Gypsy endogenous retrovirus maintains potential infectivity in several species of Drosophilids

<p>Abstract</p> <p>Background</p> <p>Sequences homologous to the <it>gypsy </it>retroelement from <it>Drosophila melanogaster </it>are widely distributed among drosophilids. The structure of <it>gypsy </it>includes an open reading frame resembling the retroviral gene <it>env</it>, which is responsible for the infectious properties of retroviruses.</p> <p>Results</p> <p>In this study we report molecular and phylogeny analysis of the complete <it>env </it>gene from ten species of the <it>obscura </it>group of the genus <it>Drosophila </it>and one species from the genus <it>Scaptomyza</it>.</p> <p>Conclusion</p> <p>The results indicate that in most cases <it>env </it>sequences could produce a functional Env protein and therefore maintain the infectious capability of <it>gypsy </it>in these species.</p

Modeling a Novel Variant of Glycogenosis IXa Using a Clonal Inducible Reprogramming System to Generate &ldquo;Diseased&rdquo; Hepatocytes for Accurate Diagnosis

The diagnosis of inherited metabolic disorders is a long and tedious process. The matching of clinical data with a genomic variant in a specific metabolic pathway is an essential step, but the link between a genome and the clinical data is normally difficult, primarily for new missense variants or alterations in intron sequences. Notwithstanding, elucidation of the pathogenicity of a specific variant might be critical for an accurate diagnosis. In this study, we described a novel intronic variant c.2597 + 5G &gt; T in the donor splice sequence of the PHKA2 gene. To investigate PHKA2 mRNA splicing, as well as the functional consequences on glycogen metabolism, we generated hepatocyte-like cells from a proband&rsquo;s fibroblasts by direct reprogramming. We demonstrated an aberrant splicing of PHKA2, resulting in the incorporation of a 27 bp upstream of intron 23 into exon 23, which leads to an immediate premature STOP codon. The truncated protein was unable to phosphorylate the PYGL protein, causing a 4-fold increase in the accumulation of glycogen in hepatocyte-like cells. Collectively, the generation of personalized hepatocyte-like cells enabled an unequivocal molecular diagnosis and qualified the sister&rsquo;s proband, a carrier of the same mutation, as a candidate for a preimplantation genetic diagnosis. Additionally, our direct reprogramming strategy allows for an unlimited source of &ldquo;diseased&rdquo; hepatocyte-like cells compatible with high-throughput platforms

Derivation of healthy hepatocyte-like cells from a female patient with ornithine transcarbamylase deficiency through X-inactivation selection

Autologous cell replacement therapy for inherited metabolic disorders requires the correction of the underlying genetic mutation in patient's cells. An unexplored alternative for females affected from X-linked diseases is the clonal selection of cells randomly silencing the X-chromosome containing the mutant allele, without in vivo or ex vivo genome editing. In this report, we have isolated dermal fibroblasts from a female patient affected of ornithine transcarbamylase deficiency and obtained clones based on inactivation status of either maternally or paternally inherited X chromosome, followed by differentiation to hepatocytes. Hepatocyte-like cells derived from these clones display indistinct features characteristic of hepatocytes, but express either the mutant or wild type OTC allele depending on X-inactivation pattern. When clonally derived hepatocyte-like cells were transplanted into FRG® KO mice, they were able to colonize the liver and recapitulate OTC-dependent phenotype conditioned by X-chromosome inactivation pattern. This approach opens new strategies for cell therapy of X-linked metabolic diseases and experimental in vitro models for drug development for such diseases.Published versionFunding was provided by Ministerio de Ciencia e Innovacion (Grant No. SAF-51991R) and Generalitat Valenciana (Grant Nos. PROMETEO/2019/060, ACIF/2019/145)

Hepatitis C Virus Infection Epidemiology among People Who Inject Drugs in Europe: A Systematic Review of Data for Scaling Up Treatment and Prevention

Background: People who inject drugs (PWID) are a key population affected by hepatitis C virus (HCV). Treatment options are improving and may enhance prevention; however access for PWID may be poor. The availability in the literature of information on seven main topic areas (incidence, chronicity, genotypes, HIV co-infection, diagnosis and treatment uptake, and burden of disease) to guide HCV treatment and prevention scale-up for PWID in the 27 countries of the European Union is systematically reviewed. Methods and Findings: We searched MEDLINE, EMBASE and Cochrane Library for publications between 1 January 2000 and 31 December 2012, with a search strategy of general keywords regarding viral hepatitis, substance abuse and geographic scope, as well as topic-specific keywords. Additional articles were found through structured email consultations with a large European expert network. Data availability was highly variable and important limitations existed in comparability and representativeness. Nine of 27 countries had data on HCV incidence among PWID, which was often high (2.7-66/100 person-years, median 13, Interquartile range (IQR) 8.7-28). Most common HCV genotypes were G1 and G3; however, G4 may be increasing, while the proportion of traditionally ‘difficult to treat’ genotypes (G1+G4) showed large variation (median 53,IQR 43-62). Twelve countries reported on HCV chronicity (median 72, IQR 64-81) and 22 on HIV prevalence in HCV-infected PWID (median 3.9%, IQR 0.2-28). Undiagnosed infection, assessed in five countries, was high (median 49%, IQR 38-64), while of those diagnosed, the proportion entering treatment was low (median 9.5%, IQR 3.5-15). Burden of disease, where assessed, was high and will rise in the next decade. Conclusion: Key data on HCV epidemiology, care and disease burden among PWID in Europe are sparse but suggest many undiagnosed infections and poor treatment uptake. Stronger efforts are needed to improve data availability to guide an increase in HCV treatment among PWID

Bacterial infections and nutrition - a primer

Bacteria are the predominant organisms in the human microbiome. They can be beneficial to the host, or they can cause focal and invasive diseases and clinical infections. The chapter explores the broad diversity of bacteria and ways in which they interact with the host. It considers the influence of host nutritional status and specific nutrients on colonization, invasion, severity, and mortality of bacterial infections. Overnutrition and metabolic diseases also affect risks of bacterial diseases, but are not a focus of this chapter. The effects of undernutrition on responses to vaccines against bacterial pathogens and the effects of antimicrobials on growth are addressed. Most examples are taken from malnutrition in children as, globally, they bear the greatest burden both of undernutrition and serious morbidity from bacterial infections and of disruptions in the commensal bacterial populations in the gastrointestinal tract that affect normal child growth and development. Where clinical trials are discussed, the main focus is on whether the trials demonstrate differences in bacterial disease incidence or mortality in response to nutrient interventions