Molecular evolution of dentin phosphoprotein among toothed and toothless animals

<p>Abstract</p> <p>Background</p> <p>Dentin sialophosphoprotein (DSPP) is the largest member of the SIBLING family and is the most abundant noncollagenous protein in dentin. DSPP is also expressed in non-mineralized tissues including metabolically active ductal epithelia and some cancers. Its function, however, is poorly defined. The carboxy-terminal fragment, dentin phosphoprotein (DPP) is encoded predominantly by a large repetitive domain that requires separate cloning/sequencing reactions and is, therefore, often incomplete in genomic databases. Comparison of DPP sequences from at least one member of each major branch in the mammalian evolutionary tree (including some "toothless" mammals) as well as one reptile and bird may help delineate its possible functions in both dentin and ductal epithelia.</p> <p>Results</p> <p>The BMP1-cleavage and translation-termination domains were sufficiently conserved to permit amplification/cloning/sequencing of most species' DPP. While the integrin-binding domain, RGD, was present in about half of species, only vestigial remnants of this tripeptide were identified in the others. The number of tandem repeats of the nominal SerSerAsp phosphorylation motif in toothed mammals (including baleen whale and platypus which lack teeth as adults), ranged from ~75 (elephant) to >230 (human). These repeats were not perfect, however, and patterns of intervening sequences highlight the rapidity of changes among even closely related species. Two toothless anteater species have evolved different sets of nonsense mutations shortly after their BMP1 motifs suggesting that while cleavage may be important for DSPP processing in other tissues, the DPP domain itself may be required only in dentin. The lizard <it>DSPP </it>had an intact BMP1 site, a remnant RGD motif, as well as a distinctly different Ser/Asp-rich domain compared to mammals.</p> <p>Conclusions</p> <p>The DPP domain of <it>DSPP </it>was found to change dramatically within mammals and was lost in two truly toothless animals. The defining aspect of DPP, the long repeating phosphorylation domain, apparently undergoes frequent slip replication and recombination events that rapidly change specific patterns but not its overall biochemical character in toothed animals. Species may have to co-evolve protein processing mechanisms, however, to handle increased lengths of DSP repeats. While the RGD domain is lost in many species, some evolutionary pressure to maintain integrin binding can be observed.</p

Renal expression of SIBLING proteins and their partner matrix metalloproteinases (MMPs)

Renal expression of SIBLING proteins and their partner matrix metalloproteinases (MMP).BackgroundThree members of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins have recently been shown to bind and activate specific promatrix metalloproteinases (MMPs) and to overcome the inhibition of tissue inhibitors of MMPs (TIMPs). Although usually associated with mineralized tissues, we have shown that the SIBLINGs and their MMP partners, when known, are coexpressed in salivary gland ductal cells. The present study examined the expression patterns of both the SIBLINGs and their MMP partners in adult kidney.MethodsThe expression patterns of all five SIBLINGs known to date, and their MMP partners were determined in monkey kidney using immunohistochemistry and in situ hybridization techniques.ResultsBone sialoprotein (BSP) and its partner, MMP-2, were coexpressed in both the proximal and distal tubules. Osteopontin, as previously shown, was expressed in the distal tubules while its partner MMP-3 was expressed in both the proximal tubule and distal tubles. Dentin matrix protein-1 (DMP1) and MMP-9 were coexpressed throughout the nephron, including both parietal cells of Bowman's capsule and the thin limb of the loop of Henle. Dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE) were expressed in the proximal tubule and distal tubule, and proximal tubule, respectively.ConclusionIn contrast to salivary gland in which all SIBLINGs and their MMP partners were coexpressed throughout the length of the ducts, these proteins were differentially expressed within the normal adult nephron. We hypothesize that the cells use the SIBLING/MMP pairs in the normal turnover of cell surface proteins and/or pericellular matrix proteins such as those in basement membranes

Landslides of Southeastern Ohio

Author Institution: Department of Geology, Ohio University, Athens, OhioThe Upper Pennsylvanian and Permian cyclothemic sedimentary rocks of the Ohio River valley are especially subject to downslope movements. Repairs of landslides on state highways in eastern Ohio alone cost over a million dollars annually. Eighty-seven slope failures were located within seven counties of southeastern Ohio; 50 of the larger of these movements were mapped in some detail. Earthflows and rotational slumps are the most common types of slope failures, the latter being the larger and constituting about 89 percent of the landslides mapped. Over 70 percent of the total number of slope movements occur within only one-sixth of the geologic column. Red shales predominate in the four most unstable intervals; the gray shales of the area seldom yield to sliding and the green shales vary greatly in strengths. Almost all of the red shales and one-third of the green shales slake completely within three hours after immersion in water; many of the red shales deteriorate to an ooze within minutes. There is no apparent relationship between stability and the amounts of soluble salts in each type of shale. Differential thermal analyses and rehydration tests indicate that these shales are composed largely of illitic clay minerals which, in the red shales at least, are deficient in bonding by cations of potassium. Ferric ions, presumably connate, have prevented readsorption of potassium throughout time, thus permitting a thickening of the interlayer water with resultant weakening of bonding. When interlayer water is driven off, a faster and greater regain is noted in the more unstable shales, as compared with that in the relatively stable shales. When the unstable shales are replenished with potassium, they strengthen markedly, especially those samples from which much of the inhibiting iron oxides have previously been removed

Chronic Ultraviolet Radiation Exposure Does Not Effect Nitric Oxide-Mediated Vasodilation in the Cutaneous Microvasculature

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A comprehensive analysis of normal variation and disease-causing mutations in the human DSPP gene

Within nine dentin dysplasia (type II) and dentinogenesis imperfecta (type II and III) patient/families, seven have one of four net −1 deletions within the ~2kb coding repeat domain of the DSPP gene while the remaining two patients had splice-site mutations. All frameshift mutations are predicted to change the highly soluble DSPP protein into proteins with long hydrophobic amino acid repeats that could interfere with processing of normal DSPP and/or other secreted matrix proteins. We propose that all previously reported missense, nonsense, and splice-site DSPP mutations (all associated with exons 2 and 3) result in dominant phenotypes due to disruption of signal peptide-processing and/or related biochemical events that also result in interference with protein processing. This would bring the currently known dominant forms of the human disease phenotype in agreement with the normal phenotype of the heterozygous null Dspp (−/+) mice. A study of 188 normal human chromosomes revealed a hypervariable DSPP repeat domain with extraordinary rates of change including 20 slip-replication indel events and 37 predominantly C-to-T transition SNPs. The most frequent transition in the primordial 9-bp DNA repeat was a sense-strand CpG site while a CpNpG (CAG) transition was the second most frequent SNP. Bisulfite-sequencing of genomic DNA showed that DSPP repeat can be methylated at both motifs. This suggests that, like plants and some animals, human methylate some CpNpG sequences. Analysis of 37 haplotypes of the highly variable DSPP gene from geographically diverse people suggests it may be a useful autosomal marker in human migration studies

Dose-dense adjuvant chemotherapy for primary breast cancer

Adjuvant chemotherapy has been proven to reduce significantly the risk for relapse and death in women with operable breast cancer. Nevertheless, the prognosis for patients presenting with extensive axillary lymph node involvement remains suboptimal. In an attempt to improve on the efficacy of existing chemotherapy, a phase III intergroup trial led by the Cancer and Leukemia Group B (CALGB 97-41) was designed, which tested a mathematical model of tumor growth based on the Norton–Simon hypothesis. This hypothesis, developed about 3 decades ago, and the kinetic model derived from it, created the basis of the concepts of dose density and sequential therapy, both of which were tested in CALGB 97-41. This large prospective randomized trial demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose size resulted in significant improvements in disease-free and overall survival in patients with node-positive breast carcinoma. This finding is highly relevant and has immediate implications for clinical practice

Science and Ideology in Economic, Political, and Social Thought

This paper has two sources: One is my own research in three broad areas: business cycles, economic measurement and social choice. In all of these fields I attempted to apply the basic precepts of the scientific method as it is understood in the natural sciences. I found that my effort at using natural science methods in economics was met with little understanding and often considerable hostility. I found economics to be driven less by common sense and empirical evidence, then by various ideologies that exhibited either a political or a methodological bias, or both. This brings me to the second source: Several books have appeared recently that describe in historical terms the ideological forces that have shaped either the direct areas in which I worked, or a broader background. These books taught me that the ideological forces in the social sciences are even stronger than I imagined on the basis of my own experiences. The scientific method is the antipode to ideology. I feel that the scientific work that I have done on specific, long standing and fundamental problems in economics and political science have given me additional insights into the destructive role of ideology beyond the history of thought orientation of the works I will be discussing

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.