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191.
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
192.
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
193.
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
194.
195.
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
196.
Rong An Gabriela da Silva Xavier Francesca Semplici Saharnaz Vakhshouri Jared Rutter Flavio Meggio Guy A. Rutter 《Biochemical and biophysical research communications》2010,399(2):155-161
Pancreatic and duodenal homeobox 1 (PDX1) regulates pancreatic development and mature β-cell function. We demonstrate by mass spectrometry that serine residue at position 269 in the C-terminal domain of PDX1 is phosphorylated in β-cells. Besides we show that the degree of phosphorylation, assessed with a phospho-Ser-269-specific antibody, is decreased by elevated glucose concentrations in both MIN6 β-cells and primary mouse pancreatic islets. Homeodomain interacting protein kinase 2 (HIPK2) phosphorylates PDX1 in vitro; phosphate incorporation substantially decreases in PDX1 S269A mutant. Silencing of HIPK2 led to a 51 ± 0.2% decrease in Ser-269 phosphorylation in MIN6 β-cells. Mutation of Ser-269 to phosphomimetic residue glutamic acid (S269E) or de-phosphomimetic residue alanine (S269A) exerted no effect on PDX1 half-life. Instead, PDX1 S269E mutant displayed abnormal changes in subnuclear localization in response to high glucose. Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell differentiation and function. 相似文献
197.
198.
James B Koprich Tom H Johnston M Gabriela Reyes Xuan Sun Jonathan M Brotchie 《Molecular neurodegeneration》2010,5(1):43
Background
The pathological hallmarks of Parkinson's disease (PD) include the presence of alpha-synuclein (α-syn) rich Lewy bodies and neurites and the loss of dopaminergic (DA) neurons of the substantia nigra (SN). Animal models of PD based on viral vector-mediated over-expression of α-syn have been developed and show evidence of DA toxicity to varying degrees depending on the type of virus used, its concentration, and the serotype of vector employed. To date these models have been variable, difficult to reproduce, and slow in their evolution to achieve a desired phenotype, hindering their use as a model for testing novel therapeutics. To address these issues we have taken a novel vector in this context, that can be prepared in high titer and which possesses an ability to produce neuronally-directed expression, with expression dynamics optimised to provide a rapid rise in gene product expression. Thus, in the current study, we have used a high titer chimeric AAV1/2 vector, to express human A53T α-syn, an empty vector control (EV), or green fluorescent protein (GFP), the latter to control for the possibility that high levels of protein in themselves might contribute to damage.Results
We show that following a single 2 μl injection into the rat SN there is near complete coverage of the structure and expression of A53T α-syn or GFP appears throughout the striatum. Within 3 weeks of SN delivery of their respective vectors, aggregations of insoluble α-syn were observed in SN DA neurons. The numbers of DA neurons in the SN were significantly reduced by expression of A53T α-syn (52%), and to a lesser extent by GFP (24%), compared to EV controls (both P < 0.01). At the level of the striatum, AAV1/2-A53T α-syn injection produced dystrophic neurites and a significant reduction in tyrosine hydroxylase levels (by 53%, P < 0.01), this was not seen in the AAV1/2-GFP condition.Conclusions
In the current implementation of the model, we recapitulate the primary pathological hallmarks of PD, although a proportion of the SN damage may relate to general protein overload and may not be specific for A53T α-syn. Future studies will thus be required to optimise the dose of AAV1/2 employed before fully characterizing this model. The dynamics of the evolution of the pathology however, provide advantages over current models with respect to providing an initial screen to assess efficacy of novel treatments that might prevent/reverse α-syn aggregation.199.
N Stollenwerk S van Noort J Martins M Aguiar F Hilker A Pinto G Gomes 《Journal of biological dynamics》2010,4(6):634-649
Recently, the notion of a reinfection threshold in epidemiological models of only partial immunity has been debated in the literature. We present a rigorous analysis of a model of reinfection which shows a clear threshold behaviour at the parameter point where the reinfection threshold was originally described. Furthermore, we demonstrate that this threshold is the mean field version of a transition in corresponding spatial models of immunization. The reinfection threshold corresponds to the transition between annular growth of an epidemics spreading into a susceptible area leaving recovered behind and compact growth of a susceptible-infected-susceptible region growing into a susceptible area. This transition between annular growth and compact growth was described in the physics literature long before the reinfection threshold debate broke out in the theoretical biology literature. 相似文献
200.
Saad Z Usmani Robert D Bona Gabriela Chiosis Zihai Li 《Journal of hematology & oncology》2010,3(1):1-8