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61.
62.
Michael Letko Guido Silvestri Beatrice H. Hahn Frederick Bibollet-Ruche Omer Gokcumen Viviana Simon Marcel Ooms 《Journal of virology》2013,87(21):11861-11871
APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) and other lentiviruses. Most of these viruses encode a Vif protein that directly binds A3G and leads to its proteasomal degradation. Both Vif proteins of HIV-1 and African green monkey simian immunodeficiency virus (SIVagm) bind residue 128 of A3G. However, this position does not control the A3G degradation by Vif variants derived from HIV-2 and SIVmac, which both originated from SIV of sooty mangabey monkeys (SIVsmm), suggesting that the A3G binding site for Vif proteins of the SIVsmm/HIV-2 lineage differs from that of HIV-1. To map the SIVsmm Vif binding site of A3G, we performed immunoprecipitations of individual A3G domains, Vif/A3G degradation assays and a detailed mutational analysis of human A3G. We show that A3G residue 129, but not the adjacent position 128, confers susceptibility to degradation by SIVsmm Vif. An artificial A3G mutant, the P129D mutant, was resistant to degradation by diverse Vifs from HIV-1, HIV-2, SIVagm, and chimpanzee SIV (SIVcpz), suggesting a conserved lentiviral Vif binding site. Gorilla A3G naturally contains a glutamine (Q) at position 129, which makes its A3G resistant to Vifs from diverse lineages. We speculate that gorilla A3G serves as a barrier against SIVcpz strains. In summary, we show that Vif proteins from distinct lineages bind to the same A3G loop, which includes positions 128 and 129. The multiple adaptations within this loop among diverse primates underscore the importance of counteracting A3G in lentiviral evolution. 相似文献
63.
Giovanni Forte Beatrice Bocca Angela Peruzzu Francesco Tolu Yolande Asara Cristiano Farace Riccardo Oggiano Roberto Madeddu 《Biological trace element research》2013,156(1-3):79-90
Mechanisms for the onset of diabetes and the development of diabetic complications remain under extensive investigations. One of these mechanisms is abnormal homeostasis of metals, as either deficiency or excess of metals, can contribute to certain diabetic outcomes. Therefore, this paper will report the blood levels of chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), mercury (Hg), nickel (Ni), lead (Pb), selenium (Se), and zinc (Zn) in subjects with type 1 diabetes (n?=?192, mean age 48.8 years, mean disease duration 20.6 years), type 2 diabetes (n?=?68, mean age 68.4 years, mean disease duration 10.2 years), and in control subjects (n?=?59, mean age 57.2 years), and discuss the results indicating their possible role in diabetes. The metal concentrations were measured by sector field inductively coupled plasma mass spectrometry after microwave-induced acid digestion of blood samples. The accuracy was checked using a blood-based certified reference material, and recoveries of all elements were in the range of 92–101 % of certified values. Type 1 diabetes was found to be associated with Cr (p?=?0.02), Mn (p?<?0.001), Ni (p?<?0.001), Pb (p?=?0.02), and Zn (p?<?0.001) deficiency, and type 2 diabetes with Cr (p?=?0.014), Mn (p?<?0.001), and Ni (p?<?0.001) deficiency. These deficiencies were appreciated also subdividing the understudied patients for gender and age groups. Furthermore, in type 1 diabetes, there was a positive correlation between Pb and age (p?<?0.001, ρ?=?0.400) and Pb and BMI (p?<?0.001, ρ?=?0.309), while a negative correlation between Fe and age (p?=?0.002, ρ?=??0.218). In type 2 diabetes, there was a negative correlation between Fe and age (p?=?0.017, ρ?=??0.294) and Fe and BMI (p?=?0.026, ρ?=??0.301). Thus, these elements may play a role in both forms of diabetes and combined mineral supplementations could have beneficial effects. 相似文献
64.
Justin M. Greene Jennifer J. Lhost Paul J. Hines Matthew Scarlotta Max Harris Benjamin J. Burwitz Melisa L. Budde Dawn M. Dudley Ngoc Pham Brian Cain Caitlin E. Mac Nair Madelyn K. Weiker Shelby L. O'Connor Thomas C. Friedrich David H. O'Connor 《Journal of virology》2013,87(13):7382-7392
The live attenuated simian immunodeficiency virus (SIV) SIVmac239Δnef is the most effective SIV/human immunodeficiency virus (HIV) vaccine in preclinical testing. An understanding of the mechanisms responsible for protection may provide important insights for the development of HIV vaccines. Leveraging the uniquely restricted genetic diversity of Mauritian cynomolgus macaques, we performed adoptive transfers between major histocompatibility complex (MHC)-matched animals to assess the role of cellular immunity in SIVmac239Δnef protection. We vaccinated and mock vaccinated donor macaques and then harvested between 1.25 × 109 and 3.0 × 109 mononuclear cells from multiple tissues for transfer into 12 naive recipients, followed by challenge with pathogenic SIVmac239. Fluorescently labeled donor cells were detectable for at least 7 days posttransfer and trafficked to multiple tissues, including lung, lymph nodes, and other mucosal tissues. There was no difference between recipient macaques'' peak or postpeak plasma viral loads. A very modest difference in viral loads during the chronic phase between vaccinated animal cell recipients and mock-vaccinated animal cell recipients did not reach significance (P = 0.12). Interestingly, the SIVmac239 challenge virus accumulated escape mutations more rapidly in animals that received cells from vaccinated donors. These results may suggest that adoptive transfers influenced the course of infection despite the lack of significant differences in the viral loads among animals that received cells from vaccinated and mock-vaccinated donor animals. 相似文献
65.
Roger Fuoco Patrizia Bogani Gabriele Capodaglio Massimo Del Bubba Ornella Abollino Stefania Giannarelli Maria Michela Spiriti Beatrice Muscatello Saer Doumett Clara Turetta Roberta Zangrando Vincenzo Zelano Marcello Buiatti 《Journal of plant physiology》2013
Recently our findings have shown that the integration of the gene coding for the rat gluco-corticoid receptor (GR receptor) in Nicotiana langsdorffii plants induced morphophysiological effects in transgenic plants through the modification of their hormonal pattern. Phytohormones play a key role in plant responses to many different biotic and abiotic stresses since a modified hormonal profile up-regulates the activation of secondary metabolites involved in the response to stress. In this work transgenic GR plants and isogenic wild type genotypes were exposed to metal stress by treating them with 30 ppm cadmium(II) or 50 ppm chromium(VI). Hormonal patterns along with changes in key response related metabolites were then monitored and compared. Heavy metal up-take was found to be lower in the GR plants. The transgenic plants exhibited higher values of S-abscisic acid (S-ABA) and 3-indole acetic acid (IAA), salicylic acid and total polyphenols, chlorogenic acid and antiradical activity, compared to the untransformed wild type plants. Both Cd and Cr treatments led to an increase in hormone concentrations and secondary metabolites only in wild type plants. Analysis of the results suggests that the stress responses due to changes in the plant's hormonal system may derive from the interaction between the GR receptor and phytosteroids, which are known to play a key role in plant physiology and development. 相似文献
66.
Recent advances in fluorescence localization microscopy have made it possible to image chemically fixed and living cells at 20 nm lateral resolution. We apply this methodology to simultaneously record receptor organization and dynamics on the ventral surface of live RBL-2H3 mast cells undergoing antigen-mediated signaling. Cross-linking of IgE bound to FcεRI by multivalent antigen initiates mast cell activation, which leads to inflammatory responses physiologically. We quantify receptor organization and dynamics as cells are stimulated at room temperature (22°C). Within 2 min of antigen addition, receptor diffusion coefficients decrease by an order of magnitude, and single-particle trajectories are confined. Within 5 min of antigen addition, receptors organize into clusters containing ∼100 receptors with average radii of ∼70 nm. By comparing simultaneous measurements of clustering and mobility, we determine that there are two distinct stages of receptor clustering. In the first stage, which precedes stimulated Ca2+ mobilization, receptors slow dramatically but are not tightly clustered. In the second stage, receptors are tightly packed and confined. We find that stimulation-dependent changes in both receptor clustering and mobility can be reversed by displacing multivalent antigen with monovalent ligands, and that these changes can be modulated through enrichment or reduction in cellular cholesterol levels. 相似文献
67.
Mark Weber-Krüger Klaus Gr?schel Meinhard Mende Joachim Seegers Rosine Lahno Beatrice Haase Cord-Friedrich Niehaus Frank Edelmann Gerd Hasenfu? Rolf Wachter Raoul Stahrenberg 《PloS one》2013,8(6)
Background
Detecting paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia is challenging. Frequent premature atrial complexes (PAC/h) and the longest supraventricular run on 24-h-Holter (SV-run24 h), summarised as excessive supraventricular ectopic activity (ESVEA), may help selecting patients for extended ECG-monitoring, especially in combination with echocardiographic marker LAVI/a’ (left atrial volume index/late diastolic tissue Doppler velocity).Methods
Retrospective analysis from the prospective monocentric observational trial Find-AF (ISRCTN-46104198). Patients with acute stroke or TIA were enrolled at the University Hospital Göttingen, Germany. Those with sinus rhythm at presentation received 7-day Holter-monitoring. ESVEA was quantified in one 24-hour interval free from PAF. Echocardiographic parameters were assessed prospectively.Results
PAF was detected in 23/208 patients (11.1%). The median was 4 [IQR 1; 22] for PAC/h and 5 [IQR 0; 9] for SV-run24 h. PAF was more prevalent in patients with ESVEA: 19.6% vs. 2.8% for PAC/h >4 vs. ≤4 (p<0.001); 17.0% vs. 4.9% for SV-run24 h >5 vs. ≤5 beats (p = 0.003). Patients with PAF showed more supraventricular ectopic activity: 29 PAC/h [IQR 9; 143] vs. 4 PAC/h [1]; [14] and longest SV-run24 h = 10 [5]; [21] vs. 0 [0; 8] beats (both p<0.001). Both markers discriminated between the PAF- and the Non-PAF-group (area under receiver-operator-characteristics-curve 0.763 [95% CI 0.667; 0.858] and 0.716 [0.600; 0.832]). In multivariate analyses log(PAC/h) and log(SV-run24 h) were independently indicative of PAF. In Patients with PAC/h ≤4 and normal LAVI/a’ PAF was excluded, whereas those with PAC/h >4 and abnormal LAVI/a’ showed high PAF-rates.Conclusions
ESVEA discriminated PAF from non-PAF beyond clinical factors including LAVI/a’ in patients with cerebral ischemia. Normal LAVI/a’+PAC/h ≤4 ruled out PAF, while prevalence was high in those with abnormal LAVI/a’+PAC/h >4. 相似文献68.
J. Pedro Fernández-Murray Sergey V. Prykhozhij J. Noelia Dufay Shelby L. Steele Daniel Gaston Gheyath K. Nasrallah Andrew J. Coombs Robert S. Liwski Conrad V. Fernandez Jason N. Berman Christopher R. McMaster 《PLoS genetics》2016,12(1)
Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia. 相似文献
69.
Mathew Seymour Omaththage P. Perera Howard W. Fescemyer Ryan E. Jackson Shelby J. Fleischer Craig A. Abel 《Ecology and evolution》2016,6(10):3198-3207
Seasonal climatic shifts create peripheral habitats that alternate between habitable and uninhabitable for migratory species. Such dynamic peripheral habitats are potential sites where migratory species could evolve high genetic diversity resulting from convergence of immigrants from multiple regionally distant areas. Migrant populations of Helicoverpa zea (Boddie) captured during two different seasons were assessed for genetic structure using microsatellite markers and for host plant type using stable carbon isotope analysis. Individuals (N = 568) were genotyped and divided into 13 putative populations based on collection site and time. Fixation indices (F‐statistics), analysis of molecular variance (AMOVA), and discriminant analysis of principal components (DAPC) were used to examine within and among population genetic variation. Mean number of alleles per locus was 10.25 (± 3.2 SD), and allelic richness ranged from 2.38 to 5.13 (± 3.2 SD). The observed and expected heterozygosity ranged from 0.07 to 0.48 and 0.08 to 0.62, respectively. Low FST (0.01 to 0.02) and high FIS (0.08 to 0.33) values suggest captured migrants originated from breeding populations with different allele frequencies. We postulate that high genetic diversity within migrant populations and low genetic differentiation among migrant populations of H. zea are the result of asymmetrical immigration due to the high dispersal and reproductive behavior of H. zea, which may hinder the adaptation and establishment of H. zea to peripheral habitat. These findings highlight the importance of assessing peripheral population structure in relation to ecological and evolutionary dynamics of this and other highly reproductive and dispersive species. 相似文献
70.