Endogenous Retroviruses and the Immune System

Initial sequencing of the human and mouse genomes revealed that substantial fractions were composed of retroelements (REs) and endogenous retroviruses (ERVs), the latter being relics of ancestral retroviral infection. Further study revealed ERVs constitute up to 10% of many mammalian genomes. Despite this abundance, comparatively little is known about their interactions, beneficial or detrimental, with the host. This thesis details two distinct sets of interactions with the immune system. Firstly, the presentation of ERV-derived peptides to developing lymphocytes was shown to exert a control on the immune response to infection with Friend Virus (FV). A self peptide encoded by an ERV negatively selected a significant fraction of polyclonal FV-specific CD4+ T cells and resulted in an impaired immune response. However, CD4+ T cell-mediated antiviral activity was fully preserved and repertoire analysis revealed a deletional bias according to peptide affinity, resulting in an effective enrichment of high-affinity CD4+ T cells. Thus, ERVs exerted a significant influence on the immune response, a mechanism that may partially contribute to the heterogeneity seen in human immune responses to retroviral infections. Secondly, a requirement for specific antibodies was shown in the control of ERVs. In a range of mice displaying distinct deficiencies in antibody production, products from the intestinal microbiota potentially induce ERV expression. Subsequent recombinational correction of a defective murine leukaemia virus (MLV) results in the emergence of infectious virus. In the long term, this leads to retrovirus-induced lymphomas and morbidity. ERVs, therefore, provide a potential link between the intestinal microbiota and a range of pathologies, including cancer. Finally, a new computational tool, REquest, was developed for use in the above studies. REquest allows the mining of retroelement (RE) and ERV expression data from the majority of commercially available human and murine microarray platforms and allows rapid hypothesis testing with publicly available data

Plasma electrons above Saturn's main rings: CAPS observations

We present observations of thermal ( similar to 0.6 - 100eV) electrons observed near Saturn's main rings during Cassini's Saturn Orbit Insertion (SOI) on 1 July 2004. We find that the intensity of electrons is broadly anticorrelated with the ring optical depth at the magnetic footprint of the field line joining the spacecraft to the rings. We see enhancements corresponding to the Cassini division and Encke gap. We suggest that some of the electrons are generated by photoemission from ring particle surfaces on the illuminated side of the rings, the far side from the spacecraft. Structure in the energy spectrum over the Cassini division and A-ring may be related to photoelectron emission followed by acceleration, or, more likely, due to photoelectron production in the ring atmosphere or ionosphere

Structure of Drosophila melanogaster ARC1 reveals a repurposed molecule with characteristics of retroviral Gag

The tetrapod neuronal protein ARC and its Drosophila melanogaster homolog, dARC1, have important but differing roles in neuronal development. Both are thought to originate through exaptation of ancient Ty3/Gypsy retrotransposon Gag, with their novel function relying on an original capacity for self-assembly and encapsidation of nucleic acids. Here, we present the crystal structure of dARC1 CA and examine the relationship between dARC1, mammalian ARC, and the CA protein of circulating retroviruses. We show that while the overall architecture is highly related to that of orthoretroviral and spumaretroviral CA, there are substantial deviations in both amino- and carboxyl-terminal domains, potentially affecting recruitment of partner proteins and particle assembly. The degree of sequence and structural divergence suggests that Ty3/Gypsy Gag has been exapted on two separate occasions and that, although mammalian ARC and dARC1 share functional similarity, the structures have undergone different adaptations after appropriation into the tetrapod and insect genomes

Discovery of heavy negative ions in Titan's ionosphere

Titan's ionosphere contains a rich positive ion population including organic molecules. Here, using CAPS electron spectrometer data from sixteen Titan encounters, we reveal the existence of negative ions. These ions, with densities up to similar to 100 cm similar to 3, are in mass groups of 10-30, 30-50, 50-80, 80-110, 110-200 and 200+ amu/charge. During one low encounter, negative ions with mass per charge as high as 10,000 amu/q are seen. Due to their unexpectedly high densities at similar to 950 km altitude, these negative ions must play a key role in the ion chemistry and they may be important in the formation of organic-rich aerosols (tholins) eventually falling to the surface

Magnetic signatures of plasma-depleted flux tubes in the Saturnian inner magnetosphere

Initial Cassini observations have revealed evidence for interchanging magnetic flux tubes in the inner Saturnian magnetosphere. Some of the reported flux tubes differ remarkably by their magnetic signatures, having a depressed or enhanced magnetic pressure relative to their surroundings. The ones with stronger fields have been interpreted previously as either outward moving mass-loaded or inward moving plasma-depleted flux tubes based on magnetometer observations only. We use detailed multi-instrumental observations of small and large density depletions in the inner Saturnian magnetosphere from Cassini Rev. A orbit that enable us to discriminate amongst the two previous and opposite interpretations. Our analysis undoubtedly confirms the similar nature of both types of reported interchanging magnetic flux tubes, which are plasma-depleted, whatever their magnetic signatures are. Their different magnetic signature is clearly an effect associated with latitude. These Saturnian plasma-depleted flux tubes ultimately may play a similar role as the Jovian ones

Tetracycline-inducible gene regulation in mycobacteria

A system for the tetracycline-inducible regulation of gene expression in mycobacteria has been developed. We have sub-cloned the tetRO region from the Corynebacterium glutamicum TetZ locus into a mycobacterial shuttle plasmid, making expression of genes cloned downstream of tetRO responsive to tetracycline. Using the luxAB-encoded luciferase from Vibrio harveyi as a reporter (pMind-Lx), we observed a 40-fold increase in light output from Mycobacterium smegmatis cultures 2 h after adding 20 ng ml(−1) of tetracycline. Similarly, exposure to the drug resulted in up to 20-fold increase in relative light units from M.bovis BCG carrying the reporter construct, and a 10-fold increase for M.tuberculosis. Tetracycline induction was demonstrated in log and stationary phase cultures. To evaluate whether this system is amenable to use in vivo, J774 macrophages were infected with M.bovis BCG[pMind-Lx], treated with amikacin to kill extracellular bacteria, and then incubated with tetracycline. A 10-fold increase in light output was measured after 24 h, indicating that intracellular bacteria are accessible and responsive to exogenously added tetracycline. To test the use of the tetracycline-inducible system for conditional gene silencing, mycobacteria were transformed with a pMind construct with tetRO driving expression of antisense RNA for the ftsZ gene. Bacterial cells containing the antisense construct formed filaments after 24 h exposure to tetracycline. These results demonstrate the potential of this tetracycline-regulated system for the manipulation of mycobacterial gene expression inside and outside cells

Self-esteem, stress and self-rated health in family planning clinic patients

BACKGROUND: The independent effects of stress on the health of primary care patients might be different for different types of clinic populations. This study examines these relationships in a low-income female population of patients attending a family planning clinic. METHODS: This study investigated the relevance of different sources of personal stress and social support to self-rated health, adjusting for mental health, health behavior and demographic characteristics of subjects. Five hundred women who attended family planning clinics were surveyed and 345 completed the form for a response rate of 72 percent. RESULTS: Multiple logistic regression analysis revealed that liking oneself was related to good self-rated health (Odds ratio = 7.11), but stress or support from children, parents, friends, churches or spouses were not significant. White non-Hispanic and non-white non-Hispanic respondents had lower odds of reporting good self-rated health than Hispanic respondents (odds ratios were 2.87 and 2.81, respectively). Exercising five or more days per week also was related to good self-rated health. Smoking 20 or more cigarettes per day, and obese III were negatively related to good self-rated health (odds ratios were .19 and .22, respectively with corresponding p-values equal to .0043 and .0332). CONCLUSIONS: Among younger low-income women, addressing low self-esteem might improve health status

The core phageome and its interrelationship with preterm human milk lipids

\ua9 2023 The AuthorsPhages and lipids in human milk (HM) may benefit preterm infant health by preventing gastrointestinal pathobiont overgrowth and microbiome modulation. Lipid association may promote vertical transmission of phages to the infant. Despite this, interrelationships between lipids and phages are poorly characterized in preterm HM. Shotgun metagenomics and untargeted lipidomics of phage and lipid profiles from 99 preterm HM samples reveals that phages are abundant and prevalent from the first week and throughout the first 100 days of lactation. Phage-host richness of preterm HM increases longitudinally. Core phage communities characterized by Staphylococcus- and Propionibacterium-infecting phages are significantly correlated with long-chain fatty acid abundances over lactational age. We report here a phage-lipid interaction in preterm HM, highlighting the potential importance of phage carriage in preterm HM. These results reveal possible strategies for phage carriage in HM and their importance in early-life microbiota development

A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals.

A database of 91 chemicals with published data from both transgenic rodent mutation (TGR) and rodent comet assays has been compiled. The objective was to compare the sensitivity of the two assays for detecting genotoxicity. Critical aspects of study design and results were tabulated for each dataset. There were fewer datasets from rats than mice, particularly for the TGR assay, and therefore, results from both species were combined for further analysis. TGR and comet responses were compared in liver and bone marrow (the most commonly studied tissues), and in stomach and colon evaluated either separately or in combination with other GI tract segments. Overall positive, negative, or equivocal test results were assessed for each chemical across the tissues examined in the TGR and comet assays using two approaches: 1) overall calls based on weight of evidence (WoE) and expert judgement, and 2) curation of the data based on a priori acceptability criteria prior to deriving final tissue specific calls. Since the database contains a high prevalence of positive results, overall agreement between the assays was determined using statistics adjusted for prevalence (using AC1 and PABAK). These coefficients showed fair or moderate to good agreement for liver and the GI tract (predominantly stomach and colon data) using WoE, reduced agreement for stomach and colon evaluated separately using data curation, and poor or no agreement for bone marrow using both the WoE and data curation approaches. Confidence in these results is higher for liver than for the other tissues, for which there were less data. Our analysis finds that comet and TGR generally identify the same compounds (mainly potent mutagens) as genotoxic in liver, stomach and colon, but not in bone marrow. However, the current database content precluded drawing assay concordance conclusions for weak mutagens and non-DNA reactive chemicals

The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes

Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies