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181.
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183.
Gabriela E. Davey Bin Wu Yuancai Dong Uttam Surana Curt A. Davey 《Nucleic acids research》2010,38(6):2081-2088
DNA stretching in the nucleosome core can cause dramatic structural distortions, which may influence compaction and factor recognition in chromatin. We find that the base pair unstacking arising from stretching-induced extreme minor groove kinking near the nucleosome centre creates a hot spot for intercalation and alkylation by a novel anticancer compound. This may have far reaching implications for how chromatin structure can influence binding of intercalator species and indicates potential for the development of site selective DNA-binding agents that target unique conformational features of the nucleosome. 相似文献
184.
Andrea Harničarová Horáková Gabriela Galiová Soňa Legartová Stanislav Kozubek Pavel Matula Eva Bártová 《Journal of structural biology》2010,169(1):124-133
The epigenetic modification of histones dictates the formation of euchromatin and heterochromatin domains. We studied the effects of a deficiency of histone methyltransferase, SUV39h, and trichostatin A-dependent hyperacetylation on the structural stability of centromeric clusters, called chromocentres. We did not observe the expected disintegration of chromocentres, but both SUV39h deficiency and hyperacetylation in SUV39h+/+ cells induced the re-positioning of chromocentres closer to the nuclear periphery. Conversely, TSA treatment of SUV39h?/? cells re-established normal nuclear radial positioning of chromocentres. This structural re-arrangement was likely caused by several epigenetic events at centromeric heterochromatin. In particular, reciprocal exchanges between H3K9me1, H3K9me2, H3K9me3, DNA methylation, and HP1 protein levels influenced chromocentre nuclear composition. For example, H3K9me1 likely substituted for the function of H3K9me3 in chromocentre nuclear arrangement and compaction. Our results illustrate the important and interchangeable roles of epigenetic marks for chromocentre integrity. Therefore, we propose a model for epigenetic regulation of nuclear stability of centromeric heterochromatin in the mouse genome. 相似文献
185.
Zhenfa Zhang Marharyta Pivavarchyk Karunai Leela Subramanian A. Gabriela Deaciuc Linda P. Dwoskin Peter A. Crooks 《Bioorganic & medicinal chemistry letters》2010,20(4):1420-1423
By linking two or three mecamylamine or 2,2,6,6-tetramethylpiperidine (TMP) molecules together via a linear lipophilic bis-methylene linker or a specially designed conformationally restricted tris-linker, a series of bis- and tris-tertiary amine analogs has been synthesized and evaluated as potent antagonists at nAChRs mediating nicotine-evoked [3H]dopamine release from rat striatal slices. Compounds 7e, 14b and 16 demonstrated high potency in decreasing nicotine-evoked [3H]dopamine release (IC50 = 2.2, 46, and 107 nM, respectively). The preliminary structure–activity data obtained with these new analogs suggest the importance of the length of the methylene linker in the bis-analog series. Such bis-tertiary amino analogs may provide a new strategy for the design of drugable ligands that have high inhibitory potency against nAChRs mediating nicotine-evoked dopamine release in striatum, which have been suggested to be target receptors of interest in the development of potential smoking cessation therapies. 相似文献
186.
Javier García‐Nafría Gabriela Ondrovičová Elena Blagova Vladimir M. Levdikov Jacob A. Bauer Carolyn K. Suzuki Eva Kutejová Anthony J. Wilkinson Keith S. Wilson 《Protein science : a publication of the Protein Society》2010,19(5):987-999
ATP‐dependent proteases are crucial for cellular homeostasis. By degrading short‐lived regulatory proteins, they play an important role in the control of many cellular pathways and, through the degradation of abnormally misfolded proteins, protect the cell from a buildup of aggregates. Disruption or disregulation of mammalian mitochondrial Lon protease leads to severe changes in the cell, linked with carcinogenesis, apoptosis, and necrosis. Here we present the structure of the proteolytic domain of human mitochondrial Lon at 2 Å resolution. The fold resembles those of the three previously determined Lon proteolytic domains from Escherichia coli, Methanococcus jannaschii, and Archaeoglobus fulgidus. There are six protomers in the asymmetric unit, four arranged as two dimers. The intersubunit interactions within the two dimers are similar to those between adjacent subunits of the hexameric ring of E. coli Lon, suggesting that the human Lon proteolytic domain also forms hexamers. The active site contains a 310 helix attached to the N‐terminal end of α‐helix 2, which leads to the insertion of Asp852 into the active site, as seen in M. jannaschii. Structural considerations make it likely that this conformation is proteolytically inactive. When comparing the intersubunit interactions of human with those of E. coli Lon taken with biochemical data leads us to propose a mechanism relating the formation of Lon oligomers with a conformational shift in the active site region coupled to a movement of a loop in the oligomer interface, converting the proteolytically inactive form seen here to the active one in the E. coli hexamer. 相似文献
187.
Cecilia Vanesa Compagnucci Gabriela Edith Compagnucci Christian Esteban Lezón Ana Patricia Chiarenza Juan Carlos Elverdin Patricia Mónica Boyer 《Endocrinología y nutrición》2010,57(5):187-195
ObjectiveMild and chronic energy restriction results in growth retardation with puberal delay, a nutritional disease known as nutritional dwarfing (ND). The aim of the present study was to assess the profile of hypothalamic luteinizing hormone-releasing hormone (LHRH) release, at baseline and under glutamate stimulation, in ND rats to elucidate gonadotrophic dysfunction. Reproductive ability during refeeding was also studied.Material and methodsAt weaning, 60 male rats were assigned to two groups of 30 animals each: a control and an experimental group. Control rats were fed ad libitum with a balanced rodent diet. The experimental group received 80% of the diet consumed by the control group for 4 weeks. After 4 weeks of food restriction, the ND group was fed freely for 8 weeks. Ten rats from each group were sacrificed every 4 weeks for assays.ResultsAt week 4, body weight and length were significantly diminished in the experimental group vs. the control group (p<0.001). No changes were observed in LHRH baseline release, pulse frequency or amplitude in the experimental group compared with the control group at any time. However, under glutamate stimulation, LHRH release was significantly higher in ND rats than in control rats at week 4 (p<0.05). Refeeding the ND group allowed the rats to reach overall growth and reproductive ability.ConclusionsThe results of the present study suggest that the response to the facilitatory effect of glutamate on LHRH release in post-restricted ND rats is probably related to a lesser central nervous system maturation in relation to their chronological age. The adequate somatic growth and normal reproductive ability attained with refeeding suggest the reversibility of the two energetically costly processes compromised by global, mild and chronic food restriction. 相似文献
188.
Gabriela Bugla-Płoskońska Jacek Rybka Bożena Futoma-Kołoch Agnieszka Cisowska Andrzej Gamian Włodzimierz Doroszkiewicz 《Microbial ecology》2010,59(3):601-613
Sialic acid (N-acetylneuraminic acid, NeuAc) plays an essential role in protecting gram-negative bacteria against the bactericidal
activity of serum and may contribute to the pathogenicity of bacteria by mimicking epitopes that resemble host tissue components
(molecular mimicry). The role of sialic acid (NeuAc)-containing lipopolysaccharides (LPS) of Salmonella O48 strains in the complement activation of normal human serum (NHS) was investigated. NeuAc-containing lipooligosaccharides
cause a downregulation of complement activation and may serve to camouflage the bacterial surface from the immunological response
of the host. Serotype O48 Salmonella strains have the O-antigen structure containing NeuAc while its serovars differ in outer membrane protein composition. In
this study, the mechanisms of complement activation responsible for killing Salmonella O48 serum-sensitive rods by NHS were established. Four of such mechanisms involving pathways, which are important in the
bactericidal mechanism of complement activation, were distinguished: only the classical/lectin pathways, independent activation
of the classical/lectin or alternative pathway, parallel activation of the classical/lectin and alternative pathways, and
only the alternative pathway important in the bactericidal action of human serum. To further study the role of NeuAc, its
content in bacterial cells was determined by gas-liquid chromatography-mass spectrometry in relation to 3-deoxy-D-manno-2-octulosonic
acid (Kdo), an inherent constituent of LPS. The results indicate that neither the presence of sialic acid in LPS nor the length
of the O-specific part of LPS containing NeuAc plays a decisive role in determining bacterial resistance to the bactericidal
activity of complement and that the presence of sialic acid in the structure of LPS is not sufficient to block the activation
of the alternative pathway of complement. We observed that for three strains with a very high NeuAc/Kdo ratio the alternative
pathways were decisive in the bactericidal action of human serum. The results indicated that those strains are not capable
of inhibiting the alternative pathway very effectively. As the pathogenicity of most Salmonella serotypes remains undefined, research into the interactions between these bacterial cells and host organisms is indispensable. 相似文献
189.
190.
Greg Clark Michael Wu Noel Wat James Onyirimba Trieu Pham Niculin Herz Justin Ogoti Delmy Gomez Arinda A. Canales Gabriela Aranda Misha Blizard Taylor Nyberg Anne Terry Jonathan Torres Jian Wu Stanley J. Roux 《Plant molecular biology》2010,74(4-5):423-435
Root hairs secrete ATP as they grow, and extracellular ATP and ADP can trigger signaling pathways that regulate plant cell growth. In several plant tissues the level of extracellular nucleotides is limited in part by ectoapyrases (ecto-NTPDases), and the growth of these tissues is strongly influenced by their level of ectoapyrase expression. Both chemical inhibition of ectoapyrase activity and suppression of the expression of two ectoapyrase enzymes by RNAi in Arabidopsis resulted in inhibition of root hair growth. As assayed by a dose-response curve, different concentrations of the poorly hydrolysable nucleotides, ATPγS and ADPβS, could either stimulate (at 7.5–25 μM) or inhibit (at ≥ 150 μM) the growth rate of root hairs in less than an hour. Equal amounts of AMPS, used as a control, had no effect on root hair growth. Root hairs of nia1nia2 mutants, which are suppressed in nitric oxide (NO) production, and of atrbohD/F mutants, which are suppressed in the production of H2O2, did not show growth responses to applied nucleotides, indicating that the growth changes induced by these nucleotides in wild-type plants were likely transduced via NO and H2O2 signals. Consistent with this interpretation, treatment of root hairs with different concentrations of ATPγS induced different accumulations of NO and H2O2 in root hair tips. Two mammalian purinoceptor antagonists also blocked the growth responses induced by extracellular nucleotides, suggesting that they were initiated by a receptor-based mechanism. 相似文献