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Genetics,
2019]
The Genetics Society of America's (GSA) Thomas Hunt Morgan Medal honors researchers for lifetime achievement in genetics. The recipient of the 2018 Morgan Medal, Barbara J. Meyer of the Howard Hughes Medical Institute and the University of California, Berkeley, is recognized for her career-long, groundbreaking investigations of how chromosome behaviors are controlled. Meyer's work has revealed mechanisms of sex determination and dosage compensation in <i>Caenorhabditis elegans</i> that continue to serve as the foundation of diverse areas of study on chromosome structure and function today, nearly 40 years after she began her work on the topic.
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Adv Genet,
1990]
As recognized by T. H. Morgan, the problems of genetics and development are interwoven. Morgan noted that understanding how the genotype of an organism specifies its phenotype would require knowing the fundamental mechanisms of gene action, how genes interact to specify the properties of cells, and how cells interact to specify each adult character. We now have a basic understanding of the primary effects of genes (to encode protein or RNA products). However, little is known about how the genes of a zygote specify a complex pattern of cell divisions, the generation of diverse cell types, and the arrangement of those cells into specific morphological structures. A "favorable material" (as Morgan put it) for investigating these problems would be a simple organism in which development could be analyzed at the level of single genes and single cells. The small free-living soil nematode Caenorhabditis elegans is such an organism...
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Mol Genet Genomics,
2002]
Mutations in the Drosophila miniature-dusky ( m-dy) gene complex were first reported by Morgan and Bridges about 90 years ago. m-dy mutants have abnormally small wings, a phenotype attributed to a cell-autonomous reduction in the size of the epidermal cells comprising the differentiated wing. Using a molecular genetic approach, we have characterized the m-dy chromosomal interval and identified a pair of adjacent transcription units corresponding to m and dy. A dy mutant known as dy (And) has a single base substitution within the protein-coding region that is predicted to result in an amber stop codon and premature translational termination. We show that dy mRNA is expressed at two discrete periods during the life cycle - one during embryonic development and early larval instars, the second during adult development, coincident with wing differentiation. In agreement with the phenotypic similarity of m and dy mutants, sequence comparisons reveal a similarity between the predicted MINIATURE and DUSKY proteins, and indicate that the m and dy genes are members of a larger Drosophila gene family. Both m and dy, as well as other members of this superfamily, are predicted to encode transmembrane proteins with similarity to C. elegans cuticle proteins known as cuticulins. We postulate that m, dy and other members of this protein superfamily function as structural components of the Drosophila cuticulin layer. Such a role for m and dy products in wing differentiation is sufficient to explain the morphological phenotypes associated with m-dy mutants.
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Dev Cell,
2016]
Variation in the activity of the spindle assembly checkpoint has been observed in different cell types, yet the reason for this variability remains poorly understood. Reporting in Developmental Cell, Galli and Morgan (2016) show that checkpoint activity increases during development as cell size, and the cytoplasm-to-kinetochore ratio, decreases.
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Biochemistry,
2012]
Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.
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International C. elegans Meeting,
1999]
It is thought that increased ethanol tolerance in humans leads to increased risk of alcoholism. Unfortunately, not much is known about the genetics and physiology of ethanol tolerance, and therefore we have begun a set of preliminary experiments on this topic using Caenorhabditis elegans as a model system. Individuals were tested for initial tolerance over a wide range of ethanol concentrations, yielding a determination of the lethal concentration. Initial tolerance to ethanol after five minutes of exposure was surprisingly high, with a tolerance threshold of approximately 36% with an LD50 of 19.5%. The tolerance considered here is of an extreme type (lethality) compared to an intoxication response such as lack of movement (Morgan and Sedensky 1995) or mating ability (Crowder et al. 1996), but is very straightforward to assay and is compatible with many similar studies in Drosophila. Determination of the lethal concentration of wild type worms allows for a simplified screening method for obtaining genetic mutants with higher ethanol tolerances. We are currently in the process of searching for such mutants. We also hope to study the influence of previous exposure to ethanol by contrasting tolerance of naive individuals to that of individuals exposed as larvae. Crowder, C. M., Shebester, L. D., Schedl, T. 1996. Behavioral effects of volatile anesthetics in Caenorhabditis elegans . Anesthesiology 85:901-912. Morgan, P. G., Sedensky, M. M. 1995. Mutations affecting sensitivity to ethanol in the nematode, Caenorhabditis elegans . Alcoholism: Clinical and Experimental Research 19:1423-1429.
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Mol Neurodegener,
2015]
The original version of this article [1] unfortunately contained a mistake. The author list contained a spelling error for the author Hannah V. McCue. The original article has been corrected for this error. The corrected author list is given below:Xi Chen, Hannah V. McCue, Shi Quan Wong, Sudhanva S. Kashyap, Brian C. Kraemer, Jeff W. Barclay, Robert D. Burgoyne and Alan Morgan
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J Infect Dis,
2015]
BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.
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[
Worm Breeder's Gazette,
1976]
We have studied maternal effects in 23 zyg ts mutants to estimate the times of expression of genes whose products are required in embryogenesis. We have used the following three tests, called arbitrarily A, B, and C. A test: Heterozygous (m/+) L4's are shifted to 25 C and allowed to self-fertilize. If 100% of their eggs yield larvae (25% of which express the mutant phenotype as adults), then the mutant is scored as maternal (M). If 25% of the F1 eggs fail to hatch, then the mutant is scored as non-maternal (N). An M result indicates that expression of the + allele in the parent allows m/m zygotes to hatch and grow to adulthood. A result of N indicates the opposite: that the + allele must be expressed in the zygote for hatching to occur. Out of 23 zyg mutants tested, 3 were scored N and 20 were scored M in the A test. Therefore, for most of the genes defined by these mutants, expression in the parent is sufficient for zygote survival, even if the gene is not expressed in the zygote. B test: Homozygous (m/m) hermaphrodites reared at 25 C are mated with N2 (+/+) males. If eggs fail to hatch at 25 C, but mated hermaphrodites shifted to 16 C produce cross progeny to give proof of mating, then the mutant is scored M. If cross progeny appear in the 25 C mating, then the mutant is scored N. An M result indicates that expression of the + allele in the zygote is not sufficient to allow m/+ progeny of an m/m hermaphrodite to survive. Conversely an N result indicates either that zygotic expression of the + allele is sufficient for survival, or that a sperm function or factor needed for early embryogenesis can be supplied paternally (see C test below). Out of the 23 zyg mutants tested, 11 were scored M and 12 were scored N. The combined results of A and B tests and their simplest interpretation are as follows. Ten mutants are M,M; the genes defined by these mutants must be expressed in the hermaphrodite parent for the zygote to survive. Ten mutants are M,N; these genes can be expressed either in the parent or in the zygote. Two mutants are N,N; these genes must be expressed in the zygote. One mutant is N,M; this gene must be expressed both in the maternal parent and in the zygote. C test: Homozygous (m/m) hermaphrodites reared at 25 C are mated with heterozygous (m/+) males. If rescue by a +/+ male in the B test depends on the + allele, then only half the cross progeny zygotes of a C test mating (m/+ male x m/m hermaphrodite) should survive. However, if rescue depends on a function or cytoplasmic component from the male sperm, then all the cross progeny zygotes in a C test should survive. Of the 10 M,N mutants, 6 have been C tested; one exhibited paternal rescue independent of the + allele. The A and B tests also were carried out on 16 mutants that arrest before the L3 molt (acc mutants). In the A test on 2 of these mutants, all m/m progeny of m/+ parents grew to adulthood at 25 C. Therefore, parental contributions are sufficient to overcome a progeny mutational block as late as the L2 stage. All 16 acc mutants scored N in the B test.
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Worm Breeder's Gazette,
1994]
cej-1 Encodes a Novel Protein with Poly-Threonine Motif M. L. A. Khanl, M. Tabish, T. Fukushigel1 S. Tsukita2, M. Itoh , Sh. Tsukita , and S. S. Siddiqui. (1): Lab. of Molecular Biology, Dept of Ecological Engg. Toyohashi Univ. Technology, Toyohashi 441, and (2). National Institute for Physiological Sciences, Okazaki 444, Japan.