57 research outputs found

    Collaborative Language Planning Project: Report from First Meeting

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    Report from the first meeting of the Collaborative Language Planning Project, held May 17, 2018 at the University of Montana\u27s Native American Center

    Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene.

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    BACKGROUND AND AIMS: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. RESULTS: The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∌2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∌14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r(2) > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10(-05)). CONCLUSIONS: Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering

    Practical Challenges for Digital Watermarking Applications

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    <p/> <p>The field of digital watermarking has recently seen numerous articles covering novel techniques, theoretical studies, attacks, and analysis. In this paper, we focus on an emerging application to highlight practical challenges for digital watermarking applications. Challenges include design considerations, requirements analysis, choice of watermarking techniques, speed, robustness, and the tradeoffs involved. We describe common attributes of watermarking systems and discuss the challenges in developing real world applications. Our application uses digital watermarking to connect ordinary toys to the digital world. The application captures important aspects of watermarking systems and illustrates some of the design issues faced.</p

    Nickel‐Catalyzed Anionic Cross‐Coupling Reaction of Lithium Sulfonimidoyl Alkylidene Carbenoids With Organolithiums

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    The mechanistic platform for a novel nickel(0)-catalyzed anionic cross-coupling reaction (ACCR) of lithium sulfonimidoyl alkylidene carbenoids (metalloalkenyl sulfoximines) with organometallic reagents is reported herein, affording substituted alkenylmetals and lithium sulfinamides. The Ni-0-catalyzed ACCR of three different types of metalloalkenyl sulfoximines, including acyclic, axially chiral and exocyclic derivatives, with sp(2) organolithiums and sp(2) and sp(3) Grignard reagents has been studied. The ACCR of metalloalkenyl sulfoximines with PhLi in the presence of the Ni-0-catalyst and precatalyst Ni(PPh3)(2)Cl-2 afforded alkenyllithiums, under inversion of configuration at the C atom and complete retention at the S atom. In a combination of experimental and DFT studies, we propose a catalytic cycle of the Ni-0-catalyzed ACCR of lithioalkenyl sulfoximines. Computational studies reveal two distinctive pathways of the ACCR, depending on whether a phosphine or 1,5-cyclooctadiene (COD) is the ligand of the Ni atom. They rectify the underlying importance of forming the key Ni-0-vinylidene intermediate through an indispensable electron-rich Ni-0-center coordinated by phosphine ligands. Fundamentally, we present a mechanistic study in controlling the diastereoselectivity of the alkenyllithium formation via the key lithium sulfinamide coordinated Ni-0-vinylidene complex, which consequently avoids an unselective formation of an alkylidene carbene Ni-complex and ultimately racemic alkenyllithium. T 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinhei
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