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31.
Human immunodeficiency virus type-1 (HIV-1) fitness has been associated with virus entry, a process mediated by the envelope glycoprotein (Env). We previously described Env genetic diversification in a Zambian, subtype C infected, slow-progressor child (1157i) in parallel with an evolving neutralizing antibody response. Because of the role the Variable-3 loop (V3) plays in transmission, cell tropism, neutralization sensitivity, and fitness, longitudinally isolated 1157i C2-V4 alleles were cloned into HIV-1NL4-3-eGFP and -DsRed2 infectious molecular clones. The fluorescent reporters allowed for dual-infection competitions between all patient-derived C2-V4 chimeras to quantify the effect of V3 diversification and selection on fitness. ‘Winners’ and ‘losers’ were readily discriminated among the C2-V4 alleles. Exceptional sensitivity for detection of subtle fitness differences was revealed through analysis of two alleles differing in a single synonymous amino acid. However, when the outcomes of N = 33 competitions were averaged for each chimera, the aggregate analysis showed that despite increasing diversification and divergence with time, natural selection of C2-V4 sequences in this individual did not appear to be producing a ‘survival of the fittest’ evolutionary pattern. Rather, we detected a relatively flat fitness landscape consistent with mutational robustness. Fitness outcomes were then correlated with individual components of the entry process. Env incorporation into particles correlated best with fitness, suggesting a role for Env avidity, as opposed to receptor/coreceptor affinity, in defining fitness. Nevertheless, biochemical analyses did not identify any step in HIV-1 entry as a dominant determinant of fitness. Our results lead us to conclude that multiple aspects of entry contribute to maintaining adequate HIV-1 fitness, and there is no surrogate analysis for determining fitness. The capacity for subtle polymorphisms in Env to nevertheless significantly impact viral fitness suggests fitness is best defined by head-to-head competition. 相似文献
32.
Dipankar Ray Shirish Shukla Uday Sankar Allam Abigail Helman Susmita Gurjar Ramanand Linda Tran Michael Bassetti Pranathi Meda Krishnamurthy Matthew Rumschlag Michelle Paulsen Lei Sun Thomas P. Shanley Mats Ljungman Mukesh K. Nyati Ming Zhang Theodore S. Lawrence 《PloS one》2013,8(2)
The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy) either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy) and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (−/−) mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTPSer178 phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT. 相似文献
33.
Mark I. Melhorn Abigail S. Brodsky Jessica Estanislau Joseph A. Khoory Ben Illigens Itaru Hamachi Yasutaka Kurishita Andrew D. Fraser Anne Nicholson-Weller Elena Dolmatova Heather S. Duffy Ionita C. Ghiran 《The Journal of biological chemistry》2013,288(43):31139-31153
Humans and other higher primates are unique among mammals in using complement receptor 1 (CR1, CD35) on red blood cells (RBC) to ligate complement-tagged inflammatory particles (immune complexes, apoptotic/necrotic debris, and microbes) in the circulation for quiet transport to the sinusoids of spleen and liver where resident macrophages remove the particles, but allow the RBC to return unharmed to the circulation. This process is called immune-adherence clearance. In this study we found using luminometric- and fluorescence-based methods that ligation of CR1 on human RBC promotes ATP release. Our data show that CR1-mediated ATP release does not depend on Ca2+ or enzymes previously shown to mediate an increase in membrane deformability promoted by CR1 ligation. Furthermore, ATP release following CR1 ligation increases the mobility of the lipid fraction of RBC membranes, which in turn facilitates CR1 clustering, and thereby enhances the binding avidity of complement-opsonized particles to the RBC CR1. Finally, we have found that RBC-derived ATP has a stimulatory effect on phagocytosis of immune-adherent immune complexes. 相似文献
34.
Eva Matalova Herve Lesot Eva Svandova Tom Vanden Berghe Paul T. Sharpe Christopher Healy Peter Vandenabeele Abigail S. Tucker 《Development, growth & differentiation》2013,55(5):615-621
Apoptosis during tooth development appears dependent on the apoptotic executioner caspase‐3, but not caspase‐7. Instead, activated caspase‐7 has been found in differentiated odontoblasts and ameloblasts, where it does not correlate with apoptosis. To further investigate these findings, the mouse incisor was used as a model. Analysis of caspase‐7‐deficient mice revealed a significant thinner layer of hard tissue in the adult incisor. Micro computed tomography scan confirmed this decrease in mineralized tissues. These data strongly suggest that caspase‐7 might be directly involved in functional cell differentiation and regulation of the mineralization of dental matrices. 相似文献
35.
Michael Mueller Paula Barros Abigail?S. Witherden Amy?L. Roberts Zhou Zhang Helmut Schaschl Chack-Yung Yu Matthew?E. Hurles Catherine Schaffner R.?Andres Floto Laurence Game Karyn?Meltz Steinberg Richard?K. Wilson Tina?A. Graves Evan?E. Eichler H.?Terence Cook Timothy?J. Vyse Timothy?J. Aitman 《American journal of human genetics》2013,92(1):28-40
Reduced FCGR3B copy number is associated with increased risk of systemic lupus erythematosus (SLE). The five FCGR2/FCGR3 genes are arranged across two highly paralogous genomic segments on chromosome 1q23. Previous studies have suggested mechanisms for structural rearrangements at the FCGR2/FCGR3 locus and have proposed mechanisms whereby altered FCGR3B copy number predisposes to autoimmunity, but the high degree of sequence similarity between paralogous segments has prevented precise definition of the molecular events and their functional consequences. To pursue the genomic pathology associated with FCGR3B copy-number variation, we integrated sequencing data from fosmid and bacterial artificial chromosome clones and sequence-captured DNA from FCGR3B-deleted genomes to establish a detailed map of allelic and paralogous sequence variation across the FCGR2/FCGR3 locus. This analysis identified two highly paralogous 24.5 kb blocks within the FCGR2C/FCGR3B/FCGR2B locus that are devoid of nonpolymorphic paralogous sequence variations and that define the limits of the genomic regions in which nonallelic homologous recombination leads to FCGR2C/FCGR3B copy-number variation. Further, the data showed evidence of swapping of haplotype blocks between these highly paralogous blocks that most likely arose from sequential ancestral recombination events across the region. Functionally, we found by flow cytometry, immunoblotting and cDNA sequencing that individuals with FCGR3B-deleted alleles show ectopic presence of FcγRIIb on natural killer (NK) cells. We conclude that FCGR3B deletion juxtaposes the 5′-regulatory sequences of FCGR2C with the coding sequence of FCGR2B, creating a chimeric gene that results in an ectopic accumulation of FcγRIIb on NK cells and provides an explanation for SLE risk associated with reduced FCGR3B gene copy number. 相似文献
36.
37.
Abigail Doucette Xiaohui Jiang Jon Fryzek Jenna Coalson Kimmie McLaurin Christopher S. Ambrose 《PloS one》2016,11(4)
BackgroundRespiratory syncytial virus (RSV) causes significant pediatric morbidity and is the most common cause of bronchiolitis. Bronchiolitis hospitalizations declined among US infants from 2000‒2009; however, rates in infants at high risk for RSV have not been described. This study examined RSV and unspecified bronchiolitis (UB) hospitalization rates from 1997‒2012 among US high-risk infants.MethodsThe Kids’ Inpatient Database (KID) infant annual RSV (ICD-9 079.6, 466.11, 480.1) and UB (ICD-9 466.19, 466.1) hospitalization rates were estimated using weighted counts. Denominators were based on birth hospitalizations with conditions associated with high-risk for RSV: chronic perinatal respiratory disease (chronic lung disease [CLD]); congenital airway anomalies (CAA); congenital heart disease (CHD); Down syndrome (DS); and other genetic, metabolic, musculoskeletal, and immunodeficiency conditions. Preterm infants could not be identified. Hospitalizations were characterized by mechanical ventilation, inpatient mortality, length of stay, and total cost (2015$). Poisson and linear regression were used to test statistical significance of trends.ResultsRSV and UB hospitalization rates were substantially elevated for infants with higher-risk CHD, CLD, CAA and DS without CHD compared with all infants. RSV rates declined by 47.0% in CLD and 49.7% in higher-risk CHD infants; no other declines in high-risk groups were observed. UB rates increased in all high-risk groups except for a 22.5% decrease among higher-risk CHD. Among high-risk infants, mechanical ventilation increased through 2012 to 20.4% and 13.5% of RSV and UB hospitalizations; geometric mean cost increased to $31,742 and $25,962, respectively, and RSV mortality declined to 0.9%.ConclusionsAmong high-risk infants between 1997 and 2012, RSV hospitalization rates declined among CLD and higher-risk CHD infants, coincident with widespread RSV immunoprophylaxis use in these populations. UB hospitalization rates increased in all high-risk groups except higher-risk CHD, suggesting improvement in the health status of higher-risk CHD infants, potentially due to enhanced surgical interventions. Mechanical ventilation use and RSV and UB hospitalization costs increased while RSV mortality declined. 相似文献
38.
Joseph Khoory Jessica Estanislau Abdallah Elkhal Asmae Lazaar Mark I. Melhorn Abigail Brodsky Ben Illigens Itaru Hamachi Yasutaka Kurishita Alexander R. Ivanov Sergey Shevkoplyas Nathan I. Shapiro Ionita C. Ghiran 《PloS one》2016,11(1)
Acute, inflammatory conditions associated with dysregulated complement activation are characterized by significant increases in blood concentration of reactive oxygen species (ROS) and ATP. The mechanisms by which these molecules arise are not fully understood. In this study, using luminometric- and fluorescence-based methods, we show that ligation of glycophorin A (GPA) on human red blood cells (RBCs) results in a 2.1-fold, NADPH-oxidase-dependent increase in intracellular ROS that, in turn, trigger multiple downstream cascades leading to caspase-3 activation, ATP release, and increased band 3 phosphorylation. Functionally, using 2D microchannels to assess membrane deformability, GPS-ligated RBCs travel 33% slower than control RBCs, and lipid mobility was hindered by 10% using fluorescence recovery after photobleaching (FRAP). These outcomes were preventable by pretreating RBCs with cell-permeable ROS scavenger glutathione monoethyl ester (GSH-ME). Our results obtained in vitro using anti-GPA antibodies were validated using complement-altered RBCs isolated from control and septic patients. Our results suggest that during inflammatory conditions, circulating RBCs significantly contribute to capillary flow dysfunctions, and constitute an important but overlooked source of intravascular ROS and ATP, both critical mediators responsible for endothelial cell activation, microcirculation impairment, platelet activation, as well as long-term dysregulated adaptive and innate immune responses. 相似文献
39.
Abigail H. Davies Joanna McGlashan Mareike G. Posner April K. Roberts Clifford C. Shone K. Ravi Acharya 《Biochemistry and Biophysics Reports》2016
Clostridium difficile binary toxin (CDT) is an ADP-ribosyltransferase which is linked to enhanced pathogenesis of C. difficile strains. CDT has dual function: domain a (CDTa) catalyses the ADP-ribosylation of actin (enzymatic component), whereas domain b (CDTb) transports CDTa into the cytosol (transport component). Understanding the molecular mechanism of CDT is necessary to assess its role in C. difficile infection. Identifying amino acids that are essential to CDTa function may aid drug inhibitor design to control the severity of C. difficile infections. Here we report mutations of key catalytic residues within CDTa and their effect on CDT cytotoxicity. Rather than an all-or-nothing response, activity of CDTa mutants vary with the type of amino acid substitution; S345A retains cytotoxicity whereas S345Y was sufficient to render CDT non-cytotoxic. Thus CDTa cytotoxicity levels are directly linked to ADP-ribosyltransferase activity. 相似文献