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121.
122.
Copeland RA Marcinkeviciene J Haque TS Kopcho LM Jiang W Wang K Ecret LD Sizemore C Amsler KA Foster L Tadesse S Combs AP Stern AM Trainor GL Slee A Rogers MJ Hobbs F 《The Journal of biological chemistry》2000,275(43):33373-33378
We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the dihydroorotate dehydrogenase of Helicobacter pylori but that do not inhibit the cognate enzymes from Gram-positive bacteria or humans. In culture these compounds inhibit the growth of H. pylori selectively, showing no effect on other Gram-negative or Gram-positive bacteria or human cell lines. These compounds represent the first examples of H. pylori-specific antibacterial agents. Cellular activity within this structural class appears to be due to dihydroorotate dehydrogenase inhibition. Minor structural changes that abrogate in vitro inhibition of the enzyme likewise eliminate cellular activity. Furthermore, the minimum inhibitory concentrations of these compounds increase upon addition of orotate to the culture medium in a concentration-dependent manner, consistent with dihydroorotate dehydrogenase inhibition as the mechanism of cellular inhibition. The data presented here suggest that targeted inhibition of de novo pyrimidine biosynthesis may be a valuable mechanism for the development of antimicrobial agents selective for H. pylori. 相似文献
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125.
Exposure to air pollutants, including particulate matter, results in activation of the brain inflammatory response and Alzheimer disease (AD)-like pathology in dogs and humans. However, the length of time required for inhalation of ambient particulate matter to influence brain inflammation and AD pathology is less clear. Here, we studied the effect of 3 and 9 months of air particulate matter (<2.5 μm diameter, PM2.5) exposure on brain inflammatory phenotype and pathological hallmarks of AD in C57BL/6 mice. Using western blot, ELISA, and cytokine array analysis we quantified brain APP, beta-site APP cleaving enzyme (BACE), oligomeric protein, total Aβ 1–40 and Aβ 1–42 levels, inducible nitric oxide synthase (iNOS), nitrotyrosine-modified proteins, HNE-Michael adducts, vascular cell adhesion molecule 1 (VCAM-1), glial markers (GFAP, Iba-1), pre- and post- synaptic markers (synaptophysin and PSD-95), cyclooxygenase (COX-1, COX-2) levels, and the cytokine profile in PM2.5 exposed and filtered air control mice. Only 9 month PM2.5 exposure increased BACE protein levels, APP processing, and Aβ 1–40 levels. This correlated with a concomitant increase in COX-1 and COX-2 protein levels and a modest alteration in the cytokine profile. These data support the hypothesis that prolonged exposure to airborne particulate matter has the potential to alter brain inflammatory phenotype and promote development of early AD-like pathology. 相似文献
126.
We present evidence for the expression of three alpha-dystroglycan glycoforms in skeletal muscle cells, including two minor glycoforms marked by either patent or latent reactivity with the N-acetylgalactosamine-specific lectin Vicia villosa agglutinin. Both minor glycoforms co-isolated with beta-dystroglycan, but not with other dystrophin/utrophin-glycoprotein complex components, suggesting that they may perform distinct or modified cellular functions. We also confirmed that both patent and latent V. villosa agglutinin-reactive alpha-dystroglycan glycoforms are expressed in C2C12 myotubes. However, we found that the combined effect of saturating concentrations of V. villosa agglutinin and laminin-1 were strictly additive with respect to acetylcholine receptor cluster formation in C2C12 myotubes, which suggests that laminin-1 and V. villosa agglutinin do not compete for the same binding site on the cell surface. Finally, although beta-N-acetylhexosaminidase digestion dramatically inhibited agrin-, V. villosa agglutinin-, and laminin-1-induced acetylcholine receptor clustering in C2C12 myotubes, treatment with this enzyme had no effect on the amount of alpha-dystroglycan that was bound to V. villosa agglutinin-agarose. We conclude that alpha-dystroglycan is not the V. villosa agglutinin receptor implicated in acetylcholine receptor cluster formation. However, our data provide new support for the hypothesis that different glycoforms of alpha-dystroglycan may perform distinct functions even within the same cell. 相似文献
127.
Wang H Smith KP Combs E Blake T Horsley RD Muehlbauer GJ 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2012,124(1):111-124
Over the past two decades many quantitative trait loci (QTL) have been detected; however, very few have been incorporated
into breeding programs. The recent development of genome-wide association studies (GWAS) in plants provides the opportunity
to detect QTL in germplasm collections such as unstructured populations from breeding programs. The overall goal of the barley
Coordinated Agricultural Project was to conduct GWAS with the intent to couple QTL detection and breeding. The basic idea
is that breeding programs generate a vast amount of phenotypic data and combined with cheap genotyping it should be possible
to use GWAS to detect QTL that would be immediately accessible and used by breeding programs. There are several constraints
to using breeding program-derived phenotype data for conducting GWAS namely: limited population size and unbalanced data sets.
We chose the highly heritable trait heading date to study these two variables. We examined 766 spring barley breeding lines
(panel #1) grown in balanced trials and a subset of 384 spring barley breeding lines (panel #2) grown in balanced and unbalanced
trials. In panel #1, we detected three major QTL for heading date that have been detected in previous bi-parental mapping
studies. Simulation studies showed that population sizes greater than 384 individuals are required to consistently detect
QTL. We also showed that unbalanced data sets from panel #2 can be used to detect the three major QTL. However, unbalanced
data sets resulted in an increase in the false-positive rate. Interestingly, one-step analysis performed better than two-step
analysis in reducing the false-positive rate. The results of this work show that it is possible to use phenotypic data from
breeding programs to detect QTL, but that careful consideration of population size and experimental design are required. 相似文献
128.
Mahmoud L. Soliman Kendra L. Puig Colin K. Combs Thad A. Rosenberger 《Journal of neurochemistry》2012,123(4):555-567
Acetate supplementation increases brain acetyl‐CoA and histone acetylation and reduces lipopolysaccharide (LPS)‐induced neuroglial activation and interleukin (IL)‐1β expression in vivo. To determine how acetate imparts these properties, we tested the hypothesis that acetate metabolism reduces inflammatory signaling in microglia. To test this, we measured the effect acetate treatment had on cytokine expression, mitogen‐activated protein kinase (MAPK) signaling, histone H3 at lysine 9 acetylation, and alterations of nuclear factor‐kappa B (NF‐κB) in primary and BV‐2 cultured microglia. We found that treatment induced H3K9 hyperacetylation and reversed LPS‐induced H3K9 hypoacetylation similar to that found in vivo. LPS also increased IL‐1β, IL‐6, and tumor necrosis factor‐alpha (TNF‐α) mRNA and protein, whereas treatment returned the protein to control levels and only partially attenuated IL‐6 mRNA. In contrast, treatment increased mRNA levels of transforming growth factor‐β1 (TGF‐β1) and both IL‐4 mRNA and protein. LPS increased p38 MAPK and JNK phosphorylation at 4 and 2–4 h, respectively, whereas treatment reduced p38 MAPK and JNK phosphorylation only at 2 h. In addition, treatment reversed the LPS‐induced elevation of NF‐κB p65 protein and phosphorylation at serine 468 and induced acetylation at lysine 310. These data suggest that acetate metabolism reduces inflammatory signaling and alters histone and non‐histone protein acetylation. 相似文献
129.
A vitamin B12 deficiency in chicks has been found to significantly increase the blood levels of nonprotein nitrogen, amino nitrogen, urea nitrogen, creatinine, and glucose as compared with those of chicks receiving crystalline vitamin B12. The level of uric acid was not consistently affected. These findings further suggest that vitamin B12 is involved in nitrogen metabolism in the chick. 相似文献
130.
Refaei MA Combs A Kojetin DJ Cavanagh J Caperelli C Rance M Sapitro J Tsang P 《Journal of biomolecular NMR》2011,49(1):3-7
NMR spectroscopy has distinct advantages for providing insight into protein structures, but faces significant resolution challenges
as protein size increases. To alleviate such resonance overlap issues, the ability to produce segmentally labeled proteins
is beneficial. Here we show that the S. aureus transpeptidase sortase A can be used to catalyze the ligation of two separately expressed domains of the same protein, MecA
(B. subtilis). The yield of purified, segmentally labeled MecA protein conjugate is ~40%. The resultant HSQC spectrum obtained from this
domain-labeled conjugate demonstrates successful application of sortase A for segmental labeling of multi-domain proteins
for solution NMR study. 相似文献