Assessment of material loss of retrieved magnetically controlled implants for limb lengthening

PURPOSE: We aimed to understand wear from the telescopic component of PRECICE nails, which are used for distraction osteogenesis of the femur or tibia. We also aimed to identify any correlation between implant performance and patient factors. METHODS: This retrieval study involved 11 magnetically controlled intramedullary nails from nine patients who had achieved the targeted leg length. All the nails were assessed macroscopically and microscopically for wear. All implants were radiographed to assess the internal mechanism. A Talyrond 365 (Taylor Hobson, Leicester, UK) roundness measuring machine was used to generate three-dimensional surface maps of the telescopic components to allow for measurement of wear. RESULTS: Visual assessment of all the nails showed evidence of wear from the telescopic component. The radiographs revealed that all the nails had intact internal mechanism and no evidence of fractured pins. The roundness measuring machine showed that the quantity of wear was lowest in the latest design of the PRECICE nail. There was no significant correlation between wear and the two patient factors (duration of the lengthening phase, the time of implantation) included in this study. CONCLUSION: This study is the first to investigate the performance of the three different designs of the PRECICE system with a focus on wear. We found that the latest design had the best implant performance. We are confident of the continued success of the PRECICE system and reassure surgeons and patients that they are unlikely to encounter problems with the implant related to wear

Many LINE1 elements contribute to the transcriptome of human somatic cells

Over 600 LINE 1 elements are shown to be transcribed in humans; 400 of these are full-length elements in the reference genome

HIV patients stable on ART retain evidence of a high CMV load but changes to Natural Killer cell phenotypes reflect both HIV and CMV

Background: Whilst ART corrects many effects of HIV disease, T cell populations retain features of accelerated immunological aging. Methods: Here we analyse phenotypic changes to natural killer (NK) cells in HIV patients who began ART with <200 CD4 T-cells/µl and maintained virological control for 12-17 years, compared with CMV seropositive and seronegative healthy control donors. Results: Humoral responses to CMV antigens (lysate, gB, IE-1) remain elevated in the patients (P <0.0001) despite the long duration of ART. Patient's NK cells responded poorly to K562 cells when assessed by CD107a and IFNγ, but this could not be attributed to CMV as responses were low in CMV-seronegative controls. Moreover HIV (and not CMV) increased expression of CD57 on CD56lo cells. Conclusions: Comparisons with published studies suggest that CMV accelerates age-related increases in CD57 expression but levels plateau by 60-70 years of age, so the effect of CMV disappears. In HIV patients the plateau is higher and perhaps reached sooner

BarA-UvrY Two-Component System Regulates Virulence of Uropathogenic E. coli CFT073

Uropathogenic Escherichia coli (UPEC), a member of extraintestinal pathogenic E. coli, cause ∼80% of community-acquired urinary tract infections (UTI) in humans. UPEC initiates its colonization in epithelial cells lining the urinary tract with a complicated life cycle, replicating and persisting in intracellular and extracellular niches. Consequently, UPEC causes cystitis and more severe form of pyelonephritis. To further understand the virulence characteristics of UPEC, we investigated the roles of BarA-UvrY two-component system (TCS) in regulating UPEC virulence. Our results showed that mutation of BarA-UvrY TCS significantly decreased the virulence of UPEC CFT073, as assessed by mouse urinary tract infection, chicken embryo killing assay, and cytotoxicity assay on human kidney and uroepithelial cell lines. Furthermore, mutation of either barA or uvrY gene reduced the production of hemolysin, lipopolysaccharide (LPS), proinflammatory cytokines (TNF-α and IL-6) and chemokine (IL-8). The virulence phenotype was restored similar to that of wild-type by complementation of either barA or uvrY gene in trans. In addition, we discussed a possible link between the BarA-UvrY TCS and CsrA in positively and negatively controlling virulence in UPEC. Overall, this study provides the evidences for BarA-UvrY TCS regulates the virulence of UPEC CFT073 and may point to mechanisms by which virulence regulations are observed in different ways may control the long-term survival of UPEC in the urinary tract

Transcriptional activity and strain-specific history of mouse pseudogenes

Abstract: Pseudogenes are ideal markers of genome remodelling. In turn, the mouse is an ideal platform for studying them, particularly with the recent availability of strain-sequencing and transcriptional data. Here, combining both manual curation and automatic pipelines, we present a genome-wide annotation of the pseudogenes in the mouse reference genome and 18 inbred mouse strains (available via the mouse.pseudogene.org resource). We also annotate 165 unitary pseudogenes in mouse, and 303, in human. The overall pseudogene repertoire in mouse is similar to that in human in terms of size, biotype distribution, and family composition (e.g. with GAPDH and ribosomal proteins being the largest families). Notable differences arise in the pseudogene age distribution, with multiple retro-transpositional bursts in mouse evolutionary history and only one in human. Furthermore, in each strain about a fifth of all pseudogenes are unique, reflecting strain-specific evolution. Finally, we find that ~15% of the mouse pseudogenes are transcribed, and that highly transcribed parent genes tend to give rise to many processed pseudogenes

IFITM proteins inhibit HIV-1 protein synthesis

Interferon induced transmembrane proteins (IFITMs) inhibit the cellular entry of a broad range of viruses, but it has been suspected that for HIV-1 IFITMs may also inhibit a post-integration replicative step. We show that IFITM expression reduces HIV-1 viral protein synthesis by preferentially excluding viral mRNA transcripts from translation and thereby restricts viral production. Codon-optimization of proviral DNA rescues viral translation, implying that IFITM-mediated restriction requires recognition of viral RNA elements. In addition, we find that expression of the viral accessory protein Nef can help overcome the IFITM-mediated inhibition of virus production. Our studies identify a novel role for IFITMs in inhibiting HIV replication at the level of translation, but show that the effects can be overcome by the lentiviral protein Nef.Wellcome Trust-University of Edinburgh Institutional Strategic Support Fun

Impact of non-LTR retrotransposons in the differentiation and evolution of anatomically modern humans

Background: Transposable elements are biologically important components of eukaryote genomes. In particular, non-LTR retrotransposons (N-LTRrs) played a key role in shaping the human genome throughout evolution. In this study, we compared retrotransposon insertions differentially present in the genomes of Anatomically Modern Humans, Neanderthals, Denisovans and Chimpanzees, in order to assess the possible impact of retrotransposition in the differentiation of the human lineage. Results: We first identified species-specific N-LTRrs and established their distribution in present day human populations. These analyses shortlisted a group of N-LTRr insertions that were found exclusively in Anatomically Modern Humans. These insertions are associated with an increase in the number of transcriptional/splicing variants of those genes they inserted in. The analysis of the functionality of genes containing human-specific N-LTRr insertions reflects changes that occurred during human evolution. In particular, the expression of genes containing the most recent N-LTRr insertions is enriched in the brain, especially in undifferentiated neurons, and these genes associate in networks related to neuron maturation and migration. Additionally, we identified candidate N-LTRr insertions that have likely produced new functional variants exclusive to modern humans, whose genomic loci show traces of positive selection. Conclusions: Our results strongly suggest that N-LTRr impacted our differentiation as a species, most likely inducing an increase in neural complexity, and have been a constant source of genomic variability all throughout the evolution of the human lineage