Morris Hooke A et al. (2000) East Coast Worm Meeting "Caenorhabditis elegans: A Model for Studying the Virulence of Burkholderia cepacia"

Green AD, Morris Hooke A

[East Coast Worm Meeting, 2000]

Burkholderia cepacia and Pseudomonas aeruginosa are opportunistic pathogens that infect the lungs of cystic fibrosis patients. Animal models developed for studying the pathogenesis and virulence factors of these organisms are less than optimal and usually require large numbers of mice compromised in some way. A recently described model for testing the virulence of P. aeruginosa in the nematode Caenorhabditis elegans prompted us to test its suitability for studies with B. cepacia. B. cepacia strain Pc224c, a clinical isolate that produces phospholipase C, was grown in tryptic soy broth to early-, mid-, or late-log growth phase. We spread 1x108 cfu from each phase on nematode growth agar and allowed the plate to dry; 20 nematodes (both L4 stages and adults) were placed on each of three plates; controls were placed on nematode growth agar with Escherichia coli as a food source. Dead and live nematodes were recorded every 6 h for approximately 84 h or until all the nematodes on the experimental plates had died. The time required to kill 50% of the nematodes (LT50) was calculated (Systat 9.0). The LT50 for the nematodes placed on late-log phase B. cepacia was 60 h; the LT50 tended to increase when similar numbers of mid-log and early-log phase organisms were used. Death of the nematodes was usually due to matricide - the worms were unable to lay their eggs, which hatched inside them and literally consumed the parents from within. This model should prove useful for the study of potential virulence factors of B. cepacia.

Zhao C et al. (1993) Worm Breeder's Gazette "Cloning of the lin-32 Gene"

Emmons SW, Zhao C

[Worm Breeder's Gazette, 1993]

Cloning of the lin-32 gene Connie Zhao and Scott W. Emmons, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461

Emmons SW et al. (1994) Worm Breeder's Gazette "Strain Names for non-C. elegans Species."

Emmons SW, Fitch DHA, Leroi AM

[Worm Breeder's Gazette, 1994]

Strain names for non-C. elegans species Scott W. Emmonst, Armand Leroit, and David Fitch, Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, Department of Biology, New York University, RmlOO9 Main Bldg., Washington Square, New York, NY 10003

Zhu Z et al. (2019) Eur J Med Chem "Inhibiting A toxicity in Alzheimer's disease by a pyridine amine derivative."

Zhu Z, Xu C, Yin E, Wang X, Zhang L, Yang T, Liu L, Guo Z, Zhang C

[Eur J Med Chem, 2019]

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid -peptide (A) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced A aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the A-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C.elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of A toxicity. PAT also inhibits the activity of acetylcholinesterase in C.elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both invitro and invivo studies demonstrate that PAT is effective in counteracting A toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.

Tissenbaum HA et al. (1995) International C. elegans Meeting "GENETIC AND MOLECULAR ANALYSIS OF daf-2 AND daf-16."

Gottlieb S, Lee L, Tissenbaum HA, Ruvkun GB, Lam F

[International C. elegans Meeting, 1995]

We have been studying the genetic interactions between the genes daf-2, daf-23 and daf-16 (Gottlieb and Ruvkun 1994). These genes either act in a branch separate from the daf-11/daf-21 and daf-7 group of the genetic epistasis pathway for dauer formation or further downstream in the pathway ( Riddle et al. 1981; Vowels and Thomas 1992; Thomas et al. 1993; Gottlieb and Ruvkun 1994). Molecular analysis of daf-2, daf-16 as well as daf-23 (see abstract by Morris et al. this meeting) will help to elucidate function (e.g. neurons vs. target tissues) as well as shed light on the complex genetic interactions of these genes.

Zhi D et al. (2017) Sci Rep "Dianxianning improved amyloid -induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic C. elegans."

Zhu S, Yang W, Wang N, Zhi D, Fei D, Duan Z, Zhang Z, Dong J, Wang X, Wang M, Li H, Wang D

[Sci Rep, 2017]

Dianxianning (DXN) is a traditional Chinese formula, and has been approved in China for treating epilepsy since 1996. Here anti-Alzheimer's disease activity of DXN has been reported. DXN improved AD-like symptoms of paralysis and 5-HT sensitivity of transgenic A1-42 C. elegans. In worms, DXN significantly increased A monomers and decreased the toxic A oligomers, thus reducing A toxicity. DXN significantly suppressed the expression of hsp-16.2 induced by juglone, and up-regulated sod-3 expression. These results indicated that DXN increased stress resistance and protected C. elegans against oxidative stress. Furthermore, DXN could significantly promote DAF-16 nuclear translocation, but it did not activate SKN-1. The inhibitory effect of DXN on the A toxicity was significantly reverted by daf-16 RNAi, rather than skn-1 RNAi or hsf-1 RNAi. These results indicated that DAF-16 is at least partially required for the anti-AD effect of DXN. In conclusion, DXN improved A-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic worms. Together with our data obtained by Morris water maze test, the results showed that DXN markedly ameliorated cognitive performance impairment induced by scopolamine in mice. All the results support that DXN is a potential drug candidate to treat Alzheimer's diseases.

Dee R Denver et al. (2001) International C. elegans Meeting "Rates and Patterns of Mutation in the Nuclear and Mitochondrial Genomes of Caenorhabditis elegans"

Larissa Vassilieva, Katherine Harris, Dee R Denver, Suzanne Randall Estes, W Kelley Thomas, Krystalynne Morris, Michael Lynch

[International C. elegans Meeting, 2001]

Mutations are the ultimate source of genetic disorders and offer important data for phylogenetic, forensic and population genetic studies. We directly assayed the rates and patterns of mutation in a set of 74 Caenorhabditis elegans mutation accumulation (MA) lines, where mutations accumulate over time in an effectively neutral manner as each MA line is propagated across generations as a single, random hermaphrodite (Vassilieva and Lynch, 1999). We performed a uniquely direct assay for the underlying rates and patterns of mutation in the MA lines with large-scale DNA sequence collection and analysis from both the nuclear and mitochondrial genomes. The mitochondrial DNA assays revealed a mutation rate that is two orders of magnitude higher than previous indirect estimates, a highly biased mutational spectrum, multiple mutations affecting coding function and mutational hotspots at homopolymeric nucleotide runs (Denver et.al ., 2000). Mutational hotspots have also been identified in the nuclear DNA sequence assays. Furthermore, we have analyzed the same mitochondrial and nuclear loci in C. elegans natural isolates to evaluate the relative roles of mutation and natural selection in shaping molecular variation observed in natural populations. References: L.L. Vassilieva and M. Lynch , Genetics 151 , 119 (1999). D.R. Denver, K. Morris, M. Lynch, L.L. Vassilieva and W.K. Thomas, Science 289 , 2342 (2000).

Krystalynne Morris et al. (2001) International C. elegans Meeting "Abundance, Distribution and Mutation Rate of Homopolymeric Nucleotide Runs in the Genome of Caenorhabditis elegans"

Dee R Denver, Suzanne Randall Estes, Michael Lynch, W Kelley Thomas, Avinash Kewalramani, Katherine Harris, Krystalynne Morris

[International C. elegans Meeting, 2001]

Homopolymeric nucleotide runs are a ubiquitous feature of eukaryotic genomes. Although their dominance in nuclear genomes is clear, homopolymer origins and mechanisms of maintenance and mutation are less obvious. To address these questions, we comprehensively examined the abundance and distribution of homopolymer loci ≥8 nucleotides in length in the genome of C. elegans . There are 148,625 homopolymer loci in the C. elegans genome. The four specific homopolymers are evenly distributed with respect to (+/-) strands of each chromosome. Homopolymer loci are under-represented in exons, show significant clustering in the arms of autosomes, and have significantly different densities between chromosomes. Homopolymers are over-represented in C. elegans genome compared to expectations based on individual nucleotide frequencies. A/T homopolymers vastly outnumber C/G homopolymers, and the size distributions of AT and CG homopolymers differ significantly, particularly for homopolymer loci less than 20 nucleotides in length. A direct investigation of mutation rates at numerous homopolymer loci in a set of C. elegans mutation accumulation lines (Denver, et al. 2000) revealed a significantly higher rate of mutation at C/G loci than at A/T loci. The abundance and distribution of homopolymer loci taken together with direct measures of their mutation rate suggest that differential stability may play a significant role in the maintenance of homopolymer loci. Literature cited: Denver, D.R., Morris, K., Lynch, M., Vassilieva, L., Thomas, W.K. "High direct estimate of the mutation rate in the mitochondrial genome of Caenorhabditis elegans " Science 289:2342-2344.

Maiti P et al. (2020) Int J Mol Sci "Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer's Disease."

Dunbar GL, Manna J, Larkin JD, Burch ZN, Flaherty DB, Maiti P

[Int J Mol Sci, 2020]

Alzheimer's disease (AD) is characterized by amyloid (A) aggregation, hyperphosphorylated tau, neuroinflammation, and severe memory deficits. Reports that certain boronic compounds can reduce amyloid accumulation and neuroinflammation prompted us to compare trans-2-phenyl-vinyl-boronic-acid-MIDA-ester (TPVA) and trans-beta-styryl-boronic-acid (TBSA) as treatments of deficits in in vitro and in vivo models of AD. We hypothesized that these compounds would reduce neuropathological deficits in cell-culture and animal models of AD. Using a dot-blot assay and cultured N₂a cells, we observed that TBSA inhibited A42 aggregation and increased cell survival more effectively than did TPVA. These TBSA-induced benefits were extended to <i>C. elegans</i> expressing A42 and to the 5xFAD mouse model of AD. Oral administration of 0.5 mg/kg dose of TBSA or an equivalent amount of methylcellulose vehicle to groups of six- and 12-month-old 5xFAD or wild-type mice over a two-month period prevented recognition- and spatial-memory deficits in the novel-object recognition and Morris-water-maze memory tasks, respectively, and reduced the number of pyknotic and degenerated cells, A plaques, and GFAP and Iba-1 immunoreactivity in the hippocampus and cortex of these mice. These findings indicate that TBSA exerts neuroprotective properties by decreasing amyloid plaque burden and neuroinflammation, thereby preventing neuronal death and preserving memory function in the 5xFAD mice.

Raviprakash T Sitaram et al. (2003) International Worm Meeting "A genetic screen for modifiers of body size."

Raviprakash T Sitaram, Simon Tuck

[International Worm Meeting, 2003]

Mutations in genes encoding a signal transduction pathway activated by a ligand in the TGF- family, DBL-1, can profoundly affect body size in C. elegans. Loss-of-function mutations in genes in the pathway cause a Sma phenotype characterized by a marked reduction in body size whereas constitutive activation of the pathway increases body length (Lon). Worms displaying the Sma or Lon phenotypes appear to have the same number of cells as wild type suggesting that the pathway affects body size by affecting cell size rather than cell number. The pathway may excert its effects in part by affecting endoreduplication of hypodermal nuclei, and in part by regulating expression of components of the cuticle. One target of the pathway appears to be lon-3, a cuticle collagen, which is negatively regulated at a post-transcriptional level1, 2. Loss-of-function mutations in lon-3 cause a Lon phenotype similar to that caused by overexpression of DBL-1; elevated levels on the other hand cause a Dpy phenotype. In order to identify new genes involved in body length regulation we are screening for mutations that suppress the Dpy phenotype caused by elevated levels of lon-3. To date we have isolated 14 extrageneic suppressor mutations of the Dpy phenotype conferred by svIs32[lon-3(+)]. One is an allele of lon-2 X, a known negative regulator of dbl-1; the remainder define other genes (they are not X-linked). One mutation causes a thin phenotype without affecting body length. Three confer a Lon phenotype in the presence or absence of svIs32. The others, while acting as efficient suppressors, do not appear to cause a marked increase in body length in an otherwise wild-type background. We are presently mapping the mutations further and screening for more suppressors. (1) Nystrom J., Z. Z. Shen, M. Aili, A. J. Flemming, A. Leroi, and S. Tuck. Genetics 161: 83-97 (2002); (2) Suzuki Y., G. A. Morris, M. Han, and W. B. Wood. Genetics 162:1631-1639 (2002).