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61.
Parker MF Bronson JJ Barten DM Corsa JA Du W Felsenstein KM Guss VL Izzarelli D Loo A McElhone KE Marcin LR Padmanabha R Pak R Polson CT Toyn JH Varma S Wang J Wong V Zheng M Roberts SB 《Bioorganic & medicinal chemistry letters》2007,17(21):5790-5795
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported. 相似文献
62.
WHAP: haplotype-based association analysis 总被引:7,自引:0,他引:7
We describe a software tool to perform haplotype-based association analysis, for quantitative and qualitative traits, in population and family samples, using single nucleotide polymorphism or multiallelic marker data. A range of tests is offered: omnibus and haplotype-specific tests; prospective and retrospective likelihoods; covariates and moderators; sliding window analyses; permutation P-values. We focus on the ability to flexibly impose constraints on haplotype effects, which allows for a range of conditional haplotype-based likelihood ratio tests: for example, whether an allele has an effect independent of its haplotypic background, or whether a single variant can explain the overall association at a locus. We illustrate using these tests to dissect a multi-locus association. AVAILABILITY: WHAP is a C/C++ program, freely available from the author's website: http://pngu.mgh.harvard.edu/purcell/whap/ 相似文献
63.
Yun H. S. Lee J. H. Choo Y. S. Pak J. H. Kim H. S. Kim Y. S. Yoon H. S. 《Microbiology》2022,91(6):801-817
Microbiology - Ulleungdo is a volcanic island with an oceanic climate seasonally affected by warm and cold currents. The freshwater ecosystems of Ulleungdo Island act as an ecological indicator... 相似文献
64.
Pak N. Kwong Michael Chambers Ajay A. Vashisht Wiam Turki-Judeh Tak Yu Yau James A. Wohlschlegel Albert J. Courey 《The Journal of biological chemistry》2015,290(50):30119-30130
Groucho (Gro) is a Drosophila co-repressor that regulates the expression of a large number of genes, many of which are involved in developmental control. Previous studies have shown that its central region is essential for function even though its three domains are poorly conserved and intrinsically disordered. Using these disordered domains as affinity reagents, we have now identified multiple embryonic Gro-interacting proteins. The interactors include protein complexes involved in chromosome organization, mRNA processing, and signaling. Further investigation of the interacting proteins using a reporter assay showed that many of them modulate Gro-mediated repression either positively or negatively. The positive regulators include components of the spliceosomal subcomplex U1 small nuclear ribonucleoprotein (U1 snRNP). A co-immunoprecipitation experiment confirms this finding and suggests that a sizable fraction of nuclear U1 snRNP is associated with Gro. The use of RNA-seq to analyze the gene expression profile of cells subjected to knockdown of Gro or snRNP-U1-C (a component of U1 snRNP) showed a significant overlap between genes regulated by these two factors. Furthermore, comparison of our RNA-seq data with Gro and RNA polymerase II ChIP data led to a number of insights, including the finding that Gro-repressed genes are enriched for promoter-proximal RNA polymerase II. We conclude that the Gro central domains mediate multiple interactions required for repression, thus functioning as a regulatory hub. Furthermore, interactions with the spliceosome may contribute to repression by Gro. 相似文献
65.
Dingge Ying Pak Chung Sham David Keith Smith Lu Zhang Yu Lung Lau Wanling Yang 《Genome biology》2015,16(1)
Recent founder mutations may play important roles in complex diseases and Mendelian disorders. Detecting shared haplotypes that are identical by descent (IBD) could facilitate discovery of these mutations. Several programs address this, but are usually limited to detecting pair-wise shared haplotypes and not providing a comparison of cases and controls. We present a novel algorithm and software package, HaploShare, which detects extended haplotypes that are shared by multiple individuals, and allows comparisons between cases and controls. Testing on simulated and real cases demonstrated significant improvements in detection power and reduction of false positive rate by HaploShare relative to other programs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0662-9) contains supplementary material, which is available to authorized users. 相似文献66.
Wyffels L Gray BD Barber C Moore SK Woolfenden JM Pak KY Liu Z 《Bioorganic & medicinal chemistry》2011,19(11):3425-3433
The aim of this study was the development of (??m)Tc labeled bis(zinc(II)-dipicolylamine) (Zn2?-DPA) coordination complexes, and the in vivo evaluation of their usefulness as radiotracers for the detection of cell death. DPA ligand 1 was labeled with (??m)Tc via the (??m)Tc-tricarbonyl core ([(??m)Tc(CO)?-1]3?) or via HYNIC ((??m)Tc-HYNIC-1) in good radiochemical yields. Highest in vitro stabilities were demonstrated for [(??m)Tc(CO)?-1]3?. A mouse model of hepatic apoptosis (anti-Fas mAb) was used to demonstrate binding to apoptotic cells. (??m)Tc-HYNIC-1 showed the best targeting of apoptotic hepatic tissue with a 2.2 times higher liver uptake in anti-Fas treated mice as compared to healthy animals. A rat model of ischemia-reperfusion injury was used to further explore the ability of the (??m)Tc-labeled Zn2?-DPA coordination complexes to target cell death. Selective accumulation could be detected for both tracers in the area at risk, correlating with histological proof of cell death. Area at risk to normal tissue uptake ratios were 3.82 for [(??m)Tc(CO)?-1]3? and 5.45 for (??m)Tc-HYNIC-1. 相似文献
67.
Chaudhary S Pak JE Pedersen BP Bang LJ Zhang LB Ngaw SM Green RG Sharma V Stroud RM 《Methods (San Diego, Calif.)》2011,55(4):273-280
It is often an immense challenge to overexpress human membrane proteins at levels sufficient for structural studies. The use of Human Embryonic Kidney 293 (HEK 293) cells to express full-length human membrane proteins is becoming increasingly common, since these cells provide a near-native protein folding and lipid environment. Nevertheless, the labor intensiveness and low yields of HEK 293 cells and other mammalian cell expression systems necessitate the screening for suitable expression as early as possible. Here we present our methodology used to generate constructs of human membrane proteins and to rapidly assess their suitability for overexpression using transiently transfected, glycosylation-deficient GnT I-HEK 293 cells (HEK 293S). Constructs, in the presence or absence of a C-terminal enhanced green fluorescence protein (EGFP) molecule, are made in a modular manner, allowing for the rapid generation of several combinations of fusion tags and gene paralogues/orthologues. Solubilization of HEK 293S cells, using a range of detergents, followed by Western blotting is performed to assess relative expression levels and to detect possible degradation products. Fluorescence-detection size exclusion chromatography (FSEC) is employed to assess expression levels and overall homogeneity of the membrane proteins, to rank different constructs for further downstream expression trials. Constructs identified as having high expression are instantly suitable for further downstream large scale transient expression trials and stable cell line generation. The method described is accessible to all laboratory scales and can be completed in approximately 3 weeks. 相似文献
68.
Kantyka T Plaza K Koziel J Florczyk D Stennicke HR Thogersen IB Enghild JJ Silverman GA Pak SC Potempa J 《Biological chemistry》2011,392(5):483-489
Bacterial proteases are considered virulence factors and it is presumed that by abrogating their activity, host endogenous protease inhibitors play a role in host defense against invading pathogens. Here we present data showing that Staphylococcus aureus cysteine proteases (staphopains) are efficiently inhibited by Squamous Cell Carcinoma Antigen 1 (SCCA1), an epithelial-derived serpin. The high association rate constant (k(ass)) for inhibitory complex formation (1.9×10(4) m/s and 5.8×10(4) m/s for staphopain A and staphopain B interaction with SCCA1, respectively), strongly suggests that SCCA1 can regulate staphopain activity in vivo at epithelial surfaces infected/colonized by S. aureus. The mechanism of staphopain inhibition by SCCA1 is apparently the same for serpin interaction with target serine proteases whereby the formation of a covalent complex result in cleavage of the inhibitory reactive site peptide bond and associated release of the C-terminal serpin fragment. Interestingly, the SCCA1 reactive site closely resembles a motif in the reactive site loop of native S. aureus-derived inhibitors of the staphopains (staphostatins). Given that S. aureus is a major pathogen of epithelial surfaces, we suggest that SCCA1 functions to temper the virulence of this bacterium by inhibiting the staphopains. 相似文献
69.
70.
Li Y Fu L Wong AM Fan YH Li MX Bei JX Jia WH Zeng YX Chan D Cheung KM Sham P Chua D Guan XY Song YQ 《PloS one》2011,6(1):e14562
Nasopharyngeal carcinoma (NPC) is a malignancy of epithelial origin. The etiology of NPC is complex and includes multiple genetic and environmental factors. We employed case-control analysis to study the association of chromosome 6p regions with NPC. In total, 360 subjects and 360 healthy controls were included, and 233 single nucleotide polymorphisms (SNPs) on 6p were examined. Significant single-marker associations were found for SNPs rs2267633 (p = 4.49 × 10(-5)), rs2076483 (most significant, p = 3.36 × 10(-5)), and rs29230 (p=1.43 × 10(-4)). The highly associated genes were the gamma-amino butyric acid B receptor 1 (GABBR1), human leukocyte antigen (HLA-A), and HLA complex group 9 (HCG9). Haplotypic associations were found for haplotypes AAA (located within GABBR1, p-value = 6.46 × 10(-5)) and TT (located within HLA-A, p = 0.0014). Further investigation of the homozygous genotype frequencies between cases and controls suggested that micro-deletion regions occur in GABBR1 and neural precursor cell expressed developmentally down-regulated 9 (NEDD9). Quantitative real-time polymerase chain reaction (qPCR) using 11 pairs of NPC biopsy samples confirmed the significant decline in GABBR1 and NEDD9 mRNA expression in the cancer tissues compared to the adjacent non-tumor tissue (p<0.05). Our study demonstrates that multiple chromosome 6p susceptibility loci contribute to the risk of NPC, possibly though GABBR1 and NEDD9 loss of function. 相似文献