The Cardiff self‐injury inventory (English version): convergent validity and psychometric properties

Background and Aims: The Cardiff Self‐Injury Inventory (CSII) is a short (1 min), relatively nonintrusive, measure of previous self‐injury behaviors written in English. It measures self‐injury with suicidal intent and without such intent, covers actions versus thoughts, and has two time periods (lifetime vs recent [defined as the last 3 months]). The study aimed to examine its psychometric properties and its relationship to more well‐established measures. Methods: A UK community sample of 184 participants completed the CSII and two other measures of self‐harming (Deliberate Self‐Harm Inventory [DSHI] and Suicidal Behaviors Questionnaire–Revised [SBQ‐R]) in March 2020–May 2020. Fifty participants also repeated these measurements 1–2 weeks later. Results: The CSII showed strong psychometric properties with internal reliability of 0.87 and a test–retest of 0.82. The subscales also showed strong psychometric properties. The CSII showed strong concurrent validity to the other measures of self‐injury (SBQ‐R, r = 0.70; DSHI, r = 0.81). A factor analysis supported the idea that there are two distinct components to the overall CSII score arising due to the distinction between suicidal and nonsuicidal behaviors. Conclusion: The CSII has good psychometric properties in this population and can be used as a fast, nonintrusive, measure of different self‐injurious behaviors for clinical or research purposes

Temperature sensitive influenza A virus genome replication results from low thermal stability of polymerase-cRNA complexes

BACKGROUND: The RNA-dependent RNA polymerase of Influenza A virus is a determinant of viral pathogenicity and host range that is responsible for transcribing and replicating the negative sense segmented viral genome (vRNA). Transcription produces capped and polyadenylated mRNAs whereas genome replication involves the synthesis of an alternative plus-sense transcript (cRNA) with unmodified termini that is copied back to vRNA. Viral mRNA transcription predominates at early stages of viral infection, while later, negative sense genome replication is favoured. However, the "switch" that regulates the transition from transcription to replication is poorly understood. RESULTS: We show that temperature strongly affects the balance between plus and minus-sense RNA synthesis with high temperature causing a large decrease in vRNA accumulation, a moderate decrease in cRNA levels but (depending on genome segment) either increased or unchanged levels of mRNA. We found no evidence implicating cellular heat shock protein activity in this effect despite the known association of hsp70 and hsp90 with viral polymerase components. Temperature-shift experiments indicated that polymerase synthesised at 41°C maintained transcriptional activity even though genome replication failed. Reduced polymerase association with viral RNA was seen in vivo and in confirmation of this, in vitro binding assays showed that temperature increased the rate of dissociation of polymerase from both positive and negative sense promoters. However, the interaction of polymerase with the cRNA promoter was particularly heat labile, showing rapid dissociation even at 37°C. This suggested that vRNA synthesis fails at elevated temperatures because the polymerase does not bind the promoter. In support of this hypothesis, a mutant cRNA promoter with vRNA-like sequence elements supported vRNA synthesis at higher temperatures than the wild-type promoter. CONCLUSION: The differential stability of negative and positive sense polymerase-promoter complexes explains why high temperature favours transcription over replication and has implications for the control of viral RNA synthesis at physiological temperatures. Furthermore, given the different body temperatures of birds and man, these finding suggest molecular hypotheses for how polymerase function may affect host range

Identification of the Rem-responsive element of mouse mammary tumor virus

Mouse mammary tumor virus (MMTV) has previously been shown to encode a functional homolog of the human immunodeficiency virus-1 (HIV-1) nuclear export protein Rev, termed Rem. Here, we show that deletion of the rem gene from a MMTV molecular clone interfered with the nucleo-cytoplasmic transport of genomic length viral mRNA and resulted in a loss of viral capsid (Gag) protein production. Interestingly, nuclear export of single-spliced env mRNA was only moderately affected, suggesting that this transcript is, at least to some extent, transported via a distinct, Rem-independent export mechanism. To identify and characterize a cis-acting RNA element required for Rem responsiveness (RmRE), extensive computational and functional analyses were performed. By these means a region of 490 nt corresponding to positions nt 8517–nt 9006 in the MMTV reference strain was identified as RmRE. Deletion of this fragment, which spans the env-U3 junction region, abolished Gag expression. Furthermore, insertion of this sequence into a heterologous HIV-1-based reporter construct restored, in the presence of Rem, HIV-1 Gag expression to levels determined for the Rev/RRE export system. These results clearly demonstrate that the identified region, whose geometry resembles that of other retroviral-responsive elements, is capable to functionally substitute, in the presence of Rem, for Rev/RRE and thus provide unequivocal evidence that MMTV is a complex retrovirus

Atomic Scale Structure and Chemical Composition across Order-Disorder Interfaces

Through a combination of aberration-corrected high-resolution scanning transmission electron microscopy and three-dimensional atom probe tomography, the true atomic-scale structure and change in chemical composition across the complex order-disorder interface in a metallic alloy has been determined. The study reveals the presence of two interfacial widths, one corresponding to an order-disorder transition, and the other to the compositional transition across the interface, raising fundamental questions regarding the definition of the interfacial width in such systems

Adaptation of avian influenza virus to a swine host

The emergence of pathogenic RNA viruses into new hosts can have dramatic consequences for both livestock and public health. Here we characterize the viral genetic changes that were observed in a previous study which experimentally adapted a field isolate of duck influenza virus to swine respiratory cells. Both pre-existing and $\textit{de novo}$ mutations were selected during this adaptation. We compare the $\textit{in vitro}$ growth dynamics of the adapted virus with those of the original strain as well as all possible reassortants using reverse genetics. This full factorial design showed that viral gene segments are involved in complex epistatic interactions on virus fitness, including negative and sign epistasis. We also identify two point mutations at positions 67 and 113 of the HA2 subunit of the hemagglutinin protein conferring a fast growth phenotype on the naïve avian virus in swine cells. These HA2 mutations enhance the pH dependent, HA-mediated membrane fusion. A global H1 maximum-likelihood phylogenetic analysis, combined with comprehensive ancestry reconstruction and tests for directional selection, confirmed the field relevance of the mutation at position 113 of HA2. Most notably, this mutation was associated with the establishment of the H1 ‘avian-like’ swine influenza lineage, regarded as the most likely to cause the next influenza pandemic in humans. This multidisciplinary approach to study the genetics of viral adaptation provides unique insights on the underlying processes leading to influenza emergence in a new host species, and identifies specific targets for future surveillance and functional studies.This work was supported by a grant from DEFRA and HEFCE under the Veterinary Training and Research Initiative to the Cambridge Infectious Diseases Consortium (VB, LT), the French Ministry of Agriculture and INRA (VB, AT, J-LG), BBSRC grants BB/H014306/1 (LT) and BB/G00479X/1 (LT, JL), and the Medical Research Council Methodology Research Programme grant MR/J013862/1 (SDWF)

Comorbidity in multiple sclerosis: its temporal relationships with disease onset and dose effect on mortality

© 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. Background and purpose: We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS. Methods: This study used data from 2526 patients with incident MS and 9980 age-, sex- and physician-matched controls without MS identified from the UK Clinical Practice Research Datalink. Results: Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1–2, 3–4 or ≥5 was 131 [95% confidence interval (CI), 1.17–1.47], 1.65 (95% CI, 1.20–2.26) or 3.26 (95% CI, 1.58–6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00–1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81–2.73) after adjusting for comorbidities. There was a dose effect of pre-existing comorbidities on mortality. Conclusions: Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre-existing comorbidities have an impact on survival

Epilepsy and associated mortality in patients with multiple sclerosis

Background and purpose: We aimed to determine the prevalence of epilepsy in patients with multiple sclerosis (MS) at diagnosis, the risk of developing epilepsy after the diagnosis of MS and the relative risk of mortality associated with epilepsy.Methods: We used the UK Clinical Practice Research Data‐link to identify 2526 patients with incident MS and 9980 age‐, sex‐ and index year‐matched non‐MS controls from 1997 to 2006. Logistic regression was used to estimate odds ratios [95% confidence interval (CI)] for epilepsy and Cox regression was used to estimate hazard ratios (HRs) (95% CI) for epilepsy and mortality.Results: Patients with incident MS were on average 45 years old and 70.9% were female. At diagnosis, the prevalence of epilepsy in patients with MS was 1.30% compared with 0.57% in non‐MS controls. At diagnosis, MS was associated with an adjusted odds ratio (95% CI) of 2.11 (1.36–3.27) for pre‐existing epilepsy. Among epilepsy‐free patients, the cumulative probabilities of developing epilepsy, first recorded within 10 years of the index date, were 2.77% for patients with MS and 0.90% for controls. MS was associated with an adjusted HR (95% CI) of 6.01 (2.94–12.29) for epilepsy. Among patients with MS, epilepsy was associated with an HR (95% CI) of 2.23 (1.02–4.84) for all‐cause mortality.Conclusions: This population‐based study found an increased prevalence of epilepsy in patients with MS at diagnosis when compared with non‐MS controls and the risk of developing epilepsy was also higher following the MS diagnosis. Patients with MS with epilepsy had a higher risk of mortality compared with those without

Microstructure and Porosity of Laser Welds in Cast Ti-6Al-4V with Addition of Boron

Addition of small amounts of boron to cast Ti-6Al-4V alloy has shown to render a finer microstructure and improved mechanical properties. For such an improved alloy to be widely applicable for large aerospace structural components, successful welding of such castings is essential. In the present work, the microstructure and porosity of laser welds in a standard grade cast Ti-6Al-4V alloy as well as two modified alloy versions with different boron concentrations have been investigated. Prior-β grain reconstruction revealed the prior-β grain structure in the weld zones. In fusion zones of the welds, boron was found to refine the grain size significantly and rendered narrow elongated grains. TiB particles in the prior-β grain boundaries in the cast base material restricted grain growth in the heat-affected zone. The TiB particles that existed in the as cast alloys decreased in size in the fusion zones of welds. The hardness in the weld zones was higher than in the base material and boron did not have a significant effect on hardness of the weld zones. The fusion zones were smaller in the boron-modified alloys as compared with Ti-6Al-4V without boron. Computed tomography X-ray investigations of the laser welds showed that pores in the FZ of the boron modified alloys were confined to the lower part of the welds, suggesting that boron addition influences melt pool flow

Analysis of the EIAV Rev-Responsive Element (RRE) Reveals a Conserved RNA Motif Required for High Affinity Rev Binding in Both HIV-1 and EIAV

A cis-acting RNA regulatory element, the Rev-responsive element (RRE), has essential roles in replication of lentiviruses, including human immunodeficiency virus (HIV-1) and equine infection anemia virus (EIAV). The RRE binds the viral trans-acting regulatory protein, Rev, to mediate nucleocytoplasmic transport of incompletely spliced mRNAs encoding viral structural genes and genomic RNA. Because of its potential as a clinical target, RRE-Rev interactions have been well studied in HIV-1; however, detailed molecular structures of Rev-RRE complexes in other lentiviruses are still lacking. In this study, we investigate the secondary structure of the EIAV RRE and interrogate regulatory protein-RNA interactions in EIAV Rev-RRE complexes. Computational prediction and detailed chemical probing and footprinting experiments were used to determine the RNA secondary structure of EIAV RRE-1, a 555 nt region that provides RRE function in vivo. Chemical probing experiments confirmed the presence of several predicted loop and stem-loop structures, which are conserved among 140 EIAV sequence variants. Footprinting experiments revealed that Rev binding induces significant structural rearrangement in two conserved domains characterized by stable stem-loop structures. Rev binding region-1 (RBR-1) corresponds to a genetically-defined Rev binding region that overlaps exon 1 of the EIAV rev gene and contains an exonic splicing enhancer (ESE). RBR-2, characterized for the first time in this study, is required for high affinity binding of EIAV Rev to the RRE. RBR-2 contains an RNA structural motif that is also found within the high affinity Rev binding site in HIV-1 (stem-loop IIB), and within or near mapped RRE regions of four additional lentiviruses. The powerful integration of computational and experimental approaches in this study has generated a validated RNA secondary structure for the EIAV RRE and provided provocative evidence that high affinity Rev binding sites of HIV-1 and EIAV share a conserved RNA structural motif. The presence of this motif in phylogenetically divergent lentiviruses suggests that it may play a role in highly conserved interactions that could be targeted in novel anti-lentiviral therapies

The Cytoplasmic Location of Chicken Mx Is Not the Determining Factor for Its Lack of Antiviral Activity

Chicken Mx belongs to the Mx family of interferon-induced dynamin-like GTPases, which in some species possess potent antiviral properties. Conflicting data exist for the antiviral capability of chicken Mx. Reports of anti-influenza activity of alleles encoding an Asn631 polymorphism have not been supported by subsequent studies. The normal cytoplasmic localisation of chicken Mx may influence its antiviral capacity. Here we report further studies to determine the antiviral potential of chicken Mx against Newcastle disease virus (NDV), an economically important cytoplasmic RNA virus of chickens, and Thogoto virus, an orthomyxovirus known to be exquisitely sensitive to the cytoplasmic MxA protein from humans. We also report the consequences of re-locating chicken Mx to the nucleus.Chicken Mx was tested in virus infection assays using NDV. Neither the Asn631 nor Ser631 Mx alleles (when transfected into 293T cells) showed inhibition of virus-directed gene expression when the cells were subsequently infected with NDV. Human MxA however did show significant inhibition of NDV-directed gene expression. Chicken Mx failed to inhibit a Thogoto virus (THOV) minireplicon system in which the cytoplasmic human MxA protein showed potent and specific inhibition. Relocalisation of chicken Mx to the nucleus was achieved by inserting the Simian Virus 40 large T antigen nuclear localisation sequence (SV40 NLS) at the N-terminus of chicken Mx. Nuclear re-localised chicken Mx did not inhibit influenza (A/PR/8/34) gene expression during virus infection in cell culture or influenza polymerase activity in A/PR/8/34 or A/Turkey/50-92/91 minireplicon systems.The chicken Mx protein (Asn631) lacks inhibitory effects against THOV and NDV, and is unable to suppress influenza replication when artificially re-localised to the cell nucleus. Thus, the natural cytoplasmic localisation of the chicken Mx protein does not account for its lack of antiviral activity