52 research outputs found
Human XPC-hHR23B interacts with XPA-RPA in the recognition of triplex-directed psoralen DNA interstrand crosslinks
DNA interstrand crosslinks (ICLs) represent a severe form of damage that blocks DNA metabolic processes and can lead to cell death or carcinogenesis. The repair of DNA ICLs in mammals is not well characterized. We have reported previously that a key protein complex of nucleotide excision repair (NER), XPA-RPA, recognizes DNA ICLs. We now report the use of triplex technology to direct a site-specific psoralen ICL to a target DNA substrate to determine whether the human global genome NER damage recognition complex, XPC-hHR23B, recognizes this lesion. Our results demonstrate that XPC-hHR23B recognizes psoralen ICLs, which have a structure fundamentally different from other lesions that XPC-hHR23B is known to bind, with high affinity and specificity. XPC-hHR23B and XPA-RPA protein complexes were also observed to bind psoralen ICLs simultaneously, demonstrating not only that psoralen ICLs are recognized by XPC-hHR23B alone, but also that XPA-RPA may interact cooperatively with XPC-hHR23B on damaged DNA, forming a multimeric complex. Since XPC-hHR23B and XPA-RPA participate in the recognition and verification of DNA damage, these results support the hypothesis that interplay between components of the global genome repair sub-pathway of NER is critical for the recognition of psoralen DNA ICLs in the mammalian genome
Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances bacillus Calmette-Guerin vaccine efficacy against tuberculosis
Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy
Thermal and Conductivity Studies of VO2+ Doped Methacrylic Acid - Ethyl Acrylate (MAA:EA) Copolymer Films
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Interplay between human high mobility group protein 1 and replication protein A on psoralen-cross-linked DNA.
Interplay between Human High Mobility Group Protein 1 and Replication Protein A on Psoralen-Cross-linked DNA †
Synthesis and biochemical evaluation of benzyl propargyl ethers as inhibitors of 5-lipoxygenase
264-273A series of benzyl propargyl ethers were
synthesized and tested as inhibitors of 5- lipoxygenase, the key enzyme involved
in leukotriene biosynthesis. Among these, optimum activity was displayed by
1-(2-heptynyloxymethyl) benzene 12 (IC50 1.2 µ<i style="mso-bidi-font-style:
normal">M)<span style="font-size:14.0pt;font-family:HiddenHorzOCR;
mso-hansi-font-family:" times="" new="" roman";mso-bidi-font-family:hiddenhorzocr;="" mso-ansi-language:en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">. Addition of carboxyl group at the end of the alkyl
side chain attached to the acetylenic group abolished the inhibition. Selective
reduction of the acetylenic group to cis or trails double bond
reduced the inhibitory potential, the cis
isomer 24 showing more than
20-fold higher inhibition than the trans isomer 25.
Introduction of sulphur in place of oxygen in th e alkyl side chain attached to
the (carboxyalkyl) benzyl group also reduced the inhibition. The IC50value
of <span style="font-size:14.0pt;font-family:Arial;mso-fareast-font-family:
" times="" new="" roman";mso-ansi-language:en-us;mso-fareast-language:en-us;="" mso-bidi-language:ar-sa"="">12, <span style="font-size:14.0pt;font-family:
" times="" new="" roman";mso-fareast-font-family:"times="" roman";mso-ansi-language:="" en-us;mso-fareast-language:en-us;mso-bidi-language:ar-sa"="">towards rabbit reticulocyte
15-LOX is > 50 fold higher than that of 5-LOX. These results indicate that
compound 12 is a specific inhibitor
of 5-LOX.</span
Selective inhibition of cyclooxygenase-2 by C-phycocyanin, a biliprotein from Spirulina platensis
We report data from two related assay systems (isolated enzyme assays and whole blood assays) that C-phycocyanin a biliprotein from Spirulina platensis is a selective inhibitor of cyclooxygenase-a (COX-2) with a very low IC50 COX-2/IC50 COX-1 ratio (0.04). The extent of inhibition depends on the period of preincubation of phycocyanin with COX-2, but without any effect on the period of preincubation with COX-1. The IC50 value obtained for the inhibition of COX-2 by phycocyanin is much lower (180 nM) as compared to those of celecoxib (255 nM) and rofecoxib (401 nM), the well-known selective COX-2 inhibitors. In the human whole blood assay, phycocyanin very efficiently inhibited COX-2 with an IC50 value of 80 nM. Reduced phycocyanin and phycocyanobilin, the chromophore of phycocyanin are poor inhibitors of COX-2 without COX-2 selectivity. This suggests that apoprotein in phycocyanin plays a key role in the selective inhibition of COX-2. The present study points out that the hepatoprotective, anti-inflammatory, and anti-arthritic properties of phycocyanin reported in the literature may be due, in part, to its selective COX-2 inhibitory property, although its ability to efficiently scavenge free radicals and effectively inhibit lipid peroxidation may also be involved. (C) 2000 Academic Press
A versatile cobalt(II)-Schiff base catalyzed oxidation of organic substrates with dioxygen: scope and mechanism
Cobalt(II) complex 1a-f derived from Schiff bases act as efficient catalysts during the oxidation of wide range of organic substrates(e.g. alkenes, alcohols, benzylic compounds and aliphatic hydrocarbons) with dioxygen in the presence of aliphatic aldehydes or ketones or ketoesters. EPR studies on 1a-f complexes suggest that the aliphatic carbonyl compounds promote the formation of a cobalt(III)-superoxo species responsible for the oxidation of organic compounds. These studies also demonstrate the role of ligands on cobalt in controlling the chemoselectivity of these oxidations. A plausible mechanistic rational is also provided for these oxidations
Cobalt catalyzed regioselective allylation of 1,3-dicarbonyl compounds
Catalytic amount of Cobalt(II) chloride in 1,2-dichloroethane promotes the allylation of 1,3-dicarbonyl compounds with allyl acetates in high yields. The allylation of pentane-2,4-dione is highly regioselective as compared with methylacetoacetate and ethyl 2-oxocyclopentanecarboxylate
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