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71.
72.
Steven A. Li Melissa M. Cadelis Kenneth Sue Marine Blanchet Nicolas Vidal Jean Michel Brunel Marie-Lise Bourguet-Kondracki Brent R. Copp 《Bioorganic & medicinal chemistry》2019,27(10):2090-2099
The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with polyamine 3 also displaying in vitro antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa. A series of 6-bromo derivatives (5–15) were prepared and biologically evaluated, identifying analogues with enhanced antibacterial activity towards Escherichia coli and with moderate to excellent antifungal properties. Polyamine 3, which includes a spermine chain, was the most potent of the series – its mechanism of action was attributed to rapid membrane permeabilization and depolarization in both Gram-positive and Gram-negative bacteria. 相似文献
73.
Jane Zochling Felicity Newell Jac C Charlesworth Paul Leo Jim Stankovich Adrian Cortes Yuan Zhou Wendy Stevens Joanne Sahhar Janet Roddy Peter Nash Kathleen Tymms Maureen Rischmueller Sue Lester Susanna Proudman Matthew A Brown 《Arthritis research & therapy》2014,16(5)
Introduction
The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population.Methods
We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls.Results
A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10−10) in anti-centromere antibody (ACA) positive cases.Conclusions
This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0438-8) contains supplementary material, which is available to authorized users. 相似文献74.
The structure and function of polynucleotide phosphorylase (PNPase) and the exosome, as well as their associated RNA-helicases
proteins, are described in the light of recent studies. The picture raised is of an evolutionarily conserved RNA-degradation
machine which exonucleolytically degrades RNA from 3′ to 5′. In prokaryotes and in eukaryotic organelles, a trimeric complex
of PNPase forms a circular doughnut-shaped structure, in which the phosphorolysis catalytic sites are buried inside the barrel-shaped
complex, while the RNA binding domains create a pore where RNA enters, reminiscent of the protein degrading complex, the proteasome.
In some archaea and in the eukaryotes, several different proteins form a similar circle-shaped complex, the exosome, that
is responsible for 3′ to 5′ exonucleolytic degradation of RNA as part of the processing, quality control, and general RNA
degradation process. Both PNPase in prokaryotes and the exosome in eukaryotes are found in association with protein complexes
that notably include RNA helicase. 相似文献
75.
76.
The behavioral responses of sexually experienced male hamsters toward a pair of anesthetized conspecifics were investigated. Males spent significantly more time licking, sniffing, and mounting neonatally and adult castrated males than intact males. Adult castrated males receiving oil injections were preferred over castrates receiving exogenous testosterone propionate (TP). Ovariectomized females were preferred over intact males, adult castrated males, or spayed females receiving exogenous TP. It was concluded that the absence of an androgen-dependent factor(s) renders an animal more sexually attractive. 相似文献
77.
Liang GB Qian X Feng D Fisher M Brown CM Gurnett A Leavitt PS Liberator PA Misura AS Tamas T Schmatz DM Wyvratt M Biftu T 《Bioorganic & medicinal chemistry letters》2007,17(13):3558-3561
Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed. 相似文献
78.
The fang-like jaws of the marine polychaete Nereis virens possess remarkable mechanical properties considering their high protein content and lack of mineralization. Hardness and stiffness properties in the jaw tip are comparable to human dentin and are achieved by extensive coordination of Zn (2+) by a histidine-rich protein framework. In the present study, the predominant protein in the jaw tip, Nvjp-1, was purified and characterized by partial peptide mapping and molecular cloning of a partial cDNA from a jaw pulp library. The deduced amino acid sequence revealed an approximately 38 kDa histidine-rich protein rich in glycine and histidine (approximately 36 and 27%, respectively) with no well-defined repetitive motifs. The effects of pH and metal treatment on aggregation, secondary structure, and hydrodynamic properties of recombinant Nvjp-1 are described. Notably, Zn treatment induced the formation of amyloid-like fibers. 相似文献
79.
Mutagenic effects of abasic and oxidized abasic lesions in Saccharomyces cerevisiae 总被引:1,自引:0,他引:1 下载免费PDF全文
Kow YW Bao G Minesinger B Jinks-Robertson S Siede W Jiang YL Greenberg MM 《Nucleic acids research》2005,33(19):6196-6202
2-Deoxyribonolactone (L) and 2-deoxyribose (AP) are abasic sites that are produced by ionizing radiation, reactive oxygen species and a variety of DNA damaging agents. The biological processing of the AP site has been examined in the yeast Saccharomyces cerevisiae. However, nothing is known about how L is processed in this organism. We determined the bypass and mutagenic specificity of DNA containing an abasic site (AP and L) or the AP analog tetrahydrofuran (F) using an oligonucleotide transformation assay. The tetrahydrofuran analog and L were bypassed at 10-fold higher frequencies than the AP lesions. Bypass frequencies of lesions were greatly reduced in the absence of Rev1 or Polζ (rev3 mutant), but were only marginally reduced in the absence of Polη (rad30 mutant). Deoxycytidine was the preferred nucleotide inserted opposite an AP site whereas dA and dC were inserted at equal frequencies opposite F and L sites. In the rev1 and rev3 strains, dA was the predominant nucleotide inserted opposite these lesions. Overall, we conclude that both Rev1 and Polζ are required for the efficient bypass of abasic sites in yeast. 相似文献
80.
Yutaka Kano Danielle J Padilla Brad J Behnke K Sue Hageman Timothy I Musch David C Poole 《Journal of applied physiology》2005,99(4):1516-1522
A single bout of eccentric exercise results in muscle damage, but it is not known whether this is correlated with microcirculatory dysfunction. We tested the following hypotheses in the spinotrapezius muscle of rats either 1 (DH-1; n = 6) or 3 (DH-3; n = 6) days after a downhill run to exhaustion (90-120 min; -14 degrees grade): 1) in resting muscle, capillary hemodynamics would be impaired, and 2) at the onset of subsequent acute concentric contractions, the decrease of microvascular O(2) pressure (Pmv(o(2))), which reflects the dynamic balance between O(2) delivery and O(2) utilization, would be accelerated compared with control (Con, n = 6) rats. In contrast to Con muscles, intravital microscopy observations revealed the presence of sarcomere disruptions in DH-1 and DH-3 and increased capillary diameter in DH-3 (Con: 5.2 +/- 0.1; DH-1: 5.1 +/- 0.1; DH-3: 5.6 +/- 0.1 mum; both P < 0.05 vs. DH-3). At rest, there was a significant reduction in the percentage of capillaries that sustained continuous red blood cell (RBC) flux in both DH running groups (Con: 90.0 +/- 2.1; DH-1: 66.4 +/- 5.2; DH-3: 72.9 +/- 4.1%, both P < 0.05 vs. Con). Capillary tube hematocrit was elevated in DH-1 but reduced in DH-3 (Con: 22 +/- 2; DH-1: 28 +/- 1; DH-3: 16 +/- 1%; all P < 0.05). Although capillary RBC flux did not differ between groups (P > 0.05), RBC velocity was lower in DH-1 compared with Con (Con: 324 +/- 43; DH-1: 212 +/- 30; DH-3: 266 +/- 45 mum/s; P < 0.05 DH-1 vs. Con). Baseline Pmv(O(2)) before contractions was not different between groups (P > 0.05), but the time constant of the exponential fall to contracting Pmv(O(2)) values was accelerated in the DH running groups (Con: 14.7 +/- 1.4; DH-1: 8.9 +/- 1.4; DH-3: 8.7 +/- 1.4 s, both P < 0.05 vs. Con). These findings are consistent with the presence of substantial microvascular dysfunction after downhill eccentric running, which slows the exercise hyperemic response at the onset of contractions and reduces the Pmv(O(2)) available to drive blood-muscle O(2) delivery. 相似文献