Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization

The region of human chromosome 22q11 is prone to rearrangements. The resulting chromosomal abnormalities are involved in Velo-cardio-facial and DiGeorge syndromes (VCFS and DGS) (deletions), “cat eye” syndrome (duplications), and certain types of tumors (translocations). As a prelude to the development of mouse models for VCFS/DGS by generating targeted deletions in the mouse genome, we examined the organization of genes from human chromosome 22q11 in the mouse. Using genetic linkage analysis and detailed physical mapping, we show that genes from a relatively small region of human 22q11 are distributed on three mouse chromosomes (MMU6, MMU10, and MMU16). Furthermore, although the region corresponding to about 2.5 megabases of the VCFS/DGS critical region is located on mouse chromosome 16, the relative organization of the region is quite different from that in humans. Our results show that the instability of the 22q11 region is not restricted to humans but may have been present throughout evolution. The results also underscore the importance of detailed comparative mapping of genes in mice and humans as a prerequisite for the development of mouse models of human diseases involving chromosomal rearrangements.

Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis

Peroxynitrite activates the cyclooxygenase activities of constitutive and inducible prostaglandin endoperoxide synthases by serving as a substrate for the enzymes’ peroxidase activities. Activation of purified enzyme is induced by direct addition of peroxynitrite or by in situ generation of peroxynitrite from NO coupling to superoxide anion. Cu,Zn-superoxide dismutase completely inhibits cyclooxygenase activation in systems where peroxynitrite is generated in situ from superoxide. In the murine macrophage cell line RAW264.7, the lipophilic superoxide dismutase-mimetic agents, Cu(II) (3,5-diisopropylsalicylic acid)2, and Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin dose-dependently decrease the synthesis of prostaglandins without affecting the levels of NO synthase or prostaglandin endoperoxide synthase or by inhibiting the release of arachidonic acid. These findings support the hypothesis that peroxynitrite is an important modulator of cyclooxygenase activity in inflammatory cells and establish that superoxide anion serves as a biochemical link between NO and prostaglandin biosynthesis.

The ATM homologue MEC1 is required for phosphorylation of replication protein A in yeast

Replication protein A (RPA) is a highly conserved single-stranded DNA-binding protein, required for cellular DNA replication, repair, and recombination. In human cells, RPA is phosphorylated during the S and G2 phases of the cell cycle and also in response to ionizing or ultraviolet radiation. Saccharomyces cerevisiae exhibits a similar pattern of cell cycle-regulated RPA phosphorylation, and our studies indicate that the radiation-induced reactions occur in yeast as well. We have examined yeast RPA phosphorylation during the normal cell cycle and in response to environmental insult, and have demonstrated that the checkpoint gene MEC1 is required for the reaction under all conditions tested. Through examination of several checkpoint mutants, we have placed RPA phosphorylation in a novel pathway of the DNA damage response. MEC1 is similar in sequence to human ATM, the gene mutated in patients with ataxia-telangiectasia (A-T). A-T cells are deficient in multiple checkpoint pathways and are hypersensitive to killing by ionizing radiation. Because A-T cells exhibit a delay in ionizing radiation-induced RPA phosphorylation, our results indicate a functional similarity between MEC1 and ATM, and suggest that RPA phosphorylation is involved in a conserved eukaryotic DNA damage-response pathway defective in A-T.

Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex.

Calcium-dependent homotypic cell-cell adhesion, mediated by molecules such as E-cadherin, guides the establishment of classical epithelial cell polarity and contributes to the control of migration, growth, and differentiation. These actions involve additional proteins, including alpha- and beta-catenin (or plakoglobin) and p120, as well as linkage to the cortical actin cytoskeleton. The molecular basis for these interactions and their hierarchy of interaction remain controversial. We demonstrate a direct interaction between F-actin and alpha (E)-catenin, an activity not shared by either the cytoplasmic domain of E-cadherin or beta-catenin. Sedimentation assays and direct visualization by transmission electron microscopy reveal that alpha 1(E)-catenin binds and bundles F-actin in vitro with micromolar affinity at a catenin/G-actin monomer ratio of approximately 1:7 (mol/mol). Recombinant human beta-catenin can simultaneously bind to the alpha-catenin/actin complex but does not bind actin directly. Recombinant fragments encompassing the amino-terminal 228 residues of alpha 1(E)-catenin or the carboxyl-terminal 447 residues individually bind actin in cosedimentation assays with reduced affinity compared with the full-length protein, and neither fragment bundles actin. Except for similarities to vinculin, neither region contains sequences homologous to established actin-binding proteins. Collectively these data indicate that alpha 1 (E)-catenin is a novel actin-binding and -bundling protein and support a model in which alpha 1(E)-catenin is responsible for organizing and tethering actin filaments at the zones of E-cadherin-mediated cell-cell contact.

Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.

We report the results of two studies examining the genetic overlap between schizophrenia and velocardiofacial syndrome. In study A, we characterize two interstitial deletions identified on chromosome 22q11 in a sample of schizophrenic patients. The size of the deletions was estimated to be between 1.5 and 2 megabases. In study B, we examine whether variations in deletion size are associated with the schizophrenic phenotype in velocardiofacial syndrome patients. Our results show that a region of the genome that has been previously implicated by genetic linkage analysis can harbor genetic lesions that increase the susceptibility to schizophrenia. Our findings should facilitate identification and cloning of the schizophrenia susceptibility gene(s) in this region and identification of more homogeneous subgroups of patients.

U-M Softball Team, 1987

Front Row: Pam Wright, Mary Ann Daviera, Lynn Vismara, Nan Payne, Martha Rogers, Lisa Juzysta, April Bagley, Beth Mueller, Kim Funk

Back row: head coach Carol Hutchins, Mari Foster, Bridget Venturi, Vicki Morrow, Sarah Dyksterhouse, Michelle Bolster, Julie Clark, Jennifer Allard, Alicia Seegert, Assistant Coach Maria Resendez, Manager Jean Waters

Single vehicle accident study. Volume II: technical report. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Candle in the night.

Mode of access: Internet.

Single vehicle accident study. Volume I: executive summary. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Single vehicle accident study. Volume III: appendices. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

61st service squadron.

Edited by James E. Morrow. cf. p. 117.

With Napoleon in Russia; the memoirs of General de Caulaincourt, duke of Vicenza;

Translation of Memoires du général de Caulaincourt.

Forestry publication.

No. 53. Survey of forest plantations of Ottawa, Sandusky, and Seneca Counties, Ohio.--no. 54. Survey of forest plantations of Erie and Huron Counties.--no. 55. Survey of forest plantations of Mercer, Allen, Auglaize, and Shelby Counties, Ohio.--no. 56. Survey of forest plantations of Lorain and Medina Counties.--no. 57. Survey of forest plantations of Wayne County, Ohio.-- no. 58. Survey of forest plantations of Wyandot, Hardin, Marion, Logan, Union and Champaign Co.--no. 59. Forest resources of Preble County, Ohio. no. 62. Survey of forest plantations of Crawford and Morrow Counties.--no. 63. Survey of forest plantations of Franklin and Delaware Counties.--no. 64. Survey of forest plantations of Butler, Hamilton, Warren and Clermont Counties.--no. 65. Forest resources of Wayne County, Ohio. no. 68. Forest resources of Lorain County, Ohio.--no. 69. Forest resources of Medina County, Ohio.--no. 71. Ohio forest survey. A manual of procedure.--no. 73. Fires today and poverty tomorrow.--no. 74. Laws of Ohio relating to forest fires.--no. 75. Twenty-year plan for establishing a more adequate system of state forests and forest parks in Ohio.--no. 76. Ohio's forest resources. 1944.--no. 80. Growing conifers from seed.

The New England cook book of fine old recipes /

Includes index.