55 research outputs found

    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3â€Č-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    Get PDF
    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

    Right to Repair: Whose Right is it Anyway?

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    Mental Health and Ideals of Citizenship: Patient Care at St. Elizabeths Hospital in Washington, D.C., 1903--1962

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    367 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2010.The post-World War II era witnessed important changes in both psychiatrists' vision of U.S. citizenship and the institutional culture at St. Elizabeths. Physicians took an increasingly liberal view of race relations under Winfred Overholser, who succeeded White as superintendent in 1937 and was prompted by national developments to integrate the hospital in 1954. These same psychiatrists promoted a restrictive domestic ideal for their female patients, in spite of the fact that middle-class married women were entering the labor market in unprecedented numbers. Physicians charted a cautious middle path in debates on homosexuality, maintaining that same-sex desires signified deep psychological maladjustment even as they protested policies criminalizing consensual sexual contact between adults. These developments occurred in the context of a general liberalization of institutional culture in the postwar decades. Through their own efforts as well as through innovations in clinical psychiatry, patients in the 1940s and 1950s found new opportunities for self-expression and began to articulate a novel sense of shared identity. By the time the major tranquilizers appeared, the appropriateness of long-term custodial care for psychologically-impaired men and women had already come into question.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

    Tethered particle motion with single DNA molecules Single molecule λ -DNA stretching studied by microfluidics and single particle tracking Electrophoretic stretching of DNA molecules using microscale T junctions Mechanical characteristic of ssDNA∕dsDNA mo

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    A simple method for tethering microbeads using single molecules of DNA is explained. We describe how to use video microscopy and particle tracking to measure the trajectories of the microbeads&apos; motion. The trajectories are analyzed and compared to different models of tethered particle motion. In addition, the data are used to measure the elasticity of the DNA (its spring constant), and the DNA persistence length

    6-Anilinouracil-based inhibitors of Bacillus subtilis DNA polymerase III: antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3

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    6-Anilinouracils (6-AUs) are dGTP analogues which selectively inhibit the DNA polymerase III of Bacillus subtilis and other Gram-positive bacteria. To enhance the potential of the 6-AUs as antimicrobial agents, a structure-activity relationship was developed involving substitutions of the uracil N3 position in two 6-AU platforms: 6-(3,4-trimethyleneanilino)uracil (TMAU) and 6-(3-ethyl-4-methylanilino)uracil (EMAU). Series of N3-alkyl derivatives of both 6-AUs were synthesized and tested for their ability to inhibit purified B. subtilis DNA polymerase III and the growth of B. subtilis in culture. Alkyl groups ranging in size from ethyl to hexyl enhanced the capacity of both platforms to bind to the polymerase, and with the exception of hexyl, they also significantly enhanced their antimicrobial potency. N3 substitution of the EMAU platform with more hydrophilic hydroxyalkyl and methoxyalkyl groups marginally enhanced anti-polymerase III activity but enhanced antibacterial potency severalfold. In sum, the results of these studies indicate that the ring N3 of 6-anilinouracils can tolerate substituents of considerable size and structural variety and, thus, can be manipulated to significantly enhance the antibacterial potency of this novel class of polymerase III-specific inhibitors
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