CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls

Bacterial infections play an important role in the multifactorial etiology of rheumatoid arthritis. The arthropathic properties of Gram-positive bacteria have been associated with peptidoglycan–polysaccharide complexes (PG-PS), which are major structural components of bacterial cell walls. There is little agreement as to the identity of cellular receptors that mediate innate immune responses to PG-PS. A glycosylphosphatidylinositol-linked cell surface protein, CD14, the lipopolysaccharide receptor, has been proposed as a PG-PS receptor, but contradictory data have been reported. Here, we examined the inflammatory and pathogenic responses to PG-PS in CD14 knockout mice in order to examine the role for CD14 in PG-PS-induced signaling. We found that PG-PS-induced responses in vitro, including transient increase in intracellular calcium, activation of nuclear factor-κB, and secretion of the cytokines tumor necrosis factor-α and interleukin-6, were all strongly inhibited in CD14 knockout macrophages. In vivo, the incidence and severity of PG-PS induced acute polyarthritis were significantly reduced in CD14 knockout mice as compared with their wild-type counterparts. Consistent with these findings, CD14 knockout mice had significantly inhibited inflammatory cell infiltration and synovial hyperplasia, and reduced expression of inflammatory cytokines in PG-PS arthritic joints. These results support an essential role for CD14 in the innate immune responses to PG-PS and indicate an important role for CD14 in PG-PS induced arthropathy

A 'large and valuable' Siwalik fossil collection in the archives of the Oxford University Museum of Natural History

This article describes results from a review of South Asian fossils in the Oxford University Museum of Natural History. These materials include two early 19th century collections of fossils from the Siwalik Hills in India. While this assemblage was summarised in 1837 by William Buckland as ‘large and valuable collections of fossil bones’, it has remained largely unstudied and unpublished in any detail since collection. Here, as a precursor to a comprehensive re-evaluation, we establish a chronological and geographical context of one collection event, provide details of its donor, and outline its history after arrival in Oxford. We then describe select taxa in the collection, including a well-preserved maxilla and toothrow of the large extinct giraffid, Sivatherium giganteum, as a basis to justify our current understanding of the biostratigraphic affinity of the assemblage. Conservatively, the collection is a ‘classic’ Upper Siwalik Plio-Pleistocene fauna, possibly the first to be transported to the UK. While further analyses will realise the scientific potential of the fossils, the narrative of their journey from India to Oxford remains incomplete. Further investigation of the hidden history of the collection is warranted

Tuning the excited state of water-soluble IrIII-based DNA intercalators that are isostructural with [RuII(NN)2(dppz)] light-switch complexes

The synthesis of two new IrIII complexes which are effectively isostructural with well-established [Ru(NN)2-(dppz)]2+ systems is reported (dppz = dipyridophenazine; NN = 2,2′-bipyridyl, or 1,10-phenanthroline). One of these IrIII complexes is tricationic and has a conventional N6 coordination sphere. The second dicationic complex has a N5C coordination sphere, incorporating a cyclometalated analogue of the dppz ligand. Both complexes show good water solubility. Experimental and computational studies show that the photoexcited states of the two complexes are very different from each other and also differ from their RuII analogues. Both of the complexes bind to duplex DNA with affinities that are two orders of magnitude higher than previously reported Ir(dppz)-based systems and are comparable with RuII(dppz) analogues

The architectures of translation : a magic carpet-ride through space and time (or, the awkward story of how we dis/placed Krisztina Tóth’s short fiction from Hungarian to English)

This interdisciplinary paper unfolds an account of a collaborative translation project, which draws on Ellen Eve Frank’s concept of “literary architecture” to propose a process of “architectural translation”. Our proposal is illustrated by a detailed account of our experiences translating the short fiction of contemporary Hungarian writer, Krisztina Tóth (b. 1967) into English. Staged as a journey through space, time and text, our enquiry frames the process in Barbara Godard’s terms as one of dis/placement, finding resonances with Rosi Braidotti’s nomadic subject and practices of feminist mimesis. Situating Tóth’s fiction in a European feminist literary heritage, we deploy a range of concepts drawn from translation, architecture, literary criticism and feminist philosophy to synthesise a translation strategy which engages the spatial, not only as a metaphor but a methodology for our project. In this account, we propose an architectural methodology as a tool for radical translators, and offer the process of translation as a way of thinking about internal and external spaces in postcolonial contexts

Social deprivation and exposure to health promotion. A study of the distribution of health promotion resources to schools in England

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - Copyright @ 2010 Chivu and ReidpathBACKGROUND: Area deprivation is a known determinant of health. It is also known that area deprivation is associated with lower impact health promotion. It is less well known, however, whether deprived areas are less responsive to health promotion, or whether they are less exposed. Using data from a national, school-based campaign to promote vaccination against the human papilloma virus (HPV), the relationship between area deprivation and exposure was examined. METHODS: Taking advantage of a health promotion campaign to provide information to schools about HPV vaccination, a cross sectional study was conducted to examine the relationship between area level, social deprivation, and take-up of (i.e., exposure to) available health promotion material. The sample was 4,750 schools across England, including government maintained and independent schools. The relationship between area deprivation and exposure was examined using bi- and multivariate logistic regression. RESULTS: It was found that schools in the least deprived quintile had 1.32 times the odds of requesting health promotion materials than schools in the most deprived areas (p = .01). This effect was independent of the school size, the type of school, and the geographic region. Conclusion The relationship between area deprivation and the impact of health promotion may be due, at least in part, to differential levels of exposure. The study was limited in scope, pointing to the need for more research, but also points to potentially important policy implications

An open-source high-frequency lock-in amplifier

We present characterization of a lock-in amplifier based on a field programmable gate array capable of demodulation at up to 50 MHz. The system exhibits 90 nV/sqrt(Hz) of input noise at an optimum demodulation frequency of 500 kHz.The passband has a full-width half-maximum of 2.6 kHz for modulation frequencies above 100 kHz. Our code is opensource and operates on a commercially available platform

eXtended Reality (XR) virtual practical and educational eGaming to provide effective immersive environments for learning and teaching in forensic science

Online virtual learning resources have been available for learning and teaching in forensic science for some years now, but the recent global COVID-19 related periods of irregular lockdown have necessitated the rapid development of these for teaching, learning and CPD activities. However, these resources do need to be carefully constructed and grounded in pedagogic theory to be effective. This article details eXtended Reality (XR) learning and teaching environments to facilitate effective online teaching and learning for forensic geoscientists. The first two case studies discussed in this article make use of Thinglink software to produce virtual learning and teaching XR resources through an internet system, which was delivered to undergraduate students in 2021. Case one details an XR virtual laboratory-based XRF equipment resource, providing a consistent, reliable and asynchronous learning and teaching experience, whilst the second case study presents an XR virtual learning applied geophysics resource developed for a 12-week CPD training programme. This programme involves recorded equipment video resources, accompanying datasets and worksheets for users to work through. Both case studies were positively received by learners, but there were issues encountered by learners with poor internet connections or computer skills, or who do not engage well with online learning. A third case study showcases an XR educational forensic geoscience eGame that was developed to take the user through a cold case search investigation, from desktop study through to field reconnaissance and multi-staged site investigations. Pedagogic research was undertaken with user questionnaires and interviews, providing evidence that the eGame was an effective learning and teaching tool. eGame users highly rated the eGame and reported that they raised awareness and understanding of the use of geophysics equipment and best practice of forensic geoscience search phased investigations. These types of XR virtual learning digital resources, whilst costly to produce in terms of development time and staff resource, provide a complementary virtual learning experience to in-situ practical sessions, and allow learners to asynchronously familiarise themselves with equipment, environments and techniques resulting in more efficient use of in situ time. The XR resources also allow learners to reinforce learning post in-situ sessions. Finally, XR resources can provide a more inclusive and authentic experience for learners who cannot attend or complete work synchronously

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes

Copyright: © 2010 Stimpson et al.Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extrachromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.This work was supported by the Tumorzentrum Heidelberg/Mannheim grant (D.10026941)and by March of Dimes Research Foundation grant #1-FY06-377 and NIH R01 GM069514

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a\u27s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes

Infrapopliteal angioplasty using a combined angiosomal reperfusion strategy

Introduction Infra-popliteal angioplasty continues to be widely performed with minimal evidence to guide practice. Endovascular device selection is contentious and there is even uncertainty over which artery to treat for optimum reperfusion. Direct reperfusion (DR) targets the artery supplying the ischaemic tissue. Indirect reperfusion (IR) targets an artery supplying collaterals to the ischaemic area. Our unit practice for the last eight years has been to attempt to open all tibial arteries at the time of angioplasty. When successful, this results in both direct and indirect; or combined reperfusion (CR). The aim was to review the outcomes of CR and compare them with DR or IR alone. Methods An eight year retrospective review from a single unit of all infra-popliteal angioplasties was undertaken. Wound healing, limb salvage, amputation-free and overall survival data as well as re-intervention rates were captured for all patients. Subgroup analysis for diabetics was undertaken. Kaplan Meier curves are presented for survival outcomes. All odds and hazard ratios (HR) and p values were corrected for bias from confounders using multivariate analysis. Results 250 procedures were performed: 22 (9%) were CR; 115 (46%) DR and 113 (45%) IR. Amputation- free survival (HR 0.504, p = 0.039) and re-intervention and amputation-free survival (HR 0.414, p = 0.005) were significantly improved in patients undergoing CR compared to IR. Wound healing was similarly affected by reperfusion strategy (OR = 0.35, p = 0.047). Effects of CR over IR were similar when only diabetic patients were considered. Conclusions Combined revascularisation can only be achieved in approximately 10% of patients. However, when successful, it results in significant improvements in wound healing and amputation- free survival over simple indirect reperfusion techniques