214 research outputs found

    Different Modes of Retrovirus Restriction by Human APOBEC3A and APOBEC3G In Vivo

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    The apolipoprotein B editing complex 3 (A3) cytidine deaminases are among the most highly evolutionarily selected retroviral restriction factors, both in terms of gene copy number and sequence diversity. Primate genomes encode seven A3 genes, and while A3F and 3G are widely recognized as important in the restriction of HIV, the role of the other genes, particularly A3A, is not as clear. Indeed, since human cells can express multiple A3 genes, and because of the lack of an experimentally tractable model, it is difficult to dissect the individual contribution of each gene to virus restriction in vivo. To overcome this problem, we generated human A3A and A3G transgenic mice on a mouse A3 knockout background. Using these mice, we demonstrate that both A3A and A3G restrict infection by murine retroviruses but by different mechanisms: A3G was packaged into virions and caused extensive deamination of the retrovirus genomes while A3A was not packaged and instead restricted infection when expressed in target cells. Additionally, we show that a murine leukemia virus engineered to express HIV Vif overcame the A3G-mediated restriction, thereby creating a novel model for studying the interaction between these proteins. We have thus developed an in vivo system for understanding how human A3 proteins use different modes of restriction, as well as a means for testing therapies that disrupt HIV Vif-A3G interactions.United States. Public Health Service (Grant R01-AI-085015)United States. Public Health Service (Grant T32-CA115299 )United States. Public Health Service (Grant F32-AI100512

    GEICO (Spanish Group for Investigation on Ovarian Cancer) treatment guidelines in ovarian cancer 2012

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    In 2006, under the auspices of The Spanish Research Group for Ovarian Cancer (Spanish initials GEICO), the first “Treatment Guidelines in Ovarian Cancer” were developed and then published in Clinical and Translational Oncology by Poveda Velasco et al. (Clin Transl Oncol 9(5):308–316, 2007). Almost 6 years have elapsed and over this time, we have seen some important developments in the treatment of ovarian cancer. Significant changes were also introduced after the GCIG-sponsored 4th Consensus Conference on Ovarian Cancer by Stuart et al. (Int J Gynecol Cancer 21:750–755, 2011). So we decided to update the treatment guidelines in ovarian cancer and, with this objective, a group of investigators of the GEICO group met in February 2012. This study summarizes the presentations, discussions and evidence that were reviewed during the meeting and during further discussions of the manuscript

    Use of dentifrices to prevent erosive tooth wear: harmful or helpful?

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    Dental erosion is the loss of dental hard tissues caused by non-bacterial acids. Due to acid contact, the tooth surface becomes softened and more prone to abrasion from toothbrushing. Dentifrices containing different active agents may be helpful in allowing rehardening or in increasing surface resistance to further acidic or mechanical impacts. However, dentifrices are applied together with brushing and, depending on how and when toothbrushing is performed, as well as the type of dentifrice and toothbrush used, may increase wear. This review focuses on the potential harmful and helpful effects associated with the use of dentifrices with regard to erosive wear. While active ingredients like fluorides or agents with special anti-erosive properties were shown to offer some degree of protection against erosion and combined erosion/abrasion, the abrasive effects of dentifrices may increase the surface loss of eroded teeth. However, most evidence to date comes from in vitro and in situ studies, so clinical trials are necessary for a better understanding of the complex interaction of active ingredients and abrasives and their effects on erosive tooth wear

    Analysis with respect to instrumental variables for the exploration of microarray data structures

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    BACKGROUND: Evaluating the importance of the different sources of variations is essential in microarray data experiments. Complex experimental designs generally include various factors structuring the data which should be taken into account. The objective of these experiments is the exploration of some given factors while controlling other factors. RESULTS: We present here a family of methods, the analyses with respect to instrumental variables, which can be easily applied to the particular case of microarray data. An illustrative example of analysis with instrumental variables is given in the case of microarray data investigating the effect of beverage intake on peripheral blood gene expression. This approach is compared to an ANOVA-based gene-by-gene statistical method. CONCLUSION: Instrumental variables analyses provide a simple way to control several sources of variation in a multivariate analysis of microarray data. Due to their flexibility, these methods can be associated with a large range of ordination techniques combined with one or several qualitative and/or quantitative descriptive variables

    Fluoride content and recharge ability of five glassionomer dental materials

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    <p>Abstract</p> <p>Background</p> <p>The relationship between fluoride content and fluoride release for glass-ionomer cements is not well understood. The aim of this laboratory study was: to determine the fluoride concentrations at the surfaces of glass-ionomer materials with respect to different storage media and different pH environments; to examine the recharge ability of the materials after NaF immersion; and to assess the morphological changes at the material surfaces using scanning electron microscope and energy dispersive spectroscopic techniques (SEM/EDS).</p> <p>Methods</p> <p>Five glass-ionomer materials, Fuji Triage (FT), Fuji II LC (FII), Fuji VIII (FVIII), Fuji IX GP (FIX), and Ketac N100 (KN), were analyzed in this study. Resin-based fluoride releasing material Helioseal F (HSF) was used as a comparison material. The sample consisted of 120 cured cement disks (n = 20 disks of each tested material, 10 × 1.5 mm). Five disks of each material were stored in 4 different storage media (I- saline, II- acidic solution ph = 2.5, III- acid solution ph = 5.5, IV- NaF solution (c = 500/106). After 7 days, two disks of each material were transferred from media I, II and III to the NaF solution for 3 min. EDS analysis was conducted in 3 randomly selected spots of each experimental disk. SEM was used to determine morphological characteristics of the material surface. Differences between the experimental groups have been analyzed using Student's t-test with the level of significance set at p < 0.001.</p> <p>Results</p> <p>FT showed the highest fluoride content at the surface of the material. The lowest amounts of fluoride ions were detected at the surfaces of the FT disks stored at low pH environments, and this difference was statistically significant (p < 0.001). Glass-ionomers showed significantly higher fluoride concentrations when compared to the HSF (p < 0.001). After immersion in the NaF solution, fluoride concentrations at the surfaces of the disks increased when compared with previous storage media (FT>FVIII>KN>FII>FIX). SEM analysis of the surface morphology revealed numerous voids, cracks and microporosities in all experimental groups, except for KN and HSF. More homogenous material structure with more discrete cracks was observed in samples stored at neutral pH environment, compared to disks stored in acidic solutions.</p> <p>Conclusion</p> <p>The tested materials could be considered as promising dental materials with potential prophylactic characteristics due to their relatively high fluoride content, but also the ability to extensively reabsorb fluoride ions, especially in acidic environments.</p

    Cell Type Mediated Resistance of Vesicular Stomatitis Virus and Sendai Virus to Ribavirin

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    Ribavirin (RBV) is a synthetic nucleoside analog with broad spectrum antiviral activity. Although RBV is approved for the treatment of hepatitis C virus, respiratory syncytial virus, and Lassa fever virus infections, its mechanism of action and therapeutic efficacy remains highly controversial. Recent reports show that the development of cell-based resistance after continuous RBV treatment via decreased RBV uptake can greatly limit its efficacy. Here, we examined whether certain cell types are naturally resistant to RBV even without prior drug exposure. Seven different cell lines from various host species were compared for RBV antiviral activity against two nonsegmented negative-strand RNA viruses, vesicular stomatitis virus (VSV, a rhabdovirus) and Sendai virus (SeV, a paramyxovirus). Our results show striking differences between cell types in their response to RBV, ranging from virtually no antiviral effect to very effective inhibition of viral replication. Despite differences in viral replication kinetics for VSV and SeV in the seven cell lines, the observed pattern of RBV resistance was very similar for both viruses, suggesting that cellular rather than viral determinants play a major role in this resistance. While none of the tested cell lines was defective in RBV uptake, dramatic variations were observed in the long-term accumulation of RBV in different cell types, and it correlated with the antiviral efficacy of RBV. While addition of guanosine neutralized RBV only in cells already highly resistant to RBV, actinomycin D almost completely reversed the RBV effect (but not uptake) in all cell lines. Together, our data suggest that RBV may inhibit the same virus via different mechanisms in different cell types depending on the intracellular RBV metabolism. Our results strongly point out the importance of using multiple cell lines of different origin when antiviral efficacy and potency are examined for new as well as established drugs in vitro

    Expression of APOBEC3G/3F and G-to-A Hypermutation Levels in HIV-1-Infected Children with Different Profiles of Disease Progression

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    OBJECTIVE: Increasing evidence has accumulated showing the role of APOBEC3G (A3G) and 3F (A3F) in the control of HIV-1 replication and disease progression in humans. However, very few studies have been conducted in HIV-infected children. Here, we analyzed the levels of A3G and A3F expression and induced G-to-A hypermutation in a group of children with distinct profiles of disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Perinatally HIV-infected children were classified as progressors or long-term non-progressors according to criteria based on HIV viral load and CD4 T-cell counts over time. A group of uninfected control children were also enrolled in the study. PBMC proviral DNA was assessed for G-to-A hypermutation, whereas A3G and A3F mRNA were isolated and quantified through TaqMan® real-time PCR. No correlation was observed between disease progression and A3G/A3F expression or hypermutation levels. Although all children analyzed showed higher expression levels of A3G compared to A3F (an average fold of 5 times), a surprisingly high A3F-related hypermutation rate was evidenced in the cohort, irrespective of the child's disease progression profile. CONCLUSION: Our results contribute to the current controversy as to whether HIV disease progression is related to A3G/A3F enzymatic activity. To our knowledge, this is the first study analyzing A3G/F expression in HIV-infected children, and it may pave the way to a better understanding of the host factors governing HIV disease in the pediatric setting
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