The role of the conserved N -terminal domain of STAT3 in STAT3 dephosphorylation and nuclear export

Rapid redistribution of STAT subcellular localization is an essential feature of cytokine signaling. To elucidate the molecular basis of STAT3 function, which plays a critical role in controlling innate immune responses in vivo, we initiated studies to determine the mechanisms controlling STAT3 nuclear trafficking. We found that STAT3 is transported to the nucleus in the absence of cytokine treatment, as judged by indirect immunofluorescence studies in the presence of leptomycin B, an inhibitor of CRM1-dependent nuclear export, suggesting that the non-phosphorylated STAT3 protein contains a functional nuclear import signal. An isoform lacking the STAT3 N-terminal domain (Δ133STAT3) retains the ability to undergo constitutive nuclear localization, indicating that this region is not essential for cytokine-independent nuclear import. Δ133STAT3 is also transported to the nucleus following stimulation with interleukin-6 (IL-6). Interestingly, IL-6-dependent tyrosine phosphorylation of Δ133STAT3 appears to be prolonged and the nuclear export of the protein delayed in cells expressing endogenous STAT3, consistent with defective Δ133STAT3 dephosphorylation. Endogenous STAT3 does not promote the nuclear export of Δ133STAT3, although dimerization between endogenous Stat3 and Δ133STAT3 is detected readily. Thus, the STAT3 N-terminal domain is not required for dimerization with full-length STAT3, yet appears to play a role in proper export of Stat3 from the nucleus following cytokine stimulation. STAT3-deficient cells reconstituted with Δ133STAT3 show enhanced and prolonged Stat1 signaling in response to IL-6, suggesting that induction of the STAT3-dependent negative regulator SOCS3 is impaired. In fact, Δ133STAT3 fails to induce SOCS3 mRNA efficiently. These studies collectively indicate that the STAT3 N-terminal region may be important for IL-6-dependent target gene activation and nuclear dephosphorylation, while dispensable for nuclear import. STAT3 is an oncogene. STAT3 is constitutively activated in primary tumors of many types. Thus far, research in the design of STAT3 protein inhibitors has focused on the SH2 and DNA-binding domains of STAT3. Interference with these domains eliminates all signaling through STAT3. If the N-terminal domain is involved in tetramerization on a subset of target genes, inhibition of this region may lead to a more selective inhibition of some STAT3 functions while leaving others intact. ^

(Table T1) Geochemical composition of tochilinite and related minerals of ODP Hole 173-1068A

Tochilinite (approximately FeS(Mg,Fe)(OH)2) is locally abundant in Hole 1068A serpentinites from Cores 173-1068A-21R and 22R. It occurs in veins, as fillings in void space, and in intergrowths with serpentine and andradite. An apparently related mineral, but with Ca and Al largely replacing Mg, occurs in association with, and possibly as a replacement of, pyrrhotite in serpentinite breccias from the bottom of Core 173-1068A-20R. The transition from Mg-Fe-rich brucite tochilinites to Ca- and S-rich carbonate tochilinites is consistent with increasing sulfur and oxygen activity upsection. Tochilinite has been reported at other sites on the Iberia Abyssal Plain and is abundant to the point of being a rock-forming mineral in several samples from Site 1068. Rather than being a mineralogical curiosity, tochilinite appears to be common and a major sink for sulfur in the upper serpentinites of the Iberia Abyssal Plain.

Tsetse thrombin inhibitor: Bloodmeal-induced expression of an anticoagulant in salivary glands and gut tissue of Glossina morsitans morsitans

The tsetse thrombin inhibitor, a potent and specific low molecular mass (3,530 Da) anticoagulant peptide, was purified previously from salivary gland extracts of Glossina morsitans morsitans (Diptera: Glossinidae). A 303-bp coding sequence corresponding to the inhibitor has now been isolated from a tsetse salivary gland cDNA library by using degenerate oligonucleotide probes. The full-length cDNA contains a 26-bp untranslated segment at its 5′ end, followed by a 63-bp sequence corresponding to a putative secretory signal peptide. A 96-bp segment codes for the mature tsetse thrombin inhibitor, whose predicted molecular weight matches that of the purified native protein. Based on its lack of homology to any previously described family of molecules, the tsetse thrombin inhibitor appears to represent a unique class of naturally occurring protease inhibitors. Recombinant tsetse thrombin inhibitor expressed in Escherichia coli and the chemically synthesized peptide are both substantially less active than the purified native protein, suggesting that posttranslational modification(s) may be necessary for optimal inhibitory activity. The tsetse thrombin inhibitor gene, which is present as a single copy in the tsetse genome, is expressed at high levels in salivary glands and midguts of adult tsetse flies, suggesting a possible role for the anticoagulant in both feeding and processing of the bloodmeal.

Retinoic acid alters the intracellular trafficking of the mannose-6-phosphate/insulin-like growth factor II receptor and lysosomal enzymes

Previously, we showed that retinoic acid (RA) binds to the mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) with high affinity, suggesting that M6P/IGF2R may be a receptor for RA. Here, we show that RA, after 2–3 h of incubation with cultured neonatal-rat cardiac fibroblasts, dramatically alters the intracellular distribution of M6P/IGF2R as well as that of cathepsin B (a lysosomal protease bearing M6P). Immunofluorescence techniques indicate that this change in intracellular distribution is characterized by a shift of the proteins from the perinuclear area to cytoplasmic vesicles. The effect of RA was neither blocked by an RA nuclear receptor antagonist (AGN193109) nor mimicked by a selective RA nuclear-receptor agonist (TTNPB). Furthermore, the RA-induced translocation of cathepsin B was not observed in M6P/IGF2R-deficient P388D1 cells but occurred in stably transfected P388D1 cells expressing the receptor, suggesting that the effect of RA might be the result of direct interaction with M6P/IGF2R, rather than the result of binding to the nuclear receptors. These observations not only support the idea that M6P/IGF2R mediates an RA-response pathway but also indicate a role for RA in control of intracellular trafficking of lysosomal enzymes. Therefore, our observations may have important implications for the understanding of the diverse biological effects of retinoids.

V(D)J recombination is not activated by demethylation of the kappa locus

V(D)J recombination is thought to be regulated by changes in the accessibility of target sites, such as modulation of methylation. To test whether demethylation of the kappa locus can activate recombination, we generated two recombinationally active B cell lines in which the gene for maintenance of genomic DNA methylation, Dnmt1, was flanked with loxP sites. Transduction with a retrovirus expressing both the cre recombinase and green fluorescent protein allowed us to purify recombinationally active cells devoid of methylation. Loss of methylation of the kappa locus was not sufficient to activate recombination, although transcription was activated in one line. It appears that demethylation of the kappa locus is not the rate-limiting step for altering accessibility and thus regulated demethylation does not generate specificity of recombination.

Gestational drive and the green-bearded placenta.

A "green beard" refers to a gene, or group of genes, that is able to recognize itself in other individuals and direct benefits to these individuals. Green-beard effects have been dismissed as implausible by authors who have implicitly assumed sophisticated mechanisms of perception and complex behavioral responses. However, many simple mechanisms for genes to "recognize" themselves exist at the maternal-fetal interface of viviparous organisms. Homophilic cell adhesion molecules, for example, are able to interact with copies of themselves on other cells. Thus, the necessary components of a green-beard effect -- feature, recognition, and response -- can be different aspects of the phenotype of a single gene. Other green-beard effects could involve coalitions of genes at closely linked loci. In fact, any form of epistasis between a locus expressed in a mother and a closely linked locus expressed in the fetus has the property of "self-recognition." Green-beard effects have many formal similarities to systems of meiotic drive and, like them, can be a source of intragenomic conflict.

Lowell, Massachusetts, 1841 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the city of Lowell : surveyed in 1841 by order of the municipal authorities, by I.A. Beard & J. Hoar ; engraved by G.W. Boynton. It was published in 1842. Scale [ca. 1:4,500]. Covers a portion of the City of Lowell. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Massachusetts State Plane Coordinate System, Mainland Zone (in Feet) (Fipszone 2001). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows features such as roads, railroads, drainage, public buildings, schools, churches, cemeteries, industry locations (e.g. mills, factories, mines, etc.), private buildings, boarding houses, hotels, city districts and more. Includes a an index to points of interest. This layer is part of a selection of digitally scanned and georeferenced historic maps of Massachusetts from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of regions, originators, ground condition dates (1755-1922), scales, and purposes. The digitized selection includes maps of: the state, Massachusetts counties, town surveys, coastal features, real property, parks, cemeteries, railroads, roads, public works projects, etc.

The story of my life and work : an autobiography /

Salesman's sample for edition that was never published?

1999 University of Michigan Football Team

U-M Softball Team, 1997

Front Row: Sara Griffin, Kellyn Tate, Jessica Lang (captain), Kelly Holmes, Jen Smith, Tracy Taylor, Jen McKittrick, Lisa Kelley.

Back Row: Cathy Davie, Traci Conrad, Stacey Judd, Jamie Gillies, Melissa Gentile, Karmen Lappo, Pam Kosanke, Tammy Mika, Lisa Beard.

Not Pictured: Mary Adams.

U-M Softball Team, 1999

Front Row: Pam Kosanke, Blanca LeBron (mgr.), Traci Conrad (captain), Catherine Davie, Tammy Mika (captain), Carrie Silver (mgr.).

Middle Row: Rebecca Tune, Marie Barda, Melissa Gentile, Jamie Gillies, Courtney Murdock, Kate Eiland, Karmen Lappo.

Back Row: Kristen Hunter, Stefanie Volpe, Mary Conner, Kelsey Kollen, Chrissy Garza, Melissa Taylor, Lisa Beard, Kim Bugel.

Traffic accident simulation. Final report.

Louisiana Transportation Research Center, Baton Rouge

Casserole cookbook: meat, fish, poultry, vegetables, soufflés, desserts. Over 250 easy, exciting recipes for 2 to 20 people.

Mode of access: Internet.

Treasury of outdoor cooking.

Mode of access: Internet.

Readings in modern European history; a collection of extracts from the sources chosen with the purpose of illustrating some of the chief phases of development of Europe during the last two hundred years,

"We have borrowed to some extent from the second volume of Robinson's Readings in European history."--Pref., v. 1.