How the Cervical Microbiota Contributes to Cervical Cancer Risk in Sub-Saharan Africa

Despite ongoing efforts, sub-Saharan Africa faces a higher cervical cancer burden than anywhere else in the world. Besides HPV infection, definitive factors of cervical cancer are still unclear. Particular states of the cervicovaginal microbiota and viral infections are associated with increased cervical cancer risk. Notably, HIV infection, which is prevalent in sub-Saharan Africa, greatly increases risk of cervicovaginal dysbiosis and cervical cancer. To better understand and address cervical cancer in sub-Saharan Africa, a better knowledge of the regional cervicovaginal microbiome is required This review establishes current knowledge of HPV, HIV, cervicovaginal infections, and the cervicovaginal microbiota in sub-Saharan Africa. Because population statistics are not available for the region, estimates are derived from smaller cohort studies. Microbiota associated with cervical inflammation have been found to be especially prevalent in sub-Saharan Africa, and to associate with increased cervical cancer risk. In addition to high prevalence and diversity of HIV and HPV, intracellular bacterial infections such as Chlamydia, Gonorrhea, and Mycoplasma hominis are much more common than in regions with a low burden of cervical cancer. This suggests the prevalence of cervical cancer in sub-Saharan Africa may be partially attributed to increased cervical inflammation resulting from higher likelihood of cervical infection and/or microbial dysbiosis

Translation of MMTV Gag requires nuclear events involving splicing motifs in addition to the viral Rem protein and RmRE

<p>Abstract</p> <p>Background</p> <p>Retroviral Gag proteins are encoded in introns and, because of this localization, they are subject to the default pathways of pre-mRNA splicing. Retroviruses regulate splicing and translation through a variety of intertwined mechanisms, including 5'- post-transcriptional control elements, 3'- constitutive transport elements, and viral protein RNA interactions that couple unspliced and singly spliced mRNAs to transport machinery. Sequences within the <it>gag </it>gene termed inhibitory or instability sequences also appear to affect viral mRNA stability and translation, and the action of these sequences can be countered by silent mutation or the presence of RNA interaction proteins like HIV-1 Rev. Here, we explored the requirements for mouse mammary tumor virus (MMTV) Gag expression using a combination of <it>in vivo </it>and <it>in vitro </it>expression systems.</p> <p>Results</p> <p>We show that MMTV <it>gag </it>alleles are inhibited for translation despite possessing a functional open reading frame (ORF). The block to expression was post-transcriptional and targeted the mRNA but was not a function of mRNA transport or stability. Using bicistronic reporters, we show that inhibition of <it>gag </it>expression imparted a block to both cap-dependent and cap-independent translation onto the mRNA. Direct introduction of <it>in vitro </it>synthesized <it>gag </it>mRNA resulted in translation, implying a nuclear role in inhibition of expression. The inhibition of expression was overcome by intact proviral expression or by flanking <it>gag </it>with splice sites combined with a functional Rem-Rem response element (RmRE) interaction.</p> <p>Conclusions</p> <p>Expression of MMTV Gag requires nuclear interactions involving the viral Rem protein, its cognate binding target the RmRE, and surprisingly, both a splice donor and acceptor sequence to achieve appropriate signals for translation of the mRNA in the cytoplasm.</p

Lack of CD8+ T-cell co-localization with Kaposi’s sarcoma- associated herpesvirus infected cells in Kaposi’s sarcoma tumors

Despite the close association between Kaposi’s sarcoma (KS) and immune dysfunction, it remains unclear whether tumor infiltrating immune cells (TIIC), by their absence, presence, or dysfunction, are mechanistically correlated with KS pathogenesis. Therefore, their potential capacity to serve as prognostic biomarkers of KS disease progression or control is unclear. Because epidemic-KS (EpKS) occurs with HIV-1 co-infection, it is particularly important to compare TIIC between EpKS and HIV-negative African endemic-KS (EnKS) to dissect the roles of HIV-1 and Kaposi Sarcoma-associated herpesvirus (KSHV) in KS pathogenesis. This cross-sectional study of 13 advanced KS (4 EnKS, 9 EpKS) patients and 3 healthy controls utilized single-color immunohistochemistry and dual-color immunofluorescence assays to characterize and quantify KSHV infected cells in relation to various TIIC in KS biopsies. Analysis of variance (ANOVA) and Mann-Whitney tests were used to assess differences between groups where P-values \u3c 0.05 were considered significant. The abundance of KSHV infected cells was heterogeneous in KS biopsies. Despite the presence of T-cell chemoattractant chemokine CxCL-9 in biopsies, CD8+ T-cells were sparsely distributed in regions with evident KSHV infected cells but were readily detectable in regions devoid of KSHV infected cells (P \u3c 0.0001). CD68+ (M1) macrophages were evenly and diffusely distributed in KS biopsies, whereas, the majority of CD163+ (M2) macrophages were localized in regions devoid of KSHV infected cells (P \u3c 0.0001). Overall, the poor immune cell infiltration or co-localization in KS biopsies independent of HIV-1 co-infection suggests a fundamental tumor immune evasion mechanism that warrants further investigation

Scientific Visualization Using the Flow Analysis Software Toolkit (FAST)

Over the past few years the Flow Analysis Software Toolkit (FAST) has matured into a useful tool for visualizing and analyzing scientific data on high-performance graphics workstations. Originally designed for visualizing the results of fluid dynamics research, FAST has demonstrated its flexibility by being used in several other areas of scientific research. These research areas include earth and space sciences, acid rain and ozone modelling, and automotive design, just to name a few. This paper describes the current status of FAST, including the basic concepts, architecture, existing functionality and features, and some of the known applications for which FAST is being used. A few of the applications, by both NASA and non-NASA agencies, are outlined in more detail. Described in the Outlines are the goals of each visualization project, the techniques or 'tricks' used lo produce the desired results, and custom modifications to FAST, if any, done to further enhance the analysis. Some of the future directions for FAST are also described

Do supplemental list frames for subpopulations increase subpopulation sampling efficiency? Evidence from the National Household Food Acquisition and Purchase Survey

Multiple-frame sampling has been regarded as a device for increasing efficiency in identifying small subpopulations. However, there has been a lack of empirical evidence in supporting the efficiency of the multiple-frame approach and in guiding best practices. The current study focuses on a special scenario in which two frames were used to recruit sample members. Using paradata from the U.S. National Household Food Acquisition and Purchase Survey (FoodAPS), the current analysis focuses on recruiting households that received Supplementary Nutrition Assistance Program (SNAP) as a sub-goal of the survey sampling. SNAP households account for around one-fifth of the general U.S. population, compared to a survey goal of 30 percent of responding households. Our findings were consistent with theoretical expectations. Having and using additional SNAP list frames improved the efficiency of identifying SNAP households as opposed to screening a general address-based sample frame. This efficiency remained even as the SNAP list frames aged

TeV scale resonant leptogenesis from supersymmetry breaking

We propose a model of TeV-scale resonant leptogenesis based upon recent models of the generation of light neutrino masses from supersymmetry-breaking effects with TeV-scale right-handed (rhd) neutrinos, $N_i$. The model leads to naturally large cosmological lepton asymmetries via the resonant behaviour of the one-loop self-energy contribution to $N_i$ decay. Our model addresses the primary problems of previous phenomenological studies of low-energy leptogenesis: a rational for TeV-scale rhd neutrinos with small Yukawa couplings so that the out-of equilibrium condition for $N_i$ decay is satisfied; the origin of the tiny, but non-zero mass splitting required between at least two $N_i$ masses; and the necessary non-trivial breaking of flavour symmetries in the rhd neutrino sector. The low mass-scale of the rhd neutrinos and their superpartners, and the TeV-scale $A$-terms automatically contained within the model offer opportunities for partial direct experimental tests of this leptogenesis mechanism at future colliders.Comment: 10 Pages latex, version for JHE

Modulation of Human Herpesvirus 8/Kaposi’s Sarcoma-Associated Herpesvirus Replication and Transcription Activator Transactivation by Interferon Regulatory Factor 7

Human herpesvirus 8 (HHV-8)/Kaposi’s sarcoma-associated herpesvirus infection goes through lytic and latent phases that are regulated by viral gene products, but very little is known about the involvement of host proteins. The replication and transcription activator (RTA) is a viral protein sufficient to initiate lytic replication by activating downstream genes, including the viral early gene open reading frame 57 (ORF 57), which codes for a posttranscriptional activator. In this study, we demonstrate that cellular interferon regulatory factor 7 (IRF-7) negatively regulates this process by competing with RTA for binding to the RTA response element in the ORF 57 promoter to down-regulate RTA-induced gene expression. We also show that alpha interferon represses RTA-mediated transactivation and that repression involves IRF-7. Our study indicates that upon HHV-8 infection, the host responds by suppression of lytic gene expression through binding of IRF-7 to the lytic viral gene promoter. These findings suggest that HHV-8 has developed a novel mechanism to induce but then subvert the innate antiviral response, specifically the interferon-signaling pathway, to regulate RTA activity and ultimately the viral latent/lytic replicative cycle

Genetic Variation in Mother-Child Acute Seroconverter Pairs from Zambia

Objective: To characterize the envelope (env) glycoprotein of HIV-1 in mother-infant pairs (MIP) that underwent near simultaneous or acute-phase seroconversion, we examined the env sequence of the transmitted viruses and compare viral evolution within the pair. Design: Three MIP from a Zambian cohort that seroconverted at the same sampling time were identified and followed longitudinally. Methods: The V1-V5 region of the HIV-1 env gene was sequenced for each sample collected. Phylogenetic and population genetics analyses were carried out to subtype the viruses, estimate relationships among viral genotypes, and compare molecular evolution between the viral populations. Results: Genetic analyses demonstrated a close intrapair relationship between viral sequences from each MIP. Transmission involved several closely related viral genotypes and did not result in a reduction in viral diversity. Amino acid changes were not evenly distributed along env V1-V5 but concentrated in concordant areas within each MIP. Several positions under positive selection were shared between the MIP viruses. Interestingly, selective pressure on the virus was higher in the infants than in the mothers. Conclusions: In contrast to most cases of perinatal transmission of HIV-1 from chronically infected mothers, there is no evidence of a genetic bottleneck in the transmitted viruses in these three instances of acute seroconversion. The longitudinal changes in the amino acids are in similar positions in env for the MIP, suggesting shared evolutionary constrains among the closely related viruses infecting the MIP; such constrains may lead to similar genetic changes in the virus in two different hosts