analysis of data from stress experiments with the nematode worm Caenorhabditis elegans."

Boyko SI, Johnson TE, Yashin AI, Novoseltsev VN, Cypser JR, Michalski AI

[Mech Ageing Dev, 2001]

Stress experiments performed on a population of sterilised nematode worms (Caenorhabditis elegans) show a clear hormesis effect after short exposure and clear debilitation effects after long exposure to heat shock. An intermediate duration of exposure results in a mixture of these two effects. In this latter case the survival curves for populations in the stress and control groups intersect. In this paper we develop an adaptation model of stress and apply it to the analysis of survival data from three such stress experiments. We show that the model can be used to explain empirical age-patterns of mortality and survival observed in these experiments. We discuss possible biological mechanisms involved in stress response and directions for further research.

Sternberg, P.W. et al. (2019) International Worm Meeting "WormBase 2019: using Artificial and Real Intelligence."

Consortium, WormBase, Sternberg, P.W.

[International Worm Meeting, 2019]

WormBase (www.wormbase.org) has been serving the scientific community for 19 years as a central repository of genomic and genetic information for C. elegans and other nematodes. We continually enlarge and enrich the included data, develop tools and displays for exploring those data on the website, and improve the back-end database and infrastructure to allow us to capture more data and serve it faster. For example, we are now up-to-date on protein-protein interactions and are developing new displays for these data, and ParaSite now has over 100 nematode genomes! We are fully engaged in the Alliance of Genome Resources (www.alliancegenome.org), which uses the combined expertise of seven information resources to deliver better services to all our communities: advances at WormBase such as our AI-generated descriptions of gene function are now used across the Alliance while advances at the Alliance such as Gene Ontology (GO) ribbons that concisely summarize annotations or enrichment of human disease model annotations are now visible on www.wormbase.org. We are using AI to make the best use of your time: after publication, we have been emailing authors to help us extract information. We are now using AI on a revised Author First Pass form for authors to confirm rather than enter data in their papers, thereby saving keystrokes. Our experiment in making the publication process knowledge-base compatible, www.microPublication.org has taken on a life of its own. Our curators have started to visit various universities and regional meetings to give on-site tutorials and get direct feedback; please contact us if you are interested.